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Psychosis is a symptom of mental illnesses characterized by a distorted or nonexistent sense of reality. 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%, but patients with schizophrenia exhibit features that extend beyond those seen in other psychotic illnesses. The positive symptoms of psychotic disorders include: hallucinations, delusions, disorganized speech, and disorganized or agitated behavior. Schizophrenia patients also suffer from negative symptoms (apathy, avolition, alogia), and cognitive deficits, particularly deficits in working memory, processing speed, and social cognition.

The dopamine (DA) hypothesis of psychosis was derived from the discovery that chlorpromazine and reserpine exhibited therapeutic antipsychotic properties in schizophrenia by decreasing dopaminergic neurotransmission. The DA overactivity hypothesis led to the development of the first therapeutic class of antipsychotic agents, now referred to as typical or first-generation antipsychotic drugs. The term "neuroleptic" refers to typical antipsychotic drugs that act through D2 receptor blockade but are associated with extrapyramidal side effects.

The DA hypothesis has its limitations: it does not account for the cognitive deficits associated with schizophrenia and does not explain the psychotomimetic effects of LSD (e.g., d-lysergic acid, a potent serotonin 5HT2 receptor agonist) or the effects of phencyclidine and ketamine, antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor. Advances in treatment have emerged from exploration of alternative (nondopaminergic) mechanisms for psychosis and from experience with atypical antipsychotic agents such as clozapine. The newer atypical antipsychotics potently antagonize the 5HT2 receptor, while blocking D2 receptors less potently than older typical antipsychotic agents, resulting in antipsychotic efficacy with limited extrapyramidal side effects. Promising medications target glutamate and 5HT7 receptor subtypes, receptors for γ-aminobutyric acid (GABA) and acetylcholine (both muscarinic and nicotinic), and peptide hormone receptors (e.g., oxytocin).


The 12th edition of the parent text reviews the relevant pathophysiology and the general goals of pharmacotherapy of psychosis and mania. Regardless of the underlying pathology, the immediate goal of antipsychotic treatment is a decrease in the acute symptoms that induce patient distress, particularly behavioral symptoms (e.g., hostility, agitation) that may present a danger to the patient or others. The dosing, route of administration, and choice of antipsychotic depend on the underlying disease state, clinical acuity, drug-drug interactions with concomitant medications, and patient sensitivity to short- or long-term adverse effects. With the exception of clozapine's superior efficacy in treatment-refractory schizophrenia, neither the clinical presentation nor biomarkers predict the likelihood of response to a specific antipsychotic class or agent. As a result, avoidance of adverse effects based upon patient and drug characteristics and exploitation of certain medication properties (e.g., sedation related to histamine H1 or muscarinic antagonism) are the principal determinants for choosing initial antipsychotic therapy.

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