Nefazodone Buspirone

Landen M, Eriksson O, Sundblad C, et al. Compounds with affinity for serotonergic receptors in the treatment of premenstrual dysphoria A comparison of buspirone, nefazodone and placebo. Psychopharmacology (Berl) 2001 155 292-298. 

Drugs that affect nefazodone include general anesthetics, sibutramine, sumatriptan, buspirone, carbamazepine, and propranolol. Drugs that may be affected by nefazodone include alcohol, benzodiazepines, buspirone, carbamazepine, cisapride, digoxin, haloperidol, HMG-CoA reductase inhibitors, MAOIs, propranolol, St. John s wort, cyclosporine, and tacrolimus. 

Dykens, J.A. et al. (2008) In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone and buspirone. Toxicological Sciences, 10.1093/toxsci/kfh056. 

Buspirone is metabolized by CYP 3A3/4. Therefore, the initial dose should be lower in patients who are also taking medications known to inhibit these enzymes, such as nefazodone. 

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. 

Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is l-(2-pyrimidyl)-piperazine (1-PP), which has K2-adrenoceptor-blocking actions and which enters the central nervous system to reach higher levels than the parent drug. It is not known what role (if any) 1-PP plays in the central actions of buspirone. The elimination half-life of buspirone is 2-4 hours, and liver dysfunction may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. 

A4/3A5 Midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, triazolam Atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin Rifampin, carbamazepine... 

Nefazodone competes for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22, 39) (SEDA-22, 41). 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

Antidote Buspirone, bupropion, nefazodone, gingko biloba, sildenafil, cyproheptadine, yohimbine, methylphenidate, etc. 

CYP450 3A4 inhibitors (e.g., fluxotine, fluvoxamine, nefazodone) may reduce clearance of buspirone and raise its plasma levels, so the dose of buspirone may need to be lowered when given concomitantly with these agents... 

Via CYP450 3A4, nefazodone may increase plasma concentrations of buspirone, so buspirone dose may need to be reduced... 

Proof-of-concept studies have demonstrated that lOOx Cmax is a reasonable scaling factor to differentiate hepatotoxic (or positive) versus nontoxic (or negative) drugs.108 For example, in a family of antidepressant drugs, nefazodone was consistently positive, whereas buspirone and fluoxetine remained negative, but all tested at 100x of their respective single-dose therapeutic Cmax.108... 

Figure 6-4 Differences in oxidative stability of the para-hydroxyphenyl-piperazinyl and -pyrimidinyl motifs in nefazodone and buspirone, respectively.

Drugs that inhibit cytochrome P450 3A4 (e.g., verapamil, dUtiazem, itraconazole, fluvoxamine, nefazodone, and erythromycin) can increase buspirone levels. Rifampin caused a 10-fold reduction in buspirone levels. Buspirone reportedly increases haloperidol levels and elevates blood pressure in patients taking a monoamine oxidase inhibitor (MAOI). 

Nefazodone 250 mg twice daily caused a 20-fold increase in the maximum plasma levels of huspirone 2.5 or 5 mg twice daily and a 50-fold increase in its AUC. Buspirone 5 mg twice daily raised the AUC of nefazodone by 23%, which is unlikely to be clinically significant. The manufacturer recommended that huspirone 2.5 mg daily should be used if nefazodone is given. ... 

Buspirone does not appear to interact with amitriptyline, cimetidine or terfenadine. An isolated report describes mania when an alcoholic patient taking huspirone was given disulfiram. Nefazodone greatly increases huspirone levels. 

There are isolated cases of apparent interactions between clozapine, and ampicillin, buspirone, caffeine, haloperidol, loperamide, modafinil, nefazodone, nicotinic acid, tryptophan, or vitamin C. Grapefruit juice, influenza vaccine mirtazapine, reboxetine, or venlafaxine do not appear to interact Cocaine levels may increase when taken with clozapine. 

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