A Perspective on Adjunctive/Combination Therapy in Major Depressive Disorder: What Have We Learned from Studies of Atypical Antipsychotics?

Background and Objectives: To examine studies of atypical antipsychotics in the treatment of major depressive disorder (MDD), identify unmet needs in adjunctive therapy or combination therapy with antidepressant(s) in MDD, and discuss future directions in this area. Materials and Methods: The PubMed database was used to search for studies addressing definitions of treatment response in MDD and pivotal studies of adjunctive or combination therapy with atypical antipsychotics to an antidepressant in the treatment of MDD. The study designs and primary outcomes were extracted from original publications. The differences in study designs and reporting were narratively analyzed. Relevant systematic reviews with or without meta-analysis were also examined. Results: Eight atypical antipsychotics were studied in the treatment of MDD as an adjunctive therapy to an antidepressant or as a combination therapy with an antidepressant. Six of them were sponsored by pharmaceutical companies with an indication for MDD. Olanzapine and fluoxetine combination (OFC) was approved for treatment-resistant depression (TRD), and aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine-XR were approved as an adjunctive therapy to an antidepressant for patients with MDD with “inadequate response”. The study designs, especially inclusion and exclusion criteria and methodology to determine treatment response, were diverse. The study reporting in publications was inconsistent, and systematic reviews and meta-analyses commonly lumped all studies with different designs together for reporting and analyses. Conclusions: Standardized study designs and consistent reporting of clinical trials in adjunctive/combination therapy for MDD are urgent needs. Collaborations among regulatory agencies, pharmaceutical companies, and academics are essential to establish standard study designs for each indication. Journals and publishers should require detailed and unified reporting methods of clinical trials, especially for phase III trials, for indirect comparisons among the studies with systematic reviews and network meta-analyses.