Clozapine for comorbid substance use disorder and schizophrenia: Do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine?

Alcohol and other drugs of abuse are commonly used by persons with schizoph renia 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 us e in this population. While recognizing the likelihood that substance use d ecreases negative symptoms las well as extrapyramidal symptoms) in persons with schizophrenia, we hypothesize that the biological basis of substance u se relates to a "reward-deficiency syndrome" secondary to dysfunctional dop amine-mediated mesocorticolimbic neurons in these individuals. We further s uggest that clozapine's beneficial effect in patients with comorbid schizop hrenia and substance use disorders may relate to its presumed ability to am eliorate the deficits in both the mesocortical and mesolimbic dopaminergic neuronal projections through its various actions on dopaminergic, serotoner gic, and particularly noradrenergic neurons.