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sychosis is a major contributor to adverse quality of life in residents of skilled nursing facilities (SNFs). It also can lead to high levels of stress in facility caregivers who care for affected individuals. Psychosis is a psychiatric disorder in which the patient loses touch with reality and is characterized by the triad of hallucinations, paranoia, and delusions. These three closely related signs of schizophrenia are the so-called “positive” signs (in contrast to the “negative” signs of apathy, withdrawal, catatonia, etc.). Hallucinations can be visual (e.g., seeing things that are not there), auditory (hearing voices that are not real), gustatory (taste), olfactory (smell), and tactile (e.g., feeling insects, which are not there, crawling on the skin) in nature. Delusions are fixed false beliefs. Paranoia involves pathologic suspicion of other individuals when there is no reason to do so (e.g., poisoning, marital infidelity, “thought transfer”). It should be remembered that an individual can be psychotic and not have schizophrenia or schizoaffective disorder.
       The drugs of choice for psychosis and related pathology are the neuroleptics (formerly called “major tranquilizers” and “antipsychotics”). These agents can be divided into two major classes: traditional and atypical. Each will be described in detail.

Traditional Neuroleptics

       These agents have been marketed for many years, starting with chlorpromazine in the 1950s. Since that time, many agents have been developed that all act in the same fashion, by blocking dopamine receptors in the mesolimbic and prefrontal cortex of the brain.
       The traditional agents are classified as low potency (chlorpromazine, thioridazine), intermediate potency (loxapine, molindone), and high potency (fluphenazine, perphenazine, trifluoperazine, thiothixene, haloperidol, and pimozide). Although they work well against psychoses, these agents bind to a variety of receptor types in the body, leading to a well known cadre of side effects. Blockade of histaminergic, muscarinic cholinergic, dopaminergic, and alpha-adrenergic receptors leads to sedation, anticholinergic effects (e.g., dry mouth, tachycardia, constipation, blurred vision), abnormal involuntary muscle movements (also known as extrapyramidal effects), and orthostatic hypotension, respectively. The low potency agents tend to be highly sedating, moderately to highly anticholinergic, and have a high risk of inducing symptomatic orthostasis. In turn, the risk of extrapyramidal signs (EPS) is moderate to low. Among the intermediate potency agents, sedation, anticholinergic, and orthostasis risks are low, while the EPS risk is moderate. Among the high potency agents, which are the most commonly used traditional agents in the elderly, sedation, anticholinergic, and orthostasis risks are low to very low, while EPS risk is high to very high. As a result, even with conservative dosing strategies, these agents may contribute to falls (via sedation and orthostasis) in the elderly as well as Parkinsonian-like dystonias, dyskinesias, and akathisia, which may progress to potentially irreversible tardive dyskinesia.



Atypical Neuroleptics

       Due to the liabilities of the traditional agents, especially precipitation of abnormal involuntary muscle movements, the search began for neuroleptics that would not be associated with this specific adverse effect. Clozapine was the first so-called atypical neuroleptic followed by risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. These agents also work by blocking dopamine receptors in the brain, but because they also block and stimulate different types of serotonin receptors, their ability to precipitate EPS is low to negligible.
       Clozapine is infrequently used in the elderly because of its risk of agranulocytosis (mandating performance of weekly or biweekly white blood cell counts with differential) as well as its ability to block alpha-adrenergic, histaminergic, and muscarinic cholinergic receptors, causing the unpleasant side effects previously discussed under “Traditional Neuroleptics.” In addition, patients taking clozapine may suffer from hypersalivation, which may be extreme (mechanism unknown). However, clozapine is the atypical agent least likely to precipitate EPS and is the drug of choice (if tolerated) for treating the psychosis of Parkinson’s disease, because it will not worsen the motor symptoms of the disease. Clozapine may induce weight gain, in some cases over 30 kg, which could be an asset or liability depending on the patient. It may also induce hyperlipidemia (especially triglycerides) and glucose intolerance (even frank diabetes).
       Risperidone was the second atypical neuroleptic approved in the United States. Although much better tolerated than clozapine, risperidone is the only atypical agent that can switch from being an atypical neuroleptic to a traditional one (in terms of precipitating EPS) within its therapeutic dosage range. In the elderly, this can occur with a daily dosage as low as 1–2mg. It may also cause symptomatic orthostasis, especially immediately after initiation or a dosage increase, due to alpha-adrenergic receptor blockade. It causes less weight gain, hyperlipidemia, and glucose intolerance than clozapine or olanzapine.
       Olanzapine is an especially useful drug when the patient has symptoms or signs of a mood disorder concurrently (e.g., depression, bipolar disorder, obsessive-compulsive disorder). Similar to clozapine, olanzapine therapy usually leads to weight gain, again, in some cases, 30 or more kg, and may induce hyperlipidemia and glucose intolerance.
       Quetiapine generally does not cause weight gain, hyperlipidemia, or glucose intolerance and is the drug of choice (after clozapine) for treating Parkinsonian psychosis. Although somewhat sedating, most elders tolerate the drug reasonably well if dosage increases are small in magnitude and spaced two to four (or more) weeks apart.
       Ziprasidone is generally avoided in elders due to its greater ability (than other atypicals) to prolong the QT interval of the electrocardiogram. This electrophysiologic effect can lead to an arrhythmia called polymorphous ventricular tachycardia (“torsades de pointes”) which may degenerate into ventricular fibrillation and death. As elders frequently have risk factors for QT prolongation (e.g., electrolyte abnormalities and/or take other drugs that also produce the same effect), it is probably reasonable to avoid ziprasidone, especially as there are several alternatives available.
       There is virtually no published experience with aripiprazole, the newest of the atypical agents, in elderly patients. At this time, the drug does not appear to be associated with weight gain or metabolic abnormalities (lipids, glucose). However, it can induce symptomatic orthostasis due to alpha-adrenergic receptor blockade. In addition, it may be the subject of drug-drug interactions due to its extensive metabolism by cytochrome P450 hepatic enzymes (isozymes 3A4 and 2D6). Other agents that induce or inhibit these two isozymes may alter the pharmacokinetics of aripiprazole and mandate dosage modification.

Conclusion

       Psychosis in elderly subjects can be a terrifying experience for patients and caregivers. Rapidly effective and safe therapy should be instituted immediately in affected individuals. Although a large number of neuroleptics are available in the US, there is little reason to look beyond haloperidol and the atypical agents. Haloperidol may be an appropriate choice if the patient’s life expectancy is short (< 2 years). In most cases, atypical agents are preferred due to the EPS risks with traditional agents, especially tardive dyskinesia with long-term use. However, the atypical neuroleptics are not benign from an adverse event perspective. Careful dosage adjustment and monitoring are required to maximize benefits and minimize risks.