Oral Ketamine for Depression: A Systematic Review

Objective: Intravenous (IV) ketamine has rapid and robust antidepressant effects; however, poor accessibility of the IV route often limits its use. Numerous alternative routes of administration are being investigated. Oral ketamine is particularly appealing for its ease of use with the potential for high accessibility. The objective of the current systematic review, in accordance with PRISMA, is to determine the efficacy, safety, tolerability, and dose range of oral ketamine for bipolar and unipolar depression.

Data Sources: The MEDLINE/PubMed, EMBASE, and Google Scholar databases were systematically searched for relevant articles, written in English, published prior to July 2018 using relevant keywords for all variants of ketamine, oral, and depression.

Study Selection: All clinical studies assessing oral ketamine for bipolar or unipolar depression were included. A total of 13 published articles were identified, of which 2 were proof-of-concept, randomized controlled trials (RCTs); 1 was a prospective open-label trial; 5 were retrospective chart reviews; and 5 were case reports.

Data Extraction: Included articles were qualitatively analyzed to determine antidepressant efficacy, tolerability, safety, dose range, antisuicide effects, time to effect, and efficacy in treatment-resistant depression and study bias.

Results: Both RCTs demonstrated antidepressant efficacy with good tolerability; however, significant changes in depressive symptom severity were observed only after 2-6 weeks of treatment (P < .05). Both RCTs had high risk for bias, due to inadequate intent-to-treat analysis and adverse effect monitoring. Rapid antidepressant effects (ie, within 24 hours), antisuicide effects, and efficacy in treatment-resistant depression were reported only in retrospective studies. Dosages and frequency of administration were variable (ie, 0.5-7.0 mg/kg 3 times daily to once monthly), with most studies providing dosages of 1-2 mg/kg every 1-3 days. No clinically significant adverse effects were reported.

Conclusions: A small number of clinical studies assessed the antidepressant effects of oral ketamine. Initial results suggest that oral ketamine has significant antidepressant effects with good overall tolerability; however, antidepressant effects are not as rapid as those associated with IV ketamine. Antisuicide effects and efficacy in treatment-resistant depression have yet to be demonstrated. Additional well-designed RCTs are warranted.