All studies are not created equal: A systematic narrative review of bipolar depression clinical trial...

Several bipolar depression treatment guidelines have been designed to assist clinicians with medication selection. When ranking medications, none explicitly considered the inclusion/exclusion criteria or baseline severity scores of the reviewed clinical trials. This article aimed to determine if sufficient differences exist in these variables to justify their consideration when designing treatment guidelines.

Using Ovid and PubMed databases in May and September 2022, all published, short-term cross-over or parallel-group design studies comparing second generation antipsychotics (SGAs), mood stabilizers, or antidepressants versus placebo in bipolar depressed patients were identified. Included studies must have enrolled adult bipolar I/II depressed patients, randomized patients into two or more treatment groups, utilized a double-blind, prospective design written in English, and had primary outcome results that were statistically significant in favor of the investigational treatment.

Thirty studies met eligibility criteria, comprising a total of 8791 patients. Among those studies, there were seventeen antipsychotic trials, six lithium trials, one lamotrigine trial, three valproate trials, two carbamazepine trials, and two antidepressant trials. The analysis revealed substantial differences among the studies. Although this was seen among all the different drug classes, these differences are clearest when comparing the lithium trials to those of the SGAs.

Limitations included the selection of severity scores from the treatment arm with the most severe score and the exclusive focus on mood stabilizers, antidepressants, and SGAs.

Severity of the enrolled patient sample and treatment-resistance should be considered in addition to other factors when ranking medications in bipolar depression treatment guidelines.