STEP-BD

1. Sytematic Treatment Enhancement
Program for Bipolar Disorder(STEP-BD)
STEP-BD 1
BY WASIM
UNDER GUIDANCE OF
DR ANIL TAMBI

2. What is STEP-BD??
• The NIMH-funded Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD) was a long-
term outpatient study designed to find out which
treatments, or combinations of treatments, were most
effective for treating episodes of depression and mania
and for preventing recurrent episodes in people with
bipolar disorder.
• Largest, federally-funded treatment study ever
conducted for bipolar disorder.
• Long-term outpatient study that enrolled 4,361
participants from 22 sites over 7 years (1998 to 2005).
STEP-BD 2

3. Baseline Instruments used
• Mini international neuropsychiatric interview
• Affective disorder evaluation form
• Clinical monitoring form
• Self-administered waiting-room form
STEP-BD 3

4. Who participated in STEP-BD??
• 4,361 individuals(with a diagnosis of bipolar
disorder) were enrolled in STEP-BD.
• Ages Eligible for Study: 15 Years and older
• Genders Eligible for Study: Both
• Periodic evaluations(3 monthly for 1st year and 6
monthly therefter) and/or treatment
adjustments.
• Participants also completed various self-
evaluation forms but they could decline to
answer any questions, and could remain in the
study even if their participation was inconsistent.
STEP-BD 4

5. Criteria:
General Inclusion Criteria:
• current age 15 or older (Best Practice Pathway) or
18 years or older (Randomized Care Pathways);
• able to give informed consent;
• meet DSM-IV criteria for Bipolar I Disorder,
Bipolar II Disorder, Bipolar Disorder NOS, or
Cyclothymic Disorder;
• undergo a complete standard evaluation
including clinical interview, self ratings, and
laboratory studies;
STEP-BD 5

6. General Exclusion Criteria:
• Unwilling or unable to adhere to basic study
requirements (i.e., complete rating forms, or
attend scheduled evaluations);
• Not competent to give informed consent in
the opinion of the investigator (e.g.,
psychotic).
• Needing acute substance use disorder
detoxification.
STEP-BD 6

7. • Because STEP-BD was designed to manage
and evaluate participants’ long-term
outcomes, the research program was active
for seven years, and participants were
involved for as long as they wanted during this
time.
• Those participants who were involved in any
randomized studies and who responded well
to their treatment were asked to stay on that
study medication for up to six months.
STEP-BD 7

8. Standard Care Pathways
STEP-BD 8
Acute Depression
 Refractory Depression
 Acute Mania
 Refractory Mania
 Rapid Cycling
 Relapse Prevention
 Pregnancy
 Substance Abuse
 Other Comorbidity

9. Randomized Care Pathways
STEP-BD 9
 Acute Depression: mood stabilizers +
antidepressants (paroxetine or buproprion) vs. mood
stabilizers + placebo
Acute Depression with Concurrent Manic
Symptoms: mood stabilizers +antidepressants vs.
mood stabilizers + placebo
Impact of Bipolar Specific Psychotherapies:
-CCP: Collaborative Care Program
-CBT: Cognitive Behavioral Therapy
-FFT: Family Focused Treatment
-IPSRT: Interpersonal and Social Rhythm Therapy

10. What treatment did participants
receive in STEP-BD??
• STEP-BD assessed the outcomes of many of the most
established treatments:
 mood-stabilizers;
 antidepressants;
 atypical antipsychotics; and
 standardized psychosocial interventions that included
family-focused treatment, interpersonal and social rhythm
therapy, and cognitive behavioral therapy, all of which
were compared to a brief psychosocial control treatment.
• Medication and dosing recommendations were derived from published,
evidence-based treatment guidelines.
STEP-BD 10

11. Best Practice Pathway treatments
• Participants: of age >=15 yrs,
• Received individualized care based on their
symptoms, past history, medical conditions etc.
• Most received mood-stabilizers and, if 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.
STEP-BD 11

12. Randomized Trials
• Participants in the Best Practice Pathway who were
18 years and older.
• The randomized trials studied treatment options for
the acute depression, refractory depression and
relapse prevention.
• 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.
STEP-BD 12

13. • Having both a Best Practice Pathway and
Randomized Clinical Trials allowed the
researchers to compare outcomes from each
trial (all of which focused on a specific research question)
with outcomes from those who remained in
the Best Practice Pathway.
• This is important because it gave researchers
an opportunity to understand if the results
might differ for subjects willing to accept
treatment assigned at random under double
— blind conditions, versus those who might
find such treatment unacceptable.
STEP-BD 13

14. Interventions used in STEP-BD
• Drug: lithium
Drug: valproate
Drug: bupropion
Drug: paroxetine
Drug: lamotrigine
Drug: risperidone
Drug: inositol
Drug: tranylcypromine
Behavioral: Cognitive Behavioral Therapy
Behavioral: Family-focused Therapy
Behavioral: Interpersonal and Social Rhythms
Therapy
STEP-BD 14

15. Use of placebos in STEP-BD
• Participants received at least one type of active mood
stabilizer throughout the study; at no time were
participants ever medication-free.
• However, in the double-blind randomized clinical trial
involving the use of antidepressants to treat bipolar
depression, placebo (in combination with mood
stabilizing medications) was used as a control.
•
STEP-BD 15
Participant
Mood stabilizer +
Antidepressant(as
adjunctive)
Mood stabilizer +
Placebo(as
adjunctive)

16. Three Major Findings from the
STEP-BD Study .
STEP-BD 16
Comorbidity findings
Psychopharmacology findings
Psychotherapy findings

17. The most common comorbidities
findings
any anxiety disorder
Bipolar I 52.8%
Bipolar II 46.1%
2 to 3 fold increase in the history of suicide attempt
Earlier age of onset of Bipolar Disorder (age 15.6 vs 19.4)
Shortened duration of well intervals
Substance and alcohol abuse
37% Substance Abuse or Dependence
Alcohol abuse or Dependence
Bipolar I 46.2%
Bipolar II 39.2%
Poorer outcome STEP-BD 17

18. ADHD
5.9% current; 9.5% lifetime
Bipolar I > Bipolar II
More likely associated with with multiple comorbidities
especially Anxiety Disorders and Substance Use Disorders .
More disabling course, earlier age of onset and higher rates
of suicide attempts
Eating disorder (2.0%)
drug use disorder (7.3%),
 General medical comorbidities were not determined, with the
exception of current thyroid disease at 18%.
STEP-BD 18

19. Psychopharmacology Findings
Psychopharmacology findings concern which
medications are most effective for Bipolar
Disorder, which are least effective, whether
there are associations between certain
medications and undesirable effects such as
switching and suicide, and the interaction
between medications and psychotherapy.
STEP-BD 19

20. Acute Depression
• Randomized N = 366
• Mood Stabilizer + Adjunctive Antidepressant
(paroxetine or buproprion) vs Mood Stabilizer +
Placebo
• Primary Outcome is Durable Recovery (>or= 8
weeks euthymia) euthymia)
• No difference in outcome (24% with AD vs 27%
Placebo)
• No difference in affective switch (10.1% AD vs
10.7% Placebo)
STEP-BD 20

21. Acute Depression with Concomitant
Manic Symptoms
• Randomized N = 335
• Syndromal depression with 2 or more manic
symptom
• Mood stabilizer + AD vs mood stabilizer +
placebo
• Primary outcome: time to recovery from
depression
No difference in time to recovery
• Higher manic severity levels at follow-up in AD vs
placebo group.
STEP-BD 21

22. Psychotherapy Findings
• Psychotherapy findings concern outcome studies
comparing three “ branded” Bipolar-Specific
psychotherapies with a control condition for
treating Bipolar Disorder, and the relative
effectiveness of these Psychotherapies when
compared to pharmacotherapy.
• “Branded ” psychotherapies designed specifically to
treat Bipolar Disorder have been developed in
recent years.
• These therapies have been developed in response
to the fact that pharmacotherapy response to alone
is often inadequate to fully treat Bipolar Disorder .
STEP-BD 22.

23. Psychosocial Interventions for Bipolar
Depression
• Randomized N = 293
• Primary Outcome is time to recovery and % patients
well each of 12 months
• “Collaborative Care ”: 3 session control condition
(education , coping strategies , treatment planning)
• Intensive Interventions (up to 30 sessions)
-Cognitive Behavioural Therapy
-Interpersonal and Social Rhythm Therapy
-Family Focused Treatment
• Intensive Psychotherapies separate from Collaborative
do not separate from each other
STEP-BD 23

24. Interventions and Functional
Outcomes
• Randomized N = 152
• Primary Outcome is score on functional
assessment tool every 3 months for 9 months
• Collaborative Care vs Intensive Psychosocial
Intensive (CBT,IPSRT or FFT)
• Intensive Psychosocial Treatment enhances
relationship function and life satisfaction.
• No difference in work/role function or recreation
scores
• No difference between Intensive Interventions
STEP-BD 24

25. Important OBSERVATIONS and
RESULTS derived from STEP-BD
STEP-BD 25

26. • For the full STEP-BD sample:
mean age- 40,
56% were female and
85% were non-Hispanic white.
53% had a high school education
40% had obtained a bachelors degree or
above.
STEP-BD 26

27. (1)Longitudinal study of Recovered Individuals
• For 858 pts. (from best practice pathway) who entered
STEP-BD in a symptomatic state and achieved remission
within 2 years of prospective follow-up:
Mean age-40 yrs
At study entry-
o 70% had bipolar 1 disorder,
o 30% were in a major depressive episode;
o 10% were in a manic or hypomanic episode;
o 8% were in a mixed episode;
o the remainder had subsyndromal symptoms.
About three-fourth of the patients (N = 644) recovered, of
which 22.4% subsequently suffered a new major depressive
episode and 6.4% suffered a new manic, hypomanic, or
mixed episode.
STEP-BD 27

28. • Risk of manic/hypomanic/mixed
recurrence was increased by:
rapid cycling within the past year,
bipolar I subtype,
current substance abuse,
number of lifetime manic episodes,
presence of residual manic symptoms, and
number of depressive episodes within the
past year.
STEP-BD 28

29. • Risk of depressive recurrence was increased
by:
history of an eating disorder,
rapid cycling within the past year,
current comorbid anxiety disorder,
number of lifetime depressive episodes,
presence of residual manic symptoms, and
presence of residual depressive symptoms.
• The presence of residual symptoms manic was the largest independent
predictor of risk of recurrence for both depressive and
manic/hypomanic/mixed episodes.
STEP-BD 29

30. (2)Predictors of adherence and function
• In a 3640-patient, 1-year longitudinal study,
24% reported poorer adherence, with more
severe baseline illness predicting poorer
adherence,which in turn predicted less
functional improvement at 1 year.
• In a 2024-patient, baseline cross-sectional
study, 32% had short and 23% had long sleep
duration, both of which were associated with
poorer function and quality of life.
STEP-BD 30

31. • In a 2000-patient, baseline cross-sectional
study, depressive symptoms were associated
with poorer mental and overall quality of life.
• Serious adverse events (SAEs) were common,
and associated with more severe baseline
illness. In a 1000-patient, 1-year longitudinal
study, 12% had SAEs, with hospitalization for
suicidal ideation being the most frequent SAE
[20]. More severe baseline illness predicted
SAEs.
STEP-BD 31

32. (3)Impact of Substance Use Disorders
on Course and Treatment
• It has been accepted clinical wisdom that bipolar
patients with substance abuse have worse mood
outcomes, but data from STEP-BD suggest that
this is not necessarily the case.
• In a prospective analysis of 3950 subjects with
bipolar I and II disorder, time to recovery from an
index episode of major depression was not longer
for subjects who had an alcohol use disorder or a
drug use disorder, either past or present, than
those with no such history.
STEP-BD 32

33. • Subjects with any history of substance use disorder in
STEP-BD lagged in functioning compared to those with
no such history; in spite of a lack of difference in
prospectively observed mood episodes, the deleterious
effects of comorbid substance use disorders were clear.
• What also was apparent is that earlier age of first onset
of bipolar illness, (collected retrospectively), was associated
with higher likelihood of developing a substance use
disorder later, and that early onset subjects were likely
to have shorter periods of recovery than those whose
onset was in adulthood.
STEP-BD 33

34. • Cigarette smoking in the STEP-BD cohort
appeared to be associated with increased risk of
suicide attempts, suicide measures, and
impulsiveness.
• So, Substance use disorders were common in the
STEP-BD cohort, associated with earlier onset
of illness, suicide attempts, and worse
functioning, but did not appear to be directly
associated with poorer mood outcomes.
STEP-BD 34

35. (4) Predictors of Outcome
• Among the 1469 patients who were symptomatic at
study entry, 858 (58%) subsequently achieved remission
during follow-up. Nearly 50% of these patients
experienced recurrence during up to 2 years of follow-up.
• Secondary analyses suggested increased risk of
recurrence among benzodiazepine-treated patients.
Benzodiazepines used for treatment of sleep disturbance,
or anxiety, individually or in combination, have
contributed to the 21% greater chances for relapse
amongst the 1365 patients who had achieved remission.
STEP-BD 35

36. • Risk factors for transition to mania did not appear to
differ substantially between individuals with, and
without, antidepressant treatment.
• A third line of investigation examined the consistency
of mood symptoms across episodes—to what extent
were mood symptoms stable across episodes. In
general, STEP-BD results suggested that symptoms
differ greatly in their stability, but some (most notably
suicidality) did appear to recur with some consistency
and thus might allow planning interventions for future
episodes.
STEP-BD 36

37. (5)Antidepressant Use and Outcome
• On comparing the efficacy of an antidepressant
plus mood stabilizer (MS) (n = 179) to MS alone
(n = 187) in bipolar depression did not
differentiate between the two groups in the rates
of recovery.
• There was no difference between the two groups
in the rate of treatment-emergent affective switch.
However, adjunctive antidepressant use was
associated with significantly higher mania
symptom severity.
STEP-BD 37

38. • In an open, randomized study patients who attained
recovery with antidepressants plus MS were assigned
to continue on antidepressants plus MS or MS alone.
• There were no significant differences between the two
groups in prevalence or severity of new depressive or
manic episodes, or overall time in remission. However,
antidepressant continuation was associated with
greater likelihood of depressive relapse in those with
rapid cycling course.
• Additionally, antidepressant use did not hasten time to
recovery relative to treatment with mood stabilizers
alone.
STEP-BD 38

39. • For treatment resistant bipolar depression-
lamotrigine>inositol>risperidone.
• Of the 425 who experienced a prospectively
observed, new onset major depressive
episode without initial suicidal ideation, 24
participants developed new onset suicidality,
with no association with antidepressant use.
STEP-BD 39

40. (6)Psychosocial Interventions
• STEP-BD found that intensive psychosocial treatments
(cognitivebehavior therapy, family-focused therapy, or
interpersonal and social rhythm therapy) as adjuncts to
pharmacotherapy were more beneficial (had better total
functioning, relationship functioning,and life satisfaction
scores ) than a brief psychoeducational treatment
(collaborative care) in enhancing stabilization from bipolar
depression.
• Patients receiving intensive psychotherapy had significantly
higher year end recovery rates and shorter times to recovery
than patients in collaborative care. (Intensive psychotherapy was given
weekly and biweekly for up to 30 sessions in 9 months. Collaborative care consisted of
3 sessions in 6 weeks).
STEP-BD 40

41. • No statistically significant differences were
observed in the outcomes of the three intensive
psychotherapies.
• It was noteworthy that regardless of
assignment to the intensive psychotherapy or
brief psychoeducation intervention, recovery
rates were more than 20% higher for patients
randomized in the adjunctive psychotherapy
trial compared to those randomized in the
adjunctive antidepressant trial.
STEP-BD 41

42. How is the STEP-BD study different
from other treatment studies of
bipolar disorder?
STEP-BD 42

43. • Has real-world applicability:- Most other clinical
research studies exclude people with co-existing
disorders.
• Long-term continuity of care:- In most clinical trials,
individuals are usually asked to participate for a
relatively short period of time (e.g., 8-12 weeks), and
receive only one of a few treatments being studied.
• Assessed participants’clinical status every three to six
months:- other bipolar illness clinical studies measure
treatment’s success with only a single measurement at
one point in time.
• Unlike other trials, doctors participating in STEP-BD
were extensively trained in the use of evidence-based
treatments to become “STEP certified.”
STEP-BD 43

44. Unanswered??
• Best treatment to prevent mood episodes and
restore functioning?
• Best treatments for comorbid conditions
(anxiety, substance abuse, ADHD)?
• What can decrease suicide?
• Do bipolar-II patients really need mood
stabilizers?
• Any biomarkers to personalize acute and long
term treatments?
STEP-BD 44

45. Where was the study conducted?
• NIMH selected the Massachusetts General Hospital in
Boston, MA to implement the STEP-BD study.
• The trial was led by Dr. Gary S. Sachs of the
Massachusetts General Hospital and Harvard Medical
School, with the help of Dr. Michael E. Thase of the
University of Pittsburgh Western Psychiatric Institute
and Clinic, and Dr. Mark S. Bauer of the Providence
Veterans Affairs Medical Center and Department of
Psychiatry and Human Behavior, Brown University.
• The Epidemiology Data Center at the University of
Pittsburgh, led by Dr. Stephen R. Wisniewski, collected
and analyzed the study data.
STEP-BD 45

46. • Over the course of the seven years of the study, 22 research centers around the
United States enrolled and treated participants. Thirteen centers participated for
the majority of the active project, and participants from these centers comprise 90
percent of the total number enrolled.
 Baylor College of Medicine; Houston, TX
Principal Investigator, Lauren B. Marangell, MD
 Case Western Reserve University; Cleveland, OH
Principal Investigator, Joseph R. Calabrese, MD
 University of Colorado Health Sciences Center; Denver, CO
Principal Investigator, Michael Allen, MD
 University of Louisville School of Medicine; Louisville, KY
Principal Investigator, Rif El-Mallakh, MD
 Massachusetts General Hospital and Harvard School of Medicine; Boston, MA
Principal Investigator, Andrew A. Nierenberg, MD
 University of Massachusetts Medical School; Worcester, MA
Principal Investigator, Jayendra Patel, MD
 University of Missouri School of Medicine; Kansas City, MO
Principal Investigator, Kemal Sagduyu, MD
 University of Oklahoma College of Medicine - Tulsa; Tulsa, OK
Principal Investigator, Mark D. Fossey, MD
 University of Pennsylvania School of Medicine and Medical Center; Philadelphia, PA
Principal Investigator, Laszlo Gyulai, MD
 University of Pittsburgh Western Psychiatric Institute and Clinic; Pittsburgh, PA
Principal Investigator, Michael E. Thase, MD
 Portland Veteran’s Administration Medical Center; Portland, OR
Principal Investigator, Peter Hauser, MD
 Stanford University School of Medicine; Stanford, CA
Principal Investigator, Terence A. Ketter, MD
 University of Texas Health Science Center at San Antonio, San Antonio, TX
Principal Investigator, Charles Bowden, MD STEP-BD 46

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STEP-BD 47

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STEP-BD 49

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