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Chapter 29: Psychopharmacological Treatment

Table 29.23-1 Adverse Reactions Reported with Nefazodone (300–600 mg a Day)

trial leading to the approval of the extended-release formulation, the most common adverse events were somnolence or sedation, dizziness, constipation, and blurred vision. Surprisingly, only 4 percent of patients in the trazodone group discontinued treat- ment because of somnolence or sedation.

Reaction

Patients (%)

Headache Dry mouth Somnolence

36 25 25 22 17 14 11 11 10

Nefazodone Pharmacologic Actions

Nausea

Dizziness

Nefazodone is rapidly and completely absorbed but is then extensively metabolized so that the bioavailability of active compounds is about 20 percent of the oral dose. Its half-life is 2 to 4 hours. Steady-state concentrations of nefazodone and its principal active metabolite, hydroxynefazodone, are achieved within 4 to 5 days. Metabolism of nefazodone in elderly per- sons, especially women, is about half of that seen in younger persons, so lowered doses are recommended for elderly persons. An important metabolite of nefazodone is meta-chlorophenylpi- perazine (mCPP), which has some serotonergic effects and may cause migraine, anxiety, and weight loss. Although nefazodone is an inhibitor of serotonin uptake and, more weakly, of norepinephrine reuptake, its antagonism of serotonin 5-HT A receptors is thought to produce its antianxiety and antidepressant effects. Nefazodone is also a mild antagonist of the a 1 -adrenergic receptors, which predisposes some persons to orthostatic hypotension but is not sufficiently potent to pro- duce priapism. Therapeutic Indications Nefazodone is effective for the treatment of major depression. The usual effective dosage is 300 to 600 mg a day. In direct com- parison with SSRIs, nefazodone is less likely to cause inhibition of orgasm or decreased sexual desire. Nefazodone is also effec- tive for treatment of panic disorder and panic with comorbid depression or depressive symptoms, generalized anxiety disor- der, and premenstrual dysphoric disorder and for management of chronic pain. It is not effective for the treatment of OCD. Nefazodone increases rapid eye movement (REM) sleep and increases sleep continuity. Nefazodone is also of use in patients with PTSD and chronic fatigue syndrome. It may also be effec- tive in patients who have been treatment resistant to other anti- depressant drugs. Precautions and Adverse Reactions The most common reasons for discontinuing nefazodone use are sedation, nausea, dizziness, insomnia, weakness, and agita- tion. Many patients report no specific side effect but describe a vague sense of feeling medicated. Nefazodone also causes visual trails, in which patients see an afterimage when looking at moving objects or when moving their heads quickly. A major safety concern with the use of nefazodone is severe elevation of hepatic enzymes, and, in some instances, liver fail- ure. Accordingly, serial hepatic function tests need to be done when patients are treated with nefazodone. Hepatic effects can be seen early in treatment and are more likely to develop when nefazodone is combined with other drugs metabolized in the liver.

Constipation

Insomnia Weakness

Lightheadedness Blurred vision

9 9 8 7 7

Dyspepsia Infection Confusion Scotomata

Some patients taking nefazodone may experience a decrease in blood pressure that can cause episodes of postural hypoten- sion. Nefazodone should therefore be used with caution by per- sons with underlying cardiac conditions or history of stroke or heart attack, dehydration, or hypovolemia or by persons being treated with antihypertensive medications. Patients switched from SSRIs to nefazodone may experience an increase in side effects, possibly because nefazodone does not protect against SSRI withdrawal symptoms. One of its metabolites, mCPP, may actually intensify these discontinuation symptoms. Patients have survived nefazodone overdoses in excess of 10 g, but deaths have been reported when it has been combined with alcohol. Nausea, vomiting, and somnolence are the most common signs of toxicity. The effects of nefazodone in human mothers are not as well understood as those of the SSRIs, mainly because of the pau- city of its clinical use. Nefazodone should therefore be used during pregnancy only if the potential benefit to the mother out- weighs the potential risks to the fetus. It is not known whether nefazodone is excreted in human breast milk. Therefore, it should be used with caution by lactating mothers. The nefazo- done dosage should be lowered in persons with severe hepatic disease, but no adjustment is necessary for persons with renal disease (Table 29.23-1). Drug Interactions and Laboratory Interferences Nefazodone should not be given concomitantly with MAOIs. In addition, nefazodone has particular drug–drug interactions with the triazolobenzodiazepines triazolam (Halcion) and alprazolam (Xanax) because of the inhibition of CYP3A4 by nefazodone. Potentially elevated levels of each of these drugs can develop after administration of nefazodone, but the levels of nefazodone are generally not affected. The dose of triazolam should be lowered by 75 percent, and the dose of alprazolam should be lowered by 50 percent when given concomitantly with nefazodone. Nefazodone may slow the metabolism of digoxin; therefore, digoxin levels should be monitored carefully in persons taking