23 - 29.23 Nefazodone and Trazodone

29.23 Nefazodone and Trazodone

antidepressant drug treatments. Brain Res. 2008;1211:37. Baker GB, Sowa S, Todd KG. Amine oxidases and their inhibitors: What can they tell us about neuroprotection and the development of drugs for neuropsychiatric disorders? J Psychiatr Neurosci. 2007;32:313. Elmer LW, Bertoni JM. The increasing role of monoamine oxidase type B inhibitors in Parkinson’s disease therapy. Expert Opin Pharmacother. 2008;9:2759. Frampton JE, Plosker GL, Masand PS. Selegiline transdermal system in the treatment of major depressive disorder. Drugs. 2007;67:257. Goldberg JF, Thase ME. Monoamine oxidase inhibitors revisited: What you should know. J Clin Psychiatry. 2013;74(2):189–191. Holt A, Berry MD, Boulton AA. On the binding of monoamine oxidase inhibitors to some sites distinct from the MAO active site, and effects thereby elicited. Neurotoxicology. 2004;25:251. Kennedy SH, Holt A, Baker GB. Monoamine oxidase inhibitors. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins: 2009:3154. Maruyama W, Naoi M. “70th birthday professor riederer” induction of glial cell line-derived and brain-derived neurotrophic factors by rasagiline and (-)deprenyl: A way to a disease-modifying therapy? J Neural Transm. 2013;120(1):83–89. McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D report. Am J Psychiatry. 2006;163:1531. Nolen WA, Kupka RW, Hellemann G, Frye MA, Altshuler LL. Tranylcypromine vs. lamotrigine in the treatment of refractory bipolar depression: A failed but clinically useful study. Acta Psychiatr Scand. 2007;115:360. Salsali M, Holt A, Baker GB. Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C6, and CYP2D6. Cell Mol Neurobiol. 2004;24:63. Stahl SM, Felker A. Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants. CNS Spectr. 2008;13:855. Tulen JH, Volkers AC, van den Broek WW, Bruijn JA. Sustained effects of phenelzine and tranylcypromine on orthostatic challenge in antidepressant-refractory depression. J Clin Psychopharmacol. 2006;26:542. Verena H, Mergl R, Allgaier AK, Kohnen R, Möller HJ. Treatment of depression with atypical features: A meta-analytic approach. Psychiatry Res. 2006;141:89. Wood PL, Khan MA, Moskal JR, Todd KG, Tanay VAMI. Aldehyde load in ischemia-reperfusion injury: Neuroprotection by neutralization of reactive aldehydes with phenelzine. Brain Res. 2006;184. 29.23 Nefazodone and Trazodone Nefazodone (Serzone) and Trazodone (Desyrel, Oleptro) are mechanistically and structurally related drugs approved as treatments for depression. Nefazodone (Serzone) is an analog of trazodone. When nefazodone was introduced in 1995, there were expectations that it would become widely used because it did not cause the sexual side effects and sleep disruption associated with the selective SSRIs. Although it was devoid of these side effects, it was nevertheless found to produce problematic sedation, nausea, dizziness, and visual disturbances. Consequently, nefazodone was never extensively adopted in clinical practice. This fact, as well as reports of rare cases of sometimes fatal

hepatotoxicity, led the original manufacturer to discontinue production of branded nefazodone in 2004. Generic nefazodone remains available in the United States. Trazodone received Food and Drug Administration (FDA) approval in 1981 as a treatment for major depressive disorder (MDD). Its novel triazolopyridine chemical structure distinguished it from the TCAs, and clinical trials suggested improved safety and tolerability compared with TCAs. There were high expectations that it would replace the older drugs as a mainstay of treatment for depression. However, the extreme sedation associated with trazodone, even at subtherapeutic doses, limited the clinical effectiveness of the drug. However, its soporific properties made trazodone a favorite alternative to standard hypnotics as a sleep-inducing agent. Unlike conventional sleeping pills, trazodone is not a controlled substance. In 2010, the FDA approved an extended-release, once-daily formulation (Oleptro) as a treatment for MDD in adults. In the 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 treatment because of somnolence or sedation. NEFAZODONE Pharmacologic Actions 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 persons, 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-chlorophenylpiperazine (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-HTA receptors is thought to produce its antianxiety and antidepressant effects. Nefazodone is also a mild antagonist of the α1-adrenergic receptors, which predisposes some persons to orthostatic hypotension but is not sufficiently potent to produce 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 comparison with SSRIs, nefazodone is less likely to cause inhibition of orgasm or decreased sexual desire. Nefazodone is also effective for treatment of panic disorder and panic with comorbid depression or depressive symptoms, generalized anxiety disorder, 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 effective in patients who have been treatment resistant to other antidepressant drugs. Precautions and Adverse Reactions The most common reasons for discontinuing nefazodone use are sedation, nausea, dizziness, insomnia, weakness, and agitation. 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 failure. 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. Some patients taking nefazodone may experience a decrease in blood pressure that can cause episodes of postural hypotension. Nefazodone should therefore be used with caution by persons 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 paucity of its clinical use. Nefazodone should therefore be used during pregnancy only if the potential benefit to the mother outweighs 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 nefazodone dosage should be lowered in persons with severe hepatic disease, but no adjustment is necessary for persons with renal disease (Table 29.23-1). Table 29.23-1 Adverse Reactions Reported with Nefazodone (300–600 mg a Day)

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 both medications. Nefazodone also slows the metabolism of haloperidol (Haldol) so that the dosage of haloperidol should be reduced in persons taking both medications. Addition of nefazodone may also exacerbate the adverse effects of lithium carbonate (Eskalith). There are no known laboratory interferences associated with nefazodone. Dosage and Clinical Guidelines Nefazodone is available in 50-, 200-, and 250-mg unscored tablets and 100- and 150-mg scored tablets. The recommended starting dosage of nefazodone is 100 mg twice a day, but 50 mg twice a day may be better tolerated, especially by elderly persons. To limit the development of adverse effects, the dosage should be slowly raised in increments of 100 to 200 mg a day at intervals of no less than 1 week per increase. The optimal dosage is 300 to 600 mg daily in two divided doses. However, some studies report that nefazodone is effective when taken once a day, especially at bedtime. Geriatric persons should receive dosages about two-thirds of the usual nongeriatric dosages, with a maximum of 400 mg a day. Similar to other antidepressants, clinical benefit of nefazodone usually appears after 2 to 4 weeks of treatment. Patients with premenstrual syndrome are treated with a flexible dosage that averages about 250 mg a day. TRAZODONE

Pharmacologic Actions Trazodone is readily absorbed from the GI tract and reaches peak plasma levels in about 1 hour. It has a half-life of 5 to 9 hours. Trazodone is metabolized in the liver, and 75 percent of its metabolites are excreted in the urine. Trazodone is a weak inhibitor of serotonin reuptake and a potent antagonist of serotonin 5-HT2A and 5-HT2C receptors. The active metabolite of trazodone is mCPP, which is an agonist at 5-HT2C receptors and has a half-life of 14 hours. mCPP has been associated with migraine, anxiety, and weight loss. The adverse effects of trazodone are partially mediated by α1-adrenergic receptor antagonism. Therapeutic Indications Depressive Disorders. The main indication for the use of trazodone is MDD. There is a clear dose–response relationship, with dosages of 250 to 600 mg a day being necessary for trazodone to have therapeutic benefit. Trazodone increases total sleep time, decreases the number and the duration of nighttime awakenings, and decreases the amount of REM sleep. Unlike tricyclic drugs, trazodone does not decrease stage 4 sleep. Trazodone is thus useful for depressed persons with anxiety and insomnia. Insomnia. Trazodone is a first-line agent for the treatment of insomnia because of its marked sedative qualities and favorable effects on sleep architecture (see above) combined with its lack of anticholinergic effects. Trazodone is effective for insomnia caused by depression or use of drugs. When used as a hypnotic, the usual initial dosage is 25 to 100 mg at bedtime. Erectile Disorder. Trazodone is associated with an increased risk of priapism. Trazodone can potentiate erections resulting from sexual stimulation. It has thus been used to prolong erectile time and turgidity in some men with erectile disorder. The dosage for this indication is 150 to 200 mg a day. Trazodone-triggered priapism (an erection lasting more than 3 hours with pain) is a medical emergency. The use of trazodone for treatment of male erectile dysfunction has diminished considerably since the introduction of phosphodiesterase (PDE)-5 agents (see Chapter 25). Other Indications. Trazodone may be useful in low dosages (50 mg a day) for controlling severe agitation in children with developmental disabilities and elderly persons with dementia. At dosages above 250 mg a day, trazodone reduces the tension and apprehension associated with generalized anxiety disorder. It has been used to treat depression in patients with schizophrenia. Trazodone may have a beneficial effect on insomnia and nightmares in persons with PTSD. Precautions and Adverse Reactions

The most common adverse effects associated with trazodone are sedation, orthostatic hypotension, dizziness, headache, and nausea. Some persons experience dry mouth or gastric irritation. The drug is not associated with anticholinergic adverse effects, such as urinary retention, weight gain, and constipation. A few case reports have noted an association between trazodone and arrhythmias in persons with preexisting premature ventricular contractions or mitral valve prolapse. Neutropenia, usually not of clinical significance, may develop, which should be considered if persons have fever or sore throat. Trazodone may cause significant orthostatic hypotension 4 to 6 hours after a dose is taken, especially if taken concurrently with antihypertensive agents or if a large dose is taken without food. Administration of trazodone with food slows absorption and reduces the peak plasma concentration, thus reducing the risk of orthostatic hypotension. Because suicide attempts often involve ingestion of sleeping pills, it is important to be familiar with the symptoms and treatment of trazodone overdose. Patients have survived trazodone overdoses of more than 9 g. Symptoms of overdose include lethargy, vomiting, drowsiness, headache, orthostasis, dizziness, dyspnea, tinnitus, myalgias, tachycardia, incontinence, shivering, and coma. Treatment consists of emesis or lavage and supportive care. Forced diuresis may enhance elimination. Treat hypotension and sedation as appropriate. Trazodone causes priapism, prolonged erection in the absence of sexual stimuli, in one of every 10,000 men. Trazodone-induced priapism usually appears in the first 4 weeks of treatment but may occur as late as 18 months into treatment. It can appear at any dose. In such cases, trazodone use should be discontinued, and another antidepressant should be used. Painful erections or erections lasting more than 1 hour are warning signs that warrant immediate discontinuation of the drug and medical evaluation. The first step in the emergency management of priapism is intracavernosal injection of an α1-adrenergic agonist pressor agent, such as metaraminol (Aramine) or epinephrine. In about one-third of reported cases, surgical intervention was required. In some cases, permanent impairment of erectile function or impotence resulted. The use of trazodone is contraindicated in pregnant and nursing women. Trazodone should be used with caution in persons with hepatic and renal diseases. Drug Interactions Trazodone potentiates the CNS depressant effects of other centrally acting drugs and alcohol. Concurrent use of trazodone and antihypertensives may cause hypotension. No cases of hypertensive crisis have been reported when trazodone has been used to treat MAOI-associated insomnia. Trazodone can increase levels of digoxin and phenytoin. Trazodone should be used with caution in combination with warfarin. Drugs that inhibit CYP3A4 can increase levels of trazodone’s major metabolite, mCPP, leading to an increase in side effects. Laboratory Interferences

No known laboratory interferences are associated with the administration of trazodone. Dosage and Clinical Guidelines Trazodone is available in 50-, 100-, 150-, and 300-mg tablets. Once-a-day dosing is as effective as divided dosing and reduces daytime sedation. The usual starting dose is 50 mg before sleep. The dosage can be increased in increments of 50 mg every 3 days if sedation or orthostatic hypotension does not become a problem. The therapeutic range for trazodone is 200 to 600 mg a day in divided doses. Some reports indicate that dosages of 400 to 600 mg a day are required for maximal therapeutic effects; other reports indicate that 250 to 400 mg a day is sufficient. The dosage may be titrated up to 300 mg a day; then the person can be evaluated for the need for further dosage increases on the basis of the presence or the absence of signs of clinical improvement. Once-daily trazodone is available as bisectable tablets of 150 mg or 300 mg. The starting dosage of the extended-release formulation is 150 mg once daily. It may be increased by 75 mg per day every 3 days. The maximum dosage is 375 mg per day. Dosing should be at the same time every day in the late evening, preferably at bedtime, on an empty stomach. Tablets should be swallowed whole or broken in half along the score line. REFERENCES Ciraulo DA, Knapp C, Rotrosen J, Sarid-Segal O, Seliger C. Nefazodone treatment of cocaine dependence with comorbid depressive symptoms. Addiction. 2005;100(Suppl 1):23. DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother. 2007;41(7):1201. Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, Smith AR, Will Y. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci. 2008;103(2):335. Goldberg JF. A preliminary open trial of nefazodone added to mood stabilizers for bipolar depression. J Affect Disord. 2013;144(1–2):176–178. Hettema JM, Kornstein SG. Trazodone. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins: 2009:3253. Khan AA, Kornstein SG. Nefazodone. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins: 2009:3164. Kocsis JH, Leon AC, Markowitz JC, Manber R, Arnow B, Klein DN, Thase ME. Patient preference as a moderator of outcome for chronic forms of major depressive disorder treated with nefazodone, cognitive behavioral analysis system of psychotherapy, or their combination. J Clin Psychiatry. 2009;e1–e8, pii. Kostrubsky SE, Strom SC, Kalgutkar AS, Kulkarni S, Atherton J. Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol Sci. 2006;90(2):451. Owens MJ, Dole KC, Knight DL, Nemeroff CB. Preclinical evaluation of the putative antidepressant nefazodone. Depression. 2008;1(6):315. Papakostas GI, Fava M. A meta-analysis of clinical trials comparing the serotonin (5HT)-2 receptor antagonists trazodone and nefazodone with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. Eur Psychiatry. 2007;22(7):444. Passos SR, Camacho LA, Lopes CS, dos Santos MA. Nefazodone in out-patient treatment of inhaled cocaine dependence: A