A consensus statement on the use of ketamine in the treatment of mood disorders

Sanacora and colleagues situate this consensus statement in the context of accumulating, mostly small studies reporting that ketamine hydrochloride can produce rapid and robust antidepressant effects in patients with treatment-resistant mood and anxiety disorders. Earlier randomized, placebo-controlled trials (seven such trials comprising 147 treated patients) and multiple case series have generated substantial clinical and public interest, but the authors note important uncertainties: small sample sizes, short durations of follow-up, limited safety data for psychiatric use, no US Food and Drug Administration approval for psychiatric indications, and no postmarketing surveillance for ketamine used in psychiatry. This report from the American Psychiatric Association Council of Research Task Force Subgroup on Treatment Recommendations for Clinical Use of Ketamine aims to provide an overview and expert clinical opinion about off-label ketamine use for mood disorders. It is intended to complement an existing APA meta-analysis and other reviews by highlighting critical issues clinicians should consider when contemplating ketamine treatment for major depressive episodes, rather than to serve as a formal guideline, policy, or standard of care.

The document is a narrative consensus statement and clinical review produced by an APA task-force subgroup; the extracted text does not present a formal systematic review protocol, search strategy, or explicit methods for literature selection. Sanacora and colleagues draw on published randomized trials, meta-analyses, case series, and clinical reports to formulate practical suggestions for patient selection, clinical setting, dosing, monitoring, and follow-up. Several supplemental items (an eTable, eBox items, and a Table) are referenced but not fully reproduced in the extracted text. Recommendations are framed around the typical antidepressant ketamine regimen used in most trials (0.5 mg/kg administered intravenously over 40 minutes) and on available safety and efficacy reports. Where evidence is limited or heterogeneous the authors explicitly note uncertainty and recommend conservative clinical practice (for example, supervised administration, thorough pretreatment assessment, and limiting frequency of administration). The statement emphasises that its suggestions are advisory, not mandatory, and that precise credentialing, monitoring, and operational procedures should be adapted to local standards of practice.

Key evidence and practical recommendations presented in the statement are summarised across domains. Efficacy: The review reiterates that randomized, placebo-controlled trials indicate rapid antidepressant effects of ketamine, but that most trials assessed outcomes only over the first week after a single infusion. A pooled body of seven placebo-controlled trials included approximately 147 treated patients. The authors highlight one randomized trial of 68 patients with treatment-resistant major depressive disorder that compared ketamine, 0.5 mg/kg over 40 minutes IV, given either twice-weekly or three-times-weekly for up to 2 weeks versus saline placebo. Mean change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores were large for ketamine versus placebo (for twice-weekly ketamine: mean change −18.4 [SD 12.0] v −5.7 [10.2] for placebo; for thrice-weekly ketamine: −17.7 [7.3] v −3.1 [5.7] for placebo). After 2 weeks, response rates for the twice-weekly ketamine arm were 69% with remission in 37.5% (placebo 15% response, 7.7% remission); for three-times-weekly the response was 53.8% with 23.1% remission (placebo 6% response, 0% remission). In an open-label extension to 4 weeks among subsets who continued their assigned frequency, reductions in MADRS remained large. The authors conclude that, on limited evidence, twice-weekly dosing appears at least as efficacious as three-times-weekly dosing for up to 4 weeks. Dosing and routes: Most clinical trials used the standard ketamine dose of 0.5 mg/kg IV over 40 minutes. A meta-analysis cited compared this standard dose (6 trials) with very low doses or alternative delivery (3 trials) and suggested superior efficacy of the standard dose, but heterogeneity across trials and small participant numbers limited firm conclusions. The authors note emerging but inconclusive reports of benefit with alternative doses, infusion rates, or routes, and recommend that any deviations from the standard regimen be disclosed during informed consent and accompanied by appropriate precautions. They raise the possibility of dosing adjustments for patients with high body mass index but point out very limited supporting data. Safety and adverse events: Published safety data in the extracted text include reports of 833 ketamine infusions in healthy individuals with peak plasma concentrations similar to the antidepressant regimen; three individuals transiently became non-responsive to verbal stimuli but required no respiratory support. In a study of 84 otherwise healthy patients with depression receiving 205 infusions, no persistent medical complications or significant oxygen desaturation were reported. Transient mean (SD) peak increases in blood pressure were observed during infusions (systolic +19.6 [12.8] mm Hg; diastolic +13.4 [9.8] mm Hg), and roughly 30% of patients had blood pressure exceed 180/100 mm Hg or heart rate exceed 110 beats per minute during treatment. A single serious cardiovascular-related event occurred, representing 0.49% of infusions in that series and was attributed to a vasovagal episode. The authors conclude that the typical antidepressant dose does not generally compromise respiratory function in medically healthy patients but can cause meaningful cardiovascular and transient behavioural or dissociative effects in some patients. Clinical delivery, setting and training: The statement recommends that ketamine be administered in a clinical setting equipped to monitor basic cardiovascular (blood pressure, electrocardiogram) and respiratory (oxygen saturation or end-tidal CO2) parameters and to provide immediate stabilisation if needed, including oxygen delivery, necessary medications, and transfer plans to hospital care for sustained cardiovascular events. They advise that a licensed clinician authorised to prescribe a Schedule III medication (typically an MD or DO) with Advanced Cardiac Life Support certification administer or supervise treatment, and that clinicians be prepared to manage transient dissociation or psychotomimetic effects and assess behavioural risk before discharge. Site-specific standard operating procedures are recommended, covering pretreatment confirmation of informed consent and baseline vitals, a ‘‘time-out’’ verification, ongoing assessments during infusion (respiratory status, cardiovascular function, level of consciousness such as the Modified Observer’s Assessment of Alertness/Sedation Scale), defined stopping criteria, and immediate post-treatment evaluation including return to baseline physiological and mental status and ensuring a responsible adult to escort the patient home. Repeated and longer-term administration: Evidence on repeated dosing is limited. Most studies examine under 1 month of treatment; small case series and a few randomized trials provide suggestive but not definitive guidance. The authors note that the largest treatment effects typically occur early, with some reports of cumulative benefit from continued treatment and rare reports of response after more than three infusions. There are extremely limited published data on longer-term effectiveness and safety; many clinics empirically use 2–3 week induction courses followed by tapering or individualized maintenance, but the authors stress lack of published support for these regimens. They recommend limiting the number and frequency of treatments to the minimum necessary, avoiding frequent dosing, and advising against at-home self-administration. Safety monitoring for prolonged exposure: Because of concerns extrapolated from nonmedical chronic ketamine use—cognitive impairment, cystitis, and substance-use liability—the statement recommends periodic assessment of cognitive function, urinary symptoms, and substance use when repeated administrations are provided. Clinicians should monitor for signs of ketamine use disorder, employ intermittent urine toxicology if suspicion arises, and guard against patients seeking additional uncontrolled dosing at other centres. The authors suggest discontinuation if dosing cannot be spaced to at least one dose per week by the second month of treatment.

Sanacora and colleagues interpret the current evidence as indicative of ketamine’s potential to produce rapid, robust but transient antidepressant effects in some patients with treatment-resistant mood disorders, while emphasising important unanswered questions about durability and long-term safety. They position their recommendations as practical, conservative measures intended to improve patient safety and support evidence-based clinical decision making in the face of limited and heterogeneous data. The authors stress that enthusiasm for ketamine should be balanced with caution because of small sample sizes in existing trials, short follow-up periods, absence of large-scale Phase III pivotal trials for racemic ketamine in psychiatry, no FDA-approved psychiatric indication, and lack of postmarketing surveillance data for psychiatric use. They note that economic and market considerations make it unlikely that large-scale trials of racemic ketamine will be completed, increasing the importance of federally or foundation-funded research and clinician participation in those trials. Key limitations acknowledged include the narrative, non-systematic nature of the review (the extracted text does not report a formal systematic search or risk-of-bias assessment), heterogeneity across studies in dose and delivery, and the scarcity of long-term safety and efficacy data. The authors therefore recommend conservative clinical practices: careful patient selection, thorough pre-treatment evaluation and informed consent, treatment in monitored clinical settings by appropriately credentialled clinicians, standardised delivery procedures, close follow-up, avoidance of unsupervised or at-home dosing, and limiting frequency and duration of exposure until more data accumulate. For future research and clinical practice, the statement recommends prioritising enrolment of patients in standardised clinical trials and developing coordinated registries to collect real-world data on efficacy, safety, and rare adverse events. The authors argue that such efforts are essential to answer critical questions about optimal dosing schedules, long-term outcomes, and the balance of benefit and risk when ketamine is used to treat mood disorders.

The suggestions in this consensus statement are intended to facilitate clinical decision making and encourage an evidence-based, safety-oriented approach to off-label ketamine treatment for psychiatric disorders given the limited information available. The report supplies practical considerations related to patient selection, clinician training, treatment setting, dosing, monitoring, and follow-up that should be considered to help ensure patient safety, while noting that these are advisory recommendations and not formal policy of the American Psychiatric Association.