A 2019 review of reviews, meta-analyses, and randomized controlled trials (not included in the other reviewed literature) found that low-dose intravenous ketamine provides a rapid antidepressant effect at 24 hours. Validated depression rating scales showed that administration of ketamine changed scores in as little as 40 mins with effects lasting at least 1-2 weeks. Still, there is limited and inconsistent data for ketamine having efficacy in depressive patients after 2 weeks. Remission symptoms have been observed at 80 mins, 1 day, and up to 2 weeks. Two studies showed a reduction of suicidal thoughts after 1-2 days after a single dose of ketamine, but this effect was not seen after 3 weeks in a third study. Studied doses of ketamine included 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg. Most infusion times reported were over 40 minutes, with one study delivering six 0.5 mg/kg infusions over 45 mins thrice weekly for three weeks (no efficacy was observed in this study). [1], [2], [3]
Ketamine as an antidepressant was shown to be well tolerated and adverse events usually occurred with very high doses administered over an extended period of time. Some of the most common adverse events were dizziness, dissociation, nausea, headaches, vertigo, and dysgeusia which usually resolve spontaneously. No long-term psychotomimetic side effects have been reported in any o the studies, but one isolated case of suicide attempt was reported in one study. The dose, mode of administration, and long-term effects of ketamine need to be further explored to optimize its antidepressant effects. [1], [2], [3]
A 2020 meta-analysis evaluated the effects of intravenous (IV) ketamine infusion in patients with treatment-resistant depression (TRD) using data from 19 studies (7 randomized controlled trials and 12 open-label trials; N= 818). All included studies utilized a single dose of IV ketamine infusion of 0.5 mg/kg, with outcomes measured up to 7 days post-infusion. The overall effects of ketamine were noted as early as 4 hours, peaked at 24 hours, but gradually diminished from days 2 to 7. Subgroup analysis of depression scores in patients receiving ketamine compared to placebo demonstrated a standard mean difference (SMD) of 0.77 (95% CI 0.46 to 1.08) at 24 hours and 0.49 (95% 0.20 to 0.78) at 7 days. Overall, IV ketamine was associated with a significantly improved SMD in depression scores (0.68; 95% 0.46 to 0.90). Similarly, better clinical response and clinical remission were also observed in ketamine recipients. Though a quantitative analysis was not performed for multiple versus single ketamine infusions, results demonstrated that multiple infusions (0.5 mg/kg, 3 times/week over 2 weeks) led to enhanced effectiveness and delayed clinical relapse. This was also observed when ketamine was used in a maintenance schedule with patients who responded to the initial treatment. However, long-term data are still required to investigate the safety and efficacy of ketamine in patients presenting with resistant symptoms. [5]
An international group of mood disorder experts provided a synthesis of the literature regarding the safety, efficacy, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. It was recommended to start the administration of IV ketamine at a dose of 0.5 mg/kg with an infusion time of 40 minutes. While the efficacy at lower doses (0.1-0.2 mg/kg) may be inferior, doses may be lowered in cases of intolerability. The upper dosing limit for ketamine infusions in this patient population is not established, but studies show no evidence of superiority of 1 mg/kg over 0.5 mg/kg. The panel recommended the utilization of ideal body weight in patients who are overweight or obese, as this patient population may show a higher response rate to ketamine. A follow-up assessment should be conducted after completing four to six IV infusions to determine the intervention's overall efficacy. If the individual presented with a minimal response (i.e., ≤20% improvement from baseline in total depression symptom severity) after four to six infusions, that individual would be considered non-responsive and further infusions would not be warranted. There is insufficient data regarding the dosing and frequency of the administration of IV ketamine as a maintenance treatment, but studies have also shown no difference in efficacy between twice-weekly and thrice-weekly 0.5 mg/kg infusions over 40 minutes. It was suggested that practitioners perform periodic evaluations of the need for ongoing treatment on a monthly to bi-monthly basis. [4]
A proof-of-concept study published in 2021 evaluated prolonged ketamine infusions for treatment-resistant depression in 27 adults. Eligible participants were admitted for 5 days to receive a continuous 96-hour infusion of ketamine, started at 0.15 mg/kg/hour and titrated twice daily (as tolerated) to a target rate of 0.6 mg/kg/hour. This titration was based on an expected plasma concentration of 400 ng/mL, corresponding to an estimated 50% blockade of NMDA receptors. All patients were also started on PO clonidine 0.1 mg (titrated to 0.3 mg) approximately a week before the infusion; clonidine was stopped at the completion of the infusion. Side effects were generally mild and improved over the course of the infusion. Resulting Montgomery-Asberg Depression Rating Scale (MADRS) scores significantly fell after the ketamine infusion before slowly rising over the next 8 weeks. One day after the infusion, 59% of patients were in remission (MADRS <10). At 8 weeks post-infusion found that 33% of patients were in remission; of the responders at 2 weeks, 73% (8/11) remained in remission. [6]