Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: Evidence from the bench and the bedside

Abstract

Understanding substance use disorders (SUDs) and the problems associated with abstinence has grown in recent years. Nonetheless, highly efficacious treatment targeting relapse prevention has remained elusive, and there remains no FDA-approved pharmacotherapy for psychostimulant dependence. Preclinical and clinical investigations assessing the utility of classical antidepressants, which block monoamine reuptake, show mixed and often contradictory results. Mirtazapine (Remeron®) is a unique FDA-approved antidepressant, with negligible affinity for reuptake proteins, indirectly augments monoamine transmission presumably through antagonist activity at multiple receptors including the norepinephrine (NE)α2, and serotonin (5-HT)2A/C receptors. Historically, mirtazapine was also considered to be a 5-HT2C antagonist, but recent evidence indicates that mirtazapine is an inverse agonist at this receptor subtype. Suggesting a promising role for mixed-action serotonergic drugs for addiction pharmacotherapy, mirtazapine attenuates psychostimulant-induced behaviors in several rodent models of substance abuse, and antagonizes methamphetamine-induced biochemical and electrophysiological alterations in rats. Preclinical findings are confirmed through published case studies documenting successful outcomes with mirtazapine therapy across a number of SUDs. To date, a large scale clinical trial assessing the utility of mirtazapine in substance abuse pharmacotherapy has yet to be conducted. However, as reviewed here, accumulating preclinical and clinical evidence argues that mirtazapine, or compounds that emulate aspects of its pharmacological profile, may prove useful in helping treat addictions.

Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease

“…5, chronic mirtazapine infusion did not alter the improvements in akinesia provided by PPX; however, PPX-enhanced risk-taking was attenuated (albeit, modestly). This trend is in keeping with the ability of mirtazapine to reduce motivated behaviors sustained by abused drugs in rats and humans [18–22,24,45] and ICSS-mediated decision-making in rats [46]. Outcomes also indicate that the systems engaged by mirtazapine may be more relevant to ICD than motor function.…”

“…Thus, we postulated that therapies which hold promise for addiction may provide relief from ICDs. Mirtazapine, an atypical antidepressant, reduces behaviors associated with substance use disorders in rats [18–22] and humans [23,24]. Moreover, mirtazapine has been used to treat anxiety, depression, and psychosis in PD patients, and is well-tolerated by PD patients on dopamine agonist therapy with little to no effect on the motor benefits afforded by the agonist [25–30].…”

Mirtazapine and ketanserin alter preference for gambling-like schedules of reinforcement in rats

“…Mirtazapine is an atypical antidepressant with a complex pharmacological profile that includes antagonism at 5-HT 2A/2C receptors (De Boer, 1995;Wikstrom et al, 2002). Mirtazapine attenuates various behaviors motivated by abused drugs, including methamphetamine (Herrold et al, 2009;Voigt et al, 2011;Graves and Napier, 2011;Voigt and Napier, 2011) and morphine (Graves et al, 2012a) in rats, and reduces cocaine intake in humans (Graves et al, 2012b). We recently revealed that mirtazapine reduces the capacity of the dopamine D2/D3 receptor agonist, pramipexole, to induce risky decision-making by rats performing a probability discounting task (Holtz et al, 2016).…”

A Review Of The Literature Of Mirtazapine In Co-Occurring Depression And An Alcohol Use Disorder

“…Findings from preclinical studies involving rats and published case studies in humans suggest that mirtazapine therapy may contribute to successful outcomes across a number of substance use disorders, including alcohol use disorders, amphetamine dependence, and other substance use disorders [11,12]. Consequently, those recent reviews have suggested that preliminary findings suggest a promising role for mirtazapine in addiction pharmacotherapy.…”

“…Consequently, those recent reviews have suggested that preliminary findings suggest a promising role for mirtazapine in addiction pharmacotherapy. However, a large scale clinical trial assessing the utility of mirtazapine in the treatment of substance use disorders has not yet been conducted [12]. …”