Safety of Ketamine Augmentation to Monoamine Oxidase Inhibitors in Treatment-Resistant Depression: A Systematic Literature Review and Case Series.

Objective: Ketamine is increasingly prescribed for treatment-resistant depression (TRD), often as add-on to regular antidepressants. Augmentation of ketamine to monoamine oxidase inhibitors (MAOIs) is advised against, as this practice might increase blood pressure or cause serotonin syndrome. Despite the potential relevance for patients, little is known about actual side effects of combined use. We summarize literature on the safety and add results of our case series.Evidence Review: PubMed and Embase were searched from inception to July 2021 for English-language articles describing concomitant use of ketamine and MAOIs. The search strategy included terms for "ketamine" AND "monoamine oxidase inhibitor" including generic and brand names. Additionally, we describe the safety of twice weekly oral esketamine administration over the course of 5 weeks to 9 months in 8 TRD patients using MAOIs.Findings: After deduplication, we screened 138 articles and assessed 43 full texts. Twelve studies were included with a total of 39 patients receiving ketamine and MAOIs. Blood pressure and heart rate increased in multiple cases, though this was deemed clinically insignificant in all but 1 patient. No signs of hypertensive crisis or serotonin syndrome were observed. In our case series, we observed minor elevations in blood pressure and heart rate and no serious adverse events.Conclusions and Relevance: The results suggest that combined use of MAOIs and esketamine is less prone to severe side effects than presumed. The investigated sample size was small, and prescribed doses of MAOIs were relatively low. Further research is required before definite conclusions about the safety of this combination can be drawn.

The antidepressant effect and safety of non-intranasal esketamine: A systematic review.

BACKGROUND: The introduction of esketamine into the field of psychiatry comes on the heels of excitement from studies on racemic ketamine. While the intranasal route has been the most studied to date, other modes of administration of esketamine may also be of interest in the management of depression. AIMS: To systematically review the literature on non-intranasal esketamine for depression in terms of its antidepressant effect and safety. METHODS: We searched PubMed, Embase, the Cochrane Library, and Google Scholar from inception up to February 2021. Search terms included a combination of Medical Subject Headings and text words indicative of esketamine and depression. We selected both controlled and uncontrolled studies examining non-intranasal esketamine for the treatment of depression. RESULTS: We identified four randomized controlled trials (RCTs) on intravenous esketamine and 15 open-label studies on intravenous (n = 80), subcutaneous (n = 73), and oral (n = 5) esketamine. We found intravenous, subcutaneous, and possibly oral administration of esketamine to be effective in reducing depressive symptoms in most patients with major depressive disorder, bipolar depression, and (severe) treatment-resistant depression. Clinical response to repeated administration of esketamine persisted over the course of treatment. Esketamine was well tolerated by most patients, but open-label data indicate marked psychotomimetic symptoms in exceptional cases. The overall quality of the controlled studies was considered high, the overall quality of the uncontrolled studies low to moderate. CONCLUSIONS: Intravenous, subcutaneous, and possibly oral esketamine may offer an effective and safe addition to the depression treatment armamentarium. However, as most included studies lacked a control group and had small sample sizes, the quality of our results is limited. Different types and formulations of ketamine remain to be compared directly.