Joan Rosenbaum Asarnow

Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression: The TORDIA Randomized Controlled Trial

CONTEXT Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy. OBJECTIVE To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006. INTERVENTIONS Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy. MAIN OUTCOME MEASURES Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Childrens Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. RESULTS Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medication switch alone (40.5%; 95% CI, 33%-48%; P = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%-55%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment. CONCLUSIONS For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00018902.

Psychiatric Comorbidity in Children after the 1988: Earthquake in Armenia

OBJECTIVE To determine current rates of posttraumatic stress disorder (PTSD), depressive disorder, and separation anxiety disorder (SAD) among children 1 1/2 years after the 1988 earthquake in Armenia; to determine current rates of comorbid PTSD and depressive disorder; and to assess the contribution of exposure, gender, loss of family members, and loss of residence. METHOD Two hundred eighteen school-age children from three cities at increasing distances from the epicenter were evaluated using the Child Posttraumatic Stress Disorder Reaction Index, the Depression Self-Rating Scale, and the section on SAD from the Diagnostic Interview for Children and Adolescents. RESULTS On the basis of these evaluations, high rates of current PTSD, depressive disorder, and their co-occurrence were found among victims residing in the two heavily impacted cities. SAD was comparatively less frequent, although symptoms of SAD had been pervasive throughout the region. Severity of posttraumatic stress and depressive reactions were highly correlated. Extent of loss of family members was independently correlated with each. CONCLUSION After a catastrophic natural disaster, children are at risk for comorbid PTSD and secondary depression. Based on the findings, an interactive model is proposed of postdisaster psychopathology. Early clinical intervention is recommended to prevent chronic posttraumatic stress reactions and secondary depression.

Suicide attempts and nonsuicidal self-injury in the treatment of resistant depression in adolescents: Findings from the TORDIA study

OBJECTIVE To evaluate the clinical and prognostic significance of suicide attempts (SAs) and nonsuicidal self-injury (NSSI) in adolescents with treatment-resistant depression. METHOD Depressed adolescents who did not improve with an adequate SSRI trial (N = 334) were randomized to a medication switch (SSRI or venlafaxine), with or without cognitive-behavioral therapy. NSSI and SAs were assessed at baseline and throughout the 24-week treatment period. RESULTS Of the youths, 47.4% reported a history of self-injurious behavior at baseline: 23.9% NSSI alone, 14% NSSI+SAs, and 9.5% SAs alone. The 24-week incidence rates of SAs and NSSI were 7% and 11%, respectively; these rates were highest among youths with NSSI+SAs at baseline. NSSI history predicted both incident SAs (hazard ratio [HR]= 5.28, 95% confidence interval [CI] = 1.80-15.47, z = 3.04, p = .002) and incident NSSI (HR = 7.31, z = 4.19, 95% CI = 2.88-18.54, p < .001) through week 24, and was a stronger predictor of future attempts than a history of SAs (HR = 1.92, 95% CI = 0.81-4.52, z = 2.29, p = .13). In the most parsimonious model predicting time to incident SAs, baseline NSSI history and hopelessness were significant predictors, adjusting for treatment effects. Parallel analyses predicting time to incident NSSI through week 24 identified baseline NSSI history and physical and/or sexual abuse history as significant predictors. CONCLUSIONS NSSI is a common problem among youths with treatment-resistant depression and is a significant predictor of future SAs and NSSI, underscoring the critical need for strategies that target the prevention of both NSSI and suicidal behavior. CLINICAL TRIAL REGISTRATION INFORMATION Treatment of SSRI-Resistant Depression in Adolescents (TORDIA). URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00018902.

Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5–10% of children and adolescents and persisting into adulthood in 30–50% or more of cases.1,2 Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity.3–5 Because stimulant intervention is effective in reducing ADHD symptoms in about 70–80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups.6–8 In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues9 found an increase of a 7-repeat variant of a 48-bp VNTR in exon 310 among ADHD subjects compared to controls. Swanson and colleagues11 replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT)12 and a mean test of identity-by-descent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.13

Family-expressed emotion, childhood-onset depression, and childhood-onset schizophrenia spectrum disorders: Is expressed emotion a nonspecific correlate of child psychopathology or a specific risk factor for depression?

Expressed emotion (EE) was examined, using the brief Five Minute Speech Sample measure, in families of (1) children with depressive disorders, (2) children with schizophrenia spectrum disorders, and (3) normal controls screened for the absence of psychiatric disorder. Consistent with the hypothesis of some specificity in the association between EE and the form of child disorder, rates of EE were significantly higher among families of depressed children compared to families of normal controls and families of children with schizophrenia spectrum disorders. Within the depressed group, the presence of a comorbid disruptive behavior disorder was associated with high levels of critical EE, underscoring the need to attend to comorbid patterns and subtypes of EE in future research.

Predictors of Spontaneous and Systematically Assessed Suicidal Adverse Events in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study

OBJECTIVE The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment. METHOD Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants. RESULTS Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events. CONCLUSIONS Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to self-harm events requires further study and clinical caution.

Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response.

OBJECTIVE To advance knowledge regarding strategies for treating selective serotonin reuptake inhibitor (SSRI)-resistant depression in adolescents, we conducted a randomized controlled trial evaluating alternative treatment strategies. In primary analyses, cognitive-behavioral therapy (CBT) combined with medication change was associated with higher rates of positive response to short-term (12-week) treatment than medication alone. This study examines predictors and moderators of treatment response, with the goal of informing efforts to match youths to optimal treatment strategies. METHOD Youths who had not improved during an adequate SSRI trial (N = 334) were randomized to an alternative SSRI, an alternative SSRI plus CBT, venlafaxine, or venlafaxine plus CBT. Analyses examined predictors and moderators of treatment response. RESULTS Less severe depression, less family conflict, and absence of nonsuicidal self-injurious behavior predicted better treatment response status. Significant moderators of response to CBT + medication (combined) treatment were number of comorbid disorders and abuse history; hopelessness was marginally significant. The CBT/combined treatment superiority over medication alone was more evident among youths who had more comorbid disorders (particularly attention-deficit/hyperactivity disorder and anxiety disorders), no abuse history, and lower hopelessness. Further analyses revealed a stronger effect of combined CBT + medication treatment among youths who were older and white and had no nonsuicidal self-injurious behavior and longer prestudy pharmacotherapy. CONCLUSIONS Combined treatment with CBT and antidepressant medication may be more advantageous for adolescents whose depression is comorbid with other disorders. Given the additional costs of adding CBT to medication, consideration of moderators in clinical decision making can contribute to a more personalized and effective approach to treatment.

Depression in Child Psychiatric Inpatients: Cognitive and Attributional Patterns.

Cognitive and learned helplessness models of depression view maladaptive cognitive and attributional patterns as core features of depressive disorders. This study examined cognitive and attributional patterns in depressed children, nondepressed children, and a subgroup of remitting depressives who had histories of depression but were not reporting depressive symptoms when evaluated during the first 2 weeks of hospitalization. When compared with nondepressed controls, depressed children reported significantly more hopelessness, more negative self-perceptions, and negative self-perceptions across a wider variety of domains, and they displayed more dysfunctional attributional styles. While 55% of depressed children displayed pervasive maladaptive cognitive patterns, the other 45% of depressed children scored more similarly to nondepressed children, suggesting that childhood depressive disorders may be heterogeneous with respect to cognitive patterns. Contrary to the notion of traitlike depressive cognitive and attributional patterns that persist after the remission of depressive episodes, children with remitting depressions scored similarly to nondepressed children.

Anhedonia Predicts Poorer Recovery Among Youth With Selective Serotonin Reuptake Inhibitor Treatment–Resistant Depression

OBJECTIVE To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. METHOD The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication switch, or a medication switch plus CBT. This study examined five established symptom dimensions (Child Depression Rating Scale-Revised) at baseline as they predicted recovery over 24 weeks of acute and continuation treatment. The two indices of recovery that were evaluated were time to remission and number of depression-free days. RESULTS Multivariate analyses examining all five depression symptom dimensions simultaneously indicated that anhedonia was the only dimension to predict a longer time to remission, and also the only dimension to predict fewer depression-free days. In addition, when anhedonia and CDRS-total score were evaluated simultaneously, anhedonia continued to uniquely predict longer time to remission and fewer depression-free days. CONCLUSIONS Anhedonia may represent an important negative prognostic indicator among treatment-resistant depressed adolescents. Further research is needed to elucidate neurobehavioral underpinnings of anhedonia, and to test treatments that target anhedonia in the context of overall treatment of depression.

Integrated Medical-Behavioral Care Compared With Usual Primary Care for Child and Adolescent Behavioral Health: A Meta-analysis

IMPORTANCE Recent health care legislation and shifting health care financing strategies are transforming health and behavioral health care in the United States and incentivizing integrated medical-behavioral health care as a strategy for improving access to high-quality care for behavioral health conditions, enhancing patient outcomes, and containing costs. OBJECTIVE To conduct a systematic meta-analysis of randomized clinical trials to evaluate whether integrated medical-behavioral health care for children and adolescents leads to improved behavioral health outcomes compared with usual primary care. DATA SOURCES Search of the PubMed, MEDLINE, PsycINFO, and Cochrane Library databases from January 1, 1960, through December 31, 2014, yielded 6792 studies, of which 31 studies with 35 intervention-control comparisons and 13,129 participants met the study eligibility criteria. STUDY SELECTION We included randomized clinical trials that evaluated integrated behavioral health and primary medical care in children and adolescents compared with usual care in primary care settings that met prespecified methodologic quality criteria. DATA EXTRACTION AND SYNTHESIS Two independent reviewers screened citations and extracted data, with raw data used when possible. Magnitude and direction of effect sizes were calculated. MAIN OUTCOMES AND MEASURES Meta-analysis with a random effects model were conducted to examine an overall effect across all trials, and within intervention and prevention trials. Subsequent moderator analyses for intervention trials explored the relative effects of integrated care type on behavioral health outcomes. RESULTS Meta-analysis with a random-effects model indicated a significant advantage for integrated care interventions relative to usual care on behavioral health outcomes (d = 0.32; 95% CI, 0.21-0.44; P < .001). Moderator analyses indicated larger effects for treatment trials that targeted diagnoses and/or elevated symptoms (d = 0.42; 95% CI, 0.29-0.55; P < .001) relative to prevention trials (d = 0.07; 95% CI, -0.13 to 0.28; P = .49). The probability was 66% that a randomly selected youth would have a better outcome after receiving integrated medical-behavioral treatment than a randomly selected youth after receiving usual care. The strongest effects were seen for treatment interventions that targeted mental health problems and those that used collaborative care models. CONCLUSIONS AND RELEVANCE Our results, demonstrating the benefits of integrated medical-behavioral primary care for improving youth behavioral health outcomes, enhance confidence that the increased incentives for integrated health and behavioral health care in the US health care system will yield improvements in the health of children and adolescents.