Another question not yet addressed by controlled trials is how early should a recent-onset psychosis patient who does not respond to the antipsychotic drugs be switched to clozapine. On the one hand, if, as suggested, a longer duration of untreated psychosis has long-term detrimental effects37 and if most other antipsychotics are not effective in treatment-refractory Inhibitors,research,lifescience,medical psychosis,38 then the switch should occur as soon as it becomes apparent that the individual patient might not respond to the initial drug. Accumulating data indicate

that lack of response during the first 1 to 3 weeks of treatment is predictive of lack of response during the subsequent weeks.35,39,40 On the other hand, because of the rare and manageable, but potentially lethal, clozapine-induced agranulocytosis, most recentonset psychosis patients in daily clinical practice are treated with several antipsychotic drugs before they are switched to clozapine. Whether Inhibitors,research,lifescience,medical this clinical practice is also the optimal one remains to be seen. Inhibitors,research,lifescience,medical Negative symptoms and cognitive deficits In contrast to the remission or at least marked amelioration of the psychotic symptoms, most patients show inadequate improvement in negative symptoms23,24,32,33 and cognitive deficits.41 Even when negative symptoms and

cognitive deficits are improved by antipsychotic drugs, the benefit is limited to a 0.2 to 0.3 effect size. This is not surprising considering the process of drug development in schizophrenia and the nature of negative symptoms and cognitive deficits. In the absence of a good conceptual model for Inhibitors,research,lifescience,medical schizophrenia, since the serendipitous observation that chlorpromazine ameliorates psychosis, all subsequent drugs have been screened in vitro and in animal models on the basis of their similarities to chlorpromazine or to other drugs already proven to ameliorate psychosis. To reach the market, drugs had only to prove that they ameliorate Inhibitors,research,lifescience,medical psychotic symptoms in clinical trials, and not negative symptoms or cognitive

deficits. Therefore, currently available agents have not been designed or selected to affect the two later manifestations of schizophrenia, negative symptoms and cognitive deficit. It also appears that the cognitive deficits and, possibly, negative symptoms are not Resveratrol of recent onset, but are long-standing, core features of the schizophrenic disease6,10 and that cognitive impairment is inherited independently of psychosis.42 EPSs and therapeutic dose range In addition to the fact that antipsychotic drugs benefit some but not other aspects of psychosis, many recentonset psychosis patients show Wnt inhibitor enhanced sensitivity to EPSs even at doses of antipsychotic that are within accepted therapeutic ranges.43 The enhanced sensitivity to antipsychotic-induced EPSs appears to be true for both typical44 and atypical drugs.