Ketamine: A Paradigm Shift for Depression Research and Treatment

The authors recount the clinical discovery and subsequent replication literature demonstrating rapid antidepressant effects after a single subanaesthetic intravenous infusion of ketamine (most commonly 0.5 mg/kg over 40 minutes). Antidepressant effects typically begin within hours, peak at 24–72 hours, and, when not repeated, generally dissipate within about two weeks. Clinically meaningful benefits have been observed in treatment-resistant populations, including patients with bipolar disorder. From single-dose administrations, the paper reports approximately one third of patients with treatment-resistant symptoms achieve remission, and about 50%–75% demonstrate a clinical response; repeated administrations yield higher response and remission rates. Ketamine also reduces suicidal ideation. Dose–response features are emphasised as steep and variable across patients. Doses around 0.2 mg/kg are reported as subtherapeutic, 0.5 mg/kg is commonly effective and produces dissociative effects, and increasing the dose to 1.0 mg/kg does not reliably augment the rapid antidepressant response. One study is noted to have reported positive effects with 0.1 mg/kg. Acute dissociative or euphoric effects appear temporally dissociated from the antidepressant benefit, suggesting the latter is not simply intoxication; however, dissociation may indicate adequate target engagement for some patients. On maintenance and service delivery, typical induction regimens start at about twice weekly, with frequency tapered individually; in one clinic up to 40% of patients were maintained at monthly or less frequent infusions. Esketamine data and growing long-term safety/efficacy evidence support using ketamine or related agents as longer-term treatments in some patients, and the rapidity of onset raises the prospect of use in urgent settings (for example Emergency Departments) to manage acute suicide risk. The review summarises convergent mechanistic evidence from human and animal studies. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist; by blocking GluN2B-containing NMDA receptors ketamine may reduce eukaryotic elongation factor-2 (eEF2) phosphorylation, thereby increasing brain-derived neurotrophic factor (BDNF) and promoting AMPA receptor insertion at synapses. An additional, indirect mechanism is blockade of NMDA receptors on GABAergic interneurons, producing disinhibition of glutamate release and increased AMPA receptor stimulation. AMPA activation then promotes BDNF release, TrkB receptor stimulation, mTORC1 activation and local protein synthesis, leading to rapid proliferation of dendritic spines and restored synaptic connectivity. These synaptic changes have temporal correspondence with antidepressant effects in animals and are paralleled by restoration of functional connectivity on fMRI in depressed patients. Behaviourally relevant plasticity is suggested by enhanced fear extinction seen 24 hours after ketamine in animals, and preliminary human data indicate cognitive behavioural therapy may extend ketamine's benefit. The authors also note other plausible contributors to efficacy, including anti-inflammatory and epigenetic actions, effects at non-NMDA sites, and activity of ketamine isomers and metabolites ((S)- and (R)-ketamine, (S)-norketamine and (2R,6R)-hydroxynorketamine). Early evidence that GluN2B-preferring antagonists can produce antidepressant effects is mentioned. Finally, the paper outlines drug-development implications: agents that increase glutamate release or potentiate AMPA receptors, or that selectively target downstream effectors (BDNF/TrkB, mTORC1), might capture ketamine-like efficacy with improved tolerability. Safety and logistical considerations are highlighted, including abuse liability and acute dissociative effects, which currently favour administration in supervised clinical settings; alternative delivery models such as nurse-administered home treatment are proposed for exploration.

Abdallah and colleagues interpret the accumulated evidence as a paradigm shift: ketamine demonstrates that rapid, robust antidepressant effects are possible and that antidepressant mechanisms extend beyond monoamine modulation to involve synaptic plasticity and circuit-level restoration. They position ketamine both as a clinical tool — particularly for treatment-resistant depression and acute suicidality — and as a prototype that has stimulated a new generation of translational neuroscience aimed at developing mechanistically informed treatments. The authors caution that many mechanistic questions remain unresolved. It is not yet clear which of ketamine's molecular actions are essential for clinical efficacy, whether different isomers or metabolites have distinct or complementary mechanisms, or how best to balance efficacy with tolerability. Variability in patient sensitivity, steep dose–response characteristics, and limited comparative effectiveness data on long-term dosing schedules are noted as important uncertainties. The paper also stresses the need to manage safety concerns, including abuse potential and acute dissociation, typically by restricting administration to clinical settings. Looking ahead, the authors suggest combining ketamine with psychotherapies or other interventions could extend or enhance benefits, and that selectively targeting elements of ketamine's downstream cascade could produce new classes of antidepressants. They further propose that transformative treatments like ketamine may reduce stigma and alter societal perceptions of depression, though they underscore the necessity of cautious, evidence-based progress. The overall tone balances enthusiasm for ketamine's clinical and scientific implications with emphasis on remaining empirical gaps and the need for further research.