Nefazodone with benzodiazepines

Barbhaiya RH, Shukla UA, Kroboth PD, et al. Coadministration of nefazodone and benzodiazepines II. A pharmacokinetic interaction study with triazolam. J Clin Psychopharmacol 1995 15 320-326. 

Potentially clinically significant interactions include the tendency for fluvoxamine to increase circulating concentrations of oxidatively metabolized benzodiazepines, clozapine, theophylline, and warfarin. Sertraline and fluoxetine can increase levels of benzodiazepines, clozapine, and warfarin. Paroxetine increases levels of clozapine, theophylline, and warfarin. Fluoxetine also potentiates tricyclic antidepressants and some class 1C antiarrhythmics with a narrow therapeutic index (including encainide, flecainide, and propafenone). Nefazodone potentiates benzodiazepines other than lorazepam and oxazepam. 

For treatment-resistant patients who do not respond to SSRIs or TCAs, or to the combination of TCAs/SSRIs with benzodiazepines, other antidepressants have shown at least some beneficial effects in alleviating PD symptoms (e.g. mirtazapine, moclobemide, nefazodone, phenelzine, reboxetine, and venlafaxine). Other agents have also been reported to exert beneficial effects in PD, especially when combined with SSRIs/TCAs (lithium, pindolol, and propranolol). In cases where all treatments have failed, valproate or olanzapine should be considered.2 - ° In order to optimize treatment, patients should avoid or reduce the consumption of compounds that could potentially induce/exacerbate panic attacks (e.g. caffeine, alcohol, and nicotine) and should exercise regularly. i... 

The interactions of nefazodone with alprazolam, midazolam, triazolam and zopiclone are established and clinically important. The practical consequences are that the effects of alprazolam, midazolam and triazolam are expected to be increased but the extent is uncertain. Be alert for any evidence of any psychomotor impairment, drowsiness etc. and reduce the benzodiazepine dosage if necessary. More study is needed. Lorazepam does not interact with nefazodone. There seems to be no direct information about other benzodiazepines and related drugs. 

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. 

Since benzodiazepines are metabolized by the cytochrome P450 family of isozymes,1 potential inhibitors of these may produce significant increases in blood concentrations of benzodiazepines. An example of this inhibition is the drug midazolam, administered as a presurgical anesthetic. Lam et al.11 reported a mean increase in the area under the curve of midazolam by ketoconazole (772%) and nefazodone (444%) in a group of 40 healthy human subjects administered 200 mg ketoconazole per day and 400 mg nefazodone per day. The authors concluded that caution should be exercised when use of midazolam is warranted with potent CYP3A4 inhibitors.11... 

A third important CYP450 enzyme for antidepressants and mood stabilizers is 3A4. Some benzodiazepines (e.g., alprazolam and triazolam) are substrates for 3A4 (Fig. 6—17). Some antidepressants are 3A4 inhibitors, including the SSRIs fluoxetine and fluvoxamine and the antidepressant nefazodone (Fig. 6—18). Administration of a 3A4 substrate with a 3A4 inhibitor will raise the level of the substrate. For example, fluoxetine, fluvoxamine, or nefazodone will raise the levels of alprazolam or triazolam, requiring dose reduction of the benzodiazepine (Fig. 6—18). 

Benzodiazepines for anxiety, but give alprazolam cautiously with nefazodone as alprazolam levels can be much higher in the presence of nefazodone... 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by hepatic microsomal oxidation and then undergo glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. Drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., erythromycin, nefazodone, fluvoxamine, and ketoconazole) reduce the clearance of triazolam and increase its plasma concentrations."... 

Fluvoxamine inhibits liver drug-metabolizing enzymes. Dosages of alprazolam, theophylline, and warfarin must be reduced if any of these drugs are given concomitantly with fluvoxamine. Nefazodone may also decrease the metabolism of benzodiazepines, and venlafaxine may inhibit haloperidol metabolism. The answer is (B). 

A placebo-controlled study in 12 healthy subjects found that nefazodone 200 mg twice daily caused an almost twofold increase in the plasma levels of alprazolam 1 mg twice daily taken for 7 days. Another study found that impairment of psychomotor performance and increased sedation occurred when nefazodone was given with alprazolam. A case report describes benzodiazepine withdrawal symptoms in a woman taking alprazolam after nefazodone was withdrawn following several years of concurrent use. She needed an alprazolam dosage increase from 500 micrograms to 4 mg daily to control her symptoms. ... 

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