Side-effects associated with ketamine use in depression: a systematic review

This systematic review (2017) examined the reported side-effects of ketamine treatment for depression across 288 published reports and identified that headache, dizziness, dissociation, elevated blood pressure, and blurred vision were the most common in response to intravenous infusion. The most common acute psychiatric side-effect was anxiety, but there was no conclusive evidence about long-term side effects from the currently available studies.

Abstract

“Introduction: This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses.

Methods: We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria.

Results: After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depresssion. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users.

Discussion: We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.”

Authors: Brooke Short, Joanna Fong, Veronica Galvez, William Shelker & Colleen K. Loo

Summary

Introduction

Major depression affects 350 million people worldwide, making it the leading cause of disability. Ketamine is a key candidate as a new antidepressant, but there have been no investigations on its safety.

Since Berman and colleagues’ initial pilot placebo-controlled trial investigating ketamine for the treatment of depression, a plethora of articles have been published, endorsing the efficacy of ketamine in depression. However, only a few studies have been randomised controlled trials or comprehensively assessed ketamine’s safety, tolerability, and abuse potential.

Ketamine use has been associated with urinary tract symptoms, liver toxicity, cognitive changes, and dependence in patients, including those with chronic pain.

Despite the 15 years that have passed since Berman and colleagues’ report, there remains a large gap in knowledge regarding the long-term efficacy of ketamine in depression and potential long-term safety issues.

Search strategy and selection criteria

In this systematic review, we included studies that reported findings with adult human populations who had a validated diagnosis of unipolar or bipolar depression and had received one or more doses of ketamine. The studies had to describe changes in depression status as a primary outcome measure.

We searched MEDLINE, PubMed, PsycINFO, and Cochrane Database for articles on ketamine and depression. Two authors did a two-step literature search and resolved any disputes by consensus.

We collected information on study design, sample characteristics, ketamine administration details, health screening before ketamine administration, pre­existing medical morbidity, concomitant medications, and timing of side-effects assessment.

Analysis

We assessed potential side-effects of ketamine for depression and categorised them into psychiatric, psychotomimetic or dissociative, cardiovascular, neurological, and other side-effects.

We addressed the following issues that affect data quality: selective outcome reporting, withdrawal or drop­out, and presence of a control group. We gathered as much information as possible to avoid directly interpreting withdrawal or drop­out as surrogate markers for safety or tolerability because of potential bias.

A meta­analysis was initially planned, but a qualitative review of data was undertaken instead because the studies reviewed were clinically diverse.

Results

We included 60 studies in our analysis, which included 899 patients who had received at least one dose of ketamine. Acute psychiatric side­effects were reported in 23 studies, whereas psychotomimetic or dissociative side­effects were reported in 43 studies.

The most common acute psychiatric side-effect was anxiety, followed by agitation or irritability, euphoria or mood elevation, delusions or unusual thoughts, panic, and apathy. Less common side-effects included detachment, emotional blunting, psychosis, emotional lability, craving attention, and formal thought disorder.

The most common psychotomimetic side effect reported was dissociation, followed by perceptual disruption, odd or abnormal sensation, derealisation, hallucinations, feeling strange, weird, bizarre, or unreal, and depersonalisation. No long­term psychotomimetic side effects were reported.

Of the 60 studies included in this analysis, 23 (38%) reported acute changes in the cardiovascular status of patients. These effects generally resolved within 90 min of the administered dose.

Most studies reported only short-term neurological side-effects, and no cognitive side-effects were assessed.

Numerous other side-effects were reported in 32 studies, with the greatest variety reported in patients receiving intravenous ketamine. These side-effects were mainly related to the gastrointestinal, ocular, respiratory, and urological systems, with few studies following up on these side-effects beyond the acute treatment period.

The most common acute side-effects were reported at similar rates as for other study designs, but long-term side-effect risks were rarely assessed or commented on in randomised controlled trials.

Discussion

We systematically reviewed 288 published reports of studies in which ketamine was administered to people who had depression. We found that acute side­effects are common, active assessment, surveillance, and reporting of side­effects during trials of ketamine for patients with depression are inadequate, and most side­effects resolve shortly after dose administration.

Passive monitoring of side-effects relies on spontaneous reports and is very helpful to detect new, rare, and serious side-effects. Active surveillance includes a preorganized process to discover more information on side-effects, including additional detail, which usually cannot be achieved via passive monitoring methods.

Ketamine use in other adult populations has been linked with urological toxicity, hepatotoxicity, cognitive deficits, and dependency risks, including cystitis and bladder dysfunction, an increase in urinary frequency, urgency, dysuria, urge incontinence, and occasionally painful haematuria.

Ketamine use is associated with urinary tract symptoms in more than 20% of people. The mechanism of urological toxicity is not understood, but it is dose related.

Ketamine has been reported to negatively affect the liver and biliary tract. It is not understood why ketamine causes liver injury, but it might be related to metabolic events causing increased lipid peroxidation and free radical formation.

People who use ketamine frequently have severe impairments in both short­term and long­term memory, which can be caused by a regionally selective up­regulation of D1 receptor availability in the dorsolateral prefrontal cortex.

Data from studies of people with chronic pain and depression have been less conclusive. However, short-term follow­up periods make it difficult to comment on long­term risks associated with repeated use.

In patients with depression who might have other comorbid medical disorders, caution should be taken when administering ketamine. In addition, rapid acting routes of administration of ketamine should be avoided, and doses should be kept as low as possible for other administration routes.

Ketamine is a drug of recreational misuse, and repeated doses are associated with rapid development of tachyphylaxis and tolerance. Ketamine may also be addictive in susceptible individuals, and further study is required before ketamine can be used as a clinical treatment for depression.

Systematic reviews of side-effects can provide valuable information about adverse events, but they are hampered by a lack of standardised methods to report these events and the fact that side-effects are not usually the primary outcome of included studies.

Patients are more likely to report side effects when they are directly questioned about them, and screening before treatment begins could help identify those patients at risk.

Most studies on ketamine used racemic ketamine. Large depression trials using the S­isomer of ketamine are now underway.

Conclusion

Ketamine’s pharmacological profile makes it an interesting and possibly useful drug for the treatment of refractory depression. However, the safety of long­term, repeated ketamine dosing is uncertain, and more large­scale clinical trials are recommended before ketamine can be used for clinical treatment of depression.