Death From Heart Disease and Anti-Depressants

There is now a huge amount of research showing that anti-depressants probably have a slight favorable impact at decreasing heart attacks, and that there is no difference in this effect between SSRIs and tricyclics.  If I were giving an anti-depressant to someone with a recent heart attack, I would start the anti-depressant very slowly and prefer an SSRI to be on the safe side.  While it would be better to have the tricyclics analyzed by individual medication, since there are major differences in cardiac toxicity after overdose, it is very likely that nortriptyline, the safest tricyclic after overdose, would be at least as good and possibly better than the average tricyclic.  Certainly, in view of this extensive research, there is no good reason to avoid tricyclics and especially nortriptyline on purported claims of increased cardiac side-effects due to tricyclics in small studies funded by the manufacturers of SSRI medications.

Tricyclic Use for Depression Not Associated with Heart Attacks in 13-Year Prospective Study: In a 13-year follow-up of the Baltimore cohort of the Epidemiologic Catchment Area Study, a survey of psychiatric disorders in the general population, a history of major depressive episode, dysphoria (2 weeks of sadness), and psychotropic medication use were assessed in 1981, and self-reported MI was assessed in 1994. Sixty-four MIs were reported among 1551 respondents free of heart trouble in 1981. Compared with respondents with no history of dysphoria, the odds ratio for MI associated with a history of dysphoria was 2.07, and the odds ratio associated with a history of major depressive episode was 4.54, a 354% increase, independent of coronary risk factors. In multivariate models, use of barbiturates, meprobamates, phenothiazines, and lithium was associated with an increased risk of MI, whereas use of tricyclic antidepressants and benzodiazepines was not. Among individuals with no history of dysphoria, only lithium use was significantly associated with MI. Prospective data from the Baltimore ECA follow-up. Pratt LA, et al. Johns Hopkins. . Circulation. 1996 Dec 15;94(12):3123-9.

Tricyclics Did Not Increase and May Have Decreased Death from Heart Disease in Large Study: In order to study if tricyclic antidepressant drugs (TCA) in therapeutic doses increase the risk of death due to cardiovascular causes, the relative mortality from cardiovascular diseases was studied in two large groups of first hospitalized bipolar patients, one from the TCA era, the other from the period just before the introduction of TCA. Both groups were selected from the Danish Psychiatric Central Register and followed for an average of 4.5 years. Among 2662 bipolar men hospitalized between 1969 and 1976, the relative cardiovascular mortality was 1.53 compared to the general population. Among 1133 such cases admitted between 1950 and 1956, the rate was 1.87. The studies findings do not support the hypothesis that TCA contribute to the cardiovascular mortality in manic-depressives and even support suggestions that TCA treatment may lower the risk of death by cardiovascular disease, suicide, and other non-cancer causes. Cardiovascular death and manic-depressive psychosis. Weeke A, et al. Aarhus Psychiatric Hospital, Risskov, Denmark. J Affect Disord. 1987 Nov-Dec;13(3):287-92.

Adequate Tricyclic Anti-Depressant Treatment Decreased Heart Attacks: The treatments of 519 depressed patients hospitalized from 1959 to 1969 were compared in a three-year follow-up study. The electroconvulsive therapy (ECT) group had a significantly lower mortality than the inadequate antidepressant treatment group (P less than .05) and the group that received neither ECT nor antidepressants (P less than .025). The adequate antidepressant treatment group also had a low mortality. Nonsuicidal deaths (P < .005), and particularly myocardial infarctions (P < .01), were significantly more frequent in the inadequately treated group compared to the adequately treated group. The superiority of adequate treatment is especially striking among men and among the older age groups. The results underscore the importance of adequate treatment of depression, especially in the older man. Mortality in depressed patients treated with electroconvulsive therapy and antidepressants. Avery D, et al. Arch Gen Psychiatry. 1976 Sep;33(9):1029-37.

Huge Case-Control Study Found Some Increased Risk, Probably Due to Depression, with New Anti-depressant But No Difference Between Tricyclics Over SSRIs:  In a case-control analysis of 644 general practices throughout England, Scotland, Wales, and Northern Ireland covering over 60,000 cases of MI and 360,000 carefully matched controls randomly selected from the UK General Practice Research Database, researchers found an initial increased risk of MI after TCA exposure (for example, at 1-7 days after the first dothiepin prescription: OR=1.90,) or SSRI exposure (OR 2.59). In the self controlled analysis the equivalent risk estimates were an incidence rate ratio of 1.43 for tricylic and 1.66 for SSRI. The lack of specificity between types of antidepressants and the lower risks found in the self controlled analysis suggest that these associations are more likely due to factors relating to underlying depression and health services utilisation than to specific adverse drug effects. General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction. Tata LJ, et al. Nottingham. . Heart. 2005 Apr;91(4):465-71.

Largest Case Control Study Finds No Cardiac Harm from Anti-Depressants But Favors Non-SSRIs: In a study of 8887 first-time heart attack victims and 88,862 matched population-based controls in Denmark, all prescriptions for antidepressants before hospitalization for myocardial infarction were identified using a prescription database. In patients with a history of hear disease, there was a lower risk of myocardial infarction among those who used SSRIs (OR = 0.85; 95% confidence interval [CI]: 0.62 to 1.16), nonselective serotonin reuptake inhibitors (OR = 0.83; 95% CI: 0.50 to 1.38), and other antidepressants (OR = 0.55; 95% CI: 0.31 to 0.97). There were no such associations among persons without a history of cardiovascular disease. Antidepressants and risk of first-time hospitalization for myocardial infarction: a population-based case-control study. Monster TB, et al. Aarhus University Hospital, Denmark. . Am J Med. 2004 Nov 15;117(10):732-7.

Large Case-Control Study Favors SSRIs and Nortriptyline Type Anti-Depressants, But Stopping an SSRI Briefly Increases Risk: In a study using the UK General Practice Research Database (GPRD) of 8688 patients with a first-time AMI and 33,923 population-based matched controls, for current use of SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine) compared to non-use of anti-depressants, there was a significantly reduced rate of heart attack (OR=0.63; 95% CI 0.43, 0.91; p=0.02). For non-SSRIs investigated (amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nefazodone, trazodone and trimipramine), there was only a slight favorable trend compared to non-users of anti-depressants: OR=0.92 (95% CI 0.77, 1.09; p=0.32). For other antidepressants ( amoxapine, desipramine, lithium, maprotiline, mianserin, moclobemide, nortriptyline and protriptyline), the results were as good as the SSRIs, but, due to smaller numbers, slightly failed to reach statistical significance: OR=0.59 (95% CI 0.29, 1.20; p=0.14). The adjusted OR of recent past use of SSRIs (prescription running out in the month before heart attack) compared with non-use of SSRIs was a significant increased risk of heart attack: 1.42 (95% CI 1.02, 1.97; p=0.04). Current use of selective serotonin reuptake inhibitors and risk of acute myocardial infarction. Schlienger RG, et al. University Hospital Basel, Switzerland. Drug Saf. 2004;27(14):1157-65.

No Significant Affect on Heart Attacks Found From Any Anti-Depressant Group in Case-Control Study: In a population-based case-control analysis using the UK General Practice Research Database (GPRD), 3319 patients aged 75 years or younger free of clinical conditions predisposing to ischaemic heart disease, with a first-time diagnosis of heart attack (AMI) between 1992 and 1997, and 13,139 controls without AMI matched to cases for age, sex, general practice attended, and calendar time were included.  Adjusted odds ratios (with 95% CI) for current use of SSRIs, non-SSRIs, or other antidepressants, compared to the group of nonusers of antidepressants were 0.9 (95% CI 0.5,1.8), 0.9 (95% CI 0.7,1.2), and 1.3 (95% CI 0.6,2.8), respectively. As compared with nonuse of SSRIs, current use (regardless of any other antidepressants used) resulted in an adjusted OR of 1.1 (95% CI 0.7,1.6). Due to relatively small numbers of exposed subjects and the resulting wide confidence intervals, further studies may be needed to document a lack of effect of SSRIs in subjects without pre-existing diseases predisposing to AMI. Use of selective serotonin reuptake inhibitors and risk of developing first-time acute myocardial infarction. Meier CR, et al. University Hospital, Basel, Switzerland. , Br J Clin Pharmacol. 2001 Aug;52(2):179-84.

Smaller Case-Control Study Finds Apparent Benefit from SSRIs But No Harm From Tricyclics or Other Anti-Depressants: In a case-control study of first MI in 1080 patients ages 40-75 years and 4256 controls, after adjustment with multivariable logistic regression for age, gender, race, education, physical activity, quantity of cigarettes smoked per day, body mass index, aspirin use, family history of MI, and history of diabetes, hypertension, or hypercholesterolemia, the odds ratio for MI among 223 current SSRI users compared with nonusers was 0.59 (P=0.02). Increasing serotonin transporter affinity was associated with reduced odds of MI among users of all SSRIs (P for trend <0.01) but not tricyclic (P=0.77) or atypical (P=0.70) antidepressants. There was no association detected between non-SSRI antidepressant use and MI. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Sauer WH, et al. University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. Circulation. 2003 Jul 8;108(1):32-6

Non-Significantly More Heart Attacks with Tricyclics than with SSRIs in Small Study: In a 4.5 year follow-up study of 2,247 adults who received at least one prescription for an antidepressant with that of 52,750 members who did not, antidepressant users had a relative risk of myocardial infarction of 2.2 (95% confidence interval [CI] 1.3 to 3.7) compared with nonusers of antidepressants. There were 16 myocardial infarctions among 1,650 users of tricyclic antidepressants, 2 among 655 SSRI users, and none among 279 users of other antidepressants. Adjusting for age, gender, baseline heart disease, diabetes, hypertension, hyperlipidemia, anxiety, and cancer, the relative risk of myocardial infarction was non-signficantly higher at 2.2 (95% CI 1.2 to 3.8) in users of tricyclic agents vs. 0.8 (95% CI 0.2 to 3.5) in users of SSRIs, as compared with subjects who did not use antidepressants. Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents. Cohen HW, et al. Albert Einstein College of Medicine. Am J Med. 2000 Jan;108(1):2-8. Ed: This is actually a much smaller study with only 18 heart attacks among anti-depressant users. Also, there was no differentiation between different tricyclics, although in over-dose deaths some tricyclics such as amitriptyline and desipramine have much higher fatalities rates, usually due to cardiac toxicity, than nortriptyline, which has a very high safety index in overdoses.  

Risk of Cardiac Morbidity and Mortality Called Relatively Low: Fifteen depressed patients were treated with amitriptyline in a dosage ranging from 75 mg to 200 mg/day for a minimum of three weeks. The only abnormality noted prior to treatment was bradycardia in one patient. After treatment, two patients exhibited nonspecific T-wave abnormalities. Otherwise, the electrocardiograms were unremarkable. A significant increase in heart rate (p less than 0.001) was noted. The mean increase in rate was sixteen beats per minute. Those patients having a rate change greater than sixteen beats per minute had significantly higher amitriptyline levels (p less than 0.05), and total tricyclic antidepressant levels (p less than 0.05), than those patients having a mean rate increase less than sixteen. While tricyclic antidepressants can produce multiple cardiac effects, the risk of cardiac morbidity and mortality is relatively low in patients undergoing tricyclic antidepressant treatment with moderate dosages. Electrocardiographic findings in patients undergoing amitriptyline treatment. Ziegler VE, et al. Dis Nerv Syst. 1977 Sep;38(9):697-9.

Sertraline and Cognitive Behavioral Therapy Did Not Increase Depressed Heart Attack Victim Survival: In the Enhancing Recovery in Coronary Heart Disease study of patients after heart attacks who were depressed, neither cognitive behavior therapy nor sertraline patients had improved survival compared to usual care. Perhaps there were too many patients with mild, transient depression or some patients died too soon to complete the intervention. A further analysis in late mortality (>6 months) among initially depressed patients who had a Beck Depression Inventory score > or =10 and a past history of major depression, and who completed the 6-month post-treatment assessment still found that the intervention did not affect late mortality either. However, intervention patients whose depression did not improve were at higher risk for late mortality than were patients who responded to treatment. Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Carney RM et al. Washington University. . Psychosom Med. 2004 Jul-Aug;66(4):466-74

Tricyclics Are Actually Anti-Arrhythmic Medications: There have been a number of studies of the use of tricyclics in depressed patients with preexisting cardiac disease, specifically ventricular arrhythmias, impairment of left ventricular function, and conduction disease. The results have demonstrated that tricyclics are effective Class 1A antiarrhythmic drugs and that contrary to earlier expectations tricyclics do not have a deleterious effect on left ventricular function even in patients with severe preexisting left ventricular impairment, but that patients with bundle-branch block are at increased risk to develop significant conduction complications when treated with a tricyclic. Depression, heart disease, and tricyclic antidepressants. Roose SP, et al.  Columbia University, New York. J Clin Psychiatry. 1989 Jul;50 Suppl:12-6

Animal Research

Imipramine Tricyclic Reduced Mortality and Duration of Ventricular Fibrillation in Rats: The effects of the intravenously administered antidepressant drugs mianserin, imipramine, metapramine, nomifensine and amineptine against ischaemia and reperfusion arrhythmias were investigated in anaesthetized rats. Imipramine, metapramine, mianserin and high doses of nomifensine (0.5 mg.kg-1) reduced the mortality and the duration of ventricular fibrillation observed following coronary artery ligation. Amineptine was ineffective in preventing early postligation arrhythmias. With the tricyclic antidepressant drugs imipramine and metapramine, the arrhythmias were practically suppressed after 15 min following coronary artery ligation. The incidence of reperfusion arrhythmias was significantly reduced by tricyclic antidepressant drugs. In contrast, amineptine was not effective and did not alter cardiac function. It was suggested that nonspecific effects of these drugs account for their antiarrhythmic action. The most plausible explanation for their antiarrhythmic action may be a quinidine-like cardiac depressant activity. Antiarrhythmic properties of antidepressant drugs after coronary artery occlusion and reperfusion in rats. Bril A, et al. Dijon, France. Pharmacology. 1988;36(1):16-26.

Tricyclic Antidepressant Pretreatment Reduces Area of Myocardial Infarction in Cats: Dibenzepin HCl (D) and other tricyclic antidepressants (TCAD), given either before or during occlusion of the left anterior descending artery (LAD), decreased the incidence of ventricular fibrillation (VF) following occlusion and reperfusion. Moreover, once VF develops in treated animals, it changes into a transient type, reverting spontaneously to a sinus rhythm. In the treated cats, retrograde perfusion of the occluded coronary artery was observed, most likely as a result of increased collateral blood flow. This latter effect is the subject of the present study. The LAD was occluded at its origin in 43 cats, 28 of which were treated either with D or with 5-iminodibenzyl HCl; the remaining 15 were untreated controls. Two hours after the occlusion, methylene blue was injected into the left atrium to determine color demarcation between the perfused and unperfused myocardium, and the cat was then killed. After fixing for 2 or 3 days in 4% formaldehyde, the hearts were sectioned transversely. The results showed that in the 15 control cats, the blood-supplied (blue) area ranged between 16% and 56% of the left ventricular muscle (mean 39%), while in the 28 treated cats the blue area was between 44% and 83% (mean 66%). These results clearly indicate the beneficial effect of TCAD on the blood supply of the occluded area and can explain, in part, the ability of these drugs to prevent VF even if infused after the coronary occlusion, and their protective effect against VF following reperfusion. No other antiarrhythmic drugs have been shown to possess this latter action. The effect of tricyclic antidepressants on ventricular fibrillation and collateral blood supply following acute coronary occlusion. Manoach M, et al. Heart Vessels. 1986;2(1):36-40.

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com