Orthostatic hypotension is one of the most common reasons for discontinuation of tricyclic antidepressant treatment (Glassman et al. 1979). It can occur with all of the tricyclics but appears to be less pronounced with nortriptyline (Roose et al. 1981; Thayssen et al. 1981). The Ki-adrenergic blockade associated with the tricyclics contributes to orthostatic hypotension; however, it is the postural reflex that is primarily affected. Resting supine blood pressure may be unaffected or can even be elevated (Walsh et al. 1992). Orthostatic hypotension is most likely to occur or is most severe in patients who have preexisting orthostatic hypotension (Glassman et al. 1979). It is also aggravated by concurrent antihypertensive medications, especially volume-depleting diuretic agents. The elderly are more likely to have preexisting hypotension and are also more vulnerable to the consequences of orthostatic hypotension, such as falls and hip fractures.
Often, orthostatic hypotension occurs at low blood levels, so that dosage reduction is not a helpful management strategy. Gradual dose adjustment may allow accommodation to the subjective experience of light-headedness, but the actual orthostatic blood pressure changes do not accommodate within a reasonable period of time (e.g., 4 weeks) (Roose et al. 1998). Thus, unless the plasma level is elevated and the dose can be reduced, patients who experience serious symptomatic orthostatic hypotension may not be treatable with a tricyclic antidepressant. Fludrocortisone (Florinef) has been used to raise blood pressure, but in this author's experience it is not very effective. If patients are receiving antihypertensives, it may be possible and helpful to reduce the dose of these agents.
Desipramine has been reported to raise supine blood pressure in younger patients, although it is not clear this effect is limited to that age group (Walsh et al. 1992). This effect may be similar to that reported for venlafaxine.
Tachycardia occurs with all the tricyclics, not just the more anticholinergic agents. Both supine and postural pulse changes can occur, and the standing pulse can be markedly elevated. A relatively recent study of nortriptyline, dosed to a therapeutic plasma concentration, found a mean pulse rise of 11% (8 beats per minute) (Roose et al. 1998). Patients do not accommodate to the pulse rise, which can persist for months. Tachycardia is more prominent in younger patients, who appear more sensitive to sympathomimetic effects, and is one of the most common reasons for drug discontinuation in adolescents. A persistent pulse rise in older patients, however, increases cardiac work and may be clinically significant in patients with ischemic heart disease.
The effect of tricyclic antidepressants on cardiac conduction has been a subject of great interest. Cardiac arrhythmia is the principal cause of death following overdose (Biggs et al. 1977; Pimentel and Trommer 1994; Spiker et al. 1975). As a result of this observation, for many years there was great concern about the use of tricyclic antidepressants in patients with and without heart disease. The effect of these agents has now been well described. Apparently, through inhibition of Na+/K+-ATPase, the tricyclics stabilize electrically excitable membranes and delay conduction, particularly His ventricular conduction. Consequently, the tricyclics have type I antiarrhythmic qualities or quinidine-like effects.
At therapeutic blood levels, the tricyclics can have beneficial effects on ventricular excitability. In patients with preexisting conduction delay, however, the tricyclic antidepressants can further delay conduction and cause heart block (Glassman and Bigger 1981; Roose et al. 1987b). A pretreatment QTc interval of 450 milliseconds or greater indicates that conduction is already delayed, that a tricyclic may aggravate this condition, and that the patient is not a candidate for tricyclic antidepressant treatment. High drug plasma levels further increase the risk of cardiac toxicity. For example, first-degree atrioventricular heart block is increased with imipramine plasma concentrations above 350 ng/mL (Preskorn and Irwin 1982).
The tricyclic antidepressants do not reduce cardiac contractility or cardiac output (Hartling et al. 1987; Roose et al. 1987a). Studies using radionuclide angiography indicate no adverse effect of imipramine or doxepin on cardiac output, even in patients with diminished left ventricular ejection fractions. But orthostatic hypotension was common in these studies and could be severe in these patients.
Glassman et al. (1993), noting that the type I antiarrhythmic drugs given following myocardial infarction actually increased the risk of sudden death, suggested that the tricyclics may pose similar risks. The risk of sudden death is also increased when heart rate variability is reduced, and the tricyclics reduce heart rate variability (Roose et al. 1998).
As mentioned earlier (see subsection "Attention-Deficit/Hyperactivity Disorder"), sudden death has been reported in five children under the age of 12 years who were receiving desipramine (Riddle et al. 1991, 1993). It was suggested that the immature conduction system in some children might render them more vulnerable to the cardiac effects of desipramine. Subsequently, a study was conducted in 71 children with 24-hour cardiac monitoring (Biederman et al. 1993). No cardiac abnormalities were observed. Wilens et al. (1992) examined the possibility that hydroxydesipramine might reach unusually high levels in children and adolescents, but such levels were not found. A study of electrocardiographic parameters in that sample failed to show a relationship between those parameters and concentrations of desipramine or hydroxydesipramine (Wilens et al. 1993). Although these studies failed to reveal a mechanism for the sudden deaths reported, they do suggest that these events are not predictable, that they are not dose-dependent cardiac effects, and that usual blood level or electrocardiogram monitoring is not likely to identify those at risk.
To summarize the clinical implications of these cardiac effects, the clinician may wish to consider the following. In adults without cardiac disease, orthostatic hypotension may occur with tricyclic use, but conduction problems are not likely. In patients with preexisting conduction delay, the tricyclics may cause heart block. In patients with ischemic heart disease, continued use of tricyclics will increase cardiac work and reduce heart rate variability, possibly increasing the risk of sudden death. Children younger than 12 years also appear vulnerable to the risk of sudden death during tricyclic administration, possibly because of cardiac conduction effects or reduced heart rate variability. Cardiac arrhythmia is the most common cause of death with tricyclic overdose. These cardiac safety issues, coupled with the recently reported safety of the SSRI sertraline when administered for depression following myocardial infarction (Glassman et al. 2002), indicate that the tricyclics are relatively contraindicated in patients with ischemic heart disease and that their use should be reserved for patients whose illnesses are refractory to other treatments.
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