Novel Targets For Fast Antidepressant Responses (Creatine, Agmatine, Guanosine, Ascorbic Acid)

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Novel Targets for Fast Antidepressant Responses: Possible Role of Endogenous Neuromodulators

Abstract
The available medications for the treatment of major depressive disorder have limitations, particularly their limited efficacy, delayed therapeutic effects, and the side effects associated with treatment. These issues highlight the need for better therapeutic agents that provide more efficacious and faster effects for the management of this disorder. Ketamine, an N-methyl-D-aspartate receptor antagonist, is the prototype for novel glutamate-based antidepressants that has been shown to cause a rapid and sustained antidepressant effect even in severe refractory depressive patients. Considering the importance of these findings, several studies have been conducted to elucidate the molecular targets for ketamine’s effect. In addition, efforts are under way to characterize ketamine-like drugs. This review focuses particularly on evidence that endogenous glutamatergic neuromodulators may be able to modulate mood and to elicit fast antidepressant responses. Among these molecules, agmatine and creatine stand out as those with more published evidence of similarities with ketamine, but guanosine and ascorbic acid have also provided promising results. The possibility that these neuromodulators and ketamine have common neurobiological mechanisms, mainly the ability to activate mechanistic target of rapamycin and brain-derived neurotrophic factor signaling, and synthesis of synaptic proteins in the prefrontal cortex and/or hippocampus is presented and discussed.

Introduction
Major depressive disorder (MDD) is a common and chronic neuropsychiatric condition, characterized by affective and physiological impairments that cause a profound impact on the health of the affected individuals worldwide and a great economic burden.1 The World Health Organization estimates that more than 300 million individuals are affected by MDD at present, and the number of individuals affected by this disorder increased by almost 20% in the last 10 years.2 Given this scenario, MDD is now the leading cause of disability worldwide.

Despite the high prevalence of MDD, and the advances obtained in the last years in the comprehension of the neurobiological basis of this disorder, its treatment still represents a challenge. The limitations of the currently available antidepressants are related to their limited efficacy (only approximately 50% of the patients fail to achieve remission), the delayed therapeutic effects and a great number of adverse/side effects, which includes headaches, constipation, weight changes, and mainly sexual dysfunction.1,3,4 These limitations are particularly problematic for patients with elevated risk for suicide. Noteworthy, it is estimated that up to 50% of the 800,000 suicides that occur per year worldwide are associated with MDD, and patients affected by this disorder are almost 20-fold more likely to die by suicide than the general population.1,2,5 Therefore, appropriate and effective treatments are necessary to be established for a better management of this disorder. The most promising therapeutic strategy for this challenge emerged at the beginning of the 21st century, when Berman et al. demonstrated for the first time that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine caused fast and long-lasting antidepressant effects.6 This study represents the onset of a series of other studies that aimed at investigating the ability of ketamine to provide fast antidepressant responses, even in refractory patients, as well as those that have been focused on the investigation of the mechanisms underlying the fast antidepressant responses of ketamine.711 Despite the promising effects of ketamine, its prolonged use has some limitations, mainly related to side effects and the possibility of neurotoxic effects upon chronic use. In addition to these drawbacks associated with ketamine’s pharmacological/toxicological properties, the oral bioavailability of ketamine is slow.12 Thereby, ketamine is generally administered by intravenous route in hospitalized patients.13

Novel drugs that may afford fast antidepressant responses have been extensively investigated. Here, we provide a brief history and overview of the development of antidepressant drugs, the discovery of ketamine, and novel targets for fast antidepressant responses, particularly the potential role of endogenous neuromodulators.

Conclusions and Future Directions
Although ketamine is able to produce fast-onset responses following a single administration even to severely depressed individuals, its side effects and the possibility of neurotoxicity upon chronic administration have led to the investigation of novel fast-acting antidepressant agents. Our research group has focused on the investigation of endogenous mood modulators that may act as ketamine-like compounds. We provide evidence from preclinical studies that the endogenous glutamatergic neuromodulators agmatine and creatine have antidepressant behavioral profile similar to ketamine, besides presenting the ability to elicit antidepressant response by activating mTOR signaling pathway and/or acutely increasing synaptic proteins and BDNF levels in the hippocampus (creatine and agmatine) and prefrontal cortex (agmatine). Moreover, there is evidence under way in our laboratory indicating that guanosine and ascorbic acid also have the potential to afford antidepressant responses similar to ketamine. Considering that all of these compounds are safe even upon chronic use and exert these effects at very low doses, we consider that they are promising compounds to be tested in clinical studies. A particular interesting approach would be the investigation of the augmentation effect of low doses of ketamine by these compounds in order to provide efficacious fast-acting antidepressant response with lesser side effects.
 
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