Ketamine for Treatment-Resistant Unipolar and Bipolar Major Depression: Critical Review and Implications for Clinical Practice

Abstract

There is an urgent need for more rapidly effective pharmacotherapies for major depressive disorder and bipolar disorder (BP) that are efficacious and tolerable for depressed patients who respond poorly to conventional treatments. Multiple controlled trials have now demonstrated a rapid, nonsustained antidepressive response to a single intravenous infusion of ketamine. Early controlled studies of intranasal or serial infusion therapy appear promising. The effective dose for depression is lower than the typical anesthetic doses, and side-effects are generally mild and transient. The data investigating the adjunctive use of concurrent ketamine in the course of electroconvulsive therapy (ECT) for depression do not suggest efficacy or tolerability. The therapeutic potential of ketamine has stimulated considerable excitement among clinicians, patients, and industry, and has led to the increasing use of ketamine as an off-label substitute for ECT and other antidepressive treatments. This clinical review of ketamine will assess the evidence-based use of ketamine and initial clinical implications of further development of a potentially novel treatment for rapid reduction of symptoms in depressed patients.

Ketamine Treatment and Global Brain Connectivity in Major Depression

“…Thus it is not known for how long the GBCr changes would last and whether repeated ketamine would have comparable effects. To the extent the observed GBCr changes are related to depression relief and to the ketamine-induced synaptogenesis, we speculate that GBCr changes could last for about 10 days; that is the approximate length of antidepressant response in humans (Bobo et al, 2016) and of the synaptogenic effects in rodents (Duman, 2014). Frequent daily administration of ketamine could lead to repeated glutamate surge, increased extracellular glutamate, excitotoxity, and synaptic dysconnectivity comparable to chronic stress models of depression (Abdallah et al, 2015), consistent with clinical data showing impaired cognition and depressive symptomatology in ketamine abusers (Fan et al, 2016;Morgan et al, 2012).…”

What Is New about New Antidepressants?

“…An uncontrolled report has emerged of a synergistic effect between S-ketamine and ECT [56]. However, even if it prolongs seizure duration, ketamine has generally not been found to be effective in augmenting ECT [46, 49, 57], possibly because the rate of response to ECT is so high that it is difficult to augment it. In 1 or 2 doses, ketamine might be an appropriate choice for severely depressed and acutely suicidal patients while a more definitive rapidly acting treatment such as ECT is being arranged.…”

Ketamine Role in Schizoaffective Disorder Depressive Type

“…Ketamine is not FDA approved for depression, and its off-label use has become controversial because of its history as a substance of abuse. However, the use of ketamine in the treatment of severe depression continues to be an area of interest by many in the field of psychiatry due to the relatively limited number of treatment options for patients with severe treatment-resistant depression [1][2][3]7].…”

“…Early studies showed that electroconvulsive therapy reduced suicide in patients with the schizoaffective disorder [23]. Ketamine has been found helpful in both unipolar and bipolar depression [1][2][3]. In bipolar depression, Zarate at al.…”

“…Recently, there has been remarkable interest in the use of ketamine as a rapid-acting antidepressant to treat depressive episodes, both unipolar and bipolar disorders [1][2][3]. However, due to its dissociative and psychogenic effects [4].…”