Nefazodone toxicity

Certain medications (e.g., cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoxyphene, and verapamil) added to carbamazepine therapy may cause carbamazepine toxicity. 

A controlled trial of duloxetine (Cymbalta)—like venlafaxine a dual serotonin-norepinephrine reuptake inhibitor—in the treatment of GAD is currently underway. Anecdotal data suggests that nefazodone (Serzone) and mirtazapine (Remeron) may be effective in the treatment of GAD, though no controlled data is available. In addition, recent concerns regarding nefazodone and liver toxicity have limited this medication s utility. Please refer to Chapter 3 for more information regarding these antidepressants. 

In contrast to anticonvulsants and alcohol, drugs such as bupropion, fluoxetine, fluvoxamine, nefazodone, quinidine, paroxetine, and some antipsychotics can inhibit specific CYP enzymes (7, 11, 36, 37, 41, 42, 43 and 44). Thus, TCAs, certain BZDs, bupropion, some steroids, and antipsychotics can all have their metabolism inhibited by drugs such as fluoxetine. For example, fluoxetine at 20 mg/day produces on average a 500% increase in the levels of coprescribed drugs which are principally dependent on CYP 2D6 for their clearance. That can lead to serious or even life-threatening toxicity if the drug has a narrow therapeutic index and the dose is not adjusted for the change in clearance caused by the coadministration of fluoxetine. 

Nefazodone substantially decreases the clearance rate for triazolam, which results in a 400% increase in triazolam s serum levels (131). Erythromycin can also interfere with the metabolism of triazolam, resulting in decreased clearance and increased plasma levels, possibly causing toxicity. Troleandomycin and other macrolide antibiotics, such as clarithromycin, flurithromycin, josamycin, midecamycin, or roxithromycin, also may inhibit triazolam s metabolism (132). The coadministration of itraconazoie and triazolam can produce a marked elevation of triazolam plasma levels associated with statistically significant impairment of psychomotor tests and a prolongation of other effects (e.g., amnesia, lethargy, and confusion) for hours after awakening ( 133). 

BZD hypnotics such as midazolam and triazolam are primarily metabolized via the P450 3A3/4 microenzyme system. Other BZDs often used as hypnotics, such as diazepam, can also be metabolized by CYP 33/4 and CYP 2C19. Any drugs that act as inhibitors or inducers of these isoenzymes could increase or decrease BZD levels, respectively (350). Thus, ketoconazole, macrolide antibiotics (e.g., erythromycin), SSRIs (e.g., fluoxetine-norfluoxetine and fluvoxamine), and other antidepressants (especially nefazodone) may decrease clearance and increase BZD levels to potentially toxic ranges. Conversely, rifampacin, CBZ, and dexamethasone may increase clearance and decrease BZD levels to potentially subtherapeutic ranges. 

Nefazodone Inhibition of 5- 2 receptor nefazodone also blocks SERT weakly Trazodone forms a metabolite (m-cpp) that blocks 5-HT2A,2C receptors Major depression sedation and hypnosis (trazodone) Relatively short half-lives active metabolites Toxicity Modest receptor blockade (trazodone) Interactions Nefazodone inhibits CYP3A4... 

FIGURE 6—18. The antidepressants fluoxetine, fluvoxamine, and nefazodone are all inhibitors of CYP450 3A4. More potent inhibitors of this enzyme include the nonpsychotropic drugs ketoconazole, erythromycin, and protease inhibitors. If a 3A4 inhibitor is given with cisapride or astemazole, levels of these substrates can rise to toxic levels. Thus, fluoxetine, fluvoxamine, and nefazodone cannot be given with cisapride or astemazole. 

In 225 patients who had taken overdoses of antidepressant drugs in suicide attempts, venlafaxine and citalopram were more likely to be associated with seizures than mir-tazapine and nefazodone and 5HT toxicity was more common after overdose of venlafaxine (94). These findings confirm the potential toxicity of venlafaxine in overdose and also suggest a pro-convulsant effect of large doses of citalopram. 

Concentrations of nefazodone and its metabolites can be increased by fluoxetine and paroxetine (SEDA-20, 9). Combinations of serotonin agents produce serotonin toxicity, and a case of serotonin syndrome occurred when nefazodone (200 mg/day) was combined with fluoxetine (40 mg/day) in a 50-year-old man (109). The toxic symptoms settled 3 days after withdrawal of both antidepressants. 

In a controlled study in 12 healthy men the combination of carbamazepine and nefazodone led to increased plasma carbamazepine concentrations and substantially lowered plasma nefazodone concentrations (21). This interaction, which is due to inhibition of CYP3A4 by nefazodone, could lead to difficulties during treatment, since the risk of carbamazepine toxicity would have to be balanced against the loss of therapeutic effect of nefazodone. Except in special circumstances it is probably better to avoid the combination. 

However, in another case the addition of nefazodone appeared to produce clozapine toxicity (23). 

Hepatic enzyme inhibition by nefazodone can significantly raise concentrations and toxicity of haloperidol (29). 

Nefazodone can cause myositis and rhabdomyolysis in patients taking pravastatin and simvastatin (25). The postulated mechanism involves inhibition of CYP3A4, leading to reduced clearance of the HMG-CoA reductase inhibitors and muscle toxicity. 

Nefazodone Carbamazepine Risk of carbamazepine toxicity interaction poorly documented Inhibition of Carbamazepine metabolism... 

Benson BE, Mathiason M, Dahl B, Smith K, Foley MM, Easom LA, Butler AY. Toxicities and outcomes associated with nefazodone poisoning. An analysis of 1,338 exposures. Am J Emerg Med 2000 18(5) 587-92. 

Campo JV, Smith C, Perel JM. Tacrolimus toxic reaction associated with the use of nefazodone paroxetine as an alternative agent. Arch Gen Psychiatry 1998 55(ll) 1050-2. 

High suicide risk Less toxic antidepressants (fluoxetine, trazodone, paroxetine, sertraline, bupropion, venlafaxine, nefazodone)... 

Compound (VII) can be further transformed to triazo-lones, useful building blocks for pharmaceuticals such as Etoperidone or Nefazodone (see cyclisation between two nitrogen atoms, next section). In the case of Etoperidone, this transfomation avoids the use of toxic ethyl isocyanate to get the required intermediate as shown in scheme 203. 

Nefazodone. Nefazodone is an antidepressant that inhibits neuronal uptake of serotonin and norepinephrine, Nefazodone is a 5-HT2 antagonist that is rapidly absorbed and has low bioavailabiiity (20%) because it undergoes first-pass metabolism. In March of 2004, the U.S. FDA issued a Pubhc Health Advisory that called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs such as nefazodone for the treatment of major depressive disorder (MDD), Because of several cases of fiver toxicity, nefazodone (Serzone) was taken off the market in lune of 2004. An HPLC method with electrochemical detection has been published for the analysis of nefazodone. ... 

Describe the cardiovascular toxicity seen with nefazodone. 

ABBREVIATIONS O, oral tablet or capsule I, injectable NE, norepinephrine DA, dopamine 5-HT, 5-hydroxytryptamine, serotonin 0, negligible 0/-I-, minimal +, mild 2+, moderate 3-H, moderately severe 4+, severe. " Nefazodone additional side effect of impotence (-H) and some risk of hepatic toxicity. Trazodone additional side effect of priapism (-H). 

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