Innovative approaches to treatment - refractory depression: The ketamine story

Abstract

Byline: T.S. Rao, Chittaranjan. Andrade Antidepressant drugs have traditionally addressed the monoamine triumvirate: serotonin, noradrenaline, and dopamine. There have been predominantly two mechanisms recruited in drug action - inhibition of monoamine reuptake and inhibition of intravesicular monoamine catabolism. Tianeptine, which increases the synaptic reuptake of serotonin, and mirtazapine, which blocks alpha-2 adrenergic autoreceptors and heteroreceptors, are examples of the very few drugs which have other mechanisms of action. Yet, even these two antidepressants target the traditional neurotransmitters in psychiatry.[sup] [1] Recent evidence suggests that glutamate-mediated neuroplasticity may be the final common pathway of antidepressant action;[sup] [2],[3] tianeptine is the best-studied antidepressant in this regard.[sup] [4] If glutamate holds the key to recovery from depression, then treatments that directly address glutamatergic neurotransmission may exhibit greater antidepressant efficiency. Glutamate acts on metabotropic receptors and ionotropic receptors in the brain. Ionotropic receptors surround ion channels and are of three types: N-methyl-D-aspartate (NMDA) receptors, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and kainate receptors.[sup] [5] The glutamatergic system and particularly the NMDA receptor play an important role in the neurobiology of major depressive disorder, and different glutamatergic targets have been considered as treatments for depression.[sup] [6],[7] For example, antagonists of the NR2B subtype of the NMDA receptor are currently under development as potential antidepressant treatments; and traxoprodil, an NR2B antagonist, has demonstrated antidepressant effects in selective serotonin reuptake inhibitor (SSRI)-resistant patients.[sup] [7] Ketamine, the focus of this editorial, is an experimental antidepressant treatment which acts on NMDA receptors.[sup] [5] Ketamine as an Antidepressant Animal studies have shown that ketamine and other NMDA receptor antagonists have antidepressant effects in different animal models of depression.[sup] [8] About a decade ago, Berman et al.[sup] [9] described the first double-blind, placebo-controlled (crossover) study, which showed that an intravenous ketamine infusion (0.5 mg/kg) resulted in significant and rapid but short-lived antidepressant effects in seven patients with major depression. Several years later, Zarate et al.[sup] [8] described the first randomized, double-blind, placebo-controlled (crossover) study of ketamine in 18 patients with treatment-refractory major depressive disorder. Ketamine (0.5 mg/kg) was administered as an intravenous infusion in normal saline across a 40-minute period; placebo comprised normal saline alone. There was significant antidepressant benefit within 110 minutes of the ketamine infusion. One day later, the response and remission rates to ketamine were 71% and 29%, respectively, and the antidepressant effect size was 1.5. However, only six (35%) patients maintained response for one week, by which time the effect size had dropped to 0.7. In contrast, the response rate to saline infusion was 0% after both one day and one week. Adverse effects with ketamine included perceptual disturbances, confusion, euphoria, dizziness, increased libido, and elevated blood pressure; these, however, lasted only for 1-2 hours. Several case reports were subsequently published illustrating the efficacy of ketamine in medication-refractory patients. For example, Goforth and Holsinger[sup] [10] described a patient with severe, recurrent major depressive disorder who markedly improved within eight hours of receiving his first bitemporal electroconvulsive therapy (ECT) treatment under ketamine anesthesia. It is possible; however, that the dramatic response was to ECT and not necessarily to ketamine because such dramatic response to ECT has occasionally been described in literature. …