RECENT PHARMACOLOGICAL ADVANCES IN ANTIDEPRESSANT THERAPY FOR THE ELDERLY

Major depression is a common, serious, and potentially life-threatenin g illness in the elderly. Moreover, this population is perhaps the mos t difficult to treat effectively and safely for this disease. Changes in physiology associated with advancing age produce clinically signifi cant differences in drug metabolism and pharmacokinetics in these pati ents 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 pharmacokinet ic drug-drug interactions. The practicing clinician now has five disti nct classes of antidepressant medications that may be used for treatin g depression in the elderly: tricyclic antidepressants (TCAs; e.g., de sipramine, nortriptyline), monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, tranylcypromine), selective serotonin reuptake inhibito rs (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 choi ce for the treatment of elderly depressed patients, based on a number of considerations. SSRIs have a broad spectrum of antidepressant activ ity, being effective in different types of major depressive episodes ( e.g., melancholic, atypical), have a wide therapeutic index, and are f ree of many potentially serious adverse effects associated with other antidepressants, such as central nervous system and cardiovascular tox icity (TCAs, bupropion), orthostatic hypotension (TCAs, MAOIs, and tra zodone), 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 pharmacokineti cs of sertraline are the same in both elderly and younger patients, wh ereas elderly, in comparison with younger, patients develop higher pla sma levels of fluoxetine (and its active metabolite, norfluoxetine) or paroxetine, when given the same dose. Second, the SSRIs differ in the ir potential for pharmacokinetic interactions with other psychotropic and non-psychotropic drugs. Fluoxetine, norfluoxetine (the major metab olite of fluoxetine), and paroxetine are potent inhibitors of the hepa tic isoenzyme P450 IID6, whereas sertraline has much weaker inhibitory effects on its activity. Inhibition of P450 isoenzymes can cause pote ntially dangerous increases in the plasma levels of a large number of drugs, including TCAs, neuroleptics, and mood stabilizers, such as car bamazepine. Thus, sertraline has several characteristics that offer ad vantages over other members of this class of antidepressants for the t reatment of the elderly patient with major depression.