Substance use disorders and Schizophrenia: a question of shared glutamatergic mechanisms.
Schizophrenia is noted for the remarkably high prevalence of substance use disorders (SUDs) including nicotine (>85%), alcohol and stimulants. Mounting evidence supports the hypothesis that the endophenotype of schizophrenia involves hypofunction of a subpopulation of cortico-limbic NMDA receptors. Low doses of NMDA receptor antagonists such as ketamine replicate in normal volunteers positive, negative and cognitive symptoms of schizophrenia as well as associated physiologic abnormalities such as eye tracking and abnormal event related potentials. Genetic studies have identified putative risk genes that directly or indirectly affect NMDA receptors including D-amino acid oxidase, its modulator G72, proline oxidase, mGluR3 and neuregulin. Clinical trials have shown that agents that directly or indirectly enhance the function of the NMDA receptor at its glycine modulatory site (GMS) reduce negative symptoms and in the case of D-serine and sarcosine improve cognition and reduce positive symptoms in schizophrenic subjects receiving concurrent anti-psychotic medications. Notably, the GMS partial agonist D-cycloserine exacerbates negative symptoms in clozapine responders whereas full agonists, glycine and D-serine have no effects, suggesting clozapine may act indirectly as a full agonist at the GMS of the NMDA receptor. Clozapine treatment is uniquely associated with decreased substance use in patients with schizophrenia, even without psychologic intervention. Given the role of NMDA receptors in the reward circuitry and in substance dependence, it is reasonable to speculate that NMDA receptor dysfunction is a shared pathologic process in schizophrenia and co-morbid SUDs.
Coyle
Joseph T
JT
Harvard Medical School, Department of Psychiatry, McLean Hospital, Belmont, MA 02478, USA. joseph_coyle@hms.Harvard.edu
D000077443:Acamprosate; D000427:Alcohol Deterrents / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D003952:Diagnostic Imaging; D005971:Glutamates / Q000502:physiology*; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D019966:Substance-Related Disorders / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000427:Alcohol Deterrents; D014150:Antipsychotic Agents; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D013654:Taurine; D003024:Clozapine; D000077443:Acamprosate