Nefazodone side effects

A large open-label flexible dose study (Sanchez-Lacay etal, 2001) utilizing nefa-zodone in the treatment of major depression in a predominantly monolingual, Hispanic Caribbean population (Dominican Republic, Puerto Rico, and Cuba) revealed similar response rates and an endpoint mean dosage when compared to previous nefazodone trials with non-Hispanic patients. No serious adverse events were reported, but 42% of the subjects did not complete the study for various reasons including side effects, family, or work responsibilities. 

Trazodone and nefazodone cause minimal anticholinergic effects. Sedation, dizziness, and orthostatic hypotension are the most frequent dose-limiting side effects. 

Mirtazapine (Remeron) is a newer antidepressant that also blocks 5-HT reuptake, but additionally has antagonistic effects at adrenergic o2, 5-HT2, and 5-HT3 receptors (Stahl 1998). Mirtazapine appears to have indirect agonistic effects on 5-HTlA receptors, which may contribute to its antidepressant effect (Berendsen and Broekkamp 1997). Nefazodone, as well, has SSRI and 5-HT2 antagonist effects. The 5-HT2 antagonist effects of these antidepressants is believed to be responsible for their lower incidence of sexual side effects (Nutt 1997). 

Nefazodone (Serzone). Nefazodone works by weakly blocking serotonin reuptake and by blocking serotonin-2 receptors. The receptor blockade produces more specific serotouiu activity aud so reduces mauy serotonin-associated side effects. In particular, uefazodoue does not commonly induce anxiety or sexual dysfunction like the SSRIs. 

In cases where the antidepressant response has not been resounding, we prefer switching antidepressants to avoid sexual side effects. The options include bupropion, nefazodone, and mirtazapine, which all effectively treat depression but produce minimal effects on sexual function. Sometimes, if a patient has responded well to one antidepressant but experiences a side effect such as sexual dysfunction, switching within the same class can be a useful approach. 

When we talk about serotonin-blocking medications, a point of clarification must be made. In most cases, medications do not block overall serotonin activity but instead block the activity at one of the many serotonin receptor types. For example, the antidepressants trazodone, nefazodone, and mirtazapine increase total serotonin activity yet they block certain of the serotonin receptors. Mirtazapine increases both serotonin and norepinephrine activity by interfering with the alpha-2 receptor. By also blocking the serotonin-2 and serotonin-3 receptors, mirtazapine avoids the sexual dysfunction and GI side effects commonly experienced with other serotoninboosting medications. We cannot truly call these serotonin-blocking medications, because they are serotonin-boosting medications that selectively block certain serotonin receptors. 

Geriatric Considerations - Summary Eszopiclone is the only hypnotic which has been shown to maintain efficacy over long-term use (6 months) and may have a role in the management of chronic sleep problems in olderadults. Because eszopiclone is a substrate of CYP C3A, and 2E1, it should be used with caution, especially with drugs such as nefazodone, clarithromycin, and amiodarone. This agent has been newly approved for use in the US and has not been well studied in terms of falls or other geriatric side effects. 

In this chapter the basics of the available atypical antidepressants and those that may soon to come on the market have been reviewed. The atypical antidepressants are less readily used, and their benefits for treating depression and anxiety are not fully appreciated. The atypical antidepressants may provide benefit for conditions such as ADHD or offer an alternative to other antidepressants with problematic side effects (i.e., activation on SSRIs). They may also provide specific relief for troublesome symptoms (i.e., nefazodone s normalization of sleep architecture). 

It is difficult to justify, therefore, any use of trazodone in boys, adolescent males, or young men, especially given its relatively limited usefulness as an antidepressant or even a sedative. Even in girls its use is questionable. Nefazodone would appear to be a far better alternative, especially in that it has no recognized sexual side effects, is well tolerated once the patient adapts to the sedative effect, and is not associated with priapism. That is, risks do not include a known increase in priapism above the background incidence (Thompson et ah, 1990 Feiger et ah, 1996 Pecknold and Langer, 1996). 

Nefazodone is an SSRl with 5-HT2 antagonist properties. Nefazodone is licensed as an antidepressant in many countries, and the evidence for efficacy from placebo-controlled and reference-controlled studies does not suggest that this drug is associated with superior efficacy (Dillier 1982 R. Fontaine et al. 1994 Mendels et al. 1995 Rickels et al. 1994). The 5-HT2 antagonism does not appear to confer extra efficacy, which appears to be similar to that of SSRls. However, a beneficial effect on sleep and on anxiety symptoms of depression is reported. This may be attributable to 5-HT2 blockade, but some studies have demonstrated nefazodone s superior efficacy to SSRls. One attribute of nefazodone that may be related to 5-HT2 blockade is that it is associated with rather little in the way of sexual side effects. A direct comparison between nefazodone and sertraline reported significantly fewer sexual side effects with nefazodone [Baldwin 1996). 

Adverse effects. Side effects that occurred with nefazodone to a greater degree than with placebo and that were dose related included somnolence, dry mouth, nausea, and dizziness. Furthermore, there is no need to taper the dose if discontinuation is being considered (L. Friedman et al. 1992 L. H. Gold and Balster 1991]. More than 2,256 patients have been studied in clinical trials, and, to date, only two cases of overdose (>3,600 mg ingested] have been reported both patients recovered with no sequelae. 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

Nefazodone has a chemical structure related to trazodone and incorporates both 5-HT uptake properties plus 5-HT 2a receptor blockade (150, 151, 152 and 153). There is evidence from controlled trials that this agent is an effective antidepressant with a favorable side-effect profile. 

The SSRIs, venlafaxine, or nefazodone may be reasonable alternatives to earlier generation antidepressants because of their less problematic side effect profiles (486). The propensity to increase activity, the lack of sedation, gastrointestinal symptoms, and alterations in blood pressure are potential complications, however. Given AIDS-induced altered metabolism, for many of these agents, TDM may be helpful in establishing an effective, nontoxic dose. 

At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose. The starting dose of the SSRIs is usually the same as the therapeutic dose for most patients, and so titration may not be required. In addition, most SSRIs are now generically available and inexpensive. Other agents, including the SNRIs, bupropion, and mirtazapine, are also reasonable first-line agents for the treatment of MDD. Bupropion, mirtazapine, and nefazodone are the antidepressants with the least association with sexual side effects and are often prescribed for this reason. However, bupropion is not thought to be effective in the treatment of the anxiety disorders and may be poorly tolerated in anxious patients. The... 

Clinical experience suggests that nefazodone may also be useful in panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but without the 5HT2A-activating side effects associated with the SSRIs. 

Other antidepressant drugs that primarily affect serotonin reuptake include trazodone [TRAZ oh done], fluvoxamine [floo VOX a meen], nefazodone [ne FAZ oh don], paroxetine [pah ROX a teen], sertraline [SIR trah leen], and venlafaxine [vin lah FACKS in]. These SSRIs differ from fluoxetine in their relative effects on the reuptake of serotonin and norepinephrine. They do not seem to be more efficacious than fluoxetine, but their profiles of side effects are somewhat different. There is a high variability among patients in the rate of elimination of these drugs (including fluoxetine), and failure to tolerate one drug should not preclude a trial of another SSRI. 

Wynchank D, Berk M. Efficacy of nefazodone in the treatment of neuroleptic induced extrapyramidal side effects a double-blind randomised parallel group placebo-con-trolled trial. Hum Psychopharmacol 2003 18 271-5. 

Increased depressive effects when taken with other CNS depressants Inhibitors of CYP450 3A, such as nefazodone, fluvoxamine, fluoxetine, and even grapefruit juice, may decrease clearance of alprazolam and thereby raise alprazolam plasma levels and enhance sedative side effects alprazolam dose may need to be lowered... 

Masand PS, Gupta S. Long-term side effects of newer-generafion anfidepressanfs SSRIs, venlafaxine, nefazodone, bupropion, and mirtazapine. Ann Clin Psychiafry 2002 14(3) 175-82. 

Nefazodone (Serzone), like venlafaxine, is a new antidepressant that affects multiple neurotransmitter systems. Like trazodone, nefazodone is a potent 5-HT2A receptor blocker. In addition, it is both a serotonin and norepinephrine reuptake inhibitor. The most common side effects are nausea, headache, anxiety, sedation, and dizziness. Its use is contraindicated with Seldane, Hismanal, and Propulsid, and there is a warning regarding its use with Xanax. 

---