Malcolm P. Rogers, M.D.
Notes prepared for MAPP Journal Club discussion on the subject of treatment of bipolar depression on October 25, 2011
Sachs GS et al. Effectivenss of Adjunctive Antidepressant Treatment for Bipolar Depression. NEJM
356:17 1711-1722, 2007
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Authors point out that limited evidence for use of antidepressants added to mood stabilizer. In fact, they cite study in which patients on lithium did not do better with antidepressant than with placebo
(Nemeroff 2001). One positive study was for combination of olanzepine and fluoxetine (Tohen 2003)
• Double-blind, placebo-controlled study, subjects with bipolar depression were randomly assigned to 26 wks of treatment with mood stabilizer plus adjunctive antidepressant or mood stabilizer and placebo.
Main outcome measure was percentage of subjects with durable recovery (8 wks euthymia) assessed through Montgomery-Asberg Depression Scale. Also used Young Mania Scale.
• Part of NIMH STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) enrolled
4360 subjects. 2689 had at least one major depressive episode and of that group, 366 were enrolled and randomly assigned. Low recruitment rate.
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Subjects and their psychiatrists could choose either bupropion or paroxetine or either v. placebo. Some of them were already on another antidepressant that were was tapered
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Similar baseline clinical and demographics between two groups.
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42 of the 179 subjects (23.5%) receiving antidepressant had durable recovery v 27.3% of placebo, thus no significant improvement with antidepressant (Table 4). Similar lack of statistical difference for transient remission, or treatment effectiveness. Table 1 shows definitions.
• Rates of treatment-emergent affective switch were similar between the two groups.
• Might have been biased - patients who had had manic response to antidepressants previously or severe mania might have excluded themselves
Belmaker RH. Treatment of Bipolar Depression (Editorial) NEJM 356:17 1771-1773, 2007.
· 2 European reviews had shown antidepressant treatment can be highly beneficial for bipolar depression with little risk of induction of mania. (Gijsman HJ et al. Am J Psychiatry 2004) &
Moller Eur. Arch Psychiatry Clin Neurosci 2006). Gijsman study is a meta-analysis but with low numbers and majority of patients from one study. (Twelve randomized trials were included, with a total of 1,088 randomly assigned patients. Five trials compared one or more antidepressants with placebo: 75% of these patients were receiving a concurrent mood stabilizer or an atypical antipsychotic)
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Thus surprise that Sachs study (adding antidepressant to patients on one or more mood stabilizers) neither improved depression nor increased risk of switch.
· Widens gap between American and European camps about efficacy of antidepressant but narrows gap on switch issue.
· But in Sachs study 90% of patients were also on a mood stabilizer so doesn't address risk of switch in absence of that.
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SSRI's (paroxetine) and dopamine inhibitors (bupropion) were the antidepressants used and it remains possible that NSRIs or TCAs might induce mania at a higher rate
· Low recruitment rate in Sachs study might be a source of bias (patients or doctors might exclude selves if prior switch experience to antidepressant)
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Bipolar patients heterogeneous – Israel more mania; in North America more depression
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Treatment decisions likely to still be individualized – pt's clinical history and past responses to treatment will remain important factors
· If depression is severe consider ECT
Vieta E. Treatment Options for Bipolar Depression: A systematic Review of Randomized, Controlled
Studies. J Clinical Pharmacology. 30:579-590, 2010. (From Barcelona)
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Meta-analysis of treatments for bipolar depression
· Background discussion points out that the term antidepressant is potentially confusing (coming from unipolar depression) and data suggest that quetiapine and olanzepine in combination and mood stabilizers are effective antidpressant agents in bipolar depression. Guidelines are limited
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19 publications involving 6731 participants included and involved medications were: quetiapine, lamotrogine, paroxetine, lithium, olanzepine, aripiprazole, phenelzine (Nardil) and divalproex all v placebo (Table I)
· Most were trials for either quetiapine 5 or lamotrigine 6.
· Used mean changes in Montgomery-Asberg Depression Rating Scale (MADRS) or Hamilton
Depression Rating Scales (HAM-D). Different studies used different cutoff scores for defining response and remission.
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Figures 1 (MADRS) and 2 (HAM-D) show results. Figure 3 shows relative risk for response rate and Figure 4 for remission.
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Meds not associated with significant improvement: Lamotrigine, paroxetine, aripiprazole and lithium. Paroxetine only antidepressant for MADRS measure but HAM-D includes phenelzine, imipramine and paroxetine
· Meds associated with greatest improvement: olanzepine-fluoxetine combination, and quetiapine
· Imipramine and phenelzine show response
Frye , MA. Bipolar Disorder – A Focus on Depression. NEJM 364: 51-9, 2011. (January 2011)
A clinical review with focus on evaluation and treatment of depression in bipolar patients, organized around a brief clinical vignette.
Synopsis of the disorder: pointing out the severity of the condition and its association with premature death and a completed suicide rate of 25% early in course of illness. The rate is 5% even in patients who have never been hospitalized. On the other hand most disability is associated with depression. In NIMH
Collaborative study of bipolar I patients over 12 yrs, patients were symptomatic with depression almost
33% of the time.
FDA-Approved treatments
· Only 2 FDA approved treatments (quetiapine and olanzepine and fluoxetine) for depression in contrast to 10 for mania
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4 8-wk, placebo-controlled studies of quetiapine at dose of 300-600 in total of 2593 subjects show efficacy (2 of the studies included paroxetine or lithium)
· 8-wk randomized trial in 833 subjects involving olanzepine (7.4mg) and fluoxetine (40mg) as mean dosages were both superior to placebo. Combination better than olanzepine as montherapy.
Rate of switch to mania did not differ between two groups (6.4 v 6.7%)
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Antidepressant effect of olanzepine and quetiapine does not appear to generalize to other atypical antipsychotics such as aripiprazole or ziprasidone
Antiepileptic Drugs:
· Lamotrigine: inconsistent results but a recent meta-analysis of all 5 trials with 1072 subjects
(Geddes 2009) suggested a modest benefit as measured by MADRS score (50% or greater decrease)– greater effect in pts with severe depression
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Lamotrigine better than gabapentin or placebo in a small randomized crossover study
· divalproex - in meta-analysis of 4 short-term, placebo-controlled trials involving 142 patients, better than placebo as monotherapy in response and remission rates
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Antidepressant Drugs:
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Meta-analysis of 15 randomized double-blind trials in 2373 patients show no major benefit of antidepressant drugs (Sidor 2010) but also no increase in switch rates.
• Meta-analysis of 7 trials randomly assigned bipolar I and II to different antidepressants for 6 months in
350 patients had longer time for relapse or recurrence of depression but increased the risk of switch
(Ghaemi 2008)
Psychotherapy:
• Fewer symptoms of depression in patients who received intensive psychotherapy than psycho-education
Areas of Uncertainty:
Whereas in one retrospective study 40% of patients treated with an antidepressant reported a switch to mania or hypomania within 12 wks, controlled clinical trials have suggested a much lower rate. Maybe they are selected more carefully and may be more likely on a mood stabilizer.
More likely to switch if bipolar I and lack of mood stabilizer.
Mentions that APA guidelines are being revised.
Recommends the use of quetiapine for the patient in question: a 26 yo businesswoman with winter pattern of depression and history of hypomania and maybe an episode of mania.
Recommends lamotrigine as second line treatment.
Sidor MM and MacQueen GM. Antidepressants for the Acute Treatment of Bipolar Depression: A
Systematic Review and Meta-Analysis. J Clin Psychiatry 72:156-167, 2011 (February 2011)
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Management of bipolar disorder has focused on mania while depression is predominant mood and more morbidity and mortality
· Evidence that antidepressants destabilize mood by inducing an affective switch to mania or hypomania (Truman CJ. J Clin Psychiatry 2007 (STEP-BD) and others) or inducing rapid cycling
· Others find no such evidence for switch (Visser HM World J Biol Psychiatry 2005)
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Conservative current guidelines are to take an antidepressant as second line treatment but with concurrent mood stabilizing drugs.
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Approximately 50% of bipolar pts are prescribed antidepressants.
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Some reviews have suggested that antidepressants are effective (Gijsman 2004) (Meta-analysis of
12 randomized controlled studies (RTCs) but since then RTCs suggest not so effective. However
Gijsman study heavily slanted to one study.
· Thus their study presented as updated meta-analysis of RTCs of efficacy and safety of antidepressants for acute depression.
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15 double-blind RCTs of antidepressants used for acute treatment (4-16wks)
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Conclusion: Antidepressant medications not associated with statistically significant increase in efficacy compared to placebo or other pharmacological Rx. Interestingly, excluded two studies that Gijsman had used and added 3 new trials including Sachs (STEP-BD)
· Figure 1 (Clinical response, remission and switch antidepressants v placebo); Figure 2
(Antidepressants v other medications); Figure 3A (Bupropion compared to other antidepressants);
Figure 3B (Bupropion to other antidepressants in terms of switch)
· SSRIs and bupropion did not increase the risk of a switch – consistent with Gijsman and another study by Licht RW Acta Psychiatr Scand 2008)
· But one should note that the percentage of switch data depends on threshold. With sensitive subclinical measures one is more likely to find changes – but few studies reporting sub-threshold mood changes
My own conclusions:
· Danger of switch to mania or hypomania not as great although we don’t have much data for patients not on mood stabilizer.
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Probably no difference in switch rate among different antidepressants if used in comparable doses – but also need to control for whether rapid cycling or not or whether bipolar I or II (more switching in some studies for Bipolar I than II).
· Lack of sufficient data on risk of antidepressants as monotherapy and relatively few high quality RCTs because of heterogeneity of subjects, diagnostic and outcome measures, small sample size and lack of clarity about randomization process. This is a complex area that remains murky and clear guidelines are lacking.
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Quetiapine is proven effective as antidepressant in bipolar depression
· So has combination of olanzepine and fluoxetine.
· These are the only two that are FDA approved but significant side effect issues.
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Lamotrigine may also provide improvement over placebo especially if paired with lithium – but conflicting evidence as monotherapy.
· What people actually do in practice is probably different than the literature suggests.
Many use antidepressants more than the data support.
· Bottom line: treatment needs to be individualized.
· Similar to a Clinical Psychiatry News Article covering Dr. Andrew Nierenberg’s presentation at the European College of Neuropharmacology (Oct 6/2011).
· Also note that some of the discussion of the pros and cons of meta-analyses was stimulated by a chapter on the subject in S. Nassir Ghaemi's "A Clinician's Guide to
Statistics and Epidemiology in Mental Health: Measuring Truth and Uncertainty,
Cambridge University Press, 2009. This book continues to be a useful guide in interpreting the significance of many of the articles reviewed in Journal Club.
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