{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T23:19:27Z","timestamp":1794352767997,"version":"4.9.0"},"reference-count":164,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Objective: To narratively review currently available antidepressants and future potential antidepressants as monotherapy for the treatment of depressive disorders. Methods: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), dopamine reuptake inhibitor (bupropion), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) were reviewed according to the results from Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study and systematic reviews. For the rest of the antidepressants, a PubMed\/Medline search was conducted with priority for systematic reviews. For drugs in development for depressive disorders, PubMed, Google, and Clinicaltrials.gov databases were used. Results: The STAR*D Study demonstrated that sertraline, venlafaxine, and bupropion monotherapy had similar efficacy in patients with major depressive disorder (MDD) who failed citalopram. A network meta-analyses of randomized, placebo-controlled trials found that SSRIs, SNRIs, bupropion, TCAs, mirtazapine, and agomelatine had similar relative efficacy compared to placebo, but had different acceptability. Gepirone had more failed\/negative studies and smaller effect size relative to placebo compared to other antidepressants. The combination of dextromethorphan and bupropion, ketamine infusion, and intranasal esketamine had faster onset of action but similar effect size compared to monoamine-based antidepressants as monotherapy. Brexanolone and zuranolone are effective in postpartum depression (PPD), but the effect size of zuranolone in MDD as monotherapy or adjunctive therapy was very small. Psychedelics, glutamate receptor-related agents, kappa opioid receptor antagonists, orexin receptor antagonists, new anti-inflammatory agents, and biomarker-based antidepressant therapy have been under investigation for depressive disorders. Psychedelics showed faster onset of action, large effect size, and long durability. Conclusions: Monoamine-based antidepressants likely continue to be the mainstream antidepressants for depressive disorder. NMDA receptor antagonists and neurosteroid antidepressants will play a bigger role with the improvement of accessibility. Psychedelics may become a game changer if phase III studies validate their efficacy and safety in depressive disorders.<\/jats:p>","DOI":"10.3390\/medicina61040558","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T11:06:48Z","timestamp":1742555208000},"page":"558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pharmacological Monotherapy for Depressive Disorders: Current and Future\u2014A Narrative Review"],"prefix":"10.3390","volume":"61","author":[{"given":"Keming","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Mind and Body Medicine, Sichuan Lansheng Brian Hospital, Chengdu 610036, China"},{"name":"Department of Psychiatry, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA"},{"name":"Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3406-3443","authenticated-orcid":false,"given":"Evrim Bayrak","family":"Oruc","sequence":"additional","affiliation":[{"name":"Independent Researcher, Cleveland, OH 44113, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buket","family":"Koparal","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA"},{"name":"Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Psychiatry, Gazi University School of Medicine, Ankara 06500, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"key":"ref_1","unstructured":"GBD 2019 Diseases and Injuries Collaborators (2020). 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