The delineation of side effects during the treatment of depressed patients is complicated because depression itself is accompanied by a variety of somatic symptoms. For example, headache, constipation, and drowsiness—symptoms usually considered as "side effects"—have been observed in more than 50% of untreated inpatients with major depression if these symptoms were each directly assessed (Nelson et al. 1984). During treatment, patients may be quick to label these somatic symptoms as side effects even if the symptoms were preexisting. Another manifestation of this issue is the rate of spontaneously reported "side effects" on placebo in clinical trials. One of the best examples is headache. Clinical trial data for recently marketed antidepressants indicate that the rate of headaches on placebo in depressed outpatients ranges from 17% to 24% (Physicians' Desk Reference 2002). For fluoxetine, sertraline, paroxetine, and bupropion, the rate for drug was only 1%-2% higher than that for placebo. For venlafaxine XR and citalopram, the rate of headaches was higher for placebo than for drug. A strong argument can be made that headache is usually a symptom of depression. Of course, these mean values conceal the possibility that a symptom may worsen or emerge during treatment in some patients and improve with treatment in others. In groups of patients, however, the strongest predictor of overall somatic symptom severity is the severity of the depression at the time of assessment (Nelson et al. 1984), and the best intervention may be more aggressive treatment.
Another general factor contributing to side effects is the patient's vulnerability. For example, one of the best predictors of orthostatic hypotension during treatment is the presence of orthostatic hypotension prior to treatment (Glassman et al. 1979). Seizures are most likely in a patient with a history of seizures (Rosenstein et al. 1993). Cardiac conduction problems are most likely to occur in patients with preexisting conduction delay (Roose et al. 1987a).
The final manifestation of somatic symptoms during treatment is the net result of the interaction of direct effects of the medication on specific organs, the indirect effects of the medication on depression and its associated somatic symptoms, and the patient's vulnerability to certain symptoms. The attribution of cause—that is, whether a physical symptom is a "side effect" of a drug or a symptom of depression—involves a judgment about whether the symptom is new or has worsened during drug treatment.
Antidepressant drugs do, of course, have direct effects on a variety of organs and can produce adverse effects. The in vitro potency or affinity of antidepressant compounds for various receptor sites (see Table 12-1) is one method for comparing the likelihood that various agents will produce specific side effects. A related issue is how the in vitro potency of a secondary effect relates to the potency of the primary action of the drug. If the secondary effect is more potent, it will occur at concentrations below the therapeutic level of the drug. An example for the tricyclics is orthostatic hypotension, which often manifests at plasma concentrations below the usual antidepressant threshold. Alternatively, in patients without preexisting medical illness, the proarrhythmic and proconvulsant effects of the tricyclic antidepressants are uncommon at therapeutic concentrations but become more frequent at levels encountered in overdose.
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