Behavioral cardiology is an emerging field of clinical practice based on the recognition that adverse lifestyle behaviors, emotional factor, and chronic life  stress can all promote atherosclerosis and adverse cardiac events.  In recent years, the pathophysiologic understanding of how psychosocial risk factors contribute to atherosclerosis and adverse cardiac events has broadened substantially. There is also increasing evidence that interventions such as exercise training, multifactorial secondary prevention efforts that incorporate psychosocial intervention, and antidepressant medication may be effective in treating psychologic distress and improving outcomes among patients with cardiac disease1.

Psychosocial factors that promote atherosclerosis and adverse cardiac events can be divided into two general categories; emotional factor and chronic stressors.Emotional factors includes affective disorders such as major depression and anxiety disorders as well as hostility and anger. Chronic stressors include factors such as low social support, low socioeconomic status, work stress, marital stress, and caregiver strain1.

During the past two decades, a substantial body of evidence has established a a link between depression, cardiovascular disease and mortality2,3. Two large , community epidemiologic studies4,5 demonstrated a significant relationship between depression and mortality in patients with myocardial infarction. Results from another study5,6 showed that depression contributes to a greater chance of developing or dying of heart disease in persons who were initially healthy,even after controlling for smoking status, gender, weight, activity, blood pressure and cholesterol levels. Results from additional studies2 have supported the contribution of depression as an independent risk factor for cardiovascular disease in persons who were initially free of the disease. Other studies7,8 have shown that persons who are depressed and have preexisting cardiovascular disease have a 3.5 times greater risk of dying of a myocardial infarction than patients with cardiac disease who are not depressed. In a recent study9, depression was shown to be associated with an increased risk of developing coronary heart disease in men and women. Depression was shown to increase mortality related to coronary heart disease in men but had no effect on mortality in women.

A link between antihypertensive medications and depression has been suspected for more than four decades. One of the causative pathways for depression may be the dysregulation of the noradrenergic system. Several commonly used antihypertensive medications exert their effects through the sympathetic nervous system and may induce or worsen depression.

Considerable evidence exists about the ability of reserpine and methyldopa to cause depression, Reserpine depletes catecholamines from peripheral sympathetic nerve endings, the brain, and the adrenal medulla. As a result of norepinephrine depletion in the CNS, reserpine in doses greater than 0.25 mg per day can cause clinical depression and a variety of related side effects, such as decreased energy, crying spells, lethargy, and insomnia13. Reserpine rarely is used for treatment of hypertension now that better medications with fewer adverse effects are available.

Methyldopa once was widely used as an antihypertensive medication, but its use has waned in the last two decades. The drug diminishes central sympathetic outflow, resulting in sedation as its major side effect and causing depression in 4% to 10% of patients, especially in higher doses. Patients who are elderly and those with a history of depression may be more susceptible to its side effects. Other drugs with similar mechanisms of action, such as guanethidine monosulfate and clonidine hydrochloride, often cause sedation and, rarely, clinical depression13.

Beta-blockers are used for treatment of hypertension as well as CAD, cardiac arrhythmias, migraine, hyperthyroidism, glaucoma, and essential tremor. Reports linking depression to propranolol hydrochloride, which was approved for use in hypertension in 1967, and other beta-blockers have been inconclusive14, 15. Sedation may occur with all beta-blockers; insomnia and nightmares have been reported with use of propranolol13. These symptoms may have been interpreted as depressive symptoms in some studies, especially in the absence of well-defined criteria for a diagnosis of depression. Wurzelmann and colleaques14 did not find increased rates of depression with use of propranolol in a population of patients aged 75 to 85 years. Some evidence suggests that hydrophilic beta-blockers, such as atenolol and nadolol, which do not readily cross the blood-brain barrier, may cause fewer CNS side effects than other beta-blockers16.

Medications can be an important modifiable factor in causing or worsening hypertension. The importance of obtaining a complete history oh all prescription and nonprescription drugs cannot be overemphasized; depression is treated with antidepressants by psychiatrists as well as by primary care physicians. Monoamine oxidase inhibitors (MAOIs) have been known to cause or worsen hypertension. MAOIs raise blood pressure by delaying the metabolism of 5-hydroxytryptamine (serotonin) and sympathetic amines, such as phenylpropanolamine hydrochloride or pseudoephedrine sulfate. These emergencies have also occurred after ingestion of tyramine-rich foods and beverages, such as red wine or aged cheese.

Lavin and associates18  reported a series of 11 cases that suggest MAOIs may induce spontaneous hypertensive reactions, even in subjects who did not consume medications or food known to interact with MAOIs. Newer MAOIs, such as moclobemide, are safer – but not completely risk-free – with regard to hypertensive reactions19. Although MAOIs now are raely prescribed, patients taking these drugs needs blood pressure monitoring and education about interactions with serotoninergic agents, tyramine-rich foods, and sympathetic agents.

Tricylic antidepressants (TCAs) are commonly used in a variety  of applications other than depression, including treatment of migraine and pain syndromes. TCAs appears to inhibit the reuptake of norepinephrine centrally and may cause a mild increase in blood pressure in less than 5% of patients20. This nonurgent increase in blood pressure rarely is clinically significant, but patients taking TCAs needs to have their blood pressure monitored.

More important is the antagonistic effects of TCAs on alpha-adrenergic and muscarinic receptors, which may result in orthostatic blood pressure changes and small increases in resting heart rate20. These effects assume greater significance in elderly depressed patients and in patients treated with antihypertensive medications, who might be at increased risk of falls because of exaggerated orthostatic blood pressure changes. This risk appears to be more prominent with TCAs, such as amitriptyline, desipramine hydrochloride, and imipramine hydrochloride ; atypical antidepressants, such as trazodone hydrochloride;and tetracyclic antidepressants,such as amoxapine and maprotiline hydrochloride.. Although use of TCAs has declined considerably, the safest agent is the secondary TCA amine nortriptyline hydrochloride13. Arrhythmias and conduction abnormalities are uncommon with TCAs, but use of these should be avoided in patients with CAD.

Selective serotonin reuptake inhibitors (SSRIs) produce fewer cardiovascular and hemodynamic side effects compared with MAOIs and TCAs. A recent study by Amsterdam and associates21 of 796 depressed patients treated with 20mg of fluoxetine hydrochloride per day for up to 12 weeks show a low rate of sustained hypertension (1.7% versus 2.1% with placebo).

Role of SSRIs in Management of Depression with Hypertension

The safety of SSRIs in hypertensive patients with depression is a topic of much interest. SSRIs do not appear to adversely affect blood pressure or ejection fraction (EF). One study revealed that despite elevated blood levels of fluoxetine in depressed patients with heart disease, no change in blood pressure was observed22. Similar observations have been made with sertraline and paroxetine23.The SSRIs do not possess antiarrhythmic properties and are unlikely to cause conduction abnormalities, even in overdose24.

More recently, the safety and efficacy of several of the SSRIs have been evaluated in patients with existing ischemic heart disease. Although the studies have involved a limited number of patients, the available data25 suggest that SSRIs are not associated with adverse cardiovascular effects in these patients and are safer than TCAs in the treatment of depression in patients with heart disease. The prevalence of cardiovascular disease and the evidence that comorbid depression with cardiovascular disease (for example, following myocardial infarction) increases the risk of mortality. It also underscores the importance of understanding the cardiac effects of antidepressants and the need for effective antidepressants that are free of adverse cardiovascular effects. At present, the SSRIs should be considered first-line agents for the treatment of depressed patients with cardiovascular illness, particularly ischemic heart disease. Among the SSRIs, those with a lower potential for causing pharmacokinetic drug interactions generally are preferred. Among the available SSRIs only escitalopram and paroxetine have been approved in patients with comorbid cardiovascular illness.

Escitalopram

Escitalopram is the first antidepressant introduced according to chirality rules, it is an S-enantiomer of citalopram, the drug which has been used for many years. Experimental studies showed that the property of serotonin transporter inhibition – one of the main mechanisms of antidepressive action is connected with the S-enantioner of citalopram, and that escitalopram is the most selective inhibitor of this transporter. The results of most clinical studies26 in patients with depression show significant superiority of escitalopram, 10-20 mg/day, over placebo, as early as within the first week of treatment, and a faster onset of action and higher therapeutic efficacy of escitalopram, compared to citalopram, 20-40mg/day. A similar efficacy of escitalopram, 10 mg/day, and sertraline 50-200mg/day, as well as escitalopram, 20 mg/day, and venlafaxine, 225mg/day was demonstrated. It has also been shown that escitalopram, 10-20mg/day, exerts therapeutic efficacy in general anxiety disorder, panic disorder and social phobia. Escitalopram may meet many criteria for the optimal antidepressant. The drug is efficicacious in depressions of various intensity, has a rapid onset of action and, in long-term treatment, prevents the relapses of the illness. It exerts therapeutic activity in anxiety disorders. The dosing is convenient, and the drug is safe and well tolerated due to a mild profile of side-effects and favorable pharmacokinetic properties.

Cardiovascular safety of Escitalopram

Cardiac toxicity in citalopram overdoses appears to be related to QT prolongation caused by the active metabolite, didemethylcitalopram(DDCT), which is present in only minor amounts(<10%) in humans. Although escitalopram is metabolized. To S-demethylcitalopram (S-DCT) and S-DDCT, it has been reported that the level of S-DDCT is not detectable in most subjects.