Depressive disorders: systematic review of approved psychiatric medications (2009-April 2025) and pipeline phase 3 medications

BACKGROUND: Depressive disorders remain a significant public health concern, with substantial personal, social, and economic impacts worldwide. The purpose of this systematic review is to examine the psychiatric medications approved by the FDA from 2009 through early 2025, as well as investigational drugs in Phase 3 clinical trials for depressive disorders, with a focus on their mechanisms of action, indications, evidence for efficacy, dosing, and adverse effect profiles. METHODS: We conducted a systematic search of the FDALabel Database for FDA-approved medications for depressive disorders, using the criteria: labeling type "Human Prescription Drug," application type "NDA," and "depression" or "major depressive disorder" under "Indications and Usage." To identify medications in Phase 3 clinical trials or awaiting FDA approval, we searched the US Clinical Trials Registry with filters for condition "depression" or "major depressive disorder," trial phase "Phase III," and study dates from 01/01/2009 to 4/1/2025. Additional information on included drugs was obtained via a PubMed literature search. RESULTS: From 2009 through early 2025, the FDA approved 15 medications for depressive disorders, and there are currently 18 pipeline medications in Phase 3 clinical trials. Notable advancements during this period include a large number of approved and Phase 3 antidepressants with mechanisms that deviate from the monoamine hypothesis, particularly those targeting glutamatergic NMDA receptors, GABA-A receptors, and kappa-opioid receptors. Moreover, several antidepressants (approved and in development) function as partial agonists at the 5-HT1A receptor, serotonin-norepinephrine reuptake inhibitors, and previously approved neuroleptics. Of note, every oral antidepressant approved by the FDA during this time is scheduled as once-daily. CONCLUSIONS: Our results show numerous FDA approvals of medications for depressive disorders. Phase 3 psychiatric medications for depressive disorders seem to show novel mechanisms of action, modes of administration, and side effects.