Ketamine as a promising prototype for a new generation of rapid-acting antidepressants

Abdallah and colleagues frame the problem by noting that depressive disorders remain a leading cause of disability worldwide and that, despite more than five decades of antidepressant development, available medications mostly target monoaminergic systems and produce limited and slow clinical benefit for many patients. Previous large-scale clinical work has shown that fewer than one-third of depressed patients achieve remission within 12 weeks on traditional antidepressant regimens, and a substantial minority remain refractory despite multiple medication trials. This context motivates the search for novel, rapid-acting treatments. The review sets out to synthesise clinical and mechanistic evidence about ketamine as a prototype for a new generation of rapid-acting antidepressants. Specifically, the authors summarise controlled and open-label clinical trials of ketamine for depression (including treatment-resistant groups), examine preliminary data in posttraumatic stress disorder (PTSD) and cognitive outcomes, outline proposed neurobiological mechanisms and candidate clinical biomarkers, and identify knowledge gaps and priorities for future research and clinical translation.

The extracted text indicates this article is a narrative review that integrates findings from controlled trials, open-label investigations, case reports/series, and meta-analyses rather than reporting a new primary clinical trial. The authors reference multiple controlled trials, open-label studies, and three published meta-analyses that evaluate ketamine's antidepressant effects, but the extracted text does not provide a specific literature search strategy, inclusion/exclusion criteria, databases searched, or systematic review methods. Rather than detailing systematic methods, the review organises evidence around clinical efficacy (including rapidity and durability of response), studies in comorbid conditions such as PTSD, effects on neurocognitive functioning, safety and tolerability data, mechanistic research (molecular and circuit-level), and candidate clinical biomarkers. The text also refers to tables and figures summarising selected trials, dosing regimens, and pharmacokinetic information, but those items are not fully reproduced in the extracted text.

Clinical efficacy: Across controlled and open-label studies, ketamine produces rapid antidepressant effects that are evident within 2–4 hours, typically peak around 24 hours, and commonly persist for about 3–7 days after a single subanaesthetic infusion. Reported response rates vary across studies, with approximately 25%–85% responding within 24 hours and 14%–70% at 72 hours post-infusion. Early trials most often used 0.5 mg/kg administered intravenously over ~40 minutes in medication-free participants. Repeated intravenous dosing has been reported to prolong clinical benefit, and several alternative routes (intramuscular, intranasal, intrarectal, oral) have been explored. The authors note bioavailability estimates for non-intravenous routes: intramuscular ~93% bioavailability, intranasal ~50%, intrarectal ~25%, and oral ~20%. Meta-analyses and blinding issues: Three meta-analyses consistently found ketamine superior to comparators (saline or active comparator such as midazolam) for reducing depressive symptoms and increasing remission across unipolar and bipolar depression, in treatment-resistant and non-resistant samples, and in medicated or unmedicated participants. The literature also highlights important methodological limitations, notably short trial durations, transient efficacy after a single infusion, and challenges with adequate blinding because acute psychotomimetic and dissociative effects of ketamine can functionally unblind treatment — an issue partially addressed in a two-site trial using midazolam as an active comparator. PTSD: Preliminary clinical evidence suggests ketamine may reduce PTSD symptoms. Case reports and small series documented rapid symptomatic improvements without worsening of trauma-related symptoms. A double-blind crossover pilot by Feder and colleagues compared a single 0.5 mg/kg infusion of ketamine with midazolam and found significant improvement in PTSD symptoms 24 hours after ketamine; dissociative symptoms peaked around 40 minutes and resolved within about 80 minutes. Neurocognitive outcomes: Ketamine is associated with transient cognitive impairments during infusion. Evidence for post‑treatment pro-cognitive effects is limited and mixed: one randomized trial reported no differential cognitive effect versus midazolam at 24 hours but found that lower baseline processing speed predicted greater antidepressant response at 24 hours; another small study in bipolar depression reported improved cognitive performance around 72 hours post-infusion independent of mood improvement. Both investigations had small samples and lacked long-term cognitive follow-up. Safety and tolerability: Across studies, single subanaesthetic ketamine doses have been generally well tolerated. Acute side effects within the first 2 hours include transient perceptual disturbances, dissociation, dysphoria or euphoria, anxiety, dizziness, nausea, and modest increases in blood pressure and heart rate; these typically abate within minutes to a couple of hours after stopping the infusion. Chronic high-dose use is linked to ulcerative cystitis in other settings, but such effects are not commonly reported in psychiatric dosing paradigms. Case reports and small series suggest that repeated infusions (up to six given once to three times per week in some protocols) can be administered safely and may extend antidepressant benefit, but the long-term safety and addiction potential of repeated or chronic treatment remain uncertain. Mechanisms: The authors collate preclinical and clinical evidence implicating synaptic plasticity in depression and in ketamine’s rapid effects. Sustained stress and depression cause synaptic atrophy, particularly in the prefrontal cortex, associated with reduced BDNF and inhibited mTOR signalling. Ketamine at low, subanaesthetic doses appears to provoke a paradoxical glutamate surge — hypothesised to arise from preferential blockade of NMDA receptors on GABAergic interneurons, producing disinhibition of glutamatergic neurons — which then stimulates AMPA receptors, activates mTOR signalling, increases BDNF function, and promotes synaptogenesis. The authors describe these converging processes as involving a ‘‘stop’’ pathway (at-rest NMDA inhibition leading to increased BDNF via eEF2 disinhibition) and a ‘‘go’’ pathway (disinhibition → glutamate surge → AMPA activation → mTOR-driven synapse formation). Candidate biomarkers: Biomarker studies cluster around measures of prefrontal excitability/synaptic strength and BDNF signalling. Enhanced clinical response has been associated with (1) higher pre-treatment medial prefrontal cortex (mPFC) activity to fearful faces, (2) lower pre-treatment mPFC activity during working memory tasks, (3) lower mPFC–amygdala connectivity, (4) post-treatment increases in synaptic strength, and (5) lower pre-treatment mPFC (glutamate + glutamine)/glutamate ratio (with some inconsistencies). Earlier peripheral BDNF studies were negative, but more recent work finds associations between increased BDNF and clinical response; a functional BDNF variant (Val66Met) has also been linked to response in one study.

Abdallah and colleagues interpret ketamine as a proof-of-concept treatment that both demonstrates the feasibility of rapid clinical improvement in complex mood states and points to the glutamatergic system as a viable novel target for antidepressant development. They stress that ketamine’s rapid and sometimes robust effects, including reductions in suicidal ideation and benefits in populations poorly served by monoaminergic agents (for example, treatment-resistant cases, bipolar depression, and anxious depression), have opened new avenues for understanding depression’s neurobiology and identifying treatment-relevant biomarkers. The authors position these findings within earlier research by noting convergent preclinical data linking synaptic plasticity, BDNF, and mTOR signalling to antidepressant-like effects, and by highlighting meta-analytic confirmation of ketamine’s superiority over comparators. At the same time, they emphasise important limitations repeatedly identified in the literature: short trial durations, transient benefit after single infusions, incomplete blinding because of acute ketamine effects, heterogeneous dosing/routes, and sparse long-term safety data. Concerns about abuse liability, potential excitotoxicity, and the unknown threshold at which repeated administration becomes harmful are explicitly acknowledged. In terms of implications, the authors argue for continued preclinical and clinical research to define optimal dosing, preferred routes of administration, maintenance regimens to sustain benefit, and the long-term safety profile of repeated treatment. They also recommend further investigation of ketamine’s cognitive effects and its anti-suicidal properties in broader populations. Finally, the review highlights ongoing efforts to develop next-generation NMDA-receptor modulators that might replicate ketamine’s rapid antidepressant mechanism while reducing adverse effects and addiction potential.

The authors conclude that ketamine has established itself as a promising prototype for rapid-acting antidepressants and that its discovery has both therapeutic and conceptual significance: it demonstrates that rapid improvement in depression, PTSD, and suicidal symptoms is achievable and validates targeting glutamatergic mechanisms. Nonetheless, ketamine remains largely investigational in psychiatric practice because of unresolved questions about optimal dosing and route, risks associated with repeated or chronic use, and potential for abuse. The authors call for continued research to develop safer agents that preserve ketamine’s rapid efficacy and to answer key clinical questions about maintenance strategies, cognitive effects, generalisability of anti-suicidal effects, and combined psychosocial interventions such as cognitive behavioural therapy.