Ketamine pharmacotherapy for major depressive disorder: A narrative review.

Open-LabelPubMedMarch 15, 2026PMID: 41765199 DOI

Abstract

Ketamine pharmacotherapy provides a novel treatment option for major depressive disorder (MDD) and has generated a large, growing body of research regarding its biochemical and clinical properties. This narrative review summarizes the history of ketamine's development, beginning as a general anesthetic, continuing with a discovery of its antidepressant properties, and leading up to its landmark FDA approval indicating its usage for treatment-resistant depression (TRD) and MDD with suicidal ideation or behavior. It then reviews the pharmacokinetic properties of both intravenous (IV) ketamine and intranasal (IN) esketamine, including their dosing, bioavailability, onset of action, elimination, and other clinical considerations. Next, it summarizes the mechanisms of action of ketamine, including its primary classification as an NMDA receptor antagonist and the critical importance of its paradoxical AMPA-activated glutamate surge, which thereafter activates a variety of other downstream signaling pathways that promote synaptogenesis and neuroplasticity as well as alterations to mood and reward processing. It then considers the most common adverse effects, including dissociation, sedation, and hypertension, as well as key interactions with benzodiazepines, lamotrigine, antipsychotics, and CYP inhibitors such as SSRIs. Next, it summarizes the efficacy and effectiveness of IV and IN ketamine, which have demonstrated mixed-to-positive antidepressant effects in a limited-to-moderate number of outcome studies in both randomized, controlled trials and real-world, open-label studies; also, comparative outcome studies have demonstrated non-inferiority to other established treatments and combination studies have shown mixed-to-positive gains when combined with those established treatments, including electroconvulsive therapy, pharmacotherapy, transcranial magnetic therapy, and psychotherapy. Finally, this review provides predictions and recommendations for future research, including the development and enhancement of novel therapeutics, identification of predictive markers to advance personalized medicine, and potential applications in the treatment of other disorders.

Authors (13)

Chris H MillerLeadDepartment of Psychology, California State University, Fresno, USA. Electronic address: chmiller@csufresno.edu.

Angela HickmanDepartment of Psychology, California State University, Fresno, USA.

Caitlin BatenDepartment of Psychology, California State University, Fresno, USA; Department of Psychological Sciences, Institute for the Brain and Cognitive Sciences, University of Connecticut, USA.

Zulaikha AliDepartment of Psychology, California State University, Fresno, USA.

Saneh K KahlonDepartment of Psychology, California State University, Fresno, USA.

Amanda M KlassenDepartment of Psychology, California State University, Fresno, USA; Department of Psychology, Brigham Young University, USA.

Gladys ZamoraDepartment of Psychology, California State University, Fresno, USA; School of Neuroscience, Virginia Polytechnic Institute and State University, USA.

Jonah H ShepherdDepartment of Psychology, California State University, Fresno, USA.

Gabrielle VenegasDepartment of Psychology, California State University, Fresno, USA.

Jennifer A MillerDepartment of Psychology, Palo Alto University, Palo Alto, CA, USA.

Ellen WooDepartment of Psychology, California State University, Fresno, USA; Department of Psychiatry, University of California, San Francisco, CA, USA.

Matthew D SacchetDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Dawson W HedgesDepartment of Psychology, Brigham Young University, USA.

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Ketamine pharmacotherapy for major depressive disorder: A narrative review.

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Authors (13)

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