Venlafaxine and nefazodone, two pharmacologically distinct antidepressants

Venlafaxine, a phenylethylamine, and nefazodone, a phenylpiperazine compound, are the newest antidepressants to receive approval of the Food and Drug Administration and to be marketed in the United States. Both strongly inhibit serotonin (5-HT) reuptake; venlafaxine also inhibits norepinephrine reuptake, and nefazodone also exhibits 5-HT2-receptor antagonism. Venlafaxine inhibits the cytochrome P-450 2D6 isozyme to a lesser extent than the selective serotonin reuptake inhibitors (SSRIs) and is 27% protein bound. Structurally, the drugs are unrelated to SSRIs and have some clinically important differences in side effect profiles. Nausea, headache, somnolence, and dry mouth are the most frequently reported side effects with both. Sustained hypertension was reported by a limited number of venlafaxine-treated patients.