Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics

Major depressive disorder (MDD) is a leading global cause of disability with an estimated lifetime prevalence of about 17% in the United States. Existing antidepressant medications largely target monoaminergic systems, but their efficacy is limited for a substantial subgroup of patients and clinical benefit typically requires weeks to months to emerge. This delay and incomplete response in many patients create an urgent need for rapid-acting treatments with efficacy in treatment-refractory cases. Ari and colleagues present a narrative synthesis of clinical, preclinical, and biomarker research on ketamine as a prototype rapid-acting, glutamate-based antidepressant. The review summarises evidence for ketamine’s rapid antidepressant and antisuicidal effects, examines proposed neurobiological mechanisms (notably synaptic plasticity involving BDNF and mTORC1), and discusses biomarkers, safety, and the prospects for next-generation rapid-acting therapeutics for mood disorders.

The extracted text represents a narrative review rather than a systematic review; it synthesises findings from placebo-controlled clinical trials, open-label case series, preclinical (rodent) studies, and clinical biomarker investigations. The authors integrate physiological, molecular, imaging, genetic, and clinical outcome data to describe ketamine’s effects and mechanisms. The paper does not provide a methods section specifying a formal literature search strategy, inclusion or exclusion criteria, databases searched, or study selection procedures. Instead, evidence is drawn selectively from replicated controlled trials of low-dose ketamine infusions, various open-label reports of repeated dosing, preclinical mechanistic studies (electrophysiology, microdialysis, molecular signalling), and human biomarker studies using EEG, magnetoencephalography (MEG), magnetic resonance spectroscopy (1H- and 13C-MRS), and peripheral measures such as plasma BDNF. Where available, the authors note trial parameters (for example, common dosing in placebo-controlled trials) and ongoing clinical studies.

Clinical efficacy and dosing: Multiple placebo-controlled studies have replicated rapid antidepressant effects of ketamine in major depressive disorder and bipolar depression. The most commonly studied regimen was a single intravenous infusion of 0.5 mg/kg administered over 40 minutes. Antidepressant effects typically appear within about 4 hours after infusion, persist for several days (commonly 3–7 days), and in some patients last two weeks or longer. Reported response rates at 24 hours post-treatment are approximately 40–60%. The drug’s plasma redistribution half-life is about 4 minutes and the terminal plasma half-life is about 1–3 hours; the antidepressant benefit, however, emerges after the acute perceptual effects have abated. Safety and tolerability: Acute adverse effects observed during infusion include transient perceptual disturbances, dissociation, euphoria, dysphoria, anxiety, nausea, dizziness, and modest elevations in blood pressure and heart rate. These effects generally resolve within 1–2 hours after stopping the infusion. Functional unblinding due to acute side effects was a limitation of early trials; a more recent controlled trial used midazolam as an active comparator to improve blinding and still found robust ketamine effects. Long-term safety data for repeated ketamine dosing are limited; open-label series suggest that repeated low-dose infusions (often up to six sessions given once to three times weekly) can extend benefit for months, but definitive controlled long-term data were not reported in the extracted text. Alternative routes and indications: Rapid antidepressant responses have been reported following other dosing regimens and routes, including 0.2 mg/kg intravenous bolus, 50 mg intranasal, and intramuscular doses of 0.25–0.5 mg/kg. Ketamine also shows rapid reduction in suicidal ideation within hours of a single infusion; the durability and generalisability of antisuicidal effects beyond depressed populations remain to be determined. Preliminary efficacy has been reported in groups typically resistant to standard treatments, including bipolar depression and depression non-responsive to electroconvulsive therapy. Preclinical mechanisms: Rodent studies indicate that low, subanesthetic doses of ketamine trigger a cascade beginning with blockade of NMDA receptors on inhibitory GABAergic interneurons, producing presynaptic disinhibition and a prefrontal glutamate ‘‘surge.’’ This surge drives AMPA receptor activation and, together with blockade of extrasynaptic NMDA receptors, engages postsynaptic signalling pathways such as inhibition of eukaryotic elongation factor 2 (eEF2) kinase (increasing BDNF translation) and activation of mammalian target of rapamycin complex 1 (mTORC1). These events culminate in rapid synaptogenesis, increased dendritic spine density, and synaptic potentiation in prefrontal cortex circuits. The antidepressant and synaptogenic effects are dose-dependent and appear limited to subanesthetic dosing in preclinical models. NMDA receptor subtypes and localisation: The review emphasises that synaptic and extrasynaptic NMDA receptors have opposing roles; synaptic receptors (enriched in GluN2A) promote neuronal survival and synaptogenesis, whereas extrasynaptic receptors (enriched in GluN2B) promote synaptic atrophy and cell stress. This distinction supports the rationale for developing modulators that preferentially target extrasynaptic NMDA receptor signalling. Biomarkers: The authors group clinical biomarker findings into three categories: (a) markers of synaptic strength and prefrontal excitability, (b) markers of restored neurotrophic function, and (c) markers related to the ketamine-induced glutamate surge. Specific findings include: MEG studies linking pretreatment rostral anterior cingulate activity and connectivity patterns to ketamine response; EEG slow-wave changes the night after ketamine consistent with increased synaptic strength and correlating with BDNF and clinical response; and 1H-MRS and PET studies offering indirect and sometimes inconsistent evidence for changes in glutamate/glutamine cycling and regional metabolism after ketamine. Peripheral BDNF studies yielded mixed results: some small trials showed no relationship between baseline serum BDNF and response, while other, larger work reported increased plasma BDNF in responders and an association of better response with the Val/Val BDNF genotype (Val66Met functional variant). Plasma levels of ketamine and norketamine were not consistently associated with clinical response. The authors note the absence of definitive clinical data directly tying the putative glutamate surge to antidepressant efficacy, and they highlight limitations of current MRS techniques (signal overlap of glutamate/glutamine and field-strength dependence) as obstacles to a clear human demonstration.

Ari and colleagues interpret the collective evidence as demonstrating that ketamine is the prototype of a glutamate-based class of rapid-acting antidepressants that can produce clinically meaningful symptom relief within hours. They position this work against decades of monoaminergic-focused antidepressant research, arguing that ketamine’s rapid time-course and efficacy in treatment-refractory cases open a new window onto the neurobiology of depression, centred on synaptic homeostasis and prefrontal synaptic connectivity. The authors highlight convergent preclinical and biomarker data implicating BDNF and mTORC1-dependent synaptogenesis as mechanistic mediators of ketamine’s antidepressant effects. They further note that targeting the chain of events from presynaptic disinhibition and glutamate surge through AMPA activation to postsynaptic neuroplastic signalling suggests multiple potential therapeutic targets, including extrasynaptic NMDA receptor modulators, AMPA potentiators, and agents that enhance BDNF or mTORC1 signalling. Key limitations and uncertainties acknowledged include the relatively short duration of benefit after a single infusion, sparse controlled data on repeated or maintenance dosing, limited long-term safety information, and the risk of misuse given ketamine’s abuse liability and toxicity at higher or chronic doses. The problem of functional unblinding in trials and inconsistent biomarker findings (particularly regarding in vivo human measures of glutamate) are described as methodological challenges. The authors call for controlled studies to define optimal dose and route, to characterise the safety and efficacy of repeated administration or maintenance strategies, and to improve biomarker measurement (for example using higher-field 1H-MRS and 13C-MRS) to link acute glutamatergic changes to clinical outcomes. Finally, the review notes broader clinical implications that the investigators see as promising but still preliminary: ketamine’s rapid antisuicidal effects, potential benefits in PTSD, and ongoing exploration in obsessive-compulsive disorder and substance-use disorders. They advocate further research to develop safer, rapid-acting agents that harness the synaptogenic mechanisms identified with ketamine.

The authors conclude that ketamine’s well-replicated rapid antidepressant effects demonstrate the feasibility and therapeutic potential of targeting the glutamatergic system to achieve fast relief from depressive symptoms and suicidality. While a single low-dose infusion appears efficacious and generally well tolerated in the short term, long-term safety, optimal dosing strategies, and maintenance approaches remain unresolved. Ketamine research has, in their view, provided new mechanistic insights—particularly the role of BDNF and mTORC1-driven synaptogenesis—that may guide the development of next-generation rapid-acting antidepressants that are safer and more suitable for routine clinical use.