A systematic review of the incidence of medical serious adverse events in sub-anesthetic ketamine treatment of psychiatric disorders

Background: Limited published data exists that collates serious adverse outcomes involving ketamine as a psychiatric intervention. This systematic review assesses the reported incidence of medical serious adverse events (MSAEs), including but not limited to cardiovascular events, in patients receiving sub-anesthetic doses of ketamine for psychiatric disorders to guide practitioners during treatment planning, risk-benefit analyses, and the informed consent process. Methods: Pubmed database was searched for clinical trials of sub-anesthetic ketamine for psychiatric disorders in non-pregnant adult patients. Of the 2275 articles identified, 93 met inclusion criteria, over half of which were published in 2017 or later. Only studies that reported adverse events were included, and the incidence of MSAEs was calculated. Results: Of the 3756 participants who received at least one sub-anesthetic dose of ketamine, four participants experienced a MSAE, resulting in an incidence of approximately 0.1 % of individuals. The four MSAEs resolved without reported sequelae. Eighty-three percent of studies reported screening for medical illness and exclusion of high-risk patients. There were no serious cardiac adverse events or deaths observed in any participants; however, most trials' study designs excluded those with high cardiovascular complication risk. Limitations: Most studies were small, underpowered for detecting rare MSAEs, at potential high-risk of bias of non-report of MSAEs, and limited mostly to intranasal and intravenous routes. Conclusions: Findings suggest that with basic medical screening there is a very low incidence of MSAEs including adverse cardiac or cerebrovascular events in individuals receiving sub-anesthetic ketamine for psychiatric disorders.