High Risk For Bipolar Disorder Research Articles

Decision making and its associations to neurocognitive functions, psychopathology, and the home environment in seven-year-old children at familial high risk of schizophrenia or bipolar disorder: The Danish High Risk and Resilience Study VIA 7

Background: Slower and suboptimal decision making has been identified in adults with schizophrenia and bipolar disorder. Owing to the limited evidence on decision making in first-degree relatives, we aimed to investigate, whether alterations in decision making are present in young children at familial high risk of bipolar disorder or schizophrenia.Methods: In this population-based cohort study we assessed decision making in 197 children at familial high risk of schizophrenia (FHR-SZ), 115 children at familial high risk of bipolar disorder (FHR-BP), and 190 controls aged seven using the Cambridge Gambling Task. Potential associations to neurocognition, psychopathology, and the home environment were investigated.Results: Children at FHR-SZ or FHR-BP displayed intact decision making. Quality of decision making showed significant but weak cross-sectional associations to neurocognition and adequacy of the home environment. Associations to aspects of executive functions and the home environment differed across groups.Limitations: Due to the cross-sectional nature of this study, the predictive value of efficient and inefficient decision making remains to be investigated in planned follow-up studies of this cohort.Conclusions: Young children at FHR-SZ or FHR-BP do not differ from controls in decision making efficacy, which does not appear to be an early risk marker of bipolar disorder or schizophrenia. Decision making is weakly associated to neurocognition and the home environment, but not to general intelligence or psychopathology.

P.069 Effects of vortioxetine and agomelatine in the Differential Reinforcement of Low Rate (DRL) test in the rat

Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD.We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene.While viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortexSimilar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD.

Longitudinal trajectories of mood symptoms and global functioning in youth at high risk for bipolar disorder

BackgroundLittle is known about the longitudinal course of mood symptoms and functioning in youth who are at high risk for bipolar disorder (BD). Identifying distinct course trajectories and predictors of those trajectories may help refine treatment approaches. MethodsThis study examined the longitudinal course of mood symptoms and functioning ratings in 126 youth at high risk for BD based on family history and early mood symptoms. Participants were enrolled in a randomized trial of family-focused therapy and followed longitudinally (mean 2.0 years, SD = 53.6 weeks). ResultsUsing latent class growth analyses (LCGA), we observed three mood trajectories. All youth started the study with active mood symptoms. Following the index mood episode, participants were classified as having a “significantly improving course” (n = 41, 32.5% of sample), a “moderately symptomatic course” (n = 21, 16.7%), or a “predominantly symptomatic course” (n = 64, 50.8%) at follow-up. More severe depression, anxiety, and suicidality at the study's baseline were associated with a poorer course of illness. LCGA also revealed three trajectories of global functioning that closely corresponded to symptom trajectories; however, fewer youth exhibited functional recovery than exhibited symptomatic recovery. LimitationsMood trajectories were assessed within the context of a treatment trial. Ratings of mood and functioning were based on retrospective recall. ConclusionsThis study suggests considerable heterogeneity in the course trajectories of youth at high risk for BD, with a significant proportion (32.5%) showing long-term remission of symptoms. Treatments that enhance psychosocial functioning may be just as important as those that ameliorate symptoms in youth at risk for BD.

Changes in Intrinsic Brain Connectivity in Family-Focused Therapy Versus Standard Psychoeducation Among Youths at High Risk for Bipolar Disorder

We compared intrinsic network connectivity in symptomatic youths at high risk (HR) for bipolar disorder (BD) and healthy comparison (HC) youths. In HR youths, we also investigated treatment-related changes in intrinsic connectivity after family-focused therapy for high-risk youths (FFT-HR) vs standardized family psychoeducation. HR youths (N= 34; age 9-17 years; mean 14 years, 56% girls and 44% boys) with depressive and/or hypomanic symptoms and at least 1 first- or second-degree relative with BD I or II were randomly assigned to 4 months of FFT-HR (12 sessions of psychoeducation, communication, and problem-solving skills training) or enhanced care (EC; 3 family and 3 individual psychoeducation sessions). Before and after 4 months of treatment, participants underwent resting state functional magnetic resonance imaging (rs-fMRI). A whole-brain independent component analysis compared rs-fMRI networks in HR youths and 30 age-matched HC youths at a pretreatment baseline. Then we identified pretreatment to posttreatment (4-month) changes in network connectivity in HR youths receiving FFT-HR (n= 16) or EC (n= 18) and correlated these changes with depression improvement. At baseline, HR youths had greater connectivity between the ventrolateral prefrontal cortex (VLPFC) and the anterior default mode network (aDMN) than did HCs (p= .004). Over 4 months of treatment, FFT-HR-assigned HR youths had increased VLPFC-aDMN connectivity from pre- to posttreatment (p= .003), whereas HR youths in EC showed no significant change over time (p= .11) (treatment by time interaction, t31= 3.33, 95% CI= 0.27-1.14, p= .002]. Reduction in depression severity over 4 months inversely correlated with enhanced anterior DMN (r=-0.71) connectivity in the FFT-HR but not in the EC (r=-0.07) group (z=-2.17, p= .015). Compared to standard psychoeducation, FFT-HR is associated with stronger connectivity between the VLPFC and aDMN, suggesting possible enhancements of self-awareness, illness awareness, and emotion regulation. Early Intervention for Youth at Risk for Bipolar Disorder; https://clinicaltrials.gov/; NCT01483391.

Infection with Toxoplasma gondii increases the risk of psychiatric disorders in Taiwan: a nationwide population-based cohort study.

This study aimed to evaluate associations between toxoplasmosis and psychiatric disorders in Taiwan based on the National Health Insurance Research Database, Taiwan (1997-2013). Patients newly diagnosed with toxoplasmosis formed the case group (n = 259), and the control group included propensity-score matched patients without toxoplasmosis (n = 1036). The primary outcome was incidence of psychiatric disorders. Cox proportional hazards regression and stratified analyses were performed to examine risk of developing specific psychiatric disorders between patients with and without toxoplasmosis. Patients with toxoplasmosis had significantly higher incidence of psychiatric disorders than those without toxoplasmosis (P = 0.016). A significant difference was found in numbers of psychiatric disorders between the two groups during 14 years of follow-up (log-rank P < 0.001). Those with toxoplasmosis had significantly higher risk of bipolar disorder [adjusted hazard ratio (aHR = 3.60, 95% confidence interval (CI) = 2.07, 7.26), depression (aHR = 4.94, 95% CI = 2.15, 11.80) and anxiety (aHR = 5.36, 95% CI = 2.98, 25.88), but no significant between-group differences were found for schizophrenia and other psychiatric disorders. In conclusion, the present nationwide population-based analysis revealed that Toxoplasma gondii infection in Taiwan significantly increases the risk for developing bipolar disorder, depression and anxiety, but not for schizophrenia and other psychiatric disorders.

Effects of family-focused therapy on suicidal ideation and behavior in youth at high risk for bipolar disorder

BackgroundYouth who are at clinical and familial risk for bipolar disorder (BD) often have significant suicidal ideation (SI). In a randomized trial, we examined whether family-focused therapy (FFT) is associated with reductions in SI and suicidal behaviors in high-risk youth. MethodsParticipants (ages 9–17 years) met diagnostic criteria for unspecified BD or major depressive disorder with active mood symptoms and had at least one relative with BD type I or II. Participants were randomly allocated to 12 sessions in 4 months of FFT or 6 sessions in 4 months of psychoeducation (enhanced care, EC), with pharmacotherapy as needed. Clinician- and child-rated assessments of mood, suicidal thoughts and behaviors, and family conflict were obtained at baseline and 4-6 month intervals over 1-4 years. ResultsParticipants (N=127; mean 13.2±2.6 yrs., 82 female) were followed over an average of 105.9±64.0 weeks. Youth with high baseline levels of SI who received FFT had lower levels of (and fewer weeks with) SI at follow-up compared to youth with high baseline SI who received EC. Participants in FFT had longer intervals without suicidal behaviors than participants in EC. Youths’ ratings of family conflict significantly mediated the effects of treatment on SI at follow-up. LimitationsFamily conflict was based on questionnaires rather than observer ratings of family interactions. ConclusionsFamily psychoeducation with skill training can be an effective deterrent to suicidal thoughts and behaviors in youth at high risk for BD. Reducing parent/offspring conflict should be a central objective of psychosocial interventions for high-risk youth with SI.

Characteristics of youth at high risk for bipolar disorder compared to youth with bipolar I or II disorder

Significant efforts have been undertaken to characterize the phenomenology of the high-risk period for bipolar disorder (BD) through the examination of youth at familial risk (i.e., having a first- or second-degree relative with BD) or clinical high risk for the disorder (i.e., youth with BD Not Otherwise Specified [NOS] or major depressive disorder [MDD]). However, little is known about the phenomenology of youth at both familial and clinical high risk for BD. In this study, we examined the clinical and psychosocial characteristics of youth at familial and clinical high risk (HR) for BD, and compared these characteristics to those of youth with BD I and II. Both groups were recruited based on current, active mood symptoms from separate randomized trials of family therapy. A total of 127 HR youth were evaluated: 52 (40.9%) were diagnosed with BD-NOS and 75 (59.1%) were diagnosed with MDD. Compared to adolescents with BD I and II (n = 145), HR youth had higher rates of anxiety disorders, and comparable rates of attention-deficit/hyperactivity disorder and oppositional defiant disorder/conduct disorder. Manic symptom severity and psychosocial functioning were progressively more impaired consistent with diagnostic severity: BD I > BD II > BD-NOS > MDD. Nonetheless, HR youth exhibited depressive symptom severity that was comparable to adolescents with BD I. These results provide further support for the high rates of anxiety disorders and premorbid dysfunction in addition to active mood symptoms for youth at risk for BD, and suggest anxiety is an important phenomenological characteristic and treatment target in the high-risk period.

Validity of the Mood Disorder Questionnaire (MDQ) as a screening tool for bipolar spectrum disorders in anabaptist populations

The Mood Disorder Questionnaire (MDQ) is an established screening tool for bipolar spectrum disorders (BSD), but has not been validated in diverse populations and the best scoring method remains uncertain. This study assessed diagnostic validity of the MDQ among Anabaptists, an underserved population frequently involved in genetic research. 161 participants completed the MDQ and were diagnosed by a best-estimate final diagnosis (BEFD). Diagnostic agreements between alternate MDQ scoring methods and the BEFD were quantified using Cohen's Kappa (κ), sensitivity (α), and specificity (β). Scoring criteria evaluated included >7 simultaneous symptoms and at least moderate impairment, >7 simultaneous symptoms, with at least mild impairment, >7 symptoms only, with no further requirement, and three novel scoring methods that require >5 symptoms or fewer. Diagnostic agreement varied. The original method proved most specific but had the lowest κ and sensitivity. κ increased with more liberal scoring criteria, reaching a maximum under the lower-threshold symptom methods, with little loss of specificity in the 5-symptom method. Decreasing the symptom threshold below 5 conferred little or no benefit. These results support the diagnostic validity of the MDQ among this Anabaptist sample and suggest that a 5-symptom scoring method may increase diagnostic sensitivity in populations at high risk for bipolar disorder.

Effects of Family-Focused Therapy vs Enhanced Usual Care for Symptomatic Youths at High Risk for Bipolar Disorder

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. 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. 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. 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. 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. 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. 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. ClinicalTrials.gov identifier: NCT01483391.

Network analysis of mood symptoms in adolescents with or at high risk for bipolar disorder.

Network analyses of psychopathology examine the relationships between individual symptoms in an attempt to establish the causal interactions between symptoms that may give rise to episodes of psychiatric disorders. We conducted a network analysis of mood symptoms in adolescents with or at risk for bipolar spectrum disorders. The sample consisted of 272 treatment-seeking adolescents with or at high risk for bipolar disorder who had at least subsyndromal depressive or (hypo)manic symptoms. Based on symptom scores assessed via semi-structured interviews, we constructed the network of depressive and manic symptoms and identified the most central symptoms and symptom communities within the network. We used bootstrapping analyses to determine the reliability of network parameters. Symptoms within the depressive and manic mood poles were more related to each other than to symptoms of the opposing mood pole. Four communities were identified, including a depressive symptom community and three manic symptom communities. Fatigue and depressed mood were the strongest individual symptoms within the overall network (ie the most highly correlated with other symptoms), followed by motor hyperactivity. Mood lability and irritability were found to be "bridge" symptoms that connected the two mood poles. Symptoms of activity/energy (iefatigue and hyperactivity) and depressed mood are the most prominent mood symptoms among youth with bipolar spectrum disorders. Mood lability and irritability represent potential warning signs of emergent episodes of either polarity. Targeting these central and bridge symptoms would lead to more efficient assessments and therapeutic interventions for bipolar disorder.

31.2 UPDATE ON BORDERLINE PERSONALITY FEATURES IN YOUTH WITH BIPOLAR DISORDERS AND BIPOLAR OFFSPRING

Differentiating the bipolar disorders (BDs) from borderline personality disorder (BPD) can be challenging diagnostically, because certain symptoms and traits, such as depression, aggression, and interpersonal relationships, are common to both conditions. The fact that all individuals diagnosed with BD do not meet BPD criteria suggests that both unique and related facets of the 2 conditions exist. Identifying related and unrelated items between BD and BPD should improve diagnostic accuracy. In addition, assessing for BPD features in youths at high risk for bipolar disorder can be clinically relevant.

5. Emotion Network Predictors of Clinical Outcome in Youth at High Risk for Bipolar Disorder

Youth at familial risk for bipolar disorder (BD) have aberrant emotion-relevant networks. However, function of these networks leading to resilience versus the emergence of BD and other mood disorders in these high-risk youth is poorly understood.

Association of hysterectomy with bipolar disorder risk: A population-based cohort study.

Hormonal fluctuations may trigger the onset of bipolar disorder. We designed a longitudinal follow-up study to evaluate the association between hysterectomies and bipolar disorder risk. We conducted a large retrospective cohort study using Taiwan's National Health Insurance Research Database. A total of 4,337 women aged 30 to 50 years who underwent the hysterectomy during 2000-2013 were selected and 17,348 patients without hysterectomy were selected for comparison (1:4 match). Poisson regression analysis was used to calculate the incidence rate ratio (IRR) and 95% confidence interval (CI). During the follow-up of 7.93 years, 20 participants with hysterectomy and 28 without hysterectomy developed bipolar disorder. Receiving hysterectomy was associated with the risk of developing bipolar disorder (adjusted IRR = 2.80; 95% CI = 2.54-3.09). Women with hysterectomy had a higher risk of bipolar disorder in follow-up durations of <1 year (adjusted IRR = 2.18 with 95% CI = 1.94-1.45) and ≥1 year (adjusted IRR = 2.85 with 95% CI = 2.58-3.15). Endometriosis and Premarin use increased bipolar disorder incidence in the hysterectomy group (adjusted IRR = 3.17 [95% CI = 2.83-3.56] and 4.22 [95% CI = 3.71-4.80], respectively). This study concluded that women with hysterectomy have an increased risk of bipolar disorder. Endometriosis and hormone therapy may add to the risk of bipolar disorder after hysterectomy. Knowledge about how surgical or natural hormonal withdrawal influences mood is fundamental and emphasizes the importance of coordinated psychiatric and gynecological care.

Risk and coaggregation of major psychiatric disorders among first-degree relatives of patients with bipolar disorder: a nationwide population-based study.

Bipolar disorder is a highly heritable mental illness that transmits intergeneratively. Previous studies supported that first-degree relatives (FDRs), such as parents, offspring, and siblings, of patients with bipolar disorder, had a higher risk of bipolar disorder. However, whether FDRs of bipolar patients have an increased risk of schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) remains unclear. Among the entire population in Taiwan, 87 639 patients with bipolar disorder and 188 290 FDRs of patients with bipolar disorder were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with bipolar disorder. FDRs of patients with bipolar disorder were more likely to have a higher risk of major psychiatric disorders, including bipolar disorder (RR 6.12, 95% confidence interval (CI) 5.95-6.30), MDD (RR 2.89, 95% CI 2.82-2.96), schizophrenia (RR 2.64, 95% CI 2.55-2.73), ADHD (RR 2.21, 95% CI 2.13-2.30), and ASD (RR 2.10, 95% CI 1.92-2.29), than the total population did. These increased risks for major psychiatric disorders were consistent across different familial kinships, such as parents, offspring, siblings, and twins. A dose-dependent relationship was also found between risk of each major psychiatric disorder and numbers of bipolar patients. Our study was the first study to support the familial coaggregation of bipolar disorder with other major psychiatric disorders, including schizophrenia, MDD, ADHD, and ASD, in a Taiwanese (non-Caucasian) population. Given the elevated risks of major psychiatric disorders, the public health government should pay more attention to the mental health of FDRs of patients with bipolar disorder.

Sustained Attention and Interference Control Among 7-Year-Old Children With a Familial High Risk of Schizophrenia or Bipolar Disorder—A Nationwide Observational Cohort Study

BackgroundGiven the partially shared genetic liability between schizophrenia and bipolar disorder, we aimed to assess whether 7-year-old children with a familial high risk of schizophrenia or bipolar disorder display specific deficits of sustained attention and interference control compared with each other and with control children. MethodsAn observational cohort was identified through Danish registries and consisted of 522 children 7 years of age with no, one, or two parents with a diagnosis of schizophrenia or bipolar disorder. Control subjects were matched based on age, sex, and municipality. Sustained attention and interference control were assessed using Conners’ Continuous Performance Test II and a modified Eriksen flanker task. Assessors were blinded to group membership of participants. The effect of higher genetic loading was not considered in the statistical models owing to low numbers. ResultsAt 7 years of age, children with a familial high risk of schizophrenia displayed deficits of sustained attention and subtle deficits in interference control compared with control children and children with a familial high risk of bipolar disorder. Children with a familial high risk of bipolar disorder displayed similar abilities of sustained attention and interference control as control children except in terms of a lower accuracy. ConclusionsOur findings suggest distinct neurodevelopmental characteristics in middle childhood of sustained attention and interference control for children of parents with schizophrenia or bipolar disorder.

25.4 Pharmacotherapy in Youth at High Risk for Bipolar Disorder

25.4 Pharmacotherapy in Youth at High Risk for Bipolar Disorder

27.1 Family Approaches to Bipolar Disorder in Transitional Age Youth

Psychoeducation, communication skills training, problem solving, and parenting strategies may improve the course of early-onset bipolar disorder (BD). This presentation addresses complexities of conducting family-focused treatment (FFT) with adolescents and young adults (transitional-aged youth, or TAY) who have been diagnosed with or are at high risk for BD.

A Double-Blind and Placebo-Controlled Trial of Aripiprazole in Symptomatic Youths at Genetic High Risk for Bipolar Disorder.

To determine if acute treatment with aripiprazole (APZ) would be superior to treatment with placebo in reducing dysfunctional symptoms of elevated mood and/or irritability in symptomatic children and adolescents at familial high risk for bipolar disorder (BPD) whose mood episodes occur spontaneously. These are patients we have previously referred to as suffering from "cyclotaxia." This was single-site, randomized, double-blind, placebo-controlled outpatient clinical trial in which youths aged 5-17 years who met diagnostic criteria for either cyclothymic disorder (CYC) or BPD not otherwise specified (BP-NOS) were randomly assigned to receive either APZ or placebo. Eligible participants had at least one parent with BPD, another first- or second-degree relative afflicted with a mood disorder, and also had not responded to psychotherapy. Treatment with APZ was initiated at a dose of approximately 0.1 mg/kg/day and could be increased by approximately 0.05 mg/kg/day at each study visit. Patients were seen weekly for 4 weeks and then every other week thereafter for 12 weeks. The primary outcome measure was mean change from baseline on Young Mania Rating Scale (YMRS) total score. A total of 59 patients (30 APZ, 29 placebo) aged 11.8 (SD = 2.7) years were randomized and returned for at least one postbaseline assessment. The mean total daily doses of active APZ and placebo were 7.1 mg (SD = 3.7) and 7.4 mg (SD = 4.2), respectively. At the 12-week time point, APZ was superior to placebo on the primary outcome measure (p < 0.005). Most adverse events were mild and transient in nature. There was a significant difference in weight gain from baseline between patients who received APZ (2.3 kg [SD = 3.3]) and those who received placebo (0.7 kg [SD = 1.8]). This double-blind trial found that APZ was significantly more efficacious than placebo in reducing symptoms of mania in children and adolescents with cyclotaxia.

A Pharmacologic Algorithm for Youth Who Are at High Risk for Bipolar Disorder.

Depression and brief periods of manic symptoms are linked to a significant risk of progression to bipolar disorder (BD) in children who have a first-degree relative with BD I or II. However, little evidence exists to guide the pharmacologic management of children with these high-risk phenotypes. We propose a pharmacological treatment algorithm for high-risk youth and present results on its use in a study of children with a first-degree relative with BD. Subjects were 40 youth (mean 12.7 years, range 9-17 years) who had (1) a first-degree relative with lifetime history of BD I or II, (2) DSM-IV-TR diagnoses of BD not otherwise specified, major depressive disorder or cyclothymic disorder, and (3) active symptoms of depression, mania, or hypomania. Participants and their families were enrolled in a randomized trial examining the effects of two psychosocial interventions on the 1-year course of mood disorder. At study intake, participants received a psychiatric evaluation and were offered medications or had existing medications optimized to decrease symptom severity. During the 1-year study, psychiatrists treated participants using a medication algorithm to treat depressive or manic symptoms as well as comorbid anxiety and/or attention-deficit/hyperactivity disorder. At study entry, 25 of 40 (62.5%) of the participants were taking at least one psychiatric medication. At 1 year, nearly an identical proportion were taking medications (22 of 35, 63%). Independent ratings indicated that in 84.7% of the study visits, physicians maintained adherence to the algorithm. No patients experienced antidepressant- or stimulant-induced mania during the study. An algorithmic approach to pharmacologic interventions may aid in the management of youth (i.e., age <18) at high risk for BD. Future studies should compare outcomes in high-risk patients receiving algorithm-prescribed treatment versus those receiving treatment as usual. Early Family-Focused Treatment for Youth at Risk for Bipolar Disorder; www.clinicaltrials.gov/ ; NCT00943085.

Anomalous prefrontal-limbic activation and connectivity in youth at high-risk for bipolar disorder

ObjectiveAbnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD. MethodsWe examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene. ResultsWhile viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortex ConclusionsSimilar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD.