Evidence-Based Reviews

7-point checkup: Defuse cardiovascular and psychiatric risks in schizophrenia outpatients

Current Psychiatry. 2007 January;6(1):21-32

References

1. Weiden P, Glazer M. Assessment and treatment selection for “revolving door” inpatients with schizophrenia. Psychiatr Q. 1997;68(4):377-92.

2. Lieberman JA, Stroup TS, McEvoy JP, et al. for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;22;353(12):1209-23.

3. Marder SR, Glynn SM, Wirshing WC, et al. Maintenance treatment of schizophrenia with risperidone or haloperidol: 2-year outcomes. Am J Psychiatry 2003;160:1405-12.

4. Jones PB, Barnes TRE, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079-87.

5. Leucht S, Barnes TR, Kissling W, et al. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 2003;160:1209-22.

6. Davis JM, Kane JM, Marder SR, et al. Dose response of prophylactic antipsychotics. J Clin Psychiatry 1993;54(3, suppl):24-30.

7. Brown S. Excess mortality of schizophrenia. A meta-analysis. Br J Psychiatry 1997;171:502-8.

8. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry 1998;173:11-53.

9. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis [serial online] 2006 Apr [date cited]. Available from: http://www.cdc.gov/pcd/issues/2006/apr/05_0180.htm.

10. NCEP Expert Panel. 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(25):3143-421.

11. Newcomer JW, Haupt DW. The metabolic effects of antipsychotic medications. Can J Psychiatry 2006;51(8):480-91.

12. et al. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596-601.

13. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.

14. Stroup TS, Liberman JA, McEvoy JP, et al. for the CATIE Investigators. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006;163:4:611-22.

15. McQuade RD, Stock E, Marcus R, et al. A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomized, double-blind study. J Clin Psychiatry 2004;65(suppl 18):47-56.

16. Marder SR, Essock SM, Miller AL, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004;161:1334-49.

17. Lehman AF, Kreyenbuhl J, Buchanan RW, et al. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2003. Schizophr Bull 2004;30:193-217.

18. Siris SG, Morgan V, Fagerstrom R, et al. Adjunctive imipramine in the treatment of postpsychotic depression. Arch Gen Psychiatry 1987;44:533-9.

19. Braga RJ, Petrides G, Figueira I. Anxiety disorders in schizophrenia. Compr Psychiatry 2004;45(6):460-8.

Recent evidence, however, has cast doubt on the idea that SGAs are clinically superior to FGAs. The CUtLASS trial,⁴ for example, found no quality-of-life differences in patients using either class. Both FGAs and SGAs reduce the risk of relapse in stable patients, although SGAs may have an advantage over FGAs in preventing relapse. An analysis by Leucht et al⁵ found lower relapse/treatment failure rates in 6 placebo-controlled SGA trials (total 983 patients), compared with 11 FGA trials (total 2,032 patients).

Although the data comparing SGAs with FGAs are controversial, SGAs seem to have lower EPS potential. Regardless of the type of antipsychotic, however, studies have shown that patients who relapse while taking antipsychotics have less-severe episodes than those who relapse after discontinuing their medications.

For patients who frequently forget or incorrectly take oral medications, long-acting depot antipsychotics may increase adherence and decrease relapse rates during the stable phase.⁶

3. Weight gain, cardiovascular risk

Cardiovascular disease is the leading cause of death among persons with schizophrenia,^7,8 whose life span is 10 to 20 years shorter than the population at large.⁹ Schizophrenia patients may be genetically predisposed to cardiovascular disease and metabolic syndrome (Table 3),¹⁰ exacerbated by typically sedentary lifestyles, high smoking rates, and poor diets. Certain SGAs add to the risk of weight gain and metabolic abnormalities.¹¹

Table 3

Does your patient have metabolic syndrome?

Metabolic syndrome is defined as having any 3 of these findings:
Abdominal obesity	Waist circumference
	>102 cm (40 in) in men
	>88 cm (35 in) in women
Elevated triglycerides	≥150 mg/dL
Low HDL
Low HDL
Hypertension	≥130/85 mm/Hg
Hyperglycemia	Fasting blood glucose ≥110 mg/dL
Source: National Cholesterol Education Program Adult Treatment Panel III guidelines, reference 10

Metabolic syndrome. Being familiar with the 2004 consensus report of the American Diabetes Association/American Psychiatric Association (ADA/APA)¹² can help differentiate SGAs’ relative risks of causing weight gain, type 2 diabetes, and hyperlipidemia. The report recommends monitoring blood pressure, weight, and lipid and fasting glucose levels when antipsychotics are initiated and at least yearly thereafter (Table 4).

Table 4

Monitoring protocol for patients taking second-generation antipsychotics*

	Short-term				Long-term
	Baseline	4 wk	8 wk	12 wk	Quarterly	Annually	Every 5 yrs
Personal/family history	X					X
Weight (BMI)	X	X	X	X	X
Waist circumference	X					X
Blood pressure	X			X		X
Fasting plasma glucose	X			X		X
Fasting lipid profile	X			X			X
* More-frequent assessments may be warranted, based on clinical status.
BMI: body mass index
Source: Reference 12

Because of schizophrenia patients’ risk of metabolic abnormalities, consider:

using treatments that do not increase the risk for cardiovascular disease
switching to agents with less weight gain liability if a patient’s weight increases >7% or his or her body mass index (BMI) increases 1 unit during antipsychotic therapy.

Mr. K smokes a pack a day and shows no interest in cutting down or quitting. He is African-American (which increases his cardiovascular risk), sedentary, and has a family history of heart disease. Thus, monitoring these risk factors and referring him for primary care are priorities in his treatment plan.

Mr. K remained stable on olanzapine for several years, but his blood glucose, cholesterol, and triglycerides have risen dramatically and he has gained 40 lbs. Although we were concerned that he might not respond as well to another SGA, we reviewed the risks and benefits with specific concern about his cardiovascular health. As a result, we switched him to aripiprazole, 15 mg/d, with close monitoring and supervision for signs of relapse.

SGAs’ heterogeneity. The ADA/APA statement and multiple clinical trials support differential risks of weight gain and metabolic abnormalities with SGAs (Table 5). Patients in CATIE phase 1 who were randomly assigned to olanzapine experienced greater total weight gain and monthly weight gain (mean +2 lb/month) than patients taking any other antipsychotic.¹³ In an analysis of change from baseline to last observation, 30% of patients in the olanzapine group gained >7% of their baseline weight, compared with 7% to 16% of patients taking other antipsychotics.

Table 5

Differential risks of weigh gain and metabolic abnormalities with SGAs

Risk	Antipsychotics
Highest	Clozapine, olanzapine
Intermediate/low	Risperidone, quetiapine
Lowest	Aripiprazole, ziprasidone
SGAs: Second-generation antipsychotics

Patients in the CATIE trial tended to stay on olanzapine longer than on any of the other antipsychotics, however. Average time to discontinuation for any cause was 9.2 months, versus 3.5, 4.6, 4.8, and 5.6 months for ziprasidone, quetiapine, risperidone, and perphenazine, respectively. Thus, in clinical practice, it is important to balance longer duration of treatment against increased risk of weight gain.^14,15

Mr. K remains free of positive symptoms after taking aripiprazole for several months. He complains less of daytime sedation and has lost >10 lbs. We are awaiting repeat glucose, cholesterol, and triglyceride serum levels. We will continue to monitor his weight and metabolic values and ensure that he receives primary care follow-up.