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Both bipolar depression and refractory unipolar depression are highly difficult to treat. Because few randomized controlled trials (RCTs) address these conditions, clinicians often try medications either from the same class as proven-effective agents or that are effective for related conditions. These two large, well-conducted RCTs remind us that such clinical strategies may be neither sound nor effective.
The only two FDA-approved treatments for bipolar depression are quetiapine and olanzapine–fluoxetine combination. To examine the efficacy and safety of the atypical antipsychotic ziprasidone (20–80 mg daily) added to stable mood stabilizers (≥4 weeks of lamotrigine, lithium, or valproate), Sachs and colleagues conducted a placebo-controlled, 78-site, 6-week study in 298 depressed patients with bipolar I disorder. No difference in the primary depression outcome was found between the two treatments (P>0.79).
Lamotrigine, an antiepileptic drug thought to prevent future depressive episodes, is FDA-approved only for maintenance treatment of bipolar depression, although recent meta-analyses seemed to show its effectiveness in acute treatment. Barbee and colleagues' 19-site RCT involved 183 patients with unipolar depression, who had not responded to at least one antidepressant and who were then treated for 8 weeks with paroxetine. Ninety-six patients who still had Hamilton Rating Scale for Depression scores of 15 or higher were randomized to adjunctive lamotrigine (≤400 mg) or placebo for 10 weeks. The two groups did not differ in the main depression outcome.
Sachs GS et al. Efficacy and safety of adjunctive oral ziprasidone for aute treatment of depression in patients with bipolar I disorder: A randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2011 Oct; 72:1413.
Barbee JG et al. A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. J Clin Psychiatry 2011 Oct; 72:1405.
Comment
In Sachs's study, quality control showed varied diagnoses across the sites; dosing may have been inadequate; and some subjects had mixed-state features. These characteristics may have played some role in the null findings. Barbee's group provided numerous secondary analyses suggesting some efficacy; baseline imbalances (lamotrigine patients were more depressed) and a relatively low stage of treatment resistance (increasing the probability of placebo response) may have contributed to the null results. Nonetheless, the absence of a definitive signal in these large studies suggests that clinicians should use these drugs for these indications only after trying more-effective treatments.