Dr. Goff began with a description of three major approaches to the treatment of negative symptoms associated with schizophrenia. The first involves dopamine D2 receptor antagonists, the second atypical antipsychotics, and the third glutamatergic agents.

Medication trials conducted by the National Institute of Mental Health in the 1960s reported reduction of negative symptoms during treatment with phenothiazines. Brier's small, placebo-controlled study showed significantly more improvement of negative symptoms in patients treated with fluphenazine than in patients treated with placebo. The response of positive symptoms did not correlate with that of negative symptoms.

These studies triggered debate among psychiatrists: Some considered negative symptoms, such as reduced motivation, social withdrawal, self-neglect, and affective blunting to be primary symptoms of schizophrenia, while others considered negative symptoms secondary to positive psychotic symptoms, such as delusions and hallucinations. According to Goff, there is still no satisfactory consensus among psychiatrists.

Negative symptoms improve during treatment with very low dosages of typical antipsychotics. The therapeutic window for improvement of negative symptoms is narrow, however, and improvement is lost as extrapyramidal adverse effects emerge.

Clozapine is significantly more effective for negative symptoms than the older, typical antipsychotic medications. Kane's 1988 study compared clozapine with chlorpromazine plus benztropine. Using the anergia subscale of the Brief Psychiatric Rating Scale to assess negative symptoms, Kane and colleagues found that clozapine had a large beneficial effect on negative symptoms that had not reached a plateau by the end of the six-week trial.

Dr. Goff then discussed glutamate systems in general and N-methyl-D-aspartate (NMDA) receptors in particular. When the NMDA agonist ketamine is given to normal subjects, it induces psychotic symptoms resembling those of schizophrenia. If ketamine is administered to schizophrenic patients who are stabilized on haloperidol, they show dramatic worsening of psychotic symptoms that can be prevented by clozapine.

Dr. Goff speculates that prevention by clozapine of ketamine-induced psychotic worsening in patients whose positive symptoms have been stabilized by haloperidol suggests that NMDA receptor activity may be involved in the pathophysiology of schizophrenic negative symptoms. He believes that further study of NMDA neurotransmission may yield clinically significant findings and that NMDA antagonists may be promising candidates for antipsychotic drug development.