Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?

Andrade opens by situating this article within a series that has previously reviewed ketamine’s efficacy, adverse effects, mechanisms, indications, and choice of enantiomer versus racemate. The present paper focuses specifically on practical treatment parameters: dose, rate of administration, route of delivery, duration of treatment, and session frequency when ketamine is used at subanesthetic doses for depression, with particular attention to treatment‑resistant depression. The introduction frames these topics as unresolved in clinical practice despite nearly two decades of research. The authors aim to synthesise available clinical reports and trials to provide guidance on these core practical issues, while recognising that much of the evidence is uncontrolled or limited and that definitive comparative trials are lacking.

The extracted text does not present a formal methods section describing a systematic search strategy, databases searched, inclusion/exclusion criteria, or dates of coverage. Throughout the article Andrade reviews and summarises published clinical trials, crossover studies, case reports, open‑label series, and a limited number of randomized controlled trials pertaining to dosing, infusion rate, routes of administration, treatment duration, and frequency. Because the paper is a narrative or qualitative review rather than a systematic review or meta‑analysis, the synthesis emphasises recurring findings across diverse study designs and highlights practical points drawn from both controlled and uncontrolled literature. The authors repeatedly note the heterogeneity of study designs and frequently limited sample sizes, and they identify where RCT evidence is absent or where trials lacked placebo controls or formal dose‑finding methodology.

Dose: Ketamine has most often been administered intravenously at 0.5 mg/kg, a convention that originated with early pioneering studies. Reported effective doses in the literature range from about 0.1 mg/kg up to 0.75 mg/kg. Some small crossover and dose‑escalation studies found individual patients responding at doses as low as 0.1 mg/kg, whereas others required higher doses. One open‑label series in 10–14 treatment‑resistant patients used 0.5 mg/kg for three sessions then 0.75 mg/kg for three further sessions and reported response rates rising from 7% after the first three infusions to 42% after six infusions, with a 17% remission rate; most responders relapsed within 2 weeks. A small double‑blind, placebo‑controlled, dose‑escalation crossover (n = 15) showed variable individual dose responses and higher adverse effects at higher doses. Singh and colleagues’ single‑dose multicentre RCT (n = 30) with S‑ketamine (0.2 mg/kg or 0.4 mg/kg) reported mean Montgomery‑Åsberg Depression Rating Scale (MADRS) score reductions of about 17 points in both active groups versus about 4 points with placebo at 1 day. Overall, the literature supports antidepressant effects across a range of subanesthetic doses but lacks adequately powered dose‑ranging RCTs to establish an optimal dose; 0.5 mg/kg remains the de facto standard. Rate of administration: The conventional IV infusion duration in many studies is 40 minutes, reflecting the protocol of early trials. Nevertheless, reported administration rates span a wide range: IV infusions as brief as 2–5 minutes, bolus IM or SC injections, and prolonged IV infusions of up to 100 minutes. Published reports do not show clear differences in efficacy or tolerability attributable to infusion duration, but no head‑to‑head trials directly compare session lengths. A small pilot RCT and anecdotal reports have also examined continuous infusions over 4–5 days; the pilot trial did not demonstrate superiority of prolonged infusion over single‑session treatment, leaving the case for extended infusions unestablished. Route of administration and bioavailability: IV administration is the most extensively studied route. Other routes with reported antidepressant effects include oral, sublingual/transmucosal, intranasal, intramuscular (IM), and subcutaneous (SC). Bioavailability estimates vary: oral bioavailability is low (reported values include about 8% for S‑ketamine and about 24% for racemic ketamine), sublingual formulations achieve roughly 24%–30%, and intranasal absorption can be near complete unless significant drug is swallowed. Parenteral routes (IV, IM, SC) are effectively complete, though a small study reported plasma ketamine concentrations about double after IV dosing compared with IM or SC administration. Clinical reports include case series and small trials showing benefit with oral daily dosing in hospice patients, sublingual low‑dose regimens with sustained improvement in some refractory cases, intranasal S‑ketamine RCTs demonstrating efficacy, and small crossover trials reporting comparable short‑term reductions in depression scores with IV, IM, and SC dosing. Duration and frequency of treatment: Single IV treatments often produce rapid, pronounced antidepressant effects in some patients, but benefits typically wane and not all patients respond to a single session. Multiple sessions can convert nonresponders to responders in some uncontrolled and small controlled studies, although dose escalation in later sessions sometimes confounds interpretation. A multicentre RCT (n = 67) comparing twice‑weekly versus thrice‑weekly 0.5 mg/kg ketamine found mean MADRS reductions of about 18 points after 15 days in both ketamine groups versus 3–6 points in placebo groups. Open and small controlled series report various schedules: alternate‑day, twice weekly, thrice weekly for short courses, and once‑weekly continuation regimens. Typical relapse intervals after a short course ranged from about 6 to 45 days (mean values around 16–19 days in some series), though individual variability was large. Continuation and maintenance treatment have been described for months to years in mainly anecdotal reports; one small study administering four once‑weekly IV sessions to five remitted patients maintained improvement during the continuation phase but only one patient remained in remission four weeks after stopping. Safety and adverse effects: Adverse effects tend to increase with higher ketamine doses. Small studies reported greater adverse effects at higher doses in dose‑escalation trials. Practical issues with different routes were noted: oral ketamine’s bitter taste, potential local irritant effects with SC injections, pain with IM injections, and intranasal tolerability if sessions are prolonged. A non‑psychiatric example from low‑resource settings showed 18% minor adverse event rate in 191 ketamine administrations by nurses, cited to contextualise risk, but the authors state that formal safety evaluation is required before broader ambulatory or domiciliary use is recommended. The risk of abuse is specifically highlighted when considering domiciliary long‑term treatment.

Andrade interprets the assembled literature as indicating that ketamine has reproducible rapid antidepressant effects across a variety of doses, infusion rates, and routes, but stresses that the evidence base is heterogeneous and often limited by small samples, lack of placebo controls, and confounding changes in dosing across sessions. The authors emphasise that 0.5 mg/kg IV over 40 minutes has become the default regimen by historical convention, yet individual response profiles and small studies suggest some patients may respond at much lower doses while others require higher doses, with higher doses carrying greater adverse effects. The discussion positions intranasal, subcutaneous, and oral routes as practically attractive and deserving of further study because they could facilitate more convenient or domiciliary care; however, the authors caution that oral bioavailability is low and that safety, efficacy, and abuse risk need thorough evaluation before recommending routine use outside monitored settings. Andrade notes that prolonged continuous infusions over several days have not convincingly demonstrated superiority in the limited data available. Key limitations acknowledged include the predominance of uncontrolled and anecdotal data, many RCTs lacking placebo arms or adequate power for dose‑finding, and the absence of definitive trials that systematically compare doses, rates, routes, session numbers, and intersession intervals. The authors therefore stop short of firm clinical recommendations and call for well‑designed RCTs to address these gaps, including studies on continuation and maintenance strategies in treatment‑resistant depression. Finally, the discussion points out that media enthusiasm has outpaced the evidence and that rigorous research is needed to guide clinical practice, while noting that ketamine’s risk profile is not inherently more alarming than that of established but high‑risk psychiatric treatments such as ECT or clozapine.