Milestone Studies

Under the guidance of Dr Vijay Niranjan Sir

Assistant Professor
Department of Psychiatry
MGMMC, Indore

Presented by Dr Priyash Jain

Introduction
• Psychiatric illnesses have puzzled mankind for many years. But,
Psychiatry as an organized branch of science is relatively newer.
• It has come in its present form by the effort of many philosophers and
psychiatrists.
• But there has also been rise of antipsychiatry movement along with
the development of psychiatry.
• Many psychiatric studies have been conducted that have contributed
to the development of psychiatry along with curbing the
antipsychiatry movement.
Milestone Studies
• Mood Disorders
• STEP-BD
• STAR-D
• BALANCE

• Schizophrenia

• IPSS
• DOSMeD
• ISoS
• CATIE
• CAMP
• CUTLASS
Milestone Studies

• Substance Abuse
• MATCH

• ADHD
• MTA

• Other important studies

STEP-BD
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)
The STEP-BD Trial
• Antidepressants have proved to be efficacious in treating unipolar
depression, the data providing support for their use in treating bipolar
depression were minimal.
• Second, the widely held belief that Antidepressants can induce
abnormal mood elevation or accelerate the rate of cycling.
• Adequately powered, well-controlled studies were needed to show
the effectiveness of treatments for bipolar depression.
The STEP-BD Trial
• STEP-BD is the largest, federally-funded treatment study ever conducted for
bipolar disorder.
• It is a long-term outpatient study that enrolled 4,360 participants from 22
sites over seven years (1998 to 2005).
• double-blind, randomized, placebo-controlled, parallel-group study of
standard antidepressants (either bupropion or paroxetine) as adjuncts to
treatment with mood stabilizers (Li, Val,CBZ, or other FDA approved
antimanic agents)
• Subjects with bipolar I or bipolar II disorder were treated for up to 26 weeks
to evaluate the effectiveness, safety, and tolerability of the adjunctive use of
antidepressant medication.
The STEP-BD Trial
Bottom Line
• Among patients with bipolar disorder receiving mood stabilizing
agents, the addition of an antidepressant did not yield improved
symptom control compared to mood stabilizing therapy alone.
STAR*D
Sequenced Treatment Alternatives to Relieve Depression
STAR*D
• STAR*D was designed to determine which treatments are most
effective following non-remission or intolerance to an initial SSRI or to
any of a series of subsequent randomized treatments.
• Over a 37-month period, STAR*D enrolled 4041 outpatients aged 18
to 75 years with nonpsychotic MDD at 41 clinical sites across the
United States (18 primary and 23 psychiatric care settings)
• The study enrolled nonpsychotic MDD confirmed with a DSM-IV and a
score greater than or equal to 14 on the 17-item Hamilton Rating
Scale of Depression (HRSD)
STAR*D
• Employed a four-step treatment protocol to outpatients with non-psychotic depression with
total remission as the goal.

• Step 1 was citalopram only. Those with remission were entered into a 12-month follow up
protocol. Those who did not attain remission were randomly enrolled in step 2 treatment.

• Step 2 treatment which consisted of 7 different treatment options.

• As expected, remission rates were higher in earlier steps, with step 1 achieving remission
in 36.8% of patients. Among the individuals that progressed to step 2, remission was
achieved in 30.6%.

• Steps 3 and 4 achieved remission in 13.7% and 13%, respectively.

Sequenced Treatment Alternatives to Relieve Depression:
STAR*D
STAR*D
• STAR-D sheds light on the success of a specific tiered
approach at treating unipolar depression.

• However, the study was limited in part by its open-label design

and lack of a placebo control, rendering it difficult to tease out
the impact of pharmacological therapy and CBT from the
natural history of depression.
BALANCE
BALANCE- Bipolar Affective Disorder Lihium/ANti-Convulsant Evaluation.
Lithium Plus Valproate Combination versus Monotherapy
for Relapse Prevention in Bipolar I Disorder (BALANCE)

• Author- John R Geddes (chief investigator),Guy M Goodwin (Trial

Manager), Jennifer Rendell (Trial Manager) et.al.

• Published in The Lancet in the year 2010.

Lithium Plus Valproate Combination versus Monotherapy
for Relapse Prevention in Bipolar I Disorder (BALANCE)

• Lithium carbonate and valproate sodium 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.
• Aimed to establish whether lithium plus valproate was better than
monotherapy with either drug alone for relapse prevention in bipolar
I disorder.
Lithium Plus Valproate Combination versus Monotherapy
for Relapse Prevention in Bipolar I Disorder (BALANCE)

• 330 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 0·4–1·0 mmol/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.
Lithium Plus Valproate Combination versus Monotherapy
for Relapse Prevention in Bipolar I Disorder (BALANCE)

• The benefits of a lithium-valproate combination compared with

valproate alone in terms of prevention or delay of an event are
obvious from this study. However, lithium monotherapy also seems to
be superior to valproate alone and close to the combination effect.
IPSS
International Pilot Study Of Schizophrenia (WHO)
IPSS
• began in 1966 as a large-scale cross-cultural collaborative project
• carried out simultaneously in nine countries (5 developed and 4 developing)
that differ widely in their sociocultural and economic characteristics:
• Colombia,
• Czechoslovakia,
• Denmark,
• India (Indian Centre - Agra),
• Nigeria,
• China,
• the Union of Soviet Socialist Republics,
• the United Kingdom, and
• the United States of America
IPSS
• set out to lay methodological groundwork for future international
epidemiological and other research in schizophrenia as well as in other
functional psychiatric disorders
• Is it feasible to carry out a large-scale international psychiatric study that requires
the coordination and collaboration of psychiatrists and mental health workers
from different theoretical backgrounds and from widely separated countries with
different cultures and socioeconomic conditions?
• Is it possible to develop standardized research instruments and procedures for
psychiatric assessment that can be reliably applied in a variety of cultural settings?
• Can teams of research workers be trained to use such instruments and procedures
so that comparable observations can be made in developed and developing
countries?
IPSS
• initial cohort of 1,202 patients was completed
• Assessment at baseline, 2 year and 5 years

Bottomline
• Outcome of Schizophrenia better in developing countries than
developed countries.
DOSMeD
Determinants of Outcome of Severe Mental Disorders
DOSMeD
• Conducted by WHO
• 12 research sites in 10 diverse sociocultural settings
• Colombia,
• Czechoslovakia,
• Denmark,
• India,
• Ireland,
• Japan,
• Nigeria,
• Russia,
• United Kingdom, and
• United States
• unified design, stringent methods, and standardized instruments were concurrently applied.
DOSMeD
• Indian Centres – Agra and Chandigarh
• Patients and key informants were interviewed at baseline and at 1-
year and 2-year follow-up
• The Aim was to study the prevalence and the outcome in
schizophrenia
• It was once again concluded that developing countries had better
outcome. In the context of Indian population- lesser time was spent in
psychotic episodes and lesser impairment of functioning.
ISoS
International Study of Schizophrenia
ISoS
• Conducted by WHO
• Follow up of cohorts from DOSMeD and RAPyD.
• Incidence cohort as well as prevalence cohort was taken.
• Incidence cohort – 12 from DOSMed and RAPyD, Madras and
Hongkong
• Prevalence Cohort – 3 from IPSS, Beijing
• ICD 8 and 9 diagnosis were converted to ICD 10 diagnosis
ISoS
• Further bolstered the findings of IPSS and DOSMeD.
• Outcome of schizophrenia is worst compared to other psychotic
illnesses.
• Percentage of time spent experiencing psychotic symptoms during
first 2 years was the best predictor.
SOFACOS
Study of factors associated with course and outcome of schizophrenia
SOFACOS
• original site was the Department of Psychiatry, Madras Medical
College where inclusion and follow-up for the first 5 years was
completed
• The 10-year data was analysed at the Johns Hopkins Institute, USA, as
part of a collaborative venture.
• The sample of 90 first episode schizophrenia patients was largely
urban and had an equal gender distribution; (Each 45)
• The age ranged from 17 to 38 years with a mean of 24.5.
SOFACOS
• At the end of 25 years, 47 of the original ninety subjects were
assessed completely. Twenty five (26%) had died and 18 (20%) were
lost to follow-up during the 25 year period. 32 of the 47 followed up
were in partial or total remission.
• Outcome was good in 27.7%, intermediate in 52% and poor in 19%
SOFACOS
CATIE
Clinical Antipsychotic Trials for Interventions Effectiveness
CATIE

• The schizophrenia trial conducted to determine the long-term effects and

usefulness of antipsychotic medications in persons with schizophrenia.
• Designed for people with schizophrenia who may benefit from a medication
change.
• Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study, funded by
NIMS, is a clinical trial comparing the effectiveness of older and newer APs
• The aim of the CATIE study was to determine which medications provide the best
treatment for schizophrenia.
• CATIE compared 4 of the newer medications to one another, and to an older
medication.
CATIE

• Participants in CATIE were followed for 18 months so that

investigators could evaluate longer-term patient outcomes.
• CATIE was conducted at many different sites, representative of the
real life settings.
• No placebo treatments were used.
• It was the "double-blind randomized clinical trial
CATIE

• This trial consisted of 1600 patients with schizophrenia for whom a

medication change may be indicated for reasons of limited efficacy or
tolerability.
• The study involved the newer atypical antipsychotics (olanzapine,
quetiapine, risperidone, clozapine, and ziprasidone)and the typical
antipsychotics (perphenazine and fluphenazine decanoate).
CATIE
• Among patients with schizophrenia, patients receiving olanzapine
experienced a longer time to discontinuation compared with the
other antipsychotic medications, but they experienced greater weight
gain, hyperglycaemia and hyperlipidaemia.
CAMP Trial
Comparison of Antipsychotics for Metabolic Problems
The CAMP Trial
• Comparison of Antipsychotics for Metabolic Problems (CAMP): a
randomized trial examining the effectiveness of switching from
Olanzapine, quetiapine, or Risperidone to aripiprazole to reduce
metabolic risk.
• Patients with
• F20 or F25 with
• BMI ≥ 27 and
• non-HDL cholesterol (non-HDL-C) ≥ 130 mg/dl
• on a stable dosage of Olanzapine, quetiapine, or Risperidone were randomly
assigned to stay on the current medication (n=106) or switch to aripiprazole
(n=109) for 24 wks.
The CAMP Trial
• PANSS, CGI, and EPS (AIMS), the Barnes Akathisia Scales were
applied. The addition of Lithium, Valproate, lipid lowering agents such
as statins, or drugs prescribed for weight loss was not allowed
• Individuals taking stable doses of Lithium, Valproate or lipid lowering
medications at the time of study entry could continue these
treatments, but dose adjustments during the treatment period were
not allowed.
Switching Antipsychotics to Reduce Metabolic Risk: The CAMP
Trial

• Switching to aripiprazole led to improvement of non-HDL-C and other

metabolic parameters.
• Rates of efficacy failure were similar between groups, but switching to
aripiprazole was associated with a higher rate of treatment
discontinuation.
CUTLASS
Cost Utility of Atypical Antipsychotics
CUtLASS

• Cost Utility of the Latest AP Drugs in Schizophrenia Study (CUtLASS)

• The inclusion criteria were DSM-IV schizophrenia, schizoaffective
disorder, or delusional disorder; age 18 to 65 years; and psychiatrist
electing to change the current FGA or SGA treatment because of
inadequate clinical response or intolerance.
• The exclusion criteria were substance misuse or a medical disorder
considered and a history of NMS.
• Participants were randomized to receive either an FGA or an SGA.
Cost Utility of Atypical Antipsychotics:
CUtLASS
• The FGAs were Chlorpromazine, flupenthixol, Halperidol, loxapine,
methotrimeprazine, sulpiride, trifluoperazine, zuclopenthixol, and the
depot preparations of fluphenazine , flupentixol, Halperidol,
pipothiazine, and zuclopenthixol .
• Thioridazine and droperidol were also included initially but were
withdrawn during the trial.
Cost Utility of Atypical Antipsychotics:
CUtLASS
• Medication administer for up to 1 year's duration.
• The primary outcome measure was total score on the Quality of Life
Scale (QLS), assessed blindly at baseline and at Weeks 12, 26, and 52
of the study.
• Secondary outcome measures included:
• Positive and Negative Syndrome Scale (PANSS);
• Calgary Depression Scale;
• Scales for adverse medication effects;
• Participant satisfaction and
• Costs of care.
.
Cost Utility of Atypical Antipsychotics:
CUtLASS
• 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 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.
Project MATCH
Matching Alcoholism Treatment to Client Heterogeneity
Project MATCH
• No single treatment approach is effective for all persons with alcohol
problems. A more promising strategy involves assigning patients to
alternative treatments based on specific needs and characteristics of
patients.
• Project MATCH was a multisite clinical trial designed to test a series of
a priori hypotheses on how patient-treatment interactions relate to
outcome.
• Two independent but parallel matching studies was conducted, one
with clients recruited from outpatient settings, the other with
patients receiving aftercare treatment following inpatient care.
Project MATCH
• Patients are randomly assigned to
• TwelveStep Facilitation,
• Cognitive-Behavioral Coping Skills, or
• Motivational Enhancement Therapy.
• Subjects are followed at 3-month intervals for 1 year following
completion of the 12-week treatment period and evaluated for
changes in drinking patterns, functional status/quality of life, and
treatment services utilization.
• Results were interpreted as evidence that all three treatments were
quite effective.
MTA Study
Multimodal Treatment of ADHD (MTA) study
MTA study (1999)
• Several interventions are effective in treating children with ADHD, including
medications and behavior therapy.
• To examine how treatment with medications compares with intensive behavior
therapy, or with the combination of the two, NIMH sponsored the Multimodal
Treatment of ADHD (MTA) study.
• Method: The study included 579 children, ages 7-9 years, who were randomly
assigned to one of four treatment modes for up to 14 months, and compared
these treatments to routine community care.
• Medication management alone,
• behavioral treatment alone,
• combination of both or
• routine community care (the control group).
MTA study (1999)
MTA study (1999)
• MTA used immediate release methylphenidate, which was
administered 3 times a day.
• Combination treatment and medication management alone were
both superior to intensive behavioral treatment alone and to routine
community care in reducing ADHD symptoms.
• In other areas of functioning (e.g., anxiety symptoms, academic
performance, parent-child relations, and social skills), combination
treatment was consistently superior to routine community care
• The children in the combination treatment taking lower doses of
medication than the children in the medication-alone group.
Kane’s Study
Kane’s study
• Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company,
from imipramine.  
• In 1975, after reports of agranulocytosis leading to death in some clozapine treated
pts, clozapine was withdrawn.
• When Kane’s study demonstrated that clozapine was more effective against TRS than
other APs, the FDA and health authorities in most other countries approved its use
only for TRS.
• The criteria used for TRS were later on known as Kane’s criteria
Kane’s study 1988
• 319 schizophrenics(DSMIII) who had failed to respond to at least 3 different AP
underwent a single-blind trial of HPL for 6 weeks.
• Pts whose condition remained unimproved were then randomly assigned, in a
double-blind manner, to clozapine (up to 900 mg/d) or CPZ (up to 1800 mg/d) for 6
weeks.
• 268 pts were entered in the double-blind comparison. 30% of the clozapine treated
pts were categorized as responders compared with 4% of CPZ-treated patients.
• Clozapine produced significantly greater improvement on the BPRS, CGI Scale, and
Nurses' Observation Scale for Inpatient Evaluation
• Improvement included –ve as well as positive symptom
• No cases of agranulocytosis occurred during this study
Combine Study
COMBINE study 2004
• Combined pharmacotherapies and behavioral interventions for alcohol dependence: Several
behavioral t/ts and at least 2 medications approved by the FDA , naltrexone and acamprosate have
shown efficacy in the t/t of alcohol dependence.
• However it is unknown how combining these treatments may impact their effectiveness,
• Randomized controlled trial conducted among 1383 recently alcohol-abstinent volunteers with DSM
IV dx of primary alcohol dependence.
• Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or
acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral
intervention (CBI). A ninth group received CBI only . Patients were also evaluated for up to 1 year
after treatment.
• Main Outcome Measures days abstinent from alcohol and time to first heavy drinking day.
• Naltrexone reduced risk of a heavy drinking day. Acamprosate showed no significant effect on
drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both.
TORDIA Trial
TORDIA TRIAL 2006
• Only about 60% of adolescents with depression will show an adequate clinical response to t/t with
a SSRI. There are no data to guide clinicians on subsequent t/t strategy.
• To evaluate treatment strategies in adolescents who continued to have depression despite adequate
initial treatment with an SSRI.
• Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) was a randomized controlled trial of
of 334 pts aged 12 to 18 yrs with a pri dx of MDD that had not responded to a 2-months t/t with an
SSRI
• 12 wks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine); (2) switch to
a different SSRI plus CBT; (3) switch to Venl or (4) switch to Venl plus CBT.
• Main Outcome Measures: change in Clinical Global Impressions; Children's Depression Rating Scale-
Revised (CDRS-R).
• the combination of CBT and a switch to another AD resulted in a higher rate of clinical response than
did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch
to Venl.
TEOSS Study
TEOSS Study 2007
• Treatment of early-onset schizophrenia spectrum disorders (TEOSS) trial designed to
compare the therapeutic benefits, safety, and tolerability of RIS, OLA, and molindone in
youths with EOSS
• 476 youths with EOSS (ages 8-19 years) were screened, 173 were further evaluated, and 119
were randomized and were assigned to an 8-week a trial of RIS (0.5-6.0 mg/day), OLA (2.5-20
mg/day), or molindone (10-140 mg/day).
• Responders continued double-blind t/t for 44 wks.
• The pri outcome measure was responder status at 8 weeks, defined by a 20% reduction in
baseline PANSS plus improvement on CGI.
• Secondary outcome measures included assessments of functional impairment, quality of life,
and medication safety
• RIS was the well tolerated, OLA was associated with weight gain, suicides are common in this
spectrum disorder
References
• Sachs GS, et al. "Effectiveness of adjunctive antidepressant treatment
for bipolar depression". The New England Journal of Medicine. 2007.
356(17):1711-1722
• Rush AJ et al. "Acute and longer-term outcomes in depressed
outpatient requiring one or several treatment steps: A STAR*D
report". The American Journal of Psychiatry. 2006. 163(11):1905-1917
• Geddes, J. R., Rendell, J. M., & Goodwin, G. M. (2002). BALANCE: a
large simple trial of maintenance treatment for bipolar
disorder. World psychiatry : official journal of the World Psychiatric
Association (WPA), 1(1), 48–51.
References
• Jones PB, Barnes TRE, Davies L, et al. Randomized Controlled Trial of
the 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). Arch Gen
Psychiatry. 2006;63(10):1079–1087. doi:10.1001/archpsyc.63.10.1079
• Manschreck T, Boshes R. The CATIE Schizophrenia Trial: Results,
Impact, Controversy. Harvard Review of Psychiatry. 2007;15(5):245-
258.
References
• Stroup, T. S., Mcevoy, J. P., Ring, K. D., Hamer, R. H., Lavange, L. M.,
Swartz, M. S., … Lieberman, J. A. (2011). A Randomized Trial
Examining the Effectiveness of Switching From Olanzapine,
Quetiapine, or Risperidone to Aripiprazole to Reduce Metabolic Risk:
Comparison of Antipsychotics for Metabolic Problems
(CAMP). American Journal of Psychiatry, 168(9), 947–956. doi:
10.1176/appi.ajp.2011.10111609
References
• Project MATCH: Rationale and Methods for a Multisite Clinical Trial
Matching Patients to Alcoholism Treatment. Alcoholism: Clinical and
Experimental Research. 1993;17(6):1130-1145.
Thank you