Treatment of Mood Disorders: Newer and Atypical Antidepressant Agents and the Cytochrome System
Newer antidepressants including venlafaxine (a phenylpiperazine), nefazodone (a phenylethylamine), and mirtazapine (a piperazino-azepine) have also been investigated concerning their CYP interactions. Venlafaxine has shown to lack any significant effects on CYP1A2, CYP3A4, and CYP2C in vivo but is a weak inhibitor of CYP2D6 and much less significant than either paroxetine or fluoxetine. Nefazodone is a weak CYP2D6 inhibitor and potent CYP3A4 inhibitor and thus contraindicated for use with patients currently treated with cisapride, terfenadine, and astemizole. Its inhibition of CYP1A2 has been found to be 10-fold less than sertraline, fluoxetine, or paroxetine. Mirtazapine has been found to be a weak inhibitor of CYP2D6, CYP1A2, and CYP3A4 and is thought to be much less of an inhibitor than are fluvoxamine and fluoxetine.

Bupropion, buspirone, nefazodone, and venlafaxine possess their own unique side effects that must be taken into consideration when selecting an antidepressant. Bupropion, a monocyclic antidepressant, has a mode of action that involves serotonergic, adrenergic, and dopaminergic activity. Prominent side effects include nausea, insomnia, tremor, and central nervous system activation. In clinical trials, bupropion was also found to decrease seizure threshold and thus to increase risk for seizures. This risk was first reported in 1991 after a double-blind, placebo-controlled trial treating bulimic patients revealed a significantly higher occurrence of seizures in patients given bupropion. The increased risk for seizures was believed to occur as a result of high dosage and elevated serum levels of the drug because of the eating disorder. The incidence of seizure as a result of administration of bupropion is estimated to be 4 in 1,000 and is believed to be approximately equal to the seizure incidence with TCAs.

Buspirone is an azaspirone with location of action thought to be dopamine type 2 receptors and with mixed agonist/antagonist activity for the serotonin (5-hydroxytryptamine [5-HT]) receptor 5-HT_1A. 5-HT_1A lacks sedative, hypnotic, or muscle-relaxant effects and is an excellent choice for the elderly or medically ill patient. Its primary success has been seen in patients with anxiety disorder, and it is relatively less effective than either the SSRIs or TCAs for treating depression.

Trazodone and nefazodone are both 5-HT₂ receptor antagonists. Although trazodone has been found to be an effective antidepressant, its antihistaminergic activity limits its use in medically ill patients, including those with orthostasis, urinary retention, and myocardial irritability. Nefazodone is similar to trazodone in action and is as effective as trazodone in the treatment of depression. The difference between the two agents is the relative lack of antihistaminergic activity. This is postulated to occur because of the lack of α₁-adrenergic properties in nefazodone. Nefazodone does not inhibit CYP1A2 and is a weak inhibitor of CYP2D6 but a potent inhibitor of CYP3A4. Reports have shown that nefazodone did not affect the pharmacokinetics of theophylline, but a clinically significant interaction could take place between terfenadine and other active CYP3A4 medications. No clinically significant interaction has been reported between nefazodone and alcohol, lithium, warfarin, propranolol, or cimetidine.

Despite concern over liver-related drug interactions, the SSRIs are commonly used and require much less effort in monitoring. All of the SSRIs have been shown to be equally efficacious, and cost, availability, patient preference, and physician familiarity may determine choice. Specific use is determined by the prospective side effects in the context of the patient’s specific medical problems (e.g., if patient has constipation, avoiding drugs that could worsen it).