Clozapine for Comorbid Substance Use Disorder and Schizophrenia: Do Patients with Schizophrenia Have a Reward-Deficiency Syndrome That Can Be Ameliorated by Clozapine?

Abstract

Alcohol and other drugs of abuse are commonly used by persons with schizophrenia and contribute to the overall morbidity of the disorder. Standard, or typical, antipsychotic drugs do not limit such substance use and may even render it more likely. However, preliminary data from our group and others suggest that the atypical antipsychotic clozapine may decrease substance use in this population. While recognizing the likelihood that substance use decreases negative symptoms (as well as extrapyramidal symptoms) in persons with schizophrenia, we hypothesize that the biological basis of substance use relates to a "reward-deficiency syndrome" secondary to dysfunctional dopamine-mediated mesocorticolimbic neurons in these individuals. We further suggest that clozapine's beneficial effect in patients with comorbid schizophrenia and substance use disorders may relate to its presumed ability to ameliorate the deficits in both the mesocortical and mesolimbic dopaminergic neuronal projections through its various actions on dopaminergic, serotonergic, and particularly noradrenergic neurons.

Olanzapine Reduces Craving for Alcohol: A DRD4 VNTR Polymorphism by Pharmacotherapy Interaction

“…The study with olanzapine is consistent with previous work indicating that consumption of alcohol increases craving and that a traditional dopamine antagonist (ie haloperidol), that acts on D 2 and D 4 receptors, reduces alcohol-elicited craving (Modell et al, 1993). In addition to these laboratory studies on dopamine antagonists and alcohol craving, recent clinical reports have suggested that clozapine, a D 4 receptor antagonist that is similar to olanzapine, reduces substance abuse among patients with comorbid substance abuse/ dependence (Green et al, 1999) and specifically, alcohol use (Drake et al, 2000). Thus, research with humans suggests that selective targeting of dopamine receptor subtypes may be useful for developing pharmacotherapies that reduce craving.…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…These characteristics support inclusion of schizophrenia within the spectrum of the 'reward deficiency syndrome' (Green et al, 1999), which is comprised of a broad range of personality traits and mental disorders (including, but not limited to schizoid/ avoidant character styles, glucose binging and posttraumatic stress disorder) allegedly characterized by hypofunctionality of the reward circuitry, clinically manifested as diminution of drive/motivation and of capacity to enjoy or to experience pleasure (Comings and Blum, 2000).…”

“…One such possible overlap area is the neural pathways mediating reward (subjective experience of pleasure) and reinforcement (increased rate of recurrent actions), a relevant etiologic factor in both schizophrenia (Green et al, 1999;Chambers et al, 2001;Brady and Sinha, 2005) and eating behavior (Wang et al, 2001(Wang et al, , 2002(Wang et al, , 2003(Wang et al, , 2004. The following sections discuss energy balance systems and how they intersect with the brain reward and reinforcement mechanisms.…”

The Effect of Olanzapine on Craving and Alcohol Consumption

“…Thus, the effect of alcohol and alcohol cues on the activation of these dopamine pathways represents a target that may prove to be useful in terms of pharmacotherapy development, and genetic variants that alter the functioning of these pathways may prove to be important in terms of predicting the success of such a pharmacotherapy. Other research has suggested that clozapine, a D 4 receptor antagonist that is somewhat similar to olanzapine, reduced substance abuse among patients with comorbid substance abuse/dependence (Green et al, 1999) and, specifically, alcohol use (Drake et al, 2000). Thus, clinical research also supports an important role for the D 2 family of receptors, and specifically the D4 receptor.…”