The second major unmet medical need is improved efficacy across all symptom domains. While all current drugs are effective at treating the positive symptoms of schizophrenia in the majority of patients, the negative and cognitive symptoms, along with comorbid mood disorders, are not sufficiently improved. Current inabilities to treat all of the core symptoms of schizophrenia are due in part to the primacy of the DA hypothesis, which has dominated treatment strategies for over 50 years. Necessarily, drug intervention based on this hypothesis has focused on efficacy as defined by a reduction in positive symptoms. No drug has been developed or approved for human use that does not reduce positive symptoms. Yet, the challenge of achieving optimal outcome in patients with schizophrenia has not been met. A large number of patients with schizophrenia in the USA are homeless or incarcerated. By no means do current therapies normalize function and allow the afflicted individual to re-enter society. This is particularly devastating given that first signs of schizophrenia appear in the late teens and early twenties and the disorder is lifelong. Residual impairments such as negative and cognitive symptoms which escape current treatment preclude normal socialization of the patient with schizophrenia, and are more closely correlated with functional outcome than positive symptoms. Typical antipsychotic drugs, like haloperidol, fail to improve and may further impair various domains of cognition in schizophrenic patients. Newer atypical antipsychotic drugs like clozapine, risperidone, quetiapine, and olanzapine appear not to impair cognitive function in patients with schizophrenia and may improve performance in some but not all domains of cognition. It is important to note that each drug may influence different aspects of cognitive function and no drug normalizes cognitive function in all patients.
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