Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature

Introduction

Grady and colleagues situate ketamine in its clinical and pharmacological context, noting its origins from phencyclidine in the 1960s and long-standing uses as an anaesthetic and analgesic with dissociative effects. The introduction summarises the proposed mechanisms relevant to mood disorders: noncompetitive antagonism of N-methyl-D-aspartate (NMDA) glutamatergic receptors, potential interactions with norepinephrine and serotonin transporters, and active metabolites such as norketamine. Practical pharmacokinetic points highlighted include poor oral bioavailability (17% to 20%), predominant use of intravenous (IV) administration for depression, a short plasma half-life (1–3 hours), and hepatic metabolism via CYP3A4, 2B6, and 2C9. This review sets out to summarise and critique randomised controlled-trial evidence for ketamine in major depressive disorder (MDD) and bipolar depression, focusing on trials that used an IV dose of 0.5 mg/kg or an intranasal 50 mg formulation. The authors position their work as a synthesis of the small but growing randomised literature that began with early crossover trials (for example a first double-blind, placebo-controlled crossover trial using 0.5 mg/kg IV over 40 minutes) and has since expanded to include active-placebo controlled and intranasal studies. The review aims to clarify efficacy, onset and durability of antidepressant effects, and safety considerations in treatment-resistant populations.