Ketamine for Treatment-Resistant Unipolar Depression

Abstract

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.

The Use of Ketamine in Neuropathic Pain

“…It is our personal clinical experience that ketamine infusions have the greatest success in the treatment of NP with a sympathetic component responsive to pure sympathetic blockade. Of note, in patients with NP and concomitant clinical depression, we have observed a marked improvement in depression after ketamine infusions, which is in concordance with the robust expanding evidence of ketamine's rapid and potent antidepressant effects [38][39][40][41][42][43]. The effect on clinical depression has been noted before the effect on the pain.…”

“…Recent studies have also shown ketamine to induce rapid, potent, and prolonged antidepressant effects [38][39][40][41][42][43]. These growing studies are of particular interest in understanding the efficacy of ketamine in NP treatment given the integral component of mood in the affective component of pain.…”

Zinc deficiency alters responsiveness to antidepressant drugs in mice

“…Based on the antidepressantlike activity of NMDA/glutamate receptor antagonists a link between hyperactivity of the glutamate system and depression was indicated [19,48,49,53,65]. Additionally, glutamate receptor antagonists or its modulators showed antidepressant properties in treatment refractory depression [1,9,13,14,27,28,41,44,71,72]. Hyperactivity of the glutamatergic system was also observed in animals after both a 2-[63] and 4-week [58,61] zinc deficient diet.…”

Understanding Resilience

“…The dysregulation of these systems can lead to profound deficits in successful adaptation to acute and chronic stress. Pharmacological studies targeting these systems in psychiatric disorders have begun to show promising results in achieving therapeutic effects (Hill and Gorzalka, 2009;Murrough and Charney, 2010;Kirilly et al, 2012;Mathew et al, 2012;Mathews et al, 2012).…”