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Venlafaxine (Effexor) inhibits the reuptake of both serotonin and norepinephrine at their respective presy-naptic sites. This drug does not have significant effects at muscarinic, histamine, or α-adrenergic receptors and therefore is devoid of many of the side effects associ-ated with the TCAs. Venlafaxine and its active metabo- lite, O-desmethyl-venlafaxine, have half lives of 5 and 11 hours respectively, so dosing twice a day is necessary. However, an extended release preparation (Effexor XR) now allows for once-daily dosing and better toler-ance. Venlafaxine has a side effect profile similar to that of the SSRIs (Table 33.2). Higher doses of venlafaxine result in modest increases in blood pressure in approxi-mately 5% of patients. Venlafaxine has minimal effects on the cytochrome P450 enzyme system.
Bupropion (Wellbutrin) is a pharmacologically unique antidepressant, since it is a weak inhibitor of both do-pamine and norepinephrine neuronal reuptake. How-ever, its actual antidepressant activity is not well under-stood. Bupropion is generally well tolerated and does not block muscarinic, histaminergic, or adrenergic re-ceptors. Unlike the SSRIs and venlafaxine, bupropion does not cause sexual side effects. However, it can cause CNS stimulation, including restlessness and insomnia. High doses of bupropion, given as its original formula-tion, were associated with a risk of seizures in 0.4% of patients. However, this risk is lower with slow-release bupropion (Wellbutrin SR). This formulation still re-quires dosing twice a day, and bupropion is contraindi-cated in patients with a history of seizures. Bupropion inhibits the cytochrome P450 2D6 isoenzyme and may elevate blood levels of drugs metabolized by this route.
Mirtazapine (Remeron) enhances both serotonergic and noradrenergic neurotransmission. By blocking presynaptic α2-adrenoceptors, mirtazapine causes re-lease of norepinephrine. Indirectly, through noradrener-gic modulation of serotonin systems, mirtazapine also causes increased release of serotonin.
It is an antagonist at the 5-HT2A, 5HT2C, 5-HT3, and histamine receptors but has minimal affinity for muscarinic or α1-receptors. Mirtazapine does not inhibit neuronal reuptake of sero-tonin or norepinephrine. Weight gain and sedation are common side effects (Table 33.2); sedation necessitates dosing at bedtime. Mirtazapine does not have signifi-cant effects on cytochrome P450 isoenzymes.
Trazodone (Desyrel) was introduced in the early 1980s as a second-generation antidepressant. It blocks the neuronal reuptake of serotonin and is an antagonist at the 5HT2-receptor. Also, its major metabolite, m-chlorophenylpiperazine (mCPP), is a postsynaptic sero-tonin receptor agonist. When compared to the TCAs, trazodone is relatively free of antimuscarinic side ef-fects, but it does block the α-adrenoceptor. Common side effects include marked sedation, dizziness, ortho-static hypotension, and nausea (Table 33.2). Priapism is an uncommon but serious side effect requiring surgical intervention in one-third of the cases reported. Because of trazodone’s sedating quality, it is often used in low doses to counter the insomnia associated with the newer antidepressants, such as the SSRIs.
Although nefazodone (Serzone) is structurally related to trazodone, it is less sedating. It does not block α1-adrenoreceptors, and its use is not associated with pri-apism. Nefazodone inhibits the neuronal reuptake of serotonin and blocks 5HT2A receptors. Its short half-life requires dosing twice a day (Table 33.1). Nefazodone is not associated with weight gain or sexual dysfunction. It inhibits the cytochrome P450 3A4 isoenzyme that is re-sponsible for 50% of known oxidative metabolism, and therefore, nefazodone can elevate levels of drugs de-pendent on this pathway for metabolism.
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