Ketamine Infusion Therapy: An Evidence Brief for Referring Clinicians

A concise summary of the current evidence base for IV ketamine in treatment-resistant depression and related conditions, for primary care and behavioral-health colleagues considering referral.

For patients with treatment-resistant depression (TRD) — roughly a third of the depressed population — rapid-acting glutamatergic agents have reshaped the treatment landscape. This brief summarizes what the recent literature says about subanesthetic IV ketamine, so you can counsel patients and calibrate referrals. Studies referenced here were identified via PubMed; DOIs are linked at the end.

Mechanism and rationale

Unlike monoaminergic antidepressants, ketamine acts primarily through NMDA-receptor antagonism and downstream AMPA-mediated glutamatergic signaling, driving rapid synaptogenesis and neuroplasticity. Clinically, this translates to antidepressant effects within hours to days rather than weeks — a meaningful distinction for acutely symptomatic or high-risk patients. Standard dosing in trials is 0.5 mg/kg IV over ~40 minutes, typically delivered as an acute series (e.g., twice weekly) followed by individualized maintenance.

Efficacy in treatment-resistant depression

The comparative evidence is now substantial. A 2024 network meta-analysis of 69 RCTs (10,285 participants) identified ketamine among the small set of interventions clearly superior to placebo/sham for TRD, alongside ECT, rTMS, theta-burst stimulation, and aripiprazole. A separate 2024 network meta-analysis of 72 RCTs (12,105 participants) positioned ketamine and esketamine among preferred first-line augmentation strategies, weighing efficacy against tolerability.

IV ketamine infusions vs. intranasal esketamine

A 2025 systematic review and meta-analysis of head-to-head studies found comparable acute response (OR 1.26, 95% CI 0.92–1.71) and remission (OR 1.31, 95% CI 0.93–1.86) between IV ketamine and esketamine, with negligible heterogeneity; IV ketamine may act somewhat faster. The authors caution that the evidence is almost entirely observational and that adequately powered head-to-head RCTs are still needed. Practically, esketamine (Spravato) carries FDA approval — including, as of January 2025, a monotherapy indication for TRD — while IV ketamine remains an evidence-based off-label option often chosen for cost, flexibility, or route.

Comparison with ECT

The 2023 ELEKT-D trial (NEJM; n=403, predominantly outpatients) demonstrated non-inferiority of IV ketamine to ECT for non-psychotic TRD, with fewer subjective memory complaints in the ketamine arm. A 2025 meta-analysis of six comparative studies (676 patients) found no significant differences in response, remission, relapse, or adverse events between ketamine and ECT. For appropriate outpatients, ketamine is a reasonable, less burdensome alternative; ECT retains advantages in psychotic or emergently severe presentations.

Beyond unipolar depression

Signals extend to bipolar depression and to non-mood indications, though the evidence is thinner. A 2025 open-label maintenance study reported sustained benefit and good tolerability for treatment-resistant depression, PTSD, and OCD. Ketamine-assisted psychotherapy is also under active study: a 2025 RCT (Montreal model) found large and durable reductions in depression, anxiety, and suicidality in severe, highly comorbid TRD, with mystical-type experiences correlating with response. These are best framed to patients as emerging rather than established indications.

Predicting who responds

Patient selection remains largely clinical. A 2026 systematic review (122 studies, ~12,700 patients) examined 77 candidate predictors and found that most demographic and clinical variables did not reliably differentiate response. Early response to treatment and a family history of substance use disorder emerged as tentative positive signals warranting further study. The practical takeaway: there is no validated biomarker or profile to pre-select responders, so a monitored therapeutic trial with structured outcome tracking (e.g., PHQ-9/MADRS) is the pragmatic approach.

When to consider referral for ketamine infusions

• Major depressive disorder with inadequate response to ≥2 adequate antidepressant trials

• Depression with prominent, distressing suicidality where rapid symptom reduction is a priority (with appropriate safety planning)

• Patients seeking an alternative to ECT, or who cannot tolerate or decline it

• Bipolar depression, PTSD, or OCD refractory to standard care — as part of a shared, informed-consent discussion about emerging evidence

Reasonable pre-referral cautions include uncontrolled hypertension or unstable cardiovascular disease, active psychosis, current substance use disorder involving ketamine, and pregnancy. A clinician-led program will re-screen and monitor for these.

What to tell patients

Set expectations that ketamine is rapid but not permanent: an acute series establishes response, and maintenance sustains it. Effects during infusion (dissociation, transient hemodynamic changes, nausea) are expected and monitored. Bladder toxicity and dependence concerns derive chiefly from high-dose unsupervised use and are mitigated by controlled, in-clinic dosing. Framing ketamine as one tool within a broader treatment plan — alongside

psychotherapy and ongoing psychiatric care tend to serve patients best.

Refound Center provides clinician-led IV ketamine infusion therapy in North Denver and the Front Range. We offer supportive treatment plans with creative integrations and psychotherapeutic coaching, as well as welcome referrals and collaborative care, and are happy to coordinate on shared patients. Contact us to discuss a specific case or our screening and monitoring protocols.

Medical disclaimer

This article is for general educational purposes only and is not medical advice, diagnosis, or treatment. Ketamine therapy is not appropriate for everyone. Talk with a qualified clinician about your individual history, medications, and goals before starting any treatment. If you are in crisis or thinking about harming yourself, call or text 988 (the Suicide & Crisis Lifeline) in the U.S.

Sources & further reading (studies identified via PubMed):

Saelens J, et al. Relative effectiveness of antidepressant treatments in treatment-resistant depression: systematic review and network meta-analysis of RCTs. Neuropsychopharmacology, 2024. https://doi.org/10.1038/s41386-024-02044-5

Guo Q, et al. Efficacy and safety of eight enhanced therapies for treatment-resistant depression: a network meta-analysis of RCTs. Psychiatry Research, 2024. https://doi.org/10.1016/j.psychres.2024.116018

Elmosalamy A, et al. Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Ther Adv Psychopharmacol, 2025. https://doi.org/10.1177/20451253251394127

Anand A, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression (ELEKT-D). New England Journal of Medicine, 2023. https://doi.org/10.1056/NEJMoa2302399

Song G, Ugwah-Oguejiofor UC. Ketamine compared to ECT for treatment-resistant depression: systematic review and meta-analysis. Int J Psychiatry Clin Pract, 2025. https://doi.org/10.1080/13651501.2025.2576205

Beaglehole B, et al. Six weeks open-label oral ketamine for treatment-resistant depression, PTSD, or OCD. Journal of Psychopharmacology, 2025. https://doi.org/10.1177/02698811251344710

Greenway KT, et al. The Music for Subanesthetic Infusions of Ketamine RCT: ketamine as a psychedelic treatment for highly refractory depression. British Journal of Psychiatry, 2025. https://doi.org/10.1192/bjp.2025.102

Syed OA, et al. Clinical predictors of antidepressant effects of ketamine and esketamine in treatment-resistant depression: a systematic review. CNS Drugs, 2026. https://doi.org/10.1007/s40263-026-01296-7

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