Review
A review of current evidence for acetyl-l-carnitine in the treatment of depression

https://doi.org/10.1016/j.jpsychires.2014.02.005Get rights and content

Abstract

Despite numerous antidepressants available, many patients with depression do not achieve adequate response rendering needs for novel antidepressants with different mechanism of actions. Acetyl-l-carnitine (ALC) is a potential antidepressant with novel mechanism of action because of its diverse functions related with neuroplasticity. Animal and cellular models suggest that ALC's neuroplasiticity effect, membrane modulation, and neurotransmitter regulation may play an important role in treatment of depression. Four randomized clinical studies (RCT) demonstrated the superior efficacy of ALC over placebo (PBO) in patients with depression. Two RCTs showed its superior efficacy over PBO in dysthymic disorder, and 2 other RCTs showed that it is equally effective as fluoxetine and amisulpride in treatment of dysthymic disorder. ALC was also effective in improving depressive symptoms in patients with fibromyalgia and minimal hepatic encephalopathy. It was also found to be equally tolerable to PBO and better tolerable than fluoxetine and amisulpride. In conclusion, ALC may be potentially effective and tolerable next treatment option with novel action mechanisms for patients with depression, in particular older population and patients with comorbid medical conditions who are vulnerable to adverse events from antidepressants. However, more clinical trial data with adequately-powered, well-designed and advanced methodology will be mandatory to conclude whether ALC as a monotherapy or augmentation agent may be efficacious and clinically beneficial for depression.

Introduction

Major depressive disorder (MDD) is a common debilitating illness, which is the third leading cause of moderate to severe disability and of disease burden worldwide (Egede, 2007, Kessler et al., 2003). Although antidepressants with diverse mechanisms of action, mainly targeting monoamines, are already available, many patients do not achieve proper treatment outcomes (Bauer et al., 2013, Trivedi et al., 2006). Although the monoamine hypothesis of depression has been the dominating pathophysiology of depression as well as targets of pharmacological treatments for the last decades, there are serious limitations to the current monoamine theory (Massart and Mongeau, 2012). Moreover, studies suggest that these neurotransmitters are immediately affected by diverse antidepressants, but clinical improvements are not evident until few weeks later (Machado-Vieira et al., 2008). Therefore, additional novel antidepressants with different mechanism of actions are needed to enable clinicians to diversify treatment options for treatment of MDD.

Accumulated evidences indicate that impairments in neuroplasticity as core pathophysiological mechanism in MDD (Blugeot et al., 2011, Hayley et al., 2005, Massart and Mongeau, 2012, Pittenger, 2008). Studies also indicate that alterations of fatty acids and lipid metabolism, important contributors of neuroplasticity, occur in patients with depression (Peet et al., 1998). In keeping with this perspective, carnitine is an important potential substance with antidepressant effects because it is known to modulate the activity of neurotrophic factors, cell membranes, lipid metabolism, and neurotransmitters in nervous tissues (Jones and McDonald, 2010). Carnitine, an essential dietary nutrient, acts as a carrier of fatty acids across the inner membrane of mitochondria, which is the site of β-oxidation (Steiber and Kerner, 2004). High concentrations of carnitine could be found in biological tissues and cells as either free carnitine or as acylcarnitines including acetyl-l-carnitine (ALC) (Pettegrew and Levine, 2000). ALC has numerous important functions including facilitating the uptake of acetyl CoA into the mitochondria during fatty acid oxidation, enhancing acetylcholine production, stimulating protein and membrane phospholipid synthesis, and prevention of excessive neuronal cell death (Aureli et al., 2000, Di Cesare Mannelli et al., 2010, Spagnoli et al., 1991). Moreover, a preliminary study reported the efficacy of ALC in the treatment of geriatric depression through the normalization of phosphomonoester levels in the prefrontal regions (Pettegrew et al., 2002).

The purpose of this article was to review clinical and preclinical studies evaluating ALC's role as an antidepressant. We sought to elaborate ALC's diverse possible mechanism of action in treatment of depression mainly through preclinical animal studies. ALC's clinical efficacy in patients with depressive symptoms was discussed by reviewing all the randomized, placebo and/or comparator controlled clinical trials available.

Section snippets

Date search

A data search was conducted in August 2013 using the PubMed and MEDLINE databases with the key terms “carnitine” and “acetyl-l-carnitine.” The studies searched were verified for publication in English peer-reviewed journals, but date constraints were not utilized. We also used reference lists from identified articles and reviews to find additional studies. Randomized, placebo and/or comparator controlled clinical trials were principally considered for our review, so open-label studies, case

Basic experimental rationale (mechanism of action)

ALC, an endogenous compound, is the short ester of carnitine l isomer that acts as a donor of acetyl groups and facilitates the transfer of fatty acids from cytosol to mitochondria during β-oxidation (Jones and McDonald, 2010). ALC could be administered orally or intravenously, and it is absorbed in the small intestine via simple diffusion (Parnetti et al., 1992). It is transported into intra-cellular tissues through active transporters, and plasma concentrations of ALC and l-carnitine reached

Clinical evidence

Villardita et al. conducted the first randomized, double blind, placebo controlled study investigating clinical efficacy of ALC on patients with depression (Pettegrew and Levine, 2000, Villardita and Vecchio, 1993). The study compared the efficacy of ALC with placebo (PBO) in 28 patients (age 65–78) with depression. Although the diagnostic system used was not mentioned, subjects were presumed to moderately depressed according to the mean 21-item Hamilton Depression Rating Scale (HDS-21) score

Discussion

A mounting evidence suggests that large proportion of patients with depression do not show adequate response despite multiple antidepressants are available, which renders needs for novel antidepressants with different mechanism of actions (Bauer et al., 2013, Trivedi et al., 2006). ALC, an acylcarnited form of essential dietary nutrient carnitine, may have a potential antidepressant effects with novel mechanism of action because of its diverse functions related with neuroplasticity (Jones and

Contributors

Drs. Pae and Wang conceived and wrote the draft and also contributed to the final version of the manuscript. Drs. Han, Lee. Masand and Patkar contributed to the writing of the manuscript as well as performing data collection. All authors properly contributed to and finally approved the manuscript.

Role of funding source

This work was supported by a grant from the Ministry of Health and Welfare (A120004); however, the funding source had no further role in preparation, data collection, and writing of the paper.

Disclosures

The authors have reported no conflicts of interest.

Acknowledgment

This work was supported by a grant from the Ministry of Health and Welfare (A120004).

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