Effectiveness of Adjunctive Treatment for Bipolar Depression

1. Effectiveness of Adjunctive Treatment for Bipolar Depression Article Review John David Kolter, M.D.

2. Bipolar in history

3. Background • Bipolar disorder is the sixth leading cause of disability worldwide (1990 WHO statistic) • Bipolar depression is the leading cause of impairment and death among patients with bipolar disorders.

4. Study Justification • Two limitations thought to hamper use of antidepressants in bipolar disorder. • Data on these agents as bipolar depressive treatments is too scarce to guide clinical practice. • Widely held belief that antidepressants can induce abnormal mood elevations or accelerate the rate of cycling • These patients are challenging in the primary care outpatient setting.

5. Study Justification • The authors site two previous studies: • Placebo-controlled study using lithium and concurrent antidpressant (paroxetine or imipramine or placebo). No significant difference between groups. • “Only large positive trial” involved atypical antipsychotic and olanzapine or fluoxetine or placebo. Antidepressant group showed superiority to placebo.

6. Study within a study • STEP-BD is the Systematic Treatment Enhancement Program for Bipolar Disorder, a collaboration sponsored by the NIMH • Designed to provide treatment strategies and results generalizable to clinical practice • Completed data collection in 2005 • 4361 participants (366 in this study) • Billed as largest treatment study for bipolar disorder.

7. Methods • Mulitcenter, double-blind, randomized, placebo-controlled, parallel group study • “Standard” antidepressants of bupropion or paroxetine as adjunctive therapy to mood stablizers • Patients treated up to 26 weeks

8. Selection of Subjects • Subjects met DSM-IV criteria for major depressive episode assc. with Bipolar I or II disorder. • Diagnosis of bipolar confirmed at STEP-BD entry using Stuctured Clinical Interview for DSM-IV and the Mini-International Neuropsychiatric Interview • Exclusions: Intolerance to study drugs, coexistent and current substance abuse, and those requiring antipsychotic medication

9. Baseline Characteristics of Study Subjects (Table 2) No P-values were significant in demo. or clin. char. of 2 groups baseline.

10. Interventions • Assigned a double blind treatment with mood stabilizer plus adjunctive antidepressant or placebo with equipoise-stratified randomization method

11. Theraputic Selection • Paroxetine and bupropion • “standard” antidepressants • Different mechanisms of action • Mood stabilizers • Lithium, valproate, carbamazepine • STEP-BD ammended in 2004 to include any FDA-approved antimanic agent

12. Theraputic Selection • Psychotherapy • Option to remain with non-study therapist, no psychosocial intervention, or enroll in STEP-BD psychosocial intervention trial • Pre-study therapy • Antidepressants tapered and not permitted after second week

13. Dosing • Evaluated after 6 weeks • Pts with adverse effects or mania stopped drug and received open treatment • Response pts continued drug for 20 more weeks • Non-response pts offered dose increase with q2 wk follow-up

14. Effectiveness Outcomes • Clinical Monitoring Form • Composite assesment tool adapted from DSM-IV • Modified to include rating scales for depression (SUM-D) and mood elevation (SUM-ME), corelated to formal rating scales • Administered at study intitiation and each follow-up visit

15. Outcomes • Primary Outcome • Durable recovery, euthymia for 8 or more consecutive weeks • Secondary Outcomes • Table 1

16. Table 1

17. Statistical Analysis • Analysis-of-variance and chi-squared tests used to compare baseline and clinical course data • Analyses included all patients assigned to a group • Logistic regression models used to determine tx effect after adjusting for site or antidepressant preference • Powered to 80%; P value of 0.05 was significant

18. Results • 163/ 179 in antidepressant group and 169/ 187 in placebo group had at least one follow-up visit • Percentages of subjects reaching study defined outcome (Figure 1), discontinued tx prior to week 16, and rates of causes of early termination were similar in the two groups

19. Results • No significant differences in percentage meeting criteria for any effectiveness outcome. • No significant differences of rate of any primary or secondary outcome between patients receiving bupropion or paroxetine • Modest non-significant trends consistently favored placebo over antidepressant Rx. • Rates of durable recovery were similar in bipolar I, nonsignificant trend toward placebo in bipolar II

20. Table 4

21. Subgroup Analysis • Analysis of results that were adjusted for acceptance or rejection of enrollment into randomized psychosocial treatment study showed no significant difference • Augmentation of drug therapy with brief or intensive psychotherapy showed no significant benefit.

22. Subgroup analysis Percent achieving primary outcome

23. Adverse Events (Table 3) • Rate of any individual adverse event did not differ significantly • Similar percentages of each group discontinued tx for adverse events • No significant difference in prospective treatment emergent affective switch (10.1 vs 10.7 %)

24. Discussion • Unique features of this study • Not a “pure” placebo group • Enrolled bipolar I/ II disorder • Enrolled those with coexisting substance abuse and anxiety disorders and psychotic symptoms • Subjects received additional pharmacotherapy and psychotherapy

25. Discussion • Study only evaluated paroxetine and bupropion • Cannot be generalized to all antidepressants • Other studies have shown significantly higher rates of treatment emergent affective switch with venlafaxine or desipramine

26. Limitations/ Confounders • Only two antidepressants studied • Brief observation period • Last-observation-carried forward analysis (data imputation used) • Physicians enrolling patients hesitant to enroll pts at high risk or with h/o transition to mania • Pts continued some previous meds • Pts were able to use a variety of psychotherapy choices

27. Change Clinical Practice? • Unlikely to change primary care practice as these pts are routinely referred to psychiatry • Will give primary care physicians a level of comfort with pts presenting from psychiatry on antidepressant + concurrent mood stabilizer • Allow PCPs to educate patients that antidepressants are not the best treatment for depression in bipolar (as opposed to unipolar) depression

28. Editorial • Two European reviews show antidepressant tx can be highly beneficial for bipolar depression, with little risk of induction of mania • This study widens gap on depression tx but narrows the gap on safety of antidepressants • ? Bias from low number of STEP-BD pts enrolled (366/4360) • Studies show polarity of recent episode may effect response to antidepressants • Does not address mania risk off mood stabilizers (though some studies suggest little risk in this population as well)