Divalproex-ER pharmacokinetics in older children and adolescents

Valproic acid pharmacokinetic profile and tolerability after administration of divalproex sodium extended-release tablets was characterized in older children and adolescents. In this multiple-dose, open-label, pharmacokinetic study, the patients were divided into two age groups, 8-11 years (older children; N = 15) and 12-17 years (adolescents; N = 14). Once-daily administration of divalproex sodium extended-release tablets (doses ranged from 250 to 1750 mg) in older children and adolescents produced relatively flat plasma valproic acid concentration-time profiles over the entire 24-hour dosing interval, similar to the pharmacokinetic performance of this formulation in adults. The mean (standard deviation) oral clearance values for unbound valproic acid were 94.3 (51.8) and 82.3 (28.2) mL/h/kg and for total valproic acid were 11.2 (3.77) and 9.06 (2.03) mL/h/kg in older children and adolescents, respectively. Two patients discontinued for administrative reasons, whereas one discontinued for an adverse event (flulike syndrome). Adverse events reported by three or more patients were flu syndrome (5 patients, 17.2%) and headache (3 patients, 10.3%). Reported adverse events were generally mild to moderate in severity and similar to those reported in previous divalproex studies. This study demonstrates that in older children and adolescents, once-daily administration of divalproex sodium extended-release tablets may potentially be used to sustain plasma valproic acid concentrations within the usually accepted therapeutic ranges for various indications.     

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.     

Paroxetine pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. RESULTS: There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/mL.hr. Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. CONCLUSIONS: Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.     

Single-dose pharmacokinetics and safety of ziprasidone in children and adolescents

OBJECTIVE: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. METHOD: A single-dose, open-label study of ziprasidone was conducted in youths (ages 7-16 years) with Tourette's disorder or chronic tic disorder. Dosing of ziprasidone oral suspension (40 mg/mL) was weight adjusted: >60 kg, 20 mg (group 1, n = 8); 31 to 60 kg, 10 mg (group 2, n = 8); and 16 to 30 kg, 5 mg (group 3, n = 8). Patients were assessed for serum ziprasidone concentration, safety, tolerability, and electrocardiogram pre- and postdose. RESULTS: Twenty-four patients were evaluated for safety and tolerability, and 23 were evaluated for pharmacokinetics. Regression analysis of AUC(0-infinity) and Cmax values versus weight-normalized dose showed linear, dose-related changes in ziprasidone exposure. Ziprasidone was well tolerated with frequent, although transient, somnolence. No clinically significant change from baseline was observed in Bazett's or Fridericia's corrected QT(c) interval, and change in QT(c) interval was not related to serum ziprasidone concentration. CONCLUSIONS: Oral ziprasidone exhibited linear pharmacokinetics and dose-related exposure in youths with Tourette's disorder or chronic tic disorder, which are comparable to adult data. A single dose of ziprasidone was well tolerated without clinically significant effects on electrocardiograms collected around the time of maximum serum concentration.     

The effect of fluvoxamine and behavior therapy on children and adolescents with obsessive-compulsive disorder

OBJECTIVE: The efficacy of medications, consisting of serotonin partial and specific reuptake blockers, and behavior therapy, consisting of exposure and response prevention in addition to social skills training, cognitive therapy, and habit reversal, in the treatment of obsessive-compulsive disorder are well documented. The purpose of the study was to explore if adding behavior therapy to medication would enhance treatment efficacy. METHODS: Ten children/adolescents who had not previously responded to behavior therapy were randomly assigned to two groups: fluvoxamine alone or fluvoxamine with behavior therapy. All 10 patients received fluvoxamine for 10 weeks-five continued solely on fluvoxamine for one year and five engaged in behavior therapy for 20 sessions along with fluvoxamine and then continued solely on medication until the end of the year. RESULTS: Eight of 10 patients improved significantly on fluvoxamine at week 10 on the primary outcome variable, the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). According to the other measurements-National Institute of Mental Health-Global Obses-sive-Compulsive Scale, Clinical Global Impression-Improvement (assessing level of im-provement from week to week), and Clinical Global Impression-Severity of Illness Scale (as-sessing how ill the patient is from week to week)-improvement was not as evident. According to the CY-BOCS, those who received a combination of fluvoxamine and exposure with response prevention showed significantly more improvement than those who only took medication. At two-year follow-up, all patients continued to improve, with those in the combined approach improving more than those in the medication-alone group. CONCLUSIONS: Future studies should determine the specific effect of each treatment group, combined and singularly. Reasons for discrepancy in improvement ratings as noted by the different instruments are discussed. The addition of behavior therapy to fluvoxamine seems to enhance treatment efficacy, according to the CY-BOCS.     

Multiple-dose pharmacokinetics of selegiline and desmethylselegiline suggest saturable tissue binding

The goal of this study was to examine the multiple-dose pharmacokinetics of selegiline and its metabolites desmethylselegiline, 1-methamphetamine, and 1-amphetamine after oral administration of selegiline HCl. Twelve healthy volunteers received 10 mg of selegiline HCl once daily for 8 days. The pharmacokinetic profiles of selegiline and the metabolites were examined from serum samples for 24 hours (i.e., the dosing interval, tau) on days 1, 4, and 8. The results indicated significant apparent accumulation of selegiline and desmethylselegiline during the 8-day period of selegiline administration. The AUC tau S of selegiline and desmethylselegiline were increased 2.7 fold (p < 0.001) and 1.5 fold (p < 0.001), respectively, from day 1 to day 8. However, the half-lives of selegiline (range, 1.5-3.5 h) and desmethylselegiline (range, 3.4-5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation. With both of the 1-amphetamine metabolites of selegiline, steady state was reached by day 4. We suggest that the most likely explanation for the apparent accumulation of selegiline and desmethylselegiline was the saturation of the MAO-B binding sites in tissues, although decreased first-pass metabolism of selegiline cannot be ruled out. The observed increase in selegiline and desmethylselegiline concentrations on multiple dosing is not likely to significantly increase the pharmacodynamic effect or adverse effects of selegiline compared with what has been found after a single 10-mg dose.     

Pilot study: fluvoxamine treatment for depression and anxiety disorders in children and adolescents with cancer

OBJECTIVE: To evaluate the safety, tolerability, and benefit of fluvoxamine for the treatment of major depressive disorder or anxiety disorders in children and adolescents with cancer. METHOD: The study was conducted from 2001 to 2004 at a pediatric hematology-oncology center. Fifteen children and adolescents with cancer were treated with fluvoxamine 100 mg/day in an open prospective 8-week trial. Safety and tolerability were evaluated at baseline and at weeks 4 and 8 by blood tests and the Side Effects Checklist. Clinical benefit was assessed with the Clinical Global Impressions-Improvement, the Children's Depression Rating Scale-Revised, and the Pediatric Anxiety Rating Scale. RESULTS: Fluvoxamine was well tolerated by all subjects. Psychiatric symptoms improved significantly. CONCLUSIONS: In this open trial, fluvoxamine appeared to be well tolerated and was associated with a promising reduction in the depression and anxiety symptoms of pediatric patients with cancer.     

Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder

OBJECTIVE: Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder in children, adolescents, and adults. This study was conducted, in part, to evaluate the single-dose and steady-state pharmacokinetics of atomoxetine in pediatric patients. METHODS: This was an open-label, dose-titration study in pediatric patients with attention deficit hyperactivity disorder. Eligible patients could elect to participate in a single-dose or steady-state discontinuation pharmacokinetic evaluation including serial plasma sample collection over 24 hours. Plasma concentrations of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine were determined using an atmospheric pressure chemical ionization liquid chromatography/mass spectrometry/mass spectrometry assay. Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS: Twenty-one cytochrome P450 2D6 extensive metabolizer patients participated in these single-dose and steady-state pharmacokinetic evaluations. Atomoxetine was rapidly absorbed, with peak plasma concentrations occurring 1 to 2 hours after dosing. Half-life averaged 3.12 and 3.28 hours after a single dose and at steady state, respectively. Minimal accumulation occurred in plasma after multiple twice-daily dosing in extensive metabolizer pediatric patients, as expected based on single-dose pharmacokinetics. As the dose (in mg/kg) increased, proportional increases in area under the curve were observed. CONCLUSIONS: The pharmacokinetics of atomoxetine in extensive metabolizer patients were well characterized over a wide range of doses in this study. Atomoxetine pharmacokinetics in pediatric patients and adult subjects were similar after adjustment for body weight.     

Low-dose fluvoxamine treatment of children and adolescents with pervasive developmental disorders: a prospective,open-label study

The objective of this study was to assess the efficacy and tolerability of low-dose fluvoxamine (1.5 mg/kg/day) in youngsters with pervasive developmental disorders (PDDs). This was a prospective, open-label trial that included 18 subjects with a mean age of 11.3 ± 3.6 years. Fourteen children (78%) completed the 10-week study. Premature discontinuation due to behavioral activation occurred in three participants. Although there was no response for the group as a whole, eight subjects (including all four females) were considered at least partial responders in intent-to-treat analyses. Neither pubertal status nor serotonin levels predicted clinical response. Fluvoxamine can be beneficial in the treatment of select children and adolescents with PDDs. Gender differences in selective serotonin reuptake inhibitor (SSRI) response warrant further investigation.     

Efficacy and pharmacokinetics of fluvoxamine maleate in patients with mild depression undergoing hemodialysis

Seven Japanese patients on maintenance hemodialysis who were comorbid with mild depression were medicated with 50 mg/day fluvoxamine maleate for 28 days. Effectiveness was obtained in four out of seven patients (57%). The plasma fluvoxamine concentrations were examined in three patients. The plasma fuvoxamine concentration decreased by 22% by hemodialysis. There is a tendency for the dialyzed rate of fluvoxamine to become lower if the plasma albumin concentration is higher. The half-life of fluvoxamine was possibly shortened more in the patient with hypoalbuminaemia. The plasma fluvoxamine concentration reached a steady state 8 days after the start of medication and thereafter. The time required to reach steady state was lengthened when compared with the results in normal Japanese volunteers.     

Sertraline pharmacokinetics and dynamics in adolescents

OBJECTIVE: To determine the pharmacokinetics of sertraline in adolescents and assess its effect on a surrogate marker of serotonin transport. METHOD: Pharmacokinetic parameters of a single 50-mg dose of sertraline were determined in 10 adolescents. Steady-state withdrawal kinetics were determined in 12 adolescents taking 50 mg/day and in 6 adolescents taking 100 to 150 mg/day. Platelet serotonin reuptake was measured before and after 2 weeks of daily 50-mg dosing. RESULTS: The mean steady-state half-life of 50 mg was significantly shorter (15.3 +/- 3.5 hours) than the single-dose half-life (26.7 +/- 5.2 hours; t = 6.4, p < .001) and the steady-state half-life at 100 to 150 mg/day (20.4 +/- 3.4 hours; t = 2.9, p = .01). Platelet serotonin reuptake was inhibited by 61 +/- 15% after approximately 2 weeks of sertraline 50 mg/day. CONCLUSIONS: The half-life of sertraline 50 mg becomes significantly shorter from the initial dose to steady-state, and many adolescents may benefit from twice-per-day dosing. The steady-state half-life increases as the dose increases. The moderate levels of platelet reuptake inhibition at 50 mg/day indicate that most adolescents may need sertraline doses higher than 50 mg/day to attain a therapeutic response.     

氟伏沙明与氯米帕明治疗青少年强迫症的对照研究

目的 比较氟伏沙明与氯米帕明治疗青少年期强迫症的疗效和不良反应.方法 共纳入强迫症患者42例,随机分为氟伏沙明组和氯米帕明组,疗程8周.应用耶鲁-布朗强迫症量表(Y-BOCS)、汉密尔顿焦虑量表(HAMA)评定疗效,治疗中需处理的不良反应症状量表(TESS)评价不良反应.结果 氟伏沙明组治疗总有效率86.4％,氯米帕明组治疗总有效率86.4％,两组比较差异无统计学意义(P＞0.05).两组治疗后第4、8周末Y-BOCS评分、HAMA评分与治疗前比较差异有显著统计学意义(P＜0.01).氟伏沙明组与氯米帕明组不良反应发生率差异有统计学意义(P＜0.05).结论 氟伏沙明对于青少年期强迫症状的治疗是安全有效的.     

Multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the quinolizinone hypnotic Ro 41-3696 in elderly subjects

The objectives of this double-blind, placebo-controlled study were to assess the multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the hypnotic agent Ro 41-3696 in elderly men and women (55-75 y of age). On day 1 and days 3-8, doses of 1, 3, 5, and 10 mg were administered sequentially to 4 groups of 10 subjects, 2 of whom received placebo. Psychomotor performance tests (tracking and attention) were conducted just before and at 1.5, 4, and 8 hours after drug intake on days 1, 4, 6, and 8. Memory was assessed at 24 hours after drug intake on days 1 and 8 by recall of a list of 10 words, which had been learned at 2 hours after intake. Ro 41-3696 was well tolerated at all dose levels. One subject dropped out of the study because of a hypersensitive skin reaction during treatment with 10 mg. Performance in both a tracking test and a memory search test was significantly affected by a dose of 10 mg and moderately affected by doses of 3 and 5 mg. The results of the 1-mg dose were indistinguishable from those of placebo. Long-term memory, as assessed by a word learning and recall test, showed the same pattern. Partial tolerance to the impairing effects in the psychometric tests developed over the course of treatment. Pharmacokinetics of both Ro 41-3696 and its O-desethyl metabolite Ro 41-3290 were dose proportional and time independent. Ro 41-3696 was absorbed and eliminated rapidly (time of maximum plasma concentration, approximately 1 hour; elimination half-life, approximately 2 hours). Plasma levels of Ro 41-3290 were higher than those of the parent drug, and it was more slowly eliminated (values for time of maximum plasma concentration and elimination half-life, approximately 2 and approximately 7 hours, respectively).     

Treatment with fluvoxamine against self-injury and aggressive behavior in autistic children

Five autistic children underwent fluovoxamine administration. Their self-injury and aggressive behaviors did not respond psychotherapy and other medication with haloperidol, carbamazepine. The improvement of the behaviors was excellent in two patients, and partial in one patient. In a patient who received a combination of haloperidol and fluvoxamine, fluvoxamine treatment was discontinued because of severe drowsiness and could not continue. The other patients showed no obvious side effects. These results suggest that fluvoxamine treatment may be indicated for self-injury and aggressive behaviors in autistic children.     

Studies on the pharmacokinetics of total and free valproate in mono- and bitherapy with carbamazepine in epileptic children and adolescents

The aim of this study was to obtain a pharmacokinetic calculation for valproic acid (VPA) and its free fraction in 50 children and adolescents (4-18 years) treated for epilepsy in VPA monotherapy and bitherapy with carbamazepine (CBZ). The diurnal fluctuation of serum concentration of total and free VPA during monotherapy was observed. The additional antiepileptic medication of VPA and CBZ was connected with prominent diurnal free VPA serum fluctuations. Pharmacokinetic parameters of total and free VPA in monotherapy were significantly different. The change of free and total VPA pharmacokinetics during bitherapy with CBZ was observed, too. No changes in half-life time of VPA in mono- and bitherapy were noticed. The variability of pharmacokinetic parameters of free VPA suggests the need for monitoring unbound VPA plasma concentrations during bitherapy with CBZ.     

Depression in children and adolescents

Depression is a common problem in children and adolescents. The disorder may be overlooked because of the prominent irritability seen in children with depression and because of the perception that moodiness is a normal phase of childhood. Depression frequently is associated with other psychiatric problems and neurologic disorders. Therapy consists of psychotherapy and medication, with SSRIs the first choice for pharmacotherapy.     

Telemedicine in children and adolescents

Psychiatric care for children and adolescents is limited in remote and underserved areas because of the shortage of child and adolescent psychiatrists. Telepsychiatry has the potential to alleviate this problem. This article reviews the procedures used to develop telepsychiatry, equipment needed for videoconferencing in telepsychiatry, benefits and limitations of telepsychiatry, and confidentiality issues in telepsychiatry. Many questions regarding confidentiality, legality, reimbursement, cost-effectiveness, and technology still need to be resolved. However, telepsychiatry has the potential to be a useful treatment alternative.     

Hallucinations in children and adolescents

Clinicians need to consider a wide range of differential diagnoses when children and adolescents present with hallucinations. This includes considering whether it is a developmentally normal phenomenon or if there is a psychiatric, medical, or neurologic diagnosis. Nonpsychotic children with hallucinations can be differentiated from psychotic children. Nonpsychotic children who are at risk (or prodromal) for future psychosis can be differentiated from nonprodromal healthier children. We examine the epidemiology, prognosis, and neurobiological research. Lastly, we discuss treatment approaches, including medication and cognitive behavioral therapy.