Novel serotonergic mechanisms and clinical experience with nefazodone

Abstract

Chronic administration of antidepressant drugs enhances synaptic serotonergic transmission. Nefazodone, a member of a new class of antidepressants, has a pharmacologic profile that is distinct from the first-generation agents (e.g., tricyclics and monoamine oxidase inhibitors) as well as the more selectively acting second-generation agents (e.g., serotonin or norepinephrine uptake inhibitors, and serotonin type 1A partial agonists). Nefazodone acts both as a 5-HT2 receptor antagonist and as a serotonin (5-HT) reuptake inhibitor. Nefazodone's potent 5-HT2 antagonism in combination with 5-HT reuptake inhibition appears to enhance 5-HT1A-mediated neurotransmission. Nefazodone has very selective serotonergic effects, with negligible affinity for cholinergic and histamine receptors and low affinity for alpha 1-adrenergic receptors. It is also free of cardiotoxicity and is well tolerated even at high doses. The two primary effects on serotonergic neurotransmission, 5-HT2 antagonism and 5-HT reuptake inhibition, are thought to contribute importantly to nefazodone's therapeutic efficacy and clinical utility. It is postulated that 5-HT2 antagonism dampens the activating side effects experienced by some patients when treated with existing 5-HT reuptake inhibitors. Nefazodone's effectiveness as an antidepressant drug has been shown in a series of well-controlled, placebo-comparison studies of somewhat differing designs involving patients with major depression. In placebo-controlled studies comparing nefazodone and the tricyclic antidepressant imipramine, the drugs produced comparable and significant therapeutic benefit. Nefazodone is associated with fewer adverse events than imipramine. Nefazodone lacks the troublesome anticholinergic side effects of tricyclic antidepressants, as well as serotonergic/noradrenergic-mediated effects.(ABSTRACT TRUNCATED AT 250 WORDS)