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Identify Potential Side Effects Associated With Antipsychotic Medications (Both First and Second Generation Antipsychotics)

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The mechanism of action of most first- and second-generation antipsychotics (FGAs and SGAs) appears to be post-synaptic blockade of brain dopamine D2 receptors. Of the four exceptions, aripiprazole and brexpiprazole are D2 receptor partial agonists and cariprazine is a D3-preferring D3/D2 receptor partial agonist. Several lines of evidence support the role of these receptors in the activity of antipsychotics, most notably a strong correlation between D2 receptor binding and clinical potency and a consistent requirement of 65 percent D2 receptor occupancy for antipsychotic efficacy in functional imaging studies

The fourth exception, pimavanserin, is a serotonin 5HT2A inverse agonist and antagonist with no dopamine D2 affinity.

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Antipsychotics are the first‐line evidence‐based treatment for schizophrenia and other primary psychotic disorders

Some antipsychotics are also approved for treatment of bipolar disorder, treatment‐resistant depression, autism, or Tourette's disorder. In addition, these medications are prescribed off‐label for individuals with other conditions, such as borderline personality disorder, obsessive‐compulsive disorder, anorexia nervosa, insomnia, delirium, and various dementia syndromes including Alzheimer's disease. The utility of these drugs is hampered by their adverse effects, which must be weighed against their variable benefits for these conditions. The benefits of antipsychotic medications are sometimes obscured by their adverse effects. These effects range from relatively minor tolerability issues (e.g., mild sedation or dry mouth) to very unpleasant (e.g., constipation, akathisia, sexual dysfunction) to painful (e.g., acute dystonias) to disfiguring (e.g., weight gain, tardive dyskinesia) to life‐threatening (e.g., myocarditis, agranulocytosis). Importantly, adverse effect profiles are specific to each antipsychotic medication and do not neatly fit into first‐ and second‐generation classifications. This paper reviews management strategies for the most frequent side effects and identifies common principles intended to optimize net antipsychotic benefits. Only use antipsychotics if the indication is clear; only continue antipsychotics if a benefit is discernible. If an antipsychotic is providing substantial benefit, and the adverse effect is not life‐threatening, then the first management choice is to lower the dose or adjust the dosing schedule. The next option is to change the antipsychotic; this is often reasonable unless the risk of relapse is high. In some instances, behavioral interventions can be tried. Finally, concomitant medications, though generally not desirable, are necessary in many instances and can provide considerable relief. Among concomitant medication strategies, anticholinergic medications for dystonias and parkinsonism are often effective; beta‐blockers and anticholinergic medications are useful for akathisia; and metformin may lead to slight to moderate weight loss. Anticholinergic drops applied sublingually reduce sialorrhea. Usual medications are effective for constipation or dyslipidemias. The clinical utility of recently approved treatments for tardive dyskinesia, valbenazine and deutetrabenazine, is unclear.

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Patients with schizophrenia suffer from increased rates of multiple medical problems, due to their lifestyle (high smoking prevalence, high-fat diet), inherent neglect of personal care, and barriers to treatment of physical illness (Rondanelli M, Sarra S, Antoniello N., 2006). A further important contributor to adverse health outcomes is the side effect profile of antipsychotic medications. Since the introduction of the second generation or atypical antipsychotics (AAP), these agents have been widely prescribed for the management of patients with schizophrenia, bipolar disorders, other psychotic disorders or conditions with severe behavioral disturbance. The increasing use of AAP is in part due to their lower propensity to induce extrapyramidal symptoms and tardive dyskinesia compared to typical antipsychotics. Now, more than 15 years after the first atypical antipsychotic entered the market, psychiatrists have gradually come to realize that while extrapyramidal symptoms and tardive dyskinesia occur less frequently with atypical agents, these medications may present a different set of adverse effects. The quality of available evidence for the association of specific antipsychotics with particular side effects varies considerably. In this article, we review the recent findings concerning weight gain, diabetes mellitus (DM), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataract in patients receiving AAP. Forty to sixty-two percent of people with schizophrenia are overweight or obese (Wirshing DA, Wirshing WC, Kysar L., 1999). Obesity increases these patients’ risk for cardiovascular morbidity and mortality. In addition, excessive weight and obesity can have important effects on an individual’s adjustment in the community, adherence to prescribed medication, ability to participate in rehabilitation efforts, and self-image.

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In summary, tardive dyskinesia and other movement-related side-effects can develop in older adults who have used antipsychotics over a long period. Women are twice as likely as men to experience these effects

Antipsychotic medications are sometimes used to calm older adults with psychosis related to dementia. However, use of antipsychotics by older adults has been associated with an increased risk of stroke. Other ways of calming the person should always be tried first, and when antipsychotics are needed, they should only be used until symptoms are relieved.

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Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry. 2001;62(Suppl. 7):22–31.

Wirshing DA, Wirshing WC, Kysar L. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry. 1999;60:358–363.

Arvanitis LA, Miller BG. (Seroquel Trial 13 Study Group). Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry. 1997;42:233–246

Nemeroff CB. Dosing the antipsychotic medication olanzapine. J Clin Psychiatry. 1997;

Rondanelli M, Sarra S, Antoniello N. No effect of atypical antipsychotic drugs on weight gain and risk of developing type II diabetes or lipid abnormalities among nursing home elderly patients with Alzheimer’s disease. Minerva Med. 2006

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