From The Quarterly, Fall 2010

People with schizophrenia use or abuse alcohol, marijuana and cocaine at three times the rate of the general population; in the case of tobacco, it’s four times the rate. With the help of a NARSAD grant some of the most detailed studies exploring the effect of these substances on the brain in schizophrenia have been undertaken. Studies are also considering the effect of the antipsychotic medication clozapine on substance abuse.



The brain circuit that controls dopamine neurotransmission, which is impaired in schizophrenia, is also involved in the brain’s reward system. Alcohol, marijuana, cocaine and nicotine improve the reward function in schizophrenia, but only transiently. In the end, most substance abuse makes schizophrenia worse and, of course, takes a toll on general health. Cannabis use is now known to be a risk factor in people with a variant of a gene called COMT that breaks down dopamine. For those people, marijuana use in adolescence raises the risk of psychosis 10-fold.



Clozapine is the most effective antipsychotic known, but it carries the risk of serious side effects, which limits its use. Clozapine also appears to decrease substance abuse, which earlier antipsychotic drugs, such as haloperidol (Haldol), do not do. The earlier drugs block the D2 dopamine receptor in neurons. Clozapine is a weak blocker of D2, but a potent blocker of other components of the brain, in particular, and part of a different transmitter system, called the norepinephrine alpha-two system.



By taking apart the various components of clozapine, work is being done to develop a drug with clozapine’s benefits, including reducing substance abuse, but with fewer side effects. Thus far it has been tested in animal models, and is now ready to begin clinical trials.

HEALTHY MINDS ACROSS AMERICA

In partnership with

Weill Cornell Medical College

Dartmouth-Hitchcock Medical Center



April 10, 2010



presentation by



Alan I. Green, M.D.

NARSAD Independent Investigator

Raymond Sobel Professor of Psychiatry

Professor of Pharmacology and Toxicology

Chairman, Department of Psychiatry

Dartmouth Medical School