Guidelines for major depressive disorder (MDD) published by the United States Veterans Affairs (VA) and Department of Defense (DOD) very briefly mention ketamine/esketamine for treatment resistant depression (TRD). The guidelines make one weak recommendation suggesting ketamine or esketamine as an option for augmentation in patients with MDD who have not responded to several adequate pharmacologic trials. [1]
Additionally, Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force guidelines published in 2021, which included a systematic review, examined the efficacy and safety of racemic ketamine in adults diagnosed with TRD. Intravenous (IV) racemic ketamine administered as a single infusion demonstrated Level 1 evidence for efficacy in adults with TRD, with a rapid onset of antidepressant effects noted. However, the evidence supporting multiple infusions, which could be administered as an acute series or for maintenance treatment, was limited to Level 3, while non-IV formulations of racemic ketamine only exhibited Level 3 or 4 evidence. Adverse events primarily included transient dissociative symptoms and physiological effects like hypertension. The CANMAT task force recommended single-dose IV racemic ketamine as a third-line intervention for adults with TRD, emphasizing careful assessment of the need for repeated and maintenance infusions. The task force highlighted the limited evidence concerning efficacy and potential risks associated with misuse and diversion, advising that oral and other non-IV formulations be restricted to specialists with the requisite expertise and connections to tertiary or specialized centers. [2]
Several review articles have discussed esketamine use for treatment resistant depression along with therapeutic drug monitoring recommendations. Esketamine is shown in clinical trials to be effective for the short-term treatment of depression and reduction in suicidality rate as monotherapy and in combination with other antidepressants compared to placebo. Intranasal esketamine’s advantage over other antidepressants was identified as its ability to elicit an almost immediate clinical response in hours or days compared to weeks for other similarly indicated medications. Although both serious and non-serious adverse events have been reported with short-term esketamine use, most adverse events in clinical trials have been categorized as mild to moderate and transient. Overall, the authors suggest new generation antidepressants, including esketamine, are as effective as classical agents based on results from clinical studies. Providers are encouraged to personalize therapy and weigh the risk/benefit of antidepressant medication choices by monitoring for adverse effects and patient response to treatment. [3], [4]
In a 2021 systematic review and meta-analysis (N= 24 trials, 1877 participants), the efficacy and tolerability of racemic ketamine and esketamine were compared for unipolar and bipolar major depression. Overall, ketamine demonstrated a significant improvement in response (RR 2.0382, 95% CI 1.5748 to 2.6380) and remission rates (RR 2.0029, 95% CI 1.5005 to 2.6735) compared to control. A subgroup analysis was performed comparing ketamine and esketamine. When compared to intranasal esketamine, intravenous ketamine was again observed to demonstrate more significant overall response (RR 3.01 vs.1.38; p= 0.0023) and remission rates (RR 3.70 vs. 1.47; p= 0.0012). Additionally, drop-outs due to adverse events were significantly lower with ketamine (RR 0.76 vs. 1.37, p= 0.0331). [5]
A 2019 review of reviews, meta-analyses, and randomized controlled trials (not included in the other reviewed literature) found that low-dose intravenous (IV) 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). [6], [7], [8], [9]
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 of 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. [6], [7], [8], [9]
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. [9]
A 2020 meta-analysis evaluated the effects of IV ketamine infusion in patients with treatment-resistant depression 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. [10]