Overall Goals of the STEP-BD
Randomized Clinical Trials Pathway

Answer the question “What to do next?” when acute
depression doesn’t respond to monotherapy with a
mood stabilizer

See if using an antidepressant or non-antidepressant
treatment makes a difference in recovery

Test the efficacy of psychosocial therapy
as an adjunct
Sachs GS, et al. Biol Psychiatry. 2003;53:1028-1042.
Overview—Randomized Clinical Trials
Interventions
Duration
Outcomes
Acute
depression1
Mood stabilizer +
antidepressant:
bupropion or
paroxetine
26 weeks
No increased risk of TEAS
Recovery rates:
24% on MS + either antidepressant
27% on MS + placebo
No benefit seen from adding an
antidepressant
Refractory
depression2
Mood stabilizer +
nonantidepressant
adjunct:
lamotrigine, inositol, or
risperidone
16 weeks
Recovery rates:
24% on lamotrigine, 17% on inositol, 5% on
risperidone
No statistical difference in the 3 adjuncts; no
additive benefit in treating depression
Ad hoc analyses: lamotrigine may have some
modest therapeutic benefit
Psychosocial
therapy3
(for treating
depression)
Adjunctive treatment
for acute depression:
CBT, FFT, or IPSRT
Control: CC
1 year
Recovery rates:
77% in FFT, 64.5% in ISPRT, 60% in CBT,
51.5 in CC
All 3 intensive psychotherapies were
statistically superior to CC; all 3 also had
clear benefits of patients becoming well
sooner and staying well longer
Abbreviations: CBT, cognitive behavioral therapy; CC, Collaborative Care; FFT, family-focused psychoeducational
treatment; IPSRT, Interpersonal Social Rhythm Therapy; MS, Mood Stabilizer; TEAS, treatment-emergent affective switch.
1. Sachs GS, et al. N Engl J Med. 2007;356:1711-1722. 2. Nierenberg AA, et al. Am J Psychiatry. 2006;163:210-216.
3. Miklowitz DJ, et al. Arch Gen Psychiatry. 2007;64:419-427.
Advantages of Using Intensive
Psychotherapy as an Adjunct

Patients were 1.6 times more
likely to be well in any given
study month if they received
intensive psychotherapy

Patients became well an
average of 110 days faster
than those in collaborative
care
Miklowitz DJ, et al. Arch Gen Psychiatry. 2007;64:419-427.
Risk Factors that Increase the Chance
of Recurrence after Recovery
If any of the following happened the year prior to
recovery from an acute episode, the risk of recurrence
increased:


Previous lifetime episodes >20
Number of residual symptoms
– For every depressive symptom remaining, risk increases
by 14%
– For every manic symptom remaining, risk
increases by 20%

Length of time spent in prior episode (longer = worse)

Length of time with anxiety symptoms (longer = worse)
Miklowitz DJ, et al. Arch Gen Psychiatry. 2007;64:419-427.
Recovery and Recurrence in STEP-BD
Entered
STEP-BD
symptomatic
Only ~1/4 of the cohort
in this study achieved
recovery without a
relapse in ≤2 years
Achieved
recovery
1469
858
58%
Perlis RH, et al. Am J Psychiatry. 2006;163:217-224.
Recurrence
within 2 years
416
41%
Ancillary Anxiety Study in STEP-BD

ANY current anxiety disorder increases the risk of an
earlier acute recurrence1

Presence of anxiety disorder causes, on average, a loss
of 39 days being well1
As the number of anxiety disorders increase,
it increases the loss of days being well1



Anxiety disorders also increase suicide risk2
In the 239 STEP-BD patients who were tracked for
a year in follow-up, 41% of the patients with at least 1
anxiety disorder relapsed1
1. Otto MW, et al. Br J Psychiatry. 2006;189:20-25. 2. Simon NM, et al. J Psychiatr Res. 2007;41:255-264.
Ancillary ADHD Study in STEP-BD

In bipolar children, ADHD co-occurs 60%–90% of the
time

This comorbidity has not been studied at length in
adults

STEP-BD showed that bipolar adults with ADHD
– Have a poorer prognosis with bipolar disorders
– Are more symptomatic
– Are less likely to recover from mood episodes
– Are more likely to have more mania episodes
– Are more at risk for other psychiatric comorbidities
Nierenberg AA, et al. Biol Psychiatry. 2005;57:1467-1473.
Functional Impairment After Recovery

Followed 103 STEP-BD subjects who had been in remission at
least 4 weeks

The Work and Social Adjustment Scale (WSAS) was used to
assess overall functional status

Findings: bipolar patients still have substantial functional
deficits even during periods of sustained remission (in this
cohort, 4 weeks to 13 years)

Degree of functional impairment correlates with degree
of residual depressive symptoms (but not panic/mania
symptoms)

Patients may benefit from comprehensive psychosocial and
rehabilitative interventions
Nierenberg AA, et al. Biol Psychiatry. 2005;57:1467-1473.
Take-Away Messages

Despite best efforts, recurring illness is still too common in
bipolar disorders

The value of antidepressants as adjunctive therapy in acute
bipolar depression has yet to be established

Nonantidepressant adjunctive therapy may have modest
benefits in refractory bipolar depression

Intensive psychotherapy has value as perhaps the most useful
adjunct to pharmacotherapy in treating bipolar depression

Careful evaluations tracking patient symptoms at recovery can
help alter recurrences

The most important single independent predictor of risk was
residual, subthreshold mood elevation symptoms
Thase ME. Curr Psychiatry Rep. 2007;9:497-503.
Suggested Readings
Fagiolini A, Kupfer DJ, Masalehdan A, et al. Functional impairment in the remission phase of bipolar disorder.
Bipolar Disord. 2005;7:281-285.
Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression. Arch Gen Psychiatry.
2007;64:419-427.
National Institute of Mental Health. Effectiveness of Lithium Plus Optimized Medication in Treating People With
Bipolar Disorder (LiTMUS). http://clinicaltrials.gov/show/NCT00667745. Accessed November 8, 2008.
Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise
randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J
Psychiatry. 2006;163:210-216.
Perlis RH, Brown E, Baker RW, Nierenberg AA. Clinical features of bipolar depression versus major depressive
disorder in large multicenter trials. Am J Psychiatry. 2006;163:225-231.
Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the
Systemic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163:217224.
Post RM, Altschuler LL, Leverich GS, et al. Mood switch in bipolar depression: comparison of adjunctive
venlafaxine, bupropion and sertraline. Br J Psychiatry. 2006;189:124-131.
Sachs GS, Nierenberg AA, Calabrese JR. Effectiveness of adjunctive antidepressant treatment for bipolar
depression. N Engl J Med. 2007;356:1711-1722.
Suppes T, Dennehy EB, Hirschfield R, et al. The Texas implementation of medication algorithms: update to the
algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870-886.
www.grandrounds.com/v66n0710.pdf. Accessed November 8, 2008.
Suppes T, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Treatment Outcome Network II.
Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67:45-59.