Nefazodone pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of nefazodone (NFZ) in depressed children and adolescents. METHOD: Depressed youths aged 7 to 17 years were eligible to participate. Intensive sampling for pharmacokinetic analyses of NFZ and 3 of its active metabolites was performed after single and multiple dose administration. Treatment was continued for 6 more weeks and titrated to maximize clinical response. RESULTS: Twenty-eight patients were enrolled. Systemic exposure to NFZ and 3 metabolites was generally higher in children than adolescents. NFZ and metabolite disposition profiles showed high intra- and interpatient variability. Compared to published data in adults, the half-life of NFZ and 2 of its metabolites appears shorter in children and adolescents. Meta-chlorphenylpiperazine pharmacokinetic parameters were different in 5 patients determined to be poor metabolizers of cytochrome P450 2D6 (CYP2D6). NFZ was well tolerated, and administration was associated with significant reductions (p < .001) in depressive symptoms. CONCLUSIONS: The pharmacokinetics of NFZ in pediatric patients is highly variable. NFZ appears to be safe in this small, short-term study. Pediatric patients who are poor metabolizers of CYP2D6 do not appear to be at increased risk for NFZ-associated adverse events. Open-label treatment of NFZ is associated with reductions in depressive symptoms.

Discriminant validity of the SCL-90 dimensions of anxiety and depression.

Although the SCL-90 and other self-report measures of anxiety and depression have long been criticized for inadequate factor structure and unacceptably high correlations with each other, recent evidence indicates the use of homogeneous samples results in greatly improved discriminant validity. This study utilized homogeneous samples of anxious (N = 54) or depressed (N = 120) outpatients and a factor analysis was conducted on their responses to the depression and anxiety items on the SCL-90. Clearly separate factors for anxiety and depression emerged. Results are discussed with respect to implication for measures of depression and anxiety.

Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms.

OBJECTIVE: To document a case of serotonin syndrome associated with venlafaxine and fluoxetine that did not involve a monoamine oxidase inhibitor, and to examine the multiple factors, including pharmacodynamic and pharmacokinetic interactions, that likely caused this adverse drug reaction (ADR). CASE SUMMARY: A 39-year-old white woman with depression and panic attacks was being treated with fluoxetine, trazodone, clonazepam, and cimetidine. After fluoxetine and clonazepam were abruptly discontinued, venlafaxine and lorazepam were started. Within 24 hours, she developed diaphoresis, tremors, slurred speech, myoclonus, restlessness, impaired thinking, and diarrhea. This constellation meets Sternbach's criteria for serotonin syndrome. DISCUSSION: The possible contributors to this ADR are discussed, including a single drug effect (e.g., an idiosyncratic reaction to venlafaxine), a pharmacokinetic interaction, a pharmacodynamic interaction, a combined pharmacokinetic-pharmacodynamic interaction, and the patient' s panic disorder. CONCLUSIONS: As more serotonergic drugs are developed and used for psychiatric disorders, frequently in combination or close temporal proximity, clinicians must be aware of and consider the factors that may increase the risk of patients experiencing serotonin syndrome.

Inhibition of hepatic P-450 isoenzymes by serotonin selective reuptake inhibitors: in vitro and in vivo findings and their implications for patient care.

The effect on hepatic isoenzymes is emerging as the major clinically important distinguishing characteristic among the selective serotonin reuptake inhibitors (SSRIs). Although this fact has only recently gained widespread attention, the knowledge that some SSRIs inhibit hepatic metabolism dates back almost 20 years. This paper will first provide an overview of hepatic isoenzymes and then present the history and our current understanding of the effects of different SSRIs on different hepatic isoenzymes. Most of the attention in this area has focused on drug-drug interactions. This paper will also review recent work indicating that genetically determined differences in hepatic isoenzyme function can be risk factors in the development of a variety of diseases. The possible implications of this work relative to the long-term use of SSRIs will be discussed.