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Microsoft word - the iuphar compendium of basic guidelines final v1.4.doc
Chapter 22. Anxiety Disorders
Claudio A. Naranjo, M.D. 1
Lara Chayab 2
Department of Pharmacology
Psychiatry and Medicine
University of Toronto
Neuropsychopharmacology Research Program
Sunnybrook & Women’s College Health Science Centre
Department of Pharmacology
University of Toronto
Neuropsychopharmacology Research Program
Sunnybrook & Women’s College Health Science Centre
I. INTRODUCTORY REMARKS
Anxiety Disorders are the most common forms of mental illness (1). The National Comorbidity Survey
indicated that about 48% of the US population of Americans aged 15 to 54 years had at least one mental illness
in their lifetime. Of these, 24.9% reported having an anxiety disorder in their lifetime (1). Anxiety disorders
include general anxiety disorder (GAD), panic disorder (PD), and obsessive compulsive disorder (OBC) (2). Of
the three disorders, GAD has been shown to be the most prevalent in a population. Patients are required to
exhibit at least six symptoms of hyperarousal, vigilance, motor tension, and autonomic hypersensitivity to fit the
criteria of GAD in the DSM-IV (2). Pharmacotherapies of anxiety disorders include treatment with
benzodiazepines, buspirone, and antidepressants (3). Benzodiazepines have been known for their high efficacy
and their fast onset of action. However, they are only recommended for treatment of acute anxiety as long term
use of benzodiazepines leads to a wide range of adverse effects including sedation, improper coordination,
memory loss, depression, dependence, and potential for abuse (3). The use of antidepressants, venlafaxine,
imipramine, and paroxetine, in the treatment of anxiety has been shown to be efficacious; however, these drugs
exhibit a delayed onset of action and various adverse effects including nausea, insomnia, jitteryness, restlessness
and agitation. As a result, patients on antidepressants usually terminate the treatment before full recovery from
anxiety is accomplished (3). The use of TCAs, such as clomipramine, is also efficacious; however, its
anticholinergic side effects are so severe that patients also tend to end the treatment before full recovery is
reached (1). Studies with buspirone have showed that it also exhibits a more gradual onset of action and may
have a lower efficacy than benzodiazepines. Its adverse effects include GI symptoms and dizziness (3).
As a result, a newer anxiolytic agent is required that has similar or better characteristics of efficacy and
onset of action as benzodiazepines, exhibits a better profile of safety and no dependence, and indicated for
long term treatment of anxiety.
In this chapter, a double blind, placebo controlled, parallel-group study design will be used to test the
efficacy and safety of investigational drug XXX versus placebo in patients diagnosed with moderate to
severe anxiety. Previous clinical studies have shown that drug XXX is a highly potent serotonin 1A receptor
agonist, is not structurally or chemically related to benzodiazepines, has no sedative effect, does not lead to
dependence, has a fast onset of action, requires once daily dosing and is eliminated by biotransformation. In
this study design, these properties of the drug will be better characterized and its efficacy will be determined.
The example of the study design illustrated in this chapter is most applicable to trials for evaluating
anxiolytic drugs intended to be used in patients with moderate to severe anxiety as the first line of treatment.
II. PHASE II STUDIES FOR REGISTRATION OF NEW ANXIOLYTIC DRUGS
II.1. Outline of a typical development plan
This study will examine the efficacy and safety of drug XXX in men and women experiencing moderate
to severe anxiety. All patients enrolled in the study meeting inclusion/exclusion criteria and that give
consent will be randomly assigned to receive one oral daily dose of drug XXX or placebo for 6 months.
Efficacy and safety measures are going to be performed at weekly intervals up to week 4, then at 2-week
intervals up to week 12, and then at 4-week intervals up to the end of the 6 months. The study will be
randomized, double blind, placebo-controlled and patients will come back for two follow-up assessments. II.2. Long-term studies
II.2.a. Study Objectives
a. To compare the efficacy of drug XXX treatment versus placebo in reducing the symptoms of anxiety. b. To compare the safety of drug XXX treatment versus placebo
a. To determine the onset of the anxiolytic action of drug XXX b. To determine the duration of the anxiolytic effect of drug XXX c. To determine the peak anxiolytic effects of drug XXX
II.2.b. Primary Endpoints
Rating scales will be administered to assess the following dependent variables:
a. Structured Clinical Interview for DSM-IV to diagnose patients with Generalized Anxiety Disorder b. The Hamilton Rating Scale for Anxiety, HAM-A to asses severity of anxiety (score ≥ 18 for
patients with severe anxiety and a score of ≥ 2 on the HAM-A item 1 (anxious mood) and item 2 (tension)). It is a simple 14-item five step rating scale. Each item is a group of symptoms that represents one general criterion associated with the disorder. For example, the combination of worries, anticipation of the worst, apprehension, and irritability determine anxious mood. This scale is simple, specific for anxiety measurement, and sensitive to drug effects (4).
c. The Stait-Trait Anxiety, STA-IX to measure subject selection (the Trait) and treatment effects (the
Stait). It is a self-evaluation scale that consists of 20 items with a four step severity scale. The Questionnaire asks the patient to indicate how he/she feels at the moment (state) or in general (trait) by selecting “not at all”, “somewhat”, “moderately so”, or “very much so”, with the latter indicating high anxiety (4).
Responders to the anxiolytic drug XXX versus placebo, where a response is defined as:
R = a reduction from baseline (week 1) to week 8 and a similar or a further reduction from baseline to the
end of month 6 as measured by the HAM-A, in order to determine the differences in efficacy and safety
between the short-term outcome (by week 8) and the long-term outcome (by the end of month 6).
R = a reduction in anxiety measures from baseline to week 8 and a similar or further reduction from
baseline to the end of month 6 as measured by the STA-IX scale.
II.2.c. Secondary Endpoints
a. The time of onset of a consistent decrease in anxious mood as measured by the Visual Analogue
Anxiety Scale (VAAS) compared to baseline (4).
b. The day during which the greatest reduction in anxious mood is present as measured by the HAM-A. c. The number of patients that achieve HAM-A ≤ 10 or full recovery.
Adverse effects are measured by changes in blood pressure, heart rate, GI motility, and abnormal laboratory
tests (blood and liver). II.2.d. Study Design
This is a double blind, randomized, placebo-controlled, parallel-group study. The subjects will be
administered either a single oral dose of drug XXX or a single oral dose of placebo daily for 6 months. The
number of patients receiving drug XXX will equal the number of patients receiving placebo within each
group. The anxiolytic effects of drug XXX will be measured using various questionnaires (discussed below).
Objective measures, such as blood pressure, will also be obtained. The results will be compared and
analyzed between and within groups. Screening for Eligibility (Visit 1)
Subjects will be interviewed to ensure suitability for study participation a week before the commencement
of the study. The following will be required to assess eligibility:
b. Structured Clinical Interview for DSM-IV to assess psychiatric status and to rule out dependence
c. Current level of anxiety (Hamilton Depression Scale (HAM-A), State-Trait Anxiety (STA-IX)).
This is the baseline measure which all upcoming results will be compared against.
d. Brief medical examination (heart rate, blood pressure). e. Medical history. f. Review of inclusion/exclusion criteria. g. Pregnancy test for women. h. Blood and urine samples to assess liver function, hematology, biochemistry, and to detect the
i. Participants will be provided with a pager number to be used if they experience any serious side
effects and a wallet card containing information about participation in this study.
j. Patients are also given a diary in which they record drug compliance and any side effects that they
Treatment Phase (Visits 1-10, Months 1-6)
a. Eligible subjects will attend 11 treatment sessions (weekly intervals up to week 4, then at 2-week
intervals up to week 12, and then at 4-week intervals up to the end of the 6 months).
b. Medical examination. c. Medication will be dispensed (enough pills to last for the next visit at once daily dosing). d. Treatment will consist of 30 to 45 minute sessions with the research assistant. e. A psychiatrist will be available for consultation, assessment, and treatment as needed (i.e. adverse
drug reaction, increases in severity of anxious symptomatology).
f. Review Daily Diary forms on which patients record compliance with medication and any side
effects that the patient may be experiencing.
g. At each visit, the HAM-A and the STA-IX, and VAS will be completed and subjects will be
interviewed regarding concomitant illness and medication use.
h. Ask patients to return any unused medication in the vial. i. Blood will be drawn for trough drug concentrations at visits 2, 4, 6, 8, 9, 10, and 11 (weeks 2, 4, 8,
12, 16, 20, 24 after commencing medication).
j. Blood and urine will also be collected at visits 2, 4, 6, 8, 9, 10, and 11 for drug screen, complete
k. Subjects will be referred to their family physicians either at the end of the 6 months or if a subject
decides to terminate participation in the study.
l. Individuals who do not respond to drug XXX will be referred to alternate psychiatric treatment or
Follow-up visits 11 and 12 (at 8 months and at the 12 months after treatment)
a. Review daily diary. b. Medical examination. c. Psychiatrist: examine any increased anxious symptoms, interview patients for concomitant illness,
and examine potential adverse reactions.
d. Complete questionnaires: HAM-A, STAI-XI, VAS. e. Blood and urine collection for drug screen, complete biochemistry, and hematology analyses.
II.2.f. Planned Sample
Refer to Flemming’s Single Stage Procedure Subsection V (planned sample) of the Mood disorders
Section II.2.e. in Chapter 20.
II.2.f. Study Population
Male or Female over 18 years of age meeting DSM-IV criteria for GAD and who exhibit moderate to
severe anxiety or a Ham-A score of ≥ 18, and a score of ≥ 2 on the HAM-A item 1 (anxious mood) and
item 2 (tension). II.2.g. Specific Inclusion Criteria
A subject will be eligible for inclusion in the study only if all of the following criteria apply:
a. Males or females between 19 to 50 years of age. b. Socially stable. c. Meet DSM-IV criteria for general anxiety disease. d. In-patients or out-patients. e. Non smokers.
II.2.h. Specific Exclusion Criteria
Exclusion criteria must take into account the characteristics of the drug (pharmacokinetics, and
pharmacodynamics, drug-drug interactions, and adverse effects). Patients will not be eligible to
participate in the study if any of the following criteria apply:
a. If they meet criteria for comorbid anxiety and MDD, or Panic disorder, or Obsessive compulsive
b. Active suicidal ideation. c. If they meet criteria for Bipolar Disorder, schizophrenia, schizo-affective or other substance
d. Evidence of medical or surgical illness requiring treatment. e. History of psychoactive drug dependence or a positive urine test for psychoactive drugs f. Use of medications which may interfere with the study procedures (e.g. SSRIs). g. Any clinically significant abnormality evident in biochemistry or hematology test results or in
urine analysis requiring further investigation.
h. Receiving or will receive other investigational drug during the study. i. Pregnant or lactating females.
II.2.i. Tools to Assess Endpoints
The tools used to assess efficacy are shown in the following table.
Time of Assessment
decrease in anxiety symptoms Time of greatest reduction in
symptoms of anxiety Number of patients achieving
The tools to assess safety are described in Subsection II.2.i. (Tools to Assess Safety) of the Mood
Disorders Section of Chapter 20.
II.2.j. Specific criteria for early withdrawal and discontinuation
Refer to Subsection II.2.j. (Specific criteria for early withdrawal and discontinuation) of the Mood
Disorders Section of Chapter 20. II.2.k. Data Analysis Method
Refer to Subsection II.2.k. (Data Analysis Method) of the Mood Disorders Section of Chapter 20. III. REFERENCES
1. Gray J. 2003. Therapeutic Choices. 4th edition. Canadian Pharmacist Association. Ottawa, Canada.
2. American Psychiatric Association. 2000. Diagnostic Criteria From DSM-IV-TR. Washington, DC,
3. Montgomery SA, Mahe V, Haudiquet V, Hackett D. Effectiveness of venlafaxine, extended release
formulation, in the short-term and long-term treatment of generalized anxiety disorder: results of a survival analysis. J Clin Psychopharmacol 2002;22:561-567.
4. Riezen HV, Segal M. 1988. Comparative Evaluation of Rating Scales for Clinical
Psychopharmacology. NewYork, Amsterdam, Oxford. Pp:123-334, 483-458.
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