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General Principles of Antidepressant Use

Selecting an Antidepressant

The choice of antidepressant depends on a number of variables that are specific to the drug as well as to the patient. Drug-specific variables include efficacy, side-effect profile, safety, and cost. It is difficult to demonstrate that one antidepressant is consistently more effective than another. A given antidepressant is likely to lead to a significant improvement in a depressive episode 50% to 70% of the time; however, with each failure of an antidepressant, the chance of responding to a subsequent trial is reduced.

The side-effect profile differs significantly from one class of agents to another because of differing neurotransmitter effects. The TCAs are characterized by anticholinergic, antihistaminic side effects, whereas the selective serotonin-reuptake inhibitors (SSRls) produce more serotonin-specific side effects, including headache, gastrointestinal upset, and sexual dysfunction. Most of the newer antidepressants, including the SSRls, venlafaxine, bupropion, nefazodone, and mirtazapine, enjoy a much higher therapeutic index than do the TCAs and MAOIs. The newer antidepressants are rarely life­threatening when taken' in overdose alone, whereas overdoses of small amounts of TCAs may be lethal.

The cost of antidepressants is a major concern to patients, clinicians and third-party payers. Compared with generic TCAs or MAOIs, the formulary cost of newer antidepressants is considerable. A month's supply of fluoxetine may cost $85 or more compared with the $8 or so for generic imipramine. However, the formulary costs are only a fraction of the total expense of treating a depressed patient. If imipramine is prescribed, additional factors to be considered include the cost of potential electrocardiograms, periodic serum-level testing, and more frequent office visits than generally are required for a SSRl prescription. Additionally, the heavier side­effect burden of TCAs leads to a higher percentage of incomplete or inadequate treatment trials compared with the newer antidepressants. Where these other factors are considered, it seems to be more cost effective to prescribe a SSRl rather than a TCA.

Patient parameters in choosing an antidepressant include medical status, age, gender, patient preference, and history of response. For example if a patient's depression is characterized by significant psychomotor retardation, an activating antidepressant may be preferred, whereas a patient with an agitated depression or prominent insomnia may better tolerate a more sedating antidepressant. Patients with a history of cardiac disease should avoid TCAs; those with a history of seizure disorder or stroke may be advised to avoid amoxapine, maprotiline, and bupropion because their higher seizure risk; and patients with obesity probably should not take TCAs or mirtazapine as first-line agents.

Patients taking multiple medications may better tolerate drugs such as citalopram or venlafaxine because these have less potential for drug inter­action than other agents. As a rule, older patients tend to tolerate the newer antidepressants better than the TCAs and MAGIs. Nonetheless, some geriatric patients will not be able to tolerate the orthostasis associated with higher doses of trazodone, the hypertensive effects seen with high-dose venlafaxine, or the dizziness that may occur with SSRIs.

Gender differences in antidepressant response are beginning to be appreciated. Women may tolerate and respond to SSRIs better than do men. Conversely, men may respond to and tolerate TCAs better than do women. Even so, newer, less dangerous antidepressants should be considered before trying a TCA.

The patient's antidepressant history is often useful in the selection of an antidepressant. A history of response to a particular agent might lead appropriately to a retrial. Likewise, a history of intolerable sexual side effects in a patient might suggest using nefazodone, bupropion, or mirtazapine. In this information age, patients may have researched antidepressants and have specific requests. However, patients rarely have the advantage of a larger clinical perspective. It is important to consider the rationale behind the patient's request when choosing a specific antidepressant.

When all of these patient- and drug-specific characteristics are matched, it is evident that newer antidepressants, including the SSRIs, are first-line agents for most patients. The MAGIs and TCAs, by virtue of their lower therapeutic index, difficulty of use, and greater potential for serious drug interactions, are now second- or third-line agents. However, the TCAs and MAGIs still have an important place in the treatment of depression and should be considered for certain patients.


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