Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

Abstract

Background Due to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains. Methods Electronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed. Results A total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = − 0.89; 95% CI − 1.24; − 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2-3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = − 0.70; 95% CI − 1.15; − 0.25 or SMD = − 0.81; 95% CI − 1.41; − 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo. Conclusions Our meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

“…Interestingly, Vande Voort et al (2016) reported that four subjects lost remission status during the drug free post-continuation phase, but they maintained a MADRS total score not different from that evaluated 24 h after the first acute infusion suggesting an enduring ketamine effect. A recent meta-analysis of 20 randomized and controlled studies evaluated the efficacy of a single or repeated ketamine dose in different subgroups of patients with MDD and bipolar depression (Kryst et al, 2020); the authors reported that a single dose of ketamine, reduced depressive symptoms, producing the largest antidepressant effect at 24 h, however, a significant effect was seen up to 7 days after ketamine administration. In addition, ketamine's effect could be observed in TRD patients, who received ketamine in monotherapy, but also when ketamine was used as adjunctive to the current antidepressant therapy, in both unipolar and bipolar depression.…”

“…In addition, ketamine's effect could be observed in TRD patients, who received ketamine in monotherapy, but also when ketamine was used as adjunctive to the current antidepressant therapy, in both unipolar and bipolar depression. Several studies evaluated the efficacy of ketamine repeated treatments; importantly, serial ketamine administration (twice or thrice a week for three weeks) produced a significant and sustained antidepressant effect over placebo at three weeks, both in terms of depression symptoms and in terms of remission (Kryst et al, 2020).…”

Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter

“…The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) ( 14 ) and S-ketamine ( 15 ) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms ( 16 ).…”

Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression

“…Numerous early studies had consistently reported that an antagonist of glutamatergic N-methyl-D-aspartate (NMDA) receptors ketamine at subanesthetic doses could result in fast-acting and sustained antidepressant effects in individuals suffering from unipolar and bipolar depression ( Na & Kim, 2021 ; Phillips et al, 2020 ). For example, ketamine’s repeated administration had quick and enduring antidepressant and antisuicidal effects in depressed patients ( Kryst et al, 2020 ).…”