Hiroto Ito, PhD

Cardiovascular diseases are the leading cause of death in the United States and the second leading cause of death following cancer in Japan for both males and females. While scientists around the world aggressively study risk factors to prevent cardiovascular diseases, we should not underestimate the association between mental health and cardiovascular diseases. Depression and stress are known to be strongly related to cardiovascular health. Mortality rates are higher in patients with depression than those without depression after myocardial infarction (Frasure-Smith et al., 2000).

Cardiac medications such as antiarrhythmic drugs are known to prolong ventricular repolarization and result in QT interval prolongation. In addition to cardiac medications, there are many reports on the effects of noncardiac medications on QT interval prolongation (Glassman and Bigger, 2001; Hennessy et al., 2002; Yap and Camm, 2000). Noncardiac medications include antihistamines, antibiotics and psychotropic drugs (Collins et al., 2002; Yap and Camm, 2000). These drugs prolong cardiac repolarization and also induce the QT

 interval prolongation. Thus, they may trigger polymorphic ventricular tachycardia known as torsades de pointes. This life-threatening arrhythmia often manifests clinically as cardiac arrest.

Drugs prescribed by psychiatrists are emerging as a potential risk for serious adverse cardiac events. A Finnish survey of medicolegal autopsies performed revealed that phenothiazines were present in 46 of all 49 sudden-unexpected deaths associated with the use of antipsychotic or antidepressant medications (Mehtonen et al., 1991). Tricyclic antidepressants including amitriptyline, doxepin (Sinequan), desipramine (Nopramin), imipramine (Tofranil) and clomipramine (Anafranil) are associated with QT

 prolongation (Baker et al., 1997; Swanson et al., 1997, as cited in Yap and Camm, 2000). There are case reports on fluoxetine (Prozac)-induced bradycardia (Ellison et al., 1990). Antipsychotics also draw attention in relation to sudden death. Haloperidol (Haldol), chlorpromazine (Thorazine), trifluoperazine (Stelazine), pericycline, prochlorperazine (Compazine), fluphenazine (Prolixin) are all at risk of 

, but thioridazine in particular (Buckley et al., 1995, as cited in Yap and Camm, 2000; Czekalla et al., 2001). Prolongation of the QT

 interval is greatest with ziprasidone (Geodon), although this does not necessarily mean that ziprasidone is more likely than any other new generation antipsychotic medications to induce 

(Taylor, 2003; Vieweg, 2003). Magnesium levels are regarded to be associated with antipsychotic-induced QT

 prolongation (Imran et al., 2003). Antipsychotic medications prolong QT interval usually by blocking the potassium channel (Zareba and Lin, 2003).

Reilly et al. (2000) reported that in individuals over age 65, use of TCAs, thioridazine and droperidol (Inapsine) were predictors of QT

 prolongation. Caution should be taken in determining the dosage. Prolongation of the QT

 interval was more likely observed in patients on doses of antipsychotic medication above 2000 mg chlorpromazine equivalents daily (Warner et al., 1996). Even patients on moderate doses of antipsychotics (>100 mg in thioridazine equivalents) were reported to have 2.39 times greater risk of sudden cardiac death than nonusers (Ray et al., 2001).

High-Risk Group: Women With Mental Disorders

Generally, females are regarded as a high-risk group of QT

 interval has been reported to be longer in females than in males (Moss, 1993). A meta-analysis of 332 patients exposed to cardiovascular medications suggested that females were more likely to develop 

 than males in response to drugs that prolong cardiac repolarization (Makkar et al., 1993).

From this evidence, we focused on gender differences in QT

 interval distribution and its related factors in people with mental disorders (Ito et al., 2004). We retrospectively reviewed medical charts of 328 patients (145 men and 183 women) taking psychotropics at their admission discharged from a university psychiatric unit between November 1997 and December 2000. The mean QT

 interval was 0.408 (standard deviation [SD]=0.036). QT

 intervals in women were significantly longer than those in men.

Gender was a significant factor in the tests controlling for diagnosis, antipsychotics and hepatic failure. Cardiovascular disease was the only significant factor other than gender. The mean QT

 interval in those with cardiovascular diseases was significantly longer than that in those without cardiovascular diseases. Regarding psychiatric diagnosis using 

, 94 (28.7%) patients were diagnosed as suffering from schizophrenia, 95 (29.0%) from mood disorders, and 139 (42.4%) from other. There were no significant differences in QT

The results of our study suggest that a gender difference still exists in QT

 lengthening in people with mental disorders after excluding effects of cardiovascular comorbidity. QT

 intervals in females were significantly higher than in males among people with mental disorders without cardiovascular comorbidity (

Precautions Against Drug-Induced Adverse Effects

Adverse effects can be minimized by careful pretreatment evaluation, prescription and monitoring. Special attention should be paid to overdose, patients with cardiovascular disease or other risk factors (Glassman and Bigger, 2001; Yap and Camm, 2000), and concomitant administration of drugs that prolong QT

 interval (Yap and Camm, 2000). Checking for an irregular pulse and necessary electrocardiogram should be included in monitoring during treatment, and the advice of a cardiologist is recommended if the QT

Effect of Hormones Is a Matter of Controversy

It is known that the incidence of cardiovascular disease is significantly lower in premenopausal females than males and postmenopausal females, while the risk of heart disease is increasing in females after menopause. This suggests that natural estrogens have a protective effect in the development of cardiovascular diseases (Barrett-Connor and Bush, 1991; Hu et al., 1999; van der Schouw et al., 1996), and factors related to female gender such as steroid hormone receptors and ion channels may possess cardioprotective properties (Collins et al., 2002).The mechanism of hormones, however, is still unclear. Roeters van Lennep and colleagues (2002) found that estrogen alone or estrogen in combination with progestin did not affect the progression of coronary atherosclerosis.

Furthermore, people are confused by unexpected study results. In the Women's Health Initiative study on postmenopausal hormone therapy, researchers found that a combination of estrogen plus progestin did not protect females from cardiovascular diseases (Manson et al., 2003). The Women's Health Initiative estrogen-only phase was stopped because researchers found no reduction in the risk of heart disease in postmenopausal females.

The American Heart Association (2004) now recommends that hormone therapy not be used for cardiovascular prevention. Although gender hormones are regarded to be related to cardiovascular diseases, further studies are needed.

Other factors regarding effects of cardiovascular diseases include cholesterol, hypertension, diabetes, obesity, family history, homocysteine, fibrinogen, infections, inflammation and psychosocial factors (Roeters van Lennep et al., 2002). Generally, there is no strong evidence that clarifies risk factors that act on only one gender, female or male. Yet, diabetes, high-density lipoprotein (HDL) cholesterol and triglyceride levels have been found to have a greater impact on cardiovascular disease risk in females compared to males.

In addition, there are indications that risk factors, such as smoking, family history and inflammation characterized as C-reactive protein, have more of a negative influence on cardiovascular disease in females than in males (Roeters van Lennep et al., 2002).

A number of studies have shown that smoking is a stronger risk factor for myocardial infarction in middle-aged females than in males (Cullen et al., 1998; Njolstad et al., 1996; Nyboe et al., 1991). In both males and females smoking has an unfavorable affect on plasma lipoproteins, in particular a decrease in HDL cholesterol levels (Cullen et al., 1998; Njolstad et al., 1996; Taylor et al., 1981). This should be taken into account in psychiatric care because patients with mental disorders are about twice as likely to smoke as people without mental disorders (Lasser et al., 2000).

The prognosis for females with cardiovascular diseases is more devastating than for males (Kostis et al., 1994; Marrugat et al., 1998; Nettleman et al., 1997). In fact, the mortality gap between males and females is widening in the United States (American Heart Association, 2003). 

Our results suggest that female patients with mental disorders with QT

 prolongation could be at high risk of cardiovascular diseases (Ito et al., 2004). For optimal treatment and prevention of cardiovascular diseases, gender differences should be considered in combination with the effect of psychotropic medications on the cardiovascular system and other risk factors.

Dr. Ito would like to thank Toshiaki Kono for his assistance in this research.

Dr. Ito is a program officer for health sciences grants of the Ministry of Health, Labour and Welfare, Japan. Dr. Ito has conducted numerous studies as a researcher on mental health policy and management.

American Heart Association (2003), Heart disease and stroke statistics--2004 Update. Dallas: American Heart Association.

American Heart Association (2004), Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 109:672-693.

Baker B, Dorian P, Sandor P et al. (1997), Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder. J Clin Psychopharmacol 17(1):15-21.

Barrett-Connor E, Bush TL (1991), Estrogen and coronary heart disease in women. JAMA 265(14):1861-1867 [see comment].

Collins P, Stevenson JC, Mosca L (2002), Spotlight on gender. Cardiovasc Res 53(3):535-537.

Cullen P, Schulte H, Assmann G (1998), Smoking, lipoproteins and coronary heart disease risk. Data from the Munster Heart Study (PROCAM). Eur Heart J 19(11):1632-1641.

Czekalla J, Kollack-Walker S, Beasley CM Jr (2001), Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 62(suppl 2):35-40.

Ellison JM, Milofsky JE, Ely E (1990), Fluoxetine-induced bradycardia and syncope in two patients. J Clin Psychiatry 51(9):385-386 [see comment].

Frasure-Smith N, Lesperance F, Gravel G et al. (2000), Social support, depression, and mortality during the first year after myocardial infarction. Circulation 101(16):1919-1924.

Glassman AH, Bigger JT Jr (2001), Antipsychotic drugs: prolonged QT

 interval, torsade de pointes, and sudden death. Am J Psychiatry 158(11):1774-1782 [see comments].

Hennessy S, Bilker WB, Knauss JS et al. (2002), Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data. BMJ 325(7372):1070.

Hu FB, Grodstein F, Hennekens CH et al. (1999), Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 159(10):1061-1066.

Imran N, Rampes H, Rosen S (2003), Antipsychotic induced prolongation of QT

 interval treated with magnesium. J Psychopharmacol 17(3):346-349.

Ito H, Kono T, Ishida S, Maeda H (2004), Gender difference in QT

 prolongation of people with mental disorders. Ann Gen Hosp Psychiatry 3(1):3.

Kostis JB, Wilson AC, O'Dowd K et al. (1994), Sex differences in the management and long-term outcome of acute myocardial infarction. A statewide study. MIDAS Study Group. Myocardial Infarction Data Acquisition System. Circulation 90(4):1715-1730.

Lader M (1999), Some adverse effects of antipsychotics: prevention and treatment. J Clin Psychiatry 60(suppl 12):18-21.

Lasser K, Boyd JW, Woolhandler S et al. (2000), Smoking and mental illness: A population-based prevalence study. JAMA 284(20):2606-2610.

Makkar RR, Fromm BS, Steinman RT et al. (1993), Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 270(21):2590-2597.

Manson JE, Hsia J, Johnson KC et al. (2003), Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349(6):523-534 [see comments].

Marrugat J, Sala J, Masia R et al. (1998), Mortality differences between men and women following first myocardial infarction. RESCATE Investigators. Recursos Empleados en el Sindrome Coronario Agudo y Tiempo de Espera. JAMA 280(16):1405-1409 [see comments].

Mehtonen OP, Aranko K, Malkonen L, Vapaatalo H (1991), A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland. Acta Psychiatr Scand 84(1):58-64.

Moss AJ (1993), Measurement of the QT interval and the risk associated with QT

 interval prolongation: a review. Am J Cardiol 72(6):23B-25B.

Nettleman MD, Banitt L, Barry W et al. (1997), Predictors of survival and the role of gender in postoperative myocardial infarction. Am J Med 103(5):357-362.

Njolstad I, Arnesen E, Lund-Larsen PG (1996), Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark Study. Circulation 93(3):450-456.

Nyboe J, Jensen G, Appleyard M, Schnohr P (1991), Smoking and the risk of first acute myocardial infarction. Am Heart J 122(2):438-447.

Ray WA, Meredith S, Thapa PB et al. (2001), Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 58(12):1161-1167 [see comment].

Reilly JG, Ayis SA, Ferrier IN et al. (2000), QT

-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 355(9209):1048-1052 [see comments].

Roeters van Lennep JE, Westerveld HT, Erkelens DW, van der Wall EE (2002), Risk factors for coronary heart disease: implications of gender. Cardiovasc Res 53(3):538-549.

Taylor D (2003), Ziprasidone in the management of schizophrenia: the QT interval issue in context. CNS Drugs 17(6):423-430.

Taylor KG, Carter TJ, Valente AJ et al. (1981), Sex differences in the relationships between obesity, alcohol consumption and cigarette smoking and serum lipid and apolipoprotein concentrations in a normal population. Atherosclerosis 38(1-2):11-18.

van der Schouw YT, van der Graaf Y, Steyerberg EW et al. (1996), Age at menopause as a risk factor for cardiovascular mortality. Lancet 347(9003):714-718.

Vieweg WV (2003), New generation antipsychotic drugs and QT

 interval prolongation. Primary Care Companion J Clin Psychiatry 5(5):205-215.

Warner JP, Barnes TR, Henry JA (1996), Electrocardiographic changes in patients receiving neuroleptic medication. Acta Psychiatr Scand 93(4):311-313.

Yap YG, Camm J (2000), Risk of torsades de pointes with non-cardiac drugs. Doctors need to be aware that many drugs can cause qt prolongation. BMJ 430(7243):1158-1159 [see comments].

Zareba W, Lin DA (2003), Antipsychotic drugs and QT interval prolongation. Psychiatr Q 74(3):291-306.

Articles

Tricyclic antidepressants and antipsychotics are known to prolong cardiac repolarization and induce QTC interval prolongation, possibly putting patients with mental disorders at higher risk of cardiovascular diseases. The mechanism of gender difference in vulnerability for cardiovascular diseases is still unclear, but the role of hormones is one of possible explanatory factors.

Author | Hiroto Ito, PhD

Articles

Effect of Gender Differences on the Cardiovascular System in Patients With Mental Disorders