Karen Dineen Wagner

A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.

CONTEXTnThere was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.nnnOBJECTIVEnTo investigate which medication to administer first to antimanic medication-naive subjects.nnnDESIGN, SETTING, AND PARTICIPANTSnThe Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments.nnnINTERVENTIONSnSubjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg).nnnMAIN OUTCOME MEASURESnPrimary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents.nnnRESULTSnThere were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; χ(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; χ(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (χ(2)(1) = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F(1,212) = 45.5, P < .001; F(1,212) = 39.1, P < .001; and F(1,213) = 191.4, P < .001, respectively) and vs divalproex sodium (F(1,212) = 34.7, P < .001; F(1,212) = 45.3, P < .001; and F(1,213) = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001).nnnCONCLUSIONSnRisperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00057681

Impact of Physical and Sexual Abuse on Treatment Response in the Treatment of Resistant Depression in Adolescent Study (TORDIA)

OBJECTIVEnWe previously reported that a history of abuse was associated with a poorer response to combination treatment in the Treatment of Resistant Depression in Adolescents study (TORDIA). We now report on the nature and correlates of abuse that might explain these findings.nnnMETHODnYouth who did not benefit from an adequate selective serotonin re-uptake inhibitor (SSRI) trial (N = 334) were randomized to one of the following: an alternative SSRI; an alternative SSRI plus cognitive behavior therapy (CBT); venlafaxine; or venlafaxine plus CBT. Analyses examined the effect of history of abuse on response to the pharmacotherapy and combination therapy.nnnRESULTSnThose without a history of physical abuse (PA) or sexual abuse (SA) had a higher 12-week response rate to combination therapy compared with medication mono-therapy (62.8% versus 37.6%; odds ratio [OR] = 2.8, 95% confidence interval [CI] = 1.6-4.7, p < .001). Those with a history of SA had similar response rates to combination versus medication monotherapy (48.3% versus 42.3%; OR = 1.3, 95% CI = 0.4-3.7; p = .66), whereas those with history of PA had a much lower rate of response to combination therapy (18.4% versus 52.4%, OR = 0.1; 95% CI = 0.02-0.43). Even after adjusting for other clinical predictors, a history of PA moderated treatment outcome.nnnCONCLUSIONnThese results should be considered within the limitations of a post hoc analysis, lack of detailed assessment of abuse and other forms of trauma, and neuropsychological status. Depressed patients with history of abuse, especially PA may require specialized clinical approaches. Further work is needed to understand by what mechanisms a history of abuse affects treatment response.

Treatment Moderators and Predictors of Outcome in the Treatment of Early Age Mania (TEAM) Study

OBJECTIVEnBoth the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome.nnnMETHODnTEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naïve patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome.nnnRESULTSnModerator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI = 1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI = 0.8-2.2) to 10.5 (95% CI = 1.4-77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI = 1.6-3.3) for nonobese patients, but 1.1 (95% CI = 0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS.nnnCONCLUSIONSnRisperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration information--Treatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681.

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.

Do Sub-syndromal Manic Symptoms Influence Outcome in Treatment Resistant Depression in Adolescents? A Latent Class Analysis from the TORDIA study

BACKGROUNDnTo identify distinct depressive symptom trajectories in the TORDIA study and determine their correlates.nnnMETHODSnLatent Class Growth Analysis (LCGA) using the Childrens Depression Rating Scale-Revised (CDRS-R) through 72 weeks from intake.nnnRESULTSn3 classes were identified: (1) little change in symptomatic status (NO), comprising 24.9% of participants, with a 72-week remission rate of 25.3%; (2) slow, steady improvement (SLOW), comprising 47.9% of participants, with a remission rate of 60.0%, and (3) rapid symptom response (GO), comprising 27.2% of participants, with a remission rate of 85.7%. Higher baseline CDRS-R (p<0.001) and poorer functioning (p=0.03) were the strongest discriminators between NO and GO. Higher baseline CDRS (p<0.001) and scores on the Mania Rating Scale (MRS) (p=0.01) were the strongest discriminators between SLOW and GO. Other variables differentiating GO from both NO and from SLOW, were better baseline functioning, lower hopelessness, and lower family conflict. Both NO and SLOW showed increases on the MRS over time compared to GO (ps ≤ 0.04), and increasing MRS was strongly associated with lack of remission by 72 weeks (p=0.02).nnnLIMITATIONSnHigh rate of open treatment by the end of the follow-up period creates difficulty in drawing clear inferences about the long-term impact of initial randomization.nnnCONCLUSIONnAlong with depressive severity, sub-syndromal manic symptoms, at baseline, and over time emerged as important predictors and correlates of poor outcome in this sample. Further research is needed on the treatment of severe depression, and on the assessment and management of sub-syndromal manic symptoms in treatment resistant depression.

The Bi-Directional Relationship Between Parent–Child Conflict and Treatment Outcome in Treatment-Resistant Adolescent Depression

OBJECTIVEnTo examine the bidirectional relationship between parent-child discord and treatment outcome for adolescent treatment-resistant depression.nnnMETHODnDepressed youth who had not responded to an adequate course of a selective serotonin reuptake inhibitor (SSRI) were randomized to either a switch to another SSRI or venlafaxine, with or without the addition of cognitive behavior therapy (CBT) in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study. The Conflict Behavior Questionnaire was used to assess adolescent (CBQ-A) and parent-reported (CBQ-P) parent-child discord. The impact of remission on parent-child conflict, and the differential impact of medication and CBT on the CBQ-A and CBQ-P, were assessed using generalized linear models.nnnRESULTSnAlthough there were no differential treatment effects on parent or adolescent-report of conflict, remission was associated with improvement in the CBQ-P. In general, intake family conflict did not predict remission, except in the sub-group of participants whose parents reported clinically significant parent-child conflict at intake, for whom high levels of parent-reported conflict predicted a lower likelihood of remission. Conflict also did not moderate treatment response.nnnCONCLUSIONSnRemission of depression may be sufficient to reduce parent-reported parent-child conflict. However, higher parent-reported conflict, in the clinically significant range, predicts a lower likelihood of remission from depression. Clinical trial registration information-Treatment of SSRI-Resistant Depression in Adolescents (TORDIA); http://clinicaltrials.gov/; NCT00018902.

Adjunctive Sleep Medications and Depression Outcome in the Treatment of Serotonin-Selective Reuptake Inhibitor Resistant Depression in Adolescents Study

OBJECTIVEnIn the Treatment of Resistant Depression in Adolescents, study participants who received medication for sleep had a lower response rate. This report sought to clarify this finding.nnnMETHODnDepressed adolescents who had not responded to a previous adequate serotonin-selective reuptake inhibitor (SSRI) trial were randomly assigned to another SSRI, venlafaxine, another SSRI+cognitive behavior therapy (CBT), or venlafaxine+CBT. Augmentation with sleep medication was permitted as clinically indicated.nnnRESULTSnYouth who received trazodone were six times less likely to respond than those with no sleep medication (adjusted odds ratio [OR]=0.16, 95% confidence interval [CI]: 0.05-0.50, p=0.001) and were three times more likely to experience self-harm (OR=3.0, 95% CI: 1.1-7.9, p=0.03), even after adjusting for baseline differences associated with trazodone use. None (0/13) of those cotreated with trazodone and either paroxetine or fluoxetine responded. In contrast, those treated with other sleep medications had similar rates of response (60.0% vs. 50.4%, χ(2)=0.85, p=0.36) and of self-harm events (OR=0.5, 95% CI: 0.1-2.6, p=0.53) as those who received no sleep medication.nnnCONCLUSIONSnThese findings should be interpreted cautiously because these sleep agents were not assigned randomly, but at clinician discretion. Nevertheless, they suggest that the use of trazodone for the management of sleep difficulties in adolescent depression should be re-evaluated and that future research on the management of sleep disturbance in adolescent depression is needed. The very low response rate of participants cotreated with trazodone and either fluoxetine or paroxetine could be due to inhibition of CYP 2D6 by these antidepressants.

The bidirectional relationship between body mass index and treatment outcome in adolescents with treatment-resistant depression

OBJECTIVEnDepression and obesity are associated, but the impact of obesity on depression treatment outcome, or, conversely, the impact of treatment on body mass index (BMI) in depressed adolescents has not been reported. In this article, we examine the bidirectional relationships between BMI and treatment response in adolescents with treatment-resistant depression.nnnMETHODnParticipants in the Treatment of Selective Serotonin Reuptake Inhibitor (SSRI) Resistant Depression in Adolescents (TORDIA) study had height and weight assessed at baseline, weekly for the first 6 weeks, biweekly for the next 6 weeks, and monthly from weeks 12 through 24. The impact of baseline BMI as a predictor and moderator of treatment response was assessed. In addition, participants changes in BMI were assessed as a function of specific treatment assignment and treatment response.nnnRESULTSnParticipants assigned to SSRIs had a greater increase in BMI-for-age-sex z-score and weight than did those assigned to venlafaxine. Post-hoc, those treated with paroxetine or citalopram had the biggest increases in BMI, relative to fluoxetine or venlafaxine. Overweight or obesity was neither a predictor nor a moderator of treatment outcome, nor of subsequent BMI change.nnnCONCLUSIONSnOverweight status does not appear to affect treatment response in adolescents with resistant depression. The successful treatment of depression does not appear to favorably affect weight or BMI. Fluoxetine and venlafaxine are less likely to cause an increase in BMI than paroxetine or citalopram.

Treatment of Early-Age Mania: Outcomes for Partial and Nonresponders to Initial Treatment

OBJECTIVEnThe Treatment of Early Age Mania (TEAM) study evaluated lithium, risperidone, and divalproex sodium (divalproex) in children with bipolar I disorder who were naive to antimanic medication, or were partial or nonresponders to 1 of 3 study medications. This report evaluates the benefit of either an add-on or a switch of antimanic medications for an 8-week trial period in partial responders and nonresponders, respectively.nnnMETHODnTEAM is a randomized, controlled trial of individuals (Nxa0= 379) aged 6 to 15 years (mean ± SDxa0= 10.2 ± 2.7 years) with DSM-IV bipolar I disorder (mixed or manic phase). Participants (nxa0= 154) in this report were either nonresponders or partial responders to 1 of the 3xa0study medications. Nonresponders (nxa0= 89) were randomly assigned to 1 of the other 2 antimanic medications and cross-tapered. Partial responders (nxa0= 65) were randomly assigned to 1 of 2 other antimanic medications as an add-on to their initial medication. Adverse event (AE) rates are reported only for the add-on group.nnnRESULTSnResponse rate for children switched to risperidone (47.6%) was higher than for those switched to eitherxa0lithium (12.8%; pxa0= .005; number needed to treat [NNT]xa0= 3; 95% CIxa0=xa01.71-9.09) or divalproex (17.2%; pxa0=xa0.03; NNTxa0= 3; 95% CIxa0= 1.79-20.10); response rate for partial responders who added risperidone (53.3%) was higher than for those who added divalproex (0%; pxa0=xa0.0002; NNTxa0= 2; 95% CIxa0= 1.27-3.56) and trended higher for lithium (26.7%; pxa0= .07; NNTxa0= 4). Reported AEs in the add-on group were largely consistent with the known AE profile for the second medication. Weight gain (kg) was observed for all add-on medications: lithium add-on (nxa0=xa029 of 30)xa0= 1.66 ± 1.97; risperidone add-on (nxa0= 15 of 15)xa0= 2.8 ± 1.34; divalproex add-on (nxa0= 19 of 20)xa0= 1.42 ± 1.96. There was no evidence at the 5% significance level that the average weight gain was different by study medication for partial responders (pxa0=xa0.07, 1-way analysis of variance).nnnCONCLUSIONnRisperidone appears to be more useful than lithium or divalproex for children with bipolar I disorder and other comorbid conditions who are nonresponders or partial responders to an initial antimanic medication trial. Clinical trial registration information-Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents (TEAM); http://clinicaltrials.gov/; NCT00057681.

Management of Treatment-Resistant Depression in Children and Adolescents

Depression is a relatively common diagnosis in children and adolescents, and is associated with significant morbidity and suicidality in this population. Evidence-based treatment of the acute illness is imperative to try to prevent the development of treatment-resistant depression or other complications. In situations where response to acute treatment is inadequate, clinicians should first consider factors that may influence outcome, such as psychiatric or medical comorbidities, psychosocial stressors, and treatment noncompliance. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for depression in children and adolescents. For treatment-resistant depression, a switch to an alternate SSRI is recommended before trials of other antidepressants. Psychotherapy, such as cognitive behavioral therapy or interpersonal therapy, may improve treatment response. More research is needed examining medication augmentation strategies for treatment-resistant depression in children and adolescents.