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Psychosis is a symptom of mental illnesses characterized by a distorted or non-existent sense of reality. Psychotic disorders have different etiologies, each of which demands a unique treatment approach. Common psychotic disorders include mood disorders (major depression or mania) with psychotic features, substance-induced psychosis, dementia with psychotic features, delirium with psychotic features, brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophrenia. Schizophrenia has a worldwide prevalence of 1% and is considered the prototypic disorder for understanding the phenomenology of psychosis and the impact of antipsychotic treatment, but patients with schizophrenia exhibit features that extend beyond those seen in other psychotic illnesses. Hallucinations, delusions, disorganized speech, and disorganized or agitated behavior comprise the types of psychotic symptoms found individually, or rarely together, in all psychotic disorders, and are typically responsive to pharmacotherapy. In addition to positive symptoms, schizophrenia patients also suffer from negative symptoms (apathy, avolition, alogia), and cognitive deficits, particularly deficits in working memory, processing speed, social cognition, and problem solving that test 1.5-2 standard deviations below population norms (Green et al., 2004). Cognitive dysfunction is the strongest predictor of functional impairment among schizophrenia patients, yet negative symptoms and cognitive deficits show limited improvement with antipsychotic treatment (Buchanan et al., 2007). That schizophrenia is not identical to other psychoses is important for appreciating the differential impact of antipsychotic medications on psychotic symptomatology, and for understanding the rationale for non-dopaminergic antipsychotic drugs based on the underlying pathophysiology of schizophrenia (Carpenter and Koenig 2008).

The Dopamine Hypothesis. The development of our understanding of the neurobiology and pharmacotheorapy of psychoses profited from the synthesis of chlorpromazine in 1950 and of haloperidol in 1958. The DA hypothesis of psychosis derived from the fortuitous discovery of chlorpromazine's therapeutic efficacy in schizophrenia, and the subsequent elucidation by Carlsson that postsynaptic DA D2 receptor antagonism was the common mechanism that explained antipsychotic properties. Reserpine, derived from Rauwolfia, exhibited antipsychotic properties by decreasing dopaminergic neurotransmission; however, unlike D2 receptor antagonists, reserpine exerted its effects through depletion of monoamines from presynaptic nerve terminals. The dopamine theory of psychosis was reinforced by the high risk for drug-induced psychosis among substances that directly increased synaptic dopamine availability, including cocaine, amphetamines, and the Parkinson's disease treatment L-dopa (Carlsson, 1978).

The dopamine (DA) overactivity hypothesis has led to the development of the first therapeutic class of antipsychotic agents, now referred to as typical or first-generation antipsychotic drugs. These medications differed in potency, but shared the common mechanism of significant DA D2 blockade and associated risk for extrapyramidal side effects. In the past, the term "neuroleptic" was also employed to refer to typical antipsychotic drugs, literally meaning to "take hold of the nerves" in Greek, but this has been dropped from contemporary usage (as has the term "major tranquilizer") in favor of "antipsychotic drug," a term that more accurately reflects the primary clinical ...

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