Treatments for Acute Bipolar Depression: Meta-analyses of Placebo-controlled, Monotherapy Trials of Anticonvulsants, Lithium and Antipsychotics

Abstract

Background: Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. Methods: We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT). Results: We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ?50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19?40%]), and NNT was 8.2 (CI: 6.4?11). By SMD, apparent efficacy ranked: olanzapine+fluoxetine?valproate>quetiapine>lurasidone>olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had >?2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%). Discussion: Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…Quetiapine (level 1),241, 242, 243 lithium (level 2),244, 245, 246 lamotrigine (level 2)242, 247, 248 and lurasidone (level 2)249 are all recommended as first‐line treatment options with evidence for efficacy as monotherapy.…”

“…In patients who are inadequately responsive to first‐line agents, monotherapy with divalproex (level 2)242, 258 is included as a second‐line option.…”

“…In patients who fail to respond to multiple first‐ and second‐line agents, third‐line choices include monotherapy with carbamazepine (level 2)242 or olanzapine (level 1) 242…”

“…Although the pooled analysis reported separation,293 the mean difference in Montgomery–Åsberg Depression Rating Scale (MADRS) change score was only 1.12 points, which is not clinically meaningful and it is thus not recommended (level 1 negative). Ziprasidone monotherapy or adjunctive therapy (level 1 negative),242, 294 lamotrigine in combination with folic acid (level 2 negative),251 and mifepristone (adjunctive) (Leve 2 negative)295 are also not recommended due to evidence for lack of antidepressant efficacy (Table 15). …”

Bipolar Depression: An Orphan Syndrome?

“…Meta-analysis was applied to the findings from the remarkably few randomized, controlled trials (approximately 20 for all non-antidepressants) that have been reported for this condition, and virtually only for acute bipolar depression (47). Ranked by apparent efficacy, the most promising treatments were: olanzapine+fluoxetine ≥ valproate ≥ quetiapine ≥ lurasidone ≥ olanzapine alone, whereas carbamazepine, lithium, lamotrigine, ziprasidone, and aripiprazole had lesser outcomes and were not statistically effective.…”