NEW INSIGHTS INTO THE BIOLOGY OF SCHIZOPHRENIA THROUGH THE MECHANISM OF ACTION OF CLOZAPINE

Many studies have detected in the brain of schizophrenic patients vari ous morphological and structural abnormalities in various regions and in particular in the cortical and limbic areas. These abnormalities mi ght in part result from neurodevelopmental disturbances suggesting tha t schizophrenia might have organic causes. These abnormalities may be the primary event in schizophrenia and be responsible for altered dopa minergic, but not only dopaminergic, neurotransmission in these region s. If schizophrenia is in some way strictly related to brain morpholog ical abnormalities it becomes hard to believe that a curative treatmen t will ever be possible. Considering this scenario, treatment of schiz ophrenia will be restricted to symptomatic and preventive therapy and therefore, more effective and better tolerated antipsychotics are nece ssary. The widely used classical antipsychotic drugs present some disa dvantages. They do not improve all symptoms of schizophrenia, are nor effective in all patients, produce a number of unpleasant and serious, and partly irreversible, motor side effects. The atypical antipsychot ic clozapine constitutes a major advance in particular for patients no r responding to conventional neuroleptics. To explain the unique thera peutic effect of clozapine many hypotheses have been proposed. Most of the explanations given so far assume that the D-2 blockade is the bas is for the antipsychotic activity of clozapine and that the difference in respect to other antipsychotics is due to the contribution of othe r receptor interactions. Considering the dopaminergic receptor in part icular the recently discovered D-4 receptor subtype, it has been obser ved that even if several classical neuroleptics exhibit high affinity to the D-4 receptor, clozapine is more selective for this subtype comp ared to D-2 receptors. Moreover clozapine, differently from all other conventional neuroleptics, is a mixed but weak D-1/D-2 antagonist. Thi s observation has prompted speculation that the synergism between D-1 and D-2 receptors might allow antipsychotic effects to be achieved bel ow the threshold for unwanted motor side effects. Probably the D-1 ant agonistic activity exerted by clozapine at low doses enhances preferen tially the extracellular concentration of dopamine in specific areas o f the brain, such as the prefrontal cortex, where a dopaminergic hypoa ctivity has been suggested to be in part responsible for negative symp toms of schizophrenia. The clozapine enhancement of dopaminergic activ ity in this brain area might explain its efficacy against schizophreni a negative symptoms. However, it cannot be excluded that the affinitie s displayed by clozapine for other nondopaminergic receptors also cont ribute to its unique therapeutic profile. The various hypotheses menti oned in this review need to be further validated or disproved. The onl y way to do that is developing new drugs where the postulated mechanis tic profile is specifically realized and to clinically test these comp ounds.