In 2007, 5 of the 7 second-generation antipsychotics were listed in the Top 200 Drugs prescribed by retail sales in the United States. Cardiovascular disease is the leading cause of natural death in individuals with schizophrenia. Second-generation antipsychotics have been implicated with metabolic and cardiovascular adverse effects, and it is important for nonpsychiatric practitioners to be familiar with the monitoring parameters recommended for these agents. This article discusses the risk of weight gain, hyperglycemia, hyperlipidemia, hyperprolactinemia, and cardiovascular concerns associated with second-generation antipsychotic agents. It also discusses the proposed mechanisms for each of these adverse effects. Furthermore, it reviews suggested monitoring parameters to help manage cardiovascular disease in this patient population, and to improve the gap that exists between mental health care and physical health care in the schizophrenic population.
BalfGStewartTDWhiteheadR. Metabolic adverse events in patients with mental illness treated with antipsychotics: a primary care perspective. Prim Care Companion J Clin Psychiatry. 2008;10:15–24.
3.
HerzMKLibermanRPLiebermanJA. American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 1997;154(suppl 4):1–63.
4.
ArgoTRCrismonMLMillerAL. The Texas Medication Algorithm Project (TMAP) Procedural Manual: Schizophrenia Algorithm. Texas Department of State Health Services; 2007.
5.
McEvoyJPScheiferPLFrancesA. The expert consensus guidelines series: treatment of schizophrenia. J Clin Psychiatry. 1999;60(suppl 11):1–80.
6.
TandonR. Safety and tolerability: how do newer generation “atypical” antipsychotics compare?. Psychiatr Q. 2002;73:297–311.
7.
StahlS. Psychopharmacology of Antipsychotics. London: Martin Dunitz Ltd; 1999:49–79.
8.
MarderSREssockSMMillerAL. Physical health monitoring of patients with schizophrenia. Am J Psychiatry. 2004;161:1334–1349.
WirshingDA. Schizophrenia and obesity: impact of antipsychotic medications. J Clin Psychiatry. 2004;65(suppl 18):13–26.
11.
DrussBG. Improving medical care for persons with serious mental illness: challenges and solutions. J Clin Psychiatry. 2007;68(suppl 4):40–44.
12.
BermudesRAKeckPEMcElroySL eds.. Managing Metabolic Abnormalities in the Psychiatrically Ill: A Clinical Guide for Psychiatrists. Arlington, VA: American Psychiatric Publishing; 2007.
13.
TitierKGirodetPOVerdouxH. Atypical antipsychotics: from potassium channels to torsades de pointes and sudden death. Drug Safety. 2005;28:35–51.
14.
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;27:596–601.
15.
AllisonDBMentoreJLHeoM. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686–1696.
16.
LiebermanJAStroupTSMcEvoyJP. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223.
17.
MeltzerHYAlphsLGreenAI. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60:82–91.
18.
Perez-IglesiasRCrespo-FacorroBAmadoJA. A 12-week randomized clinical trial to evaluate metabolic changes in drug-naive,first-episode psychosis patients treated with haloperidol, olanzapine, or risperidone. J Clin Psychiatry. 2007;68:1733–1740.
19.
CaseyDE. Metabolic issues and cardiovascular disease in patients with psychiatric disorders. Am J Med. 2005;118(suppl 2):15S–22S.
20.
SernyakMJ. Implementation of monitoring and management guidelines for second-generation antipsychotics. J Clin Psychiatry. 2007;68(suppl 4):14–18.
21.
WuRRZhaoJPLiuZN. Effects of typical and atypical antipsychotics on glucose-insulin homeostasis and lipid metabolism in first-episode schizophrenia. Psychopharmacology. 2006;186:572–578.
22.
McEvoyJPMeyerJMGoffDC. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res. 2005;80:19–32.
23.
HendersonDC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence?CNS Drugs. 2002;16:77–89.
24.
WilsonDRD’SouzaLSarkarN. New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophr Res. 2003;59:1–6.
25.
ChiuCCChenKPLiuHC. The early effect of olanzapine and risperidone on insulin secretion in atypical-naïve schizophrenic patients. J Clin Psychopharmacol. 2006;26:504–507.
26.
EliasANHofflichH. Abnormalities in glucose metabolism in patients with schizophrenia treated with atypical antipsychotic medications. Am J Med. 2008;121:98–104.
27.
BuchholzSMorrowAFColemanPL. Atypical antipsychotic-induced diabetes mellitus: an update on epidemiology and postulated mechanisms. Intern Med J. 2008;38:602–606.
28.
ChurchCOStevensDLFugateSE. Diabetic ketoacidosis associated with aripiprazole. Diabet Med. 2005;22:1440–1443.
29.
ReddymasuSBahtaELevineS. Elevated lipase and diabetic ketoacidosis associated with aripiprazole. J Pancreas. 2006;7:303–305.
30.
GastonRLGeorgeMAzhahanN. Diabetic control and atypical antipsychotics: a case report. J Med Case Reports. 2008;2:155.
31.
van WinkelRDe HertMWampersM. Major changes in glucose metabolism, including new-onset diabetes, within 3 months after initiation of or switch to atypical antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2008;69:472–479.
32.
HendersonDCDoraiswamyPM. Prolactin-related and metabolic adverse effects of atypical antipsychotic agents. J Clin Psychiatry. 2008;69(suppl 1):32–44.
33.
GlassmanAHBiggerJTJr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes and sudden death. Am J Psychiatry. 2001;158:1774–1782.
34.
MerrillDBAhmariSEBradfordJM. Myocarditis during clozapine treatment. Am J Psychiatry. 2006;163:204–208.
35.
KollerESchneiderBBennettK. Clozapine-associated diabetes. Am J Med. 2001;111:716–723.
KollerECrossJDoraiswamyP. Risperidone-associated diabetes mellitus: a pharmacovigilance study. Pharmacotherapy. 2003;23:735–744.
38.
JinHMeyerJMJesteDV. Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Ann Clin Psychiatry. 2002;14:59–64.
39.
RettenbacherMAEbenbichlerCHoferA. Early changes of plasma lipids during treatment with atypical antipsychotics. Int Clin Psychopharmacol. 2006;21:369–372.
MeyerJM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol. 2001;21:369–374.
42.
SmithRCSegmanRHGolcer-DubnerT. Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. Pharmacogenomics J. 2008;8:228–236.
43.
YamamotoKFukudaMNogawaA. Decreased lipoprotein lipase as a risk factor for atypical neuroleptic-induced hypertriglyceridemia. J Clin Psychiatry. 2007;68:802.
44.
MeyerJM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry. 2002;63:425–433.
45.
WirshingDABoydJAMengLR. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002;63:856–865.
46.
US FDA, Psychopharmacological Drugs Advisory Committee. Briefing document for Zeldox capsules (ziprasidone hydrochloride), July 19, 2000 [online]. Available at: http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf. Accessed July 24, 2008.
47.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421.
48.
KinonBJGilmoreJALiuH. Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone. Psychoneuroendocrinology. 2003;28(suppl 2):55–68.
49.
JungDUSeoYSParkJH. The prevalence of hyperprolactinemia after long-term haloperidol use in patients with chronic schizophrenia. J Clin Psychopharmacol. 2005;25:613–615.
50.
HaddadPMWieckA. Antipsychotic-induced hyperprolactinaemia: mechanism, clinical features and management. Drugs. 2004;64:2291–2314.
51.
KapurSRemingtonG. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153:466–476.
52.
BusheCShawM. Prevalence of hyperprolactinaemia in a naturalistic cohort of schizophrenia and bipolar outpatients during treatment with typical and atypical antipsychotics. J Psychopharmacol. 2007;21:768–773.
53.
DavidsonMEmsleyRKramerM. Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res. 2007;93:117–130.
54.
MarderSRKramerMFordL. Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry. 2007;62:1363–1370.
55.
KapurSLangloisXVinkenP. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther. 2002;302:1129–1134.
56.
KapurSRoyPDaskalakisJ. Increased dopamine D2 receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine. Am J Psychiatry. 2001;158:311–314.
57.
KnegteringRBaselmansPCasteleinS. Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels. Am J Psychiatry. 2005;162:1010–1012.
58.
MelkerssonKI. Prolactin elevation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite. Hum Psychopharmacol. 2006;21:529–532.
59.
CrawfordAMBeasleyCMJrTollefsonGD. The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophr Res. 1997;26:41–54.
60.
MeltzerHYGoodeDJSchyvePM. Effect of clozapine on serum prolactin levels. Am J Psychiatry. 1979;136:1550–1555.
61.
HamnerM. The effects of atypical antipsychotics on serum prolactin levels. Ann Clin Psychiatry. 2002;14:163–173.
62.
ShimJShinJGKellyDL. Adjunctive treatment with a dopamine partial agonist aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007;164:1404–1410.
KishimotoTWatanabeKShimadaN. Antipsychotic-induced hyperprolactinemia inhibits the hypothalamo-pituitary-gonadal axis and reduces bone mineral density in male patients with schizophrenia. J Clin Psychiatry. 2008;63:385–391.
65.
MeaneyAMSmithSHowesOD. Effects of long-termprolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia. Br J Psychiatry. 2004;184:503–508.
66.
MontoutCCasadebaigFLagnaouiR. Neuroleptics and mortality in schizophrenia: prospective analysis of death in a French cohort of schizophrenia patients. Schizophr Res. 2000;57:146–156.
67.
AbdelmawlaNMitchellA. Sudden cardiac death and antipsychotics Part 2: Monitoring and Prevention. Adv Psychiatr Treat. 2006;12:100–109.
68.
ViewegWV. New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry. 2003;5:205–215.
69.
BednarMMHarriganEPAnzianoRJ. The QT interval. Prog Cardiovasc Dis. 2001;43(5 suppl 1):1–45.
70.
NemeroffCBLiebermanJAWeidenPJ. From clinical research to clinical practice: a 4-year review of ziprasidone. CNS Spectr. 2005;10:S1–S20.
71.
ZarebaWLinDA. Antipsycohtic drugs and QT interval prolongation. Psychiatr Q. 2003;74:291–306.
72.
HeinrichTWBibloLASchneiderJ. Torsades de pointes associated with ziprasidone. Psychosomatics. 2006;47:264–268.
73.
ManiniAFRaspberryDHoffmanRS. QT prolongation and torsades de pointes following overdose of ziprasidone and amantadine. J Med Toxicol. 2007;3:178–181.
74.
ZemrakWRKennaGA. Assoication of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Health-Syst Pharm. 2008;65:1029–1038.
75.
HäggSSpigsetOBateA. Myocarditis related to clozapine treatment. J Clin Psychopharmacol. 2001;21:382–388.
76.
La GrenadeLGrahamDTrontellA. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med. 2001;345:224–225.
77.
KillianJGKerrKLawrenceC. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354:1841–1845.
78.
HaddadPMSharmaSG. Adverse effects of atypical antipsychotics: differential risk and clinical implications. CNS Drugs. 2007;21:911–936.
79.
FullerMASajatovicM. Psychotropic Drug Information Handbook. Hudson, OH: Lexi-Comp Inc; 2005:701–702.
