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Adverse Effects of Antipsychotic MedicationsJOHN MUENCH, MD, MPH, Oregon Health & Science University, Portland, OregonANN M. HAMER, PharmD, BCPP, Oregon State University College of Pharmacy, Corvallis, OregonThe use of antipsychotic medications entails a difficult trade-off between the benefit of alleviating psychotic symptoms and the risk of troubling, sometimes life-shortening adverse effects. There is more variability among specificantipsychotic medications than there is between the first- and second-generation antipsychotic classes. The newersecond-generation antipsychotics, especially clozapine and olanzapine, generally tend to cause more problems relating to metabolic syndrome, such as obesity and type 2 diabetes mellitus. Also, as a class, the older first-generationantipsychotics are more likely to be associated with movement disorders, but this is primarily true of medications thatbind tightly to dopaminergic neuroreceptors, such as haloperidol, and less true of medications that bind weakly, suchas chlorpromazine. Anticholinergic effects are especially prominent with weaker-binding first-generation antipsychotics, as well as with the second-generation antipsychotic clozapine. All antipsychotic medications are associatedwith an increased likelihood of sedation, sexual dysfunction, postural hypotension, cardiac arrhythmia, and suddencardiac death. Primary care physicians should understand the individual adverse effect profiles of these medications.They should be vigilant for the occurrence of adverse effects, be willing to adjust or change medications as needed (orwork with psychiatric colleagues to do so), and be prepared to treat any resulting medical sequelae. (Am Fam Physician. 2010;81(5):617-622. Copyright 2010 American Academy of Family Physicians.) See related editorialon page 585.Antipsychotic medications effectivelydiminish the intensity of psychotichallucinations, allowing mostinstitutionalized patients withschizophrenia to be discharged into community treatment. The first-generation antipsychotics (FGAs) work through dopamine D2neuroreceptor blockade, and a subsequentseries of new antipsychotics were developedwith stronger dopamine blockade.1 To discuss differences in the adverse effect profilesof FGAs, we use the terms “low-potency”and “high-potency,” not to indicate theirclinical effectiveness, but rather to indicateTable 1. Selected Conventional or First-GenerationAntipsychoticsUsual dailymaintenance dosageDrugDopamine D2neuroreceptor potencyChlorpromazine400 mgLowThioridazine200 to 300 mgLowPerphenazine24 mgMediumFluphenazine10 to 20 mgHighHaloperidol (formerlyHaldol)10 to 15 mgHighThiothixene (Navane)30 mgHighTrifluoperazine20 mgHighMarch 1, 2010 Volume 81, Number 5www.aafp.org/afp their potency in binding to this dopamineD2 neuroreceptor. Table 1 outlines selectedFGAs, the usual maintenance dosage, andrelative potency of dopamine D2 neuroreceptor blockade.Second-generation antipsychotics (SGAs)were launched in 1989 when investigatorsfound that clozapine (Clozaril) was moreeffective than chlorpromazine, with fewerextrapyramidal symptoms.2 These new antipsychotics were considered atypical becausethey targeted neuroreceptors other than onlydopamine. Over the past two decades, SGAshave dominated prescribing preferences inthe United States under the assumption thatthey are more effective and safer than FGAs.3Table 2 lists SGAs marketed in the UnitedStates, the year in which each was introduced, and the usual daily dosage.The results of two recent publicly fundedstudies designed to evaluate the effectiveness of these treatments under real-worldconditions have called into question theseprescribing preferences. The Clinical Antipsychotic Trials of Intervention Effectiveness study was designed to compare the FGAperphenazine with several SGAs, using “allcause discontinuation” as a proxy measurefor effectiveness.4 The Cost Utility of theLatest Antipsychotic Drugs in SchizophreniaAmerican Family Physician 617Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2010 American Academy of Family Physicians. For the private, noncommercialuse of one individual user of the Web site. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.

Antipsychotic MedicationsSORT: KEY RECOMMENDATIONS FOR PRACTICEEvidenceratingReferencesFGAs with lower potency dopamine D2 neuroreceptor blockade (Table 1) are no more likely thanmost SGAs to cause extrapyramidal symptoms.A4, 5, 9FGAs and the SGA risperidone (Risperdal) commonly cause hyperprolactinemia. Physicians shouldbe vigilant for signs and symptoms of hyperprolactinemia in patients taking these medications.C6, 19Patients taking SGAs, especially clozapine (Clozaril) and olanzapine (Zyprexa), should be monitoredclosely for weight gain and other metabolic syndrome–related adverse effects (Table 4).C39Antipsychotic medications should be used with caution in older adults because of the risk ofincreased mortality from sudden cardiac death and cerebrovascular accidents.A40-42Clinical recommendationFGAs first-generation antipsychotics; SGAs second-generation antipsychotics.A consistent, good-quality patient-oriented evidence; B inconsistent or limited-quality patient-oriented evidence; C consensus, diseaseoriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.Study measured quality of life and other effectivenessmeasures.5 Neither study demonstrated a clear differencein effectiveness between FGAs and non-clozapine SGAs.With the exception that clozapine is more effective fortreatment-resistant patients,6 the choice of antipsychoticshould depend on the potential for adverse effects in individual patients. General comparisons between the FGAand SGA classes are less helpful than comparisons amongspecific medications because each presents its own challenges in terms of balancing effectiveness with safety andtolerability. This article reviews some of the more important adverse effects of antipsychotics, and includes a summary table of the comparative risks (Table 3).6,7SedationSedation is common with antipsychotic medications andis dose related. It can be a cause of poor compliance and, ifpersistent, can interfere with social and vocational functioning. Many patients become tolerant to the sedativeTable 2. Atypical or Second-GenerationAntipsychotics Marketed in the United StatesDrugYearintroducedAripiprazole (Abilify)200210 to 30 mgClozapine (Clozaril)1989300 to 600 mgOlanzapine (Zyprexa)199610 to 20 mgQuetiapine (Seroquel)1998250 to 600 mgRisperidone (Risperdal)19943 to 6 mgZiprasidone (Geodon)200140 to 80 mgUsual daily dosagenote: Paliperidone, the active metabolite of risperidone, has beenmarketed in the United States as Invega since 2007. There is insufficient long-term clinical information on this medication to include itin this review. It is likely that the adverse effect profile of Invega willbe similar to that of risperidone.618 American Family Physicianeffect over time. Low-potency FGAs and clozapine arethe most sedating, with some effect from olanzapine(Zyprexa) and quetiapine (Seroquel).6 Somnolence canbe alleviated by lowering the dosage, changing to a singlebedtime dose, or switching to a less sedating medication.HypotensionOrthostatic hypotension can occur with all antipsychoticmedications, depending on the degree of α1-adrenoreceptor antagonism, particularly with low-potency FGAs andclozapine. It can also occur with risperidone (Risperdal)and quetiapine, especially with rapid titration. This effectis more common in older adults (with risk of falls), thoseon blood pressure medications, and those who have othercardiovascular diseases. With careful dose titration,patients may become tolerant to this effect. Treatmentoptions include decreasing or dividing doses or switchingto a medication with a lesser antiadrenergic effect.6Anticholinergic EffectsAnticholinergic effects include constipation, urinaryretention, dry mouth, blurred vision and, at times, cognitive impairment. These symptoms can lead to otherproblems such as tooth decay, falls, or gastrointestinal obstruction. Low-potency FGAs and clozapine arehighly likely to cause anticholinergic effects; olanzapineand quetiapine have been shown to do so at high dosages.8 When needed, doses can be lowered or divided tohelp alleviate this problem.Extrapyramidal SymptomsAntipsychotic medications cause four main extrapyramidal symptoms: pseudoparkinsonism, akathisia, acutedystonia, and tardive dyskinesia. The first three usually begin within a few weeks of starting a new medication (or increasing the dosage). These symptoms maycause discomfort, social stigma, and poor compliance.They are more likely to occur with higher dosages ofwww.aafp.org/afpVolume 81, Number 5 March 1, 2010