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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background
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.
study justification
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.
study justification5
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.
study within a study
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.
methods
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
selection of subjects
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
baseline characteristics of study subjects table 2
Baseline Characteristics of Study Subjects (Table 2)

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

interventions
Interventions
  • Assigned a double blind treatment with mood stabilizer plus adjunctive antidepressant or placebo with equipoise-stratified randomization method
theraputic selection
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
theraputic selection12
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
dosing
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
effectiveness outcomes
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
outcomes
Outcomes
  • Primary Outcome
    • Durable recovery, euthymia for 8 or more consecutive weeks
  • Secondary Outcomes
    • Table 1
statistical analysis
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
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
results19
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
subgroup analysis
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.
subgroup analysis22
Subgroup analysis

Percent achieving primary outcome

adverse events table 3
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 %)
discussion
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
discussion25
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
limitations confounders
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
change clinical practice
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
editorial
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)
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