Noradrenergic versus serotonergic antidepressants: predictors of treatment response

Serotonin selective reuptake inhibitors (SSRIs) have generally proven to be as effective as tricyclic antidepressants (TCAs) in the treatment of major depression and have an improved side effect profile. However, data suggest that the SSRIs are not as effective as the TCAs in certain subsets of depressed patients, indicating the importance of norepinephrine reuptake inhibition for such patients. Evidence for the role of norepinephrine in depression comes from early studies on excretion of catecholamines and more recent studies on receptor function, second messenger systems, and gene modification. These data are reviewed in this article. Data from a multicenter, randomized, controlled clinical trial comparing desipramine, a relatively norepinephrine-selective TCA, and the SSRI fluoxetine in moderate to marked major depression suggest a differential response depending on the antidepressant. The 2 drugs were overall similar in efficacy; however, in severely ill patients, there was a suggestion that desipramine was more likely to induce remission than fluoxetine. Urinary metabolite 3-methoxy-4-hydroxyphenylglycol levels were a better predictor of likelihood of remission than severity of episode or drug treatment. Desipramine and fluoxetine produced different longitudinal effects in catecholamine excretion, indicating that the 2 agents act through different mechanisms. Given the good therapeutic profile but relative risks associated with TCA therapy, selective norepinephrine reuptake inhibitors, such as reboxetine, which has a good safety profile, could be a major step forward in the treatment of depression.