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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.
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).
Noncardiac Medications and QTC Prolongation
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 QTC 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 QTC 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 torsades de pointes, but thioridazine in particular (Buckley et al., 1995, as cited in Yap and Camm, 2000; Czekalla et al., 2001). Prolongation of the QTC 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 torsades de pointes (Taylor, 2003; Vieweg, 2003). Magnesium levels are regarded to be associated with antipsychotic-induced QTC 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 QTC prolongation. Caution should be taken in determining the dosage. Prolongation of the QTC 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 QTC interval prolongation. The QTC 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 torsades de pointes than males in response to drugs that prolong cardiac repolarization (Makkar et al., 1993).
From this evidence, we focused on gender differences in QTC 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 QTC interval was 0.408 (standard deviation [SD]=0.036). QTC 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 QTC interval in those with cardiovascular diseases was significantly longer than that in those without cardiovascular diseases. Regarding psychiatric diagnosis using DSM-IV, 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 QTC among the three groups.
The results of our study suggest that a gender difference still exists in QTC lengthening in people with mental disorders after excluding effects of cardiovascular comorbidity. QTC intervals in females were significantly higher than in males among people with mental disorders without cardiovascular comorbidity (Figure).
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 QTC 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 QTC interval exceeds 500 ms (Lader, 1999).
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.
Gender Differences in Other Risk Factors
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 QTC 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.
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