Ketamine for treatment-resistant depression: recent developments and clinical applications

This clinical review (2016) examines the fasting-acting effects of ketamine for alleviating symptoms of major depressive disorder (MDD), with regard to its administration method, its safety profile, and its general effects on suicidal ideation, anhedonia, cognition. It also examines which patient profiles predict the most effective response duration while highlighting that the manifestation of depressive symptoms make it challenging to predict the efficacy of ketamine, and although further research is underway to elucidate the role of genetic, central neurobiological, and peripheral measures, it is still too early to recommend their adoption in clinical practice.

Abstract

“Approximately one-third of patients with major depressive disorder (MDD) do not respond to existing antidepressants, and those who do generally take weeks to months to achieve a significant effect. There is a clear unmet need for rapidly acting and more efficacious treatments. We will review recent developments in the study of ketamine, an old anaesthetic agent which has shown significant promise as a rapidly acting antidepressant in treatment-resistant patients with unipolar MDD, focusing on clinically important aspects such as dose, route of administration and duration of effect. Additional evidence suggests ketamine may be efficacious in patients with bipolar depression, post-traumatic stress disorder and acute suicidal ideation. We then discuss the safety of ketamine, in which most neuropsychiatric, neurocognitive and cardiovascular disturbances are short lasting; however, the long-term effects of ketamine are still unclear. We finally conclude with important information about ketamine for primary and secondary physicians as evidence continues to emerge for its potential use in clinical settings, underscoring the need for further investigation of its effects.”

Authors: Jaclyn Schwartz, James W Murrough & Dan V. Iosifescu

Summary

Approximately one-third of patients with major depressive disorder do not respond to existing antidepressants, and those who do generally take weeks to months to achieve a significant effect. Ketamine has shown significant promise as a rapidly acting antidepressant in treatment-resistant patients with unipolar MDD.

INTRODUCTION

Unipolar major depressive disorder (MDD) affects 350 million people worldwide, and is the leading cause of disability. Currently prescribed antidepressant treatments targeting the monoamine system only alleviate depressive symptoms in about half of the patients.

Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate receptor antagonist, used as an anaesthetic and prescribed off-label to treat chronic pain. It has been shown to have rapid-acting antidepressant effects on patients with TRD. Ketamine has been shown to have antidepressant effects by increasing brain-derived neurotrophic factor (BDNF) translation and secretion, as well as via glycogen synthase kinase-3 (GSK-3) inhibition. The current review will focus on recent developments in the use of ketamine, as well as clinical applications for primary and secondary care.

How do patient characteristics predict response and response duration?

Multiple clinical trials suggest that a single low dose of IV ketamine results in symptom relief in patients with TRD. Ketamine’s antidepressant effect was observed in six double-blind, randomised, placebo-controlled, cross-over trials in major depressive disorder (MDD) and bipolar disorder (BD). Ketamine was associated with a greater improvement at days 1, 2, 3, 4 and 7 in participants with unipolar major depression compared with bipolar depression. Ketamine may be beneficial in populations less likely to respond to traditional antidepressants, such as those with comorbid anxiety disorder, lifetime history of antidepressant treatment, and duration of depression and current episode.

Ketamine treatment may most effectively target severely depressed patients with cognitive dysfunction or anxiety.

Does route of administration (IV vs intranasal) and adjunctive treatment affect efficacy?

The mode of administration may affect ketamine’sefficacy for treating MDD. Further studies using IN S-ketamine (the S-enantiomer of racemic ketamine) are currently underway or completed to better estimate the duration of effect and optimal dosing frequency.

Ketamine can be used with ongoing antidepressant and/or augmentation therapy, and it is not necessary to washout patients of their current antidepressant treatment.

Efficacy of single IV infusion versus repeated IV infusions

Single doses of IV and IN ketamine administration have consistently shown antidepressant efficacy for up to 7 days. Few studies have examined the effects of repeated administrations of ketamine, but both studies concluded that response to a series of repeated ketamine administrations could be predicted after the first one or two treatments.

Several studies have explored the safety and efficacy of repeated ketamine infusions, and additional clinical trials are currently underway to study the long-term effects of repeated administration in addition to ongoing antidepressant treatment.

Ketamine has been shown to decrease suicidal ideation in patients with depression, but it is still difficult to determine whether it has antisuicidal properties. Research is continuing to study the possible neuroinflammatory pathways that identify both suicidality and ketamine’s pharmacological properties.

Ketamine has been shown to reduce negative cognitions and anhedonia postketamine, and may be associated with improvements in cognitive emotional and executive functioning. It is unclear whether improvement in anhedonia is pseudo-specific (eg, caused by the antidepressant effect), or whether it is related to improvements in depression overall.

Safety and potential for abuse

Ketamine is safe and effective as an anaesthetic in children and adults at doses ranging from 1 to 3 mg/kg. It can cause short-lasting neuropsychiatric effects.

Ketamine may cause mild side effects, such as dizziness, blurred vision, headache, nausea or vomiting, dry mouth, restlessness, and impairments in coordination and concentration, up to 4 h following ketamine administration. However, patients with a history of cardiovascular illness would require careful monitoring.

THE ROLE OF PRIMARY CARE PHYSICIANS AND SPECIALISTS

Primary care physicians should be aware of the high prevalence of MDD and TRD, and the need to refer difficult-to-treat patients to psychiatrists or anaesthesiologists. Ketamine is an emerging alternative treatment for TRD, but there is no standardised administration outside of the research setting.

CONCLUSION

Ketamine has been shown to be effective in treating treatment-resistant unipolar depression, bipolar depression and PTSD. However, it is challenging to predict the efficacy of ketamine in clinical practice.

Ketamine is an effective treatment for patients with TRD, bipolar depression, PTSD and acute SI. However, more research is needed to determine optimal dosing and long-term effects.