Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability

Treatment-resistant depression presents clinicians with a challenging therapeutic landscape, and ketamine — a non-competitive NMDA receptor antagonist with established rapid antidepressant properties — has emerged as a candidate for longer-term maintenance treatment in patients who achieve an initial response. Unlike single-dose infusion protocols, maintenance ketamine therapy involves repeated administration over weeks to months, raising distinct questions about sustained efficacy, tolerability, potential for dependence, and optimal scheduling that are not fully addressed by the acute infusion literature. This systematic review sought to comprehensively evaluate the clinical evidence base for maintenance ketamine treatment in depression, synthesising data across multiple routes of administration, dosing schedules, and study designs.

A PRISMA-compliant systematic review was prospectively registered with PROSPERO (CRD42021253253). Searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials, with coverage up to March 2021. Eligible studies were required to report clinical outcomes following repeated or maintenance-phase ketamine or esketamine administration in patients with depression; risk-of-bias assessment was applied to all included studies. A total of 45 studies were identified — comprising three randomised controlled trials, eight open-label trials, and thirty case series — representing 1,495 patients. Three primary routes of administration were covered: intravenous (18 studies, 222 patients), oral (11 studies, 199 patients), and intranasal esketamine (8 studies, 997 patients), with intramuscular and subcutaneous formulations represented in smaller sub-sets.

Across the included studies, the majority of patients who responded to initial ketamine treatment maintained antidepressant benefit under ongoing maintenance dosing regimens. Intravenous ketamine showed robust sustained response rates in treatment-resistant populations; oral formulations offered flexibility with variable bioavailability; intranasal esketamine, the FDA-approved maintenance formulation, provided the largest dataset and the most structured long-term tolerability data. Serious adverse events were uncommon across all routes. Transient dissociative symptoms, nausea, and blood pressure changes were the most frequently reported side effects and were generally mild, self-limiting, and manageable in clinical settings. No systematic evidence of progressive cognitive impairment or bladder toxicity — adverse effects associated with recreational high-dose ketamine use — emerged in the maintenance clinical literature, though monitoring protocols were inconsistent across studies.

The review highlights that whilst maintenance ketamine is increasingly used in specialist clinical practice, the evidence base remains predominantly observational and heterogeneous. The absence of large randomised controlled trials examining maintenance schedules, the variability in dosing protocols, and the inconsistency of outcome measures across studies limit the strength of generalisable conclusions. The authors emphasise the need for standardised maintenance protocols, prospective long-term safety monitoring, and randomised discontinuation designs to properly characterise the risk-benefit profile of extended ketamine treatment. Whether maintenance therapy addresses underlying pathophysiology or primarily suppresses symptoms — and whether repeated NMDA blockade leads to receptor adaptation over time — is identified as a fundamental unresolved question. The relative merits of different administration routes for maintenance purposes are discussed, with intravenous and intranasal formulations offering distinct trade-offs between efficacy, patient convenience, and monitoring requirements.

This systematic review provides a comprehensive synthesis of the available evidence for maintenance ketamine treatment in depression across routes of administration, demonstrating a generally encouraging safety and efficacy profile in clinical populations. Critical gaps in the evidence base — particularly the scarcity of randomised controlled trial data on maintenance scheduling and long-term safety — are identified, and the authors make a case for rigorously designed prospective trials to establish evidence-based protocols for the sustained use of ketamine in treatment-resistant depression.