Aims and Results of the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

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Abstract
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.
REVIEW
Aims and Results of the NIMH Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD)
C.L. Bowden,
1
R.H. Perlis,
2
M.E. Thase,
3
T.A. Ketter,
4
M.M. Ostacher,
4
J.R. Calabrese,
5
N.A. Reilly-Harrington,
2
J.M. Gonzalez,
1
V. Singh,
1
A.A. Nierenberg
2
&G.S.Sachs
2
1 Department of Psychiatry, University of Texas Health Science Center at San Antonio
2 Department of Psychiatry, Partners Bipolar Treatment Center, Massachusetts General Hospital, Harvard Medical School, Boston
3 Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
4 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
5 Department of Psychiatry, Case University School of Medicine, Cleveland, OH, USA
Keywords
Neuropsychopharmacology; Mood Disorders;
Bipolar; Treatment.
Correspondence
Charles L. Bowden, 7703 Floyd Curl Drive, MC
7734, San Antonio, TX 78229, USA.
Tel.: 210 567 5405;
Fax: 1 210 567 3759;
E-mail: bowdenc@uthscsa.edu
Received 1 December 2010; revision 4 March
2011; accepted 3 May 2011
doi: 10.1111/j.1755-5949.2011.00257.x
SUMMARY
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was
funded as part of a National Institute of Mental Health initiative to develop effectiveness
information about treatments, illness course, and assessment strategies for severe mental
disorders. STEP-BD studies were planned to be generalizable both to the research knowledge
base for b ipolar disorder and to clinical care of bipolar patients. Several novel methodologies
were developed to aid in illness characterization, and were combined with existing scales
on function, quality of life, illness burden, adherence, adverse effects, and temperament to
yield a comprehensive data set. The methods integrated naturalistic treatment and random-
ized clinical trials, which a portion of STEP-BD participants participated. All investigators
and other researchers in this multisite program were trained in a collaborative care model
with the objective of retaining a high percentage of enrollees for several years. Articles from
STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional
status, recovery, relapse, and caretaker burden. The findings from these studies brought
into question the widely practiced use of antidepressants in bipolar depression as well as
substantiated the poorly responsive course of bipolar depression despite use of combination
strategies. In particular, large studies on the characteristics and course of bipolar depression
(the more pervasive pole of the illness), and the outcomes of treatments concluded that
adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes su-
perior to those achieved with mood stabilizers alone. The majority of patients with b ipolar
depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and
early age of bipolar onset were each associated with increased illness burden. STEP-BD has
established procedures that are relevant to future collaborative research programs aimed at
the systematic study of the complex, intrinsically important elements of bipolar disorders.
Introduction
The Systematic Treatment Enhancement Program for Bipolar Dis-
order (STEP-BD), was to date the largest federally funded treat-
ment study ever conducted for bipolar disorder (BD) and enrolled
4361 participants from 1999 to 2005 [1]. The broad objectives
were to determine which treatments, or regimen of treatments,
were most effective for treating the fundamental clinical states in
BD, including acute and sustained response and preventing recur-
rence of episodes. STEP-BD uniquely incorporated both random-
ized controlled clinical studies and uncontrolled, evidence-based
clinical care in designs intended to be generalizable to routine
clinical care settings. The unprecedented size, broad inclusion cri-
teria, and ethnic and socio-economic spectrum of subjects were
intended to make its findings applicable to most patients seeking
care for BD. The sample was limited mainly by the participant’s
willingness to be seen by a STEP-BD physician, agree to complete
self-ratings and have independent study assessments at baseline,
quarterly for the first year and semiannually thereafter, the ex-
clusion of patients needing acute substance use disorder detoxi-
fication, and for academic centers (which recruited the majority
of the patients), the need for medical insurance to cover the cost
of appointments with physicians. All subtypes (BD I, BD II, BD
NOS, or cyclothymia) in any phase of illness once enrolled were
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2011 Blackwell Publishing Ltd CNS Neuroscience & Therapeutics 18 (2012) 243–249 243
NIMH Systematic Treatment Enhancement Program C.L. Bowden et al.
encouraged to continue treatment until conclusion of the STEP-
BD program and were monitored systematically, even when eu-
thymic, as in any routine clinical setting. STEP-BD promulgated a
Collaborative Care approach to enhance the therapeutic alliance
between patients, their clinicians, and their family members, al-
lowing patients and their families to be more committed to treat-
ment goals via systematic instruction on managing stress, improv-
ing communication, targeting sleep disturbances, and addressing
dysfunctional cognitions [1]. STEP-BD sites were not funded to
offer free clinical care, with the exception of a subcontract for
inclusion of a public sector, medically indigent, principally eth-
nic minority subsample of 200 patients. STEP-BD otherwise re-
quired that the study group be representative of those present-
ing for treatment in the United States, with subjects continuing
to pay for care at each visit as they would if seeking routine clin-
ical care in the absence of the study, principally through health
insurance plans.
Administration and Infrastructure
Screening of sites for inclusion in STEP-BD was limited to BD spe-
cialty programs caring for at least 100 active patients, selected to
assure geographic balance and demographic diversity. Of the 22
centers engaged for the STEP-BD, 13 enrolled 90% of the total
and six contributed two thirds of patients [2–4]. A characteristic
of the six highest enrolling sites was their history of maintaining
systems of indefinite clinical care, rather than clinical research ef-
forts detached from such care provision. The treatment guidelines
in STEP-BD focused on nine clinical state “pathways,” for exam-
ple, refractory depression, relapse prevention [1]. STEP-BD uti-
lized a Clinical Monitoring Form (CMF) as the source document
for key outcome measures and also provide the progress note in
the patient’s medical record [2]. To be certified in use of the CMF
and other key clinician ratings, all treating psychiatrists completed
standardized training and met requirements for interrater agree-
ment with “gold standard” ratings. Both current and lifetime psy-
chiatric comorbidities were ascertained. The most common cur-
rent psychiatric disorder comorbidities in descending order were:
any anxiety disorder (30.5%), alcohol use disorder (11.8%), drug
use disorder (7.3%), ADHD (5.9%), and eating disorder (2.0%)
[6,7]. General medical comorbidities were not determined, with
the exception of current thyroid disease at 18% (see Table 1).
For the full STEP-BD sample, the mean age was 40, 56% were
female and 85% were non-Hispanic white. Fifty three percent had
a high school education; 40% had obtained a bachelors degree or
above; and 58% had private insurance.
Table 1 Psychiatric comorbidities among STEP-BD patients
Lifetime Current Sample size
Anxiety disorder [5] 51.2 30.5 500
Alcohol use disorder [6] 32.2 11.8 4000
Drug use disorder [6] 21.7 7.3 4000
ADHD [7] 9.5 5.9 1000
Eating disorder [8,9] 7.9 2.0 1000
Longitudinal Study of Recovered
Individuals
One major thrust of STEP-BD was to document the longitudinal
course of people with BD who were receiving guideline-based
care. The most relevant report from the follow-up concerned
858 patients who entered STEP-BD in a symptomatic state and
achieved remission within 2 years of prospective follow-up [10].
The study group was, on average, about 40 years old, and 71% had
bipolar I disorder. At study entry, 30% were in a major depressive
episode; 10% were in a manic or hypomanic episode; 8% were in
a mixed episode; 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. Risk of manic/hypomanic/mixed recurrence was signif-
icantly increased by (in order of the strength of the risk fac-
tor): rapid cycling within the past year, bipolar I subtype, cur-
rent substance abuse, number of lifetime manic episodes, presence
of residual manic symptoms, and number of depressive episodes
within the past year (i.e., a proxy of rapid cycling). Risk of depres-
sive recurrence was increased by: history of an eating disorder,
rapid cycling within the past year, current comorbid anxiety dis-
order, number of lifetime depressive episodes, presence of resid-
ual manic symptoms, and presence of residual depressive symp-
toms. The presence of residual symptoms of mood elevation was
the largest independent predictor of risk of recurrence for both
depressive and manic/hypomanic/mixed episodes. The rates of de-
velopment of new depressive episodes w as just over twice the rate
for development of manic, hypomanic, or mixed episodes [5]. Al-
though this generally consistent with other reports, it suggests that
the predominance of depressive relapse compared with manic re-
lapse is substantially lower than was reported from 6 to 12 month
interval phone interviews [11]. Direct clinical observation in the
course of care, as occurred in the STEP-BD, would be less likely to
miss brief hypomanic/manic periods than would infrequent phone
based inquiries.
Predictors of Outcome
As a cohort study, STEP-BD was intended to allow for char-
acterization of outcomes with evidence-based, optimized treat-
ments, both pharmacologic and psychosocial. Among the 1469
patients who were symptomatic at study entry, 858 (58%)
subsequently achieved remission during follow-up [10]. 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 [12]. An-
other analysis examined predictors of transition directly from
manic/hypomanic/mixed episodes to mania [13]. Earlier work
in a subset of STEP-BD patients suggested subthreshold manic
symptoms might be associated with risk for subsequent manic
symptoms with antidepressant treatment [14], consistent with
other cohorts [15]. Notably, while baseline subthreshold manic
symptomatology and other risk factors were identified, nearly
all were not specific to antidepressant-treated patients. That is,
the risk factors for transition to mania did not appear to differ
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2011 Blackwell Publishing Ltd
C.L. Bowden et al. NIMH Systematic Treatment Enhancement Program
substantially between individuals with, and without, antidepres-
sant treatment.
A third line of investigation examined the consistency of mood
symptoms across episodes—to what extent were mood symp-
toms stable across episodes [16]. In general, STEP-BD results sug-
gested that symptoms differ greatly in their stability, but some
(most notably suicidality) did appear to recur with some con-
sistency and thus might allow planning interventions f or future
episodes.
Predictors of Adherence and Function
STEP-BD studies addressed baseline correlates and longitudinal
predictors of medication nonadherence and functional outcomes.
In a 3640-patient, 1-year longitudinal study, 24% reported poorer
adherence, with more severe baseline illness predicting poorer ad-
herence, which in turn predicted less functional improvement at
1 year [17]. Thus, studies are needed to assess whether special at-
tention to adherence in patients with more severe baseline illness
yields better functional outcomes.
Sleep disturbance was common and was associated with poorer
function and quality of life. 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 [18]. Hence, studies are needed to assess how specific attention
to remediation of sleep disturbance impacts function and quality of
life.
Not surprisingly, bipolar depression was associated with poorer
quality of life. In a 2000-patient, baseline cross-sectional study, de-
pressive symptoms were associated with poorer mental and over-
all quality of life [19]. Thus, studies of interventions for bipolar
depression need to include assessments of impact upon quality of
life.
Serious adverse events (SAEs) were common, and associated
with more severe baseline illness. In a 1000-patient, 1-year lon-
gitudinal study, 12% had SAEs, with hospitalization for suicidal
ideation being the most frequent SAE [20]. More severe b aseline
illness predicted SAEs. Hence, patients with more severe baseline
illness merit special attention with respect to the risks of SAEs in
general and hospitalization for suicidality in particular.
Impact of Substance Use Disorders
on Course and Treatment
Several important findings regarding substance use disorders and
their impact on illness course arose from STEP-BD. The high co-
morbidity of substance use in BD was confirmed, even in this am-
bulatory, research setting, with nearly 50% of subjects having a
lifetime history of such comorbidity. The proportion of subjects in
STEP-BD with current substance use disorders was 12%. It is un-
clear whether or not this rate is lower than expected for patients
seeking treatment in ambulatory psychiatric setting, but it is lower
than that found in the Epidemiological Catchement Area Study
for patients seeking treatment in all alcohol, drug, and psychiatric
treatment settings [21]. Having a substance use disorder was not
an exclusion for participations in STEP-BD, with only those pa-
tients requiring acute detoxification excluded at entry, but the re-
quirements of participating in an ambulatory study may have de-
creased the overall illness severity of participants.
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 re-
covery from an index episode of major depression was not longer
for subjects who had an alcohol use disorder or a drug use disor-
der, either past or present, compared to those with no such history
[7]. Other investigators have found similar outcomes for these pa-
tients [22]. Nevertheless, this finding, in conjuction with the find-
ing that adherence is worse in subjects with alcohol use disorders,
suggested that withholding of medication treatment for patients
with comorbid substance use disorders may be misguided—and it
may be especially important to target these patients for interven-
tions to improve adherence [17]. Subjects with any history of sub-
stance 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 [23].
What also was apparent is that earlier age of first onset of bipolar
illness, collected retrospectively, was associated with higher likeli-
hood of developing a substance use disorder, and that early onset
(first mood episode by age 18) and very early onset (first mood
episode by age 13) subjects were less likely to have prolonged peri-
ods of recovery than are those whose onset was in adulthood [24].
Because of the functional consequences of substance use disorder,
the STEP-BD data underscored the importance of early recogni-
tion and early intervention in adolescents in an effort to reduce
this comorbidity.
Cigarette smoking was also greatly elevated in subjects in the
STEP-BD cohort, and appeared associated with increased risk of
suicide attempts, suicide measures, and impulsiveness. Prospective
findings from a STEP-BD ancillary study found that observed sui-
cide attempts were more frequent in a group of smokers compared
to a group that did not smoke [25]. The significant adverse medical
consequences of smoking are already well known, but STEP-BD
data indicated that its association with poor outcome in BD also
needs t o be appreciated.
Patients with BD and comorbid substance use disorder clearly
required vigilant monitoring and proactive interventions. How-
ever, an early analysis in STEP-BD found that only a negligible
number of subjects with comorbid drug or alcohol use disorders
were being prescribed approved pharmacological treatments for
substance use disorders [5]. Substance use disorders were com-
mon in the STEP-BD cohort, associated with earlier onset of ill-
ness, suicide attempts, and worse functioning, but did not appear
to be directly associated with poorer mood outcomes, again per-
haps related to excluding patients with a need for acute detoxifi-
cation at enrollment.
Combination Therapy, Comorbidity,
and Treatment Outcome
The STEP-BD findings supported the impression that BD is ac-
companied by high rates of cooccurring psychiatric comorbidity
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NIMH Systematic Treatment Enhancement Program C.L. Bowden et al.
and that complex regimens of pharmacotherapy are necessary to
achieve mood stabilization. However, only 59% of patients pre-
senting with comorbidities had previously received adequate trials
of mood stabilizers. An examination of the naturalistic pharma-
cotherapy to study whether the presence of comorbidity was asso-
ciated with adequate pharmacotherapy found that only 20% re-
ported the use of benzodiazepines for anxiety despite its evidence
base [5]. Whereas benzodiazepines were underutilized in subjects
with cooccurring anxiety, this class of medication appeared to be
over-utilized in subjects with cooccurring substance use. Another
analysis of benzodiazepines was undertaken to determine if the
concurrent use of benzodiazepines in BD was associated with re-
lapse/recurrence [24]. Of 349 subjects prescribed a benzodiazepine
at the time of remission, there did appear to be a greater risk for
recurrence of mood episodes; however, this prompted the con-
clusion that the use of this class of medication appeared to be
a marker for more severe course of illness rather than causing
relapse/recurrence. Benzodiazepines used for treatment of sleep
disturbance, for anxiety, or for anxiety as a component of mixed
states, since anxiety is prominently associated with mixed states,
could, individually or in combination, have contributed to the
21% greater hazard ratio for relapse amongst the 1365 patients
who had achieved remission. The baseline sample was also used
to ascertain if the use of antidepressants in bipolar depression was
associated with increased risk of suicidal ideation as reported else-
where for children and adults with depressive and anxiety disor-
ders. Of the 425 who e xperienced a prospectively observed, new-
onset major depressive episode without initial suicidal ideation, 24
participants developed new onset suicidality, with no association
with antidepressant use [26,27].
Antidepressant Use and Outcome
Antidepressants continue to be widely used, acutely and long
term, to treat bipolar depression despite the paucity of evidence
to support this strategy. Additionally, there is a lack of data on
the role of antidepressant in affective switches as well as treat-
ment options in nonresponsive patients with bipolar depression.
A randomized double-blind, placebo-controlled study comparing
the efficacy of an antidepressant (sertraline or bupropion) plus
mood stabilizer (MS; n = 179) to MS alone (n = 187) in bipo-
lar depression did not differentiate between the two groups in the
rates of recovery (23.5% vs. 27.3%; P = 0.40) [4]. Patients in the
MS alone group also demonstrated nonsignificant superiority on
secondary outcome measures. There was no difference between
the two groups in the rate of treatment-emergent affective switch.
The study used a broad definition for mood stabilizers, allowing
lithium, valproate, antipsychotic drugs, or lamotrigine to so qual-
ity. At least some acute antidepressant activity has been described
for lithium, valproate, quetiapine, in randomized trials; however
not for other antipsychotic drugs or, at least acutely for lamotrig-
ine. Therefore one interpretation of the results is that the two an-
tidepressants did not further augment a bona fide benefit of some
of the mood stabilizers.
In an open, randomized study patients who attained recovery
with antidepressants plus MS were assigned to continue on antide-
pressants plus MS or MS alone. Long term, there were no signifi-
cant 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, versus those with-
out rapid cycling course [19]. A naturalistic study of 335 STEP-BD
participants who did or did not receive antidepressants along with
mood stabilizers for a depressive episode found that adjunctive
antidepressant use was associated with significantly higher mania
symptom severity at the 3-month follow-up. Additionally, antide-
pressant use did not hasten time to recovery relative to treatment
with mood stabilizers alone [14].
A randomized study (N = 66) assessed the effectiveness of ad-
junctive open label lamotrigine, inositol or risperidone, in patients
with bipolar depression who failed to respond to a combination
antidepressant plus MS. No difference in efficacy was observed
between the three agents, although limited statistical power may
have contributed to this negative finding [3].
Findings from these studies brought into question the widely
practiced use of antidepressants in bipolar depression as well as
substantiated the poorly responsive course of bipolar depression
despite use of combination strategies.
Psychosocial Interventions
STEP-BD found that intensive psychosocial treatments (cognitive-
behavior therapy, family-focused therapy, or interpersonal and so-
cial rhythm therapy) as adjuncts to pharmacotherapy were more
beneficial than a brief psychoeducational treatment (collabora-
tive care) in enhancing stabilization from bipolar depression. Two
hundred ninety three depressed outpatients with bipolar I or II
disorder were randomly assigned to an intensive psychotherapy
(n = 163) or collaborative care (n = 130). Intensive psychotherapy
was given weekly and biweekly for up to 30 sessions in 9 months.
Collaborative care consisted of three sessions in 6 weeks. Patients
receiving intensive psychotherapy had significantly higher year-
end recovery rates and shorter times to recovery than patients
in collaborative care. Patients in intensive psychotherapy were
1.58 times more likely to be clinically well during any study month
than those in collaborative care. No statistically significant differ-
ences were observed in the outcomes of the three intensive psy-
chotherapies [28]. It was noteworthy that regardless of assignment
to the intensive psychotherapy or brief psychoeducation interven-
tion, recovery rates were more than 20% higher for patients ran-
domized in the adjunctive psychotherapy trail compared to those
randomized in the adjunctive antidepressant trial, indicating that
bipolar depression patients who are willing to accept even the pos-
sibility of assignment to intensive psychotherapy may have better
outcomes.
In a subset (n = 152) of the above sample, STEP-BD also exam-
ined the impact of intensive psychosocial treatment plus pharma-
cotherapy on the functional outcomes of patients with BD over the
9 months following a depressive episode. Patients in intensive psy-
chotherapy had better total functioning, relationship functioning,
and life satisfaction scores over 9 months than patients in collab-
orative care, even after accounting for pretreatment functioning
and concurrent depression scores [29].
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While intensive psychotherapy may be most applicable to
severely ill patients with BD, a prospective, naturalistic examina-
tion of psychotherapy use among STEP-BD participants found that
briefer treatments may be adequate for less severely ill patients
[30].
Ethnic and Provider Burden
At study entry, African Americans reported fewer medication
prescriptions and Hispanics reported fewer specialty treatment
visits than Caucasian control subjects. African Americans had
increased rates of psychosis, while Hispanics reported higher
current and past alcohol comorbidity [31]. Despite such dispar-
ities, African Americans, Hispanics and non-Hispanic whites did
not differ on outcomes. Using the final STEP-BD data set (n =
4100), we prospectively compared outcomes for African Amer-
icans (n = 155) and Hispanics (n = 152). African Americans
and Hispanics were more likely than non-Hispanic whites to dis-
continue STEP-BD within the first year. African American and
Hispanics experienced similar recovery on depression and days
spent well as non-Hispanic whites. African Americans had lower
GAF scores and a trend toward worse overall clinical status. Psy-
chosis was a predictor of poor depression outcomes for African
Americans [32]. These results suggested that while outcomes
differences should be considered in treatment planning, when
evidence-based treatments are provided outcomes can be simi-
lar across ethnic groups, thus remediating baseline illness severity
disparities.
In an ancillary study, 500 STEP-BD caregivers were as-
sessed with regard to stigma, mood, burden, and coping along-
side patient assessments of clinical status [33]. Greater subjec-
tive caregiver burden was associated with episodes of patient
depression and fewer patient days well over the previous year.
Perceived stigma was common among caregivers not only while
patients were actively symptomatic, but also when they were do-
ing well [34]. Greater mental illness stigma was associated with
bipolar I disorder, less social support for the caregiver, fewer
caregiver social interactions, and being Hispanic. In a patient
group selected for overall better clinical status, greater stigma
was associated with being an adult offspring of a parent with
BD, a college education, fewer social interactions, and female
gender.
Genomic Analyses of STEP Sample
STEP-BD collected DNA from more than 2300 participants.
This genetics repository, the largest DNA collection formed ex-
clusively from persons with BD, has been included in land-
mark genomic analyses in BD [35,36]. In addition to facilitat-
ing disease association studies, STEP-BD was utilized for the first
genome-wide association study of lithium response, and recur-
rence risk [37]. While no single locus achieved a genome-wide
significance threshold, these results provided an important re-
source for ongoing investigations of lithium, implicating candi-
dates for future study including genes related to glutamatergic
neurotransmission.
Summing Up
STEP-BD substantially impacted both clinical practice and research
perspectives on future BD studies. The combination of unprece-
dented sample size and a multifaceted series of clinical studies on
key current issues challenging both clinical practice and research
designs have in numerous areas of study summarized here pro-
vided adequately powered studies and subset analyses not gen-
erally achieved in earlier small studies. For example, the key-
stone randomized study on adjunctive antidepressants, reviewed
here, did not indicate that the adjunctive antidepressants provided
greater benefits than mood stabilizers alone. However, others who
have systematically reviewed STEP-BD activities reasonably have
questioned whether patients not enrolled or accepting of partici-
pation in the study might have had different, and plausibly better
experiences with adjunctive antidepressant use [9,38]. In a sep-
arate randomized study, STEP-BD patients in depressed episode
who had initially responded to treatment with antidepressants
plus mood stabilizers, and had been euthymic for 2 months, were
openly assigned to antidepressant continuation versus discontin-
uation for 1–3 years. Mood stabilizers were continued in both
groups. Continuing antidepressants yielded no significant benefit
in prevalence or severity of new depressive or manic episodes, or
in overall time in remission [39]. An investigation of patients en-
tering the STEP-BD program showed significantly increased risk
for affective polarity switch amongst patients who had previously
switched to mania/hypomania while taking tricyclic antidepres-
sants (OR = 7.80), serotonin reuptake inhibitors (OR = 3.73),
or bupropion OR = 4.28 [40]. Finally, STEP-BD established that
strictly DSM-IV defined bipolar depressive episodes without some
manic symptomatology were infrequent, occurring in only 31%
of the 1380 patients who entered in a depressive episode [41].
Thus, the multifaceted individual studies, coupled with the broad
research and clinical backgrounds of multiple scientists, combined
to provide a comprehensive set of results on this treatment and
illness course issue.
STEP-BD also took initiatives to define longitudinal outcomes
in BD to incorporate sustained benefits, multifaceted symptomatic
recovery, and functional as well as syndromal/symptomatic recov-
eries. These efforts enhanced the generalizability of results to clin-
icians caring for bipolar patients and highlighted the need to re-
consider the overly simplistic single point in time relapse designs
favored in recent registration studies [38].
STEP-BD established the feasibility of a large consortium to
aggregate subjects to yield investigations simply not possible, or
sorely underpowered in single site or small collaborative studies
regarding pathophysiologically important questions, but ones not
central to day to day management of BDs. The 60 plus STEP-BD
studies published to date included reliable information regarding
many such subjects, for example, lithium compared with other
mood stabilizer impact on suicidal behavior [42], handedness in
BD [43], cigarette use and its impacts [25], comorbidities [5], and
caretaker b urden and illness stigma [33].
STEP-BD also had several limitations that are relevant to per-
sons accessing the resulting reports, as well as planning collab-
orative research ventures. The choice of the instruments rou-
tinely completed represented a compromise between compre-
hensiveness and practicability in terms of staff and subject time.
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NIMH Systematic Treatment Enhancement Program C.L. Bowden et al.
Moreover, certain symptom areas that at present seem particu-
larly important in terms of b ipolar pathophysiology, for example,
discrete aspects of anxiety, affective, or mood instability and im-
pulsivity, have little or no representation in the data set. Although
the study has generally excellent generalizability due to minimal
exclusionary criteria; in fact this, or any prospective intervention
trial only engages persons sufficiently motivated to collaborate ac-
tively with a treatment and evaluation team. This results in some
under representation of persons with impaired insight regarding
their clinical state and the need for treatment, likely also unnder-
studying persons with active substance use disorders. Although
the large sample and multiple sites allows for confidence in data
based on adequately powered and not site idiosyncratic results,
such a study is not t he primary place to look for epidemiologi-
cal data about BDs. Although we were able to conduct important
and meaningful randomized studies along with the naturalistic in-
vestigation of illness course, for many purposes a free standing
randomized efficacy or comparative effectiveness study of a par-
ticular intervention, or with a specific subset of bipolar patients,
will likely be a more effective design strategy. To base recruitment
of such discrete intervention protocols on persons who agreed to
participate in the primary study because of a more general interest
in their illness management may partially exclude subjects with
the specific features important for the instant trial.
Additional results relevant to contemporary treatment can be
expected from this unprecedented data set. The STEP-BD data
set is now available through NIMH to qualified investigators for
application to hypotheses beyond those planned by the group
of investigators who have contributed to the work summarized
here.
Supported by NIMH Contract N01MH80001, 1998–2005,
GS Sachs, P.I. Massachusetts General Hospital, Boston. Addi-
tional detail on STEP-BD can be located at http://www.nimh.
nih.gov/health/trials/practical/step-bd/questions-and-answers-
for-the-systematic-treatment-enhancement-program-for-bipolar-
disorder-step-bd-study-background.shtml.
Authors’ Contributions
Dr. Bowden Dr. Perlis, Dr. Thase, Dr. Ketter, Dr. Ostacher, Dr.
Calabrese, Dr. Reilly-Harrington, Dr. Gonzalez, and Dr. Singh par-
ticipated in the concept, data collection, analysis, drafting and ap-
proval of this article.
Dr. Nierenberg participated in data collection, analysis, and ap-
proval of this article.
Dr. Sach participated in the concept, data collection, analysis, ap-
proval and securing of funding for the study.
Conflict of Interest
The authors have no conflict of interest.
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    • "Bipolar disorder (BPD) represents a group of common, disabling conditions of mood dysregulation. The improved ability to control overt illness symptoms through psychopharmacological and psychosocial treatments, as highlighted in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study [1], has afforded new opportunities for people with mental illness. However, studies suggest that functional and psychological wellbeing of individuals with bipolar disorders is not consistently predicted by symptom severity [2,3]. "
    [Show abstract] [Hide abstract] ABSTRACT: Bipolar disorder (BPD) is a common condition associated with significant morbidity and reduced quality of life. In addition to challenges caused by their mood symptoms, parents affected with BPD harbor concerns about the mental health of their children. Among adult parents who perceive themselves to have BPD, this study aims to examine participants' coping methods; identify predictors of adaptation; assess parental perceptions of risks for mood disorders among their children; and describe the relationships among illness appraisals, coping, adaptation to one's own illness, and perceived risk to one's children. Parents who self-identified as having BPD completed a web-based survey that assessed dispositional optimism, coping, perceived illness severity, perceived etiology of BPD, perceived risk to offspring, and adaptation to BPD. Participants had at least one unaffected child who was 30 years of age or below. 266 parents were included in the analysis. 87% of parents endorsed a "somewhat greater" or "much greater" risk for mood disorders in one's child(ren) than someone without a family history. Endorsing a genetic/familial etiology to BPD was positively correlated with perceived risk for mood disorders in children (rs = .3, p < 0.01) and active coping with BDP (r = .2, p < 0.01). Increased active coping (beta = 0.4, p < 0.001) and dispositional optimism (beta = 0.3, p < 0.001) were positively associated with better adaptation, while using denial coping was negatively associated with adaptation (beta = -0.3, p < 0.001). The variables explained 55.2% of the variance in adaptation (F = 73.2, p < 0.001). Coping mediated the effect of perceived illness severity on adaptation. These data inform studies of interventions that extend beyond symptom management and aim to improve the psychological wellbeing of parents with BPD. Interventions targeted at illness perceptions and those aimed at enhancing coping should be studied for positive effects on adaptation. Parents with BPD may benefit from genetic counseling to promote active coping with their condition, and manage worry about perceived risk to their children.
    Full-text · Article · Dec 2013
    • "The remission rate after acute treatment for mania is in the range of 40%–50%, and for depression is 25%–60%.7 In a recent large cohort study, only 60% of patients achieved remission during a 2-year follow-up period.8 Chronic persistence of symptoms can be expected in about 20% of cases, and social incapacity in about 30%.6 Judd et al9 carried out a follow-up study over 13 years and reported that bipolar patients were symptomatic during about half of the follow-up period. "
    [Show abstract] [Hide abstract] ABSTRACT: Lurasidone is a benzisothiazol derivative and an atypical antipsychotic approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia (October 2010) and bipolar 1 depression (June 2013). Lurasidone has a strong antagonistic property at the D2, serotonin (5-HT)2A, and 5-HT7 receptors, and partial agonistic property at the 5-HT1A receptor. Lurasidone also has lower binding affinity for the α2C and 5-HT2C receptor. Lurasidone is rapidly absorbed (time to maximum plasma concentration: 1-3 hours), metabolized mainly by CYP3A4 and eliminated by hepatic metabolism. In two large, well-designed, 6-week trials in adult patients with bipolar 1 depression, lurasidone monotherapy and adjunctive therapy with mood stabilizers were significantly more effective than placebo at improving depressive symptoms assessed using the Montgomery-Åsberg Depression Rating Scale total score. In both trials, lurasidone also reduced the Clinical Global Impression-Bipolar Severity depression score to a greater extent than placebo. In these two trials, discontinuation rates due to adverse events in the lurasidone group were small (<7%) and were not different from those of the placebo group. The most common adverse events in the lurasidone group were headache, nausea, somnolence, and akathisia. The changes in lipid profiles, weight, and parameters of glycemic control were minimal, and these findings were in line with those observed in schizophrenia trials. Further active comparator trials and long-term tolerability and safety data in bipolar patients are required. Lurasidone may be an option for the management of depressive symptoms in patients with bipolar 1 disorder, and it may be considered as a treatment alternative for patients who are at high risk for metabolic abnormalities.
    Full-text · Article · Oct 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Developing novel therapeutics and diagnostic tools based upon an understanding of neuroplasticity is critical in order to improve the treatment and ultimately the prevention of a broad range of nervous system disorders. In the case of mood disorders, such as major depressive disorder and bipolar disorder, where diagnoses are based solely on nosology rather than pathophysiology, there exists a clear unmet medical need to advance our understanding of the underlying molecular mechanisms and to develop fundamentally new mechanism experimental medicines with improved efficacy. In this context, recent preclinical molecular, cellular, and behavioral findings have begun to reveal the importance of epigenetic mechanisms that alter chromatin structure and dynamically regulate patterns of gene expression that may play a critical role in the pathophysiology of mood disorders. Here, we will review recent advances involving the use of animal models in combination with genetic and pharmacological probes to dissect the underlying molecular mechanisms and neurobiological consequence of targeting this chromatin-mediated neuroplasticity. We discuss evidence for the direct and indirect effects of mood stabilizers, antidepressants, and antipsychotics, among their many other effects, on chromatin-modifying enzmyes and on the epigenetic state of defined genomic loci, in defined cell types and in specific regions of the brain. These data, as well as findings from patient-derived tissue, have also begun to reveal alterations of epigenetic mechanisms in the pathophysiology and treatment of mood disorders. We summarize growing evidence supporting the notion that selectively targeting chromatin-modifying complexes, including those containing histone deacetylases (HDACs), provides a means to reversibly alter the acetylation state of neuronal chromatin and benefically impact neuronal activity-regulated gene transcription and mood-related behaviors. Looking beyond current knowledge, we discuss how high-resolution, whole-genome methodologies, such as RNA-sequencing (RNA-Seq) for transcriptome analysis and chromatin immunoprecipitation-sequencng (ChIP-Seq) for analyzing genome-wide occupancy of chromatin-associated factors, are beginning to provide an unprecedented view of both specific genomic loci as well as global properties of chromatin in the nervous system. These methodologies when applied to the characterization of model systems, including those of patient-derived induced pluripotent (iPS) cell and induced neurons (iNs), will greatly shape our understanding of epigenetic mechanisms and the impact of genetic variation on the regulatory regions of the human genome that can affect neuroplasticty. Finally, we point out critical unanswered questions and areas where additional data are needed in order to better understand the potential to target mechanisms of chromatin-mediated neuroplasticity for novel treatments of mood and other psychiatric disorders.
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