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Primary Care Issues in Patients with Mental Illness BERNADETTE KIRALY, MD; KAREN GUNNING, PharmD, BCPS; and JENNIFER LEISER, MD, University of Utah School of Medicine, Salt Lake City, Utah

Family physicians commonly care for patients with serious mental illness. Patients with psy- chotic and bipolar disorders have more comorbid medical conditions and higher mortality rates than patients without serious mental illness. Many prescribed for serious men- tal illness have significant metabolic and cardiovascular adverse effects. Patients treated with second-generation should receive preventive counseling and treatment for obe- sity, hyperglycemia, diabetes, and hyperlipidemia. First- and second-generation antipsychot- ics have been associated with QT prolongation. Many common medications can interact with antipsychotics, increasing the risk of cardiac arrhythmias and sudden death. Drug interactions can also lead to increased adverse effects, increased or decreased drug levels, toxicity, or treat- ment failure. Physicians should carefully consider the risks and benefits of second-generation medications, and patient care should be coordinated between primary care phy- sicians and mental health professionals to prevent serious adverse effects. (Am Fam Physician. 2008;78(3):355-362, 363-364. Copyright © 2008 American Academy of Family Physicians.)

T See related editorial erious mental illness (i.e., schizo- cancer screening, tobacco-use counseling, on page 314. phrenia, nonaffective psychotic dis- and immunizations.6 Patients with mental T Patient information: orders, bipolar spectrum disorders, illnessarealsolesslikelytoreceiveappro- A handout on mental substance dependence, and suicidal- priate treatment for acute problems, such as illness, written by the Sity) affects 6 percent of adults in the United coronary revascularization procedures fol- authors of this article, is 1 9 provided on page 363. States. Patients with these disorders have a lowinganacutemyocardialinfarction. higher risk of mortality associated with clini- A study that surveyed family physicians caldiseaseandunnaturalcauses(e.g.,suicide, about patients with common complaints homicide, accidents).2,3 Common medical (severeheadacheorabdominalpain)and conditions in patients with serious mental comorbid mental illness showed that physi- illness include metabolic disorders, cardio- cians underestimate the pretest probability vascular disease, chronic pulmonary disease, of disease and, consequently, obtain fewer gastrointestinal disorders, and obesity.4,5 appropriate tests.10 Patients with mental ill- Historically, efforts to improve the health ness who have been diagnosed with diabe- of patients with mental illness focused solely tes and hyperlipidemia are only 29 percent on pharmacologic treatment. However, as likely to be prescribed a statin medica- recenteffortshavealsoincludedmedical tion as patients without mental health prob- comorbidities and quality of medical care.6,7 lems.11 Patients with mental illness report poor coordination of care between primary Causes of Poor Health care physicians and mental health profes- Several factors contribute to poor health sionals.12 Lifestyle and behavioral factors and increased mortality in patients with also contribute to increased comorbidities seriousmentalillness.Thesepatientsmay in these patients. Patients with schizophre- have decreased access to health insurance niainparticularhavepoorerdietaryhabits, and medical care and may delay seeking smoke more, and exercise less than the gen- care because of cost.8 One study showed eral population.13,14 that persons with mental illness were less adverse effects and interac- likely to receive preventive care, including tions contribute to medical comorbidities.

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence Clinical recommendation rating References

Patients using second-generation antipsychotics should receive counseling C24 to prevent obesity, hyperlipidemia, and diabetes.* When possible, primary care physicians should avoid prescribing drugs that C19, 33-35 interact with psychiatric medications in patients with serious mental illness. To avoid medication-related adverse outcomes, primary care physicians C47 and mental health professionals should coordinate the care of patients with serious mental illness.

*—Recommendation from consensus guidelines of the American Diabetes Association, American Psychiatric Associ- ation, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see http://www.aafp.org/afpsort.xml.

Primary care physicians and mental health glucoseintolerance,diabetes,andhyper- professionalsmaynotbeawareofeach lipidemia. Both antipsychotic classes are medicationthesepatientshavebeenpre- associated with cardiovascular adverse scribed, increasing the risk of interactions. effects, particularly QT prolongation. Many common psychiatric medications (Table 1) cause serious adverse effects. First- OBESITY AND WEIGHT GAIN generation antipsychotics cause extrapy- Obesity associated with serious mental ill- ramidal adverse effects, including tardive ness is multifactorial.5 Medication effects, dyskinesia, whereas second-generation poor nutrition, difficulty with meal plan- antipsychotics may cause metabolic adverse ning,poorimpulsecontrol,andlackof effects, including weight gain, obesity, exercise contribute to weight gain.15 Second- generation antipsychotics can cause rapid weight gain in the first few months of therapy 16-19 Table 1. Common Antipsychotic Medications (Table 2 ), anditcantakeuptooneyear forbodyweighttostabilize.Averageweight First-generation antipsychotics* Thiothixene (Navane) gainvariesfrom1lb,2oz(0.5kg)to11lb (Thorazine†) Trifluoperazine (Stelazine†) (5.0kg)withinthefirst10weeksoftherapy. The mechanism of antipsychotic-induced (Prolixin†) Second-generation (Haldol) antipsychotics‡ weight gain is unknown. Loxapine (Loxitane) (Abilify) DIABETES (Serentil); this medication has (Clozaril) been discontinued in the United States (Zyprexa) Before the availability of antipsychotic medi- (Moban) (Invega) cations, the prevalence of diabetes in patients (Trilafon†) (Seroquel) with was estimated at 2.5 to 20 (Orap) (Risperdal) 4.2 percent. Arecentcross-sectionalstudy (Compro) (Geodon) of patients in Holland with schizophrenia (Mellaril†) and schizoaffective disorder, showed that theprevalenceofhyperglycemiaanddiabe- *—Also called typical antipsychotics; associated with an increased incidence of extra- tes are 7.0 and 14.5 percent, respectively.21 pyramidal symptoms and increased cognitive impairment. †—Brand no longer available in the United States. The increased risk of type 2 diabetes ‡—Also called atypical antipsychotics; associated with a decreased incidence of extra- in patients with schizophrenia or bipolar pyramidal symptoms. disorder is associated with the increased use of second-generation antipsychotics.22,23

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Although the exact mechanism for hyper- glycemiaisunknown,itmaybecausedby Table 2. Selected Antipsychotics Associated drug-induced insulin resistance from associ- with Weight Gain ated weight gain, changes in body fat distri- bution, or direct effects on insulin-sensitive Medication Effect on weight gain 24 target tissues. First-generation Weight gain is generally less than with second- New-onset diabetes, worsening of known antipsychotics generation antipsychotics, but the effects are diabetes, and hyperglycemic crises have widely variable been reported after the initiation of second- Second-generation antipsychotics* generation antipsychotics. The U.S. Food and Aripiprazole (Abilify) Similar to placebo16 Drug Administration requires that labels for Clozapine (Clozaril) Average weight gain at 10 weeks: all second-generation antipsychotics include 9 lb, 13 oz (4.45 kg)17,18 warnings about the risk of hyperglycemia and Olanzapine (Zyprexa) Average weight gain at 10 weeks: 17,18 diabetes. Clozapine (Clozaril) and olanzapine 9 lb, 2 oz (4.15 kg) (Zyprexa) are associated with the greatest risk. Quetiapine (Seroquel) Weight gain ranges from minimal to a mean gain of 5 lb, 8 oz (2.49 kg) at six weeks17 Clinical trials of ziprasidone (Geodon) and Risperidone (Risperdal) Average weight gain at 10 weeks: aripiprazole (Abilify) lasting up to one year 4 lb, 10 oz (2.10 kg)17,18 demonstratedratesofweightgainandmeta- Ziprasidone (Geodon) Average weight gain at 10 weeks: 25 bolic changes similar to that of placebo. 1 oz (0.04 kg)18

HYPERLIPIDEMIA *—Combining second-generation antipsychotics with mood stabilizers, particularly 19 Second-generation antipsychotics are asso- and valproate (Depacon), leads to additional weight gain. ciated with increased serum triglyceride and Information from references 16 through 19. total cholesterol levels. Clozapine appears to havethestrongesteffect,increasingtriglycer- idelevelsbyupto42percent.Olanzapinehas antipsychotic therapy.24 The following section been associated with a 38 percent increase in summarizes the panel’s recommendations triglyceride levels and a 10 percent decrease on lifestyle counseling, obesity manage- in high-density lipoprotein (HDL) choles- ment, patient education, and treatment goals. terol levels, with the maximal effect occur- The recommended monitoring protocol for ring within 10 months of initiating therapy. patients receiving second-generation antipsy- Quetiapine (Seroquel) increases triglyceride choticsissummarizedinTable 3.24 levels by 17 percent and may decrease HDL cholesterol levels. Risperidone’s (Risperdal) EXERCISE AND WEIGHT MANAGEMENT effectonlipidlevelsisunclear.26 Aripipra- Patients with serious mental illness are more zoleandziprasidonehavenotbeenshown likely to be physically inactive than the general tohavesignificanteffectsonlipidlevels.26 population. Factors associated with physical Thereisnoconclusiveevidencethatthese inactivity include female sex and limited social changesinlipidprofilesleadtoincreased contacts.13 Allpatientswithmentalillness cardiovascular events.27 treated with second-generation antipsychot- ics should receive physical activity counseling, Guidelines for the Prevention and and those who are overweight or obese should Treatment of Metabolic Changes also receive nutrition counseling. TheAmericanDiabetesAssociation(ADA), If a patient’s weight increases by more than American Psychiatric Association (APA), 5percent,physiciansshouldconsiderchang- American Association of Clinical Endo- ing, using slow cross-titration, to another crinologists, and North American Asso- second-generation antipsychotic that is not ciation for the Study of Obesity convened associated with weight gain.24 If possible, a consensus panel in November 2003 to patients should be referred to a weight man- developguidelinesforthepreventionand agement program specifically tailored to treatment of metabolic changes induced by patients with serious mental illness.

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Table 3. Monitoring Recommendations for Patients Receiving Second-Generation Antipsychotics

Frequency of assessment

Assessment Baseline Four weeks Eight weeks 12 weeks Quarterly Annually Every five years

Review personal and family history X X Weight (body mass index) X X X X X Waist circumference X X Blood pressure X X X Fasting plasma glucose level X X X Fasting lipid profile X X X

NOTE: Table reflects the minimum frequency of assessments; more frequent monitoring may be appropriate in select patients based on underlying conditions and family history. Adapted with permission from American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):599.

DRUG SELECTION Cardiovascular Disease When prescribing a second-generation anti- and QT Prolongation psychotic, physicians should inform patients Ratesofcardiovascularandcerebrovascular and their caregivers about the risk of adverse diseasesarehigherinpatientswithschizo- metabolic effects and educate them about phrenia compared with the general popula- the signs and symptoms of diabetes. Patients tion.2 The calculated 10-year risk of coronary with risk factors for diabetes, who have a heart disease in patients with schizophrenia diagnosisofdiabetes,orwhoaretaking is50percenthigherinwomenand34percent other medications associated with weight higher in men, compared with the general gain may benefit from aripiprazole or zipra- population. This increased risk may be par- sidone therapy, which cause less weight gain tiallycausedbylifestylefactors;however,the than other medications. The panel recom- metabolic effects of antipsychotic medica- mendsthatpatientswhodevelopworsen- tions also may contribute.30 Physicians tend ing hyperglycemia or dyslipidemia during to treat risk factors for cardiovascular disease therapy be switched to a second-generation less aggressively in patients with diabetes who antipsychoticthathasnotbeenassociated have serious mental illness compared with with significant weight gain or diabetes. The those who do not have mental illness.11 benefits of continuing effective psychiatric Theuseofantipsychotics,evenatlowdoses, medications should be balanced with the is associated with a threefold increase in the patient’scardiovascularriskandtheability risk of cardiac sudden death in outpatients.31 toachievediabetestreatmentgoals. QT prolongation is associated with ventricu- The ADA’s therapeutic goals for blood lar arrhythmias, which can cause syncope, pressure, lipid levels, glycemic control, and ventricular fibrillation, and sudden death.32 monitoring in the general population also First- and second-generation antipsychotics apply to patients with serious mental ill- have been associated with QT prolongation ness. However, patients with mental illness to varying degrees. The antipsychotic thio- arelesslikelytoreceiverecommendedinter- ridazine (Mellaril; brand no longer available ventions.28,29 Although physicians should in the United States) has the greatest effect not alter therapeutic goals based only on on the QT interval, followed by ziprasidone, the presence of a serious mental illness, haloperidol (Haldol), quetiapine, risperi- they should prioritize therapy based on the done, and olanzapine.19 Aripiprazole has not patient’s psychiatric status. been shown to cause QT prolongation.33

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Medications known to cause QT prolonga- Drug Interactions tion (Table 434) should be avoided in patients Concurrent use of psychiatric medications with heart disease, history of syncope, fam- andsomemedicationscommonlyprescribed ily history of sudden death at any age, drug in primary care may lead to pharmacoki- oralcoholabuse,personalorfamilyhistory neticorpharmacodynamicinteractions; of congenital long QT syndrome, or electro- therefore, when possible, primary care phy- lyte imbalances as well as in older women. siciansshouldcarefullyconsiderrisksand For more information about medications benefits when prescribing medications that associated with QT prolongation, go to may interact with psychiatric therapies. http://www.arizonacert.org/medical-pros/ Pharmacokinetic interactions include those drug-lists/drug-lists.cfm. that cause changes in the metabolism of Medications that can cause QT prolongation either agent. Pharmacodynamic interactions shouldnotbeprescribedconcurrently.Medica- occur when two medications act at the same tions that inhibit the metabolism of antipsy- or related target sites, leading to additive, chotic agents should be avoided, if possible. synergistic, or antagonistic effects. However, if these medications are prescribed, Pharmacokinetic interactions often physicians should use caution because the involve alterations in medication metabo- effectsontheQTintervalappeartoberelated lism caused by the induction or inhibition of to increased serum drug concentrations.35 hepatic metabolism via the cytochrome P450 Performing baseline electrocardiography (CYP) enzyme system. Second-generation (ECG) before initiating antipsychotic therapy antipsychotics have varying effects on is controversial. However, ECG can identify this enzyme system. Clozapine and olan- patients with preexisting QT prolongation. zapine are primarily metabolized by the Monitoring electrolyte and magnesium levels CYP1A2system;risperidone,quetiapine, issuggestedinpatientsreceivingthioridazine andziprasidonebyCYP3A4; and aripipra- orziprasidonewhoareatriskofelectrolyte zole by CYP3A4 and CYP2D6.37 Medications deficiencies.36 that inhibit the metabolism of second- generation antipsychotics lead to higher drug levels and may cause toxicity or increased Table 4. Selected Medications adverseeffects.Interactionsthatinducethe Associated with QT Prolongation metabolism of second-generation antipsy- choticsmayleadtolowerdruglevels,treat- (Cordarone) ment failure, increased medication doses, Clarithromycin (Biaxin) and the potential for increased adverse effects Digoxin when the interacting drug is discontinued. Disopyramide (Norpace) Table 5 presents selected pharmacokinetic (Inapsine) interactions between second-generation Erythromycin antipsychotics and common agents.16,37-43 Flecainide (Tambocor) Family physicians should also be aware (Prozac) of pharmacodynamic interactions that Gatifloxacin (Zymar) may intensify the adverse effects of second- Ibutilide (Corvert) generation antipsychotics. As previously described, the concurrent use of medications Procainamide (Pronestyl) that can cause QT prolongation, particu- larly with ziprasidone, can increase the risk (Betapace) of clinically significant QT prolongation and Sparfloxacin (Zagam); no longer available in the United States potentially increase the risk of torsades de pointes. Because of effects on alpha receptors, second-generation antipsychotics can cause Information from reference 34. orthostatic hypotension, which may intensify the effects of antihypertensive agents.

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Alcohol and agents associated with cen- Table 5. Selected Pharmacokinetic Interactions Between tralnervoussystemdepression(e.g.,seda- Second-Generation Antipsychotics and Common Agents tives, [Catapres], , antiemetics) may have additive effects in Second- Agents that lead to Agents that lead to patients using second-generation antipsy- generation increased antipsychotic decreased antipsychotic chotics. Olanzapine, quetiapine, risperidone, antipsychotic drug levels drug levels and ziprasidone may antagonize the effects Aripiprazole Clarithromycin (Biaxin)* Barbiturates of levodopa and agonists, poten- (Abilify) Erythromycin* tially decreasing the therapeutic benefit of Grapefruit juice* (Tegretol) thedopamineagents. (Sporanox)† Phenytoin (Dilantin) Clozapine should not be used with other Ketoconazole (Nizoral)† agents that increase the risk of agranulocy- Quinidine† tosisorbonemarrowsuppression,includ- ing carbamazepine (Tegretol), ticlopidine Clozapine Caffeine Barbiturates (Ticlid), hydroxychloroquine (Plaquenil), (Clozaril) (Tagamet) Carbamazepine and propylthiouracil. Clozapine can cause Ciprofloxacin (Cipro) Nicotine additive effects when administered with (Celexa) Phenytoin other drugs that have effects. Erythromycin Rifampin (Rifadin) Aripiprazole is the antipsychotic that binds Fluoxetine (Prozac) mosttightlytodopamineD receptors and (Luvox) 2 hasthepotentialtodisplaceotherfirst-and Grapefruit juice second-generation antipsychotics from their (Paxil) binding sites; this could lead to worsening (Zoloft) disease symptoms when administered with Olanzapine Ciprofloxacin Carbamazepine other antipsychotics.38 (Zyprexa) Fluvoxamine Nicotine Omeprazole (Prilosec) Guidelines for Coordinating Patient Care Phenytoin Fragmentationofcareisaproblemformany Rifampin patients with serious mental illness, and 44,45 Quetiapine Clarithromycin Barbiturates several models address this issue. APA (Seroquel) Erythromycin Carbamazepine practice guidelines indicate that monitoring Fluconazole (Diflucan) Phenytoin for metabolic effects of medications is the 46 Grapefruit juice Rifampin responsibility of the prescribing physician. Itraconazole Theophylline Canadian guidelines recommend that psy- Ketoconazole chiatrists perform screening tests for meta- bolic problems and refer patients to primary Risperidone Clozapine Barbiturates care physicians to follow up on abnormal (Risperdal) Fluoxetine Carbamazepine test results.47 Responsibility for monitoring Paroxetine Phenytoin metabolic problems and vigilance for drug Rifampin interactions and adverse reactions should be Ziprasidone Clarithromycin Carbamazepine shared by all prescribers. (Geodon) Erythromycin Phenytoin Fluconazole The Authors Grapefruit juice BERNADETTE KIRALY, MD, is a clinical instructor in the Itraconazole Department of Family and Preventive Medicine at the Ketoconazole University of Utah School of Medicine, Salt Lake City. She received her medical degree from Albany (NY) Medical College and completed a family medicine residency at the *—Monitor for toxicity. University of Utah School of Medicine. †—Decrease aripiprazole dose by one half. KAREN GUNNING, PharmD, BCPS, is a clinical associate References 16 and 37 through 43. professor of pharmacotherapy in the College of Pharmacy and an adjunct associate professor in the Department of

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Family and Preventive Medicine at the University of Utah patients at a community mental health center. Psychiatr School of Medicine. She received her doctorate of phar- Serv. 2003;54(8):1158-1160. macy from the University of Utah College of Pharmacy, 13. Daumit GL, Goldberg RW, Anthony C, et al. Physical Salt Lake City, and completed a family medicine phar- activity patterns in adults with severe mental illness. macotherapy residency at the University of Washington J Nerv Ment Dis. 2005;193(10):641-646. School of Medicine, Seattle. 14. Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH. Smoking and mental illness: JENNIFER LEISER, MD, is a clinical assistant professor in a population-based prevalence study. JAMA. 2000; the Department of Family and Preventive Medicine at the 284(20):2606-2610. University of Utah School of Medicine. She received her 15. Goff DC, Cather C, Evins AE, et al. Medical morbidity medical degree at the University of Minnesota Medical and mortality in schizophrenia: guidelines for psychia- School, Minneapolis, where she also completed a family trists. J Clin Psychiatry. 2005;66(2):183-194. medicine residency. 16. Abilify (aripiprazole) [package insert]. Princeton, N.J.: Address correspondence to Bernadette Kiraly, MD, Sug- Bristol-Meyers Squibb; 2008. http://packageinserts. arhouse Family Health Center, 1138 Wilmington Ave., bms.com/pi/pi_abilify.pdf. Accessed June 22, 2007. Salt Lake City, UT 84106 (e-mail: bernadette.kiraly@hsc. 17. Taylor DM, McAskill R. Atypical antipsychotics and utah.edu). Reprints are not available from the authors. weight gain—a systematic review. Acta Psychiatr Scand. 2000;101(6):416-432. Author disclosure: Nothing to disclose. 18. Allison DB, Mentore JL, Heo M, et al. Antipsychotic- induced weight gain: a comprehensive research synthe- REFERENCES sis. Am J Psychiatry. 1999;156(11):1686-1696. 19. 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