Testing multiple novel mechanisms for treating schizophrenia in a single trial

Summary

Key words: Schizophrenia; clinical trial; osanetrant; NK3 antagonist; 5-HT2A/C antagonist; central cannabinoid antagonist; neurotensin antagonist.

Introduction

Schizophrenia is one of the most common and severe forms of mental illness. Its major features include psychosis, cognitive impairment, negative symptoms, and a high rate of suicide, the latter mainly due to depression and hopelessness. The treatment of schizophrenia in much of the world is largely pharmacologic, with psychosocial support and cognitive rehabilitation quite useful, but often not provided because of cost. Prior to the reintroduction of clozapine in 1990 in the USA, the major pharmacologic treatment for schizophrenia was dopamine D₂ receptor blockers, such as haloperidol, whose chief side-effects were mechanism-based blockade of D₂ receptors in the dorsal striatum, leading to a variety of acute and chronic extrapyramidal side-effects (EPS) (e.g. tardive dyskinesia). The demonstration that clozapine was more efficacious in a subgroup of patients and produced fewer EPS of all types (Meltzer, 1997; Kane et al., 1988), led to search for other drugs which were clozapine like but did not produce agranulocytosis, the side-effect which limited clozapine to use in treatment-resistant patients. The ensuing decade produced a variety of clozapine-like drugs, based on the principle of some dopamine D₂ receptor blockade, accompanied by serotonin (5-HT)_2A or 5-HT_1A, partial agonism, or both (Meltzer, 2001). The introduction of olanzapine, quetiapine, risperidone, ziprasidone, and zotepine has led to their replacing the D₂ blockers as first-line therapy. Recently, a partial dopamine D₂/D₃ agonist mechanism accompanied by 5-HT_1A partial agonism, and 5-HT_2A antagonism (i.e. aripiprazole) has been found to have similar advantages to drugs like risperidone.