clozapine and nefazodone

The cytochrome enzyme p4503A4 (CYP3A4) is thought to play a major part in the human metabolism of clozapine. Nefazodone is a potent and specific in-vivo inhibitor of CYP3A4. We co-administered nefazodone and clozapine in six patients and found that mean clozapine levels rose by 4% of baseline and norclozapine levels by 16%. Based on these observations, it is inferred that inhibition of CYP3A4 in vivo has minimal effects on clozapine metabolism. Nefazodone appears to be safe when co-administered with clozapine.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Drug Interactions; Female; Humans; Male; Piperazines; Triazoles

Topics: Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Anxiety Disorders; Asthma; Bronchodilator Agents; Buspirone; Clozapine; Comorbidity; Cooperative Behavior; Depressive Disorder, Major; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Humans; Long-Term Care; Patient Care Team; Piperazines; Referral and Consultation; Schizophrenia; Schizophrenic Psychology; Theophylline; Triazoles

The selective serotonin (5-HT) reuptake inhibitors (SSRIs) represent the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), and atypical antipsychotic drugs, which block 5-HT2A receptors, are used in augmentation strategies. Opiate drugs are also effective in treatment-refractory OCD and Tourette syndrome. The 5-HT2A-related behavior (i.e., head twitch) has been related with tics, stereotypes, and compulsive symptoms observed in Tourette syndrome and OCD.. The aim of this study was to explore whether 5-HT2A-related behavior is affected by atypical opiate drugs.. Head-twitch response was induced in mice by administration of either 5-hydroxytryptophan (5-HTP) or the 5-HT2A/C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Dose-effect curves of atypical opiate drugs [(+/-)-tramadol, (-)-methadone and levorphanol], morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms were investigated by administration of naloxone.. All the opiates tested reduced both 5-HTP and DOI-induced behavior in a naloxone-reversible fashion, atypical opiates being more effective. The effects of the other drugs depended on the protocol, clozapine being the most effective.. Combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-related behavior. These results provide behavioral evidence to support convergent effects of the 5-HT and opioid systems in discrete brain areas, offering the potential for therapeutic advances in the management of refractory stereotypes and compulsive behaviors.

Topics: 5-Hydroxytryptophan; Analgesics, Opioid; Animals; Clozapine; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Fluvoxamine; Indophenol; Levorphanol; Male; Methadone; Mice; Morphine; Naloxone; Narcotic Antagonists; Obsessive-Compulsive Disorder; Piperazines; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Stereotyped Behavior; Tics; Tourette Syndrome; Tramadol; Triazoles

Topics: Adult; Clozapine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Humans; Male; Mixed Function Oxygenases; Piperazines; Schizophrenia, Paranoid; Triazoles