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SERZONE - THE FACTS from Synopsis of Psychiatry

Posted by jimmygold70 on January 4, 2002, at 14:31:58

In reply to Re: Serzone: Does it even work? - Rick, Allison Rick, posted by allisonm on January 4, 2002, at 9:35:31

This is taken from Kaplan and Sadock's Synopsis of psychiatry, 8th Edition

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NEFAZODONE
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Nefazodone (Serzone) is an antidepressant medication structurally related to trazodone (Desyrel) and unrelated to the classical tricyclic and tetracychc drugs, the monoamine oxidase inhibitors (MAOIs), serotonin-specific reuptake inhibitors (SSRIs), and other available antidepressant drugs. Although trazodone is distinctive in having more marked sedative effects than those found with most other antidepressants, ne-fazodone is relatively free of this adverse effect and generally well tolerated. Nefazodone is less likely than the SSRIs to adversely affect sexual functioning.

CHEMISTRY

Nefazodone is a phenylpiperazine analogue of trazodone. Its molecular structure is shown in Figure 35.3.24-1.

PHARMACOLOGICAL ACTIONS

Pharmacokinetics

Nefazodone is rapidly and completely absorbed, but it is then extensively and variably metabolized so that the bioa-vailability of active compounds is about 20 percent of the oral dose. Its half-life is 2 to 4 hours, and dosing must be twice daily. Steady-state concentrations of nefazodone and its principal active metabolite, hydroxynefazodone, are achieved within 4 to 5 days. Metabolism in older people, especially women, is about half that seen in younger patients; thus lower doses are recommended in elderly patients.

Pharmacodynamics

Nefazodone is an inhibitor of serotonin uptake and, more weakly, of norepinephrine reuptake. It also acts as an antagonist of the serotonin type 2 (5-HT2) receptor, antagonism of
which is thought to treat anxiety and depression. The net effect of serotonin reuptake inhibition and 5-HT2 receptor blockade is thought to be selective activation of serotonin type 1 (5-HT1) receptor, which has been suggested to improve both anxiety and depression. Nefazodone causes mild antagonism of the a1-adrenergic receptors and can predispose some patients to orthostatic hypotension. There is no significant activity at a2- and beta-3-adrenergic, serotonin type 1A(5-HT1A), cholinergic, dopaminergic, or benzodiazepine receptors.

EFFECTS ON SPECIFIC ORGANS AND SYSTEMS

The main effects of nefazodone are on the central nervous system (CNS). The main extra-CNS effects are related to a1-adrenergic antagonism, which may cause orthostatic hypotension. Unlike its structural relative trazodone, nefazodone has not been reported to cause priapism.

Cardiovascular Effects

In premarketing trials, 5.1 percent of patients taking nefazodone experienced a significant drop in blood pressure, compared with 2.5 percent of placebo patients. Although there was no increase in true syncopal events, symptoms of postural hypotension were experienced by 2.8 percent of patients treated with nefazodone. This rate compares with postural hypotension in 0.8 percent of placebo-treated, 1.1 percent of SSRI-treated, and 10.8 percent of tricyclic antidepressant-treated patients. Sinus bradycardia was seen in 1.5 percent of nefazodone-treated patients compared with 0.4 percent of placebo-treated patients. Nefazodone should therefore be used with caution in patients with underlying cardiac conditions, history of stroke or heart attack, dehydration, and hypovolemia and in patients under treatment with antihypertensive medications.

Activation of Mania

In patients with known bipolar illness, 1.6 percent of those treated with nefazodone experienced mania, compared with 5.1 percent of tricyclic-treated patients and 0 percent of placebo-treated patients. The activation of mania in unipolar patients was no higher with nefazodone than with placebo. Therefore, nefazodone may be a drug to try earlier in the treatment of patients with a history of manic episodes. Electroconvulsive therapy and the antidepressant lithium are least likely to activate mania.

THERAPEUTIC INDICATIONS

Nefazodone has been approved for the treatment of depression on the basis of data from at least two large clinical trials. Nefazodone has been shown to be equally as efficacious as imipramine, fluoxetine, and paroxetine for treatment of moderate, severe, melancholic, nonmelancholic, chronic, and recurrent depression. Preliminary clinical reports indicate that nefazodone may also be an effective treatment for depression accompanied by anxiety, such as for panic disorder and panic with comorbid depression or depressive symptoms, for obses-
sive-compulsive disorder, for premenstrual dysphoric disorder, and for the management of chronic pain of neuropathic or non-neuropathic origin. Although small studies report that nefazodone was associated with a trend toward a reduction in obsessive thoughts, a case report documents the initial appearance of obsessive thoughts during nefazodone treatment, which ceased when the drug was discontinued. More data are needed to establish whether nefazodone is as effective for obsessive-compulsive disorder as are the SSRIs and clomipramine.

PRECAUTIONS AND ADVERSE REACTIONS

In preclinical trials, 16 percent of patients discontinued nefazodone because of an adverse event. The most common reasons for discontinuance were nausea (3.5 percent), dizziness (1.9 percent), insomnia (1.5 percent), and agitation (1.2 percent). The adverse reactions reported with nefazodone are listed in Table 35.3.24-1. The adverse events were dose dependent and tended to appear at significant levels only in the dosing range of 300 to 600 mg a day. Nefazodone causes little sexual dysfunction, weight gain, or cardiotoxicity. Nefazodone and trazodone are unusual among antidepressants, in that they do not decrease but, rather, increase REM sleep and improve sleep continuity. However, nefazodone is much less likely than trazodone to produce daytime sedation.
Nefazodone was not shown to cause cancer in laboratory animals or to cause mutagenesis in several common assays. It caused mild loss of fertility at doses comparable to 3 times the highest recommended human dose. Although no teratogenic effects were noted, early neonatal mortality of laboratory animal offspring occurred with doses in the mothers comparable to 5 times the highest recommended human dose. There are no data on the effects of nefazodone on human mothers. Nefazodone should therefore be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. It is not known whether nefazodone is excreted in human breast milk. Therefore, it should not be used by women who are breast-feeding.


Table 35.3.24-1
Adverse Reactions Reported with Nefazodone
(300-600 mg a day)
________________%
Headache 36
Dry mouth 25
Somnolence 25
Nausea 22
Dizziness 17
Constipation 14
Insomnia 11
Weakness 11
Lightheadedness 10
Blurred vision 9
Dyspepsia 9
Infection 8
Confusion 7
Scotomata 7


DRUG INTERACTIONS

As is true for all antidepressant medications, nefazodone should not be given concomitantly with MAOIs. In addition, nefazodone has particular drug-drug interactions with the tria-zolobenzodiazepines, triazolam (Halcion) and alprazolam (Xanax), with so-called third-generation antihistamines, terfen-adine (Seldane) and astemizole (Hismanal), and with cisapride (Propulsid) because of the inhibition of cytochrome P450 (CYP) isoenzyme CYP 3A4 by nefazodone. Potentially toxic levels of each of these drugs can develop after administration of nefazodone, whereas the levels of nefazodone are generally not affected. The manufacturer recommends that the dose of triazolam be lowered by 75 percent, the dose of alprazolam be lowered by 50 percent when given concomitantly with nefazodone, and terfenadine and astemizole not be used at all with nefazodone.
Nefazodone may modestly increase levels of concomitantly administered haloperidol (Haldol). Nefazodone may slow the metabolism of digoxin; therefore, digoxin levels should be followed carefully in patients taking both medications. Conversely, nefazodone appears to reduce the bioavailability of propranolol (Inderal), and concomitant use of these two drugs should prompt a reevaluation of the dose of propranolol on clinical grounds. Nefazodone should not be given within 14 days of beginning or stopping an MAOI.

LABORATORY INTERFERENCES

No laboratory interferences have been reported for nefazodone.

DOSAGE AND ADMINISTRATION

Like other antidepressant drugs, nefazodone begins to improve mood between 2 and 4 weeks of initiation of therapy. The recommended starting dose of nefazodone is 100 mg 2 times a day. To limit the development of adverse effects, the dosage should be slowly tapered up to increments of 100 to 200 mg a day at intervals of no less than 1 week per increase. Older patients should receive doses about two thirds of the usual nongeriatric doses, with a maximum of 400 mg a day. Dosages should be lowered in patients with hepatic impairment. In common with other antidepressants, clinical benefit of nefazodone usually appears after 2 to 4 weeks of treatment. Nefazodone is available in 100, 150, 200, and 250 mg tablets.

REFERENCES

Baldwin DS, Hawley CJ, Abed RT, Maragakis BP, et al: A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression. J Clin Psychiatry 57 (2, Suppl): 46, 1996.
Ellingrod VL, Perry PJ: Nefazodone: A new antidepressant. Am J Health System Pharm 52: 2799, 1995.
DeMartmis NA, Schweizer E, Rickels K: An open-label trial of nefazodone in high comorbidity panic disorder. J Clin Psychiatry 57: 245, 1996
Feiger A, Kiev A, Shnvastava RK, Wisselink PG, Wilcox CS: Nefazodone versus sertraline in outpatients with major depression. Focus on efficacy, toler-ability, and effects on sexual function and satisfaction. J Clin Psychiatry 57 (2, Suppl): 53, 1996.
Lader MH: Tolerability and safety: Essentials in antidepressant pharmacotherapy. J Clin Psychiatry 57 (2, Suppl): 39, 1996.
Marcus RN, Mendels J- Nefazodone in the treatment of severe, melancholic, and recurrent depression. J Clin Psychiatry 57 (2, Suppl): 19, 1996.
Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153: 311, 1996.
Robinson DS, Marcus RN, Archibald DG, Hardy SA: Therapeutic dose range of nefazodone in the treatment of major depression J Clin Psychiatry 57 (2, Suppl): 6, 1996.


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