Recent pharmacologic advances in antidepressant therapy for the elderly.

Major depression is a common, serious, and potentially life-threatening illness in the elderly. Moreover, this population is perhaps the most difficult to treat effectively and safely for this disease. Changes in physiology associated with advancing age produce clinically significant differences in drug metabolism and pharmacokinetics in these patients versus younger individuals. The elderly are also more likely than young patients to receive treatment for multiple illnesses. This fact increases the potential for serious pharmacodynamic and pharmacokinetic drug-drug interactions. The practicing clinician now has five distinct classes of antidepressant medications that may be used for treating depression in the elderly: tricyclic antidepressants (TCAs; e.g., desipramine, nortriptyline), monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, tranylcypromine), selective serotonin reuptake inhibitors (SSRIs; i.e., fluoxetine, sertraline, and paroxetine), aminoketones (i.e., bupropion), and triazolopyridines (i.e., trazodone). Although all are effective antidepressants, the SSRI class may be the best choice for the treatment of elderly depressed patients, based on a number of considerations. SSRIs have a broad spectrum of antidepressant activity, being effective in different types of major depressive episodes (e.g., melancholic, atypical), have a wide therapeutic index, and are free of many potentially serious adverse effects associated with other antidepressants, such as central nervous system and cardiovascular toxicity (TCAs, bupropion), orthostatic hypotension (TCAs, MAOIs, and trazodone), and sedation (TCAs, trazodone). While SSRIs as a group share a common presumed mechanism of action, there are clinically important differences among the members of this class. First, the pharmacokinetics of sertraline are the same in both elderly and younger patients, whereas elderly, in comparison with younger, patients develop higher plasma levels of fluoxetine (and its active metabolite, norfluoxetine) or paroxetine, when given the same dose. Second, the SSRIs differ in their potential for pharmacokinetic interactions with other psychotropic and nonpsychotropic drugs. Fluoxetine, norfluoxetine (the major metabolite of fluoxetine), and paroxetine are potent inhibitors of the hepatic isoenzyme P450 IID6, whereas sertraline has much weaker inhibitory effects on its activity. Inhibition of P450 isoenzymes can cause potentially dangerous increases in the plasma levels of a large number of drugs, including TCAs, neuroleptics, and mood stabilizers, such as carbamazepine. Thus, sertraline has several characteristics that offer advantages over other members of this class of antidepressants for the treatment of the elderly patient with major depression.