Sleep patterns among preschool offspring of parents with and without psychopathology: Association with the development of psychopathology in childhood.

BACKGROUND: Disturbed sleep during early childhood predicts social-emotional problems. However, it is not known how various early childhood sleep phenotypes are associated with the development of childhood psychopathology, nor whether these relationships vary as a function of parental psychopathology. We identified sleep phenotypes among preschool youth; examined whether these phenotypes were associated with child and parent factors; and determined if early sleep phenotypes predicted later childhood psychopathology. METHODS: Using data from the Pittsburgh Bipolar Offspring study, parents with bipolar disorder (BD), non-BD psychopathology, and healthy controls reported about themselves and their offspring (n = 218) when their children were ages 2-5. Offspring and parents were interviewed directly approximately every 2 years from ages 6-18. Latent class analysis (LCA) identified latent sleep classes; we compared these classes on offspring demographics, parental sleep variables, and parental diagnoses. Kaplan-Meier survival models estimated hazard of developing any new-onset Axis-I disorders, as well as BD specifically, for each class. RESULTS: The optimal LCA solution featured four sleep classes, which we characterized as (1) good sleep, (2) wake after sleep onset problems, (3) bedtime problems (e.g., trouble falling asleep, resists going to bed), and (4) poor sleep generally. Good sleepers tended to have significantly less parental psychopathology than the other three classes. Risk of developing new-onset Axis-I disorders was highest among the poor sleep class and lowest among the good sleep class. CONCLUSIONS: Preschool sleep phenotypes are an important predictor of the development of psychopathology. Future work is needed to understand the biopsychosocial processes underlying these trajectories.

Index depressive episode and antidepressant exposure were associated with illness characteristics of pediatric bipolar disorder.

OBJECTIVE: Pediatric bipolar disorder (PBD) is a serious, recurrent disorder leading to severe functional impairment. As a first mood episode, index episode could affect the long-term course of the illness. This study aimed to investigate the clinical characteristics of youth with PBD from our multicenter, nationwide, naturalistic follow-up samples and to identify (i) the effects of index mood episode and (ii) the effect of previous antidepressant treatments on the age at mania onset of PBD. METHOD: The study sample consisted of 271 youth with BD-I followed by the child and adolescent psychiatry clinics of seven different university hospitals and three research state hospitals, representing six geographic regions across Turkey. All diagnoses were made according to structured interviews, and all data were retrospectively obtained from clinical records by the clinicians. RESULTS: When patients with index depressive/mixed episodes (IDE, n=129) and patients with index (hypo)manic episodes (IME, n=142) were compared, the total number of mood episodes and rapid cycling feature were significantly higher in the IDE group than in the IME group. The Cox regression analysis adjusted for sociodemographic and illness characteristics revealed female adolescents in the IDE group treated with antidepressants were more likely to have an earlier onset of mania (hazard ratio=2.03, 95% confidence interval=1.31-3.12, p=0.001). CONCLUSION: This is the first large-scale nationwide follow-up study in Turkey that indicated prior antidepressant treatments were associated with an earlier onset of mania in youth, particularly in adolescent females. Larger prospective studies are needed to identify neurodevelopmental processes underlying PBD and initiate prevention approaches.

Prospectively ascertained mania and hypomania among young adults with child- and adolescent-onset bipolar disorder.

OBJECTIVES: While adults with bipolar disorder (BD) often report symptoms starting in childhood, continuity of mania and/or hypomania (mania/hypomania) from childhood to adulthood has been questioned. Using longitudinal data from the Course and Outcome of Bipolar Youth (COBY) study, we assessed threshold mania/hypomania in young adults who manifested BD as youth. METHODS: COBY is a naturalistic, longitudinal study of 446 youth with BD (84% recruited from outpatient clinics), 7-17 years old at intake, and over 11 years of follow-up. Focusing on youth with BD-I/II (n = 297), we examined adult mania/hypomania risk (>18 years old; mean 7.9 years of follow-up) according to child (<13 years old) versus adolescent (13-17 years old) onset. We next used penalized regression to test demographic and clinical predictors of young adult mania/hypomania. RESULTS: Most participants (64%) had child-onset mania/hypomania, 57% of whom also experienced mania/hypomania in adolescence. Among those who experienced an episode in adolescence, over 40% also had mania/hypomania during adulthood; the risk did not differ according to child versus adolescent onset. In contrast, 7% with mania/hypomania in childhood, but not adolescence, experienced mania/hypomania in adulthood. Family history (of mania and suicide attempts) predicted mania/hypomania in young adulthood (p-values <0.05); age of onset was not a significant predictor. Among participants with no mania/hypomania during adulthood, 53% (105/198) still experienced subthreshold manic episodes. DISCUSSION: We find substantial continuity across developmental stage indicating that, in this carefully characterized sample, children who experience mania/hypomania-particularly those who also experience mania/hypomania in adolescence-are likely to experience mania/hypomania in young adulthood.

A Bayesian multilevel analysis of the longitudinal associations between relationship quality and suicidal ideation and attempts among youth with bipolar disorder.

BACKGROUND: Youth with bipolar disorder (BD) are at high risk for suicidal thoughts and behaviors and frequently experience interpersonal impairment, which is a risk factor for suicide. Yet, no study to date has examined the longitudinal associations between relationship quality in family/peer domains and suicidal thoughts and behaviors among youth with BD. Thus, we investigated how between-person differences - reflecting the average relationship quality across time - and within-person changes, reflecting recent fluctuations in relationship quality, act as distal and/or proximal risk factors for suicidal ideation (SI) and suicide attempts. METHODS: We used longitudinal data from the Course and Outcome of Bipolar Youth Study (N = 413). Relationship quality variables were decomposed into stable (i.e., average) and varying (i.e., recent) components and entered, along with major clinical covariates, into separate Bayesian multilevel models predicting SI and suicide attempt. We also examined how the relationship quality effects interacted with age and sex. RESULTS: Poorer average relationship quality with parents (ß = -.33, 95% Bayesian highest density interval (HDI) [-0.54, -0.11]) or friends (ß = -.33, 95% HDI [-0.55, -0.11]) was longitudinally associated with increased risk of SI but not suicide attempt. Worsening recent relationship quality with parents (ß = -.10, 95% HDI [-0.19, -0.03]) and, to a lesser extent, friends (ß = -.06, 95% HDI [-0.15, 0.03]) was longitudinally associated with increased risk of SI, but only worsening recent relationship quality with parents was also associated with increased risk of suicide attempt (ß = -.15, 95% HDI [-0.31, 0.01]). The effects of certain relationship quality variables were moderated by gender but not age. CONCLUSIONS: Among youth with BD, having poorer average relationship quality with peers and/or parents represents a distal risk factor for SI but not suicide attempts. Additionally, worsening recent relationship quality with parents may be a time-sensitive indicator of increased risk for SI or suicide attempt.

Clinical, cortical thickness and neural activity predictors of future affective lability in youth at risk for bipolar disorder: initial discovery and independent sample replication.

We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.

Characteristics of depression among offspring at high and low familial risk of bipolar disorder.

OBJECTIVES: Having a parent with bipolar disorder (BP) is a very strong risk factor for developing BP. Similarly, depression among youth is a clinical risk factor for subsequent BP. We evaluated whether mood symptomatology in depressed youth is different between those at high and low familial risk to develop BP. METHODS: The most severe major depressive episode in BP offspring (N=61) and community control offspring (N=20) was evaluated using expanded depression and mania rating scales derived from the Schedule for Affective Disorders and Schizophrenia for Children Present Version. The results were adjusted for any between-group significant demographic differences and for multiple comparisons. RESULTS: The severity of depressive symptoms and the percentage of offspring with severe depressive symptoms, especially atypical depressive features, were significantly higher in the depressed offspring of BP parents compared to the depressed controls (Ps <.05). The depressive symptoms were helpful to identify a high-risk group (e.g., odds ratio [OR] for hypersomnia: 22.4, 95% confidence interval [CI]: 1.3-404, P=.04). In addition, there were significantly more depressed offspring of BP parents with subsyndromal manic symptoms than controls (52.5% vs 20%, OR: 4.2, 95% CI: 1.2-14.7, P<.01). CONCLUSIONS: Depressed BP offspring had more severe depression including atypical depressive symptoms, and were more likely to have subsyndromal mixed manic symptoms than depressed control offspring. Prospective studies to evaluate whether these youth are at high risk to develop BP are warranted. If replicated, the results of this study have important clinical (e.g., treatment of depression in depressed offspring of BP parents) and research implications.

Longitudinal cognitive trajectories and associated clinical variables in youth with bipolar disorder.

OBJECTIVE: There is substantial interest in delineating the course of cognitive functioning in bipolar (BP) youth. However, there are no longitudinal studies aimed at defining subgroups of BP youth based on their distinctive cognitive trajectories and their associated clinical variables. METHOD: Cognitive functioning was measured in 135 participants from the Course and Outcome of BP Youth (COBY) study using several subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Youth were prospectively evaluated three times on average every 13.75 months over 2.5 years. Clinical and functional outcomes were assessed using the Longitudinal Interval Follow-Up Evaluation (LIFE). RESULTS: Latent class growth analysis identified three longitudinal patterns of cognitive functioning based on a general cognitive index: class 1, "persistently high" (N=21; 15.6%); class 2, "persistently moderate" (N=82; 60.74%); and class 3, "persistently low" (N=32; 23.7%). All classes showed normal cognitive functioning when compared with the CANTAB normative data. After adjustment for confounders, youth from class 3 had a significantly greater percentage of time with overall, manic, and depressive syndromal symptoms than youth in the other two classes. Also, after adjustment for confounders, youth from class 3 had significantly poorer global, academic, and social functioning than youth from class 1. CONCLUSIONS: BP youth showed normal overall cognitive functioning that remained stable during the follow-up within each class. However, 24% of BP youth showed poorer cognitive functioning than the other BP youth. This subgroup had poorer mood course and functioning, and may benefit from cognitive remediation and early management with evidence-based pharmacological treatments.

Cognitive flexibility and performance in children and adolescents with threshold and sub-threshold bipolar disorder.

Greater understanding of cognitive function in children and adolescents with bipolar disorder (BD) is of critical importance to improve our ability to design targeted treatments to help with real-world impairment, including academic performance. We sought to evaluate cognitive performance among children with either BD type I, II, or "not otherwise specified" (NOS) participating in multi-site Course and Outcome of Bipolar Youth study compared to typically developing controls (TDC) without psychopathology. In particular, we sought to test the hypothesis that BD-I and BD-II youths with full threshold episodes of mania or hypomania would have cognitive deficits, including in reversal learning, vs. those BD-NOS participants with sub-threshold episodes and TDCs. N = 175 participants (BD-I = 81, BD-II = 11, BD-NOS = 28, TDC = 55) completed Cambridge Neuropsychological Automated Testing Battery (CANTAB) tasks. A priori analyses of the simple reversal stage of the CANTAB intra-/extra-dimensional shift task showed that aggregated BD-I/II participants required significantly more trials to complete the task than either BD-NOS participants with sub-syndromal manic/hypomanic symptoms or than TDCs. BD participants across sub-types had impairments in sustained attention and information processing for emotionally valenced words. Our results align with prior findings showing that BD-I/II youths with distinct episodes have specific alterations in reversal learning. More broadly, our study suggests that further work is necessary to see the interaction between neurocognitive performance and longitudinal illness course. Additional work is required to identify the neural underpinnings of these differences as targets for potential novel treatments, such as cognitive remediation.

Differences in sleep disturbances among offspring of parents with and without bipolar disorder: association with conversion to bipolar disorder.

OBJECTIVES: Disruptions in sleep and dysregulation in circadian functioning may represent core abnormalities in the pathophysiology of bipolar disorder (BP). However, it is not clear whether these dysfunctions are state or trait markers of BP. This report compared sleep and circadian phenotypes among three groups: offspring of parents with BP diagnosed with BP at intake (BP/OB; n = 47), offspring of parents with BP without BP at intake (non-BP/OB; n = 386), and offspring of matched control parents who did not have BP (controls; n = 301). We also examined the association of baseline sleep parameters with subsequent development of BP among the non-BP/OB group. METHODS: Pittsburgh Bipolar Offspring Study youth (ages 6-18 years) and their parents completed assessments every two years pertaining to the child's sleep and circadian phenotypes and current psychopathology. Mixed-effects models examined differences in baseline sleep and circadian variables among the three groups. RESULTS: BP/OB offspring who were in a mood episode differed significantly on sleep parameters from the non-BP/OB and the offspring of controls, such as having inadequate sleep. Mixed logistic regression procedures showed that baseline sleep and circadian variables, such as frequent waking during the night, significantly predicted the development of BP among non-BP/OB over longitudinal follow-up. CONCLUSIONS: While lifetime diagnostic status accounted for differences among the groups in sleep and circadian disturbances, psychopathology explained the differences even further. Additionally, sleep disturbance may be a prognostic indicator of the development of BP in high-risk youth. Future studies are required to further disentangle whether sleep and circadian disruption are state or trait features of BP.

The longitudinal course of sleep timing and circadian preferences in adults with bipolar disorder.

OBJECTIVES: To study the longitudinal course of sleep timing and circadian preferences in individuals with bipolar disorder (BP) compared to individuals with non-BP psychopathology and healthy controls. METHODS: Individuals with bipolar I and bipolar II disorder (n = 257), non-BP psychopathology (n = 105), and healthy controls (n = 55) (mean age 40.2 years, 21.3% male, 85.1% Caucasian) were followed on average every 27 months for a mean of four years. Sleep timing parameters and circadian preference were reported using the Sleep Timing Questionnaire and The Composite Scale for Morningness. Group comparisons were adjusted for multiple comparisons and between-group differences in demographic variables and psychopharmacological treatment. RESULTS: Regardless of their current mood state, individuals with BP showed more sleep onset latency (SOL), wakening after sleep onset (WASO), and evening preference in comparison to both individuals with non-BP psychopathology and healthy controls. Individuals with BP also showed less stability of bed and awakening times in comparison to the other two groups, though these results were dependent on mood state. Non-BP individuals only showed more WASO and less stability in bed and awakening times before work/school days than healthy controls. Adjusting for comorbid disorders yielded similar results. Within-group analyses found little to no effect of time and BP subtype on sleep timing and circadian preference. CONCLUSIONS: Disturbances of sleep timing are prominent in individuals with BP. These disturbances are worse during mood episodes, but still apparent during euthymic periods. Evening preference was not associated with polarity type, or mood state in BP, suggesting that this characteristic may be a trait marker.

Prospective longitudinal course of aggression among adults with bipolar disorder.

OBJECTIVES: Bipolar disorder (BP) has been associated with increased aggressive behaviors. However, all existing studies are cross-sectional and include forensic or inpatient populations and many do not take into account the effects of comorbid conditions. The goal of this study was to evaluate the longitudinal course of aggression among adult outpatients with BP compared with non-BP patients and healthy controls. METHODS: Subjects with bipolar I disorder (BP-I)/bipolar II disorder (BP-II) (n = 255), those with non-BP psychopathology (n = 85), and healthy controls (n = 84) (average 38.9 years, 78.7% female, and 84.9% Caucasian) were evaluated at intake and after two and four years of follow-up. Aggression was self-rated using the Aggression Questionnaire (AQ). Comparisons were adjusted for any significant demographic and clinical differences and for multiple comparisons. For subjects with BP, associations of AQ with subtype of BP, current versus past mood episodes, polarity and severity of the current episode, psychosis, and current pharmacological treatment were evaluated. RESULTS: In comparison with subjects with non-BP psychiatric disorders and healthy controls, subjects with BP showed persistently higher total and subscale AQ scores (raw and T-scores) during the four-year follow-up. There were no effects of BP subtype, severity or polarity of the current episode, psychosis, and current pharmacological treatments. Subjects in an acute mood episode showed significantly higher AQ scores than euthymic subjects. CONCLUSIONS: BP, particularly during acute episodes, is associated with increased self-reported verbal and physical aggression, anger, and hostility. These results provide further evidence of the need for treatments to prevent mood recurrences and prompt treatment of acute mood episodes in subjects with BP.

Dimensional psychopathology in preschool offspring of parents with bipolar disorder.

BACKGROUND: The purpose of this study is to compare the dimensional psychopathology, as ascertained by parental report, in preschool offspring of parents with bipolar disorder (BP) and offspring of community control parents. METHODS: 122 preschool offspring (mean age 3.3 years) of 84 parents with BP, with 102 offspring of 65 control parents (36 healthy, 29 with non-BP psychopathology), were evaluated using the Child Behavior Checklist (CBCL), the CBCL-Dysregulation Profile (CBCL-DP), the Early Childhood Inventory (ECI-4), and the Emotionality Activity Sociability (EAS) survey. Teachers' Report Forms (TRF) were available for 51 preschoolers. RESULTS: After adjusting for confounders, offspring of parents with BP showed higher scores in the CBCL total, externalizing, somatic, sleep, aggressive, and CBCL-DP subscales; the ECI-4 sleep problem scale; and the EAS total and emotionality scale. The proportion of offspring with CBCL T-scores ≥ 2 SD above the norm was significantly higher on most CBCL subscales and the CBCL-DP in offspring of parents with BP compared to offspring of controls even after excluding offspring with attention deficit hyperactivity disorder and/or oppositional defiant disorder. Compared to offspring of parents with BP-I, offspring of parents with BP-II showed significantly higher scores in total and most CBCL subscales, the ECI-4 anxiety and sleep scales and the EAS emotionality scale. For both groups of parents, there were significant correlations between CBCL and TRF scores (r = .32-.38, p-values ≤.02). CONCLUSIONS: Independent of categorical axis-I psychopathology and other demographic or clinical factors in both biological parents, preschool offspring of parents with BP have significantly greater aggression, mood dysregulation, sleep disturbances, and somatic complaints compared to offspring of control parents. Interventions to target these symptoms are warranted.

Dialectical Behavior Therapy for Adolescents With Bipolar Disorder: A Randomized Clinical Trial.

Importance: Early-onset bipolar disorder conveys substantial risk for suicide. No psychosocial intervention for this population expressly targets suicidal behavior. Objective: To determine whether dialectical behavior therapy (DBT) for adolescents with bipolar spectrum disorder is more effective than standard of care (SOC) psychotherapy in decreasing suicide attempts over 1 year. Design, Settings, and Participants: Adolescents aged 12 to 18 years diagnosed with bipolar spectrum disorder were recruited from a specialty outpatient psychiatric clinic between November 2014 and September 2019. Independent evaluators conducted quarterly assessments over 1 year with participants and parents. Data were analyzed from March 2021 to November 2022. Interventions: Participants were randomly assigned to 1 year of DBT (36 sessions; n = 47) or SOC psychotherapy (schedule clinically determined; n = 53). All youth received medication management via a flexible algorithm. Main Outcomes and Measures: Primary outcomes included suicide attempts over 1 year and mood symptoms and states (depression and hypomania/mania). Secondary analyses included moderation of DBT effects by history of suicide attempt and mediation through emotion dysregulation. Results: Of 100 included participants, 85 (85%) were female, and the mean (SD) age was 16.1 (1.6) years. Participants were followed up over a mean (SD) of 47 (14) weeks. Both treatment groups demonstrated significant and similar improvement in mood symptoms and episodes over 1 year (standardized depression rating scale slope, -0.17; 95% CI, -0.31 to -0.03; standardized mania rating scale slope, -0.24; 95% CI, -0.34 to -0.14). DBT and SOC participants reported similar suicide attempt rates at intake as measured on the Adolescent Longitudinal Follow-Up Evaluation (ALIFE; mean [SD] attempts, 2.0 [4.5] vs 1.8 [3.9], respectively; P = .80). DBT participants reported slightly more suicide attempts at intake as measured on the Columbia-Suicide Severity Rating Scale Pediatric Version (C-SSRS; mean [SD] attempts, 1.4 [3.6] vs 0.6 [0.9]; P = .02). DBT participants reported significantly fewer suicide attempts over follow-up compared with SOC participants via the ALIFE (mean [SD] attempts per follow-up period, 0.2 [0.4] vs 1.1 [4.3], controlling for baseline attempts: P = .03) and the C-SSRS (mean [SD] attempts per follow-up period, 0.04 [0.2] vs 0.10 [0.3], controlling for baseline attempts; P = .03). DBT was significantly more effective than SOC psychotherapy at decreasing suicide attempts over 1 year (ALIFE: incidence rate ratio [IRR], 0.32; 95% CI, 0.11-0.96; C-SSRS: IRR, 0.13; 95% CI, 0.02-0.78). Decreased rate of suicide attempts in DBT was moderated by presence of lifetime history of suicide attempt and time (IRR, 0.23; 95% CI, 0.13-0.44) and mediated by improvement in emotion dysregulation (IRR, 0.61; 95% CI, 0.42-0.89), particularly for those with high baseline emotion dysregulation (standardized ß, -0.59; 95% CI, -0.92 to -0.26). Conclusions and Relevance: In this randomized clinical trial, DBT demonstrated efficacy in decreasing suicide attempts among the high-risk population of adolescents with bipolar spectrum disorder. Trial Registration: ClinicalTrials.gov Identifier: NCT02003690.

Validation of a youth suicide risk calculator in an adult sample with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) conveys the highest risk of suicide of all mental disorders. We sought to externally validate a risk calculator (RC) of suicide attempts developed in youth with BD from the Course and Outcome of Bipolar Youth (COBY) study in an adult sample. METHODS: A prospective cohort of adults with BD from the National Institute of Mental Health Collaborative Depression Study (CDS; N = 427; mean (+/- SD) age at intake (36 +/- 13 years)) was secondarily analyzed to validate the COBY RC for one-year risk of suicide attempts/deaths. Nine of the ten predictor variables from the COBY RC were available in the CDS and used: age, age of mood disorder onset, first and second (partial) degree family history of suicide, history of psychotic symptoms, substance use disorder, prior suicide attempt, socioeconomic status, and non-suicidal self-injury (prospectively, incompletely at baseline). RESULTS: Over a mean (SD) follow-up of 19 (10) years, 29 % of the CDS sample attempted suicide. The RC predicted suicide attempts/deaths over one-year follow-up with an area under the receiver operating characteristic curve (AUC) of 0.78 (95 % CI 0.75-0.80). The RC performed slightly better in those with a younger age of mood disorder onset. LIMITATIONS: Clinical samples may limit generalizability; the RC does not assess more acute suicide risk. CONCLUSIONS: One-year risk of suicide attempts/deaths can be predicted with acceptable accuracy in youth and adults with BD, comparable to commonly used RCs to predict cardiovascular risk. This RC may help identify higher-risk individuals with BD for personalized treatment and research. https://cobysuicideattemptsrc.shinyapps.io/Shiny.

Controlled Study of Metabolic Syndrome Among Offspring of Parents With Bipolar Disorder.

Objectives: Bipolar disorder (BD) is highly heritable and associated with increased rates of metabolic syndrome (MetS). However, little is known about MetS in offspring of parents with BD. We therefore examined this topic in the Pittsburgh Bipolar Offspring Study cohort.Methods: Participants included 199 parents (n = 116 BD, diagnosed using DSM-IV; n = 83 non-BD) and 330 offspring (mean age 19.9 ± 5.3 years), including 198 high-risk offspring of parents with BD (n = 80 affected with a mood disorder) and 132 control offspring. We defined MetS and its components using International Diabetes Federation (IDF) guidelines (primary) and National Cholesterol Education Program (NCEP) guidelines (secondary). Multivariable analyses controlled for age and socioeconomic status in offspring. Sensitivity analyses controlled for psychotropic medications.Results: There was higher prevalence of MetS in parents with BD as compared to controls. NCEP-defined MetS was significantly more prevalent among affected high-risk offspring (16.3%) and controls (15.2%) vs unaffected high-risk offspring (6.0%; χ2 = 6.54, P = .04). There was greater mean number of MetS components (IDF: 1.7 ± 1.1; NCEP: 1.4 ± 1.0) among affected high-risk offspring vs unaffected high-risk offspring (IDF: 1.2 ± 1.0; NCEP: 1.0 ± 1.0) and controls (IDF: 1.3 ± 1.2; NCEP: 1.1 ± 1.1; IDF: H[2] = 10.26, P = .006; NCEP: H[2] = 9.18, P = .01). Most findings became nonsignificant in multivariable analyses. Some between-group results became nonsignificant after controlling for second-generation antipsychotics.Conclusions: This preliminary study found increased risk of MetS among affected high-risk offspring, which may be attributable to socioeconomic status. Prospective studies may determine timing of MetS onset in relation to mood disorder onset, and the role of socioeconomic status in moderating this association.

Neural markers of mania that distinguish inpatient adolescents with bipolar disorder from those with other psychopathology.

Pediatric bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders, a challenge which can result in delayed or incorrect interventions. Using neuroimaging we aimed to identify neural measures differentiating a rarified sample of inpatient adolescents with BD from other inpatient psychopathology (OP) and healthy adolescents (HC) during a reward task. We hypothesized reduced subcortical and elevated cortical activation in BD relative to other groups, and that these markers will be related to self-reported mania scores. We examined inpatient adolescents with diagnosis of BD-I/II (n = 29), OP (n = 43), and HC (n = 20) from the Inpatient Child and Adolescent Bipolar Spectrum Imaging study. Inpatient adolescents with BD showed reduced activity in right thalamus, left thalamus, and left amygdala, relative to inpatient adolescents with OP and HC. This reduced neural function explained 21% of the variance in past month and 23% of the variance in lifetime mania scores. Lower activity in regions associated with the reward network, during reward processing, differentiates BD from OP in inpatient adolescents and explains >20% of the variance in mania scores. These findings highlight potential targets to aid earlier identification of, and guide new treatment developments for, pediatric BD.

Mood lability among offspring of parents with bipolar disorder and community controls.

OBJECTIVES: Early identification of bipolar disorder (BP) symptomatology is crucial for improving the prognosis of this illness. Increased mood lability has been reported in BP. However, mood lability is ubiquitous across psychiatric disorders and may be a marker of severe psychopathology and not specific to BP. To clarify this issue, this study examined the prevalence of mood lability and its components in offspring of BP parents and offspring of community control parents recruited through the Pittsburgh Bipolar Offspring Study. METHODS: Forty-one school-age BP offspring of 38 BP parents, 257 healthy or non-BP offspring of 174 BP parents, and 192 offspring of 117 control parents completed a scale that was developed to evaluate mood lability in youth, i.e., the Children's Affective Lability Scale (CALS). RESULTS: A factor analysis of the parental CALS, and in part the child CALS, revealed Irritability, Mania, and Anxiety/Depression factors, with most of the variance explained by the Irritability factor. After adjusting for confounding factors (e.g., parental and offspring non-BP psychopathology), BP offspring of BP parents showed the highest parental and child total and factor scores, followed by the non-BP offspring of BP parents, and then the offspring of the controls. CONCLUSIONS: Mood lability overall and mania-like, anxious/depressed, and particularly irritability symptoms may be a prodromal phenotype of BP among offspring of parents with BP. Prospective studies are warranted to clarify whether these symptoms will predict the development of BP and/or other psychopathology. If confirmed, these symptoms may become a target of treatment and biological studies before BP develops.

Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth.

Importance: Establishing genetic contributions to the transmission of bipolar disorder (BD) from parents to offspring may inform the risk of developing this disorder and further serve to validate BD in youth. Objective: To evaluate the specific association of BD polygenic risk scores (PRSs) on the familial transmission and validity of pediatric BD. Design, Setting, and Participants: This community-based case-control longitudinal study (Pittsburgh Biological Offspring Study) included parents with BD I/II and their offspring and parents without BD (healthy or non-BD psychopathology) and their offspring. Participants were recruited between March 2001 and May 2007, and analysis took place from December 2020 to September 2021. Exposures: PRSs for BD, major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder. Main Outcomes and Measures: Participants were prospectively evaluated using standardized interviews blind to parental diagnosis. DNA was extracted from saliva and genotyped. PRSs were constructed based on independent large-scale genome-wide association studies. Results: A total of 156 parents with BD I/II and 180 parents without BD (mean [SD] age, 39.6 [7.9] years; 241 female [72%]) as well as 251 offspring of parents with BD and 158 offspring of parents without BD (mean [SD] age, 10.4 [4.7] years; 213 female [52%]) of European ancestry were analyzed. Participants were assessed a mean of 6.7 times during a mean (SD) of 13 (3.4) years of follow-up (84% retention). More offspring of parents with BD developed BD (58 [23.1%] vs 8 [5.1%]; P < .001) and depression (126 [50.2%] vs 52 [32.9%]; P < .001) compared with offspring of parents without BD. BD PRS was higher in both parents and offspring with BD than parents and offspring without BD (parents: odds ratio, 1.50; 95% CI, 1.19-1.89; P < .001; explained 4.8% of the phenotypic variance vs offspring: hazard ratio, 1.34; 95% CI, 1.03-1.7; P = .02; explained 5.0% of the phenotypic variance). BD PRS did not differ across BD subtypes. In a model combining parental and offspring BD PRS, the parental BD PRS association with offspring BD was fully mediated by offspring BD PRS (hazard ratio, 1.40; 95% CI, 1.05-1.86; P = .02). Parental BD had a stronger direct association than parental or offspring BD PRS with offspring BD risk (hazard ratio, 5.21; 95% CI, 1.86-14.62; P = .002), explaining 30% of the variance. Parental and offspring BD PRS explained 6% of the BD onset variance beyond parental diagnosis. There were no significant between-group differences in PRSs for major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder in parents or offspring and they were not significantly associated with BD onset. Conclusions and Relevance: The findings of this study add to the extant clinical validation of BD in youth. Parental BD and offspring BD PRS independently associated with the risk of BD in offspring. Although this is promising, the association of BD PRS was relatively small and cannot be used alone to determine BD risk until further developments occur.

Risk factors preceding new onset abuse among youth with bipolar disorder: A longitudinal prospective analysis.

BACKGROUND: Childhood abuse negatively impacts the course of Bipolar Disorder (BD). Yet, no study has examined risk factors associated with prospectively evaluated physical/sexual abuse, specifically, those preceding first abuse among BD youth. We investigate past/intake/follow-up factors preceding first physical/sexual abuse among BD youth. METHODS: Childhood-onset BD participants (n = 279 youth, mean age at intake = 12, mean length of follow-up = 12 years) enrolled in the Course and Outcome of Bipolar Youth (COBY) study. Demographic, clinical and family history variables were assessed every 7 months on average using Longitudinal Interval Follow-up Evaluation and Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL). Abuse was evaluated at intake using the K-SADS-PL, over follow-up with a Traumatic Events Screen. Family psychopathology was assessed using Family History Screen/Structured Clinical Interview for Diagnostic Statistical Manual-IV. RESULTS: Fifteen-percent of youth reported new-onset abuse during follow-up (62% physical, 26% sexual; 12% both). Intake predictors included more severe depressive symptoms (HR = 1.29), low socioeconomic-status (SES) in families with substance abuse (HR = 0.84) (physical abuse), and female sex (HR = 2.41) (sexual abuse). Follow-up predictors preceding physical abuse included: older age (HR = 1.42), disruptive disorders (HR = 1.39), and the interaction between low SES and family substance abuse (HR = 0.86). For sexual abuse, female sex (HR = 4.33) and a non-biologically related father presence in the household (HR = 2.76). Good relationships with friends (prospectively evaluated) protected against physical/sexual abuse (HR = 0.72/0.70, respectively). LIMITATIONS: Prospective data was gathered longitudinally but assessed retrospectively at every follow-up; perpetrator information and abuse severity were not available. CONCLUSIONS: Identifying factors temporally preceding new onset physical/sexual abuse may hold promise for identifying high-risk youth with BD.