Next generation antidepressants

Abstract

Over the past 50 y, there have been few mechanistically distinct drugs for the treatment of major depressive disorders, despite the fact that nearly two-thirds of patients do not achieve full remission of symptoms on currently available antidepressants (1). In addition, even when adequate remission is achieved, patients require 2–4 wk of treatment before any significant effects, increasing the risk for complications, such as suicide (2). This delay in effectiveness has resulted in a major push to identify and develop novel therapeutics with more rapid effects. The recent identification of ketamine as a rapid antidepressant effective in treatment-resistant patients has been groundbreaking (3, 4). Nasca et al. (5) describe in PNAS a unique potential rapidly acting antidepressant, l-acetylcarnitine (LAC), which is a dietary supplement that acts by acetylating protein targets to control their function. LAC is reported to be well tolerated and can readily cross the blood-brain barrier (6). A recent study suggests it has promise in the treatment of Parkinson disease because of its neroprotective properties (7). Strikingly, LAC exhibits antidepressant efficacy within 2–3 d following intraperitoneal administration in rodents, compared with 2–3 wk with a standard antidepressant treatment, such as chlorimipramine. Although LAC is relatively nonspecific and can target many biological pathways, it is suggested by Nasca et al. (5) to promote rapid antidepressant responses by acetylation of histone proteins that control the transcription of BDNF and metabotropic glutamate 2 (mGlu2) receptors in the hippocampus (Hipp) and prefrontal cortex (PFC) (Fig. 1). One of the more impressive aspects of this article is that Nasca et al. (5) verify rapid antidepressant efficacy of LAC in both a genetic rat model of susceptibility [Flinders Sensitive Line (FSL)] and following chronic stress exposure, factors that are thought to be the primary cause of depression in humans. Although there is clearly far more work necessary to understand the mechanisms of antidepressant action of LAC in rodents, and the dose and relative safety profile for depression treatment in humans, these exciting results are a first step toward that goal.