Effectiveness of adjunctive treatment for bipolar depression
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Effectiveness of Adjunctive Treatment for Bipolar Depression. Article Review John David Kolter, M.D. Bipolar in history. Background. Bipolar disorder is the sixth leading cause of disability worldwide (1990 WHO statistic)

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Effectiveness of adjunctive treatment for bipolar depression l.jpg

Effectiveness of Adjunctive Treatment for Bipolar Depression

Article Review

John David Kolter, M.D.

Background l.jpg

  • 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.

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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.

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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.

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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.

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  • 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

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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

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Baseline Characteristics of Study Subjects (Table 2)

No P-values were significant in demo. or clin. char. of 2 groups baseline.

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

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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

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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

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  • 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

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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

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  • Primary Outcome

    • Durable recovery, euthymia for 8 or more consecutive weeks

  • Secondary Outcomes

    • Table 1

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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

Results l.jpg

  • 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

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  • 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

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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.

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Subgroup analysis

Percent achieving primary outcome

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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 %)

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  • 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

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  • 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

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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

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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

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  • 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)