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

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.

Interventions Duration Outcomes

Acute depression1

Mood stabilizer + antidepressant: bupropion or paroxetine

26 weeks No increased risk of TEAS

Recovery rates:24% on MS + either antidepressant27% on MS + placeboNo 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 risperidoneNo 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 IPSRTControl: CC

1 year Recovery rates:77% in FFT, 64.5% in ISPRT, 60% in CBT, 51.5 in CCAll 3 intensive psychotherapies were statistically superior to CC; all 3 also had clear benefits of patients becoming well sooner and staying well longer

Advantages of Using Intensive Psychotherapy as an Adjunct

Miklowitz DJ, et al. Arch Gen Psychiatry. 2007;64:419-427.

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

Risk Factors that Increase the Chance of Recurrence after Recovery

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)

If any of the following happened the year prior to recovery from an acute episode, the risk of recurrence increased:

Miklowitz DJ, et al. Arch Gen Psychiatry. 2007;64:419-427.

Recovery and Recurrence in STEP-BD

1469 858 58%

416 41%

Entered STEP-BD

symptomatic

Achieved recovery

Recurrence within 2 years

Only ~1/4 of the cohort in this study achieved recovery without a relapse in ≤2 years

Perlis RH, et al. Am J Psychiatry. 2006;163:217-224.

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 ReadingsFagiolini 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;163:217-224.

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.