Antidepressant exposure as a predictor of clinical outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) study.

This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram.

Disposition of chiral and racemic fluoxetine and norfluoxetine across childbearing.

OBJECTIVE: To add to the limited data on the clinical pharmacology of antidepressants during pregnancy, we examined the dose-corrected chiral and racemic levels (level/dose) of fluoxetine (FLX) and norfluoxetine (NorFLX) during pregnancy and early postpartum. METHODS: The authors evaluated 17 pregnant women who received fluoxetine therapy. Doses were recorded weekly across gestation and postpartum. At 20, 30, and 36 weeks of gestation, during delivery, and 12 weeks after delivery, the depression level was assessed with the Hamilton Rating Scale for Depression (HRS-D), and plasma samples were analyzed for levels of S- and R-FLX and S- and R-NorFLX. RESULTS: The mean ratios of the chiral parent drug (S-FLX + R-FLX) to metabolite levels (S-NorFLX + R-NorFLX) decreased across pregnancy. The differences were significant between 20-36 weeks and 30-36 weeks. After delivery, the mean dose-corrected level of the active moiety S-FLX and the mean ratio of the chiral parent drug (S-FLX + R-FLX) to metabolite level (S-NorFLX + R-NorFLX) significantly increased between delivery and 12 weeks postpartum. Most of the fluoxetine-treated subjects experienced remitted depressive episodes and euthymic mood levels during pregnancy and postpartum. CONCLUSIONS: The findings extend earlier reports of increased antidepressant metabolism during pregnancy and refractory metabolism after delivery. These data may inform treatment decisions related to dosing in patients who receive fluoxetine during pregnancy.

A pilot randomized controlled trial of combined trauma-focused CBT and sertraline for childhood PTSD symptoms.

OBJECTIVE: To examine the potential benefits of adding a selective serotonin reuptake inhibitor, sertraline, versus placebo, to trauma-focused cognitive-behavioral therapy (TF-CBT) for improving posttraumatic stress disorder and related psychological symptoms in children who have experienced sexual abuse. METHOD: Twenty-four 10- to 17-year-old female children and adolescents and their primary caretakers were randomly assigned to receive TF-CBT + sertraline or TF-CBT + placebo for 12 weeks. RESULTS: Both groups experienced significant improvement in posttraumatic stress disorder and other clinical outcomes from pre- to posttreatment with no significant group x time differences between groups except in Child Global Assessment Scale ratings, which favored the TF-CBT + sertraline group. CONCLUSIONS: Only minimal evidence suggests a benefit to adding sertraline to TF-CBT. A drawback of adding sertraline was determining whether TF-CBT or sertraline caused clinical improvement for children with comorbid depression. Current evidence therefore supports an initial trial of TF-CBT or other evidence-supported psychotherapy for most children with PTSD symptoms before adding medication.

Corrected QT Interval and Methadone Dose and Concentrations in Pregnant and Postpartum Women.

BACKGROUND: Methadone is a standard treatment for opioid dependence in pregnancy; however, its impact on maternal corrected QT interval (QTc) has not been evaluated. We studied the association between methadone dose and enantiomer-specific plasma concentrations and QTc among pregnant and postpartum women and newborns. We assessed the relevance of QTc screening guidelines for pregnant women and infants. METHODS: From 2006 to 2008, plasma methadone concentrations were measured during pregnancy, postpartum, and in cord blood in women treated for opioid dependence at a single treatment program. Electrocardiograms (ECGs) were obtained at peak methadone concentrations in mothers and within 48 hours of birth for infants. Pearson correlations were performed at each time point for QTc and R-methadone, S-methadone, and total methadone concentrations and ratio of R-methadone/S-methadone concentrations. RESULTS: Mean (SD) daily methadone dose for the 25 women was 94.2 (39.1) mg during pregnancy and 112.5 (46.6) mg postpartum. During the third trimester, higher methadone dose and R-methadone concentration correlated with longer QTc (Pearson r = 0.67, P < .001 and Pearson r = 0.49, P = .02, respectively), while S-methadone concentration, R-methadone/S-methadone concentration ratio, and total methadone concentration did not. Postpartum, QTc did not significantly correlate with dose or enantiomer concentrations. Infant QTc did not correlate with maternal dose at delivery or enantiomer-specific cord methadone concentrations. In pregnant and postpartum women, 13% and 17%, respectively, had QTc ≥ 450 ms, as did 19% of infants. CONCLUSIONS: QTc correlated with dose and R-methadone concentration during the third trimester. However, longer QTc was common among women during and after pregnancy. Given the relatively high rate of QTc > 450 ms, an ECG before and after methadone initiation is advisable for pregnant and postpartum women.

Steady-state clinical pharmacokinetics of bupropion extended-release in youths.

OBJECTIVE: To examine in children and adolescents the 24-hour, steady-state clinical pharmacokinetics of an extended-release (XL) formulation of bupropion (Wellbutrin XL). METHOD: Subjects were six male and four female patients (ages 11.5-16.2 years) prescribed bupropion XL in morning daily doses of either 150 mg (n = 5) or 300 mg (n = 5) for at least 14 days. During an overnight hospitalization, subjects had serial blood draws every 1.5 to 3 hours from an intravenous port to measure plasma levels of bupropion and its metabolites. Pharmacokinetic variables were determined by noncompartmental analysis for bupropion and exponential analyses for metabolites. RESULTS: Bupropion and metabolites demonstrated linear pharmacokinetics. Bupropion's mean maximum concentration (Cmax) was lower (p = .021) and its mean time to Cmax longer (p = .057) in the current sample on bupropion XL relative to a previously studied sample of youths on bupropion sustained-release (Wellbutrin SR). Mean 24-hour area under the curve ratios of metabolites to bupropion ranged from 1.0 for erythrohydrobupropion to 16.4 for hydroxybupropion. CONCLUSIONS: Once-daily dosing is justified in youths prescribed bupropion XL. The active metabolite hydroxybupropion probably has key pharmacodynamic effects, given its higher and more sustained levels relative to the other metabolites or to bupropion.

Platelet serotonin reuptake inhibition and response to SSRIs in depressed adolescents.

OBJECTIVE: The authors examined platelet serotonin reuptake inhibition and response to selective serotonin reuptake inhibitor (SSRI) treatment in depressed adolescents. METHOD: Twenty-three depressed adolescents participating in pharmacokinetic studies of SSRIs had platelet serotonin reuptake measured before and after 14-28 days of treatment. The Clinical Global Impression (CGI) improvement rating was determined on the basis of all clinical information and was performed blind to the platelet data. RESULTS: Improvement in depressive symptoms as rated with the CGI improvement subscale was significantly associated with the percentage change in platelet serotonin reuptake inhibition from pre- to posttreatment. Improvement in depression was also associated with absolute decrease in platelet serotonin reuptake when adjusted for the magnitude of baseline reuptake. CONCLUSIONS: Platelet serotonin reuptake inhibition may be an appropriate surrogate biological marker for the pharmacodynamic activity of SSRIs in depressed adolescents.

The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.

It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, olanzapine or sham for a 17-27 month period. The resulting plasma drug levels were comparable to those seen in subjects with schizophrenia treated with these medications. After the exposure, we observed an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in both drug-treated groups compared to sham animals. The differences were observed across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in the frontal and parietal regions. Stereological analysis of the parietal region using Cavalieri's principle revealed similar volume reductions in both gray and white matter. In addition, we assessed the subsequent tissue shrinkage due to standard histological processing and found no evidence of differential shrinkage due to drug exposure. However, we observed a pronounced general shrinkage effect of approximately 20% and a highly significant variation in shrinkage across brain regions. In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume. Antipsychotic medication may confound post-mortem studies and longitudinal imaging studies of subjects with schizophrenia that depend upon volumetric measures.

Weight changes in postpartum women with remitted depression.

OBJECTIVE: To compare weight loss after birth in women who took the antidepressants nortriptyline or sertraline or placebo in 2 clinical studies designed to prevent recurrent postpartum major depression. METHOD: Data were collected from 1995 to 2001. All subjects had at least 1 prior episode of Research Diagnostic Criteria- or DSM-IV-defined major depressive disorder. Data on weight were available for 467 weeks from 60 women who were weighed 8 times from 2 to 17 weeks postpartum. The dependent measures were weight at weeks 11 and 17 and weight change from weeks 2 to 17 postpartum. RESULTS: At week 17, the women's weights ranged from 109 to 268 lb. Their weight change ranged from +14 to -19 lb over the 15-week postpartum period (mean = -1.8, SD = 5.1 lb). After controlling for week 2 weights, the mean weights at week 17 for the women treated with nortriptyline, sertraline, or placebo were not significantly different. Of 60 women with 3 or more weight assessments, those who were randomly assigned to nortriptyline lost weight more rapidly than the other 2 groups; however, the mean weight change across all groups was only -1.8 lb (SD = 5.1 lb). CONCLUSIONS: Weight loss was not compromised by antidepressant pharmacotherapy. Postpartum weight retention occurred in this group of nondepressed women with previous histories of major depression independent of drug treatment.

Steady-state pharmacokinetics of bupropion SR in juvenile patients.

OBJECTIVE: To examine the steady-state pharmacokinetic properties of bupropion sustained release (SR) and their potential developmental differences in youths. METHOD: Eleven boys and eight girls aged 11 to 17 years old were prescribed bupropion SR monotherapy for attention-deficit/hyperactivity disorder (n = 16) and/or depressive disorders (n = 16). Bupropion SR was given in morning doses of 100 mg/day (n = 11) or 200 mg/day (n = 8) for 14 days or less, with five subjects studied on both doses. All subjects had blood draws from an intravenous port every 1 to 3 hours for 24 hours after their usual morning doses. Pharmacokinetic variables were determined by noncompartmental and compartmental analyses for bupropion and metabolites, respectively. RESULTS: Bupropion and its metabolites exhibited linear pharmacokinetics. Areas under the concentration curves for the hydroxybupropion, threohydrobupropion, and erythrohydrobupropion were 20, 12, and 2.7 times higher, respectively, than for bupropion. Relative to adults, the mean half-lives of bupropion (12.1 hours) and threohydrobupropion (26.3 hours) were significantly shorter, and areas under the concentration curve ratios of metabolites to bupropion were 19% to 80% higher. CONCLUSIONS: Youths metabolize bupropion SR faster to hydroxybupropion and other active metabolites than adults. Until the clinical importance of bupropion's metabolites is clarified, bupropion SR should be given in divided doses to youths, as the manufacturer recommends for adults taking higher doses.

Prevention of postpartum episodes in women with bipolar disorder.

BACKGROUND: The aim of this study was to evaluate the efficacy of divalproex (VLP) to prevent episode recurrence in postpartum women with bipolar disorder. METHODS: The design was a single-blind, nonrandomized clinical trial. Subjects were enrolled during pregnancy and chose either VLP plus symptom monitoring or monitoring without medication for immediate postpartum management. Mania and depression symptoms were assessed weekly for 20 weeks by an independent evaluator. RESULTS: Data were available for 26 women. There were no significant differences between groups in the proportions of women who developed postpartum hypomania/mania, depression, or mixed states. The time to development of episodes also did not vary between groups. Women who were treated with VLP tended to have lower levels of hypomanic/manic symptoms. CONCLUSIONS: Divalproex was not significantly more effective than monitoring without drug for the prevention of postpartum episodes of bipolar disorder. The most prudent pharmacologic plan is to use the drug(s) to which the individual woman has responded and prepare a plan for rapid augmentation if a breakthrough episode occurs.

Verapamil treatment for women with bipolar disorder.

BACKGROUND: Additional pharmacological treatments are needed for patients with bipolar disorder. We describe our experience with verapamil in an inclusive, sequential series of outpatient women (some pregnant) with bipolar disorder. METHODS: All women who were prescribed verapamil for bipolar disorder (n = 37) were included. We used the criterion of 50% reduction in scores on the Mania Rating Scale or the Hamilton Rating Scale for Depression to define response for women who were treated for an acute episode of bipolar hypomania/mania or depression, respectively. For euthymic women who chose verapamil maintenance treatment, we evaluated whether they met criteria for a recurrent episode during therapy. RESULTS: Treatment for acute episodes was initiated in 28 women. Of women with depression and mania, 39% and 100% responded, respectively. Seven of the nine patients (77%) with mixed states responded: all seven improved to response criterion on the mania scale, and two responded on the depression scales as well. Six of eight patients who received continuation therapy remained well. CONCLUSIONS: These data provide evidence that verapamil is effective for mania. The response rate for mania compares favorably to that for other mood stabilizers. After decades of case reports and underpowered clinical trials, we must definitively study verapamil for efficacy and gender specificity in bipolar disorder.

Prevention of postpartum depression: a pilot randomized clinical trial.

OBJECTIVE: The authors attempted to reduce the rate of postpartum depression in high-risk women and to increase the time to recurrence. METHOD: Nondepressed pregnant women with at least one past episode of postpartum major depression were recruited into a randomized clinical trial. Mothers were assigned randomly to a 17-week trial of sertraline or placebo immediately after birth and assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression. RESULTS: Of 14 subjects who took sertraline, one (7%) suffered a recurrence. Of eight subjects who were assigned to placebo, four (50%) suffered recurrences. This difference was significant. The time to recurrence was significantly longer in the sertraline-treated women than in the placebo-treated women. CONCLUSIONS: Sertraline conferred preventive efficacy for postpartum-onset major depression beyond that of placebo.

Postpartum depression recurrence versus discontinuation syndrome: observations from a randomized controlled trial.

OBJECTIVE: To differentiate characteristics of a discontinuation syndrome from a recurrence of major depressive disorder in the context of a randomized trial. METHOD: We performed a randomized clinical trial to compare the efficacy of sertraline versus placebo for the prevention of recurrent postpartum DSM-IV major depressive disorder. Women whose depression did not recur in the initial 17-week active treatment trial were followed through the taper phase (weeks 18-20). At week 17, 3 women assigned to placebo and 8 assigned to sertraline remained in the trial. Nine symptoms that characterize discontinuation syndrome were extracted from the 25-item Asberg Rating Scale for Side Effects (ASE) and assessed weekly during the taper phase. The 21-item Hamilton Rating Scale for Depression was used to evaluate depressive symptoms. RESULTS: In the taper phase, there were no significant differences between the sertraline- and placebo-treated women on the sum of the ASE-derived symptoms. Both groups had low levels of symptoms on the ASE during the weeks of taper. None of the 3 women assigned to placebo and 2 of the 8 women assigned to sertraline suffered a depressive recurrence within 6 weeks of the end of the study. CONCLUSIONS: A gradual taper of sertraline (75 mg) over 3 weeks did not lead to discontinuation syndrome; however, the systematic dissection of symptoms resulted in our conclusion that the duration of preventive therapy should be extended to 26 weeks (about 6 months) in subsequent randomized trials, consistent with the treatment guidelines for a single episode of depression.

A comparison of d, l-fenfluramine and citalopram challenges in healthy adults.

Dimensional personality characteristics (e.g. impulsivity) and related behaviors and psychiatric disorders are linked to abnormalities of central nervous system (CNS) serotonergic functioning. Although neuroendocrine [e.g. plasma prolactin (PRL)] responses to the serotonin agonist, fenfluramine, have been used widely to index CNS serotonergic responsivity, safety concerns constrain continued use of fenfluramine. Citalopram, which inhibits serotonin reuptake, may serve as an alternative pre-synaptic neuropharmacologic challenge agent, due to its high selectivity and absence of intrinsic activity at serotonin or other receptor families. Twenty-two healthy adults who had been administered a fenfluramine challenge before May 1996 completed a 5-h oral citalopram challenge 3-6 years later. PRL responsivity to citalopram correlated significantly with PRL response to fenfluramine for baseline-corrected maximal and area-under-the-curve (AUC) indices ( r's > or =0.49, P's< or =0.02). The magnitude of the correlations is notable given the length of time between challenges. The results support the use of citalopram as an alternate neuroendocrine challenge to index CNS serotonergic responsivity.

Gastrointestinal distress to serotonergic challenge: a risk marker for emotional disorder?

OBJECTIVE: Serotonin is an important mediator of gut sensation and motility. The authors' aim was to determine whether inadvertent gastrointestinal (GI) distress to serotonergic challenge predicted future major depressive and/or anxiety disorders in exposed children. METHOD: l-5-hydroxytryptophan was administered to 119 prepubertal children free of psychiatric disorder as part of a psychobiological cohort study initially designed to examine familial loading for mood disorder as the exposure of interest. Subjects were followed longitudinally with standardized psychiatric interviews to identify new-onset mood and anxiety disorders over 90.3 +/- 29.2 months, with the average assessment interval being 16.6 +/- 6.2 months. Reports of GI distress in a subgroup during serotonergic challenge led the authors to examine GI distress to infusion as an exposure post hoc and to perform survival analysis using major depressive and/or anxiety disorders as the outcomes of interest. RESULTS: GI distress to serotonergic challenge was experienced by 23 subjects, with 7 (30.4%) developing an emotional disorder during follow-up in comparison to 12 (10.4%) of 96 nondistressed subjects. The distressed group was at significantly greater risk of subsequent major depression and/or anxiety (p =.026), even after controlling for family history of psychiatric disorder. CONCLUSIONS: GI distress to serotonergic challenge in childhood is associated with heightened risk for subsequent major depressive and/or anxiety disorders. Studies of serotonergic neurotransmission may aid our understanding of nonrandom associations between functional GI symptoms and emotional symptoms and disorders.

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.

Chronic Medical Illness in Patients With Recurrent Major Depression.

The authors treated 115 elderly patients (ambulatory and without dementia) with recurrent major depression, by means of combined nortriptyline and interpersonal psychotherapy. They contrasted Cumulative Illness Rating Scale-Geriatric (CIRS-G) scores (for medical burden) in recovered and nonrecovered patients and generated a Cox proportional-hazards model of time-to-remission. The authors found no association between pretreatment chronic medical burden and acute treatment outcome in recovered (83 of 115) and nonrecovered patients and no relation of pretreatment CIRS-G scores with time-to-recovery. Findings support recent recommendations that practitioners be optimistic in treating elderly depressed, ambulatory patients whether or not significant medical burden coexists.

Nortriptyline Side Effects During Double-Blind, Randomized, Placebo-Controlled Maintenance Therapy in Older Depressed Patients.

The authors assessed the severity of nortriptyline side effects in older patients with major depression during 12 months of double-blind therapy. Data were from 40 patients completing 1 year of maintenance therapy: 26 were on nortriptyline and 14 were on placebo. The authors detected significant time-by-treatment interactions for various side effects (all greater in treated patients), but not for overall side effects score. Clinically, these differences were judged to be minor and correctable. On the other hand, total side effect scores, physical tiredness, and subjective sleep disturbance covaried significantly with Hamilton Depression scores regardless of treatment assignment. Somatic worry, tiredness, and sleep complaints appeared to reflect residual depression rather than treatment assignment.

Timing of depression recurrence in the first year after birth.

BACKGROUND: Women who have suffered from one episode of postpartum-onset major depression (PPMD) experience increased risk for recurrence in the year following another birth. METHODS: Non-depressed women (N=51) who had at least one past episode of PPMD were recruited during pregnancy. After birth, subjects were assessed prospectively each week for 20 weeks with the Hamilton Rating Scale for Depression and Research Diagnostic Criteria for recurrence of major depression. Evaluations were carried out at 24, 36, and 52 weeks to assess for episodes beyond 20 weeks postpartum. RESULTS: The data revealed a clustering of cases, with five of the 21 recurrences (24%) occurring in the first 2 weeks. Thirteen of the 21 recurrences (67%) and 19/21 recurrences (90%) occurred in the first 20 and 28 weeks following birth, respectively. LIMITATIONS: Although it is unusual for studies of this type to be prospective, the sample size is relatively small. CONCLUSIONS: The 1-year recurrence rate was 21/51 or 41%, with a clustering of cases near delivery. All recurrences except two occurred by 28 weeks postpartum.

Adolescent weight loss during treatment with olanzapine.

Antipsychotic medications are increasingly used in adolescents for a variety of psychiatric difficulties, including psychosis, bipolar disorder, and aggression. Weight gain is a significant side effect of neuroleptics, which may limit adolescents' compliance with these medications. This report presents a case of significant weight loss while on olanzapine, with a body mass index (BMI) falling from 25 to 19.5 during 8 months of treatment. Possible mechanisms for this effect are discussed.