FOI 4150 - Document 10
ESCITALOPRAM (LEXAPRO®): GAD – Attachment 4
ATTACHMENT 4
DETAILS OF THE LITERATURE
UNDER
SEARCHES CONDUCTED FO
1982
R
ACT
ESCITALOPRAM
RELEASED  GAD
BEEN  HEALTH
SUBMISSION
HAS INFORMATION
OF

OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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TABLE OF CONTENTS

1.1
INTRODUCTION ....................................................................................................................... 6
1.2
INCLUSION CRITERIA FOR CLINICAL EVIDENCE ....................................................................... 6
1.3
SEARCH STRATEGIES FOR COMPARATIVE RANDOMISED TRIALS ........................................... 12
1.3.1
EMBASE and Medline search strategy ........................................................................... 12
1.3.2
PubMed search strategy ................................................................................................. 13
1.3.3
Medline in Process search strategy ................................................................................ 18
1.3.4
Cochrane library search strategy ................................................................................... 19
1.3.5
Clinical trial registers search strategy ........................................................................... 22
1.3.6
Search of HTA databases ................................................................................................ 23
1.3.7
Search of conference abstracts ....................................................................................... 23
1.3.8
Search of the sponsor’s database for Studies ................................................................. 24
1.3.9
Manual searching ........................................................................................................... 25
UNDER
1.4
LIST OF CITATIONS AND REASONS FOR EXCLUSION............................................................... 25
1982
1.5
LISTING OF THE INCLUDED AND EXCLUDED CITATIONS WITH REASONS FOR SELECTION ....... 31
ACT
APPENDIX 1: ARTICLE ABSTRACTS FOR ESCITALOPRAM ................................................ 43
RELEASED
APPENDIX 2: FULL LIST OF ARTICLES FROM VARIOUS DATABASES FOR
BEEN
ESCITALOPRAM ............................................................................................................................... 56
HEALTH
HAS
OF
1
EMBASE AND MEDLINE ........................................................................................................ 57
INFORMATION
OF
2
PUBMED ..................................................................................................................................... 66
3
EBM DATABASES (COCHRANE) .......................................................................................... 73
DOCUMENT
4
CONFERENCE PAPERS INDEX ............................................................................................ 78
FREEDOM
DEPARTMENT
THIS
5
CLINICAL TRIALS ................................................................................................................... 79
THE  THE
BY
APPENDIX 3: ARTICLE ABSTRACTS FOR ESCITALOPRAM AND BENZODIAZEPINES 81
APPENDIX 4: FULL LIST OF ARTICLES FROM VARIOUS DATABASES FOR
ESCITALOPRAM AND BENZODIAZEPINES ............................................................................... 82
1
EMBASE + MEDLINE .............................................................................................................. 83
2
CLINICAL TRIALS ................................................................................................................... 84
APPENDIX 5: ARTICLE ABSTRACTS FOR BENZODIAZEPINES: DSM –IV ........................ 85
APPENDIX 5: ARTICLE ABSTRACTS FOR BENZODIAZEPINES: DSM –IV ........................ 85
APPENDIX 6: FULL LIST OF ARTICLES FROM VARIOUS DATABASES FOR
BENZODIAZEPINES DSM-IV ........................................................................................................ 109
1
EMBASE AND MEDLINE ...................................................................................................... 109
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2
PUBMED ................................................................................................................................... 115
3
MEDLINE IN PROCESS ......................................................................................................... 126
4
EBM DATABASES (COCHRANE) ........................................................................................ 127
5
CLINICAL TRIALS ................................................................................................................. 132
6
HAND SEARCHED REFERENCES ...................................................................................... 134

UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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LIST OF TABLES

TABLE 1:
TGA APPROVED AND PBS REIMBURSED INDICATIONS ..................................................... 8
TABLE 2:
SEARCH DETAILS FOR EMBASE+MEDLINE® EMBASE, ALL YEARS TILL 31 MAY 2007

........................................................................................................................................ 12
TABLE 3:
GENERALISED ANXIETY DISORDER AND ESCITALOPRAM AND HAMA: SEARCH DETAILS
FOR PUBMED ALL YEARS TILL 18 MAY 2007 ................................................................................. 13
TABLE 4:
GENERALISED ANXIETY DISORDER HAMA BENZODIAZEPINES: SEARCH DETAILS FOR
PUBMED ALL YEARS TILL 2JUNE 2007 ........................................................................................... 14
TABLE 5:
GENERALISED ANXIETY DISORDER AND ESCITALOPRAM AND HAMA AND
BENZODIAZEPINES: SEARCH DETAILS FOR PUBMED ALL YEARS TILL 2JUNE 2007 ......................... 16
TABLE 6
UPDATE OF EMBASE+ MEDLINE SEARCHES; 1/06/2007-4/10/2007 ..................................... 18
TABLE 7:
SEARCH DETAILS FOR MEDLINE® IN-PROCESS OVID - 8 WEEKS PRIOR TO 26 SEPTEMBER
2007
........................................................................................................................................ 19
UNDER
TABLE 8:
SEARCH DETAILS FOR COCHRANE LIBRARY DATABASE TO 2 JUNE 2007 ......................... 19
1982
TABLE 9
UPDATE EBM SEARCH, 4 OCT 2007 .................................................................................... 21
TABLE 10:
RESULTS OF THE SEARCH OF CLINICAL TRIAL REGISTRIES
ACT  , 27 AND 28 SEPTEMBER ........ 23
RELEASED
TABLE 11:
SEARCH DETAILS FOR HTA DATABASES TO 25 SEPTEMBER 2007 ................................... 23
TABLE 12:
SEARCH DETAILS FOR CONFERENCE PROCEEDINGS 1982 TO 25 SEPTEMBER 2007 ........... 24
BEEN
TABLE 13:
RESULTS OF THE SPONSOR’S DATABASE FOR STUDIES ................................
HEALTH
.................... 24
TABLE 14:
SUMMARY OF IDENTIFICATION OF DIRECT AND INDIRECT RANDOMISED TRIALS FROM THE
HAS INFORMATION
OF
LITERATURE SEARCH: ESCITALOPRAM ........................................................................................... 26
OF
TABLE 15:
SUMMARY OF IDENTIFICATION OF DIRECT RANDOMISED TRIALS FROM THE LITERATURE
SEARCH: ESCITALOPRAM AND BENZODIAZEPINES ......................................................................... 28
DOCUMENT
TABLE 16:
SUMMARY OF IDENTIFICATION OF INDIRECT RANDOMISED TRIALS FROM THE LITERATURE
FREEDOM
DEPARTMENT
SEARCH FOR BENZODIAZEPINES: DSM-IV ..................................................................................... 30
THIS  THE
TABLE 17:
SUMMARY OF INCLUSION/EXCLUSION CRITERIA FOR ESCITALOPRAM TRIALS ................ 32
THE
BY
TABLE 18:
SUMMARY OF INCLUSION/EXCLUSION CRITERIA FOR ESCITALOPRAM AND
BENZODIAZEPINE TRIALS .............................................................................................................. 35
TABLE 19:
SUMMARY OF INCLUSION/EXCLUSION CRITERIA FOR BENZODIAZEPINE TRIALS: DSM-IV .

........................................................................................................................................ 36

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ABBREVIATIONS

ABS
Australian Bureau of Statistics
ACTR
Australian Clinical Trial Register
AHA
American Heart Association
AIHW,
Australian Institute of Health and Welfare;
CADTH
Canadian Agency for Drugs and Technology in Health
CENTRAL
Central Register of Controlled Trials
CSR
Clinical Study Report
DARE
Database of Abstracts of Reviews of Effects
DoH
Department of Health
DoHA
Department of Health & Aging
EBM Databases
Includes all Cochrane Library Datasets, including CENTRAL, DARE,
Cochrane DSR, ACP Journal Club
HTA
Health technology assessment
mRCT
metaRegister of Clinical Trials
NICE
National Institute of Clinical Excellence
PBAC
Pharmaceutical Benefits Advisory Committee
UNDER
PBS
Pharmaceutical Benefits Schedule
1982
RCT
Randomised controlled clinical trial
RPBS
Repatriation Pharmaceutical Benefits Schedule
ACT
TGA
Therapeutic Goods Administration
RELEASED

BEEN  HEALTH

HAS INFORMATION
OF

OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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1.1  Introduction

The details of the literature searches relevant to Section B of this submission are
presented in this Attachment.

Attachment 2 presents the complete documentation of all search strategies, and
citations and abstracts identified from the literature searches for genralised ansiety
disorder studies. The following sources were used to search for relevant data.

1.  A search of the electronic databases EMBASE+Medline, PubMed and
MEDLINE In-Process.
UNDER
2.  A search of the EBM Databases: Cochrane Central Register of Controlled
1982
Trials (CENTRAL), DARE, Cochrane DSR and ACP Journal Club.
3.  A search of clinical trial registries through the Austra
ACT  lian Clinical Trials
RELEASED
Registry (ACTR) and ClinicalTrials.gov.
4.  Manual searching of references public
BEEN ations retrieved via the database
HEALTH
searches.
HAS INFORMATION
OF
5.  Conference Papers Index,  OF
6.  Health Technology Assessment databases (NICE)
7.  A search of Lundbeck’s internal databases.
DOCUMENT

FREEDOM
DEPARTMENT
THIS

THE  THE
BY
1.2  Inclusion criteria for clinical evidence
A literature search was undertaken for this submission in order to identify all relevant
randomised controlled trials (RCTs) for Generalised Anxiety Disorder (GAD) and
escitalopram (Lexapro®).

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Included studies were RCTs of GAD or escitalopram (Lexapro®). s38, s47E(d)

  The choice of which benzodiazepine
would be appropriate as a comparator was determined by the PBS Listing for each.
As can be seen below only diazepam and oxazepam (benzodiazepines) had a general
listing that supported their TGA indication for treatment of “anxiety disorders”. All
other benzodiazepines were PBS Authority Listed for other indications and specific
groups.

If there were no head to head RCTs comparing Escitalopram to a benzodiazepine then
an indirect comparison between escitalopram and benzodiazepines, using placebo as a
common comparator would be undertaken. The search would identify benzodiazepine
UNDER
studies for DSM-IV defined GAD that had a placebo arm.  1982
s22
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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s22
UNDER
1982
ACT
Additional Search terms included, following discussion with the PBB was:
RELEASED
•  Hamilton Anxiety Scale (HAMA or HAM-A), as the most appropriate scale to
use
BEEN  HEALTH

HAS INFORMATION
OF
The classification for GAD used was DSM-IV. After extensive review of the
OF
literature it was concluded that DSM-IV defined patients are a more restrictive group
of patients that would not include a large proportion of DSM-III-R or DSM-III
DOCUMENT
DEPARTMENT
patients. This is the key reason why the
FREEDOM
submission will look at DSM-IV patients
THIS
alone, given that these were the b
THE
asis of the Escitalopram trial.
THE
BY

Table 1:
TGA Approved and PBS Reimbursed Indications

TGA Approved Indications
PBS Indication

N05 Psycholeptics

N05B Anxiolytics

N05BA Benzodiazepine derivatives

Diazepam
VALIUM is indicated for the
General Listing
management of anxiety disorders or
for the short term relief of the
symptoms of anxiety. Anxiety or
tension associated with the stress of
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everyday life usually does not require
treatment with an anxiolytic.

In acute alcohol withdrawal, VALIUM

may be useful in the symptomatic
relief of acute agitation, tremor,
impending or acute delirium tremens
and hallucinosis.

VALIUM is a useful adjunct for the

relief of reflex muscle spasm due to
local trauma (injury, inflammation) to
muscles, bones and joints. It can also
be used to combat spasticity due to
upper motor neuron lesions such as
cerebral palsy and paraplegia, as well
as in athetosis and stiff-man
syndrome.

Intravenous VALIUM is useful in

UNDER
controlling status epilepticus and the
spasms of tetanus.
1982
Oxazepam
Management of anxiety disorders or
General Listing
for the short-term relief of the
ACT
symptoms of anxiety. Anxiety
RELEASED
associated with depression is also
responsive to oxazepam therapy.
BEEN
Anxiety or tension associated
HEALTH  with the
stress of everyday life usually does
HAS
OF
not require treatment with an
INFORMATION
anxiolytic. The physician should
OF
periodically reassess the usefulness
of the drug for the individual patient.

Alcoholics with acute tremulousness,

DOCUMENT
confusional state or anxiety
FREEDOM
DEPARTMENT
associated with alcohol withdrawal are
THIS
responsive to therapy.
THE  THE
Alprazolam
Anxiety. Short-term symptomatic
Authority Required:
BY
treatment of anxiety including
Panic disorder where
treatment of anxious patients with
other treatments
some symptoms of depression.
have failed or are
inappropriate.

Panic disorder (DSM-III-R). The

treatment of panic disorder with or
without some phobic avoidance, and
for blocking or attenuation of panic
attacks and phobias in patients who
have agoraphobia with panic attacks.
Bromazepam
Symptomatic relief of tension, anxiety
Authority Required:
and agitation. Anxiety and tension
Patients with
associated with the stress of everyday  refractory phobic or
life usually does not require treatment
anxiety states
with an anxiolytic.

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N06 Psychoanaleptics

N06A Antidepressants

N06AA Non-selective monoamine reuptake inhibitors

Amitriptyline
For the treatment of major depression.
Hydrochloride
Clomipramine
For the treatment of major depression;
Hydrochloride
obsessive-compulsive disorders and
phobias in adults; cataplexy
associated with narcolepsy.
Dothiepin Hydrochloride
For the treatment of major depression.
Doxepin Hydrochloride
For the treatment of major depression.
Imipramine
Major depression.

Hydrochloride

Nocturnal enuresis (from the age of 5

years onwards and provided the
possibility of organic causes has first
been excluded).
Nortryptyline
Major depression.

Hydrochloride
UNDER

1982
N06AB Selective serotonin reuptake inhibitors

Escitalopram Oxalate
Treatment of major depression
ACT  .

Treatment of social anxiety di
RELEASED  sorder

(social phobia).

Treatment of generalised anxiety

BEEN
disorder.
HEALTH
Citalopram
Treatment of major depression.

HAS INFORMATION
OF
Hydrobromide
Fluoxetine Hydrochloride
Major depression

OF

Obsessive Compulsive Disorder.

Premenstrual Dysphoric Disorder

(PMD
DOCUMENT  D) as defined by DSM-IV
DEPARTMENT
criteria
FREEDOM  .
Fluvoxamine Malea
THIS te
Is indicated for the treatment of major

THE  THE depression in adults. MOVOX
BY
(fluvoxamine maleate) is also
indicated for the treatment of
Obsessive Compulsive Disorder
(OCD) in children aged 8 years and
older, adolescents, and adults.
Paroxetine Hydrochloride  Major depression and for the

prevention of relapse of depressive
symptoms;

Obsessive Compulsive Disorder and

for the prevention of relapse of OCD;

Panic Disorder and for the prevention

of relapse of Panic Disorder;

Social Anxiety Disorder/Social Phobia;
and

Generalised Anxiety Disorder.

Posttraumatic Stress Disorder

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Sertraline Hydrochloride
ZOLOFT (sertraline hydrochloride) is

indicated for the treatment of major
depression, obsessive compulsive
disorder (OCD) and panic disorder.

ZOLOFT (sertraline hydrochloride) is

indicated for the treatment of social
phobia (social anxiety disorder) and
the prevention of its relapse.

ZOLOFT (sertraline hydrochloride) is

indicated for the treatment of
premenstrual dysphoric disorder
(PMDD) as defined by DSM-IV
criteria.

N06AF Monoamine oxidase inhibitors, non-selective

Phenelzine Sulfate
Treatment of major depression.

Tranylcypromine Sulfate
Treatment of major depression.

UNDER
N06AG Monoamine oxidase type A inhibitors

Moclobemide
Treatment of major depression.

1982

ACT
N06AX Other

RELEASED
antidepressants
Lithium Carbonate
Acute episodes of mania and

hypomania, and for the prophylaxis of
BEEN  HEALTH
recurrent manic depressive illness.
Mianserin Hydrochloride
For the treatment of major depression.
HAS INFORMATION
OF
Mirtazapine
Treatment of major depression

including
OF  relapse prevention.
Reboxetine Mesilate
for the treatment of major depression

and is effective in preventing the
relap
DOCUMENT se of depressive symptoms.
Venlafaxine
Major Depressi
DEPARTMENT on, including

FREEDOM
Hydrochloride
prevention of relapse and recurrence
THIS  THE where appropriate.
THE

Generalised Anxiety disorder.

BY

Social Anxiety Disorder.

Panic Disorder, including prevention

of relapse.

All trials not meeting these requirements were excluded. Prior to conducting the
literature searches, entry criteria were defined for the inclusion and exclusion of
papers, as follows:
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UNDER
1982
ACT
RELEASED
BEEN HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE THE
BY

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Analysis, Randomized Controlled Trial, Classical Article,
Clinical Conference, "Clinical Trial, Phase III", "Clinical
Trial, Phase IV", Comparative Study, Controlled Clinical
Trial, Multicenter Study, Humans
25  Search #24 and #23 Limits: English, Clinical Trial, Meta-
17:07:03 13
Analysis, Randomized Controlled Trial, Classical Article,
Clinical Conference, "Clinical Trial, Phase III", "Clinical
Trial, Phase IV", Comparative Study, Controlled Clinical
Trial, Multicenter Study, Humans
24  Search #20 or #21 Limits: English, Clinical Trial, Meta-
17:06:35 1699
Analysis, Randomized Controlled Trial, Classical Article,
Clinical Conference, "Clinical Trial, Phase III", "Clinical
Trial, Phase IV", Comparative Study, Controlled Clinical
Trial, Multicenter Study, Humans
23  Search #1 or #22 Limits: English, Clinical Trial, Meta-
17:05:40 578
Analysis, Randomized Controlled Trial, Classical Article,
Clinical Conference, "Clinical Trial, Phase III", "Clinical
Trial, Phase IV", Comparative Study, Controlled Clinical
Trial, Multicenter Study, Humans
22  Search gad Limits: English, Clinical Trial, Meta-Analysis,
17:04:59 529
UNDER
Randomized Controlled Trial, Classical Article, Clinical
Conference, "Clinical Trial, Phase III", "Clinical Trial,
1982
Phase IV", Comparative Study, Controlled Clinical Trial,
Multicenter Study, Humans
ACT
21  Search "Diazepam"[MeSH Major Topic] Limits: English,
17:04:15 1582
RELEASED
Clinical Trial, Meta-Analysis, Randomized Controlled Trial,
Classical Article, Clinical Conference, "Clinical Trial,
Phase III", "Clinical Trial, Phase IV", Comparative Study,
BEEN
Controlled Clinical Trial, Multicenter Study, Humans
HEALTH
20  Search "Oxazepam"[MeSH Major Topic] Limits: English,
17:03:18 134
HAS
OF
Clinical Trial, Meta-Analysis, Randomized Controll
INFORMATION ed Trial,
Classical Article, Clinical Conference, "Clinical Trial,
OF
Phase III", "Clinical Trial, Phase IV", Comparative Study,
Controlled Clinical Trial, Multicenter Study, Humans
19  Search #16 and #17 Limits: English, Clinical Trial, Meta-
17:01:33 1
DOCUMENT
Analysis, Randomized Controlled Trial, Classical Article,
DEPARTMENT
Clinical Conference, "Clinical T
FREEDOM  rial, Phase III", "Clinical
Trial, Phase IV", Co
THIS  mparative Study, Controlled Clinical
THE
Trial, Multicenter S
THE  tudy, Humans
18  Search #14 and #17
BY Limits: English, Clinical Trial, Meta-
17:00:11 13
Analysis, Randomized Controlled Trial, Classical Article,
Clinical Conference, "Clinical Trial, Phase III", "Clinical
Trial, Phase IV", Comparative Study, Controlled Clinical
Trial, Multicenter Study, Humans
17  Search "Hamilton anxiety scale" or "HAM-A" or "HAMA"
16:55:59 593
Limits: English, Clinical Trial, Meta-Analysis, Randomized
Controlled Trial, Classical Article, Clinical Conference,
"Clinical Trial, Phase III", "Clinical Trial, Phase IV",
Comparative Study, Controlled Clinical Trial, Multicenter
Study, Humans
16  Search "Anxiety Disorders"[MeSH] AND
16:53:09 19
"Oxazepam"[MeSH] Limits: English, Clinical Trial, Meta-
Analysis, Randomized Controlled Trial, Classical Article,
Clinical Conference, "Clinical Trial, Phase III", "Clinical
Trial, Phase IV", Comparative Study, Controlled Clinical
Trial, Multicenter Study, Humans
14  Search "Anxiety Disorders"[MeSH] AND
16:49:56 214
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UNDER
1982
ACT
RELEASED
BEEN HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE THE
BY

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ESCITALOPRAM (LEXAPRO®): GAD – Attachment 4

Review, English
#28
Search ("Anxiety Disorders"[Mesh]) and diazepam Limits:
04:04:40 237
Humans, Clinical Trial, Meta-Analysis, Randomized Controlled
Trial, Review, English
#27
Search ("Anxiety Disorders"[Mesh]) Limits: Humans, Clinical
04:04:08 8814
Trial, Meta-Analysis, Randomized Controlled Trial, Review,
English
#20
Search #17 and #14 Limits: Humans, Clinical Trial, Meta-
01:23:30 9
Analysis, Randomized Controlled Trial, Review, English
#19
Search #17 and #14
01:19:12 12
#18
Search #17 and #114
01:19:02 0
#17
Search #15 or #16
01:18:02 163
#16
Search LSAS
01:17:21 92
#15
Search Liebowitz social anxiety scale
01:17:00 136
#14
Search #12 and #13
01:16:39 168
#13
Search #10 or #11
01:16:13 2054
#12
Search #2 or #6 or #7 or #8 or #9
01:15:22 34299
#11
Search lexapro
01:12:20 10
UNDER
#10
Search escitalopram
01:11:54 2054
#9
Search social phobia
1982
01:11:18 7394
#8
Search generalised social anxiety disorder
01:10:43 42
ACT
#7
Search social anxiety disorder
01:10:15 6960
RELEASED
#6
Search "Anxiety Disorders"[MeSH Major Topic]
01:09:36 32366
#2
Search "Phobic Disorders"[MeSH Major Topic]
01:07:45 4707
BEEN

HEALTH

HAS INFORMATION
OF
Update of Embase+ Medline Searches; 1/06/2007-4/10/2007
OF
A summary of the first and final Embase + Medline search is presented below:

DOCUMENT
DEPARTMENT

Sea
FREEDOM  rch 31 May
Search 1/06/2007 to
THIS
THE  THE
04/10/07
BY
Escitalopram vs placebo
11
0
Benzodiazepines
24
0
Diazepam and
Oxazepam
Escitalopram and
0
0
Diazepam and
Oxazepam

The results of the search are presented in Table 6 .

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UNDER
1982
ACT
RELEASED
BEEN HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE THE
BY

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Table 12:
Search details for conference proceedings 1982 to 25 September 2007
Conference
Search
Results for
Conference
Papers5
Conference Papers Index
(escitalopram or lexapro) and KW=((general
1
anxiety disorder ) or (GAD))
Conference Papers Index
KW=(diazepam or oxazepam) and
0
KW=((general anxiety disorder
Conference Papers Index
KW=(diazepam or oxazepam) and
KW=((general anxiety disorder) and
0
(escitalopram or lexapro)

1.3.8  Search of the sponsor’s database for Studies
Trials identified by the Sponsor’s database are presented in Table 13.
UNDER

1982
Table 13:
Results of the Sponsor’s Database for Studies
Study
Publication
ACT
Number
SCT-MD-05
Flexible dose comparison of the safety and efficacy of Lu 26-
RELEASED 054 (i.e. escitalopram) and placebo in
the treatment of Generalised Anxiety Disorder.  24 September, 2002.
SCT-MD-06
Flexible dose comparison of the safety and efficacy of escitalopram and placebo in the treatment
BEEN
of Generalised Anxiety Disorder. 24 September, 2002.
HEALTH
SCT-MD-07
Davidson, J.R.T., et al., Escitalopram in the treatment of generalized anxiety disorder: Double-
HAS
OF
blind, placebo controlled, flexible-dose study. Depression and Anxiety, 2004. 19(4): p. 234-240.
INFORMATION
SCT-MD-17
Flexible dose comparison of the safety and efficacy of Lu 26-054 (i.e. escitalopram) and placebo in
OF
the treatment of Generalised Anxiety Disorder. 24 September, 2002.

Davidson JRT, Bose A, Wang Q. Safety and efficacy of escitalopram in the long-term treatment of
generalized anxiety disorder. Journal of Clinical Psychiatry 2005;66(11):1441-1446
SCT-MD-31
A double-blind flexible dose com
DOCUMENT  parison of escitalopram, venlafaxine XR and placebo in the
treatment of Generalised Anxiety
FREEDOM  Disorder. 2
DEPARTMENT  4 June, 2005
99815
A  double-blind,
THIS   randomised, placebo-controlled trial comparing the efficacy and safety of fixed
THE
dosages of es
THE  citalopram with that of placebo in patients with Generalised Anxiety Disorder.  27
May 2004. BY

Baldwin DS, Huusom AKT, Maehlim E. Escitalopram and Paroxetine compared to placebo in the
treatment of generalized anxiety disorder (GAD). 17th Congress of Neuropsychopharmacology,
Sweden, October 2004

Baldwin DS, Trap Huusom AK, Mæhlum E. Escitalopram and paroxetine in the treatment of
generalised anxiety disorder. British Journal of Psychiatry, 2006, 189: 264-272
99769
A  double-blind,  randomised,  placebo-controlled,  multicentre,  relapse-prevention  trial  with  20mg

escitalopram in patients with Generalised Anxiety Disorder. 9 December 2004.

Allgulander, C., I. Florea, and A.K. Huusom, Prevention of relapse in generalized anxiety disorder
by escitalopram treatment. Int J Neuropsychopharmacol, 2006. 9(5): p. 495-505.

5 This database includes other publication types but was searched only for the conference paper
abstracts
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1.3.9  Manual searching
Escitalopram
A manual search through the references of the retrieved trials and reviews examining
RCTs of escitalopram did not identify any references relevant to this submission

Benzodiazepines (Diazepam and Oxazepam)
A manual search through the references of the retrieved trials and reviews examining
RCTs of escitalopram identified several references relevant to this submission. These
are presented in Appendix 6.

1.4  List of citations and reasons for exclusion UNDER
1982
Escitalopram
ACT
The summary for the escitalopram literature search results is presented in Table 14.
RELEASED
This summary is presented as a composite of the numbers of citations identified, those
included and those excluded, with reasons.
BEEN  HEALTH
s22
HAS INFORMATION
OF
OF
DOCUMENT
DEPARTMENT

FREEDOM
THIS
The 25 citations identified in t
THE  he literature search (these do not include the study
THE
BY
reports) are listed below in alphabetical order, and reasons for their exclusion
provided in Table 17. A detailed presentation of their abstracts is presented in
Appendix 1.

A detailed presentation of all references retrieved in the individual searches is
presented in Appendix 2 (study reports not included).

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THE THE
BY

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Escitalopram and Benzodiazepines
The summary for the escitalopram and benzodiazepine literature search results is
presented in Table 15. This summary is presented as a composite of the numbers of
citations identified, those included and those excluded, with reasons.
s22
The published citation identified in the literature search is listed below in alphabetical
order, and reasons for its exclusion is provided in Table 18. The abstract is presented
in Appendix 3.
UNDER

1982
A detailed presentation of all references retrieved in the individual searches is
ACT
presented in Appendix 4.
RELEASED

BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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DOCUMENT
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THIS
THE THE
BY

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Benzodiazepines
The summary for the benzodiazepine literature search results is presented in Table 16
for DSM IV. This summary is presented as a composite of the numbers of citations
identified, those included and those excluded, with reasons.
s22
The published citations identified in the literature search are listed below in
alphabetical order, and reasons for their exclusion provided in Table 19  DSM IV (60
citations).  A detailed presentation of their abstracts is presented in Appendix 5.
UNDER

1982
A detailed presentation of all references retrieved in the individual searches is
ACT
presented in Appendix 6.
RELEASED

BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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1.5  Listing of the included and excluded citations with reasons for
selection
Presented below are the citations identified and the reasons for inclusion and
exclusion.

Escitalopram: Table 17

Escitalopram and Benzodiazepines:  Table 18

Benzodiazepines: Evidence is presented for DSM-IV in Table 19.

UNDER
Legends Followed:
1982
a
not a
randomised trial
ACT
b
not an
RELEASED
appropriate
comparator
c
not a relevant
BEEN  HEALTH
population

HAS INFORMATION
OF

OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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THIS
THE THE
BY

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9
Dhillon, S., L.J. Scott, and G.L.
E
a
relevant
Plosker, Escitalopram: A review of its
trials
use in the management of anxiety
mentioned
disorders. CNS Drugs, 2006. 20(9): p.
in
763-790.
submission
10
Goodman, W.K., A. Bose, and Q.
E
a
trial
Wang, Treatment of generalized
population
anxiety disorder with escitalopram:
mentioned
pooled results from double-blind,
refeers to
placebo-controlled trials. J Affect
Davidson
Disord, 2005. 87(2-3): p. 161-7.
et al, 2002,
2004 and
data on
file, 2002
which are
all incudled
in the
submission
.
11
Grant, J.E. and M.N. Potenza,
E
a
UNDER

Escitalopram treatment of pathological
1982
gambling with co-occurring anxiety:
An open-label pilot study with double-
ACT
blind discontinuation. International  RELEASED
Clinical Psychopharmacology, 2006.
21(4): p. 203-209.
12
Ipser, J.C., P;  Dhansay, Y;  Fakier, N
BEEN  ;   E
a

HEALTH
Seedat, S;  Stein, DJ,
Pharmacotherapy augmentatio
HAS  n
INFORMATION
OF
strategies in treatment-resistant
anxiety disorders. Cochrane Da
OF  tabase
of Systematic Reviews, 2007. 2.
13
Lenze, E.J., et al., Efficacy and
E
b

tolerability of citalopram in t
DOCUMENT  he
treatment of late-life anxiety disorde
DEPARTMENT rs:
FREEDOM
results from an 8-week randomized,
THIS
placebo-controlled tr
THE  ial. Am J
THE
Psychiatry, 2005. 162(1): p. 146-50.
BY
14
Menza, M.A., R.D. Dobkin, and H.
E
a, b

Marin, An open-label trial of
aripiprazole augmentation for
treatment-resistant generalized
anxiety disorder [3]. Journal of Clinical
Psychopharmacology, 2007. 27(2): p.
207-210.
15
Mohamed, S., et al., Escitalopram for
E
a
no
comorbid depression and anxiety in
comparator
elderly patients: A 12-week, open-
arm
label, flexible-dose, pilot trial. Am J
Geriatr Pharmacother, 2006. 4(3): p.
201-9.
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16
National Institute of Mental Health
E
a

(NIMH), Drug Therapy for Generalized
Anxiety Disorder Among the Elderly.
2006, July, Clinical Trials.
17
New York State Psychiatric Institute. ,
E
a

F.L., Cognitive-Behavioral Therapy
and Lexapro for GAD
18
Sanofi-Aventis, An Eight-Week Study
E
b

to Evaluate the Efficacy and Safety of
Saredutant in Patients With
Generalized Anxiety Disorder
19
Stein, D.J., H.F. Andersen, and W.K.
E
a
Subgroup
Goodman, Escitalopram for the
analysis
treatment of GAD: efficacy across
examined;
different subgroups and outcomes.
original
Ann Clin Psychiatry, 2005. 17(2): p.
studies
71-5.
included in
analysis -
based on
UNDER
Goodman
20
Stein, D.J., et al., Which factors
E
a

1982
predict placebo response in anxiety
disorders and major depression? An
ACT
analysis of placebo-controlled studies
RELEASED
of escitalopram. Journal of Clinical
Psychiatry, 2006. 67(11): p. 1741-
1746.
BEEN  HEALTH
21
Thase, M.E., Treatment of anxiety
E
b

disorders with venlafaxine XR.
HAS  Expert
INFORMATION
OF
Review of Neurotherapeutics, 2006.
6(3): p. 269-282.
OF
22
Varia, I. and F. Rauscher, Treatment
E
a

of generalized anxiety disorder with
citalopram. Int Clin Psycho
DOCUMENT  pharmacol,
2002. 17(3): p. 103-7.
FREEDOM
DEPARTMENT

THIS
THE  THE

BY
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Table 18:
Summary of Inclusion/Exclusion criteria for Escitalopram and
Benzodiazepine Trials
Included
Reason
/
for

Excluded  Exclusion
1
Prasko, J., et al., Influence of
E
c
personality disorder on the treatment
of panic disorder - Comparison study.
Neuroendocrinology Letters, 2005.
26(6): p. 667-674.
2
HF, S.I., Discontinuation of
E
c
Antipsychotics and Antidepressants
Among Patients With BPSD. 2006.
UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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Table 19:
Summary of Inclusion/Exclusion criteria for Benzodiazepine Trials:
DSM-IV

GAD Benzo HAMA DSM-IV
Included
Reason
Comments
/
for
Excluded  Exclusion
1
Andreatini, R., et al., Effect of valepotriates
E
c
DSM-III- R
(valerian extract) in generalized anxiety
disorder: a randomized placebo-controlled
pilot study. Phytother Res, 2002. 16(7): p.
650-4.
2
Ansseau, M., et al., Controlled comparison
E
c
DSM-III-R
of the efficacy and safety of four doses of
suriclone, diazepam, and placebo in
generalized anxiety disorder.
Psychopharmacology (Berl), 1991. 104(4):
p. 439-43.
3
Ban, T.A. and M.M. Amin, Clobazam:
E
a

uncontrolled and standard controlled clinical
UNDER
trials. Br J Clin Pharmacol, 1979. 7 Suppl 1:
p. 135S-138S.
1982
4
Basile, A.S., A.S. Lippa, and P. Skolnick,
E
a

ACT
GABAA receptor modulators as
anxioselective anxiolytics. Drug Discovery
RELEASED
Today: Therapeutic Strategies, 2006. 3(4):
p. 475-481.
BEEN
5
Bobon, D.P., et al., Time-blind videotaped
E
HEALTH
c

evaluation of injectable diazepam,
HAS INFORMATION
OF
lorazepam and placebo. Acta Psychiatr
Belg, 1978. 78(4): p. 619-34.
OF
6
Borison, RL, Albrecht, JW, Diamond, BI.
E
c
DSM-III
Efficacy and safety of a putative anxyiolitic
agent: Ipsapirone.  Psychopharmacology
DOCUMENT
Bulletin. 1990;6(26):207-209
FREEDOM
DEPARTMENT
7
Boyer, WF, Feighner, JP. A placebo-
E
c
DSM-III
THIS
controlled double-blind
THE   multicenter trial of
THE
two doses of ipsapirone versus diazepam in
BY
generalized anxiety disorder. International
Clinical Psychopharmacology 1993;8:173-
76
8
Brawman-Mintzer, O., R.G. Knapp, and P.J.  E
b

Nietert, Adjunctive risperidone in
generalized anxiety disorder: A double-
blind, placebo-controlled study. Journal of
Clinical Psychiatry, 2005. 66(10): p. 1321-
1325.
9
Casacalenda N et al. Pharmacologic
E
c
DSM-III
treatments effective in both generalized
anxiety disorder and major depressive
disorder: clinical and theoretical
implications. Canadian Journal of
Psychiatry. 1998. 43(7): 722
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10
Centre for Reviews and Dissemination, A
E
a

meta-analytic review of the efficacy of drug
treatment in generalized anxiety disorder
(Structured abstract). Database of Abstracts
of Reviews of Effects, 2007(2).
11
Centre for Reviews and Dissemination,
E
a

Long-term pharmacological treatment of
generalized anxiety disorder (Structured
abstract). Database of Abstracts of Reviews
of Effects, 2007(2).
12
Chessick, C.A., MH; Thase, ME; Batista
E
c
Review,
Miralha da Cunha, ABC; Kapczinski, FFK;
DSM-III;
de Lima, MSML; dos Santos Souza, JJSS
used to
Azapirones for generalized anxiety
identify
disorder. Cochrane Database of Systematic
indiviudal
Reviews, 2007. 2.
trials
13
Coak, AL;  Reilly, J;  Morris, S. Thioridazine  E
c
DSM-III
for anxiety and depressive disorders.
Cochrane Database of Systematic Reviews.
UNDER
2, 2007.
14
Cohn, J, Rickels, K. A pooled, double-blind
E
1982  c
M-A; DSM-
comparison of the effects of buspirone,
III; relevant
ACT
diazepam and placebo in women with
studies
chronic anxiety. Current Medical Research
RELEASED
already
and Opinion 1989;11(5):304-20
included
15
Cooper, S.J., et al., Beta 2-adrenoceptor
E
c
DSM-III
BEEN
antagonism in anxiety. Eur
HEALTH
Neuropsychopharmacol, 1990. 1(1): p. 75-
HAS INFORMATION
OF
7.
16
Cutler, N.R., J.M. Hesselink, and J.J.
E
b

OF
Sramek, A phase II multicenter dose-
finding, efficacy and safety trial of
ipsapirone in outpatients with generalized
DOCUMENT
anxiety disorder. Prog
FREEDOM
DEPARTMENT
Neuropsychopharmacol Biol Psychiatry,
THIS
1994. 18(3): p. 447-63.
THE
THE
17
DeMartinis, N, Runn, M, Rickels, K,
E
c

BY
mandos, L. Prior Benzodiazepine Use and
Buspirone Response in the Treatment of
Generalized Anxiety Disorder. The Journal
of Clinical Psychiatry 2000;61(2): 91-94
18
Downing, R.W. and K. Rickels, Early
E
b
single arm
treatment response in anxious outpatients
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treated with diazepam. Acta Psychiatr
Scand, 1985. 72(6): p. 522-8.
19
Ebadi, M. and Y. Hama, Dopamine, GABA,
E
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cholecystokinin and opioids in neuroleptic-
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THE THE
BY

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29
Heideman J, van Rijswijk E, van Lin N, de
E
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Loos S, Laurant M, Wensing M, van de
Lisdonk E, Grol R. Interventions to improve
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Jacobson, A.F., et al., Comparison of
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31
Jesinger, D.K. and N. Gostick, Anxiety
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neurosis in general practice. A double-blind
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32
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b
M-A
Schmitt, R Antidepressants for generalized
UNDER
anxiety disorder. Cochrane Database of
Systematic Reviews, 2007. 2.
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33
King Pharmaceuticals Research and
E
c
trial not
Development, A Study on the Effectiveness
completed,
ACT
and Safety of Diazepam Injection
inappropriat
RELEASED
(Vanquix™) for Patients With Epilepsy That
e patient
Receive Antiepileptic Drugs, But Still
population
BEEN
Experience Acute Repetitive Seizures
HEALTH
(Bouts or Clusters of Seizures) That
HAS
OF
Require Treatment. 2007.
INFORMATION
34
Llorca, P.M., et al., Efficacy and safety of
E
b
bromazepa
OF
hydroxyzine in the treatment of generalized
m
anxiety disorder: A 3-month double-blind
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DOCUMENT
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35
Mahe V. et al., Long-term ph
FREEDOM  armacological  E
a
M-A;
treatment of ge
THIS  neralized anxiety disorder.
individual
THE
International Clini
THE  cal psychopharmacology.
stuides
2000;15(2):99-105
BY
included in
analysis
36
Martin JL., S.-P.M.F.T.M.-S.E.S.T.G.C.,
E
a
MA - not
Review: Benzodiazepines in generalized
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37
Meoni, P., D. Hackett, and M. Lader,
E
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Re-analysis
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on somatic and psychic symptoms of
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19(2): p. 127-132.
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38
Mitte K, Noack P, Steil R, Hautzinger M.
E
a
DSM-III
Ameta-analytic review of the efficacy of
drug treatment in generalized anxiety
disorder. Journal of Clinical
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39
Miyasaka, L.A., AN; Soares, BGO Valerian
E
c
Review;
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of Systematic Reviews, 2007. 2.
Andreatini
relevant
and this is
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40
Murphy, S.M., R. Owen, and P. Tyrer,
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diazepam,
Comparative assessment of efficacy and
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41
Pecknold, J.C., et al., Evaluation of
E
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buspirone as an antianxiety agent:
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Can J Psychiatry, 1989. 34(8): p. 766-71.
UNDER
42
Pecknold, JC, Familamiri, P, Chang, H,
E
c
DSM-III
1982
Wilson, R, Alarcia, J, Mc-Clure, J.
Buspirone: Anxiolytic?. Progress in Neuro-
ACT
psychopharmacol-ogy & Biological
RELEASED
Psychiatry 1985;9:638-642
43
Pomara, N., et al., Cortisol response to
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c
measureme
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BEEN
nt of cortisol
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duration of treatment, and presence of
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HAS INFORMATION
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Psychopharmacology (Berl), 2005. 178(1):
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OF
44
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c
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discontinuation, and psychomotor effects of
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DOCUMENT  neralized
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45
Power KG et al,
THE  “A controlled comparison of  E
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46
Rickels, K., et al., Antidepressants for the
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47
Rickels, K., et al., Buspirone and diazepam
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48
Rickels, K., et al., Gepirone and diazepam
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49
Rickels, K., N. DeMartinis, and B.
E
c
DSM-III -R
Aufdembrinke, A double-blind, placebo-
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Rocca, P., et al., Paroxetine efficacy in the
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51
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buspirone
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diazepam,
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53
Schwartz, T.L. and N. Nihalani, Tiagabine
E
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UNDER
GABA
in anxiety disorders. Expert Opinion on
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ACT
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Shah, L.P., et al., A controlled double blind
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Strand, M., et al., A double-blind
HAS , controlled
OF    E
b
buspirone
INFORMATION
trial in primary care patients with
and
OF
generalized anxiety: a comparison between
oxazepam
buspirone and oxazepam. J Clin Psychiatry,
1990. 51 Suppl: p. 40-5.
56
Tyrer, P. and R. Owen, Anxi
DOCUMENT  ety in primary  E
a
DSM-III,
DEPARTMENT
care: is short-term drug treatment
crossover
FREEDOM
appropriate? J
THIS  Psychiatr Res, 1984. 18(1):
trial
THE
p. 73-8.
THE
57
Tyrer, P., et al., Th
BY  e Nottingham study of
E
c
DSM-III
neurotic disorder. Effect of personality
status on response to drug treatment,
cognitive therapy and self-help over two
years. Br J Psychiatry, 1993. 162: p. 219-
26.
58
Tyrer, P., et al., The Nottingham study of
E
c
DSM-III
neurotic disorder: comparison of drug and
psychological treatments. Lancet, 1988.
332(8605): p. 235-40.
59
University of Utah, P.C.s.M.C.F., Intranasal
E
c
trial not
Midazolam Versus Rectal Diazepam for
completed,
Treatment of Seizures. 2006.
inappropriat
e patient
population
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60
Wingerson, D.K., et al., Effect of
E
b
intravenous
benzodiazepines on plasma levels of
diazepam,
homovanillic acid in anxious patients and
plasma
control subjects. Psychiatry Res, 1996.
HVA levels
65(1): p. 53-9.

UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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Appendix 1: Article Abstracts for
Escitalopram
1. Allgulander, C., I. Florea, et al. (2006). "Prevention of relapse in
generalized anxiety disorder by escitalopram treatment." International Journal
of Neuropsychopharmacology 9(5): 495-505.

Escitalopram has demonstrated a robust and dose-dependent efficacy
in the treatment of generalized anxiety disorder (GAD) for up to 3
months. In the present study, the efficacy and tolerability of
escitalopram in the prevention of relapse in GAD was investigated. A
total of 491 patients with a primary diagnosis of GAD and a Hamilton
Anxiety (HAMA) total score (greater-than or equal to)20 received 12 wk
of open-label treatment with a fixed dose of escitalopram (20 mg/d). Of
these, 375 patients responded (HAMA total score (less-than or equal
UNDER
to)10) and were randomized to double-blind treatment with 20 mg/d
escitalopram (n=187) or placebo (n=188). Treatmen
1982 t was continued for
24-76 wk unless the patient relapsed or was withdrawn for other
ACT
reasons. Relapse was defined as either an increase in HAMA total
RELEASED
score to (greater-than or equal to)15, or lack of efficacy, as judged by
the investigator. The results of the primary analysis showed a clear
beneficial effect of escitalopram rela
BEEN  tive to placebo on the time to
HEALTH
relapse of GAD (log-rank test, p<0.001). The risk of relapse was 4.04
HAS
OF
times higher for placebo-treated patients th
INFORMATION  an for escitalopram-treated
patients; the proportion of patients who relapsed was statistically
OF
significantly higher in the placebo group (56%) than in the escitalopram
group (19%) (p<0.001). Escitalopram was well tolerated and 7% of the
escitalopram-treated patients withdrew due to adverse events, vs. 8%
DOCUMENT
of the placebo patients. The incide
DEPARTMENT  nce of discontinuation symptoms
FREEDOM
with escitalopram during tapered withdrawal was low; the symptoms
THIS
primarily being dizzi
THE  ness (10-12%), nervousness (2-6%), and insomnia
THE
(2-6%). Escitalo
BY  pram 20 mg/d significantly reduced the risk of relapse
and was well tolerated in patients with GAD. Copyright (copyright) 2005
CINP.

2. Baldwin D.S. (2006). "Escitalopram and paroxetine in the treatment of
generalised anxiety disorder." British Journal of Psychiatry 189: 262-272.

3. Bandelow, B., D. S. Baldwin, et al. (2006). "What is the threshold for
symptomatic response and remission for major depressive disorder, panic
disorder, social anxiety disorder, and generalized anxiety disorder?" J Clin
Psychiatry 67(9): 1428-34.

OBJECTIVE: Symptom-free remission is a goal for treatment in
depression and anxiety disorders, but there is no consensus regarding
the threshold for determining remission in individual disorders. We
sought to determine these thresholds by comparing, in a post hoc
analysis, scores on the Clinical Global Impressions scale (CGI) and
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disorder-specific symptom severity rating scales from all available
studies of the treatment of major depressive disorder, panic disorder,
generalized anxiety disorder, and social anxiety disorder with the same
medication (escitalopram). We also sought to compare the
standardized effect sizes of escitalopram for these 4 psychiatric
disorders. DATA SOURCES AND STUDY SELECTION: Raw data from
all randomized, double-blind, placebo-controlled, acute treatment
studies sponsored by H. Lundbeck A/S (Copenhagen, Denmark) or
Forest Laboratories, Inc. (New York, N.Y.), published through March 1,
2004, with patients treated with escitalopram for DSM-IV major
depressive disorder (5 studies), panic disorder (1 study), generalized
anxiety disorder (4 studies), or social anxiety disorder (2 studies) were
compared with regard to the standardized effect sizes of change in CGI
score and scores on rating scales that represent the "gold standard" for
assessment of these disorders (the Montgomery-Asberg Depression
Rating Scale, the Panic and Agoraphobia Scale, the Hamilton Rating
Scale for Anxiety, and the Liebowitz Social Anxiety Scale, respectively).
DATA SYNTHESIS: In all indications, treatment with escitalopram
UNDER
showed differences from placebo in treatment effect from 0.32 to 0.59
on the CGI-S and CGI-I and standardized effect sizes
1982  from 0.32 to 0.50
on the standard rating scales. There were no significant differences
ACT
among the different disorders. Moderate to high correlations were
RELEASED
found between scores on the CGI and the standard scales. The
corresponding standard scale scores for CGI-defined "response" and
"remission" were determined. CONC
BEEN  LUSION: Comparison of scores on
HEALTH
the standard scales and scores on the CGI suggest that the traditional
HAS
OF
definition of response (i.e., a 50% reduction in a standard scale) may
INFORMATION
be too conservative.
OF

4. Bielski, R. J., A. Bose, et al. (2005). "A double-blind comparison of
escitalopram and paroxetine in the long-term treatment of generalized anxiety
DOCUMENT
disorder." Annals of Clinical Psychiatry 17(2): 65-69.
FREEDOM
DEPARTMENT

Background. This study compared the efficacy and tolerability of
THIS
escitalopram, a newer
THE  SSRI, with paroxetine in the treatment of
THE
generalized anxiety disorder (GAD). Methods. Patients with DSM-IV-
BY
defined GAD were randomized to receive 24 weeks of double-blind
flexible-dose treatment with either escitalopram (10-20 mg/day) or
paroxetine (20-50 mg/day), followed by a 2-week, double-blind, down-
titration period. Mean change from baseline to endpoint (LOCF) in
Hamilton Anxiety Scale (HAMA) scores was the primary efficacy-
variable. Results. Mean baseline HAMA scores for the escitalopram
(N=60) and paroxetine (N=61) groups were 23.7 and 23.4, respectively.
After 24 weeks of treatment, mean changes in HAMA scores were -
15.3 and -13.3 for escitalopram and paroxetine, respectively (p=0.13).
Significantly fewer patients withdrew from escitalopram than paroxetine
treatment due to adverse events (6.6% vs. 22.6%; p=0.02). The
frequency of treatment-emergent adverse events was higher with
paroxetine vs. escitalopram: overall (88.7% vs. 77.0%), insomnia
(25.8% vs. 14.8%), constipation (14.5% vs. 1.6%), ejaculation disorder
(30.0% vs. 14.8%), anorgasmia (26.2% vs. 5.9%), and decreased libido
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(22.6% vs. 4.9%). Conversely, diarrhea and upper respiratory tract
infection were reported more with escitalopram than paroxetine (21.3%
vs. 8.1%, and 14.8% vs. 4.8%, respectively). Conclusions. These
results support the use of escitalopram as a first-line treatment for
GAD. Copyright (copyright) Taylor & Francis Inc.

5. Blank, S., E. J. Lenze, et al. (2006). "Outcomes of late-life anxiety disorders
during 32 weeks of citalopram treatment." J Clin Psychiatry 67(3): 468-72.

BACKGROUND: Anxiety disorders are common in later life, but little is
known about the long-term benefits and risks of pharmacotherapy.
METHOD: 30 patients aged 60 years and older, with a DSM-IV anxiety
disorder, entered a 32-week trial of citalopram. Data gathered at
baseline and follow-up included anxiety symptoms using Hamilton
Rating Scale for Anxiety (HAM-A) scores, quality of life using the
Medical Outcomes Study 36-item Short Form (SF-36), and sleep using
the Pittsburgh Sleep Quality Index (PSQI). Data analysis consisted of
mixed-effect repeated measures models of HAM-A scores and pre-post
comparison of SF-36 and PSQI scores. RESULTS: 30 persons entered
UNDER
treatment; most (27/30) had a primary DSM-IV diagnosis of generalized
anxiety disorder (2 had panic disorder; 1 had posttra
1982  umatic stress
disorder). Three subjects discontinued study medication due to side
ACT
effects, 5 were terminated because of nonresponse, and 5 dropped out
RELEASED
of the study for other reasons; thus, 17 subjects (57%) completed 32
weeks of treatment. Subjects' HAM-A scores improved significantly,
with continuing improvements up u
BEEN ntil about 20 weeks of treatment. On
HEALTH
the basis of a criterion of reduction in HAM-A to < 10 during the trial,
HAS
OF
60% (18/30) of subjects were responders. Those who completed the
INFORMATION
32-week trial had significant improvements in sleep and quality of life-
OF
including social functioning, vitality, mental health, and role difficulties
due to emotional problems. CONCLUSIONS: In this 32-week study of
citalopram for elderly persons with anxiety disorders, 60% responded.
DOCUMENT
Those who received a full course of treatment experience significant
FREEDOM
DEPARTMENT
improvements in quality of life and sleep quality.
THIS

THE  THE
6. Davidson, J. R. T., A. Bose, et al. (2004). "Escitalopram in the treatment of
BY
generalized anxiety disorder: Double-blind, placebo controlled, flexible-dose
study." Depression and Anxiety 19(4): 234-240.

Escitalopram has been shown in clinical trials to improve anxiety
symptoms associated with depression, panic disorder, and social
anxiety disorder. This study was designed to evaluate the efficacy and
tolerability of escitalopram in the treatment of generalized anxiety
disorder (GAD). Outpatients (18 years or older) who met DSM-IV
criteria for GAD, with baseline Hamilton Rating Scale for Anxiety
(HAMA) scores (greater-than or equal to)18, were randomly assigned
to double blind treatment with escitalopram (10 mg/day for the first 4
weeks and then flexibly dosed from 10-20 mg/day) or placebo for 8
weeks, following a 1-week, single-blind, placebo lead-in period. The
primary efficacy variable was the mean change from baseline in total
HAMA score at Week 8. The escitalopram group (N = 158) showed a
statistically significant, and clinically relevant, greater improvement at
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endpoint compared with placebo (N = 157) in all prospectively defined
efficacy parameters. Significant improvement in HAMA total score and
HAMA psychic anxiety subscale score for the escitalopram-treated
group vs. the placebo-treated group was observed beginning at Week
1 and at each study visit thereafter. Mean changes from baseline to
Week 8 on the HAMA total score using a last-observation-carried-
forward (LOCF) approach were -11.3 for escitalopram and -7.4 for
placebo (P < .001). Response rates at Week 8 were 68% for
escitalopram and 41% for placebo (P < .01) for completers, and 58%
for escitalopram and 38% for placebo LOCF values (P < 01).
Treatment with escitalopram was well tolerated, with low rates of
reported adverse events and an incidence of discontinuation due to
adverse events not statistically different from placebo (8.9% vs. 5.1%;
P = .27). Escitalopram 10-20 mg/day is effective, safe, and well
tolerated in the treatment of patients with GAD. (copyright) 2004 Wiley-
Liss, Inc.

7. Davidson, J. R. T., A. Bose, et al. (2005). "Safety and efficacy of
UNDER
escitalopram in the long-term treatment of generalized anxiety disorder."
Journal of Clinical Psychiatry 66(11): 1441-1446.
1982

Introduction: Generalized anxiety disorder (GAD) is a chronic disorder
ACT
that requires long-term treatment. Escitalopram has previously been
RELEASED
shown to be effective and well tolerated in the acute treatment of GAD.
Method: Three 8-week, double-blind, placebo-controlled trials of nearly
identical design were conducted of
BEEN  escitalopram in moderate-to-severe
HEALTH
GAD (DSM-IV criteria). Patients completing these trials were given the
HAS
OF
option of entering a 24-week, open-label, flexible-dose trial of
INFORMATION
escitalopram (10-20 mg/day). Data were collected from September 20,
OF
2000, to August 15, 2002. Results: Two hundred ninety-nine (56.8%) of
526 patients completed 24 weeks of open-label treatment. The mean
Hamilton Rating Scale for Anxiety (HAM-A) score at baseline of open-
DOCUMENT
label treatment was 13.1. Long-term escitalopram treatment led to
FREEDOM
DEPARTMENT
continuing improvement on all anxiety and quality-of-life (QOL) scores.
THIS
Of those completing
THE   24 weeks of treatment, 92.0% were responders
THE
(Clinical Global Impressions-Improvement scale score < 2), and the
BY
mean HAM-A score in the completer analysis was 6.9; using the last
observation carried forward (LOCF), 75.9% were responders, and the
mean HAM-A score in the LOCF analysis was 9.2 at endpoint.
Insufficient therapeutic response and adverse events led to withdrawal
of 4.2% and 9.9% of patients, respectively. Mean increase in weight
from baseline was 3.0 lb. No clinically notable changes in mean
laboratory, vital sign, or electrocardiographic values were observed.
Conclusion: These results support the long-term tolerability and
effectiveness of escitalopram in the treatment of GAD.

8. Dhillon, S., L. J. Scott, et al. (2006). "Escitalopram: A review of its use in
the management of anxiety disorders." CNS Drugs 20(9): 763-790.

Abstract: Escitalopram (Cipralex(registered trademark)
Lexapro(registered trademark) Seroplex(registered trademark)
Sipralexa(registered trademark)), the therapeutically active S-
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enantiomer of racemic citalopram (RS-citalopram), is a potent and
highly selective serotonin reuptake inhibitor. It is effective and generally
well tolerated in the treatment of moderate to severe generalised
anxiety disorder (GAD) or social anxiety disorder (SAD), panic disorder
(with or without agoraphobia) as well as obsessive-compulsive disorder
(OCD). Moreover, escitalopram is at least as effective as paroxetine for
the treatment of GAD, SAD or OCD and appears to achieve a more
rapid response than racemic citalopram in the management of panic
disorder. Generally, it has a more favourable tolerability profile than
paroxetine in terms of fewer discontinuation symptoms. In addition, a
favourable pharmacokinetic profile permits once-daily administration of
the drug. Additional comparative studies are required to definitively
position escitalopram with respect to other SSRIs and venlafaxine.
Nevertheless, available clinical data indicate that escitalopram is an
effective first-line treatment option for the management of GAD, SAD,
panic disorder and OCD. Pharmacological Properties: Escitalopram is
unique among SSRIs in that it stabilises its binding to the high-affinity
binding site of the serotonin transporter protein via an allosteric effect
UNDER
at the low-affinity binding site. In vivo and in vitro studies have shown
escitalopram to be approximately twice as potent as
1982  citalopram in
inhibiting serotonin reuptake. It is highly selective for the serotonin
ACT
transporter protein and shows no or very low affinity for other receptors
RELEASED
or ion channels. In vivo, escitalopram was four times more potent than
citalopram in reducing firing activity of presumed serotonergic neurons
in rat brain. Single and multiple once
BEEN  -daily oral doses of escitalopram
HEALTH
10-30 mg/day show linear, dose-proportional pharmacokinetics in
HAS
OF
healthy volunteers. The steady-state plasma concentration of the drug
INFORMATION
was reached within 7-10 days. Escitalopram is largely metabolised in
OF
the liver, mainly into S-demethylcitalopram (S-DCT) and S-
didemethylcitalopram (S-DDCT). Cytochrome P450 (CYP) isozymes
CYP2C19, 3A4 and 2D6 contribute equally to the metabolism of
DOCUMENT
escitalopram into S-DCT, whereas only CYP2D6 was involved in the
FREEDOM
DEPARTMENT
second demethylation of S-DCT to S-DDCT. Neither metabolite has
THIS
significant serotonin
THE  reuptake activity in vivo. Escitalopram and its
THE
metabolites are excreted primarily via the kidneys, with a small
BY
percentage of the drug excreted unchanged. The mean plasma
elimination half-life (t1/2) of escitalopram is 27-33 hours. Escitalopram
dosage adjustments are recommended in elderly patients and patients
with impaired hepatic function, and caution is advised in patients with
severe renal impairment. Therapeutic Efficacy: In well designed,
double-blind, comparative, 8- to 24-week studies in patients with
moderate to severe GAD, escitalopram was more effective than
placebo and at least as effective as paroxetine in reducing the mean
Hamilton Rating Scale for Anxiety total score (primary efficacy
parameter). Escitalopram demonstrated continued efficacy in a 24-
week open-label extension study of three 8-week double-blind trials
and a (less-than or equal to)76-week placebo-controlled, double-blind,
relapse-prevention study. Moreover, in the relapse-prevention study,
escitalopram recipients showed a significantly longer time to relapse
and reduced risk of relapse than placebo recipients, and fewer
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escitalopram than placebo recipients relapsed. Escitalopram was also
associated with better mental health-related quality of life than placebo
in a subgroup of patients from the relapse-prevention study. In two
randomised, double-blind, 12- and 24-week studies in patients with
moderate to severe SAD, apart from escitalopram 10 mg/day at 12
weeks, escitalopram was significantly more effective than placebo and
at least as effective as paroxetine in reducing the mean Liebowitz
Social Anxiety Scal total scores (primary efficacy parameter). In a 24-
week double-blind, placebo-controlled relapse-prevention study,
escitalopram recipients had a longer time to relapse and reduced risk
of relapse compared with placebo recipients, and significantly fewer
escitalopram than placebo recipients relapsed. Escitalopram was
significantly more effective than placebo in reducing the panic attack
frequency (primary efficacy parameter) with a faster onset of action
than citalopram in a randomised, double-blind trial in patients with
panic disorder. In an open-label study in elderly (>65 years) patients
with panic disorder, improvement in panic attack frequency (primary
efficacy parameter) and secondary efficacy variables occurred more
UNDER
quickly in escitalopram than citalopram recipients. In patients with
OCD, escitalopram 20 mg/day for 12 weeks was more
1982   effective than
placebo, and at least as effective as paroxetine 40 mg/day, with
ACT
respect to a mean reduction from baseline in the Yale-Brown
RELEASED
Obsessive Scale total score (primary efficacy parameter). In a relapse-
prevention study, escitalopram recipients showed a longer time to
relapse and a significantly reduced
BEEN  risk of relapse compared with those
HEALTH
receiving placebo. In addition, the proportion of patients who relapsed
HAS
OF
in the escitalopram group was significantly lower than in the placebo
INFORMATION
group. Tolerability: Escitalopram was generally well tolerated in adult
OF
patients with GAD, SAD, panic disorder or OCD. Withdrawal rates due
to treatment-emergent adverse events in escitalopram recipients were
6.0-11.8%. The profile of treatment-emergent adverse events was
DOCUMENT
generally similar in escitalopram recipients irrespective of the type of
FREEDOM
DEPARTMENT
anxiety disorder in placebo-controlled short-term trials. The most
THIS
common adverse eve
THE  nt in escitalopram and placebo recipients was
THE
headache (15-25% of patients). Other common adverse events in
BY
escitalopram recipients with GAD include nausea (18.2%), ejaculation
disorder (14.3%), insomnia (11.9%), fatigue (7.7%), decreased libido
(6.8%) and anorgasmia (5.7%). Withdrawal rates during the 12-week
open-label period of three relapse-prevention studies were 7.7-20.0%,
whereas 2.6-7.9% withdrew from the study during the (less-than or
equal to)76-week double-blind period. Furthermore, the overall
incidence of adverse events was numerically lower during the double-
blind period than the initial 12-week open-label period. Escitalopram
recipients generally reported more discontinuation symptoms than
placebo recipients after switching to placebo in two fixed-dose studies,
whereas patients continuing escitalopram treatment generally reported
fewer discontinuation symptoms than those switching to placebo in the
relapse-prevention studies. The tolerability profile of escitalopram was
generally similar to those of paroxetine or citalopram. However, in one
study, paroxetine recipients showed significantly higher rates of
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withdrawal due to treatment-emergent adverse events than
escitalopram recipients, and more paroxetine than escitalopram
recipients appeared to experience sexual adverse events (ejaculation
disorder [30.0% vs 14.8%], anorgasmia [26.2% vs 5.9%] and
decreased libido [22.6% vs 4.9%]). Some discontinuation symptoms
were reported in significantly fewer escitalopram than paroxetine
recipients, and escitalopram recipients showed significantly lower mean
changes in discontinuation emergent signs and symptoms scores than
paroxetine recipients. In large analyses of placebo-controlled and
relapse-prevention studies in patients with major depressive disorder or
anxiety disorders, there was no indication of increased risk of suicidal
behaviour in escitalopram or placebo recipients, with no completed
suicides during the first 2 weeks of escitalopram or placebo therapy.
Moreover, in an analysis of pharmacovigilance post-marketing
surveillance information, escitalopram recipients had a low suicide rate
(1.8 per million prescriptions). (copyright) 2006 Adis Data Information
BV. All rights reserved.

UNDER
9. Goodman, W. K., A. Bose, et al. (2005). "Treatment of generalized anxiety
disorder with escitalopram: Pooled results from double-blin
1982  d, placebo-
controlled trials." Journal of Affective Disorders 87(2-3): 161-167.
ACT

Background: Escitalopram 10 mg/day is an effective and well-tolerated
RELEASED
antidepressant. Three randomized controlled trials recently evaluated
the safety and efficacy of escitalopram in the treatment of generalized
anxiety disorder (GAD). Methods: T
BEEN  he trial designs were virtually
HEALTH
identical, allowing data to be pooled across studies. Male and female
HAS
OF
outpatients, ages 18-80 years, with DSM-IV-defined GAD were
INFORMATION
randomized to double-blind treatment with escitalopram or placebo for
OF
8 weeks. Escitalopram dose was fixed at 10 mg/day for the first 4
weeks, after which increases to 20 mg/day were permitted. The primary
efficacy variable was the mean change from baseline in total Hamilton
DOCUMENT
Anxiety Scale (HAMA) score. Results: Approximately 850 patients were
FREEDOM
DEPARTMENT
randomized to double-blind treatment. In each individual study,
THIS
escitalopram was sig
THE  nificantly superior to placebo (p<0.05) as
THE
measured by change from baseline in HAMA score. By-visit analyses
BY
of data pooled across studies revealed significantly greater
improvement (p<0.05) in the escitalopram group beginning at week 1
or 2 and continuing through week 8 for all primary and secondary
efficacy variables. The mean change in HAMA total score from
baseline to endpoint also was significantly greater for patients
maintained at escitalopram 10 mg/day than for those receiving placebo.
Escitalopram was generally well tolerated. Limitations: The studies
included in this analysis were of short-term duration and excluded
patients with significant medical and psychiatric comorbidities, such as
major depressive disorder. Conclusion: Results from the individual
trials and the pooled analysis demonstrate that escitalopram is effective
and well tolerated for the treatment of GAD. (copyright) 2005 Elsevier
B.V. All rights reserved.

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10. Grant, J. E. and M. N. Potenza (2006). "Escitalopram treatment of
pathological gambling with co-occurring anxiety: An open-label pilot study with
double-blind discontinuation." International Clinical Psychopharmacology
21(4): 203-209.

Although co-occurring disorders are common in pathological gambling
(PG), investigations of the response to pharmacotherapy in individuals
with PG and co-occurring psychiatric symptomatology are limited.
Thirteen subjects with DSM-IV PG and co-occurring anxiety were
treated in a 12-week open-label trial of escitalopram. Subjects were
assessed with the Yale-Brown Obsessive Compulsive Scale Modified
for Pathological Gambling (PG-YBOCS; primary outcome measure),
the Hamilton Anxiety Rating Scale (HAM-A), the Clinical Global
Impressions scale (CGI), and measures of psychosocial functioning
and quality of life. Those subjects who 'responded' (defined as a 30%
or greater reduction in PG-YBOCS total score at endpoint) were offered
inclusion in an 8-week double-blind discontinuation phase. PG-YBOCS
scores decreased from a mean of 22.2 (plus or minus) 4.5 at baseline
to 11.9 (plus or minus) 10.7 at endpoint (P = 0.002) and 61.5% were
UNDER
responders. Scores on the HAM-A decreased by 82.8% over the 12-
week period (mean of 15.9 (plus or minus) 3.2 at ba
1982 seline to a mean of
2.8 (plus or minus) 3.6 at endpoint) (P < 0.001). On the CGI, 38.5% of
ACT
subjects (n = 5) were 'very much improved' and 23.1% (n = 3) were
RELEASED
'much improved' by study endpoint. The Sheehan Disability Scale,
Perceive Stress Scale and Quality of Life Inventory all showed
improvement (P (less-than or equa
BEEN l to) 0.001, P = 0.002 and P = 0.029,
HEALTH
respectively). The mean end-of-study dose of escitalopram was 25.4
HAS
OF
(plus or minus) 6.6 mg/day. Of three subjects assigned to escitalopram
INFORMATION
during the discontinuation phase, none reported statistically significant
OF
worsening of gambling symptoms. However, one subject assigned to
placebo reported that gambling symptoms returned within 4 weeks.
Open-label escitalopram treatment was associated with improvements
DOCUMENT
in gambling and anxiety symptoms and measures of psychosocial
FREEDOM
DEPARTMENT
functioning and quality of life. Larger, longer, placebo-controlled,
THIS
double-blind studies
THE   are needed to evaluate further the safety and
THE
tolerability of escitalopram in the treatment of PG and co-occurring
BY
anxiety. (copyright) 2006 Lippincott Williams & Wilkins.

11. Ipser, J. C., P;  Dhansay, Y;  Fakier, N; Seedat, S;  Stein, DJ (2007).
"Pharmacotherapy augmentation strategies in treatment-resistant anxiety
disorders." Cochrane Database of Systematic Reviews 2.

A large proportion of patients with anxiety disorders fail to respond to
first-line medication interventions, despite evidence of the effectiveness
of these agents.

  Objectives

  To assess the effects of medication versus placebo augmentation in the
treatment of patients with anxiety disorders who have failed to respond
adequately to first-line drug therapies.

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  Search strategy

  The Cochrane Depression, Anxiety & Neurosis Group (CCDAN) specialised
registers (CCDANCTR-Studies and CCDANCTR-References) were
searched on 3/8/2005, MEDLINE (January 1966 to July 2005) and
PsycINFO (1966 to 2005, Part A). Unpublished trials were identified
through the Controlled Trials database and the National Institute of
Health's Computer Retrieval of Information on Scientific Projects
(CRISP) service (1972 to 2005). Additional studies in any language
were sought in reference lists of retrieved articles.

  Selection criteria

  All randomised controlled trials (RCTs) of the medication augmentation of
pharmacotherapy for treatment resistant anxiety disorders.

  Data collection and analysis

UNDER
  Two raters independently assessed RCTs for inclusion in the review, collated
trial data, and assessed trial quality. Investigators w
1982 ere contacted to
obtain missing data. Summary statistics were stratified by class of
ACT
augmentation agent and anxiety disorder. Overall effect estimates were
RELEASED
calculated using a random-effects model, heterogeneity was assessed
and subgroup/sensitivity analyses were undertaken.

BEEN  HEALTH
  Main results
HAS
OF

INFORMATION
  Twenty eight short-term (average of seven weeks) randomised controlled
OF
trials (740 participants) were included in the review, 20 of which
investigated augmentation of medication for treatment-resistant
obsessive compulsive disorder (OCD). Summary statistics for
DOCUMENT
responder status from nine trials demonstrate overall superiority of a
FREEDOM
DEPARTMENT
variety of medication agents to placebo (relative risk of non-response
THIS
(RR) 3.16, 95% CI 1
THE  .08 to 9.23). Similarly, symptom severity was
THE
significantly reduced in the medication groups, relative to placebo
BY
(number of trials (N) = 14, standardised mean difference (SMD) -0.87,
95% CI -1.37 to -0.36). There is no evidence of a difference between
medication and placebo in total dropout rate, or in the number of
dropouts due to adverse events.

  Authors' conclusions

  Medication augmentation can be an effective and well-tolerated short-term
treatment strategy for non-responders to first-line pharmacotherapy of
anxiety disorders. However, any conclusions must be tentative in view
of methodological and clinical heterogeneity, and the fact that much of
the relevant database is based on antipsychotic augmentation trials in
OCD patients resistant to serotonin reuptake inhibitors (SRIs).
Additional data are needed to address several areas, including the
efficacy of augmentation over the longer-term, and the value of
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medication augmentation in comparison to other strategies (eg
switching medication, adding psychotherapy).

12. Lenze, E. J., B. H. Mulsant, et al. (2005). "Efficacy and tolerability of
citalopram in the treatment of late-life anxiety disorders: results from an 8-
week randomized, placebo-controlled trial." Am J Psychiatry 162(1): 146-50.

OBJECTIVE: Anxiety disorders are highly prevalent in elderly persons.
However, to date, the efficacy of selective serotonin reuptake inhibitors
(SSRIs) for the treatment of anxiety disorders in this age group has not
been established. METHOD: Thirty-four participants age 60 and older
with a DSM-IV anxiety disorder (mainly generalized anxiety disorder)
and a Hamilton Anxiety Rating Scale score of 17 or higher were
randomly assigned under double-blind conditions to either citalopram
or placebo. Response was defined as a score of 1 (very much
improved) or 2 (much improved) on the Clinical Global Improvement
scale or a 50% reduction in the Hamilton anxiety scale score.
Response and side effects with citalopram and placebo were compared
by using chi-square tests and linear modeling. RESULTS: Eleven
UNDER
(65%) of the 17 citalopram-treated participants responded by 8 weeks,
versus four (24%) of the 17 placebo-treated participa
1982  nts. The most
common and problematic side effect in the citalopram group was
ACT
sedation. CONCLUSIONS: The authors believe this to be the first
RELEASED
prospective controlled study to test the efficacy of an SSRI in the
management of anxiety disorders among the elderly. These results
support the efficacy of citalopram in
BEEN   late-life anxiety disorders. They
HEALTH
need to be replicated in a larger study group.
HAS
OF

INFORMATION
13. Menza, M. A., R. D. Dobkin, et al. (2007). "An open-label trial of
OF
aripiprazole augmentation for treatment-resistant generalized anxiety disorder
[3]." Journal of Clinical Psychopharmacology 27(2): 207-210.

DOCUMENT
14. Mohamed, S., K. Osatuke, et al. (2006). "Escitalopram for comorbid
FREEDOM
DEPARTMENT
depression and anxiety in elderly patients: A 12-week, open-label, flexible-
THIS
dose, pilot trial." American
THE  Journal Geriatric Pharmacotherapy 4(3): 201-209.
THE

Background: Comorbid depression and anxiety may result in greater
BY
symptom severity and poorer treatment response than either condition
alone. Selective serotonin reuptake inhibitors have been found to be
effective in treating both depression and anxiety; however,
pharmacodynamic and pharmacokinetic changes associated with aging
warrant special attention in medication trials in older patients.
Objective: The objective of this study was to assess the efficacy and
tolerability of short-term (12-week) administration of escitalopram
oxalate 10 to 20 mg/d for moderate to marked comorbid depression
and anxiety in elderly patients. Methods: This open-label, flexible-dose
(10-20 mg/d), pilot trial was conducted at the Psychiatry Service,
Veterans Affairs Medical Center, Cincinnati, Ohio. Outpatients aged
(greater-than or equal to)65 years were included if they met the criteria
for comorbid major depressive disorder (MDD) and generalized anxiety
disorder (GAD), as defined in the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision, for (greater-than or
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equal to)4 weeks and had a baseline Montgomery-sberg Depression
Rating Scale (MADRS) score of >22 and a Hamilton Rating Scale for
Anxiety (HAM-A) score of (greater-than or equal to)18. All patients
received escitalopram 10 to 20 mg/d. The primary efficacy variables
were the mean changes from baseline in total MADRS and HAM-A
scores at 12 weeks (last observation carried forward). The secondary
efficacy end point was the change from baseline in Medical Outcomes
Study 36-Item Short-Form Health Survey (SF-36) 8 subscale scores.
Adverse events were assessed at each visit (treatment weeks 1, 2, 3,
4, 6, 8, 10, and 12) with the use of open-ended questioning. Results:
Twenty patients were enrolled (mean [SD] age, 73.0 [4.8] years; 6
[30%] women; race: 17 [85%] white, 2 [10%] black, and 1 [5%] "other").
Seventeen (85%) of 20 patients completed the study; 3 (15%)
withdrew: 1 (5%) due to lack of efficacy and 2 (10%) due to adverse
events (dizziness and somnolence [1 (5%) patient each]). Statistically
significant improvements from baseline to end point were found with
escitalopram treatment (MADRS: t19 = 7.38, P < 0.001, effect size =
2.93; HAM-A: t19 = 4.19, P < 0.001, effect size = 1.83). Significant
UNDER
changes from baseline in scores on 4 (Social Functioning, Role
Functioning-Emotional, Mental Health, and Energy/Fa
1982  tigue) of the 8
subscales of the SF-36 were als of ound (all, P < 0.01). Conclusion: In
ACT
this small study in elderly patients with comorbid MDD and GAD,
RELEASED
treatment with escitalopram 10 to 20 mg/d for 12 weeks was
associated with significant improvements in symptoms of depression
and anxiety. (copyright) 2006 Exce
BEEN rpta Medica, Inc.
HEALTH

HAS
OF
15. Stein, D. J., H. F. Andersen, et al. (2005). "Escitalopram for the treatment
INFORMATION
of GAD: Efficacy across different subgroups and outcomes." Annals of Clinical
OF
Psychiatry 17(2): 71-75.

Background. Generalized anxiety disorder (GAD) is characterized by
anxiety, and also frequently associated with depressive symptoms.
DOCUMENT
Benzodiazepines have commonly been used in the treatment of GAD,
FREEDOM
DEPARTMENT
but are not effective antidepressant agents. In this study, we
THIS
determined whether
THE  the selective serotonin reuptake inhibitor
THE
escitalopram, was effective across different subgroups and outcomes
BY
(anxious symptoms, depressive symptoms, and quality of life).
Methods. Three randomized, placebo controlled studies of
escitalopram in GAD have employed a similar design, allowing for
pooling of the data. The primary efficacy measure was the Hamilton
Anxiety Scale (HAMA). General linear models were used to determine
the efficacy of escitalopram across different subgroups and outcomes.
Results. Escitalopram was efficacious for GAD on a range of measures
of both anxiety and depression, and improved the associated
impairment in quality of life. There was no significant interaction of
effects on the HAMA with demographic or clinical variables.
Furthermore, escitalopram was efficacious on both primary and
secondary scales in the subgroup of subjects with above-median
severity of depressive symptoms at baseline (HAMD-17>12).
Conclusions. Escitalopram reduces anxiety and depressive symptoms
in GAD, and improves quality of life. It is equally effective in GAD
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patients, with an above-median level of depressive symptoms. Further
research is needed to determine whether these results can be
extrapolated to GAD patients with comorbid major depression.
Copyright (copyright) Taylor & Francis Inc.

16. Stein, D. J., D. S. Baldwin, et al. (2006). "Which factors predict placebo
response in anxiety disorders and major depression? An analysis of placebo-
controlled studies of escitalopram." Journal of Clinical Psychiatry 67(11):
1741-1746.

Background: The placebo response rate has increased in several
psychiatric disorders and is a major issue in the design and
interpretation of clinical trials. The current investigation attempted to
identify potential predictors of placebo response through examination of
the placebo-controlled clinical trial database for escitalopram in 3
anxiety disorders and in major depressive disorder (MDD). Method:
Raw data from placebo-controlled studies (conducted from 2002
through the end of 2004) of escitalopram in patients meeting DSM-IV
criteria for MDD and anxiety disorders (generalized anxiety disorder
UNDER
[GAD], social anxiety disorder [SAD], panic disorder) were used.
Potential predictors examined were type of disorder, lo
1982  cation of study,
dosing regimen, number of treatment arms, gender of patients, and
ACT
duration and severity of disorder. Results: Placebo response (defined
RELEASED
as the percent decrease from baseline in the reference scale) was
higher in GAD and MDD studies conducted in Europe (p < .0001 and p
= .0006, respectively) and was not
BEEN  associated with gender or duration
HEALTH
of episode. In GAD, the placebo response rate was higher in a
HAS
OF
European fixed-dose study, which also had more treatment arms. In
INFORMATION
SAD and in U.S. specialist-treated MDD, a higher placebo response
OF
rate was predicted by decreased baseline disorder severity.
Conclusion: Additional work is needed before definitive
recommendations can be made about whether standard exclusion
DOCUMENT
criteria in clinical trials of antidepressants, such as mild severity of
FREEDOM
DEPARTMENT
illness, maximize medication-to-placebo differences. This analysis in a
THIS
range of anxiety disord
THE  ers and MDD suggests that there may be
THE
instances in which the predictors of placebo response rate themselves
BY
vary across different conditions.

17. Thase, M. E. (2006). "Treatment of anxiety disorders with venlafaxine XR."
Expert Review of Neurotherapeutics 6(3): 269-282.

When venlafaxine was introduced in 1994, it was the first of the newer
generation antidepressants to be classified as a serotonin
norepinephrine reuptake inhibitor (SNRI). An extended release (XR)
formulation of venlafaxine, introduced in 1997, subsequently received
regulatory approval for treatment of three anxiety disorders:
generalized anxiety disorder, social anxiety disorder and panic
disorder. Although less extensively studied, venlafaxine XR also
appears to have efficacy for two other anxiety disorders, posttraumatic
stress disorder and obsessive-compulsive disorder. In contrast to the
treatment of depression, for which meta-analyses suggest an efficacy
advantage relative to selective serotonin reuptake inhibitors (SSRIs),
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evidence of differential efficacy has not yet been established for any of
the anxiety disorders. The overall tolerability profile of venlafaxine XR is
generally comparable to that of the SSRIs, although there is greater
incidence of noradrenergically mediated side effects (i.e., dry mouth
and constipation), as well as a dose-dependent risk of treatment-
emergent high blood pressure. Concerns about safety in overdose
have also recently emerged. Despite these caveats, venlafaxine XR is
an effective and generally well-tolerated option for treatment of anxiety
disorders. (copyright) 2006 Future Drugs Ltd.

18. Varia, I. and F. Rauscher (2002). "Treatment of generalized anxiety
disorder with citalopram." Int Clin Psychopharmacol 17(3): 103-7.

Serotonin reuptake inhibitors (SSRI), such as venalafaxine and
paroxetine, are used in the treatment of generalized anxiety disorder
(GAD). Patients with GAD frequently have comorbid psychiatric
disorders, such as depression. SSRIs are effective in the treatment of a
variety of anxiety disorders and depression. Citalopram, a newer SSRI
used in the treatment of depression, has not been studied for GAD.
UNDER
This is the first report of the use of citalopram, the most selective SSRI,
for the treatment of GAD in a retrospective case obs
1982  ervation study.
Thirteen patients diagnosed with GAD were treated with citalopram at
ACT
an academic outpatient clinic. The main outcome measures were the
RELEASED
Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Depression
Rating Scale (HAM-D) and Clinical Global Impressions of Severity
(CGI-S; at baseline) and Improvem
BEEN  ent (CGI-I). The mean age of the
HEALTH
patients was 38 years. The mean dose of citalopram at endpoint was
HAS
OF
33 mg/day (range 10-60 mg/day). After 12 weeks of treatment with
INFORMATION
citalopram, all 13 patients experienced full or partial improvement in
OF
GAD and depressive symptoms leading to meaningful improvement in
social and occupational functioning. Mean baseline HAM-A scores
(mean+/-SEM) decreased from 22.2+/-1.3 to 6.2+/-0.9 after citalopram
DOCUMENT
treatment. The mean CGI-I score was 1.8+/-0.2 with 11 of the 13
FREEDOM
DEPARTMENT
patients responding (CGI-I of 1 or 2). These data suggest that
THIS
citalopram may be a
THE  n effective treatment for GAD. Several patients
THE
who had failed previous treatment with other SSRIs responded to
BY
citalopram, suggesting that a second SSRI, such as citalopram, may be
beneficial in this population. A larger placebo-controlled study of
citalopram is warranted in GAD.

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Appendix 2: Full list of articles from
Various Databases for Escitalopram
UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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1  EMBASE and MEDLINE
Allgulander, C., I. Florea, et al. (2006). "Prevention of relapse in generalized
anxiety disorder by escitalopram treatment." International Journal of
Neuropsychopharmacology 9(5): 495-505.

Escitalopram has demonstrated a robust and dose-dependent efficacy
in the treatment of generalized anxiety disorder (GAD) for up to 3
months. In the present study, the efficacy and tolerability of
escitalopram in the prevention of relapse in GAD was investigated. A
total of 491 patients with a primary diagnosis of GAD and a Hamilton
Anxiety (HAMA) total score (greater-than or equal to)20 received 12 wk
of open-label treatment with a fixed dose of escitalopram (20 mg/d). Of
these, 375 patients responded (HAMA total score (less-than or equal
to)10) and were randomized to double-blind treatment with 20 mg/d
escitalopram (n=187) or placebo (n=188). Treatment was continued for
24-76 wk unless the patient relapsed or was withdrawn for other
UNDER
reasons. Relapse was defined as either an increase in HAMA total
score to (greater-than or equal to)15, or lack of effica
1982  cy, as judged by
the investigator. The results of the primary analysis showed a clear
ACT
beneficial effect of escitalopram relative to placebo on the time to
relapse of GAD (log-rank test, p<0.001). The ri
RELEASED  sk of relapse was 4.04
times higher for placebo-treated patients than for escitalopram-treated
patients; the proportion of patients
BEEN who relapsed was statistically
HEALTH
significantly higher in the placebo group (56%) than in the escitalopram
group (19%) (p<0.001). Escita
HAS  lopram was
OF
well tolerated and 7% of the
INFORMATION
escitalopram-treated patients withdrew due to adverse events, vs. 8%
OF
of the placebo patients. The incidence of discontinuation symptoms
with escitalopram during tapered withdrawal was low; the symptoms
primarily being dizziness (10-12%), nervousness (2-6%), and insomnia
DOCUMENT
(2-6%). Escitalopram 20 mg/d significantly reduced the risk of relapse
FREEDOM
DEPARTMENT
and was well tolerated in patients with GAD. Copyright (copyright) 2005
THIS
CINP.
THE  THE

BY
Bielski, R. J., A. Bose, et al. (2005). "A double-blind comparison of
escitalopram and paroxetine in the long-term treatment of generalized anxiety
disorder." Annals of Clinical Psychiatry 17(2): 65-69.

Background. This study compared the efficacy and tolerability of
escitalopram, a newer SSRI, with paroxetine in the treatment of
generalized anxiety disorder (GAD). Methods. Patients with DSM-IV-
defined GAD were randomized to receive 24 weeks of double-blind
flexible-dose treatment with either escitalopram (10-20 mg/day) or
paroxetine (20-50 mg/day), followed by a 2-week, double-blind, down-
titration period. Mean change from baseline to endpoint (LOCF) in
Hamilton Anxiety Scale (HAMA) scores was the primary efficacy-
variable. Results. Mean baseline HAMA scores for the escitalopram
(N=60) and paroxetine (N=61) groups were 23.7 and 23.4, respectively.
After 24 weeks of treatment, mean changes in HAMA scores were -
15.3 and -13.3 for escitalopram and paroxetine, respectively (p=0.13).
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Significantly fewer patients withdrew from escitalopram than paroxetine
treatment due to adverse events (6.6% vs. 22.6%; p=0.02). The
frequency of treatment-emergent adverse events was higher with
paroxetine vs. escitalopram: overall (88.7% vs. 77.0%), insomnia
(25.8% vs. 14.8%), constipation (14.5% vs. 1.6%), ejaculation disorder
(30.0% vs. 14.8%), anorgasmia (26.2% vs. 5.9%), and decreased libido
(22.6% vs. 4.9%). Conversely, diarrhea and upper respiratory tract
infection were reported more with escitalopram than paroxetine (21.3%
vs. 8.1%, and 14.8% vs. 4.8%, respectively). Conclusions. These
results support the use of escitalopram as a first-line treatment for
GAD. Copyright (copyright) Taylor & Francis Inc.

Davidson, J. R. T., A. Bose, et al. (2004). "Escitalopram in the treatment of
generalized anxiety disorder: Double-blind, placebo controlled, flexible-dose
study." Depression and Anxiety 19(4): 234-240.

Escitalopram has been shown in clinical trials to improve anxiety
symptoms associated with depression, panic disorder, and social
anxiety disorder. This study was designed to evaluate the efficacy and
UNDER
tolerability of escitalopram in the treatment of generalized anxiety
disorder (GAD). Outpatients (18 years or older) who
1982  met DSM-IV
criteria for GAD, with baseline Hamilton Rating Scale for Anxiety
ACT
(HAMA) scores (greater-than or equal to)18, were randomly assigned
RELEASED
to double blind treatment with escitalopram (10 mg/day for the first 4
weeks and then flexibly dosed from 10-20 mg/day) or placebo for 8
weeks, following a 1-week, single-b
BEEN  lind, placebo lead-in period. The
HEALTH
primary efficacy variable was the mean change from baseline in total
HAS
OF
HAMA score at Week 8. The escitalopram group (N = 158) showed a
INFORMATION
statistically significant, and clinically relevant, greater improvement at
OF
endpoint compared with placebo (N = 157) in all prospectively defined
efficacy parameters. Significant improvement in HAMA total score and
HAMA psychic anxiety subscale score for the escitalopram-treated
DOCUMENT
group vs. the placebo-treated group was observed beginning at Week
FREEDOM
DEPARTMENT
1 and at each study visit thereafter. Mean changes from baseline to
THIS
Week 8 on the HAM
THE  A total score using a last-observation-carried-
THE
forward (LOCF) approach were -11.3 for escitalopram and -7.4 for
BY
placebo (P < .001). Response rates at Week 8 were 68% for
escitalopram and 41% for placebo (P < .01) for completers, and 58%
for escitalopram and 38% for placebo LOCF values (P < 01).
Treatment with escitalopram was well tolerated, with low rates of
reported adverse events and an incidence of discontinuation due to
adverse events not statistically different from placebo (8.9% vs. 5.1%;
P = .27). Escitalopram 10-20 mg/day is effective, safe, and well
tolerated in the treatment of patients with GAD. (copyright) 2004 Wiley-
Liss, Inc.

Davidson, J. R. T., A. Bose, et al. (2005). "Safety and efficacy of escitalopram
in the long-term treatment of generalized anxiety disorder." Journal of Clinical
Psychiatry 66(11): 1441-1446.

Introduction: Generalized anxiety disorder (GAD) is a chronic disorder
that requires long-term treatment. Escitalopram has previously been
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shown to be effective and well tolerated in the acute treatment of GAD.
Method: Three 8-week, double-blind, placebo-controlled trials of nearly
identical design were conducted of escitalopram in moderate-to-severe
GAD (DSM-IV criteria). Patients completing these trials were given the
option of entering a 24-week, open-label, flexible-dose trial of
escitalopram (10-20 mg/day). Data were collected from September 20,
2000, to August 15, 2002. Results: Two hundred ninety-nine (56.8%) of
526 patients completed 24 weeks of open-label treatment. The mean
Hamilton Rating Scale for Anxiety (HAM-A) score at baseline of open-
label treatment was 13.1. Long-term escitalopram treatment led to
continuing improvement on all anxiety and quality-of-life (QOL) scores.
Of those completing 24 weeks of treatment, 92.0% were responders
(Clinical Global Impressions-Improvement scale score < 2), and the
mean HAM-A score in the completer analysis was 6.9; using the last
observation carried forward (LOCF), 75.9% were responders, and the
mean HAM-A score in the LOCF analysis was 9.2 at endpoint.
Insufficient therapeutic response and adverse events led to withdrawal
of 4.2% and 9.9% of patients, respectively. Mean increase in weight
UNDER
from baseline was 3.0 lb. No clinically notable changes in mean
laboratory, vital sign, or electrocardiographic values we
1982  re observed.
Conclusion: These results support the long-term tolerability and
ACT
effectiveness of escitalopram in the treatment of GAD.
RELEASED

Dhillon, S., L. J. Scott, et al. (2006). "Escitalopram: A review of its use in the
management of anxiety disorders." CNS Dru
BEEN  gs 20(9): 763-790.
HEALTH

Abstract: Escitalopram (Cipralex(registered trademark)
HAS
OF
Lexapro(registered trademark) Seroplex(registered trademark)
INFORMATION
Sipralexa(registered trademark)), the therapeutically active S-
OF
enantiomer of racemic citalopram (RS-citalopram), is a potent and
highly selective serotonin reuptake inhibitor. It is effective and generally
well tolerated in the treatment of moderate to severe generalised
DOCUMENT
anxiety disorder (GAD) or social anxiety disorder (SAD), panic disorder
FREEDOM
DEPARTMENT
(with or without agoraphobia) as well as obsessive-compulsive disorder
THIS
(OCD). Moreover, e
THE  scitalopram is at least as effective as paroxetine for
THE
the treatment of GAD, SAD or OCD and appears to achieve a more
BY
rapid response than racemic citalopram in the management of panic
disorder. Generally, it has a more favourable tolerability profile than
paroxetine in terms of fewer discontinuation symptoms. In addition, a
favourable pharmacokinetic profile permits once-daily administration of
the drug. Additional comparative studies are required to definitively
position escitalopram with respect to other SSRIs and venlafaxine.
Nevertheless, available clinical data indicate that escitalopram is an
effective first-line treatment option for the management of GAD, SAD,
panic disorder and OCD. Pharmacological Properties: Escitalopram is
unique among SSRIs in that it stabilises its binding to the high-affinity
binding site of the serotonin transporter protein via an allosteric effect
at the low-affinity binding site. In vivo and in vitro studies have shown
escitalopram to be approximately twice as potent as citalopram in
inhibiting serotonin reuptake. It is highly selective for the serotonin
transporter protein and shows no or very low affinity for other receptors
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or ion channels. In vivo, escitalopram was four times more potent than
citalopram in reducing firing activity of presumed serotonergic neurons
in rat brain. Single and multiple once-daily oral doses of escitalopram
10-30 mg/day show linear, dose-proportional pharmacokinetics in
healthy volunteers. The steady-state plasma concentration of the drug
was reached within 7-10 days. Escitalopram is largely metabolised in
the liver, mainly into S-demethylcitalopram (S-DCT) and S-
didemethylcitalopram (S-DDCT). Cytochrome P450 (CYP) isozymes
CYP2C19, 3A4 and 2D6 contribute equally to the metabolism of
escitalopram into S-DCT, whereas only CYP2D6 was involved in the
second demethylation of S-DCT to S-DDCT. Neither metabolite has
significant serotonin reuptake activity in vivo. Escitalopram and its
metabolites are excreted primarily via the kidneys, with a small
percentage of the drug excreted unchanged. The mean plasma
elimination half-life (t1/2) of escitalopram is 27-33 hours. Escitalopram
dosage adjustments are recommended in elderly patients and patients
with impaired hepatic function, and caution is advised in patients with
severe renal impairment. Therapeutic Efficacy: In well designed,
UNDER
double-blind, comparative, 8- to 24-week studies in patients with
moderate to severe GAD, escitalopram was more eff
1982  ective than
placebo and at least as effective as paroxetine in reducing the mean
ACT
Hamilton Rating Scale for Anxiety total score (primary efficacy
RELEASED
parameter). Escitalopram demonstrated continued efficacy in a 24-
week open-label extension study of three 8-week double-blind trials
and a (less-than or equal to)76-wee
BEEN  k placebo-controlled, double-blind,
HEALTH
relapse-prevention study. Moreover, in the relapse-prevention study,
HAS
OF
escitalopram recipients showed a significantly longer time to relapse
INFORMATION
and reduced risk of relapse than placebo recipients, and fewer
OF
escitalopram than placebo recipients relapsed. Escitalopram was also
associated with better mental health-related quality of life than placebo
in a subgroup of patients from the relapse-prevention study. In two
DOCUMENT
randomised, double-blind, 12- and 24-week studies in patients with
FREEDOM
DEPARTMENT
moderate to severe SAD, apart from escitalopram 10 mg/day at 12
THIS
weeks, escitalopram
THE   was significantly more effective than placebo and
THE
at least as effective as paroxetine in reducing the mean Liebowitz
BY
Social Anxiety Scal total scores (primary efficacy parameter). In a 24-
week double-blind, placebo-controlled relapse-prevention study,
escitalopram recipients had a longer time to relapse and reduced risk
of relapse compared with placebo recipients, and significantly fewer
escitalopram than placebo recipients relapsed. Escitalopram was
significantly more effective than placebo in reducing the panic attack
frequency (primary efficacy parameter) with a faster onset of action
than citalopram in a randomised, double-blind trial in patients with
panic disorder. In an open-label study in elderly (>65 years) patients
with panic disorder, improvement in panic attack frequency (primary
efficacy parameter) and secondary efficacy variables occurred more
quickly in escitalopram than citalopram recipients. In patients with
OCD, escitalopram 20 mg/day for 12 weeks was more effective than
placebo, and at least as effective as paroxetine 40 mg/day, with
respect to a mean reduction from baseline in the Yale-Brown
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Obsessive Scale total score (primary efficacy parameter). In a relapse-
prevention study, escitalopram recipients showed a longer time to
relapse and a significantly reduced risk of relapse compared with those
receiving placebo. In addition, the proportion of patients who relapsed
in the escitalopram group was significantly lower than in the placebo
group. Tolerability: Escitalopram was generally well tolerated in adult
patients with GAD, SAD, panic disorder or OCD. Withdrawal rates due
to treatment-emergent adverse events in escitalopram recipients were
6.0-11.8%. The profile of treatment-emergent adverse events was
generally similar in escitalopram recipients irrespective of the type of
anxiety disorder in placebo-controlled short-term trials. The most
common adverse event in escitalopram and placebo recipients was
headache (15-25% of patients). Other common adverse events in
escitalopram recipients with GAD include nausea (18.2%), ejaculation
disorder (14.3%), insomnia (11.9%), fatigue (7.7%), decreased libido
(6.8%) and anorgasmia (5.7%). Withdrawal rates during the 12-week
open-label period of three relapse-prevention studies were 7.7-20.0%,
whereas 2.6-7.9% withdrew from the study during the (less-than or
UNDER
equal to)76-week double-blind period. Furthermore, the overall
incidence of adverse events was numerically lower d
1982  uring the double-
blind period than the initial 12-week open-label period. Escitalopram
ACT
recipients generally reported more discontinuation symptoms than
RELEASED
placebo recipients after switching to placebo in two fixed-dose studies,
whereas patients continuing escitalopram treatment generally reported
fewer discontinuation symptoms th
BEEN an those switching to placebo in the
HEALTH
relapse-prevention studies. The tolerability profile of escitalopram was
HAS
OF
generally similar to those of paroxetine or citalopram. However, in one
INFORMATION
study, paroxetine recipients showed significantly higher rates of
OF
withdrawal due to treatment-emergent adverse events than
escitalopram recipients, and more paroxetine than escitalopram
recipients appeared to experience sexual adverse events (ejaculation
DOCUMENT
disorder [30.0% vs 14.8%], anorgasmia [26.2% vs 5.9%] and
FREEDOM
DEPARTMENT
decreased libido [22.6% vs 4.9%]). Some discontinuation symptoms
THIS
were reported in sig
THE  nificantly fewer escitalopram than paroxetine
THE
recipients, and escitalopram recipients showed significantly lower mean
BY
changes in discontinuation emergent signs and symptoms scores than
paroxetine recipients. In large analyses of placebo-controlled and
relapse-prevention studies in patients with major depressive disorder or
anxiety disorders, there was no indication of increased risk of suicidal
behaviour in escitalopram or placebo recipients, with no completed
suicides during the first 2 weeks of escitalopram or placebo therapy.
Moreover, in an analysis of pharmacovigilance post-marketing
surveillance information, escitalopram recipients had a low suicide rate
(1.8 per million prescriptions). (copyright) 2006 Adis Data Information
BV. All rights reserved.

Goodman, W. K., A. Bose, et al. (2005). "Treatment of generalized anxiety
disorder with escitalopram: Pooled results from double-blind, placebo-
controlled trials." Journal of Affective Disorders 87(2-3): 161-167.
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Background: Escitalopram 10 mg/day is an effective and well-tolerated
antidepressant. Three randomized controlled trials recently evaluated
the safety and efficacy of escitalopram in the treatment of generalized
anxiety disorder (GAD). Methods: The trial designs were virtually
identical, allowing data to be pooled across studies. Male and female
outpatients, ages 18-80 years, with DSM-IV-defined GAD were
randomized to double-blind treatment with escitalopram or placebo for
8 weeks. Escitalopram dose was fixed at 10 mg/day for the first 4
weeks, after which increases to 20 mg/day were permitted. The primary
efficacy variable was the mean change from baseline in total Hamilton
Anxiety Scale (HAMA) score. Results: Approximately 850 patients were
randomized to double-blind treatment. In each individual study,
escitalopram was significantly superior to placebo (p<0.05) as
measured by change from baseline in HAMA score. By-visit analyses
of data pooled across studies revealed significantly greater
improvement (p<0.05) in the escitalopram group beginning at week 1
or 2 and continuing through week 8 for all primary and secondary
efficacy variables. The mean change in HAMA total score from
UNDER
baseline to endpoint also was significantly greater for patients
maintained at escitalopram 10 mg/day than for those
1982   receiving placebo.
Escitalopram was generally well tolerated. Limitations: The studies
ACT
included in this analysis were of short-term duration and excluded
RELEASED
patients with significant medical and psychiatric comorbidities, such as
major depressive disorder. Conclusion: Results from the individual
trials and the pooled analysis demo
BEEN  nstrate that escitalopram is effective
HEALTH
and well tolerated for the treatment of GAD. (copyright) 2005 Elsevier
HAS
OF
B.V. All rights reserved.
INFORMATION

OF
Grant, J. E. and M. N. Potenza (2006). "Escitalopram treatment of
pathological gambling with co-occurring anxiety: An open-label pilot study with
double-blind discontinuation." International Clinical Psychopharmacology
DOCUMENT
21(4): 203-209.
FREEDOM
DEPARTMENT

Although co-occurring disorders are common in pathological gambling
THIS
(PG), investigations
THE   of the response to pharmacotherapy in individuals
THE
with PG and co-occurring psychiatric symptomatology are limited.
BY
Thirteen subjects with DSM-IV PG and co-occurring anxiety were
treated in a 12-week open-label trial of escitalopram. Subjects were
assessed with the Yale-Brown Obsessive Compulsive Scale Modified
for Pathological Gambling (PG-YBOCS; primary outcome measure),
the Hamilton Anxiety Rating Scale (HAM-A), the Clinical Global
Impressions scale (CGI), and measures of psychosocial functioning
and quality of life. Those subjects who 'responded' (defined as a 30%
or greater reduction in PG-YBOCS total score at endpoint) were offered
inclusion in an 8-week double-blind discontinuation phase. PG-YBOCS
scores decreased from a mean of 22.2 (plus or minus) 4.5 at baseline
to 11.9 (plus or minus) 10.7 at endpoint (P = 0.002) and 61.5% were
responders. Scores on the HAM-A decreased by 82.8% over the 12-
week period (mean of 15.9 (plus or minus) 3.2 at baseline to a mean of
2.8 (plus or minus) 3.6 at endpoint) (P < 0.001). On the CGI, 38.5% of
subjects (n = 5) were 'very much improved' and 23.1% (n = 3) were
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'much improved' by study endpoint. The Sheehan Disability Scale,
Perceive Stress Scale and Quality of Life Inventory all showed
improvement (P (less-than or equal to) 0.001, P = 0.002 and P = 0.029,
respectively). The mean end-of-study dose of escitalopram was 25.4
(plus or minus) 6.6 mg/day. Of three subjects assigned to escitalopram
during the discontinuation phase, none reported statistically significant
worsening of gambling symptoms. However, one subject assigned to
placebo reported that gambling symptoms returned within 4 weeks.
Open-label escitalopram treatment was associated with improvements
in gambling and anxiety symptoms and measures of psychosocial
functioning and quality of life. Larger, longer, placebo-controlled,
double-blind studies are needed to evaluate further the safety and
tolerability of escitalopram in the treatment of PG and co-occurring
anxiety. (copyright) 2006 Lippincott Williams & Wilkins.

Menza, M. A., R. D. Dobkin, et al. (2007). "An open-label trial of aripiprazole
augmentation for treatment-resistant generalized anxiety disorder [3]." Journal
of Clinical Psychopharmacology 27(2): 207-210.
UNDER

Mohamed, S., K. Osatuke, et al. (2006). "Escitalopram for c
1982  omorbid
depression and anxiety in elderly patients: A 12-week, open-label, flexible-
ACT
dose, pilot trial." American Journal Geriatric Pharmacotherapy 4(3): 201-209.
RELEASED

Background: Comorbid depression and anxiety may result in greater
symptom severity and poorer treatment response than either condition
alone. Selective serotonin reuptake
BEEN   inhibitors have been found to be
HEALTH
effective in treating both depression and anxiety; however,
HAS
OF
pharmacodynamic and pharmacokinetic changes associated with aging
INFORMATION
warrant special attention in medication trials in older patients.
OF
Objective: The objective of this study was to assess the efficacy and
tolerability of short-term (12-week) administration of escitalopram
oxalate 10 to 20 mg/d for moderate to marked comorbid depression
DOCUMENT
and anxiety in elderly patients. Methods: This open-label, flexible-dose
FREEDOM
DEPARTMENT
(10-20 mg/d), pilot trial was conducted at the Psychiatry Service,
THIS
Veterans Affairs Med
THE  ical Center, Cincinnati, Ohio. Outpatients aged
THE
(greater-than or equal to)65 years were included if they met the criteria
BY
for comorbid major depressive disorder (MDD) and generalized anxiety
disorder (GAD), as defined in the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision, for (greater-than or
equal to)4 weeks and had a baseline Montgomery-sberg Depression
Rating Scale (MADRS) score of >22 and a Hamilton Rating Scale for
Anxiety (HAM-A) score of (greater-than or equal to)18. All patients
received escitalopram 10 to 20 mg/d. The primary efficacy variables
were the mean changes from baseline in total MADRS and HAM-A
scores at 12 weeks (last observation carried forward). The secondary
efficacy end point was the change from baseline in Medical Outcomes
Study 36-Item Short-Form Health Survey (SF-36) 8 subscale scores.
Adverse events were assessed at each visit (treatment weeks 1, 2, 3,
4, 6, 8, 10, and 12) with the use of open-ended questioning. Results:
Twenty patients were enrolled (mean [SD] age, 73.0 [4.8] years; 6
[30%] women; race: 17 [85%] white, 2 [10%] black, and 1 [5%] "other").
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Seventeen (85%) of 20 patients completed the study; 3 (15%)
withdrew: 1 (5%) due to lack of efficacy and 2 (10%) due to adverse
events (dizziness and somnolence [1 (5%) patient each]). Statistically
significant improvements from baseline to end point were found with
escitalopram treatment (MADRS: t19 = 7.38, P < 0.001, effect size =
2.93; HAM-A: t19 = 4.19, P < 0.001, effect size = 1.83). Significant
changes from baseline in scores on 4 (Social Functioning, Role
Functioning-Emotional, Mental Health, and Energy/Fatigue) of the 8
subscales of the SF-36 were als of ound (all, P < 0.01). Conclusion: In
this small study in elderly patients with comorbid MDD and GAD,
treatment with escitalopram 10 to 20 mg/d for 12 weeks was
associated with significant improvements in symptoms of depression
and anxiety. (copyright) 2006 Excerpta Medica, Inc.

Stein, D. J., H. F. Andersen, et al. (2005). "Escitalopram for the treatment of
GAD: Efficacy across different subgroups and outcomes." Annals of Clinical
Psychiatry 17(2): 71-75.

Background. Generalized anxiety disorder (GAD) is characterized by
UNDER
anxiety, and also frequently associated with depressive symptoms.
Benzodiazepines have commonly been used in the t
1982  reatment of GAD,
but are not effective antidepressant agents. In this study, we
ACT
determined whether the selective serotonin reuptake inhibitor
RELEASED
escitalopram, was effective across different subgroups and outcomes
(anxious symptoms, depressive symptoms, and quality of life).
Methods. Three randomized, place
BEEN bo controlled studies of
HEALTH
escitalopram in GAD have employed a similar design, allowing for
HAS
OF
pooling of the data. The primary efficacy measure was the Hamilton
INFORMATION
Anxiety Scale (HAMA). General linear models were used to determine
OF
the efficacy of escitalopram across different subgroups and outcomes.
Results. Escitalopram was efficacious for GAD on a range of measures
of both anxiety and depression, and improved the associated
DOCUMENT
impairment in quality of life. There was no significant interaction of
FREEDOM
DEPARTMENT
effects on the HAMA with demographic or clinical variables.
THIS
Furthermore, escita
THE lopram was efficacious on both primary and
THE
secondary scales in the subgroup of subjects with above-median
BY
severity of depressive symptoms at baseline (HAMD-17>12).
Conclusions. Escitalopram reduces anxiety and depressive symptoms
in GAD, and improves quality of life. It is equally effective in GAD
patients, with an above-median level of depressive symptoms. Further
research is needed to determine whether these results can be
extrapolated to GAD patients with comorbid major depression.
Copyright (copyright) Taylor & Francis Inc.

Stein, D. J., D. S. Baldwin, et al. (2006). "Which factors predict placebo
response in anxiety disorders and major depression? An analysis of placebo-
controlled studies of escitalopram." Journal of Clinical Psychiatry 67(11):
1741-1746.

Background: The placebo response rate has increased in several
psychiatric disorders and is a major issue in the design and
interpretation of clinical trials. The current investigation attempted to
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identify potential predictors of placebo response through examination of
the placebo-controlled clinical trial database for escitalopram in 3
anxiety disorders and in major depressive disorder (MDD). Method:
Raw data from placebo-controlled studies (conducted from 2002
through the end of 2004) of escitalopram in patients meeting DSM-IV
criteria for MDD and anxiety disorders (generalized anxiety disorder
[GAD], social anxiety disorder [SAD], panic disorder) were used.
Potential predictors examined were type of disorder, location of study,
dosing regimen, number of treatment arms, gender of patients, and
duration and severity of disorder. Results: Placebo response (defined
as the percent decrease from baseline in the reference scale) was
higher in GAD and MDD studies conducted in Europe (p < .0001 and p
= .0006, respectively) and was not associated with gender or duration
of episode. In GAD, the placebo response rate was higher in a
European fixed-dose study, which also had more treatment arms. In
SAD and in U.S. specialist-treated MDD, a higher placebo response
rate was predicted by decreased baseline disorder severity.
Conclusion: Additional work is needed before definitive
UNDER
recommendations can be made about whether standard exclusion
criteria in clinical trials of antidepressants, such as m
1982  ild severity of
illness, maximize medication-to-placebo differences. This analysis in a
ACT
range of anxiety disorders and MDD suggests that there may be
RELEASED
instances in which the predictors of placebo response rate themselves
vary across different conditions.

BEEN  HEALTH
Thase, M. E. (2006). "Treatment of anxiety disorders with venlafaxine XR."
HAS
OF
Expert Review of Neurotherapeutics 6(3): 269-282.
INFORMATION

When venlafaxine was introduced in 1994, it was the first of the newer
OF
generation antidepressants to be classified as a serotonin
norepinephrine reuptake inhibitor (SNRI). An extended release (XR)
formulation of venlafaxine, introduced in 1997, subsequently received
DOCUMENT
regulatory approval for treatment of three anxiety disorders:
FREEDOM
DEPARTMENT
generalized anxiety disorder, social anxiety disorder and panic
THIS
disorder. Although le
THE  ss extensively studied, venlafaxine XR also
THE
appears to have efficacy for two other anxiety disorders, posttraumatic
BY
stress disorder and obsessive-compulsive disorder. In contrast to the
treatment of depression, for which meta-analyses suggest an efficacy
advantage relative to selective serotonin reuptake inhibitors (SSRIs),
evidence of differential efficacy has not yet been established for any of
the anxiety disorders. The overall tolerability profile of venlafaxine XR is
generally comparable to that of the SSRIs, although there is greater
incidence of noradrenergically mediated side effects (i.e., dry mouth
and constipation), as well as a dose-dependent risk of treatment-
emergent high blood pressure. Concerns about safety in overdose
have also recently emerged. Despite these caveats, venlafaxine XR is
an effective and generally well-tolerated option for treatment of anxiety
disorders. (copyright) 2006 Future Drugs Ltd.

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2  PubMed
Allgulander, C., I. Florea, et al. (2006). "Prevention of relapse in generalized
anxiety disorder by escitalopram treatment." Int J Neuropsychopharmacol
9(5): 495-505.

Escitalopram has demonstrated a robust and dose-dependent efficacy
in the treatment of generalized anxiety disorder (GAD) for up to 3
months. In the present study, the efficacy and tolerability of
escitalopram in the prevention of relapse in GAD was investigated. A
total of 491 patients with a primary diagnosis of GAD and a Hamilton
Anxiety (HAMA) total score>or=20 received 12 wk of open-label
treatment with a fixed dose of escitalopram (20 mg/d). Of these, 375
patients responded (HAMA total score<or=10) and were randomized to
double-blind treatment with 20 mg/d escitalopram (n=187) or placebo
(n=188). Treatment was continued for 24-76 wk unless the patient
relapsed or was withdrawn for other reasons. Relapse was defined as
UNDER
either an increase in HAMA total score to >or=15, or lack of efficacy, as
judged by the investigator. The results of the primary a
1982  nalysis showed
a clear beneficial effect of escitalopram relative to placebo on the time
ACT
to relapse of GAD (log-rank test, p<0.001). The risk of relapse was
RELEASED
4.04 times higher for placebo-treated patients than for escitalopram-
treated patients; the proportion of patients who relapsed was
statistically significantly higher in th
BEEN  e placebo group (56%) than in the
HEALTH
escitalopram group (19%) (p<0.001). Escitalopram was well tolerated
HAS
OF
and 7% of the escitalopram-treated patients
INFORMATION   withdrew due to adverse
events, vs. 8% of the placebo patients. The incidence of
OF
discontinuation symptoms with escitalopram during tapered withdrawal
was low; the symptoms primarily being dizziness (10-12%),
nervousness (2-6%), and insomnia (2-6%). Escitalopram 20 mg/d
DOCUMENT
significantly reduced the risk of rela
DEPARTMENT  pse and was well tolerated in
FREEDOM
patients with GAD.
THIS

THE  THE
Bandelow, B., D. S. B
BY aldwin, et al. (2006). "What is the threshold for
symptomatic response and remission for major depressive disorder, panic
disorder, social anxiety disorder, and generalized anxiety disorder?" J Clin
Psychiatry 67(9): 1428-34.

OBJECTIVE: Symptom-free remission is a goal for treatment in
depression and anxiety disorders, but there is no consensus regarding
the threshold for determining remission in individual disorders. We
sought to determine these thresholds by comparing, in a post hoc
analysis, scores on the Clinical Global Impressions scale (CGI) and
disorder-specific symptom severity rating scales from all available
studies of the treatment of major depressive disorder, panic disorder,
generalized anxiety disorder, and social anxiety disorder with the same
medication (escitalopram). We also sought to compare the
standardized effect sizes of escitalopram for these 4 psychiatric
disorders. DATA SOURCES AND STUDY SELECTION: Raw data from
all randomized, double-blind, placebo-controlled, acute treatment
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studies sponsored by H. Lundbeck A/S (Copenhagen, Denmark) or
Forest Laboratories, Inc. (New York, N.Y.), published through March 1,
2004, with patients treated with escitalopram for DSM-IV major
depressive disorder (5 studies), panic disorder (1 study), generalized
anxiety disorder (4 studies), or social anxiety disorder (2 studies) were
compared with regard to the standardized effect sizes of change in CGI
score and scores on rating scales that represent the "gold standard" for
assessment of these disorders (the Montgomery-Asberg Depression
Rating Scale, the Panic and Agoraphobia Scale, the Hamilton Rating
Scale for Anxiety, and the Liebowitz Social Anxiety Scale, respectively).
DATA SYNTHESIS: In all indications, treatment with escitalopram
showed differences from placebo in treatment effect from 0.32 to 0.59
on the CGI-S and CGI-I and standardized effect sizes from 0.32 to 0.50
on the standard rating scales. There were no significant differences
among the different disorders. Moderate to high correlations were
found between scores on the CGI and the standard scales. The
corresponding standard scale scores for CGI-defined "response" and
"remission" were determined. CONCLUSION: Comparison of scores on
UNDER
the standard scales and scores on the CGI suggest that the traditional
definition of response (i.e., a 50% reduction in a stan
1982  dard scale) may
be too conservative.
ACT

RELEASED
Bielski, R. J., A. Bose, et al. (2005). "A double-blind comparison of
escitalopram and paroxetine in the long-term treatment of generalized anxiety
disorder." Ann Clin Psychiatry 17(2): 65-9.
BEEN    HEALTH

BACKGROUND: This study compared the efficacy and tolerability of
HAS
OF
escitalopram, a newer SSRI, with paroxetine in the treatment of
INFORMATION
generalized anxiety disorder (GAD). METHODS: Patients with DSM-IV-
OF
defined GAD were randomized to receive 24 weeks of double-blind
flexible-dose treatment with either escitalopram (10-20 mg/day) or
paroxetine (20-50 mg/day), followed by a 2-week, double-blind, down-
DOCUMENT
titration period. Mean change from baseline to endpoint (LOCF) in
FREEDOM
DEPARTMENT
Hamilton Anxiety Scale (HAMA) scores was the primary efficacy
THIS
variable. RESULTS
THE : Mean baseline HAMA scores for the escitalopram
THE
(N = 60) and paroxetine (N = 61) groups were 23.7 and 23.4,
BY
respectively. After 24 weeks of treatment, mean changes in HAMA
scores were -15.3 and -13.3 for escitalopram and paroxetine,
respectively (p = 0.13). Significantly fewer patients withdrew from
escitalopram than paroxetine treatment due to adverse events (6.6%
vs. 22.6%; p = 0.02). The frequency of treatment-emergent adverse
events was higher with paroxetine vs. escitalopram: overall (88.7% vs.
77.0%), insomnia (25.8% vs. 14.8%), constipation (14.5% vs. 1.6%),
ejaculation disorder (30.0% vs. 14.8%), anorgasmia (26.2% vs. 5.9%),
and decreased libido (22.6% vs. 4.9%). Conversely, diarrhea and
upper respiratory tract infection were reported more with escitalopram
than paroxetine (21.3% vs. 8.1%, and 14.8% vs. 4.8%, respectively).
CONCLUSIONS: These results support the use of escitalopram as a
first-line treatment for GAD.

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Blank, S., E. J. Lenze, et al. (2006). "Outcomes of late-life anxiety disorders
during 32 weeks of citalopram treatment." J Clin Psychiatry 67(3): 468-72.

BACKGROUND: Anxiety disorders are common in later life, but little is
known about the long-term benefits and risks of pharmacotherapy.
METHOD: 30 patients aged 60 years and older, with a DSM-IV anxiety
disorder, entered a 32-week trial of citalopram. Data gathered at
baseline and follow-up included anxiety symptoms using Hamilton
Rating Scale for Anxiety (HAM-A) scores, quality of life using the
Medical Outcomes Study 36-item Short Form (SF-36), and sleep using
the Pittsburgh Sleep Quality Index (PSQI). Data analysis consisted of
mixed-effect repeated measures models of HAM-A scores and pre-post
comparison of SF-36 and PSQI scores. RESULTS: 30 persons entered
treatment; most (27/30) had a primary DSM-IV diagnosis of generalized
anxiety disorder (2 had panic disorder; 1 had posttraumatic stress
disorder). Three subjects discontinued study medication due to side
effects, 5 were terminated because of nonresponse, and 5 dropped out
of the study for other reasons; thus, 17 subjects (57%) completed 32
weeks of treatment. Subjects' HAM-A scores improved significantly,
UNDER
with continuing improvements up until about 20 weeks of treatment. On
the basis of a criterion of reduction in HAM-A to < 10
1982   during the trial,
60% (18/30) of subjects were responders. Those who completed the
ACT
32-week trial had significant improvements in sleep and quality of life-
RELEASED
including social functioning, vitality, mental health, and role difficulties
due to emotional problems. CONCLUSIONS: In this 32-week study of
citalopram for elderly persons with
BEEN anxiety disorders, 60% responded.
HEALTH
Those who received a full course of treatment experience significant
HAS
OF
improvements in quality of life and sleep quality.
INFORMATION

OF
Davidson, J. R., A. Bose, et al. (2004). "Escitalopram in the treatment of
generalized anxiety disorder: double-blind, placebo controlled, flexible-dose
study." Depress Anxiety 19(4): 234-40.
DOCUMENT

Escitalopram has been shown in clinical trials to improve anxiety
FREEDOM
DEPARTMENT
symptoms associated with depression, panic disorder, and social
THIS
anxiety disorder. Th
THE  is study was designed to evaluate the efficacy and
THE
tolerability of escitalopram in the treatment of generalized anxiety
BY
disorder (GAD). Outpatients (18 years or older) who met DSM-IV
criteria for GAD, with baseline Hamilton Rating Scale for Anxiety
(HAMA) scores > or = 18, were randomly assigned to double blind
treatment with escitalopram (10 mg/day for the first 4 weeks and then
flexibly dosed from 10-20 mg/day) or placebo for 8 weeks, following a
1-week, single-blind, placebo lead-in period. The primary efficacy
variable was the mean change from baseline in total HAMA score at
Week 8. The escitalopram group (N = 158) showed a statistically
significant, and clinically relevant, greater improvement at endpoint
compared with placebo (N = 157) in all prospectively defined efficacy
parameters. Significant improvement in HAMA total score and HAMA
psychic anxiety subscale score for the escitalopram-treated group vs.
the placebo-treated group was observed beginning at Week 1 and at
each study visit thereafter. Mean changes from baseline to Week 8 on
the HAMA total score using a last-observation-carried-forward (LOCF)
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approach were -11.3 for escitalopram and -7.4 for placebo (P<.001).
Response rates at Week 8 were 68% for escitalopram and 41% for
placebo (P<.01) for completers, and 58% for escitalopram and 38% for
placebo LOCF values (P<.01). Treatment with escitalopram was well
tolerated, with low rates of reported adverse events and an incidence of
discontinuation due to adverse events not statistically different from
placebo (8.9% vs. 5.1%; P=.27). Escitalopram 10-20 mg/day is
effective, safe, and well tolerated in the treatment of patients with GAD.

Davidson, J. R., A. Bose, et al. (2005). "Safety and efficacy of escitalopram in
the long-term treatment of generalized anxiety disorder." J Clin Psychiatry
66(11): 1441-6.

INTRODUCTION: Generalized anxiety disorder (GAD) is a chronic
disorder that requires long-term treatment. Escitalopram has previously
been shown to be effective and well tolerated in the acute treatment of
GAD. METHOD: Three 8-week, double-blind, placebo-controlled trials
of nearly identical design were conducted of escitalopram in moderate-
to-severe GAD (DSM-IV criteria). Patients completing these trials were
UNDER
given the option of entering a 24-week, open-label, flexible-dose trial of
escitalopram (10-20 mg/day). Data were collected fro
1982  m September 20,
2000, to August 15, 2002. RESULTS: Two hundred ninety-nine
ACT
(56.8%) of 526 patients completed 24 weeks of open-label treatment.
RELEASED
The mean Hamilton Rating Scale for Anxiety (HAM-A) score at
baseline of open-label treatment was 13.1. Long-term escitalopram
treatment led to continuing improve
BEEN  ment on all anxiety and quality-of-
HEALTH
life (QOL) scores. Of those completing 24 weeks of treatment, 92.0%
HAS
OF
were responders (Clinical Global Impressions-Improvement scale score
INFORMATION
< or = 2), and the mean HAM-A score in the completed analysis was
OF
6.9; using the last observation carried forward (LOCF), 75.9% were
responders, and the mean HAM-A score in the LOCF analysis was 9.2
at endpoint. Insufficient therapeutic response and adverse events led to
DOCUMENT
withdrawal of 4.2% and 9.9% of patients, respectively. Mean increase
FREEDOM
DEPARTMENT
in weight from baseline was 3.0 lb. No clinically notable changes in
THIS
mean laboratory, vita
THE  l sign, or electrocardiographic values were
THE
observed. CONCLUSION: These results support the long-term
BY
tolerability and effectiveness of escitalopram in the treatment of GAD.

Goodman, W. K., A. Bose, et al. (2005). "Treatment of generalized anxiety
disorder with escitalopram: pooled results from double-blind, placebo-
controlled trials." J Affect Disord 87(2-3): 161-7.

BACKGROUND: Escitalopram 10 mg/day is an effective and well-
tolerated antidepressant. Three randomized controlled trials recently
evaluated the safety and efficacy of escitalopram in the treatment of
generalized anxiety disorder (GAD). METHODS: The trial designs were
virtually identical, allowing data to be pooled across studies. Male and
female outpatients, ages 18-80 years, with DSM-IV-defined GAD were
randomized to double-blind treatment with escitalopram or placebo for
8 weeks. Escitalopram dose was fixed at 10 mg/day for the first 4
weeks, after which increases to 20 mg/day were permitted. The primary
efficacy variable was the mean change from baseline in total Hamilton
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Anxiety Scale (HAMA) score. RESULTS: Approximately 850 patients
were randomized to double-blind treatment. In each individual study,
escitalopram was significantly superior to placebo (p<0.05) as
measured by change from baseline in HAMA score. By-visit analyses
of data pooled across studies revealed significantly greater
improvement (p<0.05) in the escitalopram group beginning at week 1
or 2 and continuing through week 8 for all primary and secondary
efficacy variables. The mean change in HAMA total score from
baseline to endpoint also was significantly greater for patients
maintained at escitalopram 10 mg/day than for those receiving placebo.
Escitalopram was generally well tolerated. LIMITATIONS: The studies
included in this analysis were of short-term duration and excluded
patients with significant medical and psychiatric comorbidities, such as
major depressive disorder. CONCLUSION: Results from the individual
trials and the pooled analysis demonstrate that escitalopram is effective
and well tolerated for the treatment of GAD.

Lenze, E. J., B. H. Mulsant, et al. (2005). "Efficacy and tolerability of
UNDER
citalopram in the treatment of late-life anxiety disorders: results from an 8-
week randomized, placebo-controlled trial." Am J Psychiatry
1982   162(1): 146-50.

OBJECTIVE: Anxiety disorders are highly prevalent in elderly persons.
ACT
However, to date, the efficacy of selective serotonin reuptake inhibitors
RELEASED
(SSRIs) for the treatment of anxiety disorders in this age group has not
been established. METHOD: Thirty-four participants age 60 and older
with a DSM-IV anxiety disorder (ma
BEEN  inly generalized anxiety disorder)
HEALTH
and a Hamilton Anxiety Rating Scale score of 17 or higher were
HAS
OF
randomly assigned under double-blind conditions to either citalopram
INFORMATION
or placebo. Response was defined as a score of 1 (very much
OF
improved) or 2 (much improved) on the Clinical Global Improvement
scale or a 50% reduction in the Hamilton anxiety scale score.
Response and side effects with citalopram and placebo were compared
DOCUMENT
by using chi-square tests and linear modeling. RESULTS: Eleven
FREEDOM
DEPARTMENT
(65%) of the 17 citalopram-treated participants responded by 8 weeks,
THIS
versus four (24%) o
THE  f the 17 placebo-treated participants. The most
THE
common and problematic side effect in the citalopram group was
BY
sedation. CONCLUSIONS: The authors believe this to be the first
prospective controlled study to test the efficacy of an SSRI in the
management of anxiety disorders among the elderly. These results
support the efficacy of citalopram in late-life anxiety disorders. They
need to be replicated in a larger study group.

Mohamed, S., K. Osatuke, et al. (2006). "Escitalopram for comorbid
depression and anxiety in elderly patients: A 12-week, open-label, flexible-
dose, pilot trial." Am J Geriatr Pharmacother 4(3): 201-9.

BACKGROUND: Comorbid depression and anxiety may result in
greater symptom severity and poorer treatment response than either
condition alone. Selective serotonin reuptake inhibitors have been
found to be effective in treating both depression and anxiety; however,
pharmacodynamic and pharmacokinetic changes associated with aging
warrant special attention in medication trials in older patients.
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OBJECTIVE: The objective of this study was to assess the efficacy and
tolerability of short-term (12-week) administration of escitalopram
oxalate 10 to 20 mg/d for moderate to marked comorbid depression
and anxiety in elderly patients. METHODS: This open-label, flexible-
dose (10-20 mg/d), pilot trial was conducted at the Psychiatry Service,
Veterans Affairs Medical Center, Cincinnati, Ohio. Outpatients aged >
or =65 years were included if they met the criteria for comorbid major
depressive disorder (MDD) and generalized anxiety disorder (GAD), as
defined in the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision, for > or =4 weeks and had a baseline
Montgomery-Asberg Depression Rating Scale (MADRS) score of >22
and a Hamilton Rating Scale for Anxiety (HAM-A) score of > or =18. All
patients received escitalopram 10 to 20 mg/d. The primary efficacy
variables were the mean changes from baseline in total MADRS and
HAM-A scores at 12 weeks (last observation carried forward). The
secondary efficacy end point was the change from baseline in Medical
Outcomes Study 36-Item Short-Form Health Survey (SF-36) 8
subscale scores. Adverse events were assessed at each visit
UNDER
(treatment weeks 1, 2, 3, 4, 6, 8, 10, and 12) with the use of open-
ended questioning. RESULTS: Twenty patients were
1982   enrolled (mean
[SD] age, 73.0 [4.8] years; 6 [30%] women; race: 17 [85%] white, 2
ACT
[10%] black, and 1 [5%] "other"). Seventeen (85%) of 20 patients
RELEASED
completed the study; 3 (15%) withdrew: 1 (5%) due to lack of efficacy
and 2 (10%) due to adverse events (dizziness and somnolence [1 (5%)
patient each]). Statistically significan
BEEN  t improvements from baseline to
HEALTH
end point were found with escitalopram treatment (MADRS: t19 = 7.38,
HAS
OF
P < 0.001, effect size = 2.93; HAM-A: t19 = 4.19, P < 0.001, effect size
INFORMATION
= 1.83). Significant changes from baseline in scores on 4 (Social
OF
Functioning, Role Functioning-Emotional, Mental Health, and
Energy/Fatigue) of the 8 subscales of the SF-36 were also found (all, P
< 0.01). CONCLUSION: In this small study in elderly patients with
DOCUMENT
comorbid MDD and GAD, treatment with escitalopram 10 to 20 mg/d
FREEDOM
DEPARTMENT
for 12 weeks was associated with significant improvements in
THIS
symptoms of depression
THE
and anxiety.
THE

BY
Stein, D. J., H. F. Andersen, et al. (2005). "Escitalopram for the treatment of
GAD: efficacy across different subgroups and outcomes." Ann Clin Psychiatry
17(2): 71-5.

BACKGROUND: Generalized anxiety disorder (GAD) is characterized
by anxiety, and also frequently associated with depressive symptoms.
Benzodiazepines have commonly been used in the treatment of GAD,
but are not effective antidepressant agents. In this study, we
determined whether the selective serotonin reuptake inhibitor
escitalopram, was effective across different subgroups and outcomes
(anxious symptoms, depressive symptoms, and quality of life).
METHODS: Three randomized, placebo controlled studies of
escitalopram in GAD have employed a similar design, allowing for
pooling of the data. The primary efficacy measure was the Hamilton
Anxiety Scale (HAMA). General linear models were used to determine
the efficacy of escitalopram across different subgroups and outcomes.
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RESULTS: Escitalopram was efficacious for GAD on a range of
measures of both anxiety and depression, and improved the associated
impairment in quality of life. There was no significant interaction of
effects on the HAMA with demographic or clinical variables.
Furthermore, escitalopram was efficacious on both primary and
secondary scales in the subgroup of subjects with above-median
severity of depressive symptoms at baseline (HAMD-17 > 12).
CONCLUSIONS: Escitalopram reduces anxiety and depressive
symptoms in GAD, and improves quality of life. It is equally effective in
GAD patients, with an above-median level of depressive symptoms.
Further research is needed to determine whether these results can be
extrapolated to GAD patients with comorbid major depression.

Varia, I. and F. Rauscher (2002). "Treatment of generalized anxiety disorder
with citalopram." Int Clin Psychopharmacol 17(3): 103-7.

Serotonin reuptake inhibitors (SSRI), such as venalafaxine and
paroxetine, are used in the treatment of generalized anxiety disorder
(GAD). Patients with GAD frequently have comorbid psychiatric
UNDER
disorders, such as depression. SSRIs are effective in the treatment of a
variety of anxiety disorders and depression. Citalopram, a
1982
newer SSRI
used in the treatment of depression, has not been studied for GAD.
ACT
This is the first report of the use of citalopram, the most selective SSRI,
RELEASED
for the treatment of GAD in a retrospective case observation study.
Thirteen patients diagnosed with GAD were treated with citalopram at
an academic outpatient clinic. The
BEEN main outcome measures were the
HEALTH
Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Depression
HAS
OF
Rating Scale (HAM-D) and Clinical Global Impressions of Severity
INFORMATION
(CGI-S; at baseline) and Improvement (CGI-I). The mean age of the
OF
patients was 38 years. The mean dose of citalopram at endpoint was
33 mg/day (range 10-60 mg/day). After 12 weeks of treatment with
citalopram, all 13 patients experienced full or partial improvement in
DOCUMENT
GAD and depressive symptoms leading to meaningful improvement in
FREEDOM
DEPARTMENT
social and occupational functioning. Mean baseline HAM-A scores
THIS
(mean+/-SEM) decrea
THE  sed from 22.2+/-1.3 to 6.2+/-0.9 after citalopram
THE
treatment. The mean CGI-I score was 1.8+/-0.2 with 11 of the 13
BY
patients responding (CGI-I of 1 or 2). These data suggest that
citalopram may be an effective treatment for GAD. Several patients
who had failed previous treatment with other SSRIs responded to
citalopram, suggesting that a second SSRI, such as citalopram, may be
beneficial in this population. A larger placebo-controlled study of
citalopram is warranted in GAD.

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3  EBM Databases (Cochrane)
Allgulander C, F. I., Huusom AK (2006). "Prevention of relapse in generalized
anxiety disorder by escitalopram treatment." The international journal of
neuropsychopharmacology 9(5): 495-505.

Escitalopram has demonstrated a robust and dose-dependent efficacy
in the treatment of generalized anxiety disorder (GAD) for up to 3
months. In the present study, the efficacy and tolerability of
escitalopram in the prevention of relapse in GAD was investigated. A
total of 491 patients with a primary diagnosis of GAD and a Hamilton
Anxiety (HAMA) total score>or=20 received 12 wk of open-label
treatment with a fixed dose of escitalopram (20 mg/d). Of these, 375
patients responded (HAMA total score<or=10) and were randomized to
double-blind treatment with 20 mg/d escitalopram (n=187) or placebo
(n=188). Treatment was continued for 24-76 wk unless the patient
relapsed or was withdrawn for other reasons. Relapse was defined as
UNDER
either an increase in HAMA total score to >or=15, or lack of efficacy, as
judged by the investigator. The results of the primary a
1982  nalysis showed
a clear beneficial effect of escitalopram relative to placebo on the time
ACT
to relapse of GAD (log-rank test, p<0.001). The risk of relapse was
RELEASED
4.04 times higher for placebo-treated patients than for escitalopram-
treated patients; the proportion of patients who relapsed was
statistically significantly higher in th
BEEN  e placebo group (56%) than in the
HEALTH
escitalopram group (19%) (p<0.001). Escitalopram was well tolerated
HAS
OF
and 7% of the escitalopram-treated patients
INFORMATION   withdrew due to adverse
events, vs. 8% of the placebo patients. The incidence of
OF
discontinuation symptoms with escitalopram during tapered withdrawal
was low; the symptoms primarily being dizziness (10-12%),
nervousness (2-6%), and insomnia (2-6%). Escitalopram 20 mg/d
DOCUMENT
significantly reduced the risk of rela
DEPARTMENT  pse and was well tolerated in
FREEDOM
patients with GAD.
THIS

THE  THE
Bielski RJ, B. A., Chan
BY  g CC (2005). "A double-blind comparison of
escitalopram and paroxetine in the long-term treatment of generalized anxiety
disorder." Annals of clinical psychiatry 17(2): 65-69.

BACKGROUND: This study compared the efficacy and tolerability of
escitalopram, a newer SSRI, with paroxetine in the treatment of
generalized anxiety disorder (GAD). METHODS: Patients with DSM-IV-
defined GAD were randomized to receive 24 weeks of double-blind
flexible-dose treatment with either escitalopram (10-20 mg/day) or
paroxetine (20-50 mg/day), followed by a 2-week, double-blind, down-
titration period. Mean change from baseline to endpoint (LOCF) in
Hamilton Anxiety Scale (HAMA) scores was the primary efficacy
variable. RESULTS: Mean baseline HAMA scores for the escitalopram
(N = 60) and paroxetine (N = 61) groups were 23.7 and 23.4,
respectively. After 24 weeks of treatment, mean changes in HAMA
scores were -15.3 and -13.3 for escitalopram and paroxetine,
respectively (p = 0.13). Significantly fewer patients withdrew from
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escitalopram than paroxetine treatment due to adverse events (6.6%
vs. 22.6%; p = 0.02). The frequency of treatment-emergent adverse
events was higher with paroxetine vs. escitalopram: overall (88.7% vs.
77.0%), insomnia (25.8% vs. 14.8%), constipation (14.5% vs. 1.6%),
ejaculation disorder (30.0% vs. 14.8%), anorgasmia (26.2% vs. 5.9%),
and decreased libido (22.6% vs. 4.9%). Conversely, diarrhea and
upper respiratory tract infection were reported more with escitalopram
than paroxetine (21.3% vs. 8.1%, and 14.8% vs. 4.8%, respectively).
CONCLUSIONS: These results support the use of escitalopram as a
first-line treatment for GAD.

Davidson JR, B. A., Korotzer A, Zheng H (2004). "Escitalopram in the
treatment of generalized anxiety disorder: double-blind, placebo controlled,
flexible-dose study." Depression and anxiety. 19(4): 234-40.

Escitalopram has been shown in clinical trials to improve anxiety
symptoms associated with depression, panic disorder, and social
anxiety disorder. This study was designed to evaluate the efficacy and
tolerability of escitalopram in the treatment of generalized anxiety
UNDER
disorder (GAD). Outpatients (18 years or older) who met DSM-IV
criteria for GAD, with baseline Hamilton Rating Scale
1982   for Anxiety
(HAMA) scores > or = 18, were randomly assigned to double blind
ACT
treatment with escitalopram (10 mg/day for the first 4 weeks and then
RELEASED
flexibly dosed from 10-20 mg/day) or placebo for 8 weeks, following a
1-week, single-blind, placebo lead-in period. The primary efficacy
variable was the mean change from
BEEN   baseline in total HAMA score at
HEALTH
Week 8. The escitalopram group (N = 158) showed a statistically
HAS
OF
significant, and clinically relevant, greater improvement at endpoint
INFORMATION
compared with placebo (N = 157) in all prospectively defined efficacy
OF
parameters. Significant improvement in HAMA total score and HAMA
psychic anxiety subscale score for the escitalopram-treated group vs.
the placebo-treated group was observed beginning at Week 1 and at
DOCUMENT
each study visit thereafter. Mean changes from baseline to Week 8 on
FREEDOM
DEPARTMENT
the HAMA total score using a last-observation-carried-forward (LOCF)
THIS
approach were -11.
THE 3 for escitalopram and -7.4 for placebo (P<.001).
THE
Response rates at Week 8 were 68% for escitalopram and 41% for
BY
placebo (P<.01) for completers, and 58% for escitalopram and 38% for
placebo LOCF values (P<.01). Treatment with escitalopram was well
tolerated, with low rates of reported adverse events and an incidence of
discontinuation due to adverse events not statistically different from
placebo (8.9% vs. 5.1%; P=.27). Escitalopram 10-20 mg/day is
effective, safe, and well tolerated in the treatment of patients with GAD.

Goodman WK, B. A., Wang Q (2005). " Treatment of generalized anxiety
disorder with escitalopram: pooled results from double-blind, placebo-
controlled trials." Journal of affective disorders 87(2-3): 161-7.

BACKGROUND: Escitalopram 10 mg/day is an effective and well-
tolerated antidepressant. Three randomized controlled trials recently
evaluated the safety and efficacy of escitalopram in the treatment of
generalized anxiety disorder (GAD). METHODS: The trial designs were
virtually identical, allowing data to be pooled across studies. Male and
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female outpatients, ages 18-80 years, with DSM-IV-defined GAD were
randomized to double-blind treatment with escitalopram or placebo for
8 weeks. Escitalopram dose was fixed at 10 mg/day for the first 4
weeks, after which increases to 20 mg/day were permitted. The primary
efficacy variable was the mean change from baseline in total Hamilton
Anxiety Scale (HAMA) score. RESULTS: Approximately 850 patients
were randomized to double-blind treatment. In each individual study,
escitalopram was significantly superior to placebo (p<0.05) as
measured by change from baseline in HAMA score. By-visit analyses
of data pooled across studies revealed significantly greater
improvement (p<0.05) in the escitalopram group beginning at week 1
or 2 and continuing through week 8 for all primary and secondary
efficacy variables. The mean change in HAMA total score from
baseline to endpoint also was significantly greater for patients
maintained at escitalopram 10 mg/day than for those receiving placebo.
Escitalopram was generally well tolerated. LIMITATIONS: The studies
included in this analysis were of short-term duration and excluded
patients with significant medical and psychiatric comorbidities, such as
UNDER
major depressive disorder. CONCLUSION: Results from the individual
trials and the pooled analysis demonstrate that escit
1982  alopram is effective
and well tolerated for the treatment of GAD.
ACT

RELEASED
Ipser, J. C., P;  Dhansay, Y;  Fakier, N;  Seedat, S;  Stein, DJ (2007).
"Pharmacotherapy augmentation strategies in treatment-resistant anxiety
disorders." Cochrane Database of System
BEEN  atic Reviews 2.
HEALTH

A large proportion of patients with anxiety disorders fail to respond to
HAS
OF
first-line medication interventions, despite evidence of the effectiveness
INFORMATION
of these agents.
OF

  Objectives

DOCUMENT
  To assess the effects of medication versus placebo augmentation in the
FREEDOM
DEPARTMENT
treatment of patients with anxiety disorders who have failed to respond
THIS
adequately to first-li
THE ne drug therapies.
THE

BY
  Search strategy

  The Cochrane Depression, Anxiety & Neurosis Group (CCDAN) specialised
registers (CCDANCTR-Studies and CCDANCTR-References) were
searched on 3/8/2005, MEDLINE (January 1966 to July 2005) and
PsycINFO (1966 to 2005, Part A). Unpublished trials were identified
through the Controlled Trials database and the National Institute of
Health's Computer Retrieval of Information on Scientific Projects
(CRISP) service (1972 to 2005). Additional studies in any language
were sought in reference lists of retrieved articles.

  Selection criteria

  All randomised controlled trials (RCTs) of the medication augmentation of
pharmacotherapy for treatment resistant anxiety disorders.
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  Data collection and analysis

  Two raters independently assessed RCTs for inclusion in the review, collated
trial data, and assessed trial quality. Investigators were contacted to
obtain missing data. Summary statistics were stratified by class of
augmentation agent and anxiety disorder. Overall effect estimates were
calculated using a random-effects model, heterogeneity was assessed
and subgroup/sensitivity analyses were undertaken.

  Main results

  Twenty eight short-term (average of seven weeks) randomised controlled
trials (740 participants) were included in the review, 20 of which
investigated augmentation of medication for treatment-resistant
obsessive compulsive disorder (OCD). Summary statistics for
responder status from nine trials demonstrate overall superiority of a
variety of medication agents to placebo (relative risk of non-response
UNDER
(RR) 3.16, 95% CI 1.08 to 9.23). Similarly, symptom severity was
significantly reduced in the medication groups, relative
1982   to placebo
(number of trials (N) = 14, standardised mean difference (SMD) -0.87,
ACT
95% CI -1.37 to -0.36). There is no evidence of a difference between
RELEASED
medication and placebo in total dropout rate, or in the number of
dropouts due to adverse events.

BEEN  HEALTH
  Authors' conclusions
HAS
OF

INFORMATION
  Medication augmentation can be an effective and well-tolerated short-term
OF
treatment strategy for non-responders to first-line pharmacotherapy of
anxiety disorders. However, any conclusions must be tentative in view
of methodological and clinical heterogeneity, and the fact that much of
DOCUMENT
the relevant database is based on antipsychotic augmentation trials in
FREEDOM
DEPARTMENT
OCD patients resistant to serotonin reuptake inhibitors (SRIs).
THIS
Additional data are
THE needed to address several areas, including the
THE
efficacy of augmentation over the longer-term, and the value of
BY
medication augmentation in comparison to other strategies (eg
switching medication, adding psychotherapy).

Stein DJ, A. H., Goodman WK (2005). " Escitalopram for the treatment of
GAD: efficacy across different subgroups and outcomes." Annals of clinical
psychiatry 17(2): 71-5.

BACKGROUND: Generalized anxiety disorder (GAD) is characterized
by anxiety, and also frequently associated with depressive symptoms.
Benzodiazepines have commonly been used in the treatment of GAD,
but are not effective antidepressant agents. In this study, we
determined whether the selective serotonin reuptake inhibitor
escitalopram, was effective across different subgroups and outcomes
(anxious symptoms, depressive symptoms, and quality of life).
METHODS: Three randomized, placebo controlled studies of
escitalopram in GAD have employed a similar design, allowing for
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pooling of the data. The primary efficacy measure was the Hamilton
Anxiety Scale (HAMA). General linear models were used to determine
the efficacy of escitalopram across different subgroups and outcomes.
RESULTS: Escitalopram was efficacious for GAD on a range of
measures of both anxiety and depression, and improved the associated
impairment in quality of life. There was no significant interaction of
effects on the HAMA with demographic or clinical variables.
Furthermore, escitalopram was efficacious on both primary and
secondary scales in the subgroup of subjects with above-median
severity of depressive symptoms at baseline (HAMD-17 > 12).
CONCLUSIONS: Escitalopram reduces anxiety and depressive
symptoms in GAD, and improves quality of life. It is equally effective in
GAD patients, with an above-median level of depressive symptoms.
Further research is needed to determine whether these results can be
extrapolated to GAD patients with comorbid major depression.

UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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4  Conference Papers Index
Davidson, J. Bose., A; Wang, Q (2005). "Safety and efficacy of escitalopram
in the long-term treatment of generalized anxiety disorder." Journal of Clinical
Psychiatry 66(11): 1441-1446.

Introduction: Generalized anxiety disorder (GAD) is a chronic disorder
that requires long-term treatment. Escitalopram has previously been
shown to be effective and well tolerated in the acute treatment of GAD.
Method: Three 8-week, double-blind, placebo-controlled trials of nearly
identical design were conducted of escitalopram in moderateto-severe
GAD (DSM-IV criteria). Patients completing these trials were given the
option of entering a 24-week, open-label, flexible-dose trial of
escitalopram (10-20 mg/day). Data were collected from September 20,
2000, to August 15, 2002. Results: Two hundred ninety-nine (56.8%) of
526 patients completed 24 weeks of open-label treatment. The mean
UNDER
Hamilton Rating Scale for Anxiety (HAM-A) score at baseline of open-
label treatment was 13.1. Long-term escitalopram tre
1982  atment led to
continuing improvement on all anxiety and quality-of-life (QOL) scores.
ACT
Of those completing 24 weeks of treatment, 92.0% were responders
RELEASED
(Clinical Global impressions-Improvement scale score :5 2), and the
mean HAM-A score in the completer analysis was 6.9; using the last
observation carried forward (LOCF)
BEEN  , 75.9% were responders, and the
HEALTH
mean HAM-A score in the LOCF analysis was 9.2 at endpoint.
HAS
OF
Insufficient therapeutic response and adve
INFORMATION  rse events led to withdrawal
of 4.2% and 9.9% of patients, respectively. Mean increase in weight
OF
from baseline was 3.0 lb. No clinically notable changes in mean
laboratory, vital sign, or electrocardiographic values were observed.
Conclusion: These results support the longterm tolerability and
DOCUMENT
effectiveness of escitalopram in th
DEPARTMENT  e treatment of GAD.
FREEDOM

THIS
THE  THE
BY
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5  Clinical Trials
Bristol-Myers Squibb (2007). "Study of Pexacerfont (BMS-562086) in the
Treatment of Outpatients With Generalized Anxiety Disorder."

Purpose

The purpose of this study is to learn about the safety and efficacy of
pexacerfont in outpatients diagnosed with Generalized Anxiety
Disorder

Forest Laboratories (2005). "Cognitive-Behavioral Therapy and Lexapro for
GAD."

Purpose

The goals of this pilot study are as follows:

UNDER
1) To disseminate and examine the effectiveness of a manualized, individual,
cognitive-behavioral psychotherapy (CBT) for adults wit
1982
h Generalized
Anxiety Disorder(GAD), 2) to test the effectiveness of augmentation
ACT
(the addition of) antidepressant therapy in participants who do not fully
RELEASED
respond to CBT, and 3) to examine individual and clinical predictors of
non-response to CBT and predictors of response to augmentation
antidepressant therapy. A related g
BEEN  oal is to examine the maintenance
HEALTH
of treatment gains obtained from CBT alone and CBT with
HAS
OF
augmentation antidepressant therapy, ove
INFORMATION r a twenty-four month follow-
up period. This study will serve as a pilot investigation in preparation for
OF
a larger federally funded study using this treatment approach. We
hypothesize that CBT will result in remission (no longer having GAD)
and/or high endstate functioning (clinically meaningful improvement) in
DOCUMENT
approximately 40-50% of participa
DEPARTMENT  nts. Further, we hypothesize that
FREEDOM
augmentation antidepressant therapy in participants who do not fully
THIS
respond to CBT will
THE  result in further clinically significant improvement.
THE

BY
National Institute of Mental Health (NIMH) (2006). "Drug Therapy for
Generalized Anxiety Disorder Among the Elderly."

Purpose

This study will determine the effectiveness of escitalopram (Lexapro®), an
anti-anxiety drug, for generalized anxiety disorder (GAD) and the ways
genetics affect response to treatment for GAD in elderly individuals.

Sanofi-Aventis (2007). "An Eight-Week Study to Evaluate the Efficacy and
Safety of Saredutant in Patients With Generalized Anxiety Disorder."

Purpose

The primary objective is to evaluate the efficacy of a 100 mg dose of
saredutant compared to placebo in patients with generalized anxiety
disorder. The secondary objectives are to evaluate the efficacy of
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saredutant on disability and quality of life in patients with generalized
anxiety disorder, and to evaluate blood levels of saredutant.

UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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Appendix 3: Article Abstracts for
Escitalopram and Benzodiazepines
HF, S. I. (2006). "Discontinuation of Antipsychotics and Antidepressants
Among Patients With BPSD."

Purpose

The aim of this study is to discontinue antipsychotics and antidepressants,
and to study its effect on Behavioural- and Psychological Symptoms in
Dementia (BPSD).

Prasko, J., P. Houbova, et al. (2005). "Influence of personality disorder on the
treatment of panic disorder - Comparison study." Neuroendocrinology Letters
26(6): 667-674.
UNDER

Most clinicians tend to believe that the occurrence of the anxiety
disorder in comorbidity with a personality disorder oft
1982  en leads to longer
treatment, worsens the prognosis, and thus increasing treatment costs.
ACT
The study is designed to compare the short-term effectiveness of
RELEASED
combination of cognitive behavioral therapy and pharmacotherapy in
patient suffering with panic disorder with and without personality
disorder. Method: We compare the
BEEN  efficacy of 6th week therapeutic
HEALTH
progr am and 6th week follow up in patients suffering with panic
HAS
OF
disorder and/or agoraphobia and comorbid
INFORMATION   personality disorder (29
patients) and panic disorder and/or agoraphobia without comorbid
OF
personality disorder (31 patients). Diagnosis was done according to the
ICD-10 research diagnostic criteria confirmed with MINI and support
with psychological methods: IPDE, MCMI-III and TCI. Patients were
DOCUMENT
treated with CBT and psychopharm
DEPARTMENT  acs. They were regularly assessed
FREEDOM
in week 0, 2, 4, 6 and 12 by an independent reviewer on the CGI
THIS
(Clinical Global Imp
THE rovement) for severity and change, PDSS (Panic
THE
Disorder Severi
BY  ty Scale), HAMA (Hamilton Anxiety Rating Scale), SDS
(Sheehan Disability Scale), HDRS (Hamilton Depression Rating Scale),
and in self-assessments BAI (Beck Anxiety Inventory) and BDI (Beck
Depression Inventory). Results: A comb ination of CBT and
pharmacotherapy proved to be the effective treatment of patients
suffering with panic disorder and/or agoraphobia with or without
comorbid personality disorder. The 12th week treatment efficacy in the
patients with panic disorder without personality disorder had been
showed significantly better compared with the group with panic disorder
comorbid with personality disorder in CGI and specific inventory for
panic disorder - PDSS. Also the scores in depression inventories
HDRS and BDI showed significantly higher decrease during the
treatment comparing with group without personality disorder. But the
treatment effect between groups did not differ in objective anxiety scale
HAMA, and subjective anxiety scale BAI. (copyright)
Neuroendocrinology Letters.
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Appendix 4: Full list of articles
from Various Databases for
Escitalopram and
Benzodiazepines
UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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1  Embase + Medline
Prasko, J., P. Houbova, et al. (2005). "Influence of personality disorder on the
treatment of panic disorder - Comparison study." Neuroendocrinology Letters
26(6): 667-674.

Most clinicians tend to believe that the occurrence of the anxiety
disorder in comorbidity with a personality disorder often leads to longer
treatment, worsens the prognosis, and thus increasing treatment costs.
The study is designed to compare the short-term effectiveness of
combination of cognitive behavioral therapy and pharmacotherapy in
patient suffering with panic disorder with and without personality
disorder. Method: We compare the efficacy of 6th week therapeutic
progr am and 6th week follow up in patients suffering with panic
disorder and/or agoraphobia and comorbid personality disorder (29
patients) and panic disorder and/or agoraphobia without comorbid
personality disorder (31 patients). Diagnosis was done according to the
UNDER
ICD-10 research diagnostic criteria confirmed with MINI and support
with psychological methods: IPDE, MCMI-III and TCI.
1982   Patients were
treated with CBT and psychopharmacs. They were regularly assessed
ACT
in week 0, 2, 4, 6 and 12 by an independent reviewer on the CGI
(Clinical Global Improvement) for severity and
RELEASED  change, PDSS (Panic
Disorder Severity Scale), HAMA (Hamilton Anxiety Rating Scale), SDS
(Sheehan Disability Scale), HDRS (H
BEEN  amilton Depression Rating Scale),
HEALTH
and in self-assessments BAI (Beck Anxiety Inventory) and BDI (Beck
Depression Inventory). Resu
HAS lts: A com
OF  b ination of CBT and
INFORMATION
pharmacotherapy proved to be the effective treatment of patients
OF
suffering with panic disorder and/or agoraphobia with or without
comorbid personality disorder. The 12th week treatment efficacy in the
patients with panic disorder without personality disorder had been
DOCUMENT
showed significantly better compared with the group with panic disorder
FREEDOM
DEPARTMENT
comorbid with personality disorder in CGI and specific inventory for
THIS
panic disorder - PDS
THE  S. Also the scores in depression inventories
THE
HDRS and BDI showed significantly higher decrease during the
BY
treatment comparing with group without personality disorder. But the
treatment effect between groups did not differ in objective anxiety scale
HAMA, and subjective anxiety scale BAI. (copyright)
Neuroendocrinology Letters.

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2  Clinical Trials
Oxazepam and Escitalopram

HF, S. I. (2006). "Discontinuation of Antipsychotics and Antidepressants
Among Patients With BPSD."

Purpose

The aim of this study is to discontinue antipsychotics and antidepressants,
and to study its effect on Behavioural- and Psychological Symptoms in
Dementia (BPSD).

UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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Appendix 5: Article Abstracts for
Benzodiazepines: DSM –IV
1. Andreatini, R., V. A. Sartori, et al. (2002). "Effect of valepotriates (valerian
extract) in generalized anxiety disorder: A randomized placebo-controlled pilot
study." Phytotherapy Research 16(7): 650-654.

The aim of the present study was to carry out a controlled pilot study on
the putative anxiolytic effect of valepotriates. Thirty-six outpatients with
generalized anxiety disorder (DSM III-R), after a 2-week wash-out,
were randomized to one of the following three treatments for 4 weeks
(n = 12 per group): valepotriates (mean daily dose: 81.3 mg), diazepam
(mean daily dose: 6.5 mg), or placebo. A parallel, double-blind, flexible-
dose, placebo-controlled design was employed. No significant
difference was observed among the three groups at baseline or in the
change from baseline on the Hamilton anxiety scale (HAM-A) or in the
UNDER
trait part of the state-trait anxiety inventory (STAI-trait). Moreover, the
1982
three groups presented a significant reduction in the total HAM-A
scores. On the other hand, only the diazepam and valepotriates groups
ACT
showed a significant reduction in the psychic factor of HAM-A. The
RELEASED
diazepam group also presented a significant reduction of the STAI-trait.
Although the principal analysis (HAM-A between group comparison)
BEEN
found negative results (probably due to the small sample size in each
HEALTH
group), the preliminary data obtained in the present study suggest that
HAS
OF
the valepotriates may have a potential anxiol
INFORMATION  ytic effect on the psychic
symptoms of anxiety. However, since the number of subjects per group
OF
was very small, the present results must be viewed as preliminary.
Thus, further studies addressing this issue are warranted. Copyright
(copyright) 2002 John Wiley & Sons, Ltd.
DOCUMENT

FREEDOM
DEPARTMENT
2. Ansseau, M., J.
THIS P. Olie, et al. (1991). "Controlled comparison of the efficacy
THE
and safety of four do
THE ses of suriclone, diazepam, and placebo in generalized
anxiety disorder." Psyc
BY  hopharmacology (Berl) 104(4): 439-43.

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2,
0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared
in six parallel groups of 54-59 outpatients with generalized anxiety
disorder (DSM III-R). After a 1-week placebo run-in period, the patients
were treated for 4 weeks, with assessments at baseline and after 1, 2,
and 4 weeks by the Hamilton anxiety scale and the Clinical Global
Impressions. Results showed better improvement with active drugs as
compared to placebo, without significant differences among the four
different doses of suriclone and diazepam. The number of adverse
events, particularly drowsiness, was significantly higher with diazepam
than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ
from placebo. These results demonstrate that suriclone at daily doses
ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated
than diazepam.

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3. Ban, T. A. and M. M. Amin (1979). "Clobazam: uncontrolled and standard
controlled clinical trials." Br J Clin Pharmacol 7 Suppl 1: 135S-138S.

1 In an uncontrolled clinical trial, carried out in 11 psychiatric patients
with the clinical diagnoses of anxiety neurosis and depressive neurosis,
clobazam, a new benzodiazepine preparation, in the dosage range 10-
60 mg daily produced statistically significant improvement in the total
and both factor scores of the Hamilton Anxiety Scale (HAM-A). The
lowest mean total HAM-A scores occurred with a mean clobazam
dosage of 48 mg daily. 2 Results of the uncontrolled clinical trial were
further substantiated in a standard-controlled clinical study in which no
statistically significant difference between the therapeutic effectiveness
of clobazam and diazepam could be revealed. The lowest mean total
HAM-A scores occurred with a mean clobazam dosage of 49 mg daily.
There was a lower incidence of adverse effects reported in patients
receiving clobazam than in those taking the control drug (diazepam).

4. Basile, A. S., A. S. Lippa, et al. (2006). "GABAA receptor modulators as
anxioselective anxiolytics." Drug Discovery Today: Therapeutic Strategies
UNDER
3(4): 475-481.

Benzodiazepines are effective anxiolytics whose use
1982   is limited by
sedation, amnesia and myorelaxation, driving the search for novel,
ACT
anxioselective GABAA receptor modulators. Preclinical data from
RELEASED
'knock-in' mice and (alpha)2,3-subunit selective GABAA receptor
agonists suggest that these targets may yield anxioselective agents. In
contrast, additional preclinical and clinic
BEEN
al evidence suggests that a
HEALTH
combination of mechanisms, including partial agonism and receptor
HAS
OF
subtype selectivity, will be required to achieve anxioselectivity in the
INFORMATION
clinic. (copyright) 2006 Elsevier Ltd. All rights reserved.
OF

5. Bobon, D. P., J. Fanielle, et al. (1978). "Time-blind videotaped evaluation of
injectable diazepam, lorazepam and placebo." Acta Psychiatr Belg 78(4): 619-
DOCUMENT
34.
FREEDOM
DEPARTMENT

Eighteen inpatients suffering from a severe anxiety received in double-
THIS
blind and crossover co
THE  nditions iv and im injections of 10 mg diazepam,
THE
5 mg lorazepam or saline t.i.d. during 5 days. The morning injections
BY
was made iv in a CCTV studio. Before injection and 20 mn after it, the
patient filled out a 100 mm Visual Analogue Scale; his doctor-in-charge
proceeded to a standard interview and to physiological measurements
(tremor of hand, patellar reflexes, blood pressure, pulse rate). The
videotaped interviews were randomly, i.e. time-blind, rated by two
independent observers on 3 scales: the VAS, the Hamilton Anxiety
Scale and an ad hoc Verbal and Non-Verbal Anxiety Scale (VNVA).
The statistical analysis was completed by a logical analysis according
to Lewis Carroll. The results demonstrate the superiority of lorazepam
over diazepam on psychic anxiety, somatic anxiety, sleep and blood
pressure, the only significant side-effect being drowsiness.

6. Borison, R., Albrecht, JW, Diamond, BI. (1990). "Efficacy and safety of a
putative anxyiolitic agent: Ipsapirone."  Psychopharmacology Bulletin. 6(26):
207-209.
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7. Boyer, W., Feighner, JP. (1993). "A placebo-controlled double-blind
multicenter trial of two doses of ipsapirone versus diazepam in generalized
anxiety disorder." International Clinical Psychopharmacology 8: 173-76.

8. Brawman-Mintzer, O., R. G. Knapp, et al. (2005). "Adjunctive risperidone in
generalized anxiety disorder: A double-blind, placebo-controlled study."
Journal of Clinical Psychiatry 66(10): 1321-1325.

Objective: Although significant advances have been made in recent
years in the treatment of generalized anxiety disorder (GAD), many
patients remain symptomatic despite ongoing treatment, underscoring
the need for adjunctive new treatments to help improve response.
Method: Forty patients with a primary diagnosis of DSM-IV GAD, who
continued to experience GAD symptoms despite current anxiolytic
treatment of at least 4 weeks' duration, as evidenced by Hamilton
Rating Scale for Anxiety (HAM-A) total score (greater-than or equal to)
18 and Clinical Global Impressions-Severity of Illness scale score of
moderate or greater, completed a 1-week screening phase and were
UNDER
then randomly assigned to 5 weeks of double-blind adjunctive
treatment with placebo or risperidone at flexible dos
1982 es of 0.5 to 1.5
mg/day. Patients continued to take their anxiolytics throughout the
ACT
study. The study was conducted from June 2001 through March 2003.
RELEASED
Results: Adjunctive risperidone was associated with statistically
significant improvements in core anxiety symptoms, as demonstrated
by greater reductions in HAM-A tot
BEEN al scores (p = .034) and HAM-A
HEALTH
psychic anxiety factor scores (p = .047) compared with placebo.
HAS
OF
Although change scores on other outcome variables, including
INFORMATION
response rates, were higher in the risperidone group, differences did
OF
not achieve statistical significance. Conclusion: Study findings suggest
that risperidone at low doses may represent a useful tool in the
management of symptomatic GAD patients.
DOCUMENT

FREEDOM
DEPARTMENT
9. Casacalenda, N. e. a. (1998). "Pharmacologic treatments effective in both
THIS
generalized anxiety disorde
THE  r and major depressive disorder: clinical and
THE
theoretical implications. ." Canadian Journal of Psychiatry. . 43(7): 722.
BY

10. Centre for Reviews and Dissemination (2007). " Long-term
pharmacological treatment of generalized anxiety disorder (Structured
abstract)." Database of Abstracts of Reviews 2.

11. Centre for Reviews and Dissemination (2007). "A meta-analytic review of
the efficacy of drug treatment in generalized anxiety disorder (Structured
abstract)." Database of Abstracts of Reviews of Effects. 3.

12. Chessick, C. A., MH; Thase, ME;  Batista Miralha da Cunha, ABC;
Kapczinski, FFK;  de Lima, MSML;  dos Santos Souza, JJSS (2007).
"Azapirones for generalized anxiety disorder." Cochrane Database of
Systematic Reviews. 3.

Background

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  Azapirones are a group of drugs that work at the 5-HT1A receptor and are
used to treat patients suffering from generalized anxiety disorder
(GAD). However, several studies have shown conflicting results.
Whether azapirones are useful as first line treatment in general anxiety
disorders still needs to be answered.

  Objectives
To assess the efficacy and the acceptability of azapirones for the treatment of
GAD.

  Search strategy
Initiallyt the Cochrane Collaboration Depression, Anxiety and Neurosis
Controlled Trials Register (CCDANCTR) and The Cochrane Central
Register of Controlled Trials (CENTRAL) were searched, incorporating
results of group searches of MEDLINE (1966 to June 2005), EMBASE
(1980 to June 2005), CINAHL (1982 to June 2005), PsycLIT (1974 to
June 2005), PSYNDEX (1977 to June 2005), and LILACS (1982 to
June 2005). Subsequently the revised Cochrane Collaboration
UNDER
Depression, Anxiety and Neurosis Controlled Trials Registers
(CCDANCTR-Studies and CCDANCTR-References) w
1982  ere searched on
21-10-2005. Reference lists of relevant papers and major text books of
ACT
anxiety disorder were examined. Authors, other experts in the field and
RELEASED
pharmaceutical companies were contacted for knowledge of suitable
trials, published or unpublished. Specialist journals concerning
azapirones were handsearched.
BEEN  HEALTH

HAS
OF
  Selection criteria
INFORMATION
Randomized controlled trials of azapirones, including buspirone versus
OF
placebo and/or other medication and/or psychological treatment, were
included. Participants were males and females of all ages with a
diagnosis of generalized anxiety disorder.
DOCUMENT

FREEDOM
DEPARTMENT
  Data collection and analysis
THIS
Data were extracted from th
THE  e original reports independently by CC, MA and
THE
MT. The main outcomes studied were related to the objectives stated
BY
above. Data were analysed for generalized anxiety disorder versus
placebo, versus other medication and versus psychological treatment
separately. Data were analysed using Review Manager Version 4.2.7.

  Main results
Thirty six trials were included in the review, reporting on 5908 participants
randomly allocated to azapirones and/or placebo, benzodiazepines,
antidepressants, psychotherapy or kava kava. Azapirones, including
buspirone, were superior to placebo in treating GAD. The calculated
number needed to treat for azapirones using the Clinical Global
Impression scale was 4.4 (95% confidence interval (CI) 2.16 to 15.4).
Azapirones may be less effective than benzodiazepines and we were
unable to conclude if azapirones were superior to antidepressants,
kava kava or psychotherapy. Azapirones appeared to be well tolerated.
Fewer participants stopped taking benzodiazepines compared to
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azapirones. The length of studies ranged from four to nine weeks, with
one study lasting 14 weeks.

  Authors' conclusions
Azapirones appeared to be useful in the treatment of GAD, particularly for
those participants who had not been on a benzodiazepine. Azapirones
may not be superior to benzodiazepines and do not appear as
acceptable as benzodiazepines. Side effects appeared mild and non
serious in the azapirone treated group. Longer term studies are needed
to show that azapirones are effective in treating GAD, which is a
chronic long-term illness.

13. Coak, A. R., J;  Morris, S. (2007). "Thioridazine for anxiety and depressive
disorders. ." Cochrane Database of Systematic Reviews.(2).

14. Cohn, J., Rickels, K. (1989). "A pooled, double-blind comparison of the
effects of buspirone, diazepam and placebo in women with chronic anxiety. ."
Current Medical Research and Opinion 11(5): 304-20.
UNDER

15. Cooper, S. J., C. B. Kelly, et al. (1990). "Beta 2-adreno
1982 ceptor antagonism
in anxiety." Eur Neuropsychopharmacol 1(1): 75-7.
ACT

The relative role of beta 1- and beta 2-adrenoceptor antagonism in the
RELEASED
management of anxiety symptoms is not clear. We studied the effect of
ICI 118,551, a selective beta 2-antagonist, in 51 patients presenting
with acute anxiety symptoms and fu
BEEN  lfilling DSM-III criteria for anxiety
HEALTH
disorder. All patients received placebo during the first week of
HAS
OF
treatment followed by thrice daily diazepam (2 mg) or ICI 118,551 (50
INFORMATION
mg) or placebo for 4 weeks with double-blind, random allocation.
OF
Hamilton anxiety scale scores improved on all treatments but there was
no significant difference between treatments. Beta 2-adrenoceptor
antagonism does not appear to be effective in acute anxiety neurosis.
DOCUMENT
Some earlier literature suggests that beta 1-antagonism may be more
FREEDOM
DEPARTMENT
important.
THIS

THE  THE
16. Cutler, N. R., J. M. Hesselink, et al. (1994). "A phase II multicenter dose-
BY
finding, efficacy and safety trial of ipsapirone in outpatients with generalized
anxiety disorder." Prog Neuropsychopharmacol Biol Psychiatry 18(3): 447-63.

Benzodiazepines have been prescribed for the treatment of
Generalized Anxiety Disorder (GAD) for nearly three decades due to
their proven anxiolytic efficacy, despite a considerable side effect and
abuse liability profile. A new class of compounds, the azapirones, have
been developed as an alternative to benzodiazepine treatment.
Ipsapirone is a novel anxiolytic azapirone which has high specificity for
the 5-HT1A receptor and which has the potential for offering certain
advantages over buspirone. The present 5-week study investigated
three doses of ipsapirone (2.5mg, 5.0mg and 7.5mg tid) versus placebo
in 267 GAD outpatients. Efficacy was evaluated using the Hamilton
Anxiety Rating Scale (HAM-A), Zung Anxiety Scale (Zung-A), and
Clinical Global Impression (CGI). The study design consisted of a 1-
week placebo run-in, a 4-week double-blind treatment period, and a 1-
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week placebo washout. The 5.0mg group demonstrated consistently
superior improvement in all efficacy variables during the treatment
period, with significant differences (p < 0.05) from placebo and, at
times, the 2.5mg and 7.5mg groups. Incidence of adverse events,
primarily dizziness, nausea, sedation, and asthenia, was found to be
dose proportional, with significant increase in the 7.5mg group, which
may account for the diminished effectiveness seen with this dose. Our
results suggest that ipsapirone may represent a viable treatment for
GAD.

17. DeMartinis, N., Runn, M, Rickels, K, Mandos, L. P. (2000). "Prior
Benzodiazepine Use and Buspirone Response in the Treatment of
Generalized Anxiety Disorder. ." The Journal of Clinical Psychiatry 61(2): 91-
94.

18. Downing, R. W. and K. Rickels (1985). "Early treatment response in
anxious outpatients treated with diazepam." Acta Psychiatr Scand 72(6): 522-
8.
UNDER

Two hundred and two moderately chronic psychiatric outpatients, all
suffering from anxiety of at least moderate severity a
1982  nd all diagnosable
as cases of Generalized Anxiety Disorder, participated in a single-blind
ACT
6-week trial of diazepam (15-40 mg/day). The trial was preceded by a 1
RELEASED
week placebo washout, and provided for evaluation visits after 1, 2, 4
and 6 weeks of diazepam treatment. Patients were divided into High,
Medium and Low Initial Improvers u
BEEN  sing 1 week change in Hamilton
HEALTH
Anxiety Scale total score to assign patients to three subgroups of equal
HAS
OF
size. These groups did not differ significantly on those demographic
INFORMATION
factors and attributes of illness history which were documented, nor on
OF
assessments of symptom and illness severity, and mode of intake.
Examination of a number of patient and physician assessments of
illness severity revealed that the High group had the greatest 6-week
DOCUMENT
improvement, the Low group the least. During the first week, the High
FREEDOM
DEPARTMENT
group attained 86%, the Medium group, 65%, and the Low group, 29%
THIS
of its full 6-week drug
THE   response. Diazepam dose levels were lowest for
THE
the High group and highest for the Low group. Placebo response was
BY
least for the High group and greatest for the Low group. An attempt to
find distinctive attributes of the three initial improvement groups was
unsuccessful.

19. Ebadi, M. and Y. Hama (1988). "Dopamine, GABA, cholecystokinin and
opioids in neuroleptic-induced tardive dyskinesia." Neuroscience and
Biobehavioral Reviews 12(3-4): 179-187.

20. Falissard, B. (2003). "Statistical considerations about the question of a
selection of discriminating centres in the analysis of clinical trial. In response
to the paper: "A method for controlling for a high response rate in a
comparison of venlafaxine XR and diazepan in the short-term treatment of
patients with generalised anxiety disorder"." Eur Psychiatry 18(4): 188-9.

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21. Fontaine, R., L. Annable, et al. (1983). "Bromazepam and diazepam in
generalized anxiety: a placebo-controlled study with measurement of drug
plasma concentrations." J Clin Psychopharmacol 3(2): 80-7.

In a double-blind, placebo-controlled study, 48 anxious outpatients with
a primary diagnosis of generalized anxiety disorder were randomly
assigned to 4 weeks of treatment with bromazepam (18 mg/day),
diazepam (15 mg/day), or placebo, after a 1-week washout period.
From week 1 onward both active drugs were superior to placebo in
relieving anxiety symptoms. Bromazepam was found to be significantly
more effective than diazepam with respect to the somatic anxiety factor
and the total score for the Hamilton Anxiety Rating Scale and the
fear/anxiety factor of the Patient's Self-Rating Symptom Scale. Plasma
concentrations of diazepam plus active metabolites were correlated
significantly (r = 0.60, p less than 0.05) with the percentage reduction in
self-rating anxiety scores. Bromazepam plasma concentration
measurements showed greater variability than those of diazepam and
were not found to be correlated significantly with clinical response. It is
suggested that the use of strict diagnostic criteria (1978 draft of the
UNDER
third edition of Diagnostic and Statistical Manual of Mental Disorders),
adequate sample sizes, and a 4-week study period g
1982  ave increased
sensitivity for the detection of significant differences between the two
ACT
benzodiazepines.
RELEASED

22. Fontaine, R., P. Beaudry, et al. (1987). "Comparison of withdrawal of
buspirone and diazepam: a placebo contro
BEEN  lled study." Prog
HEALTH
Neuropsychopharmacol Biol Psychiatry 11(2-3): 189-97.
HAS
OF

In a 8-week double-blind placebo controlled study, 48 outpatients with
INFORMATION
generalized anxiety disorder were randomized to diazepam, buspirone,
OF
a non-benzodiazepine anxiolytic, or placebo. During the treatment
phase of 4 weeks duration diazepam was found to be significantly
better than placebo and buspirone. Following abrupt withdrawal by
DOCUMENT
placebo substitution the diazepam group showed a gradual relapse
FREEDOM
DEPARTMENT
maximal after two weeks while the buspirone and the placebo groups
THIS
did not differ. There we
THE  re more cases of rebound anxiety with
THE
diazepam as compared to buspirone or placebo. In addition, there were
BY
three early terminations related to rebound anxiety in the diazepam
group while there were none in the placebo and buspirone groups.
There were significantly more new symptoms in the diazepam group
than in the placebo or buspirone group.

23. Fontaine, R., G. Chouinard, et al. (1984). "Bromazepam and diazepam in
generalized anxiety: a placebo-controlled study of efficacy and withdrawal."
Psychopharmacol Bull 20(1): 126-7.

24. Fontaine, R., G. Chouinard, et al. (1984). "Rebound anxiety in anxious
patients after abrupt withdrawal of benzodiazepine treatment." Am J
Psychiatry 141(7): 848-52.

In this double-blind, placebo-controlled study of 4 weeks of
benzodiazepine treatment followed by 3 weeks of abrupt or gradual
drug withdrawal, 16 patients whose benzodiazepine was withdrawn
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abruptly were worse (p less than .05) than 13 who had received
placebo in terms of change in mean anxiety scores from the
pretreatment level. The scores of seven patients (44%) whose
benzodiazepine was withdrawn abruptly increased 10% or more on
both the Hamilton Rating Scale for Anxiety and the Self Rating
Symptom Scale. There were no cases of rebound anxiety in 14 patients
whose benzodiazepine was withdrawn gradually; fewer cases of
rebound anxiety were seen with a benzodiazepine that had a long half-
life.

25. Forest Laboratories (2007). Initiating Acamprosate Within Versus Post-
Detoxification in the Rehabilitative Treatment of Alcohol Dependence.
.

Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control,
Crossover Assignment
Further study details as provided by National Institute on Drug Abuse (NIDA):
Primary Outcome Measures:
UNDER
The mean number of adverse events rated moderate to severe;
The week of detoxification treatment discontinuation;  1982
The total amount of oxazepam given;
ACT
The rate of change in CIWA scores.
RELEASED
The mean number of adverse events rated moderate to severe;
The week of open-label treatment discontinuation;
Any reemergence of detoxification sympto
BEEN  ms;
HEALTH
Percentage of pills taken over what was proposed to be prescribed
HAS
OF
(medication exposure);
INFORMATION
Percentage days abstinent;
OF
Percentage days heavy drinking. The number of drinks per day will be used to
identify a heavy drinking day, defined as 5 or more drinks/day for males
and 4 or more drinks/day for females.
DOCUMENT

FREEDOM
DEPARTMENT
Secondary Outcome Measures:
THIS
Changes in alcohol craving
THE   will be measured by Penn Alcohol Craving Scale
THE
(PACS; Flannery et al, 1999)
BY
Changes in anxiety symptoms will be measured by the Structured Interview
Guide for the Hamilton Anxiety Rating Scale (SIGH-A; Hamilton, 1969)
Changes in depressive symptoms will be measured by the Structured
Interview Guide for the Hamilton Depression Rating Scale (SIGH-D;
Hamilton 1967)
Changes in social functioning will be measured by several of the subscales of
the Addiction Severity Index (ASI; McLellan et al, 1992); namely,
medical, legal, psychiatric, and family/social.
Quality of Life, measured by the Short Form-36 Health Status Questionnaire
(SF-36; Ware & Sherbourne, 1999)
Overall clinical impression of improvement will be measured by the Clinical
Global Impression Scale (CGI)

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26. Gao, K., D. Muzina, et al. (2006). "Efficacy of typical and atypical
antipsychotics for primary and comorbid anxiety symptoms or disorders: A
review." Journal of Clinical Psychiatry 67(9): 1327-1340.

Objective: The efficacy of antipsychotics in the treatment of primary or
comorbid anxiety disorders or anxiety symptoms in major depressive
disorder or bipolar disorder was reviewed. Data Sources: English-
language literature cited in MEDLINE from January 1, 1968, to
December 31, 2005, was searched with the keywords anxiety disorder,
anxiety symptoms, generalized anxiety disorder, panic disorder,
obsessive-compulsive disorder, posttraumatic stress disorder, social
phobia, bipolar disorder, major depressive disorder, Hamilton Rating
Scale for Anxiety, antipsychotics, typical antipsychotics, atypical
antipsychotics, fluphenazine, haloperidol, perphenazine, pimozide,
thiothixene, trifluoperazine, loxapine, molindone, chlorpromazine,
mesoridazine, thioridazine, fluspirilene, penfluridol, pipothiazine,
flupenthixol, clozapine, olanzapine, risperidone, quetiapine,
ziprasidone, aripiprazole, amisulpride, and clinical trial. Randomized,
double-blind, placebo-controlled trials and open-label studies with a
UNDER
minimum of 20 subjects with a DSM-III/IV or ICD-10 diagnosis of
anxiety disorder and studies without a DSM-III/IV or ICD
1982
-10 diagnosis
of anxiety disorder but with Hamilton Rating Scale for Anxiety (HAM-A)
ACT
scores as an outcome were prioritized. Studies on bipolar disorder or
RELEASED
major depressive disorder with the analysis of changes in anxiety
symptoms were reviewed. Early studies on neurosis/anxiety or anxious
depression without a HAM-A comp
BEEN onent were also reviewed. Data
HEALTH
Synthesis: Six trials in primary generalized anxiety disorder (GAD), 15
HAS
OF
in refractory obsessive-compulsive disorder (OCD), 8 in posttraumatic
INFORMATION
stress disorder (PTSD), 6 in neurosis with the HAM-A, 1 in social
OF
phobia, and 2 in anxiety symptoms in bipolar depression were
identified. Low doses of trifluoperazine were superior to placebo in the
treatment of GAD. Most of the less well-designed studies showed that
DOCUMENT
other typical antipsychotics might be superior to placebo or as effective
FREEDOM
DEPARTMENT
as benzodiazepines in the treatment of GAD and other anxiety
THIS
conditions. In most
THE studies, risperidone, olanzapine, and quetiapine
THE
augmentation to antidepressants was superior to placebo in treating
BY
refractory OCD and PTSD. Both olanzapine and quetiapine significantly
reduced anxiety compared to placebo in studies of bipolar depression.
Conclusion: Except for trifluoperazine, there is no large, well-designed
study of antipsychotics in the treatment of primary or comorbid anxiety
symptoms or disorders. The efficacy of these agents in various anxiety
conditions needs to be further investigated with large, well-designed
comparison studies.

27. Goldberg, H. L. and R. Finnerty (1982). "Comparison of buspirone in two
separate studies." J Clin Psychiatry 43(12 Pt 2): 87-91.

Two double-blind studies are described in which buspirone was
compared with placebo and diazepam (Study A) or clorazepate (Study
B) in outpatients with moderate to severe anxiety. Results, assessed
on the Hamilton Rating Scales for Depression and Anxiety, the SCL-56,
the Profile of Mood States, and the Covi and Raskin scales, indicated
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that buspirone consistently relieved both anxiety and associated
depression. In Study B, trends in favor of buspirone were seen on
several SCL-56 items and the Hamilton somatic factor; significant
differences in this direction were found for several POMS items.
Sedation was seen less often with buspirone than either diazepam or
clorazepate.

28. Hackett, D., V. Haudiquet, et al. (2003). "A method for controlling for a
high placebo response rate in a comparison of venlafaxine XR and diazepam
in the short-term treatment of patients with generalised anxiety disorder."
European Psychiatry 18(4): 182-187.

This randomised, double-blind, placebo-controlled study compared the
efficacy of venlafaxine XR (75 or 150 mg/d) with diazepam (15 mg/d)
over an 8-week treatment period in 540 non-depressed outpatients with
generalised anxiety disorder (GAD). At week 8, significant
improvements from baseline were observed in the venlafaxine XR,
diazepam and placebo groups. Although these improvements were
higher in the first two groups than in the placebo group for each of the
UNDER
primary efficacy variables (Hamilton Rating Scale for Anxiety (HAM-A)
total, HAM-A psychic anxiety factor, Hospital Anxiety
1982  and Depression
Scale (HAD) anxiety sub-scale and Clinical Global Impression (CGI)
ACT
improvement), there were no statistically significant differences
RELEASED
between groups. These non-positive results were thought to be due to
the very high placebo response observed in some centres. To
understand the variability of the stu
BEEN  dy, a secondary preplanned
HEALTH
analysis was performed. This involved sub-dividing the study centres
HAS
OF
according to their ability to detect a two-point mean difference between
INFORMATION
diazepam and placebo at week 8 on the HAM-A total score. Centres
OF
able to show such a difference were termed verum-sensitive.
Improvements from baseline to week 8 in venlafaxine XR-treated
patients from verum-sensitive centres were significantly greater than in
DOCUMENT
placebo on each of the primary efficacy measures (P (less-than or
FREEDOM
DEPARTMENT
equal to) 0.05). This suggests that those centres able to detect an
THIS
anxiolytic effect of d
THE  iazepam were also able to detect an anxiolytic
THE
effect of venlafaxine XR. Significant differences in baseline
BY
demographics, rates of adverse event reporting and rates of patient
discontinuations were noted between patients enrolled at verum-
sensitive and verum-insensitive sites. These results reflect the
importance of study centre selection in accurately determining efficacy
in placebo-controlled trials. (copyright) 2003 Editions scientifiques et
medicales Elsevier SAS. All rights reserved.

29. Heideman, J., van Rijswijk E, van Lin N, de Loos S, Laurant M, Wensing
M, van de Lisdonk E, Grol R. (2005). "Interventions to improve management
of anxiety disorders in general practice: a systematic review." British Journal
of General Practice. 55(520): 867-874.

30. Jacobson, A. F., R. A. Dominguez, et al. (1985). "Comparison of
buspirone and diazepam in generalized anxiety disorder." Pharmacotherapy
5(5): 290-6.
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A total of 66 outpatients meeting Diagnostic and Statistical Manual
(DSM-III) criteria for generalized anxiety disorder began treatment in a
randomized double-blind study that compared the efficacy and safety of
buspirone and diazepam. Thirty-nine outpatients completed the 4-week
trial. Both drugs were administered in a 1:1 dosage ratio; the daily
prescribed dose did not exceed 40 mg. The mean daily dose of
buspirone prescribed throughout the study was significantly higher than
that of diazepam. Diazepam had a significantly earlier onset of efficacy
than buspirone, although both drugs were equivalent after 4 weeks of
treatment. Adverse reactions were more frequent in the diazepam
group. Total scores from the Hamilton anxiety scale and physician's
global ratings show that diazepam was significantly superior to
buspirone during the initial 2 weeks of treatment. These findings are
further corroborated by the results of patients' self-rated scales.

31. Jesinger, D. K. and N. Gostick (1989). "Anxiety neurosis in general
practice. A double-blind comparative study of diazepam and clovoxamine, a
novel inhibitor of noradrenaline and serotonin reuptake." Int Clin
UNDER
Psychopharmacol 4(4): 301-11.

This was a multicentre prospectively randomized do
1982 uble-blind parallel
comparison of clovoxamine (n = 37) and diazepam (n = 35) in 72
ACT
patients suffering from anxiety neurosis, in general practice. Patients
RELEASED
were seen weekly. Treatment was for 4 weeks (50 mg clovoxamine
b.d. or 5 mg diazepam b.d.) rising according to response to a maximum
of 300 mg clovoxamine or 30 mg d
BEEN iazepam daily. Drug was tapered off
HEALTH
in week 5 and patients were seen again in week 6 after they had been
HAS
OF
off drug for at least a week. A treatment period of 4 weeks was
INFORMATION
selected in line with WHO guidelines for the testing of anxiolytic drugs.
OF
Although more patients dropped out due to intolerance on clovoxamine
(24%) compared with diazepam (11%), analysis of completed patients
showed that clovoxamine was equally effective with significant
DOCUMENT
improvement in both groups at week 4 (p less than .001) compared
FREEDOM
DEPARTMENT
with baseline Morbid Anxiety Inventory scores and Hamilton Anxiety
THIS
Scale scores. Diaze
THE  pam patients had a more rapid response which
THE
levelled off, whereas those on clovoxamine continued to improve after
BY
2 weeks. At 6 weeks after taper off the improvement on clovoxamine
was sustained whereas on diazepam there was evidence of
deterioration after stopping the drug. Clovoxamine appears to have
potential as an alternative treatment to diazepam for anxiety in general
practice.

32. Kapczinski, F. L., MS;  Souza, JS;  Cunha, A;  Schmitt, R (2007).
"Antidepressants for generalized anxiety disorder." Cochrane Database of
Systematic Reviews.(3).

Background

  Pharmacological treatments have been successfully used to treat
Generalized Anxiety Disorder (GAD). Benzodiazepine and non
benzodiazepine anxiolytics used to be the mainstay for the
pharmacological treatment of GAD. However, data emerging over the
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last two decades have shown that antidepressants may be as effective
as anxiolytics in this condition. The use of antidepressants may also be
beneficial, because GAD often coexists with major depressive disorder
(62% comorbidity) and dysthymia (37%).

  Objectives
To assess the efficacy and acceptability of antidepressants for treating
generalized anxiety disorder.

  Search strategy
Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials
Register - CCDANCTR (up to May 2002), Anxiety Neurosis (up to May
2002) and Cochrane Controlled Trials Register (CENTRAL/CCTR) (up
to May 2002), MEDLINE (1966 to May 2002), LILACS (1982 to May
2002); reference searching; personal communication; conference
abstracts and book chapters on the treatment of generalized anxiety
disorder.

UNDER
  Selection criteria
Randomized controlled trials were included. Non randomized
1982   studies and
those that included patients with both GAD and another Axis I co-
ACT
morbidity were excluded.
RELEASED

  Data collection and analysis
The data from studies were extracted inde
BEEN  pendently by two reviewers.
HEALTH
Relative risks, weighted mean difference and number needed to treat
HAS
OF
were estimated. People who died or dropped out were regarded as
INFORMATION
having had no improvement.
OF

  Main results
Antidepressants (imipramine, venlafaxine and paroxetine) were found to be
DOCUMENT
superior to placebo in treating GAD. The calculated NNT for
FREEDOM
DEPARTMENT
antidepressants in GAD is 5.15. Dropout rates did not differ between
THIS
antidepressants. On
THE  ly one study presented data on imipramine and
THE
trazodone. Imipramine was chosen as the reference drug and,
BY
therefore, data on trazodone could not be included in the meta
analysis. Only one study was conducted among children and
adolescents (Rynn 2000). This showed very promising results of
sertraline in children and adolescents with GAD, which warrants
replication in larger samples.

  Authors' conclusions
The available evidence suggests that antidepressants are superior to placebo
in treating GAD. There is evidence from one trial suggesting that
paroxetine and imipramine have a similar efficacy and tolerability.
There is also evidence from placebo-controlled trials suggesting that
these drugs are well tolerated by GAD patients. Further trials of
antidepressants for GAD will help to demonstrate which
antidepressants should be used for which patients.

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33. King Pharmaceuticals Research and Development (2007). A Study on the
Effectiveness and Safety of Diazepam Injection (Vanquix™) for Patients With
Epilepsy That Receive Antiepileptic Drugs, But Still Experience Acute
Repetitive Seizures (Bouts or Clusters of Seizures) That Require Treatment.
Clinical Trials identifier: NCT00319501.

Total Enrollment:  325
Study start: January 2006

In the United States, more than 2 million people have epilepsy. Most patients
with epilepsy are able to control their seizures with drugs and/or
surgery. However, many patients (400,000 to greater than 600,000) are
considered refractory to antiepileptic drugs and still experience acute
repetitive seizures (ARS). An ARS is an episode of multiple seizures
that differs from the patient's usual seizure pattern and is often
recognizable by the patient's family and caregivers. The ARS is usually
described as a bout or cluster of seizures that occurs over a short
period of time in which the patient regains consciousness in between
UNDER
seizures. Only one drug is currently available that persons other than
health care professionals (e.g., patient's caregiver) m
1982  ay give to control
ARS. This drug is called Diastat®. Diastat® is a diazepam rectal gel
ACT
and, although it is effective, it may be difficult, inconvenient, or
RELEASED
objectionable to use because of its rectal administration. Vanquix™
(diazepam autoinjector) also contains diazepam, but is administered by
an automated injectable device into
BEEN   the leg muscle. Vanquix™ may be
HEALTH
less difficult and more convenient to use by caregivers, however, its
HAS
OF
effectiveness and safety have not been studied in patients. This study
INFORMATION
will determine the effectiveness and safety of Vanquix™ compared to
OF
placebo for treating ARS.

34. Llorca, P. M., C. Spadone, et al. (2002). "Efficacy and safety of
DOCUMENT
hydroxyzine in the treatment of generalized anxiety disorder: A 3-month
FREEDOM
DEPARTMENT
double-blind study." Journal of Clinical Psychiatry 63(11): 1020-1027.
THIS

Background: The prev
THE  alence of generalized anxiety disorder (GAD)
THE
represents an important public health issue. Hydroxyzine, an
BY
antagonist of histamine receptors, showed both efficacy and safety in
previous short-term double-blind studies over placebo in this pathology.
The aim of the current study was to confirm those positive results over
a 3-month period in adult outpatients. Method: This multicenter, parallel
(hydroxyzine [50 mg/day]; bromazepam [6 mg/day]), randomized,
double-blind, placebo-controlled trial included 2 weeks of single-blind
run-in placebo, 12 weeks of double-blind randomized treatment, and 4
weeks of single-blind run-out placebo. Three hundred thirty-four of 369
selected outpatients with a diagnosis of GAD according to DSM-IV
criteria and a Hamilton Rating Scale for Anxiety (HAM-A) total score
(greater-than or equal to) 20 were randomized before entering the
double-blind period. The primary outcome criterion was the change in
the HAM-A score from baseline to 12 weeks of double-blind treatment
with hydroxyzine compared with placebo. Results: In the intent-to-treat
analysis, the mean (plus or minus) SD change in HAM-A scores from
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baseline to endpoint was -12.16 (plus or minus) 7.74 for hydroxyzine
and -9.64 (plus or minus) 7.74 for placebo (p = .019). Results at
endpoint for percentage of responders (p = .003) and remission rates
(p = .028), Clinical Global Impressions-Severity scale score (p = .001),
maintenance of efficacy (p = .022), and Hospital Anxiety and
Depression scale score on day 84 (p = .008) also confirmed the
efficacy of hydroxyzine over placebo. The study showed no statistically
significant difference between hydroxyzine and bromazepam. Except
for drowsiness, which was more frequent with bromazepam, safety
results were comparable in the 3 groups. Conclusion: Hydroxyzine
showed both efficacy and safety in the treatment of GAD and appears
to be an effective alternative treatment to benzodiazepine prescription.

35. Mahe, V. e. a. (2000). "Long-term pharmacological treatment of
generalized anxiety disorder. ." International Clinical psychopharmacology.
15(2): 99-105.

36. Martin JL., S.-P. M. F. T. M.-S. E. S. T. G. C. (2007). "Review:
UNDER
Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes
based on a systematic review and meta-analysis of clinical t
1982  rials." Journal of
Psychopharmacology 21(7): 774-82.
ACT

No systematic review or meta-analysis using a hard outcome has been
RELEASED
conducted on the role of benzodiazepines for generalized anxiety
disorder (GAD). The objective of this study was to assess the
effectiveness and efficacy of benzo
BEEN  diazepines in the treatment of GAD
HEALTH
based on trial drop-out rates. We used a systematic review of
HAS
OF
randomized controlled trials that compared any of the three best
INFORMATION
established benzodiazepines (diazepam, Lorazepam and aLprazolam)
OF
against placebo. Our primary outcome for effectiveness was withdrawal
for any reason. Our secondary outcome tapping efficacy was
withdrawal due to lack of efficacy, and that tapping side effects was
DOCUMENT
withdrawals due to adverse events.We included 23 trials. Pooled
FREEDOM
DEPARTMENT
analysis indicated less risk of treatment discontinuation due to lack of
THIS
efficacy for benzodiaze
THE  pines, compared to placebo, relative risk (RR)
THE
0.29 (95% CI 0.18-0.45; p < 0.00001). Nevertheless, pooled analysis
BY
showed no conclusive results for risk of all-cause patient
discontinuation, RR 0.78 (95% CI 0.62-1.00; p = 0.05). Meta-regression
model showed that 74% of the variation in logRR across the studies
was explained by year of publication (p <0.001).This systematic review
did not find convincing evidence of the short-term effectiveness of the
benzodiazepines in the treatment of GAD. On the other hand, for the
outcome of efficacy, this review found robust evidence in favour of
benzodiazepines. Due to the heterogeneity induced by year of
publication, three hypotheses are plausibLe when it comes to being
able to account for the differences between efficacy and effectiveness
observed in the outcomes (publication bias, quality of the trial literature
and a non-differential response to the placebo effect).

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37. Meoni, P., D. Hackett, et al. (2004). "Pooled analysis of venlafaxine XR
efficacy on somatic and psychic symptoms of anxiety in patients with
generalized anxiety disorder." Depression and Anxiety 19(2): 127-132.

We evaluated the relative efficacy of venlafaxine XR on the psychic
versus somatic symptoms of anxiety in patients with generalized
anxiety disorder as determined by the Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition. Data were pooled and
analyzed from 1,841 patients with generalized anxiety disorder who
participated in five short-term (8-week) double-blind, multicenter,
placebo-controlled studies, two of which had long-term (6-month)
extensions. Somatic and psychic anxieties were studied using the
Hamilton rating scale for anxiety (HAM-A) factor scores. We examined
response rates ((greater-than or equal to) 50% improvement over
baseline severity score) in the overall population and in patients with
mainly somatic symptomatology at baseline (somatizers). Venlafaxine
XR significantly reduced factor scores for both psychic and somatic
HAM-A factors compared with placebo, from the first and second
weeks of treatment, respectively. Patients treated with venlafaxine XR
UNDER
had significantly higher rates of response than patients receiving
placebo on the psychic (58% vs. 38%, P < .001 at w
1982  eek 8; 66% vs.
35% at week 24, P < .001) and somatic (56% vs. 43%, P < .001 at
ACT
week 8; 67% vs. 47% at week 24, P < .001) factors of the HAM-A.
RELEASED
There was a Treatment x Factor interaction (P < .027) in response
rates: Patients treated with venlafaxine showed similar somatic and
psychic anxiety response rates, wh
BEEN  ereas placebo-treated patients
HEALTH
showed higher somatic compared with psychic response rates.
HAS
OF
Somatizers showed similar rates of response to the total population for
INFORMATION
the somatic factor of the HAM-A in either treatment group. Patients with
OF
generalized anxiety disorder treated with venlafaxine XR showed
similar absolute rates of response on somatic and psychic symptoms,
but relative to patients treated with placebo, more improvement in
DOCUMENT
psychic than somatic symptoms. (copyright) 2004 Wiley-Liss, Inc.
FREEDOM
DEPARTMENT

THIS
38. Mitte K, N. P., Steil R,
THE Hautzinger M. (2005). "Ameta-analytic review of the
THE
efficacy of drug treatment in generalized anxiety disorder. ." Journal of Clinical
BY
Psychopharmacology. 25(2): 141-150.

39. Miyasaka, L. A., AN; Soares, BGO (2007). "Valerian for anxiety
disorders." Cochrane Database of Systematic Reviews 3.

nxiety disorders are very common mental health problems in the
general population and in primary care settings. Herbal medicines are
popular and used worldwide and mght be considered as a treatment
option for anxiety if shown to be effective and safe.

  Objectives
  To investigate the effectiveness and safety of valerian for treating anxiety
disorders.

  Search strategy
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Electronic searches: The Cochrane Collaboration Depression, Anxiety and
Neurosis Cochrane Controlled Trials Register (CCDANCTR-Studies
and CCDANCTR-References) searched on 04/08/2006, MEDLINE,
Lilacs. References of all identified studies were inspected for additional
studies. First authors of each included study, manufacturers of valerian
products, and experts in the field were contacted for information
regarding unpublished trials.

  Selection criteria
Randomised controlled trials (RCTs) and quasi-randomised trials of valerian
extract of any dose, regime, or method of administration, for people
with any primary diagnosis of general anxiety disorder, anxiety
neurosis, chronic anxiety status, or any other disorder in which anxiety
is the primary symptom (panic disorder, obsessive compulsive
disorder, social phobia, agoraphobia, other types of phobia,
postraumatic stress disorder). Effectiveness was measured using
clinical outcome measures and other scales for anxiety symptoms.

UNDER
  Data collection and analysis
Two review authors independently applied inclusion criteria
1982  , extracted and
entered data, and performed the trial quality assessments. Where
ACT
disagreements occured, the third review author was consulted.
RELEASED
Methodological quality of included trials was assessed using Cochrane
Handbook criteria. For dichotomous outcomes, relative risk (RR) was
calculated, and for continuous outco
BEEN  mes, the weighted mean difference
HEALTH
(WMD) was calculated, with their respective 95% confidence intervals.
HAS
OF

INFORMATION
  Main results
OF
One RCT involving 36 patients wih generalised anxiety disorder was eligible
for inclusion. This was a 4 week pilot study of valerian, diazepam and
placebo. There were no significant differences between the valerian
DOCUMENT
and placebo groups in HAM-A total scores, or in somatic and psychic
FREEDOM
DEPARTMENT
factor scores. Similarly, there were no significant differences in HAM-A
THIS
scores between the
THE  valerian and diazepam groups, although based on
THE
STAI-Trait scores, significantly greater symptom improvement was
BY
indicated in the diazepam group. There were no significant differences
between the three groups in the number of patients reporting side
effects or in dropout rates.

  Authors' conclusions
Since only one small study is currently available, there is insufficient evidence
to draw any conclusions about the efficacy or safety of valerian
compared with placebo or diazepam for anxiety disorders. RCTs
involving larger samples and comparing valerian with placebo or other
interventions used to treat of anxiety disorders, such as
antidepressants, are needed.

40. Murphy, S. M., R. Owen, et al. (1989). "Comparative assessment of
efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with
diazepam or buspirone." Br J Psychiatry 154: 529-34.
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Fifty-one out-patients presenting with generalised anxiety disorder were
included in a double-blind trial, and treated with either buspirone (a new
non-benzodiazepine antianxiety drug) or diazepam over 6 or 12 weeks,
after which they were abruptly withdrawn and continued on placebo to
14 weeks. Ratings of anxiety and other symptoms were administered
fortnightly and additional withdrawal symptoms noted. Forty patients
completed the study; 8 of the 11 drop-outs were taking buspirone. Both
drugs reduced anxiety, diazepam more rapidly, but with greater
withdrawal symptoms, particularly after 6 weeks. Regular treatment
with diazepam for 6 weeks leads to a significant risk of pharmacological
dependence that is not present with buspirone.

41. Pecknold, J., Familamiri, P, Chang, H, Wilson, R, Alarcia, J, Mc-Clure, J.
(1985). "Buspirone: Anxiolytic?. ." Progress in Neuro-psychopharmacol-ogy &
Biological Psychiatry 9: 638-642.

42. Pecknold, J. C., M. Matas, et al. (1989). "Evaluation of buspirone as an
antianxiety agent: buspirone and diazepam versus placebo." Can J Psychiatry
UNDER
34(8): 766-71.

Buspirone has previously been demonstrated to be e
1982  fficacious in the
treatment of anxiety. This four-week double-blind parallel study
ACT
compared buspirone to diazepam and placebo in the treatment of 119
RELEASED
outpatients diagnosed as having generalized anxiety disorder. After a
seven-day placebo washout period, eligible patients were randomized
to one of three treatment groups. B
BEEN  uspirone (5 mg) and diazepam (5
HEALTH
mg) were administered BID and individually titrated to an optimal
HAS
OF
therapeutic dose by the end of week two. Buspirone and diazepam
INFORMATION
were equally effective in reducing Hamilton Anxiety (HAM-A) total and
OF
psychic factor scores from baseline values. Buspirone alone was
significantly better than placebo in reducing the HAM-A somatic factor
score. Sixty-seven percent of both active treatment groups who were
DOCUMENT
classified as "ill" on the baseline global psychopathology rating scale
FREEDOM
DEPARTMENT
achieved a "not ill" status by study end. There were no significant
THIS
differences between
THE   treatment groups at endpoint on the 56-item
THE
Symptom Checklist self-rating scale. Buspirone was demonstrated to
BY
be as effective as diazepam in relieving anxiety in this outpatient
sample.

43. Pomara, N., L. M. Willoughby, et al. (2005). "Cortisol response to
diazepam: its relationship to age, dose, duration of treatment, and presence of
generalized anxiety disorder." Psychopharmacology (Berl) 178(1): 1-8.

OBJECTIVE: Acute diazepam administration has been shown to
decrease plasma cortisol levels consistent with decreased activity of
the hypothalamic-pituitary-adrenal axis, especially in individuals
experiencing stress. However, the effects of chronic diazepam
treatment on cortisol have been less studied, and the relationship to
age, anxiety, duration of treatment, and dose are not well understood.
METHOD: This double-blind placebo-controlled study examined acute
and chronic effects of diazepam on plasma cortisol levels in young (19-
35 years) and elderly (60-79 years) individuals with and without
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generalized anxiety disorder (GAD). Subjects received single oral
challenges of placebo or diazepam (2.5 mg or 10 mg) in a placebo-
controlled cross-over design, followed by 3 weeks of chronic daily
treatment with 2.5 mg or 10 mg diazepam or placebo taken at 10 p.m.,
and then by a final acute challenge with a single oral dose of the same
study medication received during chronic treatment. RESULTS: The
elderly experienced significant reductions in plasma cortisol levels
compared to placebo both in the initial challenge and during chronic
treatment, but the young did not. However, cortisol response to drug
was comparable in both groups. Final challenge did not produce any
significant cortisol effects in either group and the cortisol response in
the elderly was significantly reduced compared to the initial challenge.
GAD status was not a factor in plasma cortisol responses to diazepam.
CONCLUSIONS: Diazepam reduced cortisol both acutely and during
chronic treatment, but not during final challenge, consistent with some
tolerance development. This effect was most apparent in the elderly
compared with the young adults and was not modulated by GAD status
or dosage, and was not related to drug effects on performance and on
UNDER
self-ratings of sedation and tension.

1982
44. Pourmotabbed, T., D. R. McLeod, et al. (1996). "Treatment,
ACT
discontinuation, and psychomotor effects of diazepam in women with
RELEASED
generalized anxiety disorder." J Clin Psychopharmacol 16(3): 202-7.

Twenty-one women with generalized anxiety disorder (GAD)
participated in a 6-week, double-bli
BEEN  nd, placebo-controlled trial to
HEALTH
assess the treatment and abrupt withdrawal effects of diazepam on
HAS
OF
psychic and somatic symptoms of anxiety. The results confirmed those
INFORMATION
of previous studies reporting that (1) clinical doses of diazepam are
OF
effective in attenuating the symptoms of generalized anxiety to a
greater extent than placebo during the first 3 weeks of treatment; (2)
somatic symptoms are more responsive to diazepam treatment than
DOCUMENT
psychic symptoms; and (3) patients taking diazepam exhibit increased
FREEDOM
DEPARTMENT
anxiety upon abrupt withdrawal of medication. This finding, combined
THIS
with the fact that dia
THE  zepam discontinuation did not produce withdrawal
THE
effects in non-anxious volunteers, suggests that diazepam
BY
discontinuation after 6 weeks results in rebound anxiety rather than a
physical withdrawal syndrome. Diazepam did not improve psychomotor
performance in GAD patients. Psychomotor impairment after 6 weeks
of diazepam was similar to that seen in nonanxious volunteers.

45. Power, K. e. a. (1990). "A controlled comparison of cognitive-behaviour
therapy, diazepam, and placebo, alone and in combination, the the treatment
fo generalized anxiety disorder. ." J. anxiety disorder. 4(4): 267-292.

46. Rickels, K., N. DeMartinis, et al. (2000). "A double-blind, placebo-
controlled trial of abecarnil and diazepam in the treatment of patients with
generalized anxiety disorder." J Clin Psychopharmacol 20(1): 12-8.

In a multicenter, double-blind trial, 310 patients who had received a
diagnosis of generalized anxiety disorder were treated for 6 weeks with
either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of
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abecarnil or 22 mg of diazepam administered three times daily.
Patients who were improved at 6 weeks could volunteer to continue
double-blind treatment for a total of 24 weeks. The maintenance
treatment phase allowed the comparison of taper results for the three
treatments at several study periods (0-6 weeks, 7-12 weeks, and more
than 12 weeks). Slightly more diazepam (77%) and placebo (75%)
patients completed the 6-week study than abecarnil patients (66%). At
intake and baseline, after a 1-week placebo washout, the patient was
required to have a Hamilton Rating Scale for Anxiety score of > or =20.
Major adverse events for both abecarnil and diazepam were
drowsiness, dizziness, fatigue, and coordination difficulties. Clinical
improvement data showed that both abecarnil and diazepam produced
statistically significantly more symptom relief than did placebo after 1
week of treatment. At 6 weeks treatment (using last observation carried
forward analysis), however, only diazepam still differed significantly (p
< 0.01) from placebo. High placebo response (56% moderate to
marked global improvement) at 6 weeks, as well as a slightly lower
nonsignificant improvement rate observed with abecarnil, a partial y-
UNDER
aminobutyric acid (GABA) agonist, when compared with diazepam, a
full GABA agonist, most likely contributed to our find
1982  ings. Finally, taper
results showed that only diazepam and not abecarnil caused the
ACT
presence of temporary discontinuation symptoms, but only in patients
RELEASED
who had been treated for at least 12 weeks.

47. Rickels, K., R. Downing, et al. (1993).
BEEN  "Antidepressants for the treatment
HEALTH
of generalized anxiety disorder. A placebo-controlled comparison of
HAS
OF
imipramine, trazodone, and diazepam." Arch Gen Psychiatry 50(11): 884-95.
INFORMATION

OBJECTIVE: The current study examines whether antidepressants,
OF
contrary to current thinking, are safe and effective treatments for
generalized anxiety disorder (GAD) not complicated by depression or
panic disorder. DESIGN: Randomized, double-blind, placebo-
DOCUMENT
controlled, flexible-dose, 8-week treatment study comparing imipramine
FREEDOM
DEPARTMENT
hydrochloride (mean maximum daily dose, 143 mg), trazodone
THIS
hydrochloride (255
THE mg), and diazepam (26 mg). PATIENTS: Two
THE
hundred thirty patients with a DSM-III diagnosis of GAD in whom major
BY
depression and panic disorder has been excluded, and who had a
Hamilton Anxiety Scale total score of at least 18. SETTING: Seventy-
five percent of patients were treated in family practice settings in the
community, with the remainder treated in psychiatric practices, either
academic or private. RESULTS: Patients treated with diazepam
showed the most improvement in anxiety ratings during the first 2
weeks of treatment, with somatic symptoms being most responsive.
From week 3 through week 8 trazodone achieved comparable, and
imipramine somewhat better, anxiolytic efficacy when compared with
diazepam, with psychic symptoms of tension, apprehension, and worry
being more responsive to the antidepressants. Among completers,
moderate to marked improvement was reported by 73% of patients
treated with imipramine, 69% of patients treated with trazodone, 66% of
patients treated with diazepam, but only 47% of patients treated with
placebo. Overall, patients treated with antidepressants reported a
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higher rate of adverse effects than diazepam-treated patients, but
attention rates were the same across all treatments. CONCLUSIONS:
The results of the study need replication, but suggest a potentially
important role for antidepressants, particularly imipramine, in patients
suffering from GAD.

48. Rickels, K., E. Schweizer, et al. (1997). "Gepirone and diazepam in
generalized anxiety disorder: a placebo-controlled trial." J Clin
Psychopharmacol 17(4): 272-7.

This randomized, double-blind clinical trial involving 198 generalized
anxiety disorder (GAD) patients was conducted to more clearly define
gepirone's role for the treatment of anxiety in daily dosages of 10 to 45
mg compared with diazepam and placebo. A secondary goal was to
test for possible discontinuation symptoms after abrupt discontinuation
of therapy. After a 1-week washout period, patients were treated for 8
weeks and then abruptly shifted under single-blind conditions for 2
weeks on placebo. The highest attrition rate occurred with patients on
gepirone (58%) and the lowest on diazepam (34%). Medication intake
UNDER
for week 4 was 19.5 +/- 12.5 mg/day diazepam and 19.0 +/- 11.5
mg/day gepirone and was similar at week 8. The ma
1982  jor adverse events
were light-headedness, nausea, and insomnia for gepirone and
ACT
drowsiness and fatigue for diazepam. Clinical improvement data
RELEASED
showed gepirone's anxiolytic response to be delayed, being significant
from placebo beginning at week 6, whereas diazepam caused
significantly more relief than placeb
BEEN  o from week 1 onward. Taper
HEALTH
results showed that only diazepam, but not gepirone, caused a
HAS
OF
temporary worsening of anxiety symptoms or rebound.
INFORMATION

OF
49. Rickels, K., K. Weisman, et al. (1982). "Buspirone and diazepam in
anxiety: a controlled study." J Clin Psychiatry 43(12 Pt 2): 81-6.

The anxiolytic properties of buspirone were assessed in a 4-week
DOCUMENT
double-blind study in 240 anxious patients, 81 of whom received
FREEDOM
DEPARTMENT
buspirone, 81 diazepam, and 78 placebo. Patients were required to
THIS
have scores greater
THE  than or equal to 9 on the Covi and greater than or
THE
equal to 18 on the Hamilton Rating Scale for Anxiety, and to endorse at
BY
least 5 items on a 17-item Anxiety Entry Checklist. Among 212
evaluable patients, those who improved most were married, well-
educated females who had both a positive family adjustment and a low
level of depression. Diazepam produced relatively equal improvement
in females and males. Diazepam seems more effective in reducing
somatic symptoms, while buspirone appears more effective in reducing
symptoms associated with cognitive and interpersonal problems. Main
differences between the drugs were seen in side effect profiles.

50. Rocca, P., V. Fonzo, et al. (1997). "Paroxetine efficacy in the treatment of
generalized anxiety disorder." Acta Psychiatr Scand 95(5): 444-50.

Recently, there has been a renewed interest in alternatives to the
benzodiazepines for the treatment of generalized anxiety disorder
(GAD). The aim of the present study was to compare the efficacy of
paroxetine vs. imipramine and 2'-chlordesmethyldiazepam in 81
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patients with a DSM-IV diagnosis of GAD. Approximately two-thirds of
the patients who completed the study improved greatly or moderately
on all three active drugs. During the first 2 weeks of treatment, 2'-
chlordesmethyldiazepam treatment resulted in the greatest
improvement in anxiety ratings. Both paroxetine and imipramine
treatment resulted in more improvement than 2'-
chlordesmethyldiazepam by the fourth week of treatment. Paroxetine
and imipramine affect predominantly psychic symptoms, whereas 2'-
chlordesmethyldiazepam affects predominantly somatic symptoms. Our
results suggest that paroxetine is effective for the treatment of GAD.

51. Ross, C., Matas, M. (1987). "A Clinical Trial of Buspirone and Diazepam in
the Treatment of Generalized Anxiety Disorder. ." Canandian Journal of
Psychiatry 32: 351-355.

52. Rynn, M., S. Khalid-Khan, et al. (2006). "Early response and 8-week
treatment outcome in GAD." Depression and Anxiety 23(8): 461-465.

Our objective was to compare the predictive value of early response to
UNDER
treatment outcome in patients with generalized anxiety disorder (GAD)
treated with benzodiazepines, serotonin receptor (5HT
1982  -1A) partial
agonists, or placebo. Data from two double-blind GAD studies were
ACT
combined. Subjects were evaluated with the Hamilton Anxiety Scale
RELEASED
(HAM-A) and the Clinical Global Impression of Improvement (CGI-I)
scale over 8 weeks. Categories of response at weeks 1 and 2 were
defined by the HAM-A total score. A
BEEN  nalyses of covariance and Kaplan-
HEALTH
Meier survival analyses were the primary analyses used to assess 8-
HAS
OF
week end point treatment outcomes as a function of early
INFORMATION
improvement. HAM-A change from baseline to weeks 1 and 2
OF
significantly predicted last observation carried forward (LOCF)
response at week 8 for both medications and for placebo (P<.001).
Early improvement was a strong predictor for treatment outcome
DOCUMENT
irrespective of whether active medication or placebo was the treatment
FREEDOM
DEPARTMENT
agent. THIS

THE  THE
53. Schwartz, T. L. and N. Nihalani (2006). "Tiagabine in anxiety disorders."
BY
Expert Opinion on Pharmacotherapy 7(14): 1977-1987.

GABA has been implicated in both the aetiology and treatment of
anxiety. Tiagabine is currently the only selective GABA reuptake
inhibitor available in US markets; it exerts its action via GAT-1
transporter blockade presynaptically, facilitating GABA
neurotransmission. Preclinical studies and current human studies
suggest tiagabine possesses anxiolytic properties. The anxiolytic
properties of tiagabine have also been suggested in a number of case
series, open-label studies and placebo-controlled studies in patients
with different anxiety disorders. Throughout these studies, tiagabine
has been reasonably tolerated; the most commonly reported adverse
events include dizziness, headache and nausea. Tiagabine may be a
useful addition to currently available drugs for anxiety; however, the
data from small open-label investigations remain to be confirmed in
larger controlled studies. (copyright) 2006 Informa UK Ltd.
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54. Shah, L. P., et al., (1990). "A controlled double blind clinical trial of
buspirone and diazepam in generalised anxiety disorder. ." Indian Journal of
Psychiatry. 32(2): 166-169.

55. Strand, M., J. Hetta, et al. (1990). "A double-blind, controlled trial in
primary care patients with generalized anxiety: a comparison between
buspirone and oxazepam." J Clin Psychiatry 51 Suppl: 40-5.

Two hundred thirty patients with generalized anxiety and Hamilton
Rating Scale for Anxiety (HAM-A) scores greater than or equal to 18
were subdivided at random, according to a double-blind design, into
one group treated with 5-10 mg of oral buspirone t.i.d. or one group
treated with 10-20 mg of oral oxazepam t.i.d. for 6 weeks. No anxiolytic
treatment was allowed 3 months prior to trial entry. Analysis of
demographic variables revealed no significant imbalance between the
two treatment groups. Twenty patients were excluded from efficacy
analysis because of treatment withdrawal before the first efficacy
evaluation on Day 7. Another 4 patients were excluded because they
UNDER
were taking concomitant psychotropic medication. The remaining 206
patients displayed a decrease in HAM-A scores (me
1982  an +/- SD) from
23.9 +/- 4.1 to 10.6 +/- 7.7 in the buspirone group and from 23.9 +/- 4.2
ACT
to 11.5 +/- 8.0 in the oxazepam group. The two treatment groups were
RELEASED
also found to be virtually identical in an "intent to treat" analysis of all
230 patients as well as in other ratings (Hamilton Rating Scale for
Depression, Raskin Depression Sca
BEEN  le, Covi Anxiety Scale, Physicians
HEALTH
Questionnaire, global ratings, and Hopkins Symptom Checklist [HSCL]-
HAS
OF
56). However, oxazepam was never superior to buspirone in any of the
INFORMATION
efficacy analyses. Of the 230 patients, 127 spontaneously reported
OF
adverse events, including drowsiness, dizziness, headache, nausea,
and nervousness. Adverse events were relatively similar in the two
groups. In conclusion, buspirone and oxazepam appear to be equally
DOCUMENT
effective in the treatment of generalized anxiety encountered by
FREEDOM
DEPARTMENT
general practitioners. This outcome, in addition to a previously
THIS
documented absenc
THE  e of any dependency liability, makes buspirone a
THE
clinically important anxiolytic drug.
BY

56. Tyrer, P. and R. Owen (1984). "Anxiety in primary care: is short-term drug
treatment appropriate?" J Psychiatr Res 18(1): 73-8.

Thirty-six patients with generalised anxiety disorder, panic disorder or
agoraphobia with panic attacks, diagnosed by DSM-III criteria, were
treated with a new non-benzodiazepine anti-anxiety drug, buspirone,
and with diazepam and placebo, in a cross-over design. Each patient
took buspirone, diazepam and placebo for one week each in flexible
dosage and balanced order. Ratings of symptomatology using the
Comprehensive Psychopathological Rating Scale were made after
each week's treatment and a sub-scale used for measuring anxiety
change alone was used separately. There was no overall difference in
efficacy between the drugs, but when the scores for individual
symptoms were analysed, diazepam was significantly superior to the
other treatments for the symptom of muscle tension only. The results
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suggest that the common practice of giving short-term therapy with
tranquilising drugs for anxiety in primary care is pharmacologically
suspect.

57. Tyrer, P., N. Seivewright, et al. (1993). "The Nottingham study of neurotic
disorder. Effect of personality status on response to drug treatment, cognitive
therapy and self-help over two years." Br J Psychiatry 162: 219-26.

Repeated assessments of psychopathology, together with personality
status, were made over two years on 181 psychiatric out-patients with
generalised anxiety disorder (59), panic disorder (66), or dysthymic
disorder (56) diagnosed using an interview schedule for DSM-III.
Patients were randomly allocated to drug treatment, cognitive and
behaviour therapy, or a self-help treatment programme. Although there
were no overall differences in compliance rate and efficacy between
the three modes of treatment, the psychological treatment methods,
particularly self-help, were more effective in patients without personality
disorder, and those with personality disorder responded better to drug
treatment, primarily antidepressants. The findings suggest that
UNDER
assessment of personality status could be a valuable aid to selection of
treatment in neurotic disorders and that self-help ap
1982 proaches are
particularly valuable once personality disorder has been excluded.
ACT

RELEASED
Tyrer, P., N. Seivewright, et al. (1988). "The Nottingham study of neurotic
disorder: 58. comparison of drug and psychological treatments." Lancet
2(8605): 235-40.
BEEN  HEALTH

210 psychiatric outpatients with generalised anxiety disorder (71), or
HAS
OF
panic disorder (74), or dysthymic disorder (65) diagnosed by an
INFORMATION
interview schedule for DSM-III were allocated by constrained
OF
randomisation to one of five treatments: diazepam (28), dothiepin (28),
placebo (28), cognitive and behaviour therapy (84), and a self-help
treatment programme (42). All treatments were given for 6 weeks and
DOCUMENT
then withdrawn by 10 weeks. Ratings of psychopathology were made
FREEDOM
DEPARTMENT
by psychiatric assessors blind to both treatment and diagnosis before
THIS
treatment and at 2,
THE 4, 6, and 10 weeks after randomisation. 18 patients
THE
had insufficient data for analysis because of early drop-out. There were
BY
no important differences in treatment response between the diagnostic
groups, but diazepam was less effective than dothiepin, cognitive and
behaviour therapy, or self-help, these three treatments being of similar
efficacy. Significantly more patients in the placebo group took
additional psychotropic drugs in the 10 week period, and those
allocated to dothiepin and cognitive and behaviour therapy took the
least.

59. University of Utah, P. C. s. M. C. F. (2006). Intranasal Midazolam Versus
Rectal Diazepam for Treatment of Seizures.

Purpose

We will conduct a randomized controlled trial comparing the use of nasal
midazolam, using a Mucosal Atomization Devise, to rectal diazepam for
the treatment of acute seizure activity in children under the age of 18
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years with epilepsy in the community setting. Our primary hypothesis is
that nasal midazolam will be more effective and have shorter seizure
time compared to rectal diazepam in the community. Our secondary
hypotheses are that patients treated with nasal midazolam will have
less respiratory complications, Emergency Department visits and
admissions.

Total Enrollment:  200
Study start: June 2006;  Expected completion: June 2007

Study Design: This is a prospective randomized controlled study.

60. Wingerson, D. K., D. S. Cowley, et al. (1996). "Effect of benzodiazepines
on plasma levels of homovanillic acid in anxious patients and control
subjects." Psychiatry Res 65(1): 53-9.

The effects of four logarithmically increasing doses of intravenous
diazepam or placebo on plasma homovanillic acid (HVA) were
UNDER
determined in benzodiazepine-naive patients with panic disorder (PD)
or generalized anxiety disorder (GAD), and in health
1982  y controls. Plasma
HVA was measured at baseline and 3 min after the first and fourth
ACT
doses of diazepam/placebo. Mean baseline plasma HVA levels were
RELEASED
significantly lower in PD patients compared with GAD patients and
controls. Although plasma HVA levels decreased significantly with time
in all groups, there was no diazepa
BEEN m effect. This study suggests that
HEALTH
low dopaminergic activity may occur in a subset of anxious patients
HAS
OF
(PD), and that diazepam does not significantly affect dopaminergic
INFORMATION
activity as measured by plasma HVA in humans.
OF

DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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Appendix 6: Full list of articles from
Various Databases for Benzodiazepines
DSM-IV

1  EMBASE and MEDLINE
Andreatini, R., V. A. Sartori, et al. (2002). "Effect of valepotriates (valerian
extract) in generalized anxiety disorder: A randomized placebo-controlled pilot
study." Phytotherapy Research 16(7): 650-654.
UNDER

The aim of the present study was to carry out a controlled pilot study on
1982
the putative anxiolytic effect of valepotriates. Thirty-six outpatients with
generalized anxiety disorder (DSM III-R), after a 2-week wash-out,
ACT
were randomized to one of the following three treatments for 4 weeks
RELEASED
(n = 12 per group): valepotriates (mean daily dose: 81.3 mg), diazepam
(mean daily dose: 6.5 mg), or placebo. A parallel, double-blind, flexible-
dose, placebo-controlled design wa
BEEN  s employed. No significant
HEALTH
difference was observed among the three groups at baseline or in the
HAS
OF
change from baseline on the Hamilton anxiet
INFORMATION  y scale (HAM-A) or in the
trait part of the state-trait anxiety inventory (STAI-trait). Moreover, the
OF
three groups presented a significant reduction in the total HAM-A
scores. On the other hand, only the diazepam and valepotriates groups
showed a significant reduction in the psychic factor of HAM-A. The
DOCUMENT
diazepam group also presented a sig
DEPARTMENT  nificant reduction of the STAI-trait.
FREEDOM
Although the principal analysis (HAM-A between group comparison)
THIS  THE
found negative
THE   results (probably due to the small sample size in each
group), the preli
BY  minary data obtained in the present study suggest that
the valepotriates may have a potential anxiolytic effect on the psychic
symptoms of anxiety. However, since the number of subjects per group
was very small, the present results must be viewed as preliminary.
Thus, further studies addressing this issue are warranted. Copyright
(copyright) 2002 John Wiley & Sons, Ltd.

Basile, A. S., A. S. Lippa, et al. (2006). "GABAA receptor modulators as
anxioselective anxiolytics." Drug Discovery Today: Therapeutic Strategies
3(4): 475-481.

Benzodiazepines are effective anxiolytics whose use is limited by
sedation, amnesia and myorelaxation, driving the search for novel,
anxioselective GABAA receptor modulators. Preclinical data from
'knock-in' mice and (alpha)2,3-subunit selective GABAA receptor
agonists suggest that these targets may yield anxioselective agents. In
contrast, additional preclinical and clinical evidence suggests that a
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combination of mechanisms, including partial agonism and receptor
subtype selectivity, will be required to achieve anxioselectivity in the
clinic. (copyright) 2006 Elsevier Ltd. All rights reserved.

Brawman-Mintzer, O., R. G. Knapp, et al. (2005). "Adjunctive risperidone in
generalized anxiety disorder: A double-blind, placebo-controlled study."
Journal of Clinical Psychiatry 66(10): 1321-1325.

Objective: Although significant advances have been made in recent
years in the treatment of generalized anxiety disorder (GAD), many
patients remain symptomatic despite ongoing treatment, underscoring
the need for adjunctive new treatments to help improve response.
Method: Forty patients with a primary diagnosis of DSM-IV GAD, who
continued to experience GAD symptoms despite current anxiolytic
treatment of at least 4 weeks' duration, as evidenced by Hamilton
Rating Scale for Anxiety (HAM-A) total score (greater-than or equal to)
18 and Clinical Global Impressions-Severity of Illness scale score of
moderate or greater, completed a 1-week screening phase and were
then randomly assigned to 5 weeks of double-blind adjunctive
UNDER
treatment with placebo or risperidone at flexible doses of 0.5 to 1.5
mg/day. Patients continued to take their anxiolytics th
1982  roughout the
study. The study was conducted from June 2001 through March 2003.
ACT
Results: Adjunctive risperidone was associated with statistically
RELEASED
significant improvements in core anxiety symptoms, as demonstrated
by greater reductions in HAM-A total scores (p = .034) and HAM-A
psychic anxiety factor scores (p = .0
BEEN  47) compared with placebo.
HEALTH
Although change scores on other outcome variables, including
HAS
OF
response rates, were higher in the risperidone group, differences did
INFORMATION
not achieve statistical significance. Conclusion: Study findings suggest
OF
that risperidone at low doses may represent a useful tool in the
management of symptomatic GAD patients.

DOCUMENT
Ebadi, M. and Y. Hama (1988). "Dopamine, GABA, cholecystokinin and
FREEDOM
DEPARTMENT
opioids in neuroleptic-induced tardive dyskinesia." Neuroscience and
THIS
Biobehavioral Reviews 12(3
THE  -4): 179-187.
THE

BY
Gao, K., D. Muzina, et al. (2006). "Efficacy of typical and atypical
antipsychotics for primary and comorbid anxiety symptoms or disorders: A
review." Journal of Clinical Psychiatry 67(9): 1327-1340.

Objective: The efficacy of antipsychotics in the treatment of primary or
comorbid anxiety disorders or anxiety symptoms in major depressive
disorder or bipolar disorder was reviewed. Data Sources: English-
language literature cited in MEDLINE from January 1, 1968, to
December 31, 2005, was searched with the keywords anxiety disorder,
anxiety symptoms, generalized anxiety disorder, panic disorder,
obsessive-compulsive disorder, posttraumatic stress disorder, social
phobia, bipolar disorder, major depressive disorder, Hamilton Rating
Scale for Anxiety, antipsychotics, typical antipsychotics, atypical
antipsychotics, fluphenazine, haloperidol, perphenazine, pimozide,
thiothixene, trifluoperazine, loxapine, molindone, chlorpromazine,
mesoridazine, thioridazine, fluspirilene, penfluridol, pipothiazine,
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flupenthixol, clozapine, olanzapine, risperidone, quetiapine,
ziprasidone, aripiprazole, amisulpride, and clinical trial. Randomized,
double-blind, placebo-controlled trials and open-label studies with a
minimum of 20 subjects with a DSM-III/IV or ICD-10 diagnosis of
anxiety disorder and studies without a DSM-III/IV or ICD-10 diagnosis
of anxiety disorder but with Hamilton Rating Scale for Anxiety (HAM-A)
scores as an outcome were prioritized. Studies on bipolar disorder or
major depressive disorder with the analysis of changes in anxiety
symptoms were reviewed. Early studies on neurosis/anxiety or anxious
depression without a HAM-A component were also reviewed. Data
Synthesis: Six trials in primary generalized anxiety disorder (GAD), 15
in refractory obsessive-compulsive disorder (OCD), 8 in posttraumatic
stress disorder (PTSD), 6 in neurosis with the HAM-A, 1 in social
phobia, and 2 in anxiety symptoms in bipolar depression were
identified. Low doses of trifluoperazine were superior to placebo in the
treatment of GAD. Most of the less well-designed studies showed that
other typical antipsychotics might be superior to placebo or as effective
as benzodiazepines in the treatment of GAD and other anxiety
UNDER
conditions. In most studies, risperidone, olanzapine, and quetiapine
augmentation to antidepressants was superior to plac
1982  ebo in treating
refractory OCD and PTSD. Both olanzapine and quetiapine significantly
ACT
reduced anxiety compared to placebo in studies of bipolar depression.
RELEASED
Conclusion: Except for trifluoperazine, there is no large, well-designed
study of antipsychotics in the treatment of primary or comorbid anxiety
symptoms or disorders. The efficacy
BEEN  of these agents in various anxiety
HEALTH
conditions needs to be further investigated with large, well-designed
HAS
OF
comparison studies.
INFORMATION

OF
Hackett, D., V. Haudiquet, et al. (2003). "A method for controlling for a high
placebo response rate in a comparison of venlafaxine XR and diazepam in the
short-term treatment of patients with generalised anxiety disorder." European
DOCUMENT
Psychiatry 18(4): 182-187.
FREEDOM
DEPARTMENT

This randomised, double-blind, placebo-controlled study compared the
THIS
efficacy of venlafaxi
THE  ne XR (75 or 150 mg/d) with diazepam (15 mg/d)
THE
over an 8-week treatment period in 540 non-depressed outpatients with
BY
generalised anxiety disorder (GAD). At week 8, significant
improvements from baseline were observed in the venlafaxine XR,
diazepam and placebo groups. Although these improvements were
higher in the first two groups than in the placebo group for each of the
primary efficacy variables (Hamilton Rating Scale for Anxiety (HAM-A)
total, HAM-A psychic anxiety factor, Hospital Anxiety and Depression
Scale (HAD) anxiety sub-scale and Clinical Global Impression (CGI)
improvement), there were no statistically significant differences
between groups. These non-positive results were thought to be due to
the very high placebo response observed in some centres. To
understand the variability of the study, a secondary preplanned
analysis was performed. This involved sub-dividing the study centres
according to their ability to detect a two-point mean difference between
diazepam and placebo at week 8 on the HAM-A total score. Centres
able to show such a difference were termed verum-sensitive.
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Improvements from baseline to week 8 in venlafaxine XR-treated
patients from verum-sensitive centres were significantly greater than in
placebo on each of the primary efficacy measures (P (less-than or
equal to) 0.05). This suggests that those centres able to detect an
anxiolytic effect of diazepam were also able to detect an anxiolytic
effect of venlafaxine XR. Significant differences in baseline
demographics, rates of adverse event reporting and rates of patient
discontinuations were noted between patients enrolled at verum-
sensitive and verum-insensitive sites. These results reflect the
importance of study centre selection in accurately determining efficacy
in placebo-controlled trials. (copyright) 2003 Editions scientifiques et
medicales Elsevier SAS. All rights reserved.

Llorca, P. M., C. Spadone, et al. (2002). "Efficacy and safety of hydroxyzine in
the treatment of generalized anxiety disorder: A 3-month double-blind study."
Journal of Clinical Psychiatry 63(11): 1020-1027.

Background: The prevalence of generalized anxiety disorder (GAD)
represents an important public health issue. Hydroxyzine, an
UNDER
antagonist of histamine receptors, showed both efficacy and safety in
previous short-term double-blind studies over placeb
1982  o in this pathology.
The aim of the current study was to confirm those positive results over
ACT
a 3-month period in adult outpatients. Method: This multicenter, parallel
RELEASED
(hydroxyzine [50 mg/day]; bromazepam [6 mg/day]), randomized,
double-blind, placebo-controlled trial included 2 weeks of single-blind
run-in placebo, 12 weeks of double
BEEN  -blind randomized treatment, and 4
HEALTH
weeks of single-blind run-out placebo. Three hundred thirty-four of 369
HAS
OF
selected outpatients with a diagnosis of GAD according to DSM-IV
INFORMATION
criteria and a Hamilton Rating Scale for Anxiety (HAM-A) total score
OF
(greater-than or equal to) 20 were randomized before entering the
double-blind period. The primary outcome criterion was the change in
the HAM-A score from baseline to 12 weeks of double-blind treatment
DOCUMENT
with hydroxyzine compared with placebo. Results: In the intent-to-treat
FREEDOM
DEPARTMENT
analysis, the mean (plus or minus) SD change in HAM-A scores from
THIS
baseline to endpoin
THE t was -12.16 (plus or minus) 7.74 for hydroxyzine
THE
and -9.64 (plus or minus) 7.74 for placebo (p = .019). Results at
BY
endpoint for percentage of responders (p = .003) and remission rates
(p = .028), Clinical Global Impressions-Severity scale score (p = .001),
maintenance of efficacy (p = .022), and Hospital Anxiety and
Depression scale score on day 84 (p = .008) also confirmed the
efficacy of hydroxyzine over placebo. The study showed no statistically
significant difference between hydroxyzine and bromazepam. Except
for drowsiness, which was more frequent with bromazepam, safety
results were comparable in the 3 groups. Conclusion: Hydroxyzine
showed both efficacy and safety in the treatment of GAD and appears
to be an effective alternative treatment to benzodiazepine prescription.

Meoni, P., D. Hackett, et al. (2004). "Pooled analysis of venlafaxine XR
efficacy on somatic and psychic symptoms of anxiety in patients with
generalized anxiety disorder." Depression and Anxiety 19(2): 127-132.
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We evaluated the relative efficacy of venlafaxine XR on the psychic
versus somatic symptoms of anxiety in patients with generalized
anxiety disorder as determined by the Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition. Data were pooled and
analyzed from 1,841 patients with generalized anxiety disorder who
participated in five short-term (8-week) double-blind, multicenter,
placebo-controlled studies, two of which had long-term (6-month)
extensions. Somatic and psychic anxieties were studied using the
Hamilton rating scale for anxiety (HAM-A) factor scores. We examined
response rates ((greater-than or equal to) 50% improvement over
baseline severity score) in the overall population and in patients with
mainly somatic symptomatology at baseline (somatizers). Venlafaxine
XR significantly reduced factor scores for both psychic and somatic
HAM-A factors compared with placebo, from the first and second
weeks of treatment, respectively. Patients treated with venlafaxine XR
had significantly higher rates of response than patients receiving
placebo on the psychic (58% vs. 38%, P < .001 at week 8; 66% vs.
35% at week 24, P < .001) and somatic (56% vs. 43%, P < .001 at
UNDER
week 8; 67% vs. 47% at week 24, P < .001) factors of the HAM-A.
There was a Treatment x Factor interaction (P < .02
1982 7) in response
rates: Patients treated with venlafaxine showed similar somatic and
ACT
psychic anxiety response rates, whereas placebo-treated patients
RELEASED
showed higher somatic compared with psychic response rates.
Somatizers showed similar rates of response to the total population for
the somatic factor of the HAM-A in e
BEEN  ither treatment group. Patients with
HEALTH
generalized anxiety disorder treated with venlafaxine XR showed
HAS
OF
similar absolute rates of response on somatic and psychic symptoms,
INFORMATION
but relative to patients treated with placebo, more improvement in
OF
psychic than somatic symptoms. (copyright) 2004 Wiley-Liss, Inc.

Rynn, M., S. Khalid-Khan, et al. (2006). "Early response and 8-week
DOCUMENT
treatment outcome in GAD." Depression and Anxiety 23(8): 461-465.
FREEDOM
DEPARTMENT

Our objective was to compare the predictive value of early response to
THIS
treatment outcome i
THE  n patients with generalized anxiety disorder (GAD)
THE
treated with benzodiazepines, serotonin receptor (5HT-1A) partial
BY
agonists, or placebo. Data from two double-blind GAD studies were
combined. Subjects were evaluated with the Hamilton Anxiety Scale
(HAM-A) and the Clinical Global Impression of Improvement (CGI-I)
scale over 8 weeks. Categories of response at weeks 1 and 2 were
defined by the HAM-A total score. Analyses of covariance and Kaplan-
Meier survival analyses were the primary analyses used to assess 8-
week end point treatment outcomes as a function of early
improvement. HAM-A change from baseline to weeks 1 and 2
significantly predicted last observation carried forward (LOCF)
response at week 8 for both medications and for placebo (P<.001).
Early improvement was a strong predictor for treatment outcome
irrespective of whether active medication or placebo was the treatment
agent.

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Schwartz, T. L. and N. Nihalani (2006). "Tiagabine in anxiety disorders."
Expert Opinion on Pharmacotherapy 7(14): 1977-1987.

GABA has been implicated in both the aetiology and treatment of
anxiety. Tiagabine is currently the only selective GABA reuptake
inhibitor available in US markets; it exerts its action via GAT-1
transporter blockade presynaptically, facilitating GABA
neurotransmission. Preclinical studies and current human studies
suggest tiagabine possesses anxiolytic properties. The anxiolytic
properties of tiagabine have also been suggested in a number of case
series, open-label studies and placebo-controlled studies in patients
with different anxiety disorders. Throughout these studies, tiagabine
has been reasonably tolerated; the most commonly reported adverse
events include dizziness, headache and nausea. Tiagabine may be a
useful addition to currently available drugs for anxiety; however, the
data from small open-label investigations remain to be confirmed in
larger controlled studies. (copyright) 2006 Informa UK Ltd.

UNDER

1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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2  PubMed
Andreatini, R., V. A. Sartori, et al. (2002). "Effect of valepotriates (valerian
extract) in generalized anxiety disorder: a randomized placebo-controlled pilot
study." Phytother Res 16(7): 650-4.

The aim of the present study was to carry out a controlled pilot study on
the putative anxiolytic effect of valepotriates. Thirty-six outpatients with
generalized anxiety disorder (DSM III-R), after a 2-week wash-out,
were randomized to one of the following three treatments for 4 weeks
(n = 12 per group): valepotriates (mean daily dose: 81.3 mg), diazepam
(mean daily dose: 6.5 mg), or placebo. A parallel, double-blind, flexible-
dose, placebo-controlled design was employed. No significant
difference was observed among the three groups at baseline or in the
change from baseline on the Hamilton anxiety scale (HAM-A) or in the
trait part of the state-trait anxiety inventory (STAI-trait). Moreover, the
three groups presented a significant reduction in the total HAM-A
UNDER
scores. On the other hand, only the diazepam and valepotriates groups
showed a significant reduction in the psychic factor o
1982  f HAM-A. The
diazepam group also presented a significant reduction of the STAI-trait.
ACT
Although the principal analysis (HAM-A between group comparison)
RELEASED
found negative results (probably due to the small sample size in each
group), the preliminary data obtained in the present study suggest that
the valepotriates may have a poten
BEEN  tial anxiolytic effect on the psychic
HEALTH
symptoms of anxiety. However, since the number of subjects per group
HAS
OF
was very small, the present results must b
INFORMATION e viewed as preliminary.
Thus, further studies addressing this issue are warranted.
OF

Ansseau, M., J. P. Olie, et al. (1991). "Controlled comparison of the efficacy
and safety of four doses of suriclone, diazepam, and placebo in generalized
DOCUMENT
anxiety disorder." Psychopharmacology (Be
DEPARTMENT  rl) 104(4): 439-43.
FREEDOM

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2,
THIS
0.3 and 0.4 mg tid),
THE  diazepam (5 mg tid), and placebo were compared
THE
in six parallel g
BY roups of 54-59 outpatients with generalized anxiety
disorder (DSM III-R). After a 1-week placebo run-in period, the patients
were treated for 4 weeks, with assessments at baseline and after 1, 2,
and 4 weeks by the Hamilton anxiety scale and the Clinical Global
Impressions. Results showed better improvement with active drugs as
compared to placebo, without significant differences among the four
different doses of suriclone and diazepam. The number of adverse
events, particularly drowsiness, was significantly higher with diazepam
than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ
from placebo. These results demonstrate that suriclone at daily doses
ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated
than diazepam.

Ban, T. A. and M. M. Amin (1979). "Clobazam: uncontrolled and standard
controlled clinical trials." Br J Clin Pharmacol 7 Suppl 1: 135S-138S.
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1 In an uncontrolled clinical trial, carried out in 11 psychiatric patients
with the clinical diagnoses of anxiety neurosis and depressive neurosis,
clobazam, a new benzodiazepine preparation, in the dosage range 10-
60 mg daily produced statistically significant improvement in the total
and both factor scores of the Hamilton Anxiety Scale (HAM-A). The
lowest mean total HAM-A scores occurred with a mean clobazam
dosage of 48 mg daily. 2 Results of the uncontrolled clinical trial were
further substantiated in a standard-controlled clinical study in which no
statistically significant difference between the therapeutic effectiveness
of clobazam and diazepam could be revealed. The lowest mean total
HAM-A scores occurred with a mean clobazam dosage of 49 mg daily.
There was a lower incidence of adverse effects reported in patients
receiving clobazam than in those taking the control drug (diazepam).

Bobon, D. P., J. Fanielle, et al. (1978). "Time-blind videotaped evaluation of
injectable diazepam, lorazepam and placebo." Acta Psychiatr Belg 78(4): 619-
34.

Eighteen inpatients suffering from a severe anxiety received in double-
UNDER
blind and crossover conditions iv and im injections of 10 mg diazepam,
5 mg lorazepam or saline t.i.d. during 5 days. The m
1982  orning injections
was made iv in a CCTV studio. Before injection and 20 mn after it, the
ACT
patient filled out a 100 mm Visual Analogue Scale; his doctor-in-charge
RELEASED
proceeded to a standard interview and to physiological measurements
(tremor of hand, patellar reflexes, blood pressure, pulse rate). The
videotaped interviews were random
BEEN  ly, i.e. time-blind, rated by two
HEALTH
independent observers on 3 scales: the VAS, the Hamilton Anxiety
HAS
OF
Scale and an ad hoc Verbal and Non-Verbal Anxiety Scale (VNVA).
INFORMATION
The statistical analysis was completed by a logical analysis according
OF
to Lewis Carroll. The results demonstrate the superiority of lorazepam
over diazepam on psychic anxiety, somatic anxiety, sleep and blood
pressure, the only significant side-effect being drowsiness.
DOCUMENT

FREEDOM
DEPARTMENT
Cooper, S. J., C. B. Kelly, et al. (1990). "Beta 2-adrenoceptor antagonism in
THIS
anxiety." Eur Neuropsycho
THE  pharmacol 1(1): 75-7.
THE

The relative role of beta 1- and beta 2-adrenoceptor antagonism in the
BY
management of anxiety symptoms is not clear. We studied the effect of
ICI 118,551, a selective beta 2-antagonist, in 51 patients presenting
with acute anxiety symptoms and fulfilling DSM-III criteria for anxiety
disorder. All patients received placebo during the first week of
treatment followed by thrice daily diazepam (2 mg) or ICI 118,551 (50
mg) or placebo for 4 weeks with double-blind, random allocation.
Hamilton anxiety scale scores improved on all treatments but there was
no significant difference between treatments. Beta 2-adrenoceptor
antagonism does not appear to be effective in acute anxiety neurosis.
Some earlier literature suggests that beta 1-antagonism may be more
important.

Cutler, N. R., J. M. Hesselink, et al. (1994). "A phase II multicenter dose-
finding, efficacy and safety trial of ipsapirone in outpatients with generalized
anxiety disorder." Prog Neuropsychopharmacol Biol Psychiatry 18(3): 447-63.
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Benzodiazepines have been prescribed for the treatment of
Generalized Anxiety Disorder (GAD) for nearly three decades due to
their proven anxiolytic efficacy, despite a considerable side effect and
abuse liability profile. A new class of compounds, the azapirones, have
been developed as an alternative to benzodiazepine treatment.
Ipsapirone is a novel anxiolytic azapirone which has high specificity for
the 5-HT1A receptor and which has the potential for offering certain
advantages over buspirone. The present 5-week study investigated
three doses of ipsapirone (2.5mg, 5.0mg and 7.5mg tid) versus placebo
in 267 GAD outpatients. Efficacy was evaluated using the Hamilton
Anxiety Rating Scale (HAM-A), Zung Anxiety Scale (Zung-A), and
Clinical Global Impression (CGI). The study design consisted of a 1-
week placebo run-in, a 4-week double-blind treatment period, and a 1-
week placebo washout. The 5.0mg group demonstrated consistently
superior improvement in all efficacy variables during the treatment
period, with significant differences (p < 0.05) from placebo and, at
times, the 2.5mg and 7.5mg groups. Incidence of adverse events,
primarily dizziness, nausea, sedation, and asthenia, was found to be
UNDER
dose proportional, with significant increase in the 7.5mg group, which
may account for the diminished effectiveness seen with
1982   this dose. Our
results suggest that ipsapirone may represent a viable treatment for
ACT
GAD.
RELEASED

Downing, R. W. and K. Rickels (1985). "Early treatment response in anxious
outpatients treated with diazepam." Acta P
BEEN  sychiatr Scand 72(6): 522-8.
HEALTH

Two hundred and two moderately chronic psychiatric outpatients, all
HAS
OF
suffering from anxiety of at least moderate severity and all diagnosable
INFORMATION
as cases of Generalized Anxiety Disorder, participated in a single-blind
OF
6-week trial of diazepam (15-40 mg/day). The trial was preceded by a 1
week placebo washout, and provided for evaluation visits after 1, 2, 4
and 6 weeks of diazepam treatment. Patients were divided into High,
DOCUMENT
Medium and Low Initial Improvers using 1 week change in Hamilton
FREEDOM
DEPARTMENT
Anxiety Scale total score to assign patients to three subgroups of equal
THIS
size. These groups
THE  did not differ significantly on those demographic
THE
factors and attributes of illness history which were documented, nor on
BY
assessments of symptom and illness severity, and mode of intake.
Examination of a number of patient and physician assessments of
illness severity revealed that the High group had the greatest 6-week
improvement, the Low group the least. During the first week, the High
group attained 86%, the Medium group, 65%, and the Low group, 29%
of its full 6-week drug response. Diazepam dose levels were lowest for
the High group and highest for the Low group. Placebo response was
least for the High group and greatest for the Low group. An attempt to
find distinctive attributes of the three initial improvement groups was
unsuccessful.

Falissard, B. (2003). "Statistical considerations about the question of a
selection of discriminating centres in the analysis of clinical trial. In response
to the paper: "A method for controlling for a high response rate in a
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comparison of venlafaxine XR and diazepan in the short-term treatment of
patients with generalised anxiety disorder"." Eur Psychiatry 18(4): 188-9.

Hackett, D., V. Haudiquet, et al. (2003). "A method for controlling for a high
placebo response rate in a comparison of venlafaxine XR and diazepam in the
short-term treatment of patients with generalised anxiety disorder." Eur
Psychiatry 18(4): 182-7.

This randomised, double-blind, placebo-controlled study compared the
efficacy of venlafaxine XR (75 or 150 mg/d) with diazepam (15 mg/d)
over an 8-week treatment period in 540 non-depressed outpatients with
generalised anxiety disorder (GAD). At week 8, significant
improvements from baseline were observed in the venlafaxine XR,
diazepam and placebo groups. Although these improvements were
higher in the first two groups than in the placebo group for each of the
primary efficacy variables (Hamilton Rating Scale for Anxiety (HAM-A)
total, HAM-A psychic anxiety factor, Hospital Anxiety and Depression
Scale (HAD) anxiety sub-scale and Clinical Global Impression (CGI)
improvement), there were no statistically significant differences
UNDER
between groups. These non-positive results were thought to be due to
the very high placebo response observed in some ce
1982  ntres. To
understand the variability of the study, a secondary preplanned
ACT
analysis was performed. This involved sub-dividing the study centres
RELEASED
according to their ability to detect a two-point mean difference between
diazepam and placebo at week 8 on the HAM-A total score. Centres
able to show such a difference were t
BEEN  ermed verum-sensitive.
HEALTH
Improvements from baseline to week 8 in venlafaxine XR-treated
HAS
OF
patients from verum-sensitive centres were significantly greater than in
INFORMATION
placebo on each of the primary efficacy measures (P </= 0.05). This
OF
suggests that those centres able to detect an anxiolytic effect of
diazepam were also able to detect an anxiolytic effect of venlafaxine
XR. Significant differences in baseline demographics, rates of adverse
DOCUMENT
event reporting and rates of patient discontinuations were noted
FREEDOM
DEPARTMENT
between patients enrolled at verum-sensitive and verum-insensitive
THIS
sites. These results re
THE  flect the importance of study centre selection in
THE
accurately determining efficacy in placebo-controlled trials.
BY

Jacobson, A. F., R. A. Dominguez, et al. (1985). "Comparison of buspirone
and diazepam in generalized anxiety disorder." Pharmacotherapy 5(5): 290-6.

A total of 66 outpatients meeting Diagnostic and Statistical Manual
(DSM-III) criteria for generalized anxiety disorder began treatment in a
randomized double-blind study that compared the efficacy and safety of
buspirone and diazepam. Thirty-nine outpatients completed the 4-week
trial. Both drugs were administered in a 1:1 dosage ratio; the daily
prescribed dose did not exceed 40 mg. The mean daily dose of
buspirone prescribed throughout the study was significantly higher than
that of diazepam. Diazepam had a significantly earlier onset of efficacy
than buspirone, although both drugs were equivalent after 4 weeks of
treatment. Adverse reactions were more frequent in the diazepam
group. Total scores from the Hamilton anxiety scale and physician's
global ratings show that diazepam was significantly superior to
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buspirone during the initial 2 weeks of treatment. These findings are
further corroborated by the results of patients' self-rated scales.

Jesinger, D. K. and N. Gostick (1989). "Anxiety neurosis in general practice. A
double-blind comparative study of diazepam and clovoxamine, a novel
inhibitor of noradrenaline and serotonin reuptake." Int Clin Psychopharmacol
4(4): 301-11.

This was a multicentre prospectively randomized double-blind parallel
comparison of clovoxamine (n = 37) and diazepam (n = 35) in 72
patients suffering from anxiety neurosis, in general practice. Patients
were seen weekly. Treatment was for 4 weeks (50 mg clovoxamine
b.d. or 5 mg diazepam b.d.) rising according to response to a maximum
of 300 mg clovoxamine or 30 mg diazepam daily. Drug was tapered off
in week 5 and patients were seen again in week 6 after they had been
off drug for at least a week. A treatment period of 4 weeks was
selected in line with WHO guidelines for the testing of anxiolytic drugs.
Although more patients dropped out due to intolerance on clovoxamine
(24%) compared with diazepam (11%), analysis of completed patients
UNDER
showed that clovoxamine was equally effective with significant
improvement in both groups at week 4 (p less than .
1982 001) compared
with baseline Morbid Anxiety Inventory scores and Hamilton Anxiety
ACT
Scale scores. Diazepam patients had a more rapid response which
RELEASED
levelled off, whereas those on clovoxamine continued to improve after
2 weeks. At 6 weeks after taper off the improvement on clovoxamine
was sustained whereas on diazepa
BEEN  m there was evidence of
HEALTH
deterioration after stopping the drug. Clovoxamine appears to have
HAS
OF
potential as an alternative treatment to diazepam for anxiety in general
INFORMATION
practice.
OF

Murphy, S. M., R. Owen, et al. (1989). "Comparative assessment of efficacy
and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or
DOCUMENT
buspirone." Br J Psychiatry 154: 529-34.
FREEDOM
DEPARTMENT

Fifty-one out-patients presenting with generalised anxiety disorder were
THIS
included in a double
THE  -blind trial, and treated with either buspirone (a new
THE
non-benzodiazepine antianxiety drug) or diazepam over 6 or 12 weeks,
BY
after which they were abruptly withdrawn and continued on placebo to
14 weeks. Ratings of anxiety and other symptoms were administered
fortnightly and additional withdrawal symptoms noted. Forty patients
completed the study; 8 of the 11 drop-outs were taking buspirone. Both
drugs reduced anxiety, diazepam more rapidly, but with greater
withdrawal symptoms, particularly after 6 weeks. Regular treatment
with diazepam for 6 weeks leads to a significant risk of pharmacological
dependence that is not present with buspirone.

Pecknold, J. C., M. Matas, et al. (1989). "Evaluation of buspirone as an
antianxiety agent: buspirone and diazepam versus placebo." Can J Psychiatry
34(8): 766-71.

Buspirone has previously been demonstrated to be efficacious in the
treatment of anxiety. This four-week double-blind parallel study
compared buspirone to diazepam and placebo in the treatment of 119
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outpatients diagnosed as having generalized anxiety disorder. After a
seven-day placebo washout period, eligible patients were randomized
to one of three treatment groups. Buspirone (5 mg) and diazepam (5
mg) were administered BID and individually titrated to an optimal
therapeutic dose by the end of week two. Buspirone and diazepam
were equally effective in reducing Hamilton Anxiety (HAM-A) total and
psychic factor scores from baseline values. Buspirone alone was
significantly better than placebo in reducing the HAM-A somatic factor
score. Sixty-seven percent of both active treatment groups who were
classified as "ill" on the baseline global psychopathology rating scale
achieved a "not ill" status by study end. There were no significant
differences between treatment groups at endpoint on the 56-item
Symptom Checklist self-rating scale. Buspirone was demonstrated to
be as effective as diazepam in relieving anxiety in this outpatient
sample.

Pomara, N., L. M. Willoughby, et al. (2005). "Cortisol response to diazepam:
its relationship to age, dose, duration of treatment, and presence of
UNDER
generalized anxiety disorder." Psychopharmacology (Berl) 178(1): 1-8.

OBJECTIVE: Acute diazepam administration has be
1982  en shown to
decrease plasma cortisol levels consistent with decreased activity of
ACT
the hypothalamic-pituitary-adrenal axis, especially in individuals
RELEASED
experiencing stress. However, the effects of chronic diazepam
treatment on cortisol have been less studied, and the relationship to
age, anxiety, duration of treatment,
BEEN  and dose are not well understood.
HEALTH
METHOD: This double-blind placebo-controlled study examined acute
HAS
OF
and chronic effects of diazepam on plasma cortisol levels in young (19-
INFORMATION
35 years) and elderly (60-79 years) individuals with and without
OF
generalized anxiety disorder (GAD). Subjects received single oral
challenges of placebo or diazepam (2.5 mg or 10 mg) in a placebo-
controlled cross-over design, followed by 3 weeks of chronic daily
DOCUMENT
treatment with 2.5 mg or 10 mg diazepam or placebo taken at 10 p.m.,
FREEDOM
DEPARTMENT
and then by a final acute challenge with a single oral dose of the same
THIS
study medication re
THE ceived during chronic treatment. RESULTS: The
THE
elderly experienced significant reductions in plasma cortisol levels
BY
compared to placebo both in the initial challenge and during chronic
treatment, but the young did not. However, cortisol response to drug
was comparable in both groups. Final challenge did not produce any
significant cortisol effects in either group and the cortisol response in
the elderly was significantly reduced compared to the initial challenge.
GAD status was not a factor in plasma cortisol responses to diazepam.
CONCLUSIONS: Diazepam reduced cortisol both acutely and during
chronic treatment, but not during final challenge, consistent with some
tolerance development. This effect was most apparent in the elderly
compared with the young adults and was not modulated by GAD status
or dosage, and was not related to drug effects on performance and on
self-ratings of sedation and tension.

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Pourmotabbed, T., D. R. McLeod, et al. (1996). "Treatment, discontinuation,
and psychomotor effects of diazepam in women with generalized anxiety
disorder." J Clin Psychopharmacol 16(3): 202-7.

Twenty-one women with generalized anxiety disorder (GAD)
participated in a 6-week, double-blind, placebo-controlled trial to
assess the treatment and abrupt withdrawal effects of diazepam on
psychic and somatic symptoms of anxiety. The results confirmed those
of previous studies reporting that (1) clinical doses of diazepam are
effective in attenuating the symptoms of generalized anxiety to a
greater extent than placebo during the first 3 weeks of treatment; (2)
somatic symptoms are more responsive to diazepam treatment than
psychic symptoms; and (3) patients taking diazepam exhibit increased
anxiety upon abrupt withdrawal of medication. This finding, combined
with the fact that diazepam discontinuation did not produce withdrawal
effects in non-anxious volunteers, suggests that diazepam
discontinuation after 6 weeks results in rebound anxiety rather than a
physical withdrawal syndrome. Diazepam did not improve psychomotor
performance in GAD patients. Psychomotor impairment after 6 weeks
UNDER
of diazepam was similar to that seen in nonanxious volunteers.

1982
Rickels, K., R. Downing, et al. (1993). "Antidepressants for the treatment of
ACT
generalized anxiety disorder. A placebo-controlled comparison of imipramine,
RELEASED
trazodone, and diazepam." Arch Gen Psychiatry 50(11): 884-95.

OBJECTIVE: The current study examines whether antidepressants,
contrary to current thinking, are saf
BEEN e and effective treatments for
HEALTH
generalized anxiety disorder (GAD) not complicated by depression or
HAS
OF
panic disorder. DESIGN: Randomized, double-blind, placebo-
INFORMATION
controlled, flexible-dose, 8-week treatment study comparing imipramine
OF
hydrochloride (mean maximum daily dose, 143 mg), trazodone
hydrochloride (255 mg), and diazepam (26 mg). PATIENTS: Two
hundred thirty patients with a DSM-III diagnosis of GAD in whom major
DOCUMENT
depression and panic disorder has been excluded, and who had a
FREEDOM
DEPARTMENT
Hamilton Anxiety Scale total score of at least 18. SETTING: Seventy-
THIS
five percent of patie
THE  nts were treated in family practice settings in the
THE
community, with the remainder treated in psychiatric practices, either
BY
academic or private. RESULTS: Patients treated with diazepam
showed the most improvement in anxiety ratings during the first 2
weeks of treatment, with somatic symptoms being most responsive.
From week 3 through week 8 trazodone achieved comparable, and
imipramine somewhat better, anxiolytic efficacy when compared with
diazepam, with psychic symptoms of tension, apprehension, and worry
being more responsive to the antidepressants. Among completers,
moderate to marked improvement was reported by 73% of patients
treated with imipramine, 69% of patients treated with trazodone, 66% of
patients treated with diazepam, but only 47% of patients treated with
placebo. Overall, patients treated with antidepressants reported a
higher rate of adverse effects than diazepam-treated patients, but
attention rates were the same across all treatments. CONCLUSIONS:
The results of the study need replication, but suggest a potentially
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important role for antidepressants, particularly imipramine, in patients
suffering from GAD.

Rickels, K., E. Schweizer, et al. (1997). "Gepirone and diazepam in
generalized anxiety disorder: a placebo-controlled trial." J Clin
Psychopharmacol 17(4): 272-7.

This randomized, double-blind clinical trial involving 198 generalized
anxiety disorder (GAD) patients was conducted to more clearly define
gepirone's role for the treatment of anxiety in daily dosages of 10 to 45
mg compared with diazepam and placebo. A secondary goal was to
test for possible discontinuation symptoms after abrupt discontinuation
of therapy. After a 1-week washout period, patients were treated for 8
weeks and then abruptly shifted under single-blind conditions for 2
weeks on placebo. The highest attrition rate occurred with patients on
gepirone (58%) and the lowest on diazepam (34%). Medication intake
for week 4 was 19.5 +/- 12.5 mg/day diazepam and 19.0 +/- 11.5
mg/day gepirone and was similar at week 8. The major adverse events
were light-headedness, nausea, and insomnia for gepirone and
UNDER
drowsiness and fatigue for diazepam. Clinical improvement data
showed gepirone's anxiolytic response to be delaye
1982 d, being significant
from placebo beginning at week 6, whereas diazepam caused
ACT
significantly more relief than placebo from week 1 onward. Taper
RELEASED
results showed that only diazepam, but not gepirone, caused a
temporary worsening of anxiety symptoms or rebound.

BEEN  HEALTH
Rocca, P., V. Fonzo, et al. (1997). "Paroxetine efficacy in the treatment of
HAS
OF
generalized anxiety disorder." Acta Psychiatr Scand 95(5): 444-50.
INFORMATION

Recently, there has been a renewed interest in alternatives to the
OF
benzodiazepines for the treatment of generalized anxiety disorder
(GAD). The aim of the present study was to compare the efficacy of
paroxetine vs. imipramine and 2'-chlordesmethyldiazepam in 81
DOCUMENT
patients with a DSM-IV diagnosis of GAD. Approximately two-thirds of
FREEDOM
DEPARTMENT
the patients who completed the study improved greatly or moderately
THIS
on all three active d
THE rugs. During the first 2 weeks of treatment, 2'-
THE
chlordesmethyldiazepam treatment resulted in the greatest
BY
improvement in anxiety ratings. Both paroxetine and imipramine
treatment resulted in more improvement than 2'-
chlordesmethyldiazepam by the fourth week of treatment. Paroxetine
and imipramine affect predominantly psychic symptoms, whereas 2'-
chlordesmethyldiazepam affects predominantly somatic symptoms. Our
results suggest that paroxetine is effective for the treatment of GAD.

Rynn, M., S. Khalid-Khan, et al. (2006). "Early response and 8-week
treatment outcome in GAD." Depress Anxiety 23(8): 461-5.

Our objective was to compare the predictive value of early response to
treatment outcome in patients with generalized anxiety disorder (GAD)
treated with benzodiazepines, serotonin receptor (5HT-1A) partial
agonists, or placebo. Data from two double-blind GAD studies were
combined. Subjects were evaluated with the Hamilton Anxiety Scale
(HAM-A) and the Clinical Global Impression of Improvement (CGI-I)
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scale over 8 weeks. Categories of response at weeks 1 and 2 were
defined by the HAM-A total score. Analyses of covariance and Kaplan-
Meier survival analyses were the primary analyses used to assess 8-
week end point treatment outcomes as a function of early
improvement. HAM-A change from baseline to weeks 1 and 2
significantly predicted last observation carried forward (LOCF)
response at week 8 for both medications and for placebo (P<.001).
Early improvement was a strong predictor for treatment outcome
irrespective of whether active medication or placebo was the treatment
agent.

Strand, M., J. Hetta, et al. (1990). "A double-blind, controlled trial in primary
care patients with generalized anxiety: a comparison between buspirone and
oxazepam." J Clin Psychiatry 51 Suppl: 40-5.

Two hundred thirty patients with generalized anxiety and Hamilton
Rating Scale for Anxiety (HAM-A) scores greater than or equal to 18
were subdivided at random, according to a double-blind design, into
one group treated with 5-10 mg of oral buspirone t.i.d. or one group
UNDER
treated with 10-20 mg of oral oxazepam t.i.d. for 6 weeks. No anxiolytic
treatment was allowed 3 months prior to trial entry. A
1982  nalysis of
demographic variables revealed no significant imbalance between the
ACT
two treatment groups. Twenty patients were excluded from efficacy
RELEASED
analysis because of treatment withdrawal before the first efficacy
evaluation on Day 7. Another 4 patients were excluded because they
were taking concomitant psychotro
BEEN pic medication. The remaining 206
HEALTH
patients displayed a decrease in HAM-A scores (mean +/- SD) from
HAS
OF
23.9 +/- 4.1 to 10.6 +/- 7.7 in the buspirone group and from 23.9 +/- 4.2
INFORMATION
to 11.5 +/- 8.0 in the oxazepam group. The two treatment groups were
OF
also found to be virtually identical in an "intent to treat" analysis of all
230 patients as well as in other ratings (Hamilton Rating Scale for
Depression, Raskin Depression Scale, Covi Anxiety Scale, Physicians
DOCUMENT
Questionnaire, global ratings, and Hopkins Symptom Checklist [HSCL]-
FREEDOM
DEPARTMENT
56). However, oxazepam was never superior to buspirone in any of the
THIS
efficacy analyses. Of
THE   the 230 patients, 127 spontaneously reported
THE
adverse events, including drowsiness, dizziness, headache, nausea,
BY
and nervousness. Adverse events were relatively similar in the two
groups. In conclusion, buspirone and oxazepam appear to be equally
effective in the treatment of generalized anxiety encountered by
general practitioners. This outcome, in addition to a previously
documented absence of any dependency liability, makes buspirone a
clinically important anxiolytic drug.

Tyrer, P. and R. Owen (1984). "Anxiety in primary care: is short-term drug
treatment appropriate?" J Psychiatr Res 18(1): 73-8.

Thirty-six patients with generalised anxiety disorder, panic disorder or
agoraphobia with panic attacks, diagnosed by DSM-III criteria, were
treated with a new non-benzodiazepine anti-anxiety drug, buspirone,
and with diazepam and placebo, in a cross-over design. Each patient
took buspirone, diazepam and placebo for one week each in flexible
dosage and balanced order. Ratings of symptomatology using the
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Comprehensive Psychopathological Rating Scale were made after
each week's treatment and a sub-scale used for measuring anxiety
change alone was used separately. There was no overall difference in
efficacy between the drugs, but when the scores for individual
symptoms were analysed, diazepam was significantly superior to the
other treatments for the symptom of muscle tension only. The results
suggest that the common practice of giving short-term therapy with
tranquilising drugs for anxiety in primary care is pharmacologically
suspect.

Tyrer, P., N. Seivewright, et al. (1993). "The Nottingham study of neurotic
disorder. Effect of personality status on response to drug treatment, cognitive
therapy and self-help over two years." Br J Psychiatry 162: 219-26.

Repeated assessments of psychopathology, together with personality
status, were made over two years on 181 psychiatric out-patients with
generalised anxiety disorder (59), panic disorder (66), or dysthymic
disorder (56) diagnosed using an interview schedule for DSM-III.
Patients were randomly allocated to drug treatment, cognitive and
UNDER
behaviour therapy, or a self-help treatment programme. Although there
were no overall differences in compliance rate and e
1982  fficacy between
the three modes of treatment, the psychological treatment methods,
ACT
particularly self-help, were more effective in patients without personality
RELEASED
disorder, and those with personality disorder responded better to drug
treatment, primarily antidepressants. The findings suggest that
assessment of personality status co
BEEN  uld be a valuable aid to selection of
HEALTH
treatment in neurotic disorders and that self-help approaches are
HAS
OF
particularly valuable once personality disorder has been excluded.
INFORMATION

OF
Tyrer, P., N. Seivewright, et al. (1988). "The Nottingham study of neurotic
disorder: comparison of drug and psychological treatments." Lancet 2(8605):
235-40.
DOCUMENT

210 psychiatric outpatients with generalised anxiety disorder (71), or
FREEDOM
DEPARTMENT
panic disorder (74), or dysthymic disorder (65) diagnosed by an
THIS
interview schedule fo
THE  r DSM-III were allocated by constrained
THE
randomisation to one of five treatments: diazepam (28), dothiepin (28),
BY
placebo (28), cognitive and behaviour therapy (84), and a self-help
treatment programme (42). All treatments were given for 6 weeks and
then withdrawn by 10 weeks. Ratings of psychopathology were made
by psychiatric assessors blind to both treatment and diagnosis before
treatment and at 2, 4, 6, and 10 weeks after randomisation. 18 patients
had insufficient data for analysis because of early drop-out. There were
no important differences in treatment response between the diagnostic
groups, but diazepam was less effective than dothiepin, cognitive and
behaviour therapy, or self-help, these three treatments being of similar
efficacy. Significantly more patients in the placebo group took
additional psychotropic drugs in the 10 week period, and those
allocated to dothiepin and cognitive and behaviour therapy took the
least.

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Wingerson, D. K., D. S. Cowley, et al. (1996). "Effect of benzodiazepines on
plasma levels of homovanillic acid in anxious patients and control subjects."
Psychiatry Res 65(1): 53-9.

The effects of four logarithmically increasing doses of intravenous
diazepam or placebo on plasma homovanillic acid (HVA) were
determined in benzodiazepine-naive patients with panic disorder (PD)
or generalized anxiety disorder (GAD), and in healthy controls. Plasma
HVA was measured at baseline and 3 min after the first and fourth
doses of diazepam/placebo. Mean baseline plasma HVA levels were
significantly lower in PD patients compared with GAD patients and
controls. Although plasma HVA levels decreased significantly with time
in all groups, there was no diazepam effect. This study suggests that
low dopaminergic activity may occur in a subset of anxious patients
(PD), and that diazepam does not significantly affect dopaminergic
activity as measured by plasma HVA in humans.

UNDER
1982
ACT
RELEASED
BEEN  HEALTH
HAS INFORMATION
OF
OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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3  Medline in Process
Martin JL., S.-P. M. F. T. M.-S. E. S. T. G. C. (2007). "Review:
Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes
based on a systematic review and meta-analysis of clinical trials." Journal of
Psychopharmacology 21(7): 774-82.

No systematic review or meta-analysis using a hard outcome has been
conducted on the role of benzodiazepines for generalized anxiety
disorder (GAD). The objective of this study was to assess the
effectiveness and efficacy of benzodiazepines in the treatment of GAD
based on trial drop-out rates. We used a systematic review of
randomized controlled trials that compared any of the three best
established benzodiazepines (diazepam, Lorazepam and aLprazolam)
against placebo. Our primary outcome for effectiveness was withdrawal
for any reason. Our secondary outcome tapping efficacy was
withdrawal due to lack of efficacy, and that tapping side effects was
UNDER
withdrawals due to adverse events.We included 23 trials. Pooled
analysis indicated less risk of treatment discontinuatio
1982  n due to lack of
efficacy for benzodiazepines, compared to placebo, relative risk (RR)
ACT
0.29 (95% CI 0.18-0.45; p < 0.00001). Nevertheless, pooled analysis
RELEASED
showed no conclusive results for risk of all-cause patient
discontinuation, RR 0.78 (95% CI 0.62-1.00; p = 0.05). Meta-regression
model showed that 74% of the vari
BEEN ation in logRR across the studies
HEALTH
was explained by year of publication (p <0.001).This systematic review
HAS
OF
did not find convincing evidence of the sho
INFORMATION  rt-term effectiveness of the
benzodiazepines in the treatment of GAD. On the other hand, for the
OF
outcome of efficacy, this review found robust evidence in favour of
benzodiazepines. Due to the heterogeneity induced by year of
publication, three hypotheses are plausibLe when it comes to being
DOCUMENT
able to account for the differences b
DEPARTMENT  etween efficacy and effectiveness
FREEDOM
observed in the outcomes (publication bias, quality of the trial literature
THIS
and a non-differenti
THE al response to the placebo effect).
THE

BY

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4  EBM Databases (Cochrane)
Centre for Reviews and Dissemination (2007). "A meta-analytic review of the
efficacy of drug treatment in generalized anxiety disorder (Structured
abstract)." Database of Abstracts of Reviews of Effects. 3.

Chessick, C. A., MH; Thase, ME;  Batista Miralha da Cunha, ABC;
Kapczinski, FFK;  de Lima, MSML;  dos Santos Souza, JJSS (2007).
"Azapirones for generalized anxiety disorder." Cochrane Database of
Systematic Reviews. 3.

Background

  Azapirones are a group of drugs that work at the 5-HT1A receptor and are
used to treat patients suffering from generalized anxiety disorder
(GAD). However, several studies have shown conflicting results.
Whether azapirones are useful as first line treatment in general anxiety
UNDER
disorders still needs to be answered.

1982
  Objectives
ACT
To assess the efficacy and the acceptability of azapirones for the treatment of
RELEASED
GAD.

  Search strategy
BEEN  HEALTH
Initiallyt the Cochrane Collaboration Depression, Anxiety and Neurosis
HAS
OF
Controlled Trials Register (CCDANCTR) a
INFORMATION nd The Cochrane Central
Register of Controlled Trials (CENTRAL) were searched, incorporating
OF
results of group searches of MEDLINE (1966 to June 2005), EMBASE
(1980 to June 2005), CINAHL (1982 to June 2005), PsycLIT (1974 to
June 2005), PSYNDEX (1977 to June 2005), and LILACS (1982 to
DOCUMENT
June 2005). Subsequently the revised
DEPARTMENT
Cochrane Collaboration
FREEDOM
Depression, Anxiety and Neurosis Controlled Trials Registers
THIS
(CCDANCTR-Studies
THE  and CCDANCTR-References) were searched on
THE
21-10-2005. Ref
BY  erence lists of relevant papers and major text books of
anxiety disorder were examined. Authors, other experts in the field and
pharmaceutical companies were contacted for knowledge of suitable
trials, published or unpublished. Specialist journals concerning
azapirones were handsearched.

  Selection criteria
Randomized controlled trials of azapirones, including buspirone versus
placebo and/or other medication and/or psychological treatment, were
included. Participants were males and females of all ages with a
diagnosis of generalized anxiety disorder.

  Data collection and analysis
Data were extracted from the original reports independently by CC, MA and
MT. The main outcomes studied were related to the objectives stated
above. Data were analysed for generalized anxiety disorder versus
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placebo, versus other medication and versus psychological treatment
separately. Data were analysed using Review Manager Version 4.2.7.

  Main results
Thirty six trials were included in the review, reporting on 5908 participants
randomly allocated to azapirones and/or placebo, benzodiazepines,
antidepressants, psychotherapy or kava kava. Azapirones, including
buspirone, were superior to placebo in treating GAD. The calculated
number needed to treat for azapirones using the Clinical Global
Impression scale was 4.4 (95% confidence interval (CI) 2.16 to 15.4).
Azapirones may be less effective than benzodiazepines and we were
unable to conclude if azapirones were superior to antidepressants,
kava kava or psychotherapy. Azapirones appeared to be well tolerated.
Fewer participants stopped taking benzodiazepines compared to
azapirones. The length of studies ranged from four to nine weeks, with
one study lasting 14 weeks.

  Authors' conclusions
UNDER
Azapirones appeared to be useful in the treatment of GAD, particularly for
those participants who had not been on a benzodiaze
1982  pine. Azapirones
may not be superior to benzodiazepines and do not appear as
ACT
acceptable as benzodiazepines. Side effects appeared mild and non
RELEASED
serious in the azapirone treated group. Longer term studies are needed
to show that azapirones are effective in treating GAD, which is a
chronic long-term illness.
BEEN  HEALTH

HAS
OF
Kapczinski, F. L., MS;  Souza, JS;  Cunha, A;  Schmitt, R (2007).
INFORMATION
"Antidepressants for generalized anxiety disorder." Cochrane Database of
OF
Systematic Reviews.(3).

Background

DOCUMENT
  Pharmacological treatments have been successfully used to treat
FREEDOM
DEPARTMENT
Generalized Anxiety Disorder (GAD). Benzodiazepine and non
THIS
benzodiazepine anxiol
THE  ytics used to be the mainstay for the
THE
pharmacological treatment of GAD. However, data emerging over the
BY
last two decades have shown that antidepressants may be as effective
as anxiolytics in this condition. The use of antidepressants may also be
beneficial, because GAD often coexists with major depressive disorder
(62% comorbidity) and dysthymia (37%).

  Objectives
To assess the efficacy and acceptability of antidepressants for treating
generalized anxiety disorder.

  Search strategy
Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials
Register - CCDANCTR (up to May 2002), Anxiety Neurosis (up to May
2002) and Cochrane Controlled Trials Register (CENTRAL/CCTR) (up
to May 2002), MEDLINE (1966 to May 2002), LILACS (1982 to May
2002); reference searching; personal communication; conference
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abstracts and book chapters on the treatment of generalized anxiety
disorder.

  Selection criteria
Randomized controlled trials were included. Non randomized studies and
those that included patients with both GAD and another Axis I co-
morbidity were excluded.

  Data collection and analysis
The data from studies were extracted independently by two reviewers.
Relative risks, weighted mean difference and number needed to treat
were estimated. People who died or dropped out were regarded as
having had no improvement.

  Main results
Antidepressants (imipramine, venlafaxine and paroxetine) were found to be
superior to placebo in treating GAD. The calculated NNT for
antidepressants in GAD is 5.15. Dropout rates did not differ between
UNDER
antidepressants. Only one study presented data on imipramine and
trazodone. Imipramine was chosen as the reference
1982   drug and,
therefore, data on trazodone could not be included in the meta
ACT
analysis. Only one study was conducted among children and
RELEASED
adolescents (Rynn 2000). This showed very promising results of
sertraline in children and adolescents with GAD, which warrants
replication in larger samples. BEEN  HEALTH

HAS
OF
  Authors' conclusions
INFORMATION
The available evidence suggests that antidepressants are superior to placebo
OF
in treating GAD. There is evidence from one trial suggesting that
paroxetine and imipramine have a similar efficacy and tolerability.
There is also evidence from placebo-controlled trials suggesting that
DOCUMENT
these drugs are well tolerated by GAD patients. Further trials of
FREEDOM
DEPARTMENT
antidepressants for GAD will help to demonstrate which
THIS
antidepressants sho
THE  uld be used for which patients.
THE

BY
Miyasaka, L. A., AN; Soares, BGO (2007). "Valerian for anxiety disorders."
Cochrane Database of Systematic Reviews 3.

nxiety disorders are very common mental health problems in the
general population and in primary care settings. Herbal medicines are
popular and used worldwide and mght be considered as a treatment
option for anxiety if shown to be effective and safe.

  Objectives
  To investigate the effectiveness and safety of valerian for treating anxiety
disorders.

  Search strategy
Electronic searches: The Cochrane Collaboration Depression, Anxiety and
Neurosis Cochrane Controlled Trials Register (CCDANCTR-Studies
and CCDANCTR-References) searched on 04/08/2006, MEDLINE,
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Lilacs. References of all identified studies were inspected for additional
studies. First authors of each included study, manufacturers of valerian
products, and experts in the field were contacted for information
regarding unpublished trials.

  Selection criteria
Randomised controlled trials (RCTs) and quasi-randomised trials of valerian
extract of any dose, regime, or method of administration, for people
with any primary diagnosis of general anxiety disorder, anxiety
neurosis, chronic anxiety status, or any other disorder in which anxiety
is the primary symptom (panic disorder, obsessive compulsive
disorder, social phobia, agoraphobia, other types of phobia,
postraumatic stress disorder). Effectiveness was measured using
clinical outcome measures and other scales for anxiety symptoms.

  Data collection and analysis
Two review authors independently applied inclusion criteria, extracted and
entered data, and performed the trial quality assessments. Where
UNDER
disagreements occured, the third review author was consulted.
Methodological quality of included trials was assesse
1982  d using Cochrane
Handbook criteria. For dichotomous outcomes, relative risk (RR) was
ACT
calculated, and for continuous outcomes, the weighted mean difference
RELEASED
(WMD) was calculated, with their respective 95% confidence intervals.

  Main results
BEEN  HEALTH
One RCT involving 36 patients wih generalised anxiety disorder was eligible
HAS
OF
for inclusion. This was a 4 week pilot study of valerian, diazepam and
INFORMATION
placebo. There were no significant differences between the valerian
OF
and placebo groups in HAM-A total scores, or in somatic and psychic
factor scores. Similarly, there were no significant differences in HAM-A
scores between the valerian and diazepam groups, although based on
DOCUMENT
STAI-Trait scores, significantly greater symptom improvement was
FREEDOM
DEPARTMENT
indicated in the diazepam group. There were no significant differences
THIS
between the three g
THE  roups in the number of patients reporting side
THE
effects or in dropout rates.
BY

  Authors' conclusions
Since only one small study is currently available, there is insufficient evidence
to draw any conclusions about the efficacy or safety of valerian
compared with placebo or diazepam for anxiety disorders. RCTs
involving larger samples and comparing valerian with placebo or other
interventions used to treat of anxiety disorders, such as
antidepressants, are needed.

Rickels K, D. R., Schweizer E, Hassman H (1993). "Antidepressants for the
treatment of generalized anxiety disorder. A placebo-controlled comparison of
imipramine, trazodone, and diazepam." Archives of general psychiatry.
50(11): 884-95.

OBJECTIVE: The current study examines whether antidepressants,
contrary to current thinking, are safe and effective treatments for
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generalized anxiety disorder (GAD) not complicated by depression or
panic disorder. DESIGN: Randomized, double-blind, placebo-
controlled, flexible-dose, 8-week treatment study comparing imipramine
hydrochloride (mean maximum daily dose, 143 mg), trazodone
hydrochloride (255 mg), and diazepam (26 mg). PATIENTS: Two
hundred thirty patients with a DSM-III diagnosis of GAD in whom major
depression and panic disorder has been excluded, and who had a
Hamilton Anxiety Scale total score of at least 18. SETTING: Seventy-
five percent of patients were treated in family practice settings in the
community, with the remainder treated in psychiatric practices, either
academic or private. RESULTS: Patients treated with diazepam
showed the most improvement in anxiety ratings during the first 2
weeks of treatment, with somatic symptoms being most responsive.
From week 3 through week 8 trazodone achieved comparable, and
imipramine somewhat better, anxiolytic efficacy when compared with
diazepam, with psychic symptoms of tension, apprehension, and worry
being more responsive to the antidepressants. Among completers,
moderate to marked improvement was reported by 73% of patients
UNDER
treated with imipramine, 69% of patients treated with trazodone, 66% of
patients treated with diazepam, but only 47% of patie
1982  nts treated with
placebo. Overall, patients treated with antidepressants reported a
ACT
higher rate of adverse effects than diazepam-treated patients, but
RELEASED
attention rates were the same across all treatments. CONCLUSIONS:
The results of the study need replication, but suggest a potentially
important role for antidepressants,
BEEN particularly imipramine, in patients
HEALTH
suffering from GAD.
HAS
OF

INFORMATION

OF
DOCUMENT
FREEDOM
DEPARTMENT
THIS
THE  THE
BY
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5  Clinical Trials
Forest Laboratories (2007). Initiating Acamprosate Within Versus Post-
Detoxification in the Rehabilitative Treatment of Alcohol Dependence.
.

Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control,
Crossover Assignment
Further study details as provided by National Institute on Drug Abuse (NIDA):
Primary Outcome Measures:
The mean number of adverse events rated moderate to severe;
The week of detoxification treatment discontinuation;
The total amount of oxazepam given;
The rate of change in CIWA scores.
The mean number of adverse events rated moderate to severe;
The week of open-label treatment discontinuation;   UNDER
Any reemergence of detoxification symptoms;
Percentage of pills taken over what was proposed to be prescri
1982
bed
(medication exposure);
ACT
Percentage days abstinent;
RELEASED
Percentage days heavy drinking. The number of drinks per day will be used to
identify a heavy drinking day, defined as 5 or more drinks/day for males
and 4 or more drinks/day for females.
BEEN    HEALTH

HAS
OF
Secondary Outcome Measures:    INFORMATION
Changes in alcohol craving will be measured by Penn Alcohol Craving Scale
OF
(PACS; Flannery et al, 1999)
Changes in anxiety symptoms will be measured by the Structured Interview
Guide for the Hamilton Anxiety Rating Scale (SIGH-A; Hamilton, 1969)
DOCUMENT
Changes in depressive symptoms will be
DEPARTMENT   measured by the Structured
FREEDOM
Interview Guide for the Hamilton Depression Rating Scale (SIGH-D;
THIS
Hamilton 1967)
THE  THE
Changes in social fun
BY ctioning will be measured by several of the subscales of
the Addiction Severity Index (ASI; McLellan et al, 1992); namely,
medical, legal, psychiatric, and family/social.
Quality of Life, measured by the Short Form-36 Health Status Questionnaire
(SF-36; Ware & Sherbourne, 1999)
Overall clinical impression of improvement will be measured by the Clinical
Global Impression Scale (CGI)

King Pharmaceuticals Research and Development (2007). A Study on the
Effectiveness and Safety of Diazepam Injection (Vanquix™) for Patients With
Epilepsy That Receive Antiepileptic Drugs, But Still Experience Acute
Repetitive Seizures (Bouts or Clusters of Seizures) That Require Treatment.
Clinical Trials identifier: NCT00319501.

Total Enrollment:  325
Study start: January 2006

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In the United States, more than 2 million people have epilepsy. Most patients
with epilepsy are able to control their seizures with drugs and/or
surgery. However, many patients (400,000 to greater than 600,000) are
considered refractory to antiepileptic drugs and still experience acute
repetitive seizures (ARS). An ARS is an episode of multiple seizures
that differs from the patient's usual seizure pattern and is often
recognizable by the patient's family and caregivers. The ARS is usually
described as a bout or cluster of seizures that occurs over a short
period of time in which the patient regains consciousness in between
seizures. Only one drug is currently available that persons other than
health care professionals (e.g., patient's caregiver) may give to control
ARS. This drug is called Diastat®. Diastat® is a diazepam rectal gel
and, although it is effective, it may be difficult, inconvenient, or
objectionable to use because of its rectal administration. Vanquix™
(diazepam autoinjector) also contains diazepam, but is administered by
an automated injectable device into the leg muscle. Vanquix™ may be
less difficult and more convenient to use by caregivers, however, its
UNDER
effectiveness and safety have not been studied in patients. This study
will determine the effectiveness and safety of Vanqu
1982  ix™ compared to
placebo for treating ARS.
ACT

RELEASED
University of Utah, P. C. s. M. C. F. (2006). Intranasal Midazolam Versus
Rectal Diazepam for Treatment of Seizures.

Purpose
BEEN  HEALTH

HAS
OF
We will conduct a randomized controlled trial comparing the use of nasal
INFORMATION
midazolam, using a Mucosal Atomization Devise, to rectal diazepam for
OF
the treatment of acute seizure activity in children under the age of 18
years with epilepsy in the community setting. Our primary hypothesis is
that nasal midazolam will be more effective and have shorter seizure
DOCUMENT
time compared to rectal diazepam in the community. Our secondary
FREEDOM
DEPARTMENT
hypotheses are that patients treated with nasal midazolam will have
THIS
less respiratory com
THE  plications, Emergency Department visits and
THE
admissions. BY

Total Enrollment:  200
Study start: June 2006;  Expected completion: June 2007

Study Design: This is a prospective randomized controlled study.

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6  Hand Searched References
Borison, R., Albrecht, JW, Diamond, BI. (1990). "Efficacy and safety of a
putative anxyiolitic agent: Ipsapirone."  Psychopharmacology Bulletin. 6(26):
207-209.

Boyer, W., Feighner, JP. (1993). "A placebo-controlled double-blind
multicenter trial of two doses of ipsapirone versus diazepam in generalized
anxiety disorder." International Clinical Psychopharmacology 8: 173-76.

Casacalenda, N. e. a. (1998). "Pharmacologic treatments effective in both
generalized anxiety disorder and major depressive disorder: clinical and
theoretical implications. ." Canadian Journal of Psychiatry. . 43(7): 722.

Centre for Reviews and Dissemination (2007). " Long-term pharmacological
treatment of generalized anxiety disorder (Structured abstract)." Database of
UNDER
Abstracts of Reviews 2.

1982
Coak, A. R., J;  Morris, S. (2007). "Thioridazine for anxiety and depressive
ACT
disorders. ." Cochrane Database of Systematic Reviews.(2).
RELEASED

Cohn, J., Rickels, K. (1989). "A pooled, double-blind comparison of the effects
of buspirone, diazepam and placebo in wo
BEEN  men with chronic anxiety. ." Current
HEALTH
Medical Research and Opinion 11(5): 304-20.
HAS
OF

INFORMATION
DeMartinis, N., Runn, M, Rickels, K, Mandos, L. P. (2000). "Prior
OF
Benzodiazepine Use and Buspirone Response in the Treatment of
Generalized Anxiety Disorder. ." The Journal of Clinical Psychiatry 61(2): 91-
94.
DOCUMENT

FREEDOM
DEPARTMENT
Fontaine, R., L. Annable, et al. (1983). "Bromazepam and diazepam in
THIS
generalized anxiety: a place
THE  bo-controlled study with measurement of drug
THE
plasma concentrations
BY  ." J Clin Psychopharmacol 3(2): 80-7.

In a double-blind, placebo-controlled study, 48 anxious outpatients with
a primary diagnosis of generalized anxiety disorder were randomly
assigned to 4 weeks of treatment with bromazepam (18 mg/day),
diazepam (15 mg/day), or placebo, after a 1-week washout period.
From week 1 onward both active drugs were superior to placebo in
relieving anxiety symptoms. Bromazepam was found to be significantly
more effective than diazepam with respect to the somatic anxiety factor
and the total score for the Hamilton Anxiety Rating Scale and the
fear/anxiety factor of the Patient's Self-Rating Symptom Scale. Plasma
concentrations of diazepam plus active metabolites were correlated
significantly (r = 0.60, p less than 0.05) with the percentage reduction in
self-rating anxiety scores. Bromazepam plasma concentration
measurements showed greater variability than those of diazepam and
were not found to be correlated significantly with clinical response. It is
suggested that the use of strict diagnostic criteria (1978 draft of the
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third edition of Diagnostic and Statistical Manual of Mental Disorders),
adequate sample sizes, and a 4-week study period gave increased
sensitivity for the detection of significant differences between the two
benzodiazepines.

Fontaine, R., P. Beaudry, et al. (1987). "Comparison of withdrawal of
buspirone and diazepam: a placebo controlled study." Prog
Neuropsychopharmacol Biol Psychiatry 11(2-3): 189-97.

In a 8-week double-blind placebo controlled study, 48 outpatients with
generalized anxiety disorder were randomized to diazepam, buspirone,
a non-benzodiazepine anxiolytic, or placebo. During the treatment
phase of 4 weeks duration diazepam was found to be significantly
better than placebo and buspirone. Following abrupt withdrawal by
placebo substitution the diazepam group showed a gradual relapse
maximal after two weeks while the buspirone and the placebo groups
did not differ. There were more cases of rebound anxiety with
diazepam as compared to buspirone or placebo. In addition, there were
three early terminations related to rebound anxiety in the diazepam
UNDER
group while there were none in the placebo and buspirone groups.
There were significantly more new symptoms in the d
1982  iazepam group
than in the placebo or buspirone group.  ACT

RELEASED
Fontaine, R., G. Chouinard, et al. (1984). "Bromazepam and diazepam in
generalized anxiety: a placebo-controlled study of efficacy and withdrawal."
Psychopharmacol Bull 20(1): 126-7.
BEEN  HEALTH

HAS
OF
Fontaine, R., G. Chouinard, et al. (1984). "Rebound anxiety in anxious
INFORMATION
patients after abrupt withdrawal of benzodiazepine treatment." Am J
OF
Psychiatry 141(7): 848-52.

In this double-blind, placebo-controlled study of 4 weeks of
benzodiazepine treatment followed by 3 weeks of abrupt or gradual
DOCUMENT
drug withdrawal, 16 patients whose benzodiazepine was withdrawn
FREEDOM
DEPARTMENT
abruptly were worse (p less than .05) than 13 who had received
THIS
placebo in terms of
THE  change in mean anxiety scores from the
THE
pretreatment level. The scores of seven patients (44%) whose
BY
benzodiazepine was withdrawn abruptly increased 10% or more on
both the Hamilton Rating Scale for Anxiety and the Self Rating
Symptom Scale. There were no cases of rebound anxiety in 14 patients
whose benzodiazepine was withdrawn gradually; fewer cases of
rebound anxiety were seen with a benzodiazepine that had a long half-
life.

Goldberg, H. L. and R. Finnerty (1982). "Comparison of buspirone in two
separate studies." J Clin Psychiatry 43(12 Pt 2): 87-91.

Two double-blind studies are described in which buspirone was
compared with placebo and diazepam (Study A) or clorazepate (Study
B) in outpatients with moderate to severe anxiety. Results, assessed
on the Hamilton Rating Scales for Depression and Anxiety, the SCL-56,
the Profile of Mood States, and the Covi and Raskin scales, indicated
that buspirone consistently relieved both anxiety and associated
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depression. In Study B, trends in favor of buspirone were seen on
several SCL-56 items and the Hamilton somatic factor; significant
differences in this direction were found for several POMS items.
Sedation was seen less often with buspirone than either diazepam or
clorazepate.

Heideman, J., van Rijswijk E, van Lin N, de Loos S, Laurant M, Wensing M,
van de Lisdonk E, Grol R. (2005). "Interventions to improve management of
anxiety disorders in general practice: a systematic review." British Journal of
General Practice. 55(520): 867-874.

Mahe, V. e. a. (2000). "Long-term pharmacological treatment of generalized
anxiety disorder. ." International Clinical psychopharmacology. 15(2): 99-105.

Mitte K, N. P., Steil R, Hautzinger M. (2005). "Ameta-analytic review of the
efficacy of drug treatment in generalized anxiety disorder. ." Journal of Clinical
Psychopharmacology. 25(2): 141-150.

UNDER
Pecknold, J., Familamiri, P, Chang, H, Wilson, R, Alarcia, J, Mc-Clure, J.
(1985). "Buspirone: Anxiolytic?. ." Progress in Neuro-psych
1982  opharmacol-ogy &
Biological Psychiatry 9: 638-642.
ACT

RELEASED
Power, K. e. a. (1990). "A controlled comparison of cognitive-behaviour
therapy, diazepam, and placebo, alone and in combination, the the treatment
fo generalized anxiety disorder. ." J. anxie
BEEN  ty disorder. 4(4): 267-292.
HEALTH

HAS
OF
Rickels, K., N. DeMartinis, et al. (2000). "A double-blind, placebo-controlled
INFORMATION
trial of abecarnil and diazepam in the treatment of patients with generalized
OF
anxiety disorder." J Clin Psychopharmacol 20(1): 12-8.

In a multicenter, double-blind trial, 310 patients who had received a
diagnosis of generalized anxiety disorder were treated for 6 weeks with
DOCUMENT
either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of
FREEDOM
DEPARTMENT
abecarnil or 22 mg of diazepam administered three times daily.
THIS
Patients who were i
THE mproved at 6 weeks could volunteer to continue
THE
double-blind treatment for a total of 24 weeks. The maintenance
BY
treatment phase allowed the comparison of taper results for the three
treatments at several study periods (0-6 weeks, 7-12 weeks, and more
than 12 weeks). Slightly more diazepam (77%) and placebo (75%)
patients completed the 6-week study than abecarnil patients (66%). At
intake and baseline, after a 1-week placebo washout, the patient was
required to have a Hamilton Rating Scale for Anxiety score of > or =20.
Major adverse events for both abecarnil and diazepam were
drowsiness, dizziness, fatigue, and coordination difficulties. Clinical
improvement data showed that both abecarnil and diazepam produced
statistically significantly more symptom relief than did placebo after 1
week of treatment. At 6 weeks treatment (using last observation carried
forward analysis), however, only diazepam still differed significantly (p
< 0.01) from placebo. High placebo response (56% moderate to
marked global improvement) at 6 weeks, as well as a slightly lower
nonsignificant improvement rate observed with abecarnil, a partial y-
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aminobutyric acid (GABA) agonist, when compared with diazepam, a
full GABA agonist, most likely contributed to our findings. Finally, taper
results showed that only diazepam and not abecarnil caused the
presence of temporary discontinuation symptoms, but only in patients
who had been treated for at least 12 weeks.

Rickels, K., K. Weisman, et al. (1982). "Buspirone and diazepam in anxiety: a
controlled study." J Clin Psychiatry 43(12 Pt 2): 81-6.

The anxiolytic properties of buspirone were assessed in a 4-week
double-blind study in 240 anxious patients, 81 of whom received
buspirone, 81 diazepam, and 78 placebo. Patients were required to
have scores greater than or equal to 9 on the Covi and greater than or
equal to 18 on the Hamilton Rating Scale for Anxiety, and to endorse at
least 5 items on a 17-item Anxiety Entry Checklist. Among 212
evaluable patients, those who improved most were married, well-
educated females who had both a positive family adjustment and a low
level of depression. Diazepam produced relatively equal improvement
in females and males. Diazepam seems more effective in reducing
UNDER
somatic symptoms, while buspirone appears more effective in reducing
symptoms associated with cognitive and interperson
1982  al problems. Main
differences between the drugs were seen in side effect profiles.
ACT

RELEASED
Ross, C., Matas, M. (1987). "A Clinical Trial of Buspirone and Diazepam in the
Treatment of Generalized Anxiety Disorder. ." Canandian Journal of
Psychiatry 32: 351-355.
BEEN  HEALTH

HAS
OF
Shah, L. P., et al., (1990). "A controlled double blind clinical trial of buspirone
INFORMATION
and diazepam in generalised anxiety disorder. ." Indian Journal of Psychiatry.
OF
32(2): 166-169.

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Attachment 5
Detailed assessment of the measures
UNDER
taken by investigators to mini
1982  mise bias
ACT
in the randomised trials (adden
RELEASED
dum to
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Secti
HAS  on B
OF  .3)
INFORMATION
OF
DOCUMENT
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Randomisation

SCT-MD-05, SCT-MD-06, SCT-MD-07
All  patients  were  randomised  into  the  two  treatment  groups  (escitalopram  10mg/day,  possibly
increasing  to  20mg/day  or  placebo)  for  the  eight-week  double-blind  treatment  period  following  a
one-week  single-blind  placebo  lead-in  period.    A  list  of  patient  randomisation  numbers  with
corresponding assigned treatment was generated by Forest Laboratories Department of Biostatistics.
Each  study  site  was  provided  with  drug  supplies  corresponding  to  this  of  sequence  of  patient
numbers.  The first patient to enter into the study was assigned the first number in the sequence, and
each subsequent patient entered was assigned a sequential patient number

99815
This was a multinational, multicentre, randomised, double-blind, parallel-group, placebo-controlled,
UNDER
active-reference  (paroxetine),  fixed-dose  study  in  outpatients  with  GAD.    There  was  a  one-week,
1982
single-blind  placebo  run-in  period,  after  which  patients  were  randomised  to  12  weeks  of  double-
blind  treatment  with  escitalopram  (fixed  doses  of  5,  10  or  20mg
ACT /day), paroxetine (20mg/day) or
RELEASED
placebo,  followed  by  a  2-week  washout  period.    Details  of  the  paroxetine  treatment  arm  are  not
presented  in  the  submission  as  paroxetine  is  not  a  relevant  comparator.    The  randomisation  code
BEEN  HEALTH
was  generated  by  H.Lundbeck  A/S.    A  total  of  1121  randomisation  numbers  were  prepared,  with
HAS
OF
224 numbers assigned to each treatment group.  At each centre, the intention was to consecutively
INFORMATION
assign  the  lowest  randomisation  number
OF  available.    Block  randomisation  ensured  that  equal
numbers of patients entered each treatment group.

DOCUMENT
DEPARTMENT
99769
FREEDOM
THIS
This was a multinational, multicen
THE tre, fixed-dose study with a 12-week, open-label treatment period
THE
with  escitalopram  followed
BY  by  a  double-blind,  parallel-group  comparison  of  escitalopram  and
placebo  in  the  prevention  of  relapse  of  GAD.    Patients  were  in  the  double-blind  period  for  a
minimum of 24 weeks and a maximum of 76 weeks, depending on when in the accrual period they
entered the study, as all patients were to complete the double-blind period simultaneously.  Patients
who  completed  the  double-blind  period  entered  a  2-week,  double-blind,  down-tapering  period.
During the first week of the open-label period, the patients received 10mg/day escitalopram.  The
dose  was  doubled  to  20mg/day  escitalopram  from  Week  2.    No  down-titration  was  allowed.
Patients who had responded to treatment at the end of the 12-week, open-label period were eligible
for randomisation to double-blind treatment with escitalopram or placebo.  During the double-blind
period,  patients  randomised  to  placebo  received  10mg/day  escitalopram  for  one  week  and  then
continued on placebo. Patients randomised to escitalopram continued on 20mg/day escitalopram.

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Eligible patients were randomised to double-blind treatment with either placebo or escitalopram in a
1:1  ratio  according to  a randomisation  code  generated  by  H.Lundbeck  A/S.    Block  randomisation
(in  blocks  of  four)  ensured  that equal  numbers  of  patients entered  each treatment  group.    At  each
centre the 4-digit randomisation code was to be assigned consecutively (according to the timing of
Visit 7, i.e. the end of the 12-week open-label period), starting with the lowest number available.

Hackett et al.
It is stated in the publication that the study was a multicentre, randomised, double-blind, placebo-
controlled, parallel-group study. No details of the randomisation method are provided.

Blinding

UNDER
SCT-MD-05, SCT-MD-06, SCT-MD-07, SCT-MD-31
1982
For  the  double-blind  treatment  period  patients  were  supplied  with  identically  appearing  tablets
containing  either  escitalopram  or  placebo.    The  randomisation  code
ACT   was to be broken only in an
RELEASED
emergency.    The  randomisation  code  was  not  broken  and  no  patient  was  unblinded  during  the
studies.
BEEN  HEALTH

HAS
OF
99815
INFORMATION
The  study  products  were  all identical  browni
OF  sh-red capsules for oral administration.  All capsules
contained  a  tablet  (either  escitalopram,  placebo  or  paroxetine)  and  white  powder  and  were
indistinguishable from one another since they were identical in appearance, shape, taste and smell.
DOCUMENT
DEPARTMENT
The randomisation code was to be broken o
FREEDOM  n in an emergency, however the code was not broken for
THIS
any patients during the study.
THE  THE

BY
99769
Escitalopram  and  placebo  were  supplied  as  film-coated  tablets  of  identical  appearance.    The
randomisation code was to be broken on in an emergency, however the code was not broken for any
patients during the study.

Hackett et al.
It is stated that the study was a multicentre, randomised, double-blind, placebo-controlled, parallel-
group study. No details of blinding are provided.

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Basis of the analysis

SCT-MD-05, SCT-MD-06, SCT-MD-07, SCT-MD-312
The following analysis sets were defined a priori:
•  Randomised population - all patients randomised into the study
•  Safety  Population  –  all  randomised  patients  who  took  at  least  one  dose  of  double-blind
study medication
•  Intent-to-Treat  (ITT)  population  consisted  of  all  patients  in  the  safety  population  with  at
least one post-baseline efficacy assessment on the Hamilton Anxiety Scale (HAMA).

All efficacy analyses were conducted on the ITT population.  The analyses were performed using
the Last Observation Carried Forward (LOCF) approach. All safety analyses were conducted on the
Safety Population.
UNDER

1982
99815
The following analysis sets were defined a priori:
ACT
RELEASED
•  All-patients-randomised set (APRS) – all patients randomised into the study
•  All-patients  treated  set  (APTS)  –  all  randomised  patients  who  took  at  least  one  dose  of
BEEN  HEALTH
double-blind study product
HAS
OF
•
INFORMATION
  Full-analysis set (FAS) – all randomised patients who took at least one dose of double-blind
OF
study  product  and  who  had  at  least  one  post-baseline  assessment  of  the  primary  efficacy
variable.
•
DOCUMENT
  All-patients-completed-set  (APCS)  –  all  patients  in  the  FAS  who  completed  12  weeks  of
FREEDOM
DEPARTMENT
double-blind treatment
THIS  THE
•  Per-protocol set (PP
THE  S) – all patients in the FAS who received double-blind study product
BY
for at least 4 weeks, who had at least one valid assessment of the HAM-A total score at or
after the Week 4 assessment, and who had no major protocol violations

All  efficacy  analyses  were  conducted  on  the  FAS.    The  analyses  were  performed  using  the  Last
Observation  Carried  Forward  (LOCF)  approach.    Safety  analyses  (except  analyses  of
Discontinuation-Emergent Signs and Symptoms (DESS)) were conducted on the APTS.

2 At the stage the time the submission went in – there was no information available regarding 031.  However
given the similarities of the trials, this is likely to be the case.
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99769
The following analysis sets were defined a prior for the double-blind study period:
•  All-patients-randomised set (APRS) – all patients who completed the open-label period and
were randomised into double-blind study period.
•  All-patients treated set (APTS II) – all randomised patients in the APRS who took at least
one dose of study product in the double-blind period.
•  Full-analysis  set  (FAS)  –  all  patients  in  the  APRS  who  took  at  least  one  dose  of  study
product in the double-blind period.
•  All-patients-completed-set (APCS)  – all patients in the FAS who completed 12 weeks of
double-blind treatment
•  Per-protocol  set  (PPS)  –  all  patients  in  the  FAS  who  had  no  major  protocol  deviations.
Patients could be completely or partly (only selected visits) excluded from the PPS.

UNDER
To be consistent with the usual terminology used by the sponsor in the escitalopram GAD clinical
1982
trial program, both an APTS II and FAS were defined, even though the definition was the same for
ACT
both.
RELEASED

All  efficacy  analyses  in  the  double-blind  period  were  conducted  on  the  FAS.    The  analyses  were
BEEN  HEALTH
performed using the Last Observation Carried Forward (LOCF) approach, where relevant.  Safety
HAS
OF
analyses (in the double-blind period) were based on the APTS I
INFORMATION  I.
OF

Hackett et al.
DOCUMENT
FREEDOM
DEPARTMENT
Randomised patients who had received at least one dose of study medication and who had at least
THIS  THE
one evaluation on one of the pr
THE  imary efficacy parameters, either during therapy, or within 3 days of
BY
the last treatment, constituted the intent-to-treat population (ITT) for the evaluation of efficacy. The
safety population was evaluated in the randomised population. The primary efficacy analysis was
carried out using the LOCF method to impute missing data.

Adequacy of follow-up
Escitalopram versus placebo studies
The flow of participants through the individual randomised, controlled trials comparing
escitalopram with placebo was well documented in the Study Reports. Data from the majority of
patients randomised into the studies was analysed in the efficacy analyses (over 95%).

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Placebo versus benzodiazepines study
The flow of participants in each treatment arm of the study by Hackett et al. was poorly
documented, with only the number of patients discontinued and the number of patients analysed
reported.

Table B.3.2 summarises the flow of participants through the key randomised, controlled trials.
UNDER
1982
ACT
RELEASED
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Document Outline