Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant

This review (2016) investigates the risks (safety and toxicity) related to the medical use of ketamine (for depression). The most risk is found at chronic and high doses. R-ketamine is found to have greater antidepressant effects with a smaller risk of adverse events.

Abstract

“Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Conventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hindered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N-methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast-acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concern. In this review, we focus on the limitations of ketamine, including neurotoxicity, cognitive dysfunction, adverse events associated with mental status, psychotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine (esketamine) and R-ketamine, are also discussed. R-ketamine has greater antidepressant actions than S-ketamine, without ketamine-related side-effects. Future treatment strategies should consider using R-ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term ketamine use.“

Authors: Weili Zhu, Zengbo Ding, Yinan Zhang, Jie Shi, Kenji Hashimoto & Lin Lu

Summary

Ketamine, a non-competitive N-methyl-D-aspartate glutamate receptor antagonist, has been shown to have rapid antidepressant effects in both rodents and humans. However, its safety and toxicity remain a concern, and R-ketamine has greater antidepressant actions than S-ketamine without ketamine-related side-effects.

Introduction

Major depression is a serious psychiatric disorder that remains a leading cause of disability worldwide. Ketamine, a noncompetitive NMDAR antagonist, has rapid antidepressant effects within 2 h and continues to remain effective for at least 1 week.

Ketamine decreased suicidal ideation in patients with treatment-resistant depression who had suicidal thoughts following repeated intravenous infusions.

Ketamine has been shown to be a promising fast-acting antidepressant, but its safety and toxicity remain a concern. Further research is needed to mitigate its potential harm, and to develop new fast-acting antidepressants with fewer side-effects and greater efficacy.

Neurotoxic Effects of Ketamine

Ketamine may cause neuronal apoptosis in the fetus and thus decrease the functional capacity of the brain. In addition, maternal exposure to ketamine during pregnancy is associated with emotional disorders and cognitive impairment in offspring.

Ketamine’s different efficacy and side-effects are thought to underlie the different neurotoxicity and behavioral profiles of high- versus low-dose ketamine. High doses of ketamine can interact with several receptors and ion channels, and can cause learning and memory impairment, sedation, ataxia, and psychotomimetic effects.

Ketamine abusers show a persistent deficit in source memory, abnormalities in white matter in the bilateral frontal and left temporoparietal regions, and a loss of the c-aminobutyric acid (GABA)ergic phenotype of parvalbumin interneurons. These changes are closely associated with the pathophysiology of depression.

We propose that repeated infusions of low doses of ketamine are safe and effective in sustaining an antidepressant response.

Cognitive Effects of Ketamine

Ketamine infusions impair episodic and working memory, slow semantic processing, recognition memory, and procedural learning, and increase left frontal activity during a deep encoding task, suggesting that semantic memory impairments are induced by ketamine. Ketamine does not induce attentional difficulties in healthy individuals.

Effects of Ketamine on Adverse Events Associated with Mental Status

Ketamine has been associated with mild and transient adverse events, including sensations of ”very unpleasant,” ”no control, not a good feeling,” ”weird,” ”panicky,” and ”too high, walls closing in”

Psychotomimetic Effects of Ketamine

Ketamine has been shown to cause transient psychotomimetic effects but not persistent psychosis or affective switches, and to increase the power of wake-related gamma oscillations in the neocortex.

Cardiovascular Effects of Ketamine

Ketamine can cause transient elevations in blood pressure, but these elevations usually disappear within 30 min. Ketamine should be used cautiously in patients with preexisting cardiovascular disease, including ischemic heart disease and hypertension, and blood pressure should be monitored during ketamine administration.

Uropathic Effects of Ketamine

Ketamine has uropathic effects, which include severe urgency, urinary frequency, intermittent hematuria, nocturia, dysuria, and bladder pain. Treatment usually occurs symptomatically, and the symptoms are reversed by ketamine cessation.

Other Clinical Concerns

Several controlled studies of patients with depression have shown that intravenous ketamine is safe and has a rapid effect on depressive symptoms. However, intranasal ketamine may be a better option for clinical practice.

Future Directions

Ketamine is a racemic mixture that contains equal parts of S-ketamine (esketamine) and R-ketamine. It has less severe side-effect profiles than currently used antidepressants.

Esketamine has a *4-fold greater affinity for the NMDAR relative to R-ketamine, which may explain its greater anesthetic potency and more undesirable psychotomimetic side-effects. However, R-ketamine has greater potency and longer-lasting antidepressant effects than esketamine in animal models of depression. R-ketamine does not induce psychotomimetic-like side-effects or have abuse potential in rodents, but esketamine does cause loss of parvalbumin immunoreactivity in mouse brain regions, including the prefrontal cortex, and dopamine D2/3 receptors in the striatum is reduced in monkeys after esketamine but not R-ketamine.

A recent study showed that a twice-weekly infusion of ketamine was sufficient as an initial repeated-dose strategy. However, repeated use of esketamine may cause long-lasting detrimental side-effects, and R-ketamine may be a new therapeutic approach that reduces the detrimental side-effects of racemic ketamine.

Summary

Ketamine is an effective and fast-acting antidepressant for a variety of depressed patients. Its safety and tolerability profiles are generally good at low doses or with short-term treatment, and adverse events are usually associated with very high doses for prolonged periods of time.