Social impairment in relation to clinical symptoms in youth at high risk for bipolar disorder.

AIM: Social impairment is common in individuals with bipolar disorder (BD), although its role in youths at high-risk for BD (i.e., mood symptoms in the context of a family history of BD) is not well understood. Social impairment takes many forms including social withdrawal, relational aggression, physical aggression, and victimization. The aim of this study was to explore the links between social impairment and clinical symptoms in youth at high-risk for BD. METHODS: The sample included 127 youths with elevations in mood symptoms (depression or hypomania) and at least one first and/or second degree relative with BD. Measures of youths' current psychopathology (i.e., depressive and manic severity, suicidality, anxiety, and attention-deficit/hyperactivity disorder [ADHD]) were regressed onto youths' self-reports of social impairment (i.e., social withdrawal, relational aggression, physical aggression, and victimization). RESULTS: Depressive symptoms, suicidal ideation, and anxiety symptoms were related to social withdrawal. Suicidal ideation was also related to reactive aggression. ADHD symptoms related to reactive and proactive aggression as well as relational victimization. Manic symptoms were not associated with social impairment in this sample. CONCLUSIONS: Although cross-sectional, study findings point to potential treatment targets related to social functioning. Specifically, social withdrawal should be a target for treatment of childhood depressive and anxiety symptoms. Treatments that focus on social skills and cognitive functioning deficits associated with BD may also have clinical utility.

Effects of Family-Focused Therapy vs Enhanced Usual Care for Symptomatic Youths at High Risk for Bipolar Disorder: A Randomized Clinical Trial.

Importance: Behavioral high-risk phenotypes predict the onset of bipolar disorder among youths who have parents with bipolar disorder. Few studies have examined whether early intervention delays new mood episodes in high-risk youths. Objective: To determine whether family-focused therapy (FFT) for high-risk youths is more effective than standard psychoeducation in hastening recovery and delaying emergence of mood episodes during the 1 to 4 years after an active period of mood symptoms. Design, Settings, and Participants: This multisite randomized clinical trial included referred youths (aged 9-17 years) with major depressive disorder or unspecified (subthreshold) bipolar disorder, active mood symptoms, and at least 1 first- or second-degree relative with bipolar disorder I or II. Recruitment started from October 6, 2011, and ended on September 15, 2016. Independent evaluators interviewed participants every 4 to 6 months to measure symptoms for up to 4 years. Data analysis was performed from March 13 to November 3, 2019. Interventions: High-risk youths and parents were randomly allocated to FFT (12 sessions in 4 months of psychoeducation, communication training, and problem-solving skills training; n = 61) or enhanced care (6 sessions in 4 months of family and individual psychoeducation; n = 66). Youths could receive medication management in either condition. Main Outcomes and Measures: The coprimary outcomes, derived using weekly psychiatric status ratings, were time to recovery from prerandomization symptoms and time to a prospectively observed mood (depressive, manic, or hypomanic) episode after recovery. Secondary outcomes were time to conversion to bipolar disorder I or II and longitudinal symptom trajectories. Results: All 127 participants (82 [64.6%] female; mean [SD] age, 13.2 [2.6] years) were followed up for a median of 98 weeks (range, 0-255 weeks). No differences were detected between treatments in time to recovery from pretreatment symptoms. High-risk youths in the FFT group had longer intervals from recovery to the emergence of the next mood episode (χ2 = 5.44; P = .02; hazard ratio, 0.55; 95% CI, 0.48-0.92;), and from randomization to the next mood episode (χ2 = 4.44; P = .03; hazard ratio, 0.59; 95% CI, 0.35-0.97) than youths in enhanced care. Specifically, FFT was associated with longer intervals to depressive episodes (log-rank χ2 = 6.24; P = .01; hazard ratio, 0.53; 95% CI, 0.31-0.88) but did not differ from enhanced care in time to manic or hypomanic episodes, conversions to bipolar disorder, or symptom trajectories. Conclusions and Relevance: Family skills-training for youths at high risk for bipolar disorder is associated with longer times between mood episodes. Clarifying the relationship between changes in family functioning and changes in the course of high-risk syndromes merits future investigation. Trial Registration: ClinicalTrials.gov identifier: NCT01483391.

Correction.

This corrects the article DOI: 10.4088/JCP.09m05885blu.​​.

Diagnostic profiles and clinical characteristics of youth referred to a pediatric mood disorders clinic.

OBJECTIVES: This study examined the diagnostic profiles and clinical characteristics of youth (ages 6-18 years) referred for diagnostic evaluation to a pediatric mood disorders clinic that specializes in early-onset bipolar disorder. METHOD: A total of 250 youth were prescreened in an initial telephone intake, and 73 participated in a full diagnostic evaluation. Trained psychologists administered the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADSPL) to the child and to at least one parent, and a child psychiatrist conducted a separate pharmacological evaluation. Evaluators then met with a larger clinical team for a consensus diagnosticconference. RESULTS: Based on consensus diagnoses, 13 of the 73 referred youth (18%) met lifetime DSM-IV-TR criteria for a bipolar spectrum disorder (BSD; bipolar I, II or not otherwise specified disorder, or cyclothymic disorder). Of these 73, 27 (37%) were referred with a community diagnosis of a bipolar spectrum disorder, but only 7 of these 27 (26%) met DSM-IV-TR criteria for a bipolar spectrum diagnosis based on a structured interview and consensus diagnoses. The most common Axis I diagnoses (based on structured interview/consensus) were attentiondeficit/hyperactivity disorder (31/73, 42.5%) and major depressive disorder (23/73, 32%). CONCLUSIONS: When youth referred for evaluation of BSD are diagnosed using standardized interviews with multiple reporters and consensus conferences, the "true positive" rate for bipolar spectrum diagnoses is relatively low. Reasons for the discrepancy between community and research-based diagnoses of pediatric BSD- including the tendency to stretch the BSD criteria to include children with depressive episodes and only 1-2 manic symptoms-are discussed.

Incremental cost-effectiveness of combined therapy vs medication only for youth with selective serotonin reuptake inhibitor-resistant depression: treatment of SSRI-resistant depression in adolescents trial findings.

CONTEXT: Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs), and this is associated with higher costs. More effective treatment for these youth may be cost-effective. OBJECTIVE: To evaluate the incremental cost-effectiveness over 24 weeks of combined cognitive behavior therapy plus switch to a different antidepressant medication vs medication switch only in adolescents who continued to have depression despite adequate initial treatment with an SSRI. DESIGN: Randomized controlled trial. SETTING: Six US academic and community clinics. PATIENTS: Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression. INTERVENTION: Participants were randomly assigned to (1) switch to a different medication only or (2) switch to a different medication plus cognitive behavior therapy. MAIN OUTCOME MEASURES: Clinical outcomes were depression-free days (DFDs), depression-improvement days (DIDs), and quality-adjusted life-years based on DFDs (DFD-QALYs). Costs of intervention, nonprotocol services, and families were included. RESULTS: Combined treatment achieved 8.3 additional DFDs (P = .03), 0.020 more DFD-QALYs (P = .03), and 11.0 more DIDs (P = .04). Combined therapy cost $1633 more (P = .01). Cost per DFD was $188 (incremental cost-effectiveness ratio [ICER] = $188; 95% confidence interval [CI], -$22 to $1613), $142 per DID (ICER = $142; 95% CI, -$14 to $2529), and $78,948 per DFD-QALY (ICER = $78,948; 95% CI, -$9261 to $677,448). Cost-effectiveness acceptability curve analyses suggest a 61% probability that combined treatment is more cost-effective at a willingness to pay $100,000 per QALY. Combined treatment had a higher net benefit for subgroups of youth without a history of abuse, with lower levels of hopelessness, and with comorbid conditions. CONCLUSIONS: For youth with SSRI-resistant depression, combined treatment decreases the number of days with depression and is more costly. Depending on a decision maker's willingness to pay, combined therapy may be cost-effective, particularly for some subgroups. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00018902.

Long-term outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor treatment: a follow-up study of the TORDIA sample.

BACKGROUND: We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, a randomized trial of 334 adolescents (aged 12-18 years) with DSM-IV-defined major depressive disorder initially resistant to selective serotonin reuptake inhibitor (SSRI) treatment who were subsequently treated for 12 weeks with another SSRI, venlafaxine, another SSRI + cognitive-behavioral therapy (CBT), or venlafaxine + CBT. Responders then continued with the same treatment through week 24, while nonresponders were given open treatment. METHOD: For the current study, patients were reassessed 48 (n = 116) and 72 (n = 130) weeks from intake. Data were gathered from February 2001 to February 2007. Standardized diagnostic interviews and measures of depression, suicidal ideation, related psychopathology, and level of functioning were periodically administered. Remission was defined as ≥ 3 weeks with ≤ 1 clinically significant symptom and no associated functional impairment (score of 1 on the adolescent version of the Longitudinal Interval Follow-Up Evaluation [A-LIFE]), and relapse, as ≥ 2 weeks with probable or definite depressive disorder (score of 3 or 4 on the A-LIFE). Mixed-effects regression models were applied to estimate remission, relapse, and functional recovery. RESULTS: By 72 weeks, an estimated 61.1% of the randomized youths had reached remission. Randomly assigned treatment (first 12 weeks) did not influence remission rate or time to remission, but the group assigned to SSRIs had a more rapid decline in self-reported depressive symptoms and suicidal ideation than those assigned to venlafaxine (P < .03). Participants with more severe depression, greater dysfunction, and alcohol or drug use at baseline were less likely to remit. The depressive symptom trajectory of the remitters diverged from that of nonremitters by the first 6 weeks of treatment (P < .001). Of the 130 participants in remission at week 24, 25.4% relapsed in the subsequent year. CONCLUSIONS: While most adolescents achieved remission, more than one-third did not, and one-fourth of remitted patients experienced a relapse. More effective interventions are needed for patients who do not show robust improvement early in treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00018902.

An emergency department intervention for linking pediatric suicidal patients to follow-up mental health treatment.

OBJECTIVE: Suicide is the third leading cause of death among adolescents. Many suicidal youths treated in emergency departments do not receive follow-up treatment as advocated by the National Strategy for Suicide Prevention. Two strategies for improving rates of follow-up treatment were compared. METHODS: In a randomized controlled trial, suicidal youths at two emergency departments (N=181; ages ten to 18) were individually assigned between April 2003 and August 2005 to one of two conditions: an enhanced mental health intervention involving a family-based cognitive-behavioral therapy session designed to increase motivation for follow-up treatment and safety, supplemented by care linkage telephone contacts after emergency department discharge, or usual emergency department care enhanced by provider education. Assessments were conducted at baseline and approximately two months after discharge from the emergency department or hospital. The primary outcome measure was rates of outpatient mental health treatment after discharge. RESULTS: Intervention patients were significantly more likely than usual care patients to attend outpatient treatment (92% versus 76%; p=.004). The intervention group also had significantly higher rates of psychotherapy (76% versus 49%; p=.001), combined psychotherapy and medication (58% versus 37%; p=.003), and psychotherapy visits (mean 5.3 versus 3.1; p=.003). Neither the emergency department intervention nor community outpatient treatment (in exploratory analyses) was significantly associated with improved clinical or functioning outcomes. CONCLUSIONS: Results support efficacy of the enhanced emergency department intervention for improving linkage to outpatient mental health treatment but underscore the need for improved community outpatient treatment to prevent suicide, suicide attempts, and poor clinical and functioning outcomes for suicidal youths treated in emergency departments.

A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder.

OBJECTIVE: This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD). METHOD: Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes. RESULTS: Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p = .01), with a suggested trend for catechol-O-methyltransferase (COMT) (p = .04). Gene × dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p = .008), DRD4 exon 3 VNTR (p = .006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p = .02). Irritability was predicted by COMT (p = .02). Vegetative symptoms were predicted by 5HTTLPR (p = .003). No significant effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25). CONCLUSIONS: This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene × dose interactive effects.

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.