Emailing Famous Drug Trials in Psychiatry

Government of India
CENTRAL INSTITUTE OF PSYCHIATRY, RANCHI

FAMOUS DRUG TRIALS IN THE LAST TEN YEARS IN PSYCHIATRY
Chairperson: Dr. Avinash Sharma MD
Presenter: Dr Surjit Prasad Discussant: Dr Sachchidanand Singh
Venue: A. B. Davis Hall Date: 27.01.2011
PRESENTATION DISCUSSION
❖ Introduction ❖ Introduction
❖ History ❖ Types of Experimental Studies
❖ What do Clinical Drug Trials Entail ❖ Ethical Issues in Clinical Trials
❖ Types of Clinical Drug Trials ❖ Special Populations in Clinical Trials
❖ Famous Drug Trials in Psychiatry ❖ Special Problems of Trials in Psychiatry
➢ Schizophrenia ❖ Statistical Issues in Clinical Trials
I. CATIE ❖ Economic Evaluation of Trials
II. CUtLASS ❖ The Indian Context
III. EUFEST ❖ The Future of Psychiatric Trials
IV. SOHO ❖ Conclusion
V. TEOSS
➢ Mood Disorders
I. STAR*D
II. STEP-BD
III. BOLDER I
IV. BOLDER II
V. EMBOLDEN I
VI. EMBOLDEN II
VII. BALANCE
VIII. TADS
IX. ADAPT
➢ Obsessive-Compulsive Disorder
I. POTS
➢ Autism
I. STAART
II. RUPP
➢ Anxiety Disorders
I. CAAM
➢ Substance Use Disorders
I. NALMEFENE
❖ Special Populations
➢ Alzheimer’s Disease
I. CATIE-AD
II. DIADS
➢ Cardiac Disease
I. SADHART
II. CREATE
III. ENRICHD
❖ Drug Trials on Newer Psychotropics
❖ Clinical Trials In India
❖ Drug Trials In CIP
INTRODUCTION
A cornerstone of the improvements in treatment in medicine in general and psychiatry

in particular has been the introduction of an acceptable scientific approach to treatment
evaluation, i.e., the clinical trial. Such trials are also the cornerstone of the modern evidence-
based medicine movement (Sackett & Rosenberg, 1996). Initially clinical trials in psychiatry
largely involved the evaluation of drug treatments. More recently, however, psychological
therapies have also been subjected to the rigors of the clinical trial, although there has been a
growing awareness that the logistical problems of such trials differ from those of the average
drug trial.
The clinical trial is a medical experiment designed to evaluate which (if any) of two or
more treatments is more effective. It is based on one of the oldest principles of scientific
investigation that new information is obtained from a comparison of alternate states.
The three main components of a clinical trial are:
• Comparison of a group of patients given the treatment under investigation (the treatment
group) with another group of patients given either an older or standard treatment, if one exists,
or an ‘inert treatment’ generally known as a placebo (the control group).
• A method of assigning patients to the treatment and control groups.
• A means of assessing effectiveness, i.e. a measure of outcome – this may range from a simple
rating of ‘improved/not improved’ to a numerical measure of some characteristic of the patient
such as their depression. Most trials in psychiatry will involve several measures of outcome
(Everitt & Wessley, 2008).
Prasad S, Singh S, Sharma A. Famous drug trials in the last ten years in psychiatry. 1
HISTORY
Clinical trials of some sort are probably as old as civilization. James Lind, an 18th-
century Scottish physician is generally credited with having completed the first controlled trial
— of vitamin C for scurvy. The gold standard of medical experimentation, the randomized
control trial (RCT), was first used to evaluate the effects of antituberculous drugs in a trial
sponsored by the Medical Research Council and published in 1948 (Anderson & Reid 2004).
It is unclear who carried out the first truly randomized controlled trial in psychiatry.
According to Healy (1997) there can be four candidates:
• A placebo-controlled randomly allocated trial of chlorpromazine for treating schizophrenia
carried out in 1954 in Birmingham, UK, by the husband-and-wife team of Joel and Charmain
Elkes (Elkes & Elkes, 1954).
• Again in 1954 a trial performed by Linford Rees who randomly allocated 100 anxious patients
to either placebo or chlorpromazine (Rees, 1956).
• A trial undertaken at the Maudsley Hospital in London by David Davies and Michael
Shepherd to study the use of reserpine for treating depression. This trial began in 1953 but
reports of it did not appear until 1955 (Davies, 1955).
• Finally during the same time period Mogens Schou and Eric Stromgren used a randomized
trial and showed the effectiveness of lithium as a treatment for mania (Schou, 1954).
Since trials take place over many months and indeed, in some cases, years, perhaps it
is unfair to try to label any one trial as the first in psychiatry. But certainly by the 1960s trials
in psychiatry had become far more ambitious and complex than those undertaken a few years
earlier. The UK Medical Research Council clinical trial of the treatment of depressive illness
illustrates the change. This trial, the results of which were published in 1965, was hailed as a
landmark study and as a ‘breakthrough in psychiatry’s aspirations to free itself from complete
reliance on empiricism’. The trial, which was conducted in three geographically dispersed
regions within the UK, involved some 55 psychiatrists, recruited 269 patients with depression,
randomized them to one of four treatment groups (two classes of antidepressant drug, ECT,
and a placebo), and then followed them for almost six months (Everitt & Wessley, 2008).
WHAT DO CLINICAL DRUG TRIALS ENTAIL

Drug development
■New drugs can be developed by isolating the active ingredients in natural compounds,
modifying the chemistry of other drugs and from theoretical extension of basic science
knowledge.
■Only about 1 in every 10,000 potential products reaches the market, often taking 10 years or
more and after huge costs. Given the limited patent life, drug companies often adopt aggressive
marketing strategies to recoup their costs and deliver profits for shareholders.
■A new drug is first tested in animals, to establish potential for desired effects and absence of
unexpected or undesirable effects, before going through the four phases in humans:
➢ Phase I trials determine basic pharmacological parameters in human volunteers, e.g.
pharmacokinetics, adverse effects, tolerance. They are usually open or uncontrolled.
Adverse effects are often measured both subjectively and objectively (e.g. heart rate,
blood pressure, EEG, etc.). Generally require 24-hour clinical observations and often
exclude the young, women and the old because effects in humans are unknown;
however, a drug safe in adult men, for example, may not be safe in children, women
and the aged. Because studies are uncontrolled some of the effects will be placebo
effects.
➢ Phase II trials establish whether or not a given drug works in a variety of conditions.
They are usually controlled, in that some patients get placebo. In ‘dose-ranging studies’,
to determine optimal dosage, each group of patients getting a particular dose of the
drug can be thought of as a control group for the others.
➢ Phase III, sometimes called ‘comparative’ trials, seeks to determine the effects of a new
drug with reference to those commonly used in clinical practice. They are usually
randomized with a proportion of patient under placebo controlled arm. They tend to be
larger than Phase II studies. Their major aim is to satisfy regulatory authorities and
achieve a product license.
➢ Phase IV ‘clinical’ trials refer to the various methods of surveillance to establish the
frequency of any serious or unexpected adverse effects of a drug once it has been
licensed and introduced into regular clinical practice. It is similar to audit and
naturalistic outcome studies (Anderson & Reid, 2004).
Types of Clinical Drug Trials (Schulz et al., 1995)

■ Uncontrolled Trials: Establish whether a treatment works at all and also the profile of
adverse effects. However, nonspecific/placebo effects cannot be excluded in the absence of a
control group.
■ Controlled Trials: Allow evaluation against placebo or a pre-existing treatment; may reduce or
control for placebo effects; in the absence of randomization are still subject to selection bias
(conscious or unconscious). Patients getting a new treatment tend to be less severely ill and/or
have better prognosis. Beneficial effects of new drugs are typically overestimated by 30-40%.
■ Randomized Controlled Trials (RCTs): Randomization increases the scientific quality or
‘internal validity’ of a trial. There are problems with ‘external validity’, i.e. patients able to give
informed consent and willing to be randomized tend to differ from many potential participants.
This limits their representativeness and hence the generalizability of the results to all patients.
RCTs designed to show a greater effect than placebo (with sufficient statistical power) are
required to establish efficacy. RCTs against comparator drugs are frequently too poorly
powered to be able to show a difference, and claims of equal efficacy need to be treated with
caution. Recently so called non-inferiority studies have been used in this situation. These are
designed to have sufficient statistical power to detect a pre-defined difference between drugs,
which is believed to be of clinical importance.
■ Pragmatic Trials: Have more external but less internal validity. Patient groups are
representative, the interventions are routinely feasible and outcome measures are clinically
relevant. One option is to enroll patients for whom the clinician is uncertain as to which
treatment should be prescribed. Pragmatic trials are increasingly being applied in psychiatry.
■ Patient Preference Trials: Are a specific type of pragmatic trial. Patients not willing to be
randomized are given their preferred treatment. They are followed-up as in the trial and their
results are compared with those who were randomized.
■ Crossover Trials: All participants receive two (or more) interventions one after the other, with
the two groups receiving a different treatment first. These are useful in relatively rare diseases
where small numbers do not permit an RCT. However, it is difficult to ensure that the trial is
long enough to see therapeutic effects but short enough to avoid natural fluctuations
confounding the trial. Also there is the problem of carry-over effects from first treatment period
to the second, and the potential for drug interactions. ‘Wash-out periods’ of no treatment
introduce new difficulties with sudden cessation of potentially effective treatments.
■ N-of-1 trials: These are crossover trials in which a patient is given two treatments. May be
useful if it is not known which treatment they may benefit from. Require patient consent and
co-operation from the hospital pharmacy.
■ Audit and naturalistic outcome studies: These are not usually thought of as clinical trials but
are similar to Phase IV ‘trials’. These are uncontrolled and therefore unreliable even if patients
are used as their own ‘historical control’. Nevertheless may provide valuable effectiveness
information.
FAMOUS DRUG TRIALS IN PSYCHIATRY
A. SCHIZOPHRENIA
I. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (Stroup
et al., 2003)
This study, funded by National Institute of Mental Health, United States, was an RCT of
1460 patients with schizophrenia involving the following medications: perphenazine,
fluphenazine decanoate, clozapine, olanzapine, quetiapine, risperidone, ziprasidone and
aripiprazole. Patients were followed for up to 23 months and re-randomized to a new treatment
in the event of treatment failure. This trial was conducted with the following aims:
1. To determine the long-term effectiveness and tolerability of the newer atypical

antipsychotics, relative to each other.
2. To determine the long-term effectiveness and tolerability of the newer atypical
antipsychotics, relative to perphenazine, across the spectrum of schizophrenic illness. The
authors hypothesized that treatment with the newer atypical antipsychotics would be
associated with greater long-term effectiveness and tolerability than treatment with
perphenazine. 3. To determine, among patients who fail treatment with an initially assigned
newer atypical antipsychotic, the long-term effectiveness and tolerability of the newer atypical
antipsychotics, relative to clozapine. The authors expected patients with inadequate resolution
of psychopathology, or exquisite sensitivity to extra-pyramidal side effects (EPSEs), to
preferentially select this Phase 2 trial. The authors hypothesized that treatment with clozapine
would be associated with greater long-term effectiveness and tolerability than treatment with a
newer atypical drug other than the one the patient initially received. 4. To determine, among
patients who failed treatment with an initially assigned newer antipsychotic, the long-term
effectiveness and tolerability of the newer atypical antipsychotics, relative to ziprasidone. The
authors expected patients with weight gain, hyperglycemia, or hyperlipidemia would
preferentially enter this Phase 2 trial. The authors hypothesized that treatment with
ziprasidone would be associated with greater long term effectiveness and tolerability than
treatment with a newer atypical drug other than the one the patient initially received.
Figure 1: The CATIE study design
Study Design
The Schizophrenia Trial aimed to enroll 1,600 persons with schizophrenia (excluding first
episode and treatment-refractory patients).
Inclusion Criteria were as follows:
1. Patients aged 18-65 years were enrolled. 2. Patients who at the time of the trial or in the
past had met the DSM-IV criteria for schizophrenia. 3. Patients who entered the study should,
according to their own judgment in consultation with their physician, have been appropriate
for treatment with an oral medication. 4. Patients should have demonstrated adequate
decisional capacity to make a choice about participating in this research study and had to
provide informed consent to participate.
Exclusion Criteria were as follows:
1. Patients with a DSM-IV diagnosis of schizoaffective disorder, mental retardation, pervasive
developmental disorder, delirium, dementia, amnesia, or other cognitive disorders were
excluded. 2. Patients with well documented, drug-related, serious adverse reactions to even one
of the proposed treatment arms were excluded. 3. Patients in their first episode of
schizophrenia were excluded. Patients were considered to be in their first episode if the patient
first began antipsychotic drug treatment for psychosis within the previous 12 months and had
psychotic symptoms for less than 3 years. 4. Patients with well-documented histories of failure
to respond to even one of the proposed treatment arms were excluded. A treatment failure was
considered to have occurred if the patient continued to demonstrate severe psychopathology in
spite of fully adhering to treatment at an adequate dose of the medication for an appropriate
length of time.
Specific dose and duration criteria were as follows:
Olanzapine at dosages ≥30 mg/day for 6 consecutive weeks;
Quetiapine at dosages ≥800 mg/day for 6 consecutive weeks;
Perphenazine at dosages ≥32 mg/day for 6 consecutive weeks;
Risperidone at dosages ≥6 mg/day for 6 consecutive weeks;
Ziprasidone at dosages ≥160 mg/day for 6 consecutive weeks.
5. Patients currently, or in the past, treated with clozapine for treatment resistance were
excluded. Patients who had taken clozapine for reasons other than treatment resistance were
considered eligible. 6. Patients who had been stabilized on haloperidol decanoate or
fluphenazine decanoate at the time of the trial and who required long-acting injectable
medication to maintain treatment adherence were excluded. 7. Women who were pregnant or
breast-feeding were excluded. Women of child-bearing potential agreeing to use appropriate
contraception were allowed to enroll. 8. Patients with tardive dyskinesia (TD) were excluded
from assignment to conventional antipsychotic treatment arms. 9. Patients with a
contraindication to any of the drugs to which they might be assigned were excluded. 10.
Patients with a medical condition that was serious and acutely unstable were excluded. 11.
Patients with cardiac impairment were excluded. 12. Patients who had taken any
investigational drug within 30 days of the baseline visit were excluded.
PHASE 1
Patients were randomly assigned to one of 5 treatment conditions for up to 18 months: (1) 300
began double-blind treatment with perphenazine (PER) (2) 300 began double-blind treatment
with olanzapine (OLZ) (3) 300 began double-blind treatment with quetiapine (QUET) (4) 300
began double-blind treatment with risperidone (RIS) (5) 200 began double-blind treatment with
ziprasidone (ZIP).
PHASE 1A: Up to 200 patients screened and found to have TD who would otherwise be eligible
for the study were randomly assigned to one of the four atypical drugs in Phase 1A. PHASE 1B:
Patients who failed treatment with perphenazine were randomly assigned to olanzapine,
quetiapine, or ziprasidone in Phase 1B.
PHASE 2
Patients who discontinued their initial assigned treatment for any non-administrative reason
proceeded to their second assigned treatment and were followed for up to the remainder of
their 18 month participation, as follows: (1) Patients originally assigned to one of the newer
atypical antipsychotics who discontinued due to Efficacy failure were randomly assigned to
double-blind treatment with one of the other two newer atypical antipsychotics which they had
not previously received (50%) or with open label clozapine (50%). (2) Patients originally
assigned to one of the newer atypical antipsychotics who discontinued due to Tolerability
failure were randomly assigned to double blind treatment with one of the other newer atypical
antipsychotics (OLZ, RIS, QUET) (50%), or with ziprasidone (if they had not previously received
it) (50%)[see Figure 1].
PHASE 3
1. Patients who discontinued their Phase 2 treatment were recommended open treatment
based on their treatment history in the study. The treatment options included: clozapine,
newer atypical antipsychotic (OLZ, RIS, QUET, ZIP, ARP), fluphenazine decanoate, and dual
antipsychotic therapy (risperidone or perphenazine augmentation of current atypical drug).
Double-blinded Medications:
Olanzapine 5 mg recommended dose range 5-20 mg/day;
Perphenazine 8 mg recommended dose range 8-32 mg/day;
Risperidone 1.5 mg recommended dose range 1.5-6 mg/day;
Quetiapine 200mg recommended dose range 200-800 mg/day;
Ziprasidone 40mg recommended dose range 40-160 mg/day.
Primary Outcome Measure: Time to all-cause treatment failure marked by its discontinuation
was the primary outcome variable. Although symptoms, side effects, functioning, costs, etc.,
are important outcomes, this study chose treatment discontinuation as the primary outcome
because it is a distinct and “sturdy” measure that reflects both efficacy and side effects and it
is a clinically meaningful outcome.
Secondary Outcome Measures: Additional assessments included measures for clinical and
functional outcomes, safety, neuro-cognition, health service utilization and cost.
RESULTS: in Phase 1/1A, olanzapine had an advantage in time to treatment discontinuation
that was similar in magnitude compared to all other drugs in Phase 1/1A. Also in Phase 1/1A,
olanzapine showed no significant advantages over perphenazine in symptom reduction in any
analyses, but had small advantages over each of the other newer medications in at least some
analyses (Stroup et al., 2006). In Phase 2E, clozapine had longer time to treatment
discontinuation than risperidone and quetiapine. In Phase 2T, olanzapine and risperidone were
more effective than quetiapine and ziprasidone. In Phase 1B, which enrolled people who had
discontinued perphenazine, olanzapine and quetiapine were more effective than risperidone.
There were no statistically significant differences among any pair of the four second generation
antipsychotics on either total costs, quality adjusted life-years (QALYs), or the other measures
of effectiveness, with the exception of symptoms, on which olanzapine was superior to both
risperidone and quetiapine. Olanzapine was superior to other second-generation
antipsychotics, with the exception of risperidone, in cost-benefit analysis.
The study found no significant differences between medication groups and no distinct
superiority of any antipsychotic in improving psychosocial functioning, as measured by quality
of life scale. There were improvements within treatment groups compared to baseline, but
improvements were largely comparable across medication groups. At 12 months, there were
relatively modest improvements for the olanzapine (0.19), risperidone (0.26), perphenazine
(0.19), and ziprasidone (0.26) treatment groups, and somewhat less improvement for
quetiapine (0.09), although the quetiapine treatment group did roughly as well as other groups
at 6 and 18 months. Using a variety of measures of dystonia, parkinsonism, akathisia, and TD,
the analysis of incidence rates and continuous measures from CATIE showed no substantial or
statistically significant differences between modest doses of the intermediate potency first
generation antipsychotic (FGA) and second generation antipsychotics (SGA). All of the
antipsychotic treatment groups had a small improvement in neuro-cognition as measured by
the primary outcome measure for this study, that is, change in a composite score derived from
11 neuro-cognitive tests assessed at baseline and after 2 months of treatment. However, there
was no significant difference among the groups. Quite surprisingly, exploratory analyses
suggested that, after 18 months of treatment, there might be differences among the treatments,
with the older antipsychotic perphenazine demonstrating the most neuro-cognitive
improvement (Keefe et al., 2007).
The initial CATIE publications provided summary information on a core group of
metabolic parameters, including weight, serum cholesterol, hemoglobin A1C, glucose, and
triglycerides (TG) (including fasting and non-fasting values for both) . These data provide sound
confirmation of olanzapine’s metabolic liabilities, particularly the effects on weight, TG, and
glycemic control by A1C (but not serum glucose), while ziprasidone was associated with
metabolic improvement in a manner seen in previously published switch studies. Risperidone
and quetiapine were previously believed to have equivalent metabolic profiles, but there was a
clear signal for quetiapine having a significant adverse impact on TG not seen with risperidone
(Meyer et al., 2006).
Illicit drug abusers or users were more likely to be younger, male, black, with recent
major depression, recent period of homelessness, and a more recent exacerbation of symptoms.
Most notable was the history of childhood conduct symptoms among illicit substance users.
Illicit drug users and abusers were less compliant with study medications and were more likely
to discontinue their initial study medication (Swartz et al., 2006).
In violence reduction, CATIE found that violence was reduced across all treatment
groups, declining from a prevalence of 16.3% to 9.3% in the retained sample; and from 19.1%
to 14.0% in the intention-to-treat sample. No differences by medication were found, with the
exception that perphenazine showed greater reduction in violence than quetiapine in the
retained sample only. Medication compliance across all treatment groups was significantly
associated with reduced violence, except in patients with a history of childhood conduct
problems. Significant prospective predictors of violence included childhood conduct problems,
substance use, victimization history, economic deprivation, and social living situation; living
with others, rather than alone, increased violence risk. Negative psychotic symptoms predicted
lower violence.
The finding was that burden associated with patient problem behaviors was positively
associated with positive but not with negative symptoms, while perceived functional
impairment was related to negative but not positive symptoms, and resource demands and
routine disruption were related to both. Older patients were rated as significantly less
burdensome and caregivers who were black reported significantly less burden in two of the
three domains. Perceived patient helpfulness was highest when the patient resided with the
caregivers and was employed.
CONCLUSIONS: In conclusion, the CATIE findings on effectiveness and symptom reduction
were that, overall, clozapine was most effective. Olanzapine demonstrated strong efficacy but
was not clearly better than perphenazine in any analysis. The older drug perphenazine was
similar in effectiveness to the newer drugs. Cost-benefit analysis presented here, which
combined cost and benefit data in a single analysis, found perphenazine to be superior to each
of the four second-generation antipsychotics with which it was compared. The CATIE trial
provided important information on other dimensions of schizophrenia, particularly on the
health and experience of a large sample of affected patients. These observations have
substantial public health significance, illuminating substance abuse patterns, violence, and co-
occurrence of metabolic disorder, TD, and impaired cognition. The CATIE trial was not
designed as an epidemiological study, but its sample size and the geographical distribution of
study sites substantiated its value as an important estimate of national experience in the
United States in these areas (Swartz et al., 2003).
LIMITATIONS (Essock et al., 2006): Controversial dose range: Fewer than half of CATIE subjects
received the maximal drug doses permitted in the study protocol. Mean modal medication
doses were 20 mg for olanzapine, 543.4 mg for quetiapine, 3.9 mg for risperidone, 20.8 mg for
perphenazine, and 112.8 mg for ziprasidone. Some observers have asserted that the SGAs
would have separated from perphenazine in effectiveness, or at least performed somewhat
better, if more aggressive dosing had been employed. Prior medication: About 22 percent of
people were taking olanzapine prior to recruitment to the study and when randomized 23
percent of them were allotted to olanzapine again. Similar finding were also with risperidone.
This may have contributed to long time until discontinuation for olanzapine. All-cause
discontinuation as primary outcome measure: In the CATIE trial, subjects were highly aware of
the alternative drug choices available under the trial’s design. This factor may have influenced
patient decisions to switch (i.e., discontinue) their current medications. Together with the
controversial dose range, this feature may have influenced the outcome of the study.
Perphenazine as a representative FGA: Perphenazine was selected as the comparator FGA
because it falls between haloperidol and chlorpromazine. Although perphenazine was
introduced in the 1960s, and is an FGA, its first metabolite—n-dealkyl-perphenazine has
reduced dopamine receptor D2 subtype affinity and greater serotonin affinity. This pattern of
pharmacological properties may make perphenazine behave more like an SGA than an FGA
such as haloperidol or chlorpromazine.
II. Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study

(CUtLASS) (Jones et al., 2006)
INTRODUCTION: CUtLASS was a pragmatic, open, multicentre, RCT of first generation
antipsychotics (FGAs) vs. second generation antipsychotics (SGAs) for schizophrenia, with
blind rating of outcomes across 1 year. The trial was funded by the Health Technology
Assessment Program of the United Kingdom National Health Service and received no financial
support from the pharmaceutical industry. The key question was whether the additional
acquisition costs of SGAs over FGAs would be offset by improvements in health-related quality
of life or savings in the use of other health and social care services in people with schizophrenia
for whom a change in drug treatment was being considered for clinical reasons, most
commonly sub-optimal efficacy or adverse effects.
OBJECTIVE: To test the hypothesis that in people with schizophrenia requiring a change in
treatment, SGAs other than clozapine were associated with improved quality of life across 1
year compared with FGAs. DESIGN: A non-commercially funded, pragmatic, multi-site,
randomized controlled trial of antipsychotic drug classes, with blind assessments at 12, 26,
and 56 weeks using intention-to-treat analysis. SETTING: Fourteen community psychiatric
services in the English National Health Service.
Participants: Two hundred twenty-seven people aged 18 to 65 years with DSM-IV schizophrenia
and related disorders assessed for medication review because of inadequate response or
adverse effects. Interventions: Randomized prescription of either FGAs or SGAs (other than
clozapine), with the choice of individual drug made by the managing psychiatrist.
Main Outcome Measures: Quality of Life Scale scores, symptoms, adverse effects, participant
satisfaction, and costs of care.
RESULTS: The primary hypothesis of significant improvement in Quality of Life Scale scores
during the year after commencement of SGAs vs. FGAs was excluded. Participants in the FGA
arm showed a trend toward greater improvements in Quality of Life Scale and symptom scores.
Participants reported no clear preference for either drug group; costs were similar. There were
no significant difference in outcome measures of adverse effect, participation satisfaction and
cost of care between first generation and second generation antipsychotics (Lieberman, 2006).
CONCLUSIONS: In people with schizophrenia whose medication is changed for clinical reasons,
there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs
of care in using FGAs rather than non-clozapine SGAs. Neither inadequate power nor patterns
of drug discontinuation accounted for the result.
III. European First Episode Schizophrenia Trial (EUFEST)

(Fleischhacker et al., 2005)
INTRODUCTION : Most studies comparing second generation antipsychotics with classical
neuroleptics have been conducted in more or less chronic schizophrenia patients. Such studies
were usually conducted in highly selected samples, and were generally designed and financed
by the manufacturer of the drug tested. These and other facts have stimulated discussions
regarding the effectiveness of the new generation of antipsychotics. The aim of the European
First Episode Schizophrenia Trial (EUFEST) was to compare treatment with amisulpride,
quetiapine, olanzapine and ziprasidone with a low dose of haloperidol in an unselected sample
of first episode schizophrenia patients with minimal prior exposure to antipsychotics. This
study was funded by three companies Astra Zeneca, Pfizer and Sanofi Synthelabo through
European Foundation for Research in Schizophrenia, which was the governing body of this
study.
METHODOLOGY: There were a total of 50 centres in 13 European countries and Israel. Eligible
patients were 18-40 years of age and met DSM-IV criteria for schizophrenia, schizophreniform,
or schizoaffective disorder confirmed by the Mini International Neuropsychiatric Interview Plus.
Patients were excluded if: (1) more than 2 years had passed since the onset of positive
symptoms; (2) any antipsychotic had been used exceeding 2 weeks in the previous year or 6
weeks lifetime; (3) patients had a known intolerance to one of the study drugs; and (4) patients
met any of the contraindications for any of the study drugs as mentioned in the (local) package
insert texts. The investigators informed eligible patients orally and in writing on the trial and
invited them to participate. Baseline data were obtained between 4 weeks before and 1 week
after randomization on demographics, diagnoses, current treatment setting, psychopathology
(Positive And Negative Syndrome Scale), severity of illness (Clinical Global Impression), overall
psychosocial functioning (Global Assessment of Functioning Scale), extrapyramidal symptoms
(St. Hans Rating Scale), adherence with antipsychotics (at 4 weeks after baseline), and
neurocognitive performance comprising six measures: Trail Making A [time], Flexibility Index
[Trail Making B–A time], Wechsler Adult Intelligence Scale Digit-symbol coding [total correct],
Purdue pegboard [total pegs with dominant hand], Rey Auditory Verbal Learning Test –
learning index [total correct on trials I–V], and Rey Auditory Verbal Learning Test – secondary
memory [total correct on Delayed Recall trial]). After complete description of the study to the
subjects, written informed consent was obtained. The primary outcome measure was retention
in treatment, defined as time to discontinuation of study drug. Loss of retention can be the
result of insufficient clinical effect, or lack of tolerability or acceptance. Secondary measures
included changes in different dimensions of psychopathology, side-effects, compliance, social
needs, quality of life, substance abuse and cognitive functions. Patients and their treating
psychiatrists were unmasked for the assigned treatment. This reflected routine clinical practice
and thereby increased the external validity of the trial (Fleischhacker et al., 2005).
RESULTS: Within 12 months, the proportions of patients with ≥50% response were 37% for
haloperidol, 67% for amisulpride, 67% for olanzapine, 46% for quetiapine, and 56% for
ziprasidone. Comparisons with haloperidol showed a higher likelihood for ≥50% response with
amisulpride, olanzapine, and ziprasidone. Within 12 months, the proportions of patients in
remission were 17% for haloperidol, 40% for amisulpride, 41% for olanzapine, 24% for
quetiapine, and 28% for ziprasidone. Comparisons with haloperidol showed a better chance for
remission on amisulpride, olanzapine, quetiapine, and ziprasidone. Compared with patients on
haloperidol, patients on amisulpride or olanzapine showed higher remission rates. For
remission, better adherence increased the odds but substance misuse decreased it. Age,
gender, baseline akathisia, baseline parkinsonism, and baseline neuro-cognitive performance
were also predictors of response (Kahn et al., 2008).
CONCLUSIONS: EUFEST concluded that substantial proportions of first-episode patients with
schizophrenia showed clinically meaningful response and remission rates within 12 months.
The proportions of response and remission were higher for most SGAs as compared to
haloperidol.
IV. Schizophrenia Outpatient Health Outcome (SOHO) Study (Haro et al., 2003a).
INTRODUCTION: The ideas behind the SOHO study emerged from the wish to find out what
happens to people with schizophrenia who take antipsychotic drugs while in real-world,
community settings to find out why clinicians and patients change current medication, and
what factors influence these choices. The SOHO study is unique in the schizophrenia field in
its design, its duration, its size and its aims that are beguilingly simple and have been designed
to answer questions about how people suffering from schizophrenia are actually treated and
how antipsychotic treatments influence long-term outcomes in terms of health status, work
and social functioning, quality of life and cost-effectiveness. In the simplicity of its aims and
concepts, and in its size, the SOHO study is a new design paradigm in the schizophrenia field.
It is at the interface between epidemiology, health sciences research and pharmaco-
surveillance. This study was funded by Eli Lilly and Company Limited.
STUDY DESIGN: SOHO was a 3-year, prospective, observational study of the health outcomes
associated with antipsychotic treatment in Europe. Over 10,000 patients had been recruited
from 10 countries. Baseline evaluation included measures of clinical status, social functioning,
quality of life, service use and pharmacological treatment. Patients were followed for 3 years.
The primary objectives of the study were to understand the comparative costs and outcomes of
therapy for schizophrenia with olanzapine vs. other antipsychotics and to understand the
pharmacological treatment patterns for schizophrenia, how these patterns are associated with
olanzapine vs. other antipsychotics and how these patterns are associated with outcomes.
Selection criteria: Patients of at least 18 years of age, treated for schizophrenia in the out-
patient, ambulatory or community setting giving consent for the study.
Participants: There were two patient cohorts of equal size -
• Group 1: patients who initiated or changed to olanzapine therapy;
• Group 2: patients who initiated or changed to non-olanzapine antipsychotic therapy.
Study investigators: Approximately 1100 psychiatrists from different treatment settings in the
following countries – Denmark, France, Germany, Greece, Ireland, Italy, Netherlands, Portugal,
Spain and United Kingdom.
Methods • All patient care was at the discretion of the participating psychiatrists • Data
collection was conducted for a minimum of 36 months • Data collection points were baseline
assessment (T1), 3 months (T2), 6 months (T3) and then every 6 months thereafter (T4–T8).
Outcome Measures • Demographic measures such as age, gender, alcohol and substance
dependency⁄abuse • Functioning measures such as living conditions, work, social relations,
relationship with spouse or partner. Clinical status was measured by Clinical Global
Impression (CGI) • Tolerability by extra-pyramidal symptoms, TD, hyperprolactinaemia, sexual
dysfunction • Antipsychotic medication: name, dose, dosage form, reason for change • Other
medications used such as anticholinergics, antidepressants, anxiolytics ⁄ hypnotics, mood
stabilizers.
Compliance, violence, health-related quality of life was measured by EuroQol D-5(EQ-5D) (five
items and visual analogue scale). Medical resource use: Day ⁄admissions for in-patient facilities,
out-patient visits, day hospital visits. Costs: Application of local unit cost standards to resource
units (Haro et al., 2003b)
RESULTS: A total of 10,972 patients were enrolled in the study. Of these, 767 (7.0%) were
excluded from this and future analyses due to failure to meet entry criteria or failure of
treatment cohort allocation. Most investigators were psychiatrists in public (46.9%) or
combined public and private (37.2%) practice. Patients had a mean duration of illness of 11.3
years (defined as the time since first service contact for schizophrenia treatment until inclusion
in the study). Most patients had received either a typical or atypical antipsychotic in the
previous 6 months. Only 15.3% received both a typical and atypical agent. A stringent
definition of recovery that included long-lasting symptomatic and functional remission as well
as an adequate quality of life for a minimum of 24 months and until the 36-month visit was
used. Of the 6642 patients analyzed, 33% achieved long-lasting symptomatic remission, 13%
long-lasting functional remission, 27% long lasting adequate quality of life, and 4% achieved
recovery during the 3 year follow-up period. Logistic regression analysis revealed that social
functioning at study entry (having good occupational/vocational status, living independently
and being socially active) and adherence with medication were factors significantly associated
with achieving recovery. Higher negative symptom severity, higher body mass index (BMI) and
lack of effectiveness as the reason for change of medication at baseline were baseline factors
associated with a lower likelihood of achieving recovery. Treatment with olanzapine was also
associated with a higher frequency of recovery compared with risperidone, quetiapine, typical
antipsychotics (oral, depot) and patients taking 2 or more antipsychotic medications. There
were no differences among the patients taking olanzapine, clozapine and amisulpride.
Predictors of long-lasting symptomatic remission, functional remission and adequate
quality of life were also independently analyzed. They indicated that only a small proportion of
patients with schizophrenia achieve recovery and suggest that social functioning, medication
adherence and type of antipsychotic are important predictors of recovery. Findings showed that
gender was a significant predictor for response based on the CGI scale and for improvement in
quality of life measured with the EuroQol-5D (EQ-VAS) scale, with women having a better
response. The highest gender differences were found in typical antipsychotics and clozapine.
Compared with olanzapine, patients taking depot typical drugs, oral typical drugs, risperidone,
and amisulpride had a significantly higher risk of developing EPS. Differences from clozapine
were marginally significant. High baseline clinical severity was associated with a significantly
higher risk of developing EPS. The incidence of TD ranged from 2.8% (olanzapine) to 11.1%
(depot typical agent). Compared with olanzapine, patients taking depot typical agents, oral
typical agents, and risperidone had a significantly higher risk of developing TD. Baseline
factors associated with a significantly higher risk of developing TD were age, EPS, and a higher
negative CGI score. Age at onset of schizophrenia, as measured by first treatment contact with
a diagnosis of schizophrenia, was 27.6 years for males and 30.6 years for females. Overall,
there were no meaningful differences in clinical severity between males and females. Social
functioning was better in females (higher proportions of females were living independently [58%
vs. 41%] and were involved in a relationship [41% vs. 22%]). The use of concomitant
medications differed greatly among the countries participating in the SOHO study. The
presence of depressive symptoms and being female were associated with the use of
concomitant antidepressants. Certain antipsychotics were associated with less use of
concomitant medications. Significantly fewer olanzapine, quetiapine and clozapine-treated
patients used concomitant anticholinergics or anxiolytics/hypnotics. Patients using
concomitant medications had an increased incidence of sexually related side effects and extra-
pyramidal side effects. The strongest predictor of medication adherence during follow-up was
adherence at baseline. Other baseline predictors of adherence included not using
antipsychotics in the previous 4 weeks, receiving treatment for first time, being socially active,
and a higher BMI. Baseline predictors of non-adherence were alcohol dependence, substance
abuse, hospitalization in previous 6 months, living in independent housing and having hostile
behaviors. Costs incurred by patients who ever relapsed (£14,055) during three years were
almost double to those incurred by patients who never relapsed (£7417).
Substantial improvements in quality of life (QoL) and health status were seen from
baseline to 6 months across all antipsychotic treatment cohorts. Olanzapine and oral typical
cohorts had the highest proportion of patients responding for overall symptoms.
Olanzapine and quetiapine treated patients were less likely to be treated with an
anticholinergic or experience EPS compared to patients treated with other antipsychotics. The
EQ-VAS score was highest for olanzapine and quetiapine or amisulpride treated patients.
Between baseline to 6 months, weight gain occurred across all cohorts with olanzapine treated
patients experiencing more weight gain than patients treated with other antipsychotics.
Compared to olanzapine, risk of treatment discontinuation was higher with typical
antipsychotics or risperidone. A higher baseline CGI positive score was associated with a
higher risk of treatment discontinuation. Olanzapine was associated with a lower frequency of
extrapyramidal symptoms than other antipsychotics, fewer prolactin-related adverse events
than risperidone and other atypical antipsychotics, but greater weight gain than typicals and
risperidone (Haro et al., 2008).
CONCLUSIONS: Patients treated with typical antipsychotic agents (oral and depot) and
risperidone had a higher risk of developing EPS and TD than patients treated with olanzapine.
Higher baseline clinical severity was associated with EPS development, whereas age, presence
of EPS, a higher negative CGI score, and presence of gynecomastia were associated with TD
development. Women with schizophrenia tended to have a later onset and better social
adjustment. Social functioning differences were not accounted for by differences in age of
onset. Gender differences were consistent throughout Europe. Alcohol dependence, substance
abuse and living independently were associated with non-adherence. Previous adherence, being
socially active and receiving medication for the first time was associated with better adherence.
The authors’ findings confirmed the significant economic burden of relapse, and showed such
costs were mainly due to hospital stay. Gender was a predictor of clinical response to
antipsychotic treatment, but its influence was not the same for all antipsychotics. Also,
treatment effectiveness and tolerability varied among antipsychotic medications in previously
untreated patients with schizophrenia.
V. Treatment of Early-Onset Schizophrenia Spectrum Disorder (TEOSS)

Study (Sikich et al., 2008)
INTRODUCTION: Atypical (second-generation) antipsychotics are considered standard
treatment for children and adolescents with early-onset schizophrenia and schizoaffective
disorder. However, the superiority of SGAs over FGAs has not been demonstrated. This study
compared the efficacy and safety of two second-generation antipsychotics (olanzapine and
risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset
schizophrenia and schizoaffective disorder.
Study Setting and Design
Eligible subjects were randomly assigned to molindone, olanzapine, or risperidone treatment
under double blind conditions for 8 weeks. The study was designed to have a total of 168
subjects equally distributed among three groups, n = 56 in each treatment group.
Participants
Eligible participants were 8–19 years old, with a focus on primarily younger participants, so
that 30% or fewer of subjects were between 16 and 19 years old. Participants had a diagnosis
of schizophrenia, schizoaffective disorder, or schizophreniform disorder and had current
positive psychotic symptoms of at least moderate intensity, as rated on the PANSS. DSM-IV
diagnoses were made by a child psychiatrist and confirmed with the Children’s Structured
Clinical Interview for DSM-IV (KID-SCID) and a teleconference among the principal
investigators. The initial diagnosis was reviewed upon completion of the study and revised as
indicated, including re-classifying all those initially diagnosed with schizophreniform disorder.
Individuals with prior evidence of mental retardation, current major depressive episode, active
substance abuse, history of intolerance or non-response to any of the study treatments during
a prior episode, history of an adequate trial of any of the study treatments during the current
episode (defined as at least 8 weeks of treatment, including at least 2 weeks at the maximal
dose allowed in the current study), or those individuals felt to be at imminent risk of harming
themselves or others were excluded from the study. All participants with prior exposure to one
of the study medications had the opportunity for greater drug exposure during the trial. All
participants and their guardians provided written informed consent.
Interventions: Study medications were packaged in identical colour-coded capsules. Dosing was
flexible, allowing for clinician judgment within the following dose ranges: molindone, 10–140
mg/day; olanzapine, 2.5–20 mg/day; and risperidone, 0.5–6 mg/day. Medications were
initiated at the lowest dose within the range and typically increased to the middle of the dose
range within 10 days for those subjects age 12 years and older and within 14 days for those
ages 8–11 years, according to the age-specific schedules provided elsewhere. All participants
treated with molindone also received 1.0 mg benztropine; all others received a placebo identical
in appearance. Antipsychotics and side-effect medications in use at the time of random
assignment were cross-tapered during the first 2 weeks of study treatment. Individuals whose
mood symptoms had been well controlled on a stable dose of antidepressants or non-
antipsychotic mood stabilizers for at least 4 weeks prior to study entry were allowed to
continue those treatments during the study. Concomitant treatments with anticholinergic
agents, propranolol, and benzodiazepines were guided by algorithms.
Outcomes: The primary outcome was responder status at the end of the acute trial. Responder
status was defined prior as a CGI improvement score of 1 (“very much improved”) or 2 (“much
improved”), plus ≥20% reduction in baseline PANSS score and the ability to tolerate 8 weeks of
treatment. Individuals who withdrew prior to 8 weeks were considered non-responders.
Additional efficacy measures included the PANSS positive and negative symptom subscales, the
Brief Psychiatric Rating Scale for Children (BPRS-C), and the Child and Adolescent Functional
Assessment Scale. In each of these measures, higher scores reflect more severe symptoms. A
combination of adult measures and child measures was used to fully assess psychotic
symptoms and to establish validity of adult measures in this population. Secondary safety and
tolerability outcomes included neurological side-effects, changes in weight and stature, vital
signs, laboratory analyses, ECG analyses, and incidence of systematically elicited adverse
event, serious adverse events, and treatment discontinuation for any reason.
RESULTS: In total, 119 youth were randomly assigned to treatment. Of these subjects, 116
received at least one dose of treatment and thus were available for analysis. No significant
differences were found among treatment groups in response rates (molindone: 50%;
olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and
risperidone were associated with significantly greater weight gain. Olanzapine showed the
greatest risk of weight gain and significant increases in fasting cholesterol, low density
lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of
akathisia.
CONCLUSIONS: Risperidone and olanzapine did not demonstrate superior efficacy over
molindone for treating early onset schizophrenia and schizoaffective disorder. Adverse effects
were frequent but differed among medications. The results question the nearly exclusive use of
SGAs to treat early-onset schizophrenia and schizoaffective disorder. The safety findings
related to weight gain and metabolic problems raise important public health concerns, given
the widespread use of second-generation antipsychotics in youth for non-psychotic disorders.
LIMITATIONS: The most significant weakness of this study was the sample size, which was
sufficient only to detect large differences across the three treatments and limited the ability to
identify predictors of response or adverse effects. The duration of treatment in the study did
not provide information about side effects that appeared later, such as tardive dyskinesia.
Another potential limitation of the study was the 8-week duration of treatment. Different
patterns of response or risk of side effects might have emerged over a longer trial.
B. MOOD DISORDERS
I. Sequenced Treatment Alternatives to Relieve Depression (STAR*D)

(Fava et al., 2003)
INTRODUCTION: STAR*D was one of the largest, independent and most robust studies ever
undertaken by the National Institute of Mental Health (USA) to examine the effectiveness of a
variety of medications in the treatment of depression. It is considered to be one of the “gold
standards” in the world of treatment research for depression and came to a number of
important conclusions about depression medication treatment. The overall goal of the STAR*D
trial was to assess the effectiveness of depression treatments in patients diagnosed with major
depressive disorder, in both primary and specialty care settings. It was the largest and longest
study ever conducted to evaluate depression treatment. Each of the four levels of the study
tested a different medication or medication combination. The primary goal of each level was to
determine if the treatment used during that level could adequately treat participants’ major
depressive disorder (MDD). Those who did not become symptom-free could proceed to the next
level of treatment. The design of the STAR*D study reflects what is done in clinical practice
because it allowed study participants to choose certain treatment strategies most acceptable to
them and limited the randomization of each participant only to his/her range of acceptable
treatment strategies.
METHODOLOGY: Over a seven-year period, the study enrolled 4,041 outpatients, ages 18-75
years, from 41 clinical sites around the USA, which included both specialty care settings and
primary medical care settings. Participants represented a broad range of ethnic and
socioeconomic groups, so that results could be generalized to a broad group of real-world
patients. People were not eligible for the study if they had not tolerated or did not get well with
one or more of the treatments that were part of the first two STAR*D treatment steps, or if a
STAR*D treatment could not be safely used because of another medical condition or because
they were taking certain other medications. In addition, people with substance abuse disorders
that required detoxification, anorexia or bulimia, or obsessive compulsive disorder were not
eligible for the study because they required treatments that were not part of STAR*D. Of the
initial 4,041 participants, 1,165 were excluded because they either did not meet the study
requirements of having “at least moderate” depression or they chose not to participate. Thus,
2,876 “evaluable” people were included in level 1 result. Level 2 results included 1,439 people
who did not become symptom-free in level 1 and chose to continue. Level 3 results included
377 people, and Level 4 results included 142 people.
Figure 2. Sequential Therapies Evaluated in the STAR*D Trial
In level 1, participants were given the antidepressant citalopram for 12 to 14 weeks.

Those who became symptom-free during this time could move on to a 12-month follow-up
period during which the citalopram was continued, and patients were monitored. Those who
experienced intolerable side effects or did not become symptom-free during this level could go
on to level 2. Citalopram is representative of the class of antidepressant medications known as
selective serotonin reuptake inhibitors (SSRIs). It was chosen as the first treatment because it
generally is not associated with troublesome withdrawal symptoms when it is stopped, is easy
to administer (once a day), and has been shown to be safe for older adults and medically fragile
patients. It does not appear to interact unfavourably with other medications that some
participants may have been taking for other medical problems (Trivedi et al., 2006).
Level 2 was designed to help determine an appropriate next treatment step if the first
step did not work. Thus, in level 2, participants had the option of switching to a different
medication or adding on to their existing citalopram. Those who joined the “switch” group were
randomly assigned to either sertraline, bupropion sustained-release (SR), or venlafaxine
extended- release (XR). These medications were chosen for comparison because they represent
three different types of medications. Sertraline is an SSRI, the same class as the citalopram
used in level 1. Bupropion belongs to another class of antidepressant medication that works on
different neurotransmitters than SSRIs. Venlafaxine is a “dual-action” medication that works
on two neurotransmitters at the same time. Those who joined the “add-on” group were
prescribed either the non-SSRI antidepressant bupropion-SR, or buspirone, which is not an
antidepressant but enhances the action of an antidepressant medication. Participants could
also switch to, or add on, cognitive psychotherapy (Rush et al., 2006).
As in level 1, those who became symptom-free with their level 2 treatment could continue with
that treatment and entered the follow-up period. Those who did not become symptom-free, or
who experienced intolerable side-effects, could continue on to level 3.
In level 3, which like level 2 was designed to compare medications that are thought to
work differently in the brain and produce different results, participants again had the option of
either switching to a different medication or adding on to their existing medication. Those who
chose to switch their medication were randomly assigned to either mirtazapine — a different
type of antidepressant — or to nortriptyline — a tricyclic antidepressant — for up to 14 weeks.
Both work differently in the brain than the SSRIs and other medications used in levels 1 and 2
(Thase et al., 2007). In the level 3 add-on group, participants were randomly prescribed either
lithium — a mood stabilizer commonly used to treat bipolar disorder — or triiodothyronine (T3)
— a medication commonly used to treat thyroid conditions — to add to the medication they
were already taking. These medications were chosen because they have been shown to boost
the effectiveness of antidepressant medications (Nierenberg et al., 2006a).
In level 4, participants who had not become symptom-free in any of the previous levels
(and therefore considered to have highly treatment-resistant depression) were taken off all
other medications and randomly switched to one of two treatments — the monoamine oxidase
inhibitor (MAOI) tranylcypromine or the combination of venlafaxine XR with mirtazapine. These
treatments were chosen for comparison because previous research had suggested that they
may be particularly effective in people who had not received sufficient benefit from other
medications (Fava et al., 2006).
To ensure that every participant had the best chance of recovery with each treatment
strategy, a systematic approach called measurement-based care was used. This method
requires routine, consistent measurement of symptoms and side effects at each treatment visit
with easy-to-use measurement tools. It also involves the use of a treatment manual that
describes when and how to modify medication doses and dose adjustments to best tailor them
for individual participants so as to minimize side effects, maximize safety, and provide the best
chance of therapeutic benefit. This enabled STAR*D practitioners to provide consistent, high-
quality care (Fava et al., 2003; Rush et al., 2004).
RESULTS: In STAR*D, the outcome measure was a “remission” of depressive symptoms—
becoming symptom-free. This outcome was selected because people who reach this goal
generally function better socially and at work, and have a better chance of staying well than do
people who only achieve a response but not a remission.
In level 1, about one-third of the participants reached remission and about 10-15%
more responded, but did not reach remission. It took an average of 6 weeks of treatment for
participants to improve enough to reach a response and nearly seven weeks of treatment for
them to achieve a remission of depressive symptoms. In addition, participants visited their care
providers an average of 5 to 6 times. Participants who achieved remission stayed on the
treatment for an average of 12 weeks before going on to a 12-month follow-up period (Trivedi et
al., 2006).
In the level 2 switch group, about 25% of participants became symptom-free. All 3 of
the switch medications performed about the same and were equally safe and well-tolerated. In
the add-on group, about one-third of participants became symptom-free. Those who added
bupropion experienced less troublesome side effects and slightly more reduction of symptoms
than those who added buspirone (Rush et al., 2006).
In levels 2 and 3 where participants were allowed to either add-on or switch
medications, most participants found only one or the other treatment strategies acceptable.
Because most participants did not agree to be randomly assigned to one or the other treatment
strategy, the findings of the add-on and switch approaches cannot be compared. It is likely,
however, that people being treated in the real world also tend to limit their treatment
preferences to switching or adding on medications. In addition, the people in the switch and
add-on groups were a little different. The group who chose and were assigned to a switch
medication had more problematic side-effects while taking the preceding medication
(citalopram) than the group who chose and were assigned to an add-on medication (Fava et al.,
2006).
In the level 3 switch group, 12 to 20% of participants became symptom-free, and the
two medications used fared about equally well, suggesting no clear advantage for either
medication in terms of remission rates or side-effects. In the add-on group, about 20% of
participants became symptom-free, with little difference between the two treatments. However,
the T3 treatment was associated with fewer troublesome side effects than lithium (Nierenberg
et al., 2006a).
In level 4, seven to 10 percent of participants became symptom-free, with no
statistically significant differences between the medications in terms of remission, response
rates or side-effect burden. However, those taking the venlafaxine-XR/mirtazapine combination
experienced more of a reduction in depressive symptoms than those taking tranylcypromine.
Also, those who were treated with tranylcypromine were more likely to discontinue the
treatment citing side-effects as the reason. It is also possible that the dietary restrictions
associated with taking an MAOI could have limited its acceptability as a treatment (McGrath et
al., 2006.)
CONCLUSIONS: In conclusion, about half of participants in the STAR*D study became
symptom-free after two treatment levels. Over the course of all four treatment levels, almost
70% of those who did not withdraw from the study became symptom-free. However, the rate at
which participants withdrew from the trial was meaningful and rose with each level—21%
withdrew after level 1, 30% withdrew after level 2 and 42% withdrew after level 3. An overall
analysis of the STAR*D results indicates that patients with difficult-to-treat depression can get
well after trying several treatment strategies, but the odds of beating the depression diminish
with every additional treatment strategy needed. In addition, those who become symptom-free
have a better chance of remaining well than those who experience only symptom improvement.
And those who need to undergo several treatment steps before they become symptom-free are
more likely to relapse during the follow-up period. Those who required more treatment levels
tended to have more severe depressive symptoms and more co-existing psychiatric and general
medical problems at the beginning of the study than those who became well after just one
treatment level. These results underscore both the need for a better understanding of how
different people respond to different depression treatments, and the challenges in finding
broadly effective, short- and long-term depression treatments. Future research may help
identify which treatments work for which patients.
II. Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

Study (Sachs et al., 2003)
INTRODUCTION: STEP-BD is the largest, federally-funded treatment study ever conducted for
bipolar disorder in the USA. STEP- BD was designed to find out which treatments, or
combinations of treatments, are most effective for treating episodes of depression and mania
and for preventing recurrent episodes in people with bipolar disorder. Multiple treatments,
including medications and psychotherapies, currently are available for people with bipolar
disorder, but doctors are often uncertain which of these treatments actually work best for
specific aspects of the illness. STEP-BD’s size, scope and broad criteria for inclusion of
participants make its findings relevant to all patients seeking the most effective care for the
disorder, and provide much needed information to help doctors choose treatments for the
everyday care of those with the disorder (Nierenberg et al., 2006b).
METHODOLOGY: This was a large multicentre, double-blind clinical trial, a long-term
outpatient study that enrolled 4,360 participants from 22 sites over seven years (1998 to
2005). On contact with a STEP-BD treatment centre, patients with mood disorders were
informed about the study and offered standardized diagnostic evaluation with a STEP-BD
certified clinician. Those meeting criteria for any bipolar disorder were offered entry into the
study registry. Consenting patients received clinical care from a STEP-BD clinician, and all
visits were recorded using the Clinical Monitoring Form (CMF). At these follow-up visits, if the
patient’s status met eligibility criteria for a randomized study, consent was requested for entry
into that Randomized Care Pathway (RCP). Those ineligible or unwilling to consent remained in
the Standard Care Pathway. The same clinician treated the patient as they made transitions
from randomized to standard care. An independent evaluator administered formal assessments
and self-rated scales quarterly in year 1 and semi-annually thereafter. There were two kinds of
treatment "pathways" in STEP-BD, and participants had the opportunity to take part in both.
The medications and psychosocial interventions provided in these pathways are considered
among the best choices of treatment for bipolar disorder in everyday clinical practice. In the
"Best Practice Pathway," participants are followed by a STEP-BD certified doctor and all
treatment choices are individualized. Everyone enrolled in STEP-BD may participate in this
pathway. Participants and their doctors worked together to decide on the best treatment plans
and to change these plans if needed. Also, anyone who wishes to stay on his or her current
treatment upon entering STEP-BD may do so in this pathway. Adolescents and adults aged 15
years and older may participate in the Best Practice Pathway.
Best Practice Pathway participants, received individualized care based on their
symptoms, past history, medical conditions, and other factors. Most received mood-stabilizing
(anti-manic) medication and, where necessary, additional medications as indicated by best
practices guidelines. Participants and their doctors worked together to decide on the best
treatment plan, and changed these plans if needed. Those wishing to stay on their current
treatment plan upon entering STEP-BD could also do so in this pathway. Participants in the
Best Practice Pathway could enter a STEP-BD randomized clinical trial if they met certain
eligibility requirements. The largest randomized trial studied treatment options for the acute
depressive episode and included both medication and psychotherapy. In the randomized trials,
participants were never assigned medications to which they had bad reactions in the past, that
they were strongly opposed to, or that the doctor felt was unsuitable for them. Participants in
the randomized trials could return to the Best Practice Pathway for their treatment at any time
(Sachs et al., 2003).
RESULTS: The STEP-BD study was designed to answer several broad areas of investigation. It
focused on three broad areas of findings: Comorbidity findings, Psychopharmacology findings,
and Psychotherapy findings.
Lifetime comorbid anxiety disorders were common, occurring in over one-half of the
sample, and were associated with younger age at onset, decreased likelihood of recovery, poorer
role functioning and quality of life, less time euthymic, and greater likelihood of suicide
attempts. Although substance abuse disorders were particularly prevalent among patients with
anxiety disorders, comorbid anxiety appeared to exert an independent, deleterious effect on
functioning, including history of suicide attempts (Goldberg et al., 2007). STEP BD data show
that anxiety and ADHD comorbidity is common among bipolar patients. Although gender
difference exists in the course of bipolar illness, comorbidity rates seem to be similar between
genders (Nierenberg et al., 2006b). Forty-two of the 179 subjects (23.5%) receiving a mood
stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187
subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P = 0.40). Modest non-
significant trends favouring the group receiving a mood stabilizer plus placebo were observed
across the secondary outcomes. Adjunctive antidepressant use was associated with
significantly higher mania symptom severity at the 3-month follow-up. The probability of
recovery at 3 months was lower among patients with higher baseline depression severity.
Antidepressant use neither hastened nor prolonged time to recovery (Goldberg et al., 2007).
Patients receiving intensive psychotherapy had significantly higher year-end recovery rates
(64.4% vs. 51.5%) and shorter times to recovery than patients in collaborative care (hazard
ratio, 1.47; 95% confidence interval, 1.08-2.00; P=.01). Patients in intensive psychotherapy
were 1.58 times (95% confidence interval, 1.17-2.13) more likely to be clinically well during any
study month than those in collaborative care (P=.003). No statistically significant differences
were observed in the outcomes of the 3 intensive psychotherapies i.e. family-focused therapy,
interpersonal and social rhythm therapy, and cognitive behaviour therapy.
CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with
the use of mood stabilizers, was not associated with increased efficacy or with increased risk of
treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess
the benefits and risks of antidepressant therapy for bipolar disorder. Regarding co-morbid
anxiety disorder an independent association of co-morbid anxiety with greater severity and
impairment in bipolar disorder patients was demonstrated, highlighting the need for greater
clinical attention to anxiety in this population, particularly for enhanced clinical monitoring of
suicidality. In addition, it is important to determine whether effective treatment of anxiety
symptoms can lessen bipolar disorder severity, improve response to treatment of manic or
depressive symptoms, or reduce suicidality. Intensive psychosocial treatment as an adjunct to
pharmacotherapy was more beneficial than brief treatment in enhancing stabilization from
bipolar depression. The authors suggested that future studies should compare the cost
effectiveness of models of psychotherapy for bipolar disorder.
III. BipOLar DEpRession (BOLDER) I study (DelBello et al., 2009)

INTRODUCTION: Quetiapine is efficacious in the treatment of acute bipolar mania, both as
monotherapy and in combination with other mood stabilizers. Preliminary evidence for the
efficacy of quetiapine in the treatment of depressive symptoms in a variety of psychotic and
mood disorders (including bipolar disorder, rapid-cycling bipolar disorder, and adolescent
mania) has been reported in several randomized or open-label studies. Based on the need for
new treatment options for bipolar depression, the effectiveness of atypical antipsychotics in
acute mania, and the emerging evidence for their use in bipolar depression, the authors
evaluated the efficacy and safety of quetiapine compared with placebo in the treatment of
depressive episodes in patients with bipolar I or bipolar II disorder.
METHODOLOGY: Five hundred forty-two outpatients with bipolar I (n=360) or II (n=182)
disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks
of quetiapine (600 or 300 mg/day) or placebo. The primary efficacy measure was mean change
from baseline to week 8 in the Montgomery-Åsberg Depression Rating Scale total score.
Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global
Impression of severity and improvement, Hamilton Anxiety Rating Scale, Pittsburgh Sleep
Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire.
RESULTS: Quetiapine at either dose demonstrated statistically significant improvement in
Montgomery-Åsberg Depression Rating Scale total scores compared with placebo from week 1
onward. The proportions of patients meeting response criteria (≥50% Montgomery-Åsberg
Depression Rating Scale score improvement) at the final assessment in the groups taking 600
and 300 mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for placebo.
The proportions of patients meeting remission criteria (Montgomery-Åsberg Depression Rating
Scale≤12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for
placebo. Quetiapine at 600 and300 mg/day significantly improved 9 of 10 and 8 of 10
Montgomery-Åsberg Depression Rating Scale items, respectively, compared to placebo,
including the core symptoms of depression. Treatment emergent mania rates were low and
similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively).
CONCLUSIONS: This was the first randomized, parallel group, placebo-controlled trial to
evaluate the efficacy of quetiapine in bipolar depression. Quetiapine monotherapy has
significant antidepressant efficacy in a group of patients with bipolar I or II depression based
on the primary efficacy analysis (mean change in Montgomery-Åsberg Depression Rating Scale
total score from baseline to last assessment). Compared with placebo, evidence of early and
sustained efficacy was observed consistently with both doses of quetiapine and in all secondary
efficacy analyses from week 1 onward.
LIMITATIONS: First, the number of enrolled patients with bipolar II disorder was not sufficient
to draw firm conclusions regarding efficacy in this subgroup. Second, moderate rates of
sedation or somnolence were observed in both quetiapine groups, which might have
compromised the integrity of the double-blind design. Third, although the study indicated that
the two doses used—chosen because of their efficacy in bipolar mania and other disorders—
were effective, guidance on the best dosing for most patients or subgroups of patients should
be assessed in future studies.
IV. BipOLar DEpRession (BOLDER) II STUDY (Thase et al., 2006)
INTRODUCTION: This was a pilot study comparing the effects of quetiapine and placebo for the
treatment of depressive episodes in adolescents with bipolar I disorder.
METHODOLOGY: Thirty-two adolescents (ages 12–18 years) with a depressive episode
associated with bipolar I disorder were randomized to eight weeks of double-blind treatment
with quetiapine, 300–600 mg ⁄day, or placebo. This two-site study was conducted from March
2006 through August 2007. The primary efficacy measure was change in Children’s Depression
Rating Scale–Revised Version (CDRS-R) scores from baseline to endpoint. Secondary efficacy
measures included change in CDRS-R scores over the eight-week study period, changes from
baseline to endpoint in Hamilton Anxiety Rating Scale (HAM-A), Young Mania Rating Scale
(YMRS), and Clinical Global Impression–Bipolar Version Severity (CGI-BP-S) scores, as well as
response and remission rates. Safety and tolerability were assessed weekly.
RESULTS: There was no statistically significant treatment group difference in change in CDRS-
R scores from baseline to endpoint, or in the average rate of change over the eight weeks of the
study. Additionally, there were no statistically significant differences in response (placebo =
67% vs. quetiapine = 71%) or remission (placebo = 40% vs. quetiapine = 35%) rates, or change
in HAM-A, YMRS, or CGI-BP-S scores between treatment groups. Dizziness was more
commonly reported in the quetiapine (41%) than in the placebo (7%) group.
CONCLUSIONS: The results suggest that quetiapine monotherapy is no more effective than
placebo for the treatment of depression in adolescents with bipolar disorder. However,
limitations of the study, including the high placebo response rate, may have contributed to this
finding and should be considered in the design of future investigations of pharmacological
interventions for this population.
V. Efficacy of Monotherapy Seroquel in BipOLar DEpressioN (EMBOLDEN) I Study

(Young et al., 2010)
INTRODUCTION: Depression dominates the course of bipolar disorder and is associated with
significant morbidity and mortality. Nonetheless, the treatment of acute depressive episodes in
bipolar disorder remains understudied and controversial. Most treatment guidelines for bipolar
disorder advocate first-line monotherapy with conventional mood stabilizers, especially lithium,
for mild to moderate episodes of depression. However, the empirical evidence supporting the
antidepressant efficacy of lithium is currently limited. The olanzapine-fluoxetine combination
(OFC) (Tohen et al., 2003) and quetiapine have each received registrations in the United States
for acute bipolar depression. But, head-to-head comparisons between established and newer
treatments are lacking. The present study (Efficacy of Monotherapy Seroquel in BipOLar
DEpressioN I [EMBOLDEN I]) is one of 2 large similarly designed studies that compared the
efficacy and tolerability of quetiapine monotherapy with that of placebo for the acute treatment
(8 weeks) of bipolar I and II disorder (most recent episode depression) followed by a 26- to 52-
week continuation treatment phase. The study included lithium (EMBOLDEN I) as a
comparator arm. The aim of this study was to compare the efficacy and tolerability of
quetiapine and lithium monotherapy with that of placebo for a major depressive episode in
bipolar disorder.
METHODOLOGY: Eight hundred and two patients with DSM-IV defined bipolar disorder (499
bipolar I, 303 bipolar II) were randomly allocated to quetiapine 300 mg/d (n = 265), quetiapine
600 mg/d (n = 268), lithium 600 to 1800 mg/d (n = 136), or placebo (n = 133) for 8 weeks.
Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale (MADRS)
total score. The study was conducted from August 2005 to May 2007.
RESULTS: Mean MADRS total score change from baseline at week 8 was –15.4 for quetiapine
300 mg/d, –16.1 for quetiapine 600 mg/d, –13.6 for lithium, and –11.8 for placebo (P < .001 for
both quetiapine doses, P = .123 for lithium vs. placebo). Quetiapine 600 mg/d was significantly
more effective than lithium in improving MADRS total score at week 8 (P = .013). Quetiapine-
treated (both doses), but not lithium-treated, patients showed significant improvements (P <
.05) in MADRS response and remission rates, Hamilton Depression Rating Scale (HDRS),
Clinical Global Impressions- Bipolar-Severity of Illness and -Change, and Hamilton Anxiety
Rating Scale (HARS) scores at week 8 versus placebo. Both quetiapine doses were more
effective than lithium at week 8 on the HDRS and HARS. The most common adverse events
were somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with
lithium.
CONCLUSIONS: Quetiapine (300 or 600 mg/d) was more effective than placebo for the
treatment of episodes of acute depression in bipolar disorder. Lithium did not significantly
differ from placebo on the main measures of efficacy. Both treatments were generally well
tolerated. The limitations of the study were that it did not include patients with suicidal
tendency and rapid cycling.
VI. Efficacy of Monotherapy Seroquel in BipOLar DEpressioN (EMBOLDEN) II

STUDY (McElroy et al., 2010)
OBJECTIVE: This study was a further continuation of EMBOLDEN I study, aim of the study
being to evaluate the efficacy and tolerability of quetiapine and paroxetine monotherapy for
major depression in bipolar disorder.
METHOD: Seven hundred and forty patients (478 bipolar I, 262 bipolar II) with major
depressive episodes (DSM-IV) were randomly assigned to quetiapine 300 mg/d (n = 245),
quetiapine 600 mg/d (n = 247), paroxetine 20 mg/d (n = 122), or placebo (n = 126) for 8 weeks.
The primary end point was the change from baseline in Montgomery-Asberg Depression Rating
Scale (MADRS) total score. The study was conducted from May 2005 to May 2007.
RESULTS: Mean MADRS score change from baseline at 8 weeks was –16.19 for quetiapine 300
mg, –16.31 for quetiapine 600 mg, –13.76 for paroxetine, and –12.60 for placebo (P < .001 for
both quetiapine doses, P = .313 for paroxetine vs. placebo). Quetiapine-treated (both doses),
but not paroxetine-treated, patients showed significantly greater improvements (P ≤ .05) in
most secondary outcome measures at week 8 versus the placebo group. Paroxetine significantly
improved Hamilton Anxiety Rating Scale scores versus placebo (P < .05) but not MADRS or
Hamilton Depression Rating Scale (HDRS) scores. Both quetiapine doses were associated with
greater improvements than paroxetine for MADRS and HDRS scores. The most common
adverse events were dry mouth, somnolence, sedation, and dizziness with quetiapine (both
doses) and dry mouth, sedation, headache, insomnia, and nausea with paroxetine. The
incidence of treatment emergent mania/hypomania was lower with quetiapine compared with
paroxetine and placebo.
CONCLUSIONS: Quetiapine (300 or 600 mg/d), but not paroxetine, was more effective than
placebo for treating acute depressive episodes in bipolar I and II disorder. Quetiapine treatment
was generally well tolerated.
VII. Bipolar Affective disorder: Lithium/ANti -Convulsant Evaluation

(BALANCE) Study (Geddes et al., 2002)
INTRODUCTION: Lithium carbonate and valproate semisodium are both recommended as
monotherapy for prevention of relapse in bipolar disorder, but are not individually fully
effective in many patients. If combination therapy with both agents is better than monotherapy,
many relapses and consequent disability could be avoided. This study aimed to establish
whether lithium plus valproate was better than monotherapy with either drug alone for relapse
prevention in bipolar I disorder (Rendell et al., 2004).
METHODOLOGY: BALANCE was a randomized, open-label, three-group trial of maintenance
therapy, with up to 24 months of follow-up. Three hundred and thirty patients aged 16 years
and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly
allocated to open-label lithium monotherapy (plasma concentration 0·4–1·0mmol/L, n = 110),
valproate monotherapy (750–1250 mg, n = 110), or both agents in combination (n = 110), after
an active run-in of 4–8 weeks on the combination. Randomization was by computer program,
and investigators and participants were informed of treatment allocation. All outcome events
were considered by the trial management team, who were masked to treatment assignment.
Participants were followed up for up to 24 months. The primary outcome was initiation of new
intervention for an emergent mood episode, which was compared between groups by Cox
regression. Analysis was by intention to treat.
RESULTS: Fifty-nine (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in
the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event
during follow-up. Hazard ratios for the primary outcome were 0·59 (95% CI 0·42–0·83,
p=0·0023) for combination therapy versus valproate, 0·82 for combination therapy versus
lithium, and 0·71 (0·51–1·00, p=0·0472) for lithium versus valproate. 16 participants had
serious adverse events after randomization: seven receiving valproate monotherapy (three
deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).
CONCLUSIONS: For people with bipolar I disorder, for whom long-term therapy is clinically
indicated, both combination therapy with lithium plus valproate and lithium monotherapy are
more likely to prevent relapse than is valproate monotherapy. This benefit seems to be
irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could
neither reliably confirm nor refute a benefit of combination therapy compared with lithium
monotherapy. Some of the limitations of the study are: first, treatment allocation was not
masked from the investigators or participants. Second, although the eligibility criteria required
that participants were not acutely unwell, symptomatic status was not systematically assessed
and some pre-randomization selection on the basis of response to treatment could have arisen.
Finally, although around 21% of patients withdrew from the trial before 24 months, reasons for
withdrawal did not differ between groups and was mainly due to intolerance (Geddes et al.,
2002).
VIII. Treatment of Adolescents with Depression (TADS) Study (March et

al., 2004a)
INTRODUCTION: Initial treatment of major depressive disorder in adolescents may include
cognitive-behavioral therapy (CBT) or an SSRI. However, little is known about their relative or
combined effectiveness. The Treatment for Adolescents with Depression Study evaluated the
effectiveness of fluoxetine hydrochloride therapy, cognitive behavior therapy (CBT), and their
combination in adolescents with major depressive disorder.
OBJECTIVE: To evaluate the effectiveness of 4 treatments among adolescents with major
depressive disorder. To report effectiveness outcomes across 36 weeks of randomized
treatment.
METHODOLOGY: Randomized controlled trial of a volunteer sample of 439 patients between
the ages of 12 to 17 years with a primary DSM-IV-TR diagnosis of major depressive disorder.
The trial was conducted at 13 US academic and community clinics between spring 2000 and
summer 2003 in which 327 patients participated. Cognitive behavior and combination
therapies were not masked, whereas administration of placebo and fluoxetine was double-blind
through 12 weeks, after which treatments were unblinded. Patients assigned to placebo were
treated openly after week 12.
INTERVENTIONS: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT
with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and
fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were
administered unblinded.
Main Outcome Measures: The primary dependent measures rated blind to treatment status by
an independent evaluator were the Children’s Depression Rating Scale–Revised total score and
the response rate, defined as a Clinical Global Impressions–Improvement score of much or very
much improved.
RESULTS: Intention-to-treat analyses on the Children’s Depression Rating Scale–Revised
identified a significant time-treatment interaction (P <.001). Rates of response were 73% for
combination therapy, 62% for fluoxetine therapy, and 48% for CBT at week 12; 85% for
combination therapy, 69% for fluoxetine therapy, and 65% for CBT at week 18; and 86% for
combination therapy, 81% for fluoxetine therapy, and 81% for CBT at week 36. Suicidal
ideation decreased with treatment, but less so with fluoxetine therapy than with combination
therapy or CBT. Suicidal events were more common in patients receiving fluoxetine therapy
(14.7%) than combination therapy (8.4%) or CBT (6.3%).
CONCLUSIONS: In adolescents with moderate to severe depression, treatment with fluoxetine
alone or in combination with CBT accelerates the response. Adding CBT to medication
enhances the safety of medication. Taking harm and benefit into account, combined treatment
appears superior to either monotherapy as a treatment for major depression in adolescents.
Thus it can be said that combination of fluoxetine with CBT offered the most favorable trade-off
between benefit and risk for adolescents with major depressive disorder.
LIMITATIONS: the patient’s knowledge of the treatment he/she received varied across the 4
groups and across the 2 treatment modalities. Psychotherapeutic interventions cannot be
masked at the participant level for experimental purposes, and the provision of CBT was not
masked in any treatment group. Regarding pharmacotherapy, provision of fluoxetine was
masked in 2 of the 4 groups. Blinding patients in the placebo and fluoxetine-alone groups but
not in the CBT-alone group (participants knew they would not be receiving fluoxetine) and the
fluoxetine combined with CBT group (participants knew that they would be receiving
fluoxetine) may have interacted with expectancy effects regarding improvement and
acceptability of treatment assignment. Patients assigned to combined treatment experienced
somewhat greater contact time than did patients assigned to fluoxetine therapy or CBT alone.
Patients deemed at high risk for suicidal behavior because of recent attempts or pervasive
suicidal thoughts were excluded from this outpatient study.
IX. Adolescent Depression Antidepressant and Psychotherapy Trial

(ADAPT) (Goodyer et al., 2008)
INTRODUCTION: The aim of this study was to determine if, in the short term, in depressed
adolescents attending routine National Health Service (UK) Child and Adolescent Mental Health
Services (CAMHS), and receiving ongoing active clinical care, treatment with SSRIs plus
cognitive behaviour therapy (CBT) compared with SSRI alone, resulted in better healthcare
outcomes. The specific research hypotheses addressed were that compared with SSRIs alone,
combined treatment would over the length of the trial:
● result in greater psychosocial improvement ● diminish the overall level of depressive
symptoms ● result in fewer patients meeting diagnostic criteria at final evaluation ● decrease
other public service use and be more cost-effective. In order to achieve these objectives, an RCT
of adolescent patients fulfilling criteria for DSM-IV-TR major depression or with threshold
major depression (four symptoms) and marked impairment was undertaken.
METHODOLOGY: A pragmatic RCT was conducted on depressed adolescents attending CAMHS
who had not responded to a psychosocial brief initial intervention (BII) prior to randomization.
Setting: Participants were recruited from two centres, Manchester in the north-west and
Cambridge in the east of England. Six CAMHS participated: four in Manchester (total
population 831,000) and two in Cambridge (total population 517,000).
Participants: A total of 208 patients aged between 11 and17 years were recruited and
randomized.
Interventions: All participants received active routine clinical care in a CAMHS outpatient
setting and an SSRI, and half were offered CBT.
Outcome measures: The duration of the trial was a 12-week treatment phase, followed by a 16-
week maintenance phase. Follow-up assessments were at 6, 12 and 28 weeks. The primary
outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents
(HoNOSCA). Secondary outcome measures were self-report depressive symptoms, interviewer-
rated depressive signs and symptoms, interviewer-rated psychosocial impairment and clinical
global impression of response to treatment. Information on resource use was collected in
interview at baseline and at the 12- and 28-week follow-up assessments using the Child and
Adolescent Service Use Schedule.
RESULTS: Of the 208 patients randomized, 200 (96%) completed the trial to the primary end-
point at 12 weeks. By the 28-week follow-up, 174 (84%) participants were re-evaluated.
Overall, 193 (93%) participants had been assessed at one or more time points. Clinical
characteristics indicated that the trial was conducted on moderate to severely depressed group.
There was significant recovery at all time points in both arms. The findings demonstrated no
difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or
secondary outcome measures at any time point. This lack of difference held when baseline and
treatment characteristics where taken into account (age, sex, severity, co-morbid
characteristics, quality and quantity of CBT treatment, number of clinic attendances). The
SSRI + CBT group was somewhat more expensive over the 28 weeks than the SSRI-only group
and no more cost-effective. Over the trial period there was on average a decrease in suicidal
thoughts and self-harm compared with levels recorded at baseline. There was no significant
increase in disinhibition, irritability and violence compared with levels at baseline. Around 20%
(n = 40) of patients in the trial were non-responders. Of these, 17 (43%) showed no
improvement by 28 weeks and 23 (57%) were considered minimally (n = 10) or moderately to
severely worse (n = 13).
CONCLUSIONS: For moderately to severely depressed adolescents who are non-responsive to a
BII, the addition of CBT to fluoxetine plus routine clinical care in moderate to severe
depressions does not improve outcome or confer protective effects against adverse events and is
not cost-effective. SSRIs (mostly fluoxetine) are not likely to result in harmful adverse effects.
The findings are broadly consistent with the National Institute for Health and Clinical
Excellence guidelines on the treatment of moderate to severe depression. Modification is
advised for those presenting with moderate (6–8 symptoms) to severe (> 8 symptoms)
depressions and in those with either overt suicidal risk and/or high levels of personal
impairment. In such cases, the time allowed for response to psychosocial interventions should
be no more than 2–4 weeks, after which fluoxetine should be prescribed.
LIMITATION: A potential limitation of ADAPT is that psychiatrists provided both CBT and
treatment in the SSRI only arm, so cross contamination may be a possibility.
C. OBSESSIVE COMPULSIVE DISORDER
I. Pediatric OCD Treatment Study (POTS) (Franklin et al., 2003)
INTRODUCTION: Among adults with OCD, one third to one half developed the disorder during
childhood or adolescence, which suggests that early intervention in childhood, may prevent
long-term morbidity in adulthood (DeVeaugh-Geiss et al., 1992). The purpose of this study was
to evaluate the efficacy of CBT alone and medical management with the SSRI sertraline alone,
or CBT and sertraline combined, as initial treatment for children and adolescents with OCD.
METHODOLOGY: The Pediatric OCD Treatment Study was a masked randomized controlled
trial conducted in 3 academic centres in the United States and enrolled a volunteer outpatient
sample of 112 patients aged 7 through 17years with a primary DSM-IV-TR diagnosis of OCD
and a Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score of 16 or higher.
Patients were recruited between September 1997 and December 2002. Interventions:
Participants were randomly assigned to receive CBT alone, sertraline alone, combined CBT and
sertraline, or pill placebo for 12 weeks. Main Outcome Measures: Change in CY-BOCS score
over 12 weeks as rated by an independent evaluator masked to treatment status; rate of
clinical remission defined as a CY-BOCS score less than or equal to 10.
RESULTS: Ninety-seven of 112 patients (87%) completed the full 12 weeks of treatment. Intent-
to-treat random regression analyses indicated a statistically significant advantage for CBT
alone, sertraline alone, and combined treatment compared with placebo. Combined treatment
also proved superior to CBT alone and to sertraline alone, which did not differ from each other.
Site differences emerged for CBT and sertraline but not for combined treatment, suggesting
that combined treatment is less susceptible to setting-specific variations. The rate of clinical
remission for combined treatment was 53.6%, for CBT alone 39.3%, for sertraline alone 21.4%,
and for placebo 3.6%. The remission rate for combined treatment did not differ from that for
CBT alone but did differ from sertraline alone and from placebo. CBT alone did not differ from
sertraline alone but did differ from placebo, whereas sertraline alone did not. The 3 active
treatments proved acceptable and well tolerated, with no evidence of treatment-emergent harm
to self or to others (March et al., 2004b).
CONCLUSION: The study concluded that children and adolescents with OCD should begin
treatment with the combination of CBT plus an SSRI or CBT alone.
D. AUTISM
I. Sponsored Studies to Advance Autism Research and Treatment

(STAART) (Hollander et al., 2009)
INTRODUCTION: It has been suggested that there are similarities between repetitive behavior
in autism spectrum disorders (ASDs) and obsessive-compulsive disorder. Serotonin system
abnormalities have been reported in autism. SSRIs are widely prescribed for children with
autism spectrum disorders. OBJECTIVES: This study determined the efficacy and safety of
citalopram hydrobromide therapy for repetitive behaviors in children with autism spectrum
disorders.
DESIGN: National Institutes of Health sponsored randomized controlled trial. SETTING: Six
academic centres, including Mount Sinai School of Medicine, North Shore–Long Island Jewish
Health System, University of North Carolina at Chapel Hill, University of California at Los
Angeles, Yale University, and Dartmouth Medical School. PARTICIPANTS: One hundred forty-
nine volunteers 5 to 17 years old were randomized to receive citalopram (n = 73) or placebo (n =
76). Participants had autistic spectrum disorders, Asperger’s disorder, or pervasive
developmental disorder, not otherwise specified; they had illness severity ratings of at least
moderate on the Clinical Global Impressions-Severity of Illness Scale; and scored at least
moderate on compulsive behaviours measured with the Children’s Yale-Brown Obsessive
Compulsive Scales modified for pervasive developmental disorders. Interventions: Twelve weeks
of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of
citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum 20 mg/d).
Main Outcome Measures: Positive response was defined by a score of much improved or very
much improved on the Clinical Global Impressions-Improvement subscale. An important
secondary outcome was the score on the Children’s Yale-Brown Obsessive Compulsive Scales
modified for pervasive developmental disorders. Adverse events were systematically elicited
using the Safety Monitoring Uniform Report Form.
RESULTS: There was no significant difference in the rate of positive response on the Clinical
Global Impressions- Improvement subscale between the citalopram-treated group (32.9%) and
the placebo group (34.2%). There was no difference in score reduction on the Children’s Yale-
Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from
baseline for the citalopram-treated group and for the placebo group. Citalopram use was
significantly more likely to be associated with adverse events, particularly increased energy
level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhoea, insomnia,
and dry skin or pruritus.
CONCLUSION: Results of this trial do not support the use of citalopram for the treatment of
repetitive behaviour in children and adolescents with ASDs.
LIMITATION: A potential limitation of this study is the selection of repetitive behavior as the
major treatment focus. The rationale for this target is the established efficacy of SSRIs for
reducing symptoms of obsessive-compulsive disorder in children and adolescents. However, it
may be that the repetitive behavior in children with ASDs is fundamentally different from what
is observed among children with obsessive-compulsive disorder in its behavioral picture.
II. Research Units on Paediatric Psychopharmacology (RUPP) Autism Network

(RUPP Study) (Aman et al., 2005)
INTRODUCTION: Hyperactivity and inattention are common symptoms in children with autistic
disorder and related pervasive developmental disorders, but studies of stimulants in these
conditions have been inconclusive. OBJECTIVES: This study determined the efficacy and
safety of methylphenidate hydrochloride in children with pervasive developmental disorders
and hyperactivity.
METHODOLOGY: Design: Double-blind, placebo-controlled, crossover trial followed by open-
label continuation. Setting: Five academic outpatient clinics. Participants: Seventy-two drug-
free children, aged 5 to 14 years, with pervasive developmental disorders accompanied by
moderate to severe hyperactivity. Interventions: Prior to randomization, subjects entered a 1-
week test-dose phase in which each subject received placebo for 1 day followed by increasing
doses of methylphenidate (low, medium, and high doses) that were each given for 2 days. The
low, medium, and high doses of methylphenidate hydrochloride were based on weight, and
they ranged from 7.5 mg/d to 50.0 mg/d in divided doses. Subjects who tolerated the test dose
(n = 66) were assigned to receive placebo for 1 week and then 3 methylphenidate doses in
random order during a double-blind, crossover phase. Children responding to methylphenidate
then entered 8 weeks of open-label treatment at the individually determined best dose. Main
Outcome Measures: The primary outcome measure was the teacher-rated hyperactivity
subscale of the Aberrant Behavior Checklist. Response was parent-rated and/or teacher-rated
Aberrant Behavior Checklist hyperactivity subscale score defined as “much improved” or “very
much improved” on the Clinical Global Impressions.
RESULTS: Methylphenidate was superior to placebo on the primary outcome measure, with
effect sizes ranging from 0.20 to 0.54 depending on dose and rater. Thirty-five (49%) of 72
enrolled subjects were classified as methylphenidate responders. Adverse effects led to the
discontinuation of study medication in 13 (18%) of 72 subjects.
CONCLUSION: Methylphenidate was often efficacious in treating hyperactivity associated with
pervasive developmental disorders, but the magnitude of response was less than that seen in
typically developing children with attention-deficit/hyperactivity disorder. Adverse effects were
more frequent.
LIMITATION: This study did not explore high doses of methylphenidate as certain individuals
require higher doses of the drug.
E. ANXIETY DISORDERS
I. Child-Adolescent Anxiety Multimodal (CAAM) STUDY (Walkup et al.,

2008)
INTRODUCTION: Anxiety disorders are common in children and cause substantial impairment
in school, in family relationships, and in social functioning. Such disorders also predict adult
anxiety disorders and major depression. Despite a high prevalence (10 to 20%) and substantial
morbidity, anxiety disorders in childhood remain under-recognized and under-treated.
Efficacious treatments for these disorders include cognitive behavioral therapy and the use of
SSRIs. However, randomized controlled trials comparing cognitive behavioral therapy, the use
of an SSRI, or the combination of both therapies with a control are lacking. The evaluation of
combination therapy is particularly important because approximately 40 to 50% of children
with these disorders do not have a response to short-term treatment with either monotherapy.
This study, called the Child–Adolescent Anxiety Multimodal Study, was designed to address the
current gaps in the treatment literature by evaluating the relative efficacy of cognitive
behavioural therapy, sertraline, a combination of the two therapies, and a placebo drug.
METHODOLOGY: In this randomized controlled trial, 488 children between the ages of 7 and
17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety
disorder, or social phobia were assigned to receive 14 sessions of cognitive behavioural therapy,
sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive
behavioural therapy, or a placebo drug for 12 weeks in a 2:2:2:1ratio. Categorical and
dimensional ratings of anxiety severity and impairment were administered at baseline and at
weeks 4, 8, and 12.
RESULTS: The percentages of children who were rated as very much or much improved on the
Clinician Global Impression–Improvement scale were 80.7% for combination therapy, 59.7% for
cognitive behavioural therapy, and 54.9% for sertraline; all therapies were superior to placebo
(23.7%). Combination therapy was superior to both monotherapies. Results on the Pediatric
Anxiety Rating Scale documented a similar magnitude and pattern of response; combination
therapy had a greater response than cognitive behavioral therapy, which was equivalent to
sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and
homicidal ideation, were no more frequent in the sertraline group than in the placebo group.
No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness
associated with cognitive behavioral therapy than with sertraline.
CONCLUSION: Both CBT and sertraline reduced the severity of anxiety in children with anxiety
disorders; a combination of the two therapies had a superior response rate.
F. SUBSTANCE ABUSE
Nalmefene in the Treatment of Heavy Drinkers (Karhuvaara et al., 2007)

INTRODUCTION: Clinical studies with opioid antagonists for treatment of problem drinking
have mainly been conducted in specialized alcohol treatment centres, included structured
psychosocial treatment, and have focused on maintaining abstinence after a period of
abstinence from alcohol. The primary aim of this multicentre study was to determine the
efficacy and safety of targeted nalmefene, used on an ‘‘as-needed’’ basis, in reducing heavy
drinking in a primary care like setting. The setting was ‘‘naturalistic’’; inclusion was based on
participants’ self-identification of drinking problems rather than a formal diagnosis of alcohol
dependence, no treatment goals were imposed on the subjects, and the psychosocial support
was kept to a minimum. METHODS: This multisite, randomized double-blind study
investigated targeted nalmefene in reducing heavy drinking. The study was conducted at 15
sites across Finland. Five of the sites were specialist treatment clinics (A-clinics), 6 sites were
private general practice offices, 2 sites were offices for occupational health care, and 2 sites
were specialized in conducting outpatient clinical research in a variety of conditions. The
subjects were recruited mainly by means of advertisements posted in newspapers. Study
enrolment began on December 17, 2001, and the last subject completed the study on June 6,
2003. The inclusion criteria applied were as follows: (i) at least 18 years old, (ii) difficulty in
controlling drinking, (iii) at least 18 heavy drinking days (HDDs) and no more than 14
consecutive abstinence days during the 12 weeks preceding inclusion. Subjects were excluded
if they had (i) any medical, psychiatric, or social problem whose treatment would be considered
to have a priority over the treatment of the alcohol problem, or that would interfere with the
conduct of the study or impair study treatment compliance, (ii) a severe hepatic or renal
disorder, (ii) were dependent on other drugs or used illicit drugs, (iii) had previously
participated in studies with nalmefene or recently participated in other drug studies, (iv) were
recently treated with disulfiram or naltrexone, or (v) were pregnant or nursing. After providing
written informed consent, subjects underwent screening procedures including the recording of
demographic and medical history, alcohol drinking and family alcohol history, physical
examination, laboratory and electro-cardiographic (ECG) examinations, a urine drug screen, a
screening interview to assess psychiatric problems, quantification of alcohol use during the
preceding 12 weeks using the time-line follow-back (TLFB) method, Alcohol Dependence Scale;
Drinker Inventory of Consequences; Beck Depression Inventory; and Beck Anxiety Inventory
were applied. The alcohol and drug dependence section of the Structured Clinical Interview for
DSM-IV Axis I Disorders (SCID-I) was used to obtain detailed diagnostic characterization of the
subjects’ alcohol problems. It enrolled 403 subjects (328 men, 75 women). Eligible subjects
were randomly allocated to receive, in a double-blind manner, 20 mg nalmefene hydrochloride
or matching placebo tablets in 3:2 ratio. The subjects were instructed to take 1 tablet of the
study medications preferably 1 to 2 hours before any intake of alcohol, when drinking seemed
imminent. Only 1 dose of study drug was allowed per study day. After 2 weeks in treatment,
the investigators were allowed to increase the dose of an individual subject to 2 tablets at a
time if the treatment response was considered inadequate. Conversely, in case of adverse
effects, halving of the dose was allowed. During the 28-week treatment period, the subjects
returned to the study site at 1, 2, 4, 8, 12, 16, 20, 24, and 28 weeks after inclusion for data
collection, and for medication check and dispensing. At each visit, alcohol use and study
medication intake since the previous visit were recorded with the TLFB method, treatment
response was assessed with a 7-point Clinical Global Improvement scale (CGI), and any
possible adverse events were elicited. Clinical laboratory examinations were repeated at weeks
12 and 28. At the end of week 28, subjects with a favourable treatment response (i.e., much or
very much improvement, based on the CGI assessment by the investigator) in the active
treatment group were offered an opportunity to continue in the study in a double-blind
randomized withdrawal period for an additional 24 weeks. These subjects were randomly
allocated to continue with the active drug or switch to placebo. Concomitant psychosocial
intervention was minimal and no treatment goals were imposed. Alcohol consumption was
recorded using the TLFB method. Biochemical indicators of alcohol use were also measured.
RESULTS: The mean monthly number of heavy drinking days (HDDs) during the 12-week
period before inclusion was 15.5 in the nalmefene group and 16.2 in the placebo group. During
treatment, the mean numbers of HDDs were 8.6 to 9.3 in the nalmefene group and 10.6 to
12.0 in the placebo group. The levels of serum alanine aminotransferase and γ-glutamyl
transferase decreased in the nalmefene group compared with the placebo group. During the
randomized withdrawal period, subjects randomized to placebo apparently returned to heavier
drinking. Subjects receiving nalmefene reported more nausea, insomnia, fatigue, dizziness, and
malaise than subjects on placebo.
CONCLUSIONS: Nalmefene appears to be effective and safe in reducing heavy drinking, even
when accompanied by minimal psychosocial support.
LIMITATIONS: Starting dose of nalmefene was 20 mg which is at higher limit as 10 mg of this
drug is also effective in reducing heavy drinking as reported in previous studies (Mason 1999);
several subjects who had been on nalmefene had psychotropic effects. The subjects
participating in this study were more functional, i.e. were more educated and had a higher rate
of employment and fewer psychiatric problems, than the usual clients. This could have
contributed to the positive treatment result.
DRUG TRIALS IN SPECIAL POPULATIONS
A. Alzheimer’s disease
I. Clinical Antipsychotic Trials of Intervention Effectiveness- Alzheimer’s

Disease (CATIE-AD) (Schneider et al., 2001)
INTRODUCTION: Psychotic symptoms are common in Alzheimer’s disease (AD) throughout its
clinical course but essential questions remain about the nature of "psychosis" in these
patients, in part because cognitive impairment limits self-report of symptoms and hence the
ability to identify typical features of psychosis. The available evidence indicates that up to one-
half of patients with AD may develop psychosis and/or agitation at some point during their
illness (Paulsen et al., 2000). Several medications are used commonly, but which are "better"?
How long should treatment last? What are the effects of medication discontinuation? These
questions led to the development of this study and drove the design of the Clinical
Antipsychotic Trials of Intervention Effectiveness - Alzheimer’s disease (CATIE-AD). Second-
generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and
agitation in patients with Alzheimer’s disease, but their benefits are uncertain and concerns
about safety have emerged. This study assessed the effectiveness of atypical antipsychotic
drugs in outpatients with Alzheimer’s disease.
STUDY SETTING AND DESIGN: This protocol was fundamentally a randomized treatment
assignment, parallel group, and double blinded treatment conducted in 42 sites in the United
States comparing risperidone, olanzapine, quetiapine, citalopram, and placebo in AD
outpatients with delusions, hallucinations, or agitation severe enough to warrant the use of
antipsychotic medications. Subjects were outpatients with a clinical diagnosis of dementia of
the Alzheimer's type (DSM-IV-TR) or probable AD. A subject must be experiencing delusions,
hallucinations, or agitation/aggression severe enough to (1) disrupt his or her functioning, and
(2) justify medication treatment in the opinion of the investigator. There were four phases:
Phase 1: In the initial treatment phase (phase 1), subjects were randomized to treatment with
an atypical antipsychotic or placebo. This phase was no shorter than 2 weeks and could be as
long as 36 weeks, the length determined by the investigator's assessment of adequacy of
treatment intensity and effect. Phase 2: Phase 2 commenced if the patient was randomized to
treatment with a second, different medication i.e., olanzapine, quetiapine, risperidone, or
citalopram. Patients could not be randomized to placebo in this phase. Phase 3: In phase 3, the
patient was randomized to open treatment with one of the study medications not previously
received—that is, olanzapine, quetiapine, risperidone, or citalopram. Phase 4: If the investigator
determines that the subject's response to the randomized open label medication is not
sufficiently optimal, then after the first 2 weeks in phase 3, the investigator can prescribe
another medication (of the investigator's choice). The main outcome measures were the time
from initial treatment to the discontinuation of treatment for any reason and the number of
patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC)
scale at 12 weeks.
RESULTS: There were no significant differences among treatments with regard to the time to
the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine
(median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks). The
median time to the discontinuation of treatment due to a lack of efficacy favoured olanzapine
(22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and
placebo (9.0 weeks). The time to the discontinuation of treatment due to adverse events or
intolerability favoured placebo. Overall, 24% of patients who received olanzapine, 16% of
patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients
who received placebo discontinued their assigned treatment owing to intolerability. No
significant differences were noted among the groups with regard to improvement on the CGIC
scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients
assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned
to placebo (P = 0.22).
CONCLUSIONS: Antipsychotic medications may be more effective for particular symptoms,
such as anger, aggression, and paranoid ideas. Functional abilities, care needs, or quality of
life does not appear to improve with antipsychotic treatment. Although the atypical
antipsychotic drugs were more effective than placebo, adverse effects limited their overall
effectiveness, and their use may be restricted to patients who have few or no side-effects and
for whom benefits can be discerned. Overall, the rates of discontinuation of treatment among
the four study groups ranged from 77 to 85%. Although the differences among the groups may
have been significant in a larger trial, the authors’ findings suggested that there was no large
clinical benefit of treatment with atypical antipsychotic medications as compared with placebo.
Clinicians, patients, and family members must consider both risks and benefits in order to
optimize a patient’s care.
LIMITATIONS: Lower doses of quetiapine were used than in other previous studies, higher rates
of side-effects, lack of any first generation antipsychotics such as haloperidol which have been
shown to be efficacious in prior studies (Alexopoulos et al., 2004).
II. Depression In Alzheimer’s Disease Study (DIADS) (Lyketsos et al., 2003)

INTRODUCTION: Major depression affects about 25% of patients who have Alzheimer’s disease
and has serious adverse consequences for patients and caregivers. Results of prior
antidepressant treatment studies have produced contradictory findings and have not fully
assessed the benefits of depression reduction. The aim of this study was to assess the efficacy
and safety of sertraline hydrochloride for the treatment of major depression in AD, and to
evaluate the effect of depression reduction on activities of daily living, cognition, and non-mood
behavioural disturbance. DESIGN: Randomized, placebo-controlled, parallel, 12- week, flexible-
dose clinical trial with a 1-week, single blind placebo phase. The study was conducted between
January 1, 1998, and July 19, 2001. SETTING: Participants were recruited from outpatient
clinics of The Johns Hopkins Neuropsychiatry Service, The Johns Hopkins Hospital, Baltimore,
Md, or The Copper Ridge Institute, Sykesville, Md, between January 1, 1998, and July 19,
2001. PARTICIPANTS: Inclusion criteria included: diagnosis of probable AD by the National
Institute of Neurological and Communicative Disorders and Stroke – Alzheimer’s Disease and
Related Disorders Association, score of 10 or more on the Mini-Mental State Examination
(MMSE), diagnosis of major depressive episode, using DSM-IV-TR, stable medical history and
general health. Exclusion criteria were: use of sertraline therapy contraindicated in the opinion
of the study psychiatrist, a lifetime diagnosis of schizophrenia, bipolar disorder, or pre-AD
anxiety disorder, current substance use disorder, acutely suicidal or requiring inpatient
psychiatric hospitalization as determined by the study psychiatrist. Forty-four outpatients who
had probable Alzheimer’s disease and major depressive episodes were included for study.
INTERVENTION: Total 44 patients were randomized of which 24 were randomized to sertraline
hydrochloride treatment and 20 were randomized to placebo group. Mean dosage of sertraline
was 95 mg/d, or identical placebo. Patients were assessed at 3, 6, 9, 12, and 24 weeks. Main
Outcome Measures: Response rate, Cornell Scale for Depression in Dementia, Hamilton
Depression Rating Scale, Mini-Mental State Examination, Psycho-geriatric Depression Rating
Scale–activities of daily living subscale, and Neuropsychiatric Inventory to quantify patient
behaviour disturbance and caregiver distress.
RESULTS: In the sertraline-treated group 9 patients (38%) were full responders and 11 (46%)
were partial responders compared with 3 (20%) and 4 (15%), respectively, in the placebo-
treated group. The sertraline treated group had greater improvements in the scores for the
Cornell Scale for Depression in Dementia and Hamilton Depression Rating Scale, and a
statistical trend toward less decline in activities of daily living on the Psycho-geriatric
Depression Rating Scale–activities of daily living subscale. There was no difference between the
treatment groups in Mini-Mental State Examination or Neuropsychiatric Inventory ratings over
time. When full responders, partial responders, and non responders were compared, full
responders only, or full and partial responders had significantly better ratings on activities of
daily living, behavioural disturbance, and caregiver distress, but not on the Mini-Mental State
Examination. Safety monitoring indicated few differences in adverse effects between the 2
treatment groups.
CONCLUSIONS: Sertraline is superior to placebo for the treatment of major depression in
Alzheimer’s disease. Depression reduction is accompanied by lessened behaviour disturbance
and improved activities of daily living, but not improved cognition.
LIMITATIONS: Participants were recruited from specialty referral clinics and needed to meet
strict inclusion criteria for both AD and major depression. Thus, these findings might not apply
to patients with other types of dementia or with milder mood disturbances. Similarly, these
findings might not apply to patients with more severe dementia (MMSE score < 10). Also, the
study sample size was small, and the global ratings of response were derived from physicians
reviewing scale scores over time, and not from in person examinations.
B. Cardiac Disease
I. Sertraline Anti-Depressant Heart Attack Randomized Trial (SADHART)

(Glassman et al., 2002)
INTRODUCTION: Many large-scale, well-controlled studies, in which initially healthy subjects

were followed up prospectively, have identified depression as a significant independent risk
factor for both first myocardial infarction (MI) and cardiovascular mortality. Similarly, among
individuals with established ischemic heart disease, depression has been found to be
associated with an approximately 3- to 4-fold increase in the risk of subsequent cardiovascular
morbidity and mortality. Major depressive disorder (MDD) occurs in 15% to 23% of patients
with acute coronary syndromes and constitutes an independent risk factor for morbidity and
mortality. However, no published evidence existed prior to this study that antidepressant drugs
are safe or efficacious in patients with unstable ischemic heart disease (Glassman et al., 1998).
The objective of this study was to evaluate the safety and efficacy of sertraline treatment of
MDD in patients hospitalized for acute MI or unstable angina and free of other life-threatening
medical conditions.
DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in 40
outpatient cardiology centres and psychiatry clinics in the United States, Europe, Canada, and
Australia. Enrolment began in April 1997 and follow-up ended in April 2001. The patients were
screened by Diagnostic Interview Schedule (DIS) and DSM-IV-TR criteria by an expert. Beck
Depression Inventory (BDI) was also applied on them. CRITERIA: To qualify for study entry,
male or female adults were required either to have had an acute MI or to have been
hospitalized for unstable angina in the past 30 days and to be experiencing a current episode
of MDD based on DSM-IV-TR criteria. Exclusion criteria included uncontrolled hypertension,
anticipated cardiac surgery, index MI of less than three months duration, heart rate less than
40/min. PATIENTS: A total of 556 patients met the study criteria and started receiving single
blind placebo for 14 days to permit time to complete pre-treatment cardiovascular assessments
and to ensure that the symptoms of depression had been present for a minimum of 2 weeks. A
psychiatrist repeated the DIS to verify that the patient met full criteria for MDD including 2-
week duration and impairment. Some patients no longer met MDD criteria and were excluded.
Finally 369 patients were selected for randomization. Consequently, individuals meeting the
higher depression severity (HAM-D score >18) and 2 previous episodes of MDD were defined
prior as the group in whom efficacy would be evaluated. Intervention: After a 2-week single-
blind placebo run-in, patients were randomly assigned to receive sertraline in flexible dosages
of 50 to 200 mg/d (n=186) or placebo (n=183) for 24 weeks. Main Outcome Measures: The
primary (safety) outcome measure was change from baseline in left ventricular ejection fraction
(LVEF); secondary measures included surrogate cardiac measures and cardiovascular adverse
events, as well as scores on the HAM-D scale and Clinical Global Impression Improvement
scale (CGI-I) in the total randomized sample, in a group with any prior history of MDD, and in
a more severe MDD subgroup defined prior by a HAM-D score of at least 18 and history of 2 or
more prior episodes of MDD.
RESULTS: Sertraline had no significant effect on mean LVEF, treatment-emergent increase in
ventricular premature complex (VPC), QTc interval greater than 450 milliseconds at end point,
or other cardiac measures. All comparisons were statistically non-significant. The incidence of
severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo. In the
total randomized sample, the CGI-I, but not the HAM-D, favoured sertraline. The CGI-I
responder rates for sertraline were significantly higher than for placebo in the total sample, in
the group with at least 1 prior episode of depression, and in the more severe MDD group. In the
latter 2 groups, both CGI-I and HAM-D measures were significantly better in those assigned to
sertraline.
CONCLUSION: Study results suggest that sertraline is a safe and effective treatment for
recurrent depression in patients with recent MI or unstable angina and without other life-
threatening medical conditions.
LIMITATIONS: The sample size was well short of the numbers needed to identify rare adverse
events or drug-drug interactions; treatment was initiated an average of 34 days following MI, as
a result, the effect of time-to-treatment onset requires further study. The results cannot be
generalized beyond the populations that were actually examined. Patients in this study
received much more “medical attention” than do the usual post-MI patients. It is unclear if that
level of support influenced response rates, and it is possible that in the usual care setting lower
spontaneous remission rates would result and higher drug-placebo treatment differences
would emerge (Shapiro et al., 1999).
II. Canadian Cardiac Randomized Evaluation of Antidepressant and

Psychotherapy Efficacy (CREATE) Study (Frasure -Smith et al., 2007)
INTRODUCTION: It has been recognized that depression is associated with increased

morbidity and mortality in coronary artery disease (CAD). Paucity of studies has augmented
the need for evidence-based treatment guidelines. This study was a multisite, Canadian trial of
the efficacy, safety, and tolerability of interpersonal psychotherapy (IPT) - an empirically
supported, depression-focused therapy, and the SSRI citalopram, alone or in combination, in
the treatment of major depression in CAD patients. RCTs have evaluated the efficacy of
treatments for major depression in patients with coronary artery disease (CAD). None have
simultaneously evaluated an antidepressant and short-term psychotherapy. OBJECTIVE: To
document the short-term efficacy of an SSRI (citalopram) and interpersonal psychotherapy
(IPT) in reducing depressive symptoms in patients with CAD and major depression. DESIGN,
SETTING AND PARTICIPANTS: The Canadian Cardiac Randomized Evaluation of
Antidepressant and Psychotherapy Efficacy was a randomized, controlled, 12-week, parallel-
group, 2x2 factorial trial conducted from May 1, 2002 to March 20, 2006, among 284 patients
with CAD from 9 Canadian academic centres. All patients met DSM-IV-TR criteria for diagnosis
of major depression of 4 weeks’ duration or longer and had baseline 24-item Hamilton
Depression Rating Scale (HAM-D) scores of 20 or higher. Interventions: Participants underwent
2 separate randomizations: (1) to receive 12 weekly sessions of IPT plus clinical management
(n=142) or clinical management only (n=142) and (2) to receive 12 weeks of citalopram, 20 to
40mg/d (n=142), or matching placebo (n=142). Main Outcome Measures: The primary outcome
measure was change between baseline and 12 weeks on the 24-item HAM-D, administered
blindly during centralized telephone interviews; the secondary outcome measure was self-
reported Beck Depression Inventory II (BDI-II) score (Frasure-Smith et al., 2007).
RESULTS: Citalopram was superior to placebo in reducing 12-week HAM-D scores. Mean HAM-
D response and remission rates and the reduction in BDI-II scores also favoured citalopram.
There was no evidence of a benefit of IPT over clinical management, with the mean HAM-D
difference favouring clinical management. The difference on the BDI-II did not favour clinical
management.
CONCLUSION: This trial documents the efficacy of citalopram administered in conjunction
with weekly clinical management for major depression among patients with CAD and found no
evidence of added value of IPT over clinical management. Based on these results and those of
previous trials, citalopram or sertraline plus clinical management should be considered as a
first-step treatment for patients with CAD and major depression. The results of this trial will
contribute to the development of evidence-based clinical guidelines for managing depression in
the context of CAD.
LIMITATIONS: Participants were recruited through advertisements and those unwilling to
accept randomization were excluded, with both factors reducing the generalizability of results;
more women were randomized to receive IPT than clinical management alone.
III. Enhancing Recovery In Coronary Heart Disease (ENRICHD) Study (Berkman.,

et al., 2001; de Leon et al., 2002)
INTRODUCTION: Depression and low perceived social support (LPSS) after myocardial
infarction (MI) are associated with higher morbidity and mortality, but little is known about
whether this excess risk can be reduced through treatment. OBJECTIVES: To determine
whether mortality and recurrent infarction are reduced by treatment of depression and LPSS
with cognitive behavior therapy (CBT), supplemented with an SSRI antidepressant when
indicated, in patients enrolled within 28 days after MI. DESIGN, SETTING AND PATIENTS: RCT
conducted from October 1996 to April 2001 in 2481 MI patients (1084 women, 1397 men)
enrolled from 8 clinical centres. Major or minor depression was diagnosed by modified DSM-IV-
TR criteria and severity by the 17-item Hamilton Rating Scale for Depression (HRSD); LPSS was
determined by the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Social
Support Instrument (ESSI). Random allocation was to usual medical care or CBT-based
psychosocial intervention. Intervention: CBT was initiated at a median of 17 days after the
index MI for a median of 11 individual sessions throughout 6 months, plus group therapy
when feasible, with SSRIs for patients scoring higher than 24 on the HRSD or having a less
than 50% reduction in Beck Depression Inventory scores after 5 weeks. Main Outcome
Measures: Composite primary end point of death or recurrent MI; secondary outcomes
included change in HRSD (for depression) or ESSI scores (for LPSS) at 6 months.
RESULTS: Improvement in psychosocial outcomes at 6 months favoured treatment: mean (SD)
change in HRSD score, −10.1 (7.8) in the depression and psychosocial intervention group vs.
−8.4 (7.7) in the depression and usual care group (P<.001); mean (SD) change in ESSI score,
5.1 (5.9) in the LPSS and psychosocial intervention group vs. 3.4 (6.0) in the LPSS and usual
care group (P<.001). After an average follow-up of 29 months, there was no significant
difference in event-free survival between usual care (75.9%) and psychosocial intervention
(75.8%). There were also no differences in survival between the psychosocial intervention and
usual care arms in any of the 3 psychosocial risk groups (depression, LPSS and depression and
LPSS patients).
CONCLUSIONS: The intervention did not increase event-free survival. The intervention
improved depression and social isolation, although the relative improvement in the
psychosocial intervention group compared with the usual care group was less than expected
due to substantial improvement in usual care patients (de Leon et al., 2002).
DRUG TRIALS ON NEWER PSYCHOTROPICS
Lurasidone in the Treatment of Acute Schizophrenia: A Double-Blind, Placebo-

Controlled Trial (Nakamura et al., 2009)
OBJECTIVE: Lurasidone is a novel psychotropic agent with high affinity for dopamine receptor
type 2 (D2) and serotonin receptor type 2A (5-HT2A) receptors, as well as for receptors
implicated in the enhancement of cognition and mood and the reduction of negative symptoms
(5-HT7, 5-HT1A, and α2c). The primary objective of the study was to evaluate the efficacy of
lurasidone in the treatment of patients suffering from an acute exacerbation of schizophrenia.
The secondary objectives were to assess the safety and tolerability of lurasidone and to
evaluate the ability of lurasidone to improve secondary measures such as negative symptoms
and depressive symptoms. METHOD: Inclusion criteria included: men and women between 18
and 64 years of age, inclusive, who were hospitalized for an acute exacerbation of
schizophrenia meeting DSM-IV criteria (disorganized, paranoid, or undifferentiated subtypes)
based on the Structured Clinical Interview for DSM-IV Disorders - Clinician’s Version (SCID-
CV) were enrolled. Patients were also required to have (1) a minimum illness duration of at
least 1 year; (2) a Brief Psychiatric Rating Scale (BPRSd) total score, derived from the Positive
and Negative Syndrome Scale (PANSS), of at least 42, with a score of at least 4 on 2 or more
positive symptom items; (3) a Clinical Global Impressions-Severity of Illness scale (CGI-S) score
≥ 4 (illness of at least moderate severity); (4) a Simpson-Angus Scale (SAS) score of < 2; and (5)
an Abnormal involuntary Movement Scale (AIMS) score of < 3. Women were required to be at
least 1 year postmenopausal, surgically sterilized, or using a medically reliable form of birth
control. Patients were randomly assigned to 6 weeks of double-blind treatment with a fixed
dose of lurasidone 80 mg (n = 90, 75.6% male, mean age = 39.7 years, mean baseline score on
the Brief Psychiatric Rating Scale derived from the Positive and Negative Syndrome Scale
[BPRSd] = 55.1) or placebo (n = 90, 77.8% male, mean age = 41.9 years, mean BPRSd score =
56.1). The primary efficacy measure was the BPRSd. The study was conducted from May to
December 2004. RESULTS: At day 42, last-observation-carried forward end-point, treatment
with lurasidone was associated with significant improvement compared to placebo on the
BPRSd, as well as on all secondary efficacy measures, including the PANSS total score and the
PANSS positive, negative, and general psychopathology subscales. Significant improvement was
seen as early as day 3, based on BPRSd, PANSS, and Clinical Global Impressions-Severity of
Illness assessments. Treatment with lurasidone was generally well tolerated and was not
associated with adverse changes in metabolic or electrocardiogram parameters. There were no
clinically significant differences between lurasidone and placebo in objective measures of extra-
pyramidal symptoms.
CONCLUSION: The results of this study suggest that the novel psychotropic agent lurasidone
is a safe and effective treatment for patients with an acute exacerbation of schizophrenia.
LIMITATIONS: Use of a single fixed-dose of lurasidone did not permit evaluation of dose-
response effects and may have reduced the tolerability of the drug. Secondly, the absence of an
atypical antipsychotic comparator group limits the ability to draw inferences regarding the
comparative efficacy and tolerability of lurasidone. The relatively high discontinuation rate of
42% in the current study is another limitation.
CLINICAL TRIALS IN INDIA (www.ctri.nic.in)

The Clinical Trials Registry - India (CTRI) has been set up by the ICMR's National
Institute of Medical Statistics (NIMS) and is funded by the Department of Science and
Technology (DST) through the Indian Council of Medical Research (ICMR). It is the governing
body which controls drug trials in India. The CTRI is an online register of clinical trials being
conducted in India. Any researcher who plans to conduct a trial involving human participants,
of any intervention (drug, surgical procedure, preventive measures, lifestyle modifications,
devices, educational or behavioral treatment, rehabilitation strategies and complementary
therapies) are expected to register the trial in CTRI before enrollment of the first participant.
Presently several trials of psychotropic medication are underway in India, majority of them
being sponsored by pharmaceutical companies. A few of them have been completed but results
are yet to be published. Important ones among them are:
I. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study

(Khanna et al., 2005)
One of the three pivotal trials that was the basis for FDA approval for risperidone in
acute mania was a trial conducted exclusively in India. This was a placebo-controlled trial on
290 patients hospitalized during an episode of acute mania. The trial, which was reported as
being conducted in eight centres across India, was funded by Johnson & Johnson. The trial
was conducted in 2001. Patients with bipolar disorder were admitted to hospital and subjected
to a “washout” of all medications for up to three days before they were assigned to the
risperidone or placebo arm. No other psychiatric drugs could be given in addition as long as
they were enrolled in the trial. Lorazepam could be given for control of symptoms, but only for
up to the first 10 days of the trial. Those on the risperidone arm started with a 3 mg dose.
Daily doses were then reduced or increased at the discretion of the investigator. The trial lasted
for three weeks. When patients entered the trial their symptoms were evaluated on a scale, the
Young Mania Rating Scale (YMRS). The trial found that risperidone was effective in acute
mania, and also well tolerated. Extra-pyramidal symptoms (involuntary movements) were the
most frequently reported adverse effects.
II. Placebo-controlled trial of quetiapine extended release for acutely ill patients with
schizophrenia (Kahn et al., 2007)
Patients with a diagnosis of “acute schizophrenia” were considered for the trial. They
had to have a minimum PANSS score indicating that the condition was severe. A total of 588
patients were taken off their regular antipsychotic medication (as well as other supportive
drugs like mood stabilizers and antidepressants) at least 48 hours before being randomly
assigned to quetiapine extended release (XR), quetiapine immediate release (IR) or placebo. The
primary endpoint was the change in the patient’s state over the six weeks of the study. The
study was also designed to identify a clinically relevant dose range for the extended release
version of quetiapine. Four hundred forty-six patients completed the study. Patients were
recruited at 39 centres in Bulgaria, Romania, Russia, Greece, South Africa, the Philippines,
Indonesia and India (3 sites). The study was conducted between November 2004 and December
2005. The study concluded that the extended release version of quetiapine was as effective as
the immediate release version of the drug, and both were more effective than placebo in
patients with acute schizophrenia and that the drug was well tolerated.
III. A clinical trial to study the effects of two different doses of folic acid as an
augmenting agent with antidepressant drug fluoxetine in patients with depressive
episode (www.ctri.nic.in)
This study was a randomized, double blind, parallel group, single centre comparative
trial of antidepressant augmentation by high (5 mg/day) and low (1.5 mg/day) doses of folic
acid. Fluoxetine (20 mg/day) was the antidepressant. Thirty patients were recruited. Primary
outcomes were the scores on HDRS and BDI over 6 weeks. This trial was conducted and
funded by National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore.
DRUG TRIALS IN CENTRAL INSTITUTE OF PSYCHIATRY (CIP)

A study titled, “The Comparative Efficacy of Memantine and Diazepam in Alcohol
Withdrawal Syndrome: an Open Label Trial” was conducted by Kumar & Khess(2007) at CIP,
Ranchi. A total of 75 adult inpatients diagnosed with alcohol dependence syndrome were
enrolled. Twenty-five patients each were recruited consecutively to one of three fixed dose
detoxification regimen i.e. tab diazepam 10 mg tid, tab memantine 10 mg bid or a combination
of tab diazepam and tab memantine 10 mg bid for initial 8 days. The study concluded that
memantine was safe and effective in alleviating symptoms of alcohol withdrawal syndrome. It
was found to be as effective as diazepam in alleviating alcohol withdrawal syndrome but was
found to be ineffective in controlling tremors and insomnia during alcohol withdrawal.
Another trial, “The Efficacy and Side-Effect Profile of Lamotrigine in Acute Mania: a Double-
Blind Comparison with Lithium” was conducted by Kumar & Ram (2004). This study
concluded that lithium was more effective than lamotrigine in acute manic patients. Some of
the other studies conducted at CIP are: 1. Effect Size of Lithium, Sodium Valproate and
Carbamazepine in Children and Adolescent with Bipolar Disorder - a Prospective Open Label
Trial (Singh & Sinha, 2004) 2. Cognitive Improvement in Schizophrenia with Atypical
Antipsychotics: a Randomized Double-Blind Comparison between Risperidone and Olanzapine
(Ranjan & Paul, 2005).
In September 2007 CIP launched two homoeopathic interventional research projects,
“To Assess the Feasibility of Add- On Homeopathic Therapeutic Intervention in Schizophrenia:
an Open Trial” and “To Assess the Feasibility of Add-On Homeopathic Therapeutic Intervention
in Depression: an Open Trial.” These projects were funded by the Central Council for Research
in Homoeopathy, Ministry of Health and Family Welfare, New Delhi. The aim of both projects
has been to assess the efficacy of homoeopathy in the treatment of schizophrenia and
depression. Trained mental health professionals and qualified homoeopathic doctors have
contributed in this project. This project is now in its final phase. The required numbers of
patients have completed their follow-up with homeopathic intervention.
DISCUSSION
__________________________________________________________________________
INTRODUCTION
The clinical trial is the experimental procedure needed to evaluate competing

treatments. How can one say that a treatment is effective, ineffective, or even harmful? Or, if
any expert or a pharmaceutical company claims that a particular therapy is more effective
than the previous modes then the question of evidence arises. One should not rely on the
views of experts unless they produce sound empirical evidence to support their views, nor
should one credit the anecdotal evidence of people who have undergone the treatment and, in
some cases, have been ‘miraculously’ cured. One of the important changes in clinical practice
and culture during the last 100 years has been the increasing realization that it is not enough
for anybody to say that, his or her therapy works, nor it is enough for a patient to say likewise.
These types of anecdotal evidences, even with a series of anecdotes are inadequate for that
purpose (Everitt & Wessely, 2003). Hence, the need for clinical trials is felt.
Clinical trials are a major vehicle by which medical treatments now gain official
approval for widespread application from laboratory to the counter. They are the focus of much
of the major work by pharmaceutical companies, and definitely their huge expenditures. Major
regulatory bodies such as the United States Food and Drug Administration (USFDA) and other
agencies rely heavily, sometimes almost exclusively, on the results of clinical trials to approve
the marketing of pharmaceuticals (Hertzman & Adler, 2010).
TYPES OF EXPERIMENTAL STUDIES

Experimental studies are of two types (Park, 2009):
➢ Non-randomised or non-experimental trials
➢ Randomised controlled trials (RCT)
Non-randomised or non-experimental trials

In this trial study groups are not allocated for randomisation. These types of trials are
conducted when it is not always possible for ethical, administrative and other reasons to
conduct a randomised controlled trial in humans. As this is a crude approach so this is done
rarely. Due to lack of randomisation, the degree of comparability remains low and chances of
spurious results are higher. There are few examples of non-randomised trials -
❖ Uncontrolled trials: trials with no comparison groups, only cases.
❖ Natural experiments: where experimental studies are not possible in human
populations, then the investigator seeks to identify natural circumstances that mimic
an experiment.
❖ Before and after comparison studies: On the basis of recorded data outcome is
measured at the end of introduction of a particular therapy.
Randomised controlled trials

RCTs are traditionally considered as the gold standard for comparing the benefits of
treatments because of the fact that the design of RCTs makes it conceptually easier to
attribute any observed effect to the treatments being compared. The role of non-randomized
studies is doubtful. The deliberate choice of treatment for each patient implies that the
observed outcomes may be caused by differences between the individuals being given the two
treatments, rather than by the treatments alone, and unrecognized confounding factors may
interfere with attempts to correct for identified differences between groups. These
considerations support a hierarchy of evidence, with RCTs being the highest preference,
followed by observational studies that are able to control for biases, and uncontrolled studies
and opinion being the weakest form of evidence (Wells, 1999).
Hierarchy of medical evidence (in ascending order of strength of evidence) (Byar, 1977)
• Case reports
• Case series
• Database studies
• Observational studies
• Controlled clinical trials
• Randomized controlled trials
The RCT has informed the development of evidence-based medicine and meta-
analysis. Evidence-based medicine resulted in part from the realisation that clinical practice is
often poorly informed by the best available evidence, and that many widely used treatments
are either untested or have been shown to be ineffective. However, evidence-based medicine
has also been seen as a means by which policy makers, sometimes with academic support,
control clinical freedom (Williams & Garner, 2002). The primary goal of conducting an RCT is
to test whether an intervention works by comparing it to a control condition, usually either no
intervention or an alternative intervention. Secondary goals include:
- identifying factors that influence the effects of the intervention (i.e., moderators)
- understanding the processes through which an intervention influences change (i.e.,
mediators or change mechanisms that bring about the intervention effect) (West & Bonnie,
2008).
The basic steps in conducting an RCT include the following (Park, 2009):
➢ Drawing a protocol.
➢ Selecting reference and experimental populations.
➢ Randomization.
➢ Manipulation or intervention.
➢ Follow-up.
➢ Assessment of outcome.
OBSERVATIONAL vs. PRAGMATIC RCT

RCTs are used to measure the efficacy of a treatment (i.e. whether the treatment works under
more or less ideal conditions), while observational studies are necessary to evaluate
effectiveness (the effects of the treatment in real condition). Internal and external validity can
seldom both be optimized with one design and individually RCTs and observational studies
have their own limitations that must be recognized and considered (Fava et al., 1992). The
pragmatic RCT aims to bridge the gap between these methodologies. Pragmatic trials measure
effectiveness – the benefit the treatment produces in routine clinical practice (Roland &
Torgerson, 1998). The narrow eligibility criteria often appropriate for an observational trial can
make it difficult to apply the results to a broader population. And such trials often entail
substantial deviations from usual practical conditions by eliminating treatment preferences,
using specialized providers and settings, maintaining high treatment compliance, and
excluding patients with major co-morbid conditions. In contrast, the participants selected for a
pragmatic trial need to reflect variations between participants that occur in real clinical
settings, so that valid inferences can be drawn that are more likely to help to inform choices
between treatments in a larger population.
Pragmatic trials can also produce the opposite conclusion that, although a treatment
‘works’ in the pure sense of the word, it fails to deliver significant advantages in actual clinical
practice. Excellent examples are the CATIE and CUtLASS trials, both large pragmatic trials of
the typical vs. atypical antipsychotic agents. The individual trials had left no doubt that these
drugs were effective and numerous anecdotal reports from patients and clinicians suggested
they had a better side-effect profile. However, the pragmatic trials showed that in real life there
was no difference in either outcomes or dropouts – certainly nothing to justify the additional
costs (Lieberman, et al., 2006).
Pragmatic RCTs (Hotopf, 2002):
• reflect the heterogeneity of patients in general population
• minimise exclusion criteria
• focus on groups with a wide range of diagnoses
• define patient groups by presentation rather than diagnosis
• may not employ placebos
• may not be blinded
• must carefully conceal allocation during randomization.
In pragmatic RCTs, more emphasis is placed on functional outcomes that indicate more
than symptomatic improvements. Another consideration is the time span over which outcomes
are measured. Many traditional RCTs assess outcome over a 4-8 week period. Given the
relapsing and remitting nature of many psychiatric disorders, more time is needed.
Outcome measures of pragmatic RCTs

Outcome measures should reflect ‘real world’ concerns some of them being:
• return to work
• readmission to hospital
• reduction in visits to the GP
• cost-effectiveness
• suicide attempts
• death from suicide
• acts of violence.
BIASES IN CLINICAL TRIALS

Bias is any systemic error in the determination of the association between exposure
and outcome. This can severely hamper the outcome measured. Many types of biases may
arise in clinical trial:
1. Bias due to confounding - A confounding factor is defined as one which is associated both
with disease and outcome and is distributed unequally in study and control groups. This can
be removed by matching.
2. Memory or recall bias - When cases and controls are asked questions about their past
history, it may be more likely for the cases to recall certain factors. Recall bias has been noted
in STEP-BD trial in which a hypothesis was that a first depressive rather than manic episode
in bipolar disorder might herald a subsequent course notable for greater burden of depressive
symptoms. Because the retrospective reliability of hypomanic symptoms was poor, analysis
was limited to bipolar I subjects (Roy et al., 2005).
3. Selection bias - The cases and controls may not be representative of cases and controls in
the general population. This is particularly common in psychiatric trials because most of the
trials use narrow inclusion criteria and associated comorbidity. Observational studies and
pragmatic RCTs have advantage here that they mimic cases and controls of the general
population.
4. Berkesonian bias - This bias arises because of different rate of admission in the hospitals
for people with different diseases. Mainly arises in epidemiological studies.
5. Interviewer’s bias - It may occur when the interviewer knows the hypothesis and also
knows who the cases are. This type of bias can be eliminated by double-blinding.
6. Expectation bias - it may occur in open-label trials where investigator knows about
outcome of a particular treatment as in EUFEST the possibility that some investigators might
have been convinced by results of previous trials reporting advantages of SGAs over FGAs in
terms of cognitive performance; this might have led to an “expectation bias”, which could have
conferred an advantage to the SGAs over FGAs (Kahn et al., 2008).
7. Publication bias and Sponsorship Publication bias - In the hierarchy of evidence, journals
may be less willing to accept observational studies (Barton, 2000) and are less likely to publish
negative studies and both methodologies are potentially biased by the study sponsor, with
positive results often being associated with the vested interest of the sponsor (Als-Nielsen et al,
2003). However, a review of atypical antipsychotic trials and funding sources indicates that
this is not invariably so (Heres et al, 2006). Moreover, government-funded trials cannot be
assumed to be unbiased (Coyne, 2006).
8. Observer bias - The observer measuring the outcome of a therapeutic trial may be
influenced if he knows beforehand the particular therapy to which the patient has been
subjected.
9. Information bias - The bias that arises in a clinical study because of the misclassification
of the level of exposure to the agent or factor being assessed and/or misclassification of the
disease itself.
ALLOCATION CONCEALMENT, BLINDING AND MATCHING

One of the most important aspects of a clinical trial is the question of how patients
should be allocated to the treatment group and control group so that the result of the clinical
trial is more likely to provide an unbiased comparison of the difference between the two
treatments. There are some methods by which such bias can be minimised.
The randomized trial is not in itself a complete protection against all forms of potential
bias. It must be combined with allocation concealment and, when necessary, blinding. The
former refers to methods of preventing any interference with the assignment of treatment
during the randomization process, the latter to who has knowledge of what treatment is being
given or received as the trial progresses. Allocation concealment is therefore a defence against
selection bias, while blinding reduces observer and other information biases. This is clear from
the evidence that trials in which concealment of treatment is either inadequate or unclear alter
the treatment effect in unpredictable ways (Kunz & Oxman, 1998), although in general, the
problem leads to a systematic bias in favour of the new treatment (Schultz, 1994). Matching is
defined as the process by which controls are selected in such a way that they are similar to
cases with regard to certain variables which influence outcome of trial.
The fundamental idea of blinding in a clinical trial is that the study patients, the people
involved with their management, and those collecting the clinical data should not know which
treatment a patient is receiving. The benefit of blinding is that it ensures a high level of
objectivity and removes the possibility of a placebo effect creating an artefactual response in
the treatment group. In practice different degrees of blinding are often used – most common
are:
• Single-blind: the patient only is unaware of which treatment he or she is receiving.
• Double-blind: both the patient and the investigators or treating clinicians are not allowed to
know the treatment the patient is receiving.
• Triple-blind: Neither the patient, investigator nor the person(s) responsible for the
assessments know the treatment the patient is receiving.
ETHICAL ISSUES IN CLINICAL TRIALS

Randomization is a better solution to the problem of allocating patients to treatments
in a clinical trial. But the procedure poses some ethical dilemmas for clinicians and often
raises concern among individuals who are participants in a trial. It has been argued that
allowing chance to be the determining factor when assigning treatment to patients has no
place in medicine, and that only a physician can decide which treatment a patient should
receive, using his or her best judgment. But it has to be clear that the objectivity of
randomization is more likely to get the truth than the subjective impressions made from
clinical experience (Everitt & Wessely, 2003).
Ethical problems in clinical trials reflect the delicate balance between individual ethics
and collective ethics. The prime motivation for conducting a trial involves collective ethics, but
individual ethics have to be given as much attention as possible without destroying the trial’s
validity. Each individual patient receives the treatment most beneficial for his or her
condition, while evaluating competing therapies as efficiently as possible so that all future
patients might benefit from the superior treatment and, as a consequence, advance public
health through careful scientific experimentation. Naturally the physician’s responsibilities to
patients during the course of the trial are clear; if the patient’s condition deteriorates, the
ethical obligation must always and entirely outweigh any experimental conditions, without
considering final analysis of the data outcome.
PLACEBO
A further ethical problem is justification of using a placebo. This has become
particularly important in drug development, since regulatory bodies require that new agents
be tested against placebo. Drug companies are reluctant to test their products against active
compounds rather than placebos for commercial and marketing reasons. It has been argued
passionately that once an effective treatment is known, there is no place for a placebo
condition, and journals should not contemplate publishing such studies (Rothman & Michels,
1994). The Helsinki Declaration’s historical concern with placebo use in medical research is
based on the moral principle that no patient should be denied the best available treatment and
on the presumption that clinical ethics entail the same physician responsible for associated
harm of the individual patients (Levine, 2002). The first declaration, in 1964 set forth its
position on placebo controls in Article II.3, but was revised in 2000 by the new Article 29:
“The benefits, risks, burdens, and effectiveness of a new method should be tested against
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not
exclude the use of placebo, or no treatment, in studies where no proven prophylactic,
diagnostic, or therapeutic method exists.”
Although it allows the testing of new treatments, Article 29 prohibited the use of
placebo controls in clinical trials when even partially effective treatments exist, thus
continuing many of the difficulties associated with Helsinki 1996. Reacting to expressions over
Article 29, World Medical Association has given new clarifications (WMA, 2002). The
clarifications are as follows: “The WMA hereby reaffirms its position that extreme care must be
taken in making use of a placebo-controlled trial and that in general this methodology should
only be used in the absence of existing proven therapy. However, a placebo-controlled trial
may be ethically acceptable, even if proven therapy is available, under the following
circumstances: where for compelling and scientifically sound methodological reasons its use is
necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic
method; or where a prophylactic, diagnostic or therapeutic method is being investigated for a
minor condition and the patients who receive placebo will not be subject to any additional risk
of serious or irreversible harm. All other provisions of the Declaration of Helsinki must be
adhered to, especially the need for appropriate ethical and scientific review.”
This clarification narrows the injunction against placebo substitution for a proven
treatment. Clinical trials with a placebo control group would be ethically justified where there
are good reasons for placebo use or if the condition being studied is “minor” and the additional
risk is negligible. It would require a case-by-case review of the justifications for placebo use, a
process sensitive to scientific merit and study-specific risk based on subject selection and risk-
reduction procedures.
Schizophrenia is one of the disorders in which Helsinki clarification affects most
directly: there are substantial reasons to seek new medications that are more effective and
safer than the partially effective treatments that are currently available. Substituting placebo
for active medication has implications for some, but not all, aspects of the disease. Few trials
conducted in last decade had used placebo like CATIE-AD. Overall, the rates of
discontinuation of treatment among the four study groups ranged from 77 to 85%. Findings
suggest that there is no large clinical benefit of treatment with atypical antipsychotic
medications as compared with placebo (Schneider et al., 2001).
Likewise, some trials in bipolar disorder also used placebo which led to some
conclusion like BOLDER I in which effect of quetiapine was seen against placebo and the
result showed that quetiapine was better in symptomatic management than placebo as seen in
similar trials EMBOLDEN I and II. But a similar trial on bipolar depression in adolescents
(BOLDER II) shows quetiapine monotherapy was not more effective than placebo (Calabrese et
al., 2005) probably due to less effective size, mostly consisting of girls on outpatient basis with
mild psychopathology. Methodological limitations, including study entry criteria, rating scales,
and outcome measures, might have led to the high placebo response (DelBello et al., 2009).
GENERALIZABILITY
The other ethical issue is of generalizability. One argument is often made against
clinical trials (particularly explanatory trials), that of their apparent lack of generalizability to
usual clinical practice. Some opponents of clinical trials frequently point to their ‘non-real
world’ setting. Certainly, the routine aspects of care are usually performed far more
meticulously during the conduct of a trial i.e, the diagnoses are made more precisely, routine
tests are performed more often, and are rarely if ever forgotten, or the results lost, follow-up is
meticulously organized, and great steps taken to ensure that the patient does indeed attend
for review, interventions are explained more carefully, that can be missing from routine clinical
practice (Rothwell, 1995). It could be argued that there are many circumstances in which it is
unethical not to do a randomized clinical trial, although it is recognized that conducting trials
of sufficiently poor quality that they cannot make a meaningful contribution to medical
knowledge is, in itself, unethical.
INFORMED CONSENT
The importance of choice in this context has historical roots dating to the seventeenth-
century concept of free will as essential to our status as human beings, although it is well
documented that many people have at various times been involved as unwilling subjects in
medical. A subject’s or patient’s documented agreement to participate in a clinical trial as a
result of having all risks and benefits openly and clearly explained is known as the patient’s
informed consent. The aim is to protect subjects from the possibility of unwitting exploitation
by well-intended but overzealous researchers. The consent process, to be valid, must be based
on factual information presented in an intelligible fashion and in a setting in which the patient
is able to make a free choice, without fear of reprisal or prejudicial treatment. Following
general elements should be present in informed consent (Meinert, 1986):
-informed consent documents should be simply written with terms such as randomization,
placebo, masking, etc.
- the study involves research, an explanation of the research and the expected duration of the
subject’s participation, a description of the procedures, and identification of any procedures
that are experimental.
-any foreseeable risks or discomforts or benefit to the subject.
-the extent, if any, to which confidentiality of records identifying the subject will be maintained
-for research involving more than minimal risk, an explanation as to whether any
compensation or medical treatments are available if injury occurs and, if so, what they consist
of, or where further information may be obtained.
-whom to contact for answers to pertinent questions about the research and research subject’s
rights, and whom to contact in the event of research related injury.
-that participation is voluntary, refusal to participate will involve no penalty or loss of benefits
to which the subject is otherwise entitled, and the subject may discontinue participation at
any time without penalty or loss of benefits to which the subject is otherwise entitled.
-disclosure of appropriate alternative procedures or courses of treatment, if any, that might be
advantageous to the subject.
Almost all clinical trials these days are conducted with informed consent. But even the
clearest consent form may not be understandable to some patients, and obtaining informed
consent from psychiatric populations has received substantial attention aiming in particular to
assess how much such patients understand the risks and benefits of their participation in a
trial.
Are there circumstances where randomization can take place without consent? The
response to this question is no. It is seen that when the issue of post-randomization consent
(the ‘Zelen’ design) is considered, there are many investigators with this opinion. But it is not
so simple. First, there is the issue of double standards. Patients give general consent to many
aspects of treatment without giving informed consent to each. Second, it is accepted within the
Declaration of Helsinki and elsewhere that non-consented trials are permissible in certain
well-defined circumstances – for example, in research concerning serious illnesses in
unconscious patients.
THERAPEUTIC MISCONCEPTION
A randomized trial is ethical only in circumstances of "clinical equipoise" - a genuine
uncertainty within the medical community as to whether any of the treatment arms are
superior to the other. Clinical Equipoise emerged during the 1980s, philosophers interested in
research ethics recognized a tension between the obligation of physicians to offer optimal care
to their patients ("the therapeutic obligation") and the provision of medical treatment in the
context of clinical trials (Marquis, 1983). It is recognized that clinical trials are scientific
experiments, which differ from standard medical care and they are subject to regulatory
requirements which do not apply to routine medical practice. The main ethical approach to
clinical trial to view it as a scientific experiment, aimed to produce knowledge that can help
improve the care of future patients. The doctrine of clinical equipoise has emerged as the
bridge between medical care and scientific experimentation, allegedly making it possible to
conduct RCTs without sacrificing the therapeutic obligation of physicians to provide treatment
according to a scientifically validated standard of care. This constitutes a "therapeutic
misconception" concerning the ethics of clinical trials, analogous to the tendency of patient
volunteers to confuse treatment in the context of RCTs with routine medical care (Appelbaum
et al., 1987).
The tension between ethically legitimate scientific experimentation and the therapeutic
obligation of physicians could be overcome by the principle of “clinical equipoise”. Freedman
called Fried's original concept "theoretical equipoise" (sometimes called "individual equipoise")
and contrasted it with his favoured concept of "clinical equipoise" (collective equipoise). An
RCT is ethical so long as the professional community recognizes that "medicine is social rather
than individual in nature" (Freedman, 1987).
SPECIAL POPULATIONS IN CLINICAL TRIALS
Women’s issues in clinical trials

The history of women and clinical drug trials begins in the 1950s with the story of
thalidomide. In 1977, the FDA recommended exclusion of women of childbearing potential
from early (phase 1 and early phase 2) drug trials. Women were also excluded from later phase
II and phase III studies if animal studies had not been completed. Exceptions were allowed for
trials of drugs for life-threatening diseases (US FDA, 1977). Although these FDA guidelines
pertained mostly to the early phases of drug development, in practice the participation of
women in all clinical trials was negatively affected. Reproductive age women could enter phase
3 trials but, the dose range appropriate for women, generally established in earlier phases,
would not be known. In addition, it could be argued that because most drugs fail early trials,
the exclusion of women from early phases could potentially limit the identification of drugs
specifically useful for women (Prout & Fish, 2001). Despite such seeming advantages, it was
soon recognized that excluding women was neither practical nor ethical. It was not practical
because exclusion meant that relatively little was known about women’s reactions to new
drugs before these drugs became freely available on the market and women’s potential
responses over the life course, and that included undetermined effects on fetuses and
neonates.
In 1993, FDA guidelines ended the restriction on the inclusion of women of
childbearing potential in early clinical trials and emphasized appropriate representation of the
two sexes in order to facilitate detection of clinically significant differences. In 1994, the FDA
created an Office of Women’s Health, which oversees correction of gender disparities in drug
research and administration policies (Schiebinger, 2003). It was recommended that the
possibility of pregnancy termination in the case of unwanted pregnancy be discussed as part
of the consent process. Furthermore, existing pregnancy or lactation should not be a primary
exclusion criterion in clinical trials if the women were fully aware of all known risks and still
volunteered to participate (Mastroianni, 1994). All males exposed to drugs with a suspected
teratogenic potential should be advised to practice effective birth control during the exposure
and one or two cycles of spermatogenesis beyond the exposure and to avoid all semen contact
with vaginal walls during their partner’s first trimester of pregnancy (De Santis et al., 2008).
Lactating women
Lactating women are rarely recruited into clinical trials of new drugs because it is not
known how much of any drug enters the infant during breastfeeding. Therefore, when they
need medication, they are advised to discontinue breastfeeding. It is perhaps time for a
mandate to deliberately include lactating women in new drug trials (Seeman, 1996).
Adolescent females
There are particular challenges for studies that enrol adolescents under the age of 18
and authorities require permission of parents and assent of the child for enrolment
(McCullough et al., 2006). The gender differences in schizophrenia have received wide support.
A higher risk of schizophrenia in men, together with an earlier age at onset and a worse
prognosis are the most important findings (Leung & Chue, 2000). Regarding antipsychotic
treatment response, most studies with typical antipsychotics have found that women with
schizophrenia show a faster and better response to typical antipsychotics than men (Seeman,
1989), as seen in SOHO study independent of other predictor variables such as age of onset
and chronicity. The analysis of the differences in response to treatment in positive, negative,
depressive and cognitive symptoms has shown that women respond better than men in all the
different symptom dimensions. These findings are consistent with animal studies suggesting
an antidopaminergic effect of estrogens (Hafner et al., 1991). Gender differences in treatment
usually disappear with age also suggesting a protective effect of estrogens that is lost after
menopause (Seeman, 1996).
In summary, women are now being recruited into drug studies in large numbers
around the world, but gender-specific analysis of results lags behind. Although recruitment
and retention of women deserves attention, the main challenges continue to be safety and
ethics.
Paediatric population
More than 50% of medicines used in children are not licensed either for the disease
state or for that age group. The extrapolation of adult data on drugs for children is
inappropriate, which makes age and development related research important. There is a need
to develop medicines for children to assess its safety and efficacy. Researchers need to
consider conducting clinical trials in children, not only on theoretical level, but also on a
practical level in the form of ethical approval and statutory requirements (Lantos, 1999).
Geriatric population
The prevalence of psychiatric illness in the older population is expected to rise
dramatically in coming decades, so advances in geriatric psychiatry research are urgently
needed. Ethical issues in the design, conduct, and monitoring of research involving older
adults parallel these issues. It includes the assessment of capacity in populations where
cognitive disorders are more prevalent, the role of surrogate decision makers, the legal status
of surrogate consent, the advancement in directives for research participation, and research
involving suicidal individuals. Informed consent is an ethical challenge in geriatric research
protocols, particularly in studies of AD or other cognitive disorders because many participants
will have impaired decision-making capacity (Kim et al., 2001). Investigators most commonly
address the consent problem through “double consent”—i.e., obtaining consent from the
proxy, as well as from the subject, making proxy consent central to the ethical integrity of
clinical AD research (Stocking et al., 2003).
SPECIAL PROBLEMS OF TRIALS IN PSYCHIATRY

There have been a number of criticisms of the use of RCTs in the evaluation of mental
health treatments. An alternative case that has been made is that psychiatric patients are
themselves too complex to permit extrapolation from one patient to the wider community and
the results from most psychiatric trials have little relevance for the day-to-day treatment of the
mentally ill, i.e. the results are not generalizable.
Our patients are too complex
Psychiatric disorders are frequently not as straightforward as other medical conditions,
and psychiatric patients often display challenges and complex behaviours that might not be
compatible with the tightly controlled demands of most clinical trials. Broad categories such as
depression or schizophrenia hide several subgroups, whose boundaries are not clearly
delineated. Most of the psychiatric patients have more than one diagnosis, something that has
come to be labelled as co-morbidity. And it is really difficult to maintain them in a trial
according to the, often, stringent requirements of the trial protocol. Schizophrenia and
substance abuse, for example, does not seem an auspicious subject for RCT, since patients
with both problems are sometimes seen as ‘unascertainable’ (Everitt & Wessely, 2008).
In STEP BD, trial limitation was that it had not considered control for the effect of
medical and psychiatric comorbidities while there were high levels of anxiety comorbidity in
patients with bipolar disorder. Comorbidity may be an important contributor to functional
impairment and bipolar disorder outcome. For instance, substance abuse predicted poor
outcome in some studies (Young, 2001). Other trials like CATIE included substance use
disorder, OCD, depression, other anxiety disorders but excluded schizoaffective disorder,
mental retardation and other medical comorbidities (Stroup et al., 2003).
Interventions are too complex
Psychiatry is too individual a subject, and that far too many things happen during even
a single consultation, to permit evaluation by the technology of the RCT. Certainly many of the
interventions that have been developed for the treatment of mental health problems are more
complex than drug treatments (Crawford et al., 2002).
The results are not generalizable
The current vogue for pragmatic trials arises from the perception that many
explanatory clinical trials take place in ‘pure’ populations, for example, those free from all
forms of co-morbidity, with participants keen to attend follow-ups, happy to take medication,
and so on and so forth, with the consequence that the results were not considered relevant to
the vast majority of the population who do suffer from co-morbidity, and who are, in general,
reluctant to do any of the things mentioned (Rothwell 1995). The main criticism that can be
sustained against the RCT in psychiatry as currently undertaken is the issue of
generalizability (McKee, 1999). The answer, as we will discuss later, is not for psychiatry to
turn its back on the RCT, but for triallists to push for larger, simpler trials, and to lobby
against the increasing bureaucratization of the clinical trial that stands in the way of achieving
these objectives.
Strengths of trials like CATIE and STEP-BD were their large sample size to maximise
external validity, long follow-up duration, and recruitment of patients from diverse
representative sites with minimal exclusion criteria to maximise internal validity, all of which
increased the generalizability of the results. The study was also enhanced by the use of a
rigorously developed algorithm for evaluating health states specific to schizophrenia in terms
of QALY ratings that take both symptoms and side-effects into account. The SOHO study was
designed to maximize external validity while maintaining a high degree of internal validity. The
intention with the SOHO study was to collect information from a sample representative of
European out-patients with schizophrenia. External validity was maximized by having open
patient entry criteria. Patients were enrolled regardless of treatment history, comorbidity, a
history of substance abuse, compliance problems or a history of treatment resistance,
inclusion of patients from different countries, geographies, treatment settings (public, private)
and regions (metropolitan and rural areas). The SOHO study therefore attempted to overcome
generalizability problems inherent to RCTs (Robinson et al., 1996). In BOLDER I, the inclusion
of patients with bipolar II disorder and rapid cyclers into a large-scale study of acute bipolar
depression was novel and enhanced the generalizability of the findings, particularly since there
is a higher incidence of bipolar II disorder than bipolar I disorder (Calabrese et al., 2005).
However, in BOLDER II, the sample size was very small and most of the subjects were mildly
symptomatic girls so, the findings are not as generalizable as those of BOLDER I.
Follow up durations are too short
A common criticism of antipsychotic RCTs is their relatively short duration. As most of
the illnesses in psychiatry are of long duration with fluctuating course so, short duration
studies cannot ascertain impact on overall quality of life, which may take longer to occur than
improvements in clinical symptomatology. The 3-year follow up period of the SOHO study is
one of its most important assets, and allowed outcome assessment over a much longer period
than has been performed previously in schizophrenia trials (Hamilton et al., 1999).
Focus towards clinical severity
Another common criticism of many treatment outcomes of trials in psychiatry is that
evaluation is solely focused on changes in clinical severity. The SOHO study included
measures of social functioning and social adaptation that permit the analysis of how treatment
and changes in clinical severity impact on day-to-day living. These outcomes were measured
with questions that captured specific aspects that have meaning in themselves, like
involvement in a relationship, patient’s social interaction, pattern of living, independently or
with a caregiver, and the employment status (Cochrane Schizophrenia Group, 2002).
Compliance
Finally, the compliance issue affects the trial result and treatment outcome in day to
day practice. Compliance in trials means following both the intervention regimen and trial
procedures (for example, clinic visits, laboratory procedures and filling out forms). A non-
complier is a patient who fails to meet the standards of compliance as set by the investigator.
Medication non-compliance, estimated to affect 50 per cent of all psychiatric patients, has
been shown to be strongly associated with an elevated risk for relapse, readmission to
hospital, longer length of stay and suicide, resulting in increased costs across the health care
system. A high degree of patient compliance is an important aspect of a well-run trial (Everitt
& Wessely, 2008). For clinical trial investigators, particularly those working in psychiatry, it is
an inescapable fact of life that the participants in their trials often make life difficult by
missing appointments, forgetting to take their prescribed treatment from time to time, or not
taking it at all but pretending to do so. Perfect compliance is probably impossible to achieve,
particularly in drug trials where the patient may be required to take the assigned medication
at the same time of day over long periods of time. Lack of compliance can take a number of
forms: the patient may simply drop out of the trial altogether, perhaps because of some
adverse event, or even because they improve and feel they no longer need to take the
prescribed medication. Alternatively patients may continue in the trial but take their
medication at the wrong time, take extra doses, omit doses, use outdated medication or take
the wrong medication.
In drug trials one of the most commonly used methods of evaluating subject
compliance is pill or capsule count. Good rapport with the subjects will encourage cooperation
and lead to a more accurate pill count. Non-compliance may lead to the investigator
transferring a patient to the alternative therapy or withdrawing the patient from the study
altogether; often such decisions are taken out of the investigator’s hands by either the patient
being transferred to a treatment that is not mentioned in any of the arms of the trial, for
example, rescue medication, or the patient simply refusing to participate in the trial any
further and thus becoming a trial dropout (Cramer et al, 1988).
How compliance may be improved
Several attempts have been made to improve this situation by introducing compliance
therapy, a talking treatment based on motivational interviewing and cognitive behavioural
therapy (CBT). The participant is invited to review their history of illness, symptoms and side-
effects, and consider the benefits and drawbacks of drug treatment. In BOLDER I study,
significant antidepressant efficacy was demonstrated for quetiapine dosed once a day in the
evening in comparison to twice daily dosing. This has important clinical relevance because
once-daily dosing has been associated with enhanced medication adherence (Bloom 2001).
First-episode patients who discontinue their antipsychotic medication have a relapse rate
almost five times higher than that of patients who continue to take their medication (Robinson
et al., 1999). The majority (78%) of first-episode patients who discontinued neuroleptic
treatment after clinical improvement experienced a relapse within one year (Gitlin et al., 2001).
In most of the above mentioned trials, the majority of patients in each group discontinued
their assigned treatment due to inefficacy or intolerable side-effects or for other reasons. The
strict treatment restrictions of RCTs may explain these higher discontinuation rates.
STATISTICAL ISSUES IN CLINICAL TRIALS
The size or a clinical trial

A frequent question faced by a statistician dealing with investigators planning a clinical
trial is the number of participants for recruitment in each treatment group. A number of
factors should be considered for this, such as, the amount of time available for the trial, the
likely ease or difficulty in recruiting the type of patient required, and the possible financial
constraints, type of response variable and type of test involved. In addition the sample size will
need to be large to achieve a greater power and/or a more stringent significance level. Large
sample size increases external validity as also generalizability. Many of the recent trials like
CATIE, SOHO and CUtLASS involved a large sample size, so were more generalizable. The
limitation of the STEP-BD trial was its small sample size and the disproportionate number of
bipolar I (71%) vs. bipolar II (24%) patients. The sample size was too small to calculate the
incidence of other clinical status changes. The prevalence rates for most of the analyses of the
hypomanic and mixed/cycling patients could not be calculated because of insufficient sample
size (Friedman et al., 2006) but was large enough to detect moderate effect on primary
outcome.
Drug doses in clinical trials
Many questions about study designs have been raised, one of them being dosing.
Different trials use different dose of the same drug that affects the internal validity of the study
so the outcome is different. In CATIE, doses were somewhat representative of typical
outpatient treatment doses for risperidone and perhaps olanzapine, but not necessarily for
quetiapine, perphenazine, and ziprasidone. Many patients require (and tolerate) higher doses
of risperidone and ziprasidone. Some observers have asserted that the SGAs would have
separated from perphenazine in effectiveness, or at least performed somewhat better, if more
aggressive dosing had been employed. And some have argued that the slight advantage of
olanzapine may be attributed to its higher dosing in the trial, including its relatively higher
starting dose (Manschreck & Boshes, 2007). Due to flexible dosing design potential dose
effects could not be addressed in CATIE-AD. Average doses, however, in both phases 1 and 2
were from 5.5 to 5.6 (olanzapine), 56.5 to 61.1 (quetiapine), and 1.0 to 1.1 mg/day
(risperidone) (Schneider et al., 2006), but were generally lower than other Alzheimer’s disease
trials and considerably lower than doses used to treat schizophrenia or in the CATIE
schizophrenia trial (Lieberman et al., 2005).
Interim analysis
Many trials finish too early, usually because the investigators run out of patients or
money or both. But there are occasions when trials should finish before the intended
completion date. Major ethical questions arise if investigators elect to continue a trial beyond
the point at which the evidence in favour of an effective treatment is unequivocal and as the
clinical trial is a medical experiment it is ethically desirable to terminate such a trial earlier
than originally planned if one therapy is clearly shown to be superior to the alternatives under
test, or if a different concurrent study reports such a result or if there is any evidence that a
treatment is harmful to patients. In such cases interim analysis is done (Meinert, 1986).
Interim analyses are designed to avoid continuing a trial beyond the point when the
accumulated evidence indicates a clear treatment difference. In psychiatric trials this
commonly involves the suicide of patients. Fortunately such events are rare in practice but
they do occur, not least because nearly all psychiatric disorders are associated with an
increased risk of suicide. Interim analysis that was specified in the protocol of CATIE was not
conducted because there was interest in maintaining all treatment groups throughout the
study for optimal evaluation of effectiveness outcome.
Missing values and dropouts in longitudinal data
In the majority of clinical trials in psychiatry involving longitudinal data there will be
some patients who will miss one or more scheduled visits after treatment has begun and so
fail to have the required outcome measure made or who do not complete the intended follow-
up for some reason and drop out of the study before the end date specified in the protocol.
Both situations result in missing values of the outcome measure; in the first case these are
intermittent, but dropping out of a study implies that once an observation at a particular time
point is missing so are all the remaining planned observations. To understand the problems
that patients dropping out can cause for the analysis of data from a longitudinal trial it is
needed to consider a classification of dropout mechanisms (Rubin, 1976).The type of
mechanism involved has implications for which approaches to analysis are suitable and which
are not. The classification involves three types of dropout mechanisms:
• Dropout completely at random (DCAR): Here the probability that a patient drops out does not
depend on either the observed or missing values of the response. Consequently the observed
(non-missing) values effectively constitute a simple random sample of the values for all
subjects. For example the accidental death of a participant in a study, or a participant moving
to another area.
• Dropout at random (DAR): The dropout at random mechanism occurs when the probability of
dropping out depends on the outcome measures that have been observed in the past, but
given this information is conditionally independent of all the future (unrecorded) values of the
outcome variable following dropout.
• Non-ignorable (informative): The final type of dropout mechanism is one where the probability
of dropping out depends on the unrecorded missing values - observations are likely to be
missing when the outcome values that would have been observed had the patient not dropped
out are systematically higher or lower than usual.
There are various possibilities when it comes to the analysis of longitudinal data where some
of the patients drop out, including:
• Discard incomplete cases and analyse the remainder - complete-case analysis. Complete-case
analysis is no longer applied to longitudinal data with missing values; it is totally unnecessary
since other more suitable alternatives are now readily available.
• Impute or fill in the missing data with plausible values and then analyse the filled-in data.
From an operational stand point, imputation solves the missing-data problem at the outset,
enabling the analyst to proceed without further hindrance but it possibly distorts parameter
estimates, standard errors and hypothesis tests, so careful consideration is needed. Another
simple, and also widely used, imputation method is to replace the missing values due to a
participant dropping out with that participant’s last observed value. This is usually referred to
as the last observation carried forward (LOCF) procedure. ‘Last observation carried forward’
(LOCF) is the accepted method for dealing with dropouts and lost data. A more appropriate
method is some form of multiple imputation. This is a technique in which the missing data are
replaced by more than one set of imputed values, usually between 3 and 10. In each case the
missing values are predicted by applying some form of regression model extracted from the
complete observations and adding in a random error component (Schafer, 1999). Each of the
‘complete’ data sets is then analysed by standard methods and the results are later combined
to produce estimates and confidence intervals that incorporate missing data uncertainty. In
this set of assumptions, whatever was happening last in a time series is assumed to be
predictive of what would have happened ultimately. Usually this means accepting the last data
point as the endpoint of outcome.
• Analyse the incomplete data by a method that does not require a complete (rectangular) data
set.
Most statisticians would probably agree that ultimately there is no satisfactory method
for compensating for lost data. Hence, one must decide which compromises are the most
acceptable. There is now evidence that this produces bias in the final results. Most of the
recent trials such as CATIE, EUFEST and STEP-BD have used LOCF.
ECONOMIC EVALUATION OF TRIALS

Controlled clinical trials are the best source of data on the efficacy of healthcare
interventions; at one time researchers involved with clinical trials were almost exclusively
concerned with evaluating the relative clinical effectiveness of competing treatments. But with
escalating burden on the budgets of healthcare providers, it has become increasingly common
to collect data about economic outcomes, in addition to effectiveness outcomes in RCTs, in a
bid to answer questions about treatment costs. The aim is to select the most cost-effective
treatment to recommend for general use. On occasions this may be easy; where a new
treatment is quite obviously cheaper than the current standard, a trial that shows that the
new treatment is equivalent in effectiveness or more effective than the standard may be
sufficient reason to argue for the adoption of the new treatment over the old. The appeal of
economic evaluations of trials is that policy makers immediately find the results of research
more interesting and relevant, and may, as a consequence, be more likely to be persuaded by
them. But both the measurement of cost and the evaluation of cost-effectiveness are far from
straightforward and involves both direct costs, i.e. the cost of the medication itself, physician
visits, diagnostic tests, and hospitalizations, and indirect costs, i.e. the value of the changes in
health status and in productivity that the patient experiences. In practice, trials are needed to
include extended measurement protocols that can provide full treatment costs at the
individual patient level (Everitt & Wessely, 2008).
Cost-effectiveness analysis
Rising healthcare costs have increased the pressure on physicians to consider the
economic consequences of their treatment decisions. Cost-effectiveness analysis is now an
integral part of the assessment of treatments and addresses the question of whether a new
treatment or other healthcare programme offers good value for money. Cost-effectiveness
analysis attempts to measure the value of a new therapy by calculating the difference in cost
between the new therapy and the standard therapy, divided by the difference in effectiveness
of the two treatments (the cost-effectiveness ratio). Regression analysis is usually used to
evaluate factors associated with cost. But the distribution of cost by patient is typically highly
skewed, often with a small number of patients accounting for a disproportionate amount of the
costs. The development of statistical methods for the design and analysis of cost-effectiveness
studies is a growing area. The whole area of economic evaluation of treatments and cost-
effectiveness analysis is developing rapidly. This is particularly important in psychiatry where
patients require long duration treatments (Everitt & Wessely, 2008).
Recent trials such as CUtLASS and CATIE have tried to evaluate the cost-effectiveness
between FGAs and SGAs and the results showed no advantage of SGAs in terms of quality of
life or symptoms over 1 year and no significant differences in rates of objectively assessed
EPSEs. In fact, those participants who received an FGA did rather better. So these are some
factors that create burden on the healthcare system because FGAs are cheaper than SGAs
(Davies et al., 2007). In the SOHO study, country-specific as well as overall cost effectiveness
was examined while, to an extent, adjusting for gross price differences across countries.
Country effects on costs, originating from factors such as differences in treatment patterns,
may be accounted for in the analysis by introducing country and region-specific indicators.
This study found wide variation in both unit costs estimates and availability of cost data for
health service use across 9 countries. By collecting and comparing unit costs for resources in
mental health, this study has demonstrated the difficulties of arriving at relevant, robust and
comparable unit costs in international studies. The absence of nationally applicable unit cost
information on health-care resources is an obstacle to the conduct of economic evaluation
(Urdahl et al., 2003)
Role of pharmaceutical companies

Clinical trials are expensive to run and most researchers need to work with the
pharmaceutical industry since they are the ones with the drugs and the resources to study
them. Indeed the collaboration between industry and academia regarding the development and
testing of new drugs in psychiatry has been enormously productive. But such collaboration –
involving as it often does large amounts of money – clearly raises issues of possible conflicts of
interest; a question that needs to be addressed is whether there is any relationship between
industry funding and clinical trial outcomes in psychiatry. Among 397 such trials, 239
reported receiving funding from a pharmaceutical company or other interested party, and 187
studies included at least one author with a reported financial conflict of interest. Among the
162 randomized, double-blind, placebo-controlled studies examined, those that reported
conflict of interest were 4.9 times more likely to report positive results; this association was
significant only among the subset of pharmaceutical industry-funded studies. This finding is a
little disturbing but does it simply reflect that the pharmaceutical industry’s access to greater
resources allows researchers to conduct bigger studies with more power for detecting a
treatment effect). It was found that favourable outcomes were significantly more common in
studies sponsored by a drug’s manufacturer (78%), than in studies without industry
sponsorship (48%) or sponsored by a competitor. And these relationships remained after
controlling for the effects of journal, year, drug studied, and time since FDA drug approval,
diagnosis and sample size (Perlis, 2005). So, there is some evidence that industry sponsorship
and outcome of psychiatric clinical trials are related, although continuing research into this
relationship is needed (Kelly, 2006).
THE INDIAN CONTEXT

The larger context of clinical trials in India is poverty and the absence of affordable
health care. India is viewed as a favoured global site for international clinical trials of drugs.
According to the Drugs Controller General of India (DCGI), India is a preferred site for clinical
trials because, in addition to its medical infrastructure and trained English speaking
manpower, it has a “large, diverse and treatment-naïve population with six out of the seven
genetic varieties of the human race; a number of patients with both acute and chronic
diseases, an increase in the number of patients with lifestyle disorders and the highest
recruitment rates for such trials internationally”(Srinivasan & Nikarge, 2009a).The Indian
government has taken up this opportunity to change the regulatory climate here to
accommodate the needs of international clinical trials.
Clinical trials in India are regulated by Schedule Y of the Drugs and Cosmetics Rules.
The Rules are enforced by the office of the DCGI who is also responsible for approval and
monitoring of all clinical trials. For new drugs being developed in India clinical trials have to be
conducted in India from phase 1. For marketing approval of drugs already approved in other
countries, a phase 3 clinical trial is required on about 100 patients in three or more centres, in
order to establish the drug’s impact on the Indian ethnic population. An application for a new
indication of an already approved drug is treated as an application for a new drug’s approval
(Srinivasan & Nikarge, 2009a).
Till January 2005, clinical trials of new drugs being developed outside India were
permitted only with a “phase lag” i.e., a phase 2 trial could be conducted in India only after
phase 3 trials were completed elsewhere. Phase 1 trials of foreign drugs were not permitted,
except for drugs of special relevance to India. After that, an amendment of Schedule Y of the
Drugs and Cosmetics Rules (GOI, MOHF, 2005) did away with the phase lag in international
clinical trials conducted by foreign sponsors. There are no restrictions on “concurrent phase”
clinical trials in India. Phase 2 and phase 3 trials of drugs discovered abroad may now be
conducted in India in the same phase and at the same time as they are conducted in other
parts of the world. The trial sponsor must obtain approval from the DCGI before starting a trial
and that the trial would be conducted according to the principles of the Declaration of
Helsinki, Indian Good Clinical Practice guidelines, and the Indian Council of Medical
Research’s ethical guidelines for biomedical research on humans. Public hospitals are being
promoted as clinical trial sites. Monitoring systems are being set up to ensure high data
quality and meet the requirements of drug regulatory authorities abroad. Training institutes
are being encouraged to provide the manpower to run clinical trials. The trials that have been
conducted exploited the fact that most Indians do not have access to good quality and
affordable care and therefore may accept offers that might provide better quality and free
treatment. They were conducted on people who were vulnerable because they could not afford
good quality treatment or the most effective drugs. The patients were also vulnerable because
they were seriously ill. In the case of psychiatric patients, they may not have been able to
provide informed consent according to Declaration of Helsinki; as also interviews have been
unstructured (Srinivasan & Nikarge, 2009b).
THE FUTURE OF CLINICAL TRIALS
An optimist is someone who thinks the future is uncertain---Anon

What is the future of clinical trials in psychiatry? Psychiatrists have the reputation in
medical circles of never answering a straight question, and eternally fence-sitting. The
following are anticipated from psychiatric trials in the coming years purpose (Everitt &
Wessely, 2003):
1. The next move towards larger, simpler trials will accelerate and would be welcome.
2. There will be greater participant involvement in setting priorities to share understanding of
their role in protecting patients from untried and untested therapies.
3. The assessment of new interventions, combinations of drugs, psychotherapy and social
interventions will become more prominent.
4. More sophisticated methodologies are needed to be developed for incorporating qualitative
and quantitative research into the experimental evaluation.
5. More attention should be paid to issues such as the representativeness of recruitment,
values and preferences of trial participants, and broader outcome measures like functioning,
work and so on, rather than symptoms alone.
6. Promising new interventions are likely to be evaluated.
7. Involvement of special age groups should be promising.
8. Intercontinental barriers should be removed to generalize the outcome.
9. The Indian government’s long term goals (2010 to 2015) as stated by the DCGI include
changing the law to permit phase 0 and phase 1 trials. Discussions are going on to introduce
phase 0 and phase 1 trials; consultations have been ongoing with industry, researchers,
lawyers, social organisations and non-governmental organisations.
CONCLUSION
Although, clinical trials play a major role in the development of new drugs and in the
assessment of their effectiveness, they have been associated with many problems of an ethical
nature such as the issues of informed consent and the use of placebo. RCT is an important
modality of the clinical trial with wide acceptability but it too is plagued with issues relating to
generalizability and validity of its results. In recent times, a more acceptable method, the
pragmatic RCT, is being used, the results of which are more generalizable and which measures
functional outcomes rather than symptomatic improvement.
Care should be taken of the special population groups, who have received scant
attention till date. The aim of future clinical trials should be to develop more cost-effective
drugs which have better side-effect profiles. This is particularly important for developing
countries like India which have plenty of patients and resources to conduct useful drug trials.
________________________________________________
References
Alexopoulos, G.S., Streim, J., Carpenter, D., Docherty, J.P. (2004). Using Antipsychotic Agents
in Older Patients. Journal of Clinical Psychiatry, 65, 95-104.
Als-Nielsen, B., Chen, W., Gluud, C., et al. (2003). Association of funding and conclusions in
randomized drug trials: a reflection of treatment effect or adverse events?
Journal of the American Medical Association, 290, 921-28.
Aman, M.G., Shah, B., Martin, A., et al. (2005). Randomized, Controlled, Crossover Trial of
Methylphenidate in Pervasive Developmental Disorders With Hyperactivity:
Research Units on Pediatric Psychopharmacology (RUPP) Autism Network.
Archives of General Psychiatry, 62, pp.1266-74.
Anderson, M.I & Reid, C.I. (2004). Fundamentals of Clinical Psychopharmacology. 2nd ed.,
Martin Dunitz Books: London.
Appelbaum, P.S., Roth, L.H., Lidz, C.W., et al. (1987). "False Hopes and Best Data: Consent to
Research and the Therapeutic Misconception," Hastings Center Report 17, no. 2,
20-4.
Barton, S. (2000). Which clinical studies provide the best evidence? The best RCT still trumps
the best observational study. British Medical Journal, 321, 255-6.
Berkman, L., Jafe, A., Carney, R., et al. (2001). Enhancing Recovery in Coronary Heart Disease
(ENRICHD) Study Intervention: Rationale and Design. Psychosomatic Medicine,
63, 747–55.
Bloom, B.S. (2001). Daily regimen and compliance with treatment (editorial). British Medical
Journal, 323, p. 647.
British Medical Journal Books: London.
Byar, D.P. (1977). Sound advice for conducting clinical trials. New England Journal of Medicine,
297, 553-4.
Calabrese, J.R., Keck, P.E. Jr., Macfadden, W., et al. (2005). A randomized, double-blind,
placebo-controlled trial of quetiapine in the treatment of bipolar I or II
depression. American Journal of Psychiatry, 162, 1351–60.
Clinical Trials Registry-India (online) (updated on June 24, 2010) available at:
http://ctri.nic.in/clinical trials/index.jsr. [accessed 17 January, 2010].
Cochrane Schizophrenia Group. October 2002,
http://www.cochrane.org/cochrane/revabstr/g060index.htm [accessed 22
January 2011.
Coyne, J.C. (2006). Cochrane reviews vs. industry supported meta-analyses. We should read
all reviews with caution. British Medical Journal, 333, 916.
Cramer, J.A., Collins, J.F., Mallson, R.H. (1988). Can catergorization of patient background
problems be used to determine early termination in clinical trial? Controlled
Clinical Trials, 9, 47-63.
Crawford, M.J. (2002). Evaluating new treatments in psychiatry: the potential value of
combining qualitative and quantitative research methods. International Review
of Psychiatry, 14, 6–11.
Davies, D. and Shepherd, M. (1955). Reserpine in the Treatment of Anxious Patients. Lancet, I,
117–20.
Davies, L.M., Lewis, S., Jones, P.B., et al. (2007). Cost-effectiveness of first- vs. second-
generation antipsychotic drugs: results from a randomized controlled trial in
schizophrenia responding poorly to previous therapy. British Journal of
Psychiatry, 191, 14–22.
De Santis, M., Cesari, E., Cavaliere, A. et al. (2008). Paternal exposure and counselling:
experience of a Teratology Information Service. Reproductive Toxicology, 26, 42–
6.
DelBello, M.P., Chang, K., Welge, J.A., et al. (2009). A Double-Blind, Placebo-Controlled Pilot
Study of Quetiapine for Depressed Adolescents with Bipolar Disorder. Bipolar
Disorders, 11, 483–93.
Department of Health, Education, and Welfare, US Food & Drug Administration (1977).
General Considerations for the Clinical Evaluation of Drugs. Washington, DC,
Publication #HEWFDA, 88–3040.
DeVeaugh-Geiss, J., Moroz, G., Biederman, J., et al. (1992). Clomipramine hydrochloride in
Childhood and Adolescent Obsessive-Compulsive Disorder—a Multicenter Trial.
Journal of American Academics of Child and Adolescent Psychiatry, 31, 45-9.
Duggal, R. (2005). The out-of-pocket burden of healthcare. Agenda: Access to public health.
Pune, India:
Elkes, J. & Elkes, C. (1954). Effect of Chlorpromazine on the Behaviour of Chronically over-
active Psychotic Patients. British Medical Journal, I, 560–5.
Essock, S.M., Covell, N.H., Davis, S.M., et al. (2006). Effectiveness of switching antipsychotic
medications. American Journal of Psychiatry, 163, 2090–5.
Everitt, S. V. & Wessley, S. (2008). Clinical Trials in Psychiatry. 2nd Ed. Wiley & Sons: West
Sussex.
Fava, M., & Rosenbaum, J.F. (1992). Research Designs and Methods in Psychiatry. Elsevier:
Amsterdam.
Fava, M., Rush, A.J., Trivedi, M.H., et al. (2003). Background and rationale for the Sequenced
Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatric Clinics
of North America, 26, 457–94.
Fava, M., Rush, A.J., Wisniewski, S.R., et al. (2006). A Comparison of Mirtazapine and
Nortriptyline following Two Consecutive Failed Medication Treatments for
Depressed Outpatients: a STAR*D report. American Journal of Psychiatry, 163,
1161–72.
Fleischhacker, W.W., Keet, I.P., Kahn, R.S. (2005). The European First Episode Schizophrenia
Trial (EUFEST): rationale and design of the trial. Schizophrenia Research, 78,
147-56.
Franklin, M., Foa, E., March, J.S. (2003). The Pediatric Obsessive-Compulsive Disorder
Treatment Study: rationale, design, and methods. Journal of American
Academics of Child and Adolescent Psychiatry 13, S39-S51.
Frasure-Smith, N., Koszycki, D., Swenson, J.R., et al. (2006). Design and rationale for a
Randomized, Controlled Trial of Interpersonal Psychotherapy and Citalopram for
Depression in Coronary Artery Disease (CREATE). Psychosomatic Medicine, 68,
87-93.
Frasure-Smith, N., Koszycki, D., Swenson, J.R., et al. (2007). Effects of Citalopram and
Interpersonal Psychotherapy on Depression in Patients With Coronary Artery
Disease: The Canadian Cardiac Randomized Evaluation of Antidepressant and
Psychotherapy Efficacy (CREATE) Trial. Journal of the American Medical
Association, 297, 367-79.
Freedman, B. (1987). Equipoise and the Ethics of Clinical Research. New England Journal
Medicine, 317, 141-5.
Friedman, E., Gyulai, L., Bhargava, M., et al. (2006). Seasonal changes in clinical status in
bipolar disorder: A prospective study in 1000 STEP-BD patients. Acta
Psychiatrica Scandinavica, 113, 510-7.
Gasqueta, I., Harob, J.M., Novickc, M., et al. (2005). International Clinical Psychopharmacology,
20, 4.
Geddes, J.R., Rendell, J.M., Goodwin, G.M. (2002). BALANCE: a large simple trial of
maintenance treatment for bipolar disorder. World Psychiatry, 1, 48–51.
Gitlin, M., Nuechterlein, K., Subotnik, K.L., et al. (2001). Clinical outcome following neuroleptic
discontinuation in patients with remitted recent-onset schizophrenia. American
Journal of Psychiatry, 158, 1835–42.
Glassman, A.H., O’Connor, C.M., Califf, R., et al. (2002). Sertraline treatment of major
depression in patients with acute MI or unstable angina. Journal of the American
Medical Association, 288, 701–9.
Glassman, A.H., Roose, S.P., Bigger, J.T. Jr. (1998). The safety of tricyclic antidepressants in
cardiac patients: risk-benefit reconsidered. Journal of the American Medical
Association, 269, 2673–5.
Goldberg, J.F., Perlis, R.H., Ghaemi, S.N., et al. (2007). Adjunctive antidepressant use and
symptomatic recovery among bipolar depressed patients with concomitant
manic symptoms: findings from the STEP-BD. American Journal of Psychiatry
164, 1348–55.
Goodyer, I.M., Dubeica, B.,Wilkinson, P., et al. (2008). A randomized controlled trial of
cognitive behaviour therapy in adolescents with major depression treated by
selective serotonin reuptake inhibitors. The ADAPT trial. Health Technology
Assessment, 12, 14-28.
Government of India. Ministry of health and family welfare. The Drugs and Cosmetics Act and
Rules. Last updated 30th of June 2005.
http://cdsco.nic.in/html/Drugs&CosmeticAct.pdf [accessed on 20 January
2011].
Hafner, H., Behrens, S., De Vry, J., et al. (1991). An animal model for the effects of estradiol on
dopamine-mediated behavior: implications for gender differences in
schizophrenia. Psychiatry Research, 38, 125–34.
Hamilton, S.H., Revicki, D.A., Edgell, E.T., et al. (1999). Clinical and economic outcomes of
olanzapine compared with haloperidol for schizophrenia: results from a
randomised clinical trial. Pharmacoeconomics, 15, 469-80.
Haro, J.M., Jones, P.B., Alanso, J., et al. (2003a). The European Schizophrenia Outpatient
Health Outcomes (SOHO) study: rationale, methods and recruitment. Acta
Psychiatrica Scandinavica, 107, 222–32.
Haro, J.M., Jones, P.B., Alanso, J., et al. (2003b). The European Schizophrenia Outpatient
Health Outcomes (SOHO) study: rationale, methods and recruitment. Acta
Psychiatrica Scandinavica, 107, 7–15.
Haro, J.M., Jones, P.B., Alanso, J., et al. (2008). The European Schizophrenia Outpatient
Health Outcomes (SOHO) study: baseline finding across country and treatment.
Acta Psychiatrica Scandinavica, 119, 107–15.
Healy, D. (1997). The Antidepressant Era. Harvard University Press: Cambridge.
Heres, S., Davis, J., Maino, K., et al. (2006). Why olanzapine beats risperidone, risperidone
beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of
head-to-head comparison studies of second-generation antipsychotics. American
Journal of Psychiatry, 163, 185-94.
Hertzman, M. & Adler, L. (2010). Clinical Trials in Psychopharmacology. 2nd ed. Wiley & Sons:
West Sussex.
Hollander, E., James, T., Kohn, T.A., et al. (2009). Lack of Efficacy of Citalopram in Children
with Autism Spectrum Disorders and High Levels of Repetitive Behavior.
Archives of General Psychiatry, 66, 583-90.
Hotopf, M. (2002). The pragmatic randomized controlled trial. Advances in Psychiatric
Treatment, 8, 326-33.
Jones, P.B., Barnes, T.R.E., Davies, L., et al. (2006). Randomized controlled trial of effect on
quality of life of second- vs. first-generation antipsychotic drugs in
schizophrenia. Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia
Study (CUtLASS 1). Archives of General Psychiatry, 63, 1079–87.
Kahn, R., Schulz, C., Palazov, V., et al. (2007). Efficacy and tolerability of once-daily extended
release quetiapine fumarate in acute schizophrenia: A randomized, double-blind,
placebo-controlled study. Journal of Clinical Psychiatry, 68, 832–42.
Kahn, R.S., Fleischhacker, W.W., Boter, H., et al. (2008). EUFEST Study Group: Effectiveness
of antipsychotic drugs in first-episode schizophrenia and schizophreniform
disorder: an open randomised clinical trial, Lancet, 371, 1085–97.
Karhuvaara, S., Simojoki, K., Virta, A. et al. (2007). Targeted nalmefene with simple medical
management in the treatment of heavy drinkers: a randomized double-blind
placebo-controlled multicenter study. Alcoholism, Clinical and Experimental
Research, 31, 1179–87.
Keefe, S.E., Bilder, R.M., Davis, S.M., et al. (2007). Neurocognitive effects of antipsychotic
medications in patients with chronic schizophrenia in the CATIE trial. Archives
of General Psychiatry, 64, 633–47.
Kelly, R.E. (2006). Relationship between drug company funding and outcomes of clinical
psychiatric research. Psychological Medicine, 36, 1647-56.
Khanna, S., Vieta, E., Lyons, B., et al. (2005). Risperidone in the treatment of acute mania:
double-blind, placebo-controlled study. British Journal of Psychiatry, 187, 229-
34.
Kim, S.Y., Caine, E.D., Currier, G.W., et al. (2001). Assessing the competence of persons with
Alzheimer’s disease in providing informed consent for participation in research.
American Journal of Psychiatry, 158 (5), 712–7.
Kumar, M. & Khess, C.R.J. (2007). The Comparative Efficacy of Memantine and Diazepam in
Alcohol Withdrawal Syndrome: an Open Label Trial. Unpublished thesis. Ranchi
University: Ranchi.
Kumar, M. & Ram, D. (2004). The Efficacy and Side-Effect Profile of Lamotrigine in Acute
Mania: a Double-Blind Comparison with Lithium. Unpublished thesis. Ranchi
University: Ranchi.
Kunz, R., Oxman, A.D. (1998). The unpredictability paradox: review of empirical comparisons
of randomized and non-randomized clinical trials. British Medical Journal,
317,1185- 90.
Lantos, J.D. (1999). The inclusion effect in clinical trials. Journal of Paediatrics, 134,130-1.
Leung, A. & Chue, P. (2000). Gender differences in schizophrenia, a review of the literature.
Acta Psychiatrica Scandinavica, 101, 3–38.
Levine, R.J. (2002). Placebo controls in clinical trials of new therapies for which there are
known effective treatments. In The Science of the Placebo: Toward an
Interdisciplinary Research Agenda. (eds. H. A. Guess, A. Kleinman, J.W. Kusek,
et al.) pp. 264–80.
Lieberman, J. A. (2006). Comparative effectiveness of antipsychotic drugs: a commentary on
Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study
(CUtLASS1) and Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE). Archives of General Psychiatry, 63, 1069-72.
Lyketsos, C.G., Steinberg, N., Olin, J.T., et al. (2003). Treating Depression in Alzheimer Disease
Efficacy and Safety of Sertraline Therapy, and the Benefits of Depression
Reduction: The DIADS. Archives of General Psychiatry, 60, 37-46.
Manschreck, T.C & Boshes,R.A., (2007). The CATIE Schizophrenia Trial: Results, Impact,
Controversy. Harvard Review of Psychiatry, 15, 245-58.
March J. S., Franklin, M., Foa, E., et al. (2004b). Cognitive-Behavior Therapy, Sertraline, and
Their Combination for Children and Adolescents with Obsessive-Compulsive
Disorder. The Pediatric OCD Treatment Study (POTS) Randomized Controlled
Trial. Journal of the American Medical Association, 292, 1969-76.
March, J.S., Silva, S., Petrycki, S., et al. (2004a). Treatment for Adolescents with Depression
Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their
combination for adolescents with depression: Treatment for Adolescents with
Depression Study (TADS) randomized controlled trial. Journal of the American
Medical Association, 292, 807-20.
Marquis, D. (1983). "Leaving therapy to chance," Hastings Center Report 13, no.4, 40-47.
Mason, B.J., Salvato, F.R., Williams, L.D., et al. (1999). A double-blind, placebo-controlled
study of oral nalmefene for alcohol dependence. Archives of General Psychiatry,
56, 719-24.
Mastroianni, A.C., Faden, R., Federman, D. (1994). Committee on Ethical and Legal Issues
Relating to the Inclusion of Women in Clinical Studies, Institute of Medicine
(IOM) Women and Health Research, Ethical and Legal Issues of Including Women
in Clinical Studies, Vol. 1, 12-20.
McCullough, L.B., Coverdale, J.H., and Chervenak, F.A. (2006). Preventive ethics for including
women of childbearing potential in clinical trials. American Journal of Obstetrics
and Gynecology, 194, 1221–7.
McElroy, S.L., Weisler, R.H., Chang, W., et al. (2010). A double-blind, placebo controlled study
of quetiapine and paroxetine as monotherapy in adults with bipolar depression
(EMBOLDEN II). Journal of Clinical Psychiatry, 71, 163–74.
McGrath, P.J., Stewart, J.W., Fava, M., et al. (2006). Tranylcypromine versus venlafaxine plus
mirtazapine following three failed antidepressant medication trials for
depression: a STAR*D report. American Journal of Psychiatry, 163, 1531–41.
McKee, M. (1999). Interpreting the evidence: choosing between randomized and
nonrandomized studies. British Medical Journal, 319, 312–5.
Meinert, C.L. (1986). Clinical Trials – Design, Conduct and Analysis. Oxford University Press:
New York.
Mendes de Leon, C.F., DiLillo, V., Czajkowski, S., et al. (2002). The ENRICHD Investigators.
Enhancing recovery in coronary heart disease patients (ENRICHD): study design
and methods. American Heart Journal, 139, 1-9.
Meyer, J.M., Nasrallah, H.A., McEvoy, J.P., et al. 2006. The Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of
subgroups with and without the metabolic syndrome. Schizophrenia Research,
80, 9–18.
Nakamura, M., Ogasa, M., Guarino, J., et al. (2009). Lurasidone in the treatment of acute
schizophrenia: a double-blind, placebo-controlled trial. Journal of Clinical
Psychiatry, 70, 829–36.
Nierenberg, A.A., Fava, M., Trivedi, M.H., et al. (2006a). A comparison of lithium and T3
augmentation following two failed medication treatments for depression: a
STAR*D report. American Journal of Psychiatry, 16, 1519-30.
Nierenberg, A.A., Ostacher, M.J., Borrelli, D.J., et al. (2006b). The integration of measurement
and management for the treatment of bipolar disorder: a STEP-BD model of
collaborative care in psychiatry. Journal of Clinical Psychiatry, 67, 3–7.
Park, K. (2009). Park’s Textbook of Preventive and Social Medicine. 19th ed. Bhanot publication:
Jabalpur.
Perlis, R.H., Delbello, M.P., Miyahara, S., et al. (2005).Phenomenology of Rapid-Cycling Bipolar
Disorder: data from first 500 participants in the STEP-BD. Biological Psychiatry,
58, 549–53.
Prout, M.N. & Fish, S.S. (2001). Participation of women in clinical trials of drug therapies: a
context for the controversies. Medscape General Medicine, 3, 4.
Quitkin, F. (2000). Placebo effects and other non-specific factors. In New Oxford Textbook of
Psychiatry, 1st ed. (eds. M.Gelder, J.Lopez-Ibor, & N.Andreasen), pp.1269-75.
Oxford University Press: Oxford.
Ranjan, S. & Paul, S.E. (2005). Cognitive Improvement in Schizophrenia with Atypical
Antipsychotics: a Randomized Double-Blind Comparison between Risperidone
and Olanzapine. Unpublished thesis. Ranchi University: Ranchi.
Rees, W. (1956). A controlled study of the value of chlorpromazine in the treatment of anxiety
tension states. L’Encephale, 4, 547–9.
Rendell, J.M., Juszczak, E., Hainsworth, J., et al. (2004). Developing the BALANCE trial—the
role of the pilot study and start-up phase. Bipolar Disorder, 6, 26–31.
Robinson, D., Woerner, M.G., Alvir, J.M.J., et al. (1996). Predictors of relapse following
response from a first episode of schizophrenia or schizoaffective disorder.
Archives of General Psychiatry, 56, 241–7.
Robinson, D., Woerner, M.G., Pollack, S., et al. (1996). Subject selection biases in clinical
trials: data from a multicenter schizophrenia treatment study. Journal of Clinical
Psychopharmacology, 16, 170–6.
Roland, M. & Torgerson, D. (1998). Understanding controlled trials: what outcomes should be
measured? British Medical Journal, 317, 1075.
Rothman, K. & Michels, K. (1994). The continuing unethical use of placebo controls. New
England Journal of Medicine, 331, 393–8.
Rothwell, P. (1995). Can overall results of clinical trials be applied to all patients? Lancet, 345,
1616–9.
Roy, H.P., Melissa, P.D., Sachiko, M. (2005). Biological Psychiatry, 58, 549–53.
Rubin, D.B. (1976). Inference and missing data. Biometrika, 63, 581–92.
Rush, A.J., Fava, M., Wisniewski, S.R., et al. (2004). Sequenced Treatment Alternatives to
Relieve Depression (STAR*D): rationale and design. Control Clinical Trials, 25,
119-42.
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., et al. (2006). Bupropion-SR, sertraline, or
venlafaxine-XR after failure of SSRIs for depression. New England Journal of
Medicine, 354, 231-42.
Sachs, G.S., Thase, M.E., Otto, M.W., et al. (2003). Rationale, design, and methods of the
systematic treatment enhancement program for bipolar disorder (STEP-BD).
Biological Psychiatry, 53, 1028–42.
Sackett, D.L., & Rosenberg, W.M. (1996). Evidence based medicine: what it is and what it isn’t.
British Medical Journal, 312, 71–2.
Schafer, J.L. (1999). Multiple imputations: a primer. Statistical methods in Medical Research, 8,
3-16
Schiebinger, L. (2003). Women’s health and clinical trials. The Journal of Clinical Investigation,
112, 973–7.
Schneider, L.S., Tariot, P.N., Lyketsos, C.G., et al. (2001). National Institute of Mental Health
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer
disease trial methodology. American Journal of Geriatric Psychiatry, 9, 346-60.
Schou, M.J. (1954). The treatment of manic-psychoses by the administration of lithium salts.
Journal of Neurological Psychiatry, 17, 250–60.
Schultz, K. (1994). Assessing the quality of randomization from reports of controlled trials
published in obstetrics and gynecology journals. Journal of the American Medical
Association, 272, 125–8.
Schulz, K.F., Chalmers, I., Hayes, R.J., Altman, D.G. (1995). Empirical evidence of bias.
Dimensions of methodological quality associated with estimates of treatment
effects in controlled trials. Journal of the American Medical Association, 273,
408–12.
Seeman, M.V. (1989). Neuroleptic prescriptions for men and women. Social Pharmacology, 3,
219–36.
Seeman, M.V. (1996). The role of estrogen in schizophrenia. Journal of Psychiatry &
Neuroscience, 21, 123–32.
Shapiro, P.A., Lesperance, F., Frasure-Smith, N., et al. (1999). An open-label preliminary trial
of sertraline for treatment of major depression after acute myocardial infarction
(the SADHAT Trial). American Heart Journal, 137,1100–6.
Sikich, L., Frazier, J.A., Findling, R.L., et al. (2008). Double-Blind Comparison of First- and
Second-Generation Antipsychotics in Early-Onset Schizophrenia and
Schizoaffective Disorder: Findings from the Treatment of Early-Onset
Schizophrenia Spectrum Disorders (TEOSS) Study. American Journal of
Psychiatry, 165, 1420-31.
Singh, R.K. & Sinha, V.K. (2004). Effect Size of Lithium, Sodium Valproate and Carbamazepine
in Children and Adolescent with Bipolar Disorder - a Prospective Open Label
Trial. Unpublished dessertation. Ranchi University: Ranchi.
Srinivasan, S. & Nikarge, S. (2009a). Ethical concerns in clinical trials in India: an
investigation. Centre for Studies in Ethics and Rights, Mumbai. pp. 4-6.
Srinivasan, S. & Nikarge, S. (2009b). Ethical concerns in clinical trials in India: an
investigation. Centre for Studies in Ethics and Rights, Mumbai. pp. 13-4.
Stocking, C.B., Hougham, G.W., Baron, A.R., et al. (2003). Are the rules for research with
subjects with dementia changing? Views from the field. Neurology, 61, 1649–51.
Stroup, T.S., McEvoy, J.P., Swartz, M.S., et al. (2003). The National Institute of Mental Health
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project:
schizophrenia trial design and protocol development. Schizophrenia Bulletin, 29,
15–31.
Swartz, M.S., Perkins, D.O., Stroup, T.S., et al. (2003). Assessing clinical and functional
outcomes in the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) Schizophrenia Trial. Schizophrenia Bulletin, 29, 33–43.
Swartz, M.S., Wagner, H.R., Swanson, J.W., et al. (2006). Substance use in persons with
schizophrenia: Baseline prevalence and correlates from the NIMH CATIE study.
The Journal of Nervous and Mental Disease, 194, 164–72.
Thase, M.E., Friedman, E.S., Biggs, M.M., et al. (2007). Cognitive therapy versus medication in
augmentation and switch strategies as second-step treatments: a STAR*D
report. American Journal of Psychiatry, 164, 739–52.
Thase, M.E., Macfadden, W., Weisler, R.H., et al. (2006). Efficacy of quetiapine monotherapy in
bipolar I and II depression: a double-blind, placebo-controlled study (the
BOLDER II study). Journal of Clinical Psychopharmacology, 26, 600-9.
Tohen, M., Vieta, E., Calabrese, J., et al. (2003). Efficacy of olanzapine and olanzapine-
fluoxetine combination in the treatment of bipolar I depression. Archives of
General Psychiatry, 60, 1079–88.
Trivedi, M.H., Rush, A.F., Wisniewski, S.R., et al. (2006). Evaluation of outcomes with
citalopram for depression using measurement-based care in STAR*D:
implications for clinical practice. American Journal of Psychiatry, 163, 28-40.
Urdahl, H., Knapp, M., Edgell, E.T., et al. (2003). Unit costs in international economic
evaluations: resource costing of the Schizophrenia Outpatient Health Outcomes
Study. Acta Psychiatrica Scandinavica, 107 (suppl. 416), 41-7.
Vitiello, B., Rohde, P., Silva, S., et al. (2006). Functioning and quality of life in the Treatment
for Adolescents with Depression Study (TADS). Journal of American Academics of
Child and Adolescent Psychiatry, 45, 1419-26.
Walkup, J.T., Albano, A.M., Piacentini, J., et al. (2008). Cognitive Behavioral Therapy,
Sertraline, or a Combination in Childhood Anxiety. New England Journal of
Medicine, 359, 2753-66.
Wells, K.B. (1999). Treatment research at the crossroads: the scientific interface of clinical
trials and effectiveness research. American Journal of Psychiatry, 156, 5-10.
West, A. & Bonnie, S. (2008). Randomised Clinical Trial. 3rd ed. Wiley & Sons: West Sussex.
Williams, D. D. R. & Garner, J. (2002). The case against ‘the evidence’: a different perspective
on evidence-based medicine. British Journal of Psychiatry, 180, 8–12.
World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research
Involving Human Subjects (2008) (updated on 24 June, 2009).Available
at:http://www.wma.net/ e/policy/17c.pdf. [accessed 20 January, 2011]
Young, A.H., McElroy, S., Bauer, M., et al. (2010). A double-blind, placebo- controlled study of
quetiapine and lithium monotherapy in adults in the acute phase of bipolar
depression (EMBOLDEN I). Journal of Clinical Psychiatry, 71,150–62.
Young, L.T., & Joffe, R.T. (2001). A review of psychosocial outcome in patients with bipolar
disorder. Acta Psychiatrica Scandinavica, 103, 163-70.

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Government of India

CENTRAL INSTITUTE OF PSYCHIATRY, RANCHI

Chairperson: Dr. Avinash Sharma MD

Presenter: Dr Surjit Prasad Discussant: Dr Sachchidanand Singh

Venue: A. B. Davis Hall Date: 27.01.2011

A cornerstone of the improvements in treatment in medicine in general and psychiatry

WHAT DO CLINICAL DRUG TRIALS ENTAIL

Types of Clinical Drug Trials (Schulz et al., 1995)

FAMOUS DRUG TRIALS IN PSYCHIATRY

1. To determine the long-term effectiveness and tolerability of the newer atypical

II. Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study

III. European First Episode Schizophrenia Trial (EUFEST)

V. Treatment of Early-Onset Schizophrenia Spectrum Disorder (TEOSS)

I. Sequenced Treatment Alternatives to Relieve Depression (STAR*D)

Figure 2. Sequential Therapies Evaluated in the STAR*D Trial

In level 1, participants were given the antidepressant citalopram for 12 to 14 weeks.

II. Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

III. BipOLar DEpRession (BOLDER) I study (DelBello et al., 2009)

IV. BipOLar DEpRession (BOLDER) II STUDY (Thase et al., 2006)

V. Efficacy of Monotherapy Seroquel in BipOLar DEpressioN (EMBOLDEN) I Study

VI. Efficacy of Monotherapy Seroquel in BipOLar DEpressioN (EMBOLDEN) II

VII. Bipolar Affective disorder: Lithium/ANti -Convulsant Evaluation

VIII. Treatment of Adolescents with Depression (TADS) Study (March et

IX. Adolescent Depression Antidepressant and Psychotherapy Trial

C. OBSESSIVE COMPULSIVE DISORDER

I. Pediatric OCD Treatment Study (POTS) (Franklin et al., 2003)

I. Sponsored Studies to Advance Autism Research and Treatment

II. Research Units on Paediatric Psychopharmacology (RUPP) Autism Network

I. Child-Adolescent Anxiety Multimodal (CAAM) STUDY (Walkup et al.,

Nalmefene in the Treatment of Heavy Drinkers (Karhuvaara et al., 2007)

DRUG TRIALS IN SPECIAL POPULATIONS

I. Clinical Antipsychotic Trials of Intervention Effectiveness- Alzheimer’s

II. Depression In Alzheimer’s Disease Study (DIADS) (Lyketsos et al., 2003)

I. Sertraline Anti-Depressant Heart Attack Randomized Trial (SADHART)

INTRODUCTION: Many large-scale, well-controlled studies, in which initially healthy subjects

II. Canadian Cardiac Randomized Evaluation of Antidepressant and

INTRODUCTION: It has been recognized that depression is associated with increased

III. Enhancing Recovery In Coronary Heart Disease (ENRICHD) Study (Berkman.,

DRUG TRIALS ON NEWER PSYCHOTROPICS

Lurasidone in the Treatment of Acute Schizophrenia: A Double-Blind, Placebo-

CLINICAL TRIALS IN INDIA (www.ctri.nic.in)

I. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study

DRUG TRIALS IN CENTRAL INSTITUTE OF PSYCHIATRY (CIP)

The clinical trial is the experimental procedure needed to evaluate competing

TYPES OF EXPERIMENTAL STUDIES

Non-randomised or non-experimental trials

Randomised controlled trials

OBSERVATIONAL vs. PRAGMATIC RCT

Pragmatic RCTs (Hotopf, 2002):

Outcome measures of pragmatic RCTs

BIASES IN CLINICAL TRIALS

ALLOCATION CONCEALMENT, BLINDING AND MATCHING

ETHICAL ISSUES IN CLINICAL TRIALS

SPECIAL POPULATIONS IN CLINICAL TRIALS

Women’s issues in clinical trials

SPECIAL PROBLEMS OF TRIALS IN PSYCHIATRY

STATISTICAL ISSUES IN CLINICAL TRIALS

The size or a clinical trial

ECONOMIC EVALUATION OF TRIALS

Role of pharmaceutical companies