Nefazodone clozapine

CypP450 3A3 /4 Antidepressants tricyclics, nefazodone, fluoxetine, fluvoxamine, citalopram, mirtazepine, venlafaxine Antipsychotics chlorpromazine, clozapine, pimozide, quetiapine, risperidone... 

HT2 antagonists like trazodone, nefazodone, clozapine and risperidone are used in the treatment of schizophrenia and depression. They block adrenoceptors and Hi-histamine-receptors as well. Hypotension, drowsiness and weight gain can occur. 

Phenytoin, an enzyme inducer, can reduce clozapine plasma levels. There have been two reported cases of risperidone causing an increase in clozapine plasma levels however, because this agent is not an inhibitor of 1A2, the mechanisms for this increase are unclear. Nefazodone administered with clozapine has had minimal effects on clozapine s metabolism (329). 

Taylor D, Bodani M, Hubbeling A, et al. The effect of nefazodone on clozapine plasma concentrations. Int Clin Psychopharmacol 1999 14 185-187. 

Cyt 3A3/4 metabolizes clozapine, sertindole, quetiapine common substrates -tricyclic antidepressants, nefazodone, sertraline, carbamazepine, ethosuximide, terfenadine, benzodiazepines, diltiazem, nifedipine, verapamil, erythromycin, cyclosporine, lidocaine, quinidine, cisapride, paracetamol. Common inhibitors -nefazodone, fluvoxamine, fluoxetine, ketoconazole. 

Nefazodone had minimal effects on clozapine metabolism when co-administered in six patients mean clozapine concentrations rose by 4% and norclozapine concentrations by 16% (168). 

When nefazodone (400 mg/day for 3 weeks) was added to clozapine treatment in six patients with schizophrenia there was no significant change in plasma clozapine concentrations (22). This finding suggests that CYP3A4 does not play a major role in the metabolism of clozapine and that nefazodone may be a suitable adjunctive treatment for depression in clozapine-treated patients. 

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

A 40-year-old man had taken clozapine 450 mg/day and risperidone 6 mg/day for several years. Nefazodone 200 mg/day was added in an attempt to improve persistent negative symptoms, and after a week the dosage was increased to 300 mg/day. One week later, he reported anxiety and dizziness and was hypotensive. The combined concentrations of clozapine and its active metabolite norclozapine had increased from 309 ng/ml before nefazodone to 566 ng/ml. The nefazodone dosage was reduced to 200 mg/day and the anxiety, dizziness, and hypotension resolved over the next 7 days. At the same time plasma concentrations of clozapine and norclozapine fell to 370 ng/ml. 

These results suggest that in some individuals CYP3A4 plays a significant role in the metabolism of clozapine and that the combination of nefazodone and clozapine should therefore be used with caution. It is possible that in this case concomitant treatment with risperidone may have increased the effect of nefazodone to reduce the clearance of clozapine. 

Khan AY, Preskorn SH. Increase in plasma levels of clozapine and norclozapine after administration of nefazodone. J Chn Psychiatry 2001 62(5) 375-6. 

CYP450 3A4 inhibitors (e.g., nefazodone, fluvoxamine, fluoxetine) can raise clozapine levels, but dosage adjustment usually not necessary... 

A 40-year-old man had taken clozapine 450 mg/day and risperidone 6 mg/day for several years. Nefazodone... 

Antidepressants mirtazapine, nefazodone, sertraline Neuroleptics thioridazine, haloperidol, clozapine, quetiapine, risperidone, sertindole, ziprasidone Mood stabilizers carbamazepine, gabapentin, lamotrigine... 

Fluvoxamine (Luvox) Nefazodone (Serzone) Paroxetine (Paxil) CLOZAPINE, THIORIDAZINE, HALOPERIDOL, OLANZAPINE, THIOTHIXENE PHENOTHIAZINES, Risperidone, Aripiprazole Clozapine, Quetiapine, Ziprasidone QUETIAPINE, Clozapine, Ziprasidone ... 

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. 

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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