White matter predictors of worsening of subthreshold hypomania severity in non-bipolar young adults parallel abnormalities in individuals with bipolar disorder.

BACKGROUND: Identifying neural predictors of worsening subthreshold hypomania severity can help identify risk of progression to BD. While diffusion Magnetic Resonance Imaging (dMRI) studies reported white matter microstructural abnormalities in tracts supporting emotional regulation in individuals with BD, it remains unknown whether similar patterns of white matter microstructure predict worsening of subthreshold hypomania severity in non-BD individuals. METHODS: dMRI data were collected in: 81 non-BD individuals recruited across a range of subthreshold depression and hypomania, and followed for six months; and independent samples of 75 BD and 58 healthy individuals. All individuals were assessed using standardized diagnostic assessments, mood and anxiety symptom rating scales. Global probabilistic tractography and a tract-profile approach examined fractional anisotropy (FA), a measure of fiber collinearity, in tracts supporting emotional regulation shown to have abnormalities in BD: forceps minor (FMIN), anterior thalamic radiation (ATR), cingulum bundle (CB), and uncinate fasciculus (UF). RESULTS: Lower FA in left CB (middle, ß = -0.22, P = 0.022; posterior, ß = -0.32, P < 0.001), right CB (anterior, ß = -0.30, P = 0.003; posterior, ß = -0.27, P = 0.005), and right UF (frontal, ß = -0.29, P = 0.002; temporal, ß = -0.40, P < 0.001) predicted worsening of subthreshold hypomania severity in non-BD individuals. BD versus healthy individuals showed lower FA in several of these segments: middle left CB (F = 8.7, P = 0.004), anterior right CB (F = 9.8, P = 0.002), and frontal right UF (F = 7.0, P = 0.009). Non-BD individuals with worsening 6-month hypomania had lower FA in these three segments versus HC and non-BD individuals without worsening hypomania, but similar FA to BD individuals. LIMITATIONS: Relatively short follow-up. CONCLUSIONS: White matter predictors of worsening subthreshold hypomania in non-BD individuals parallel abnormalities in BD individuals, and can guide early risk identification and interventions.

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.

A Longitudinal Study of Psychiatric Disorders in Offspring of Parents With Bipolar Disorder From Preschool to Adolescence.

OBJECTIVE: To compare the prevalence of psychopathology, particularly bipolar disorder (BD), between preschool offspring of parents with BD and community controls. METHOD: A total of 116 offspring of BD-I/II parents and 98 controls (53 parents with non-BD psychopathology and 45 healthy parents) were recruited at ages 2 to 5 years and followed on average 9.6 years (on average: 2-5: 1.6 times; after age 5: 4 times) (average ages at intake/last follow-up: 3.8/13.4, retention: 98%). Participants were evaluated with standardized instruments blinded to parental diagnoses. RESULTS: After adjusting for confounders, offspring of BD parents only showed more attention-deficit/hyperactivity disorder (ADHD) during ages 2 to 5 years than the other 2 groups. After age 5, offspring of BD parents did not differ from offspring of parents with non-BD psychopathology, but they had more anxiety, ADHD, and behavior problems than offspring of healthy parents. Only offspring of BD parents developed BD-I/II: 3.4% (n = 4) and BD-not-otherwise-specified (BD-NOS): 11.2% (n = 13), with mean onset ages 11.4 and 7.4, respectively. About 70% of offspring with BD had non-BD disorders before BD. Only ADHD, diagnosed before age 6 years, and early-onset parental BD were significantly associated with BD risk. CONCLUSION: Most offspring of BD parents did not develop BD, but they were at specific high risk for developing BD, particularly those with preschool ADHD and early-onset parental BD. BD symptoms were scarce during the preschool years and increased throughout the school age, mainly in the form of BD-NOS, a disorder that conveys poor prognosis and high risk to develop BD-I/II. Developing early interventions to delay or, ideally, to prevent its onset are warranted.

Mindfulness-based intervention to decrease mood lability in at-risk youth: Preliminary evidence for changes in resting state functional connectivity.

BACKGROUND: In youth at familial risk for bipolar disorder (BD), mood lability is an important precursor to BD onset. Previous work in adults indicates that mindfulness-based interventions (MBI) may improve emotion regulation, in part by increasing resting-state functional connectivity (rsFC) between posterior cingulate cortex (PCC) and executive control network (ECN). In this pilot study, we assessed effects of an MBI on PCC-ECN rsFC and mood lability in at-risk youth. METHODS: We recruited 35 youth (10-14 years old) with a first-degree family history of BD and mood lability, and 21 age-matched healthy controls. Eligible at-risk youth were scanned pre/post an 8-week MBI and assessed three months later. Healthy controls were scanned at matched timepoints but did not participate in the MBI. The MBI used age-appropriate strategies to promote non-judgmental, present-moment awareness. We assessed pre/post changes in PCC-ECN rsFC and how rsFC changes were related to mood outcomes. RESULTS: Twenty at-risk youth were scanned pre/post MBI; 16 had high-quality rsFC data. Following MBI, at-risk youth showed increased rsFC between PCC and left dorsolateral prefrontal cortex (DLPFC) (BA 9; k = 28; corrected p=.006); healthy controls did not show this increase. Following MBI, at-risk youth reported more mindfulness (F = 7.15, p=.003), less mood lability (F = 7.2, p=.002), and less suppression of negative emotions (F = 5.05, p=.01). PCC-DLPFC rsFC increases predicted less mood lability (t=-2.25, p=.04) and less emotion suppression (t=-2.75, p=.02) at follow-up. LIMITATIONS: Small sample and lack of a control intervention. CONCLUSIONS: PCC-DLPFC rsFC may be a clinically meaningful neural target of an MBI in at-risk youth, related to improvements in mood lability.

The impact of familial risk and early life adversity on emotion and reward processing networks in youth at-risk for bipolar disorder.

A recently developed risk calculator for bipolar disorder (BD) accounts for clinical and parental psychopathology. Yet, it is understood that both familial predisposition and early life adversity contribute to the development of BD. How the interplay between these two factors influence emotion and reward processing networks in youth at risk for BD remains unclear. In this exploratory analysis, offspring of BD parents performed emotion and reward processing tasks while undergoing a fMRI scan. Risk calculator score was used to assess risk for developing BD in the next 5 years. Environmental risk was tabulated using the Stressful Life Events Schedule (SLES). Emotion and reward processing networks were investigated for genetic and/or environment interactions. Interaction effects were found between risk calculator scores, negative SLES score and activity in right amygdala and bilateral fusiform gyri during the emotion processing task, as well as activity in the fronto-, striatal, and parietal regions during the reward processing task. Our findings are preliminary; however, they support the unique and interactive contributions of both familial and environmental risk factors on emotion and reward processing within OBP. They also identify potential neural targets to guide development of interventions for youth at greatest risk for psychiatric disorders.

Longitudinal Associations Between Sleep Patterns and Psychiatric Symptom Severity in High-Risk and Community Comparison Youth.

OBJECTIVE: Sleep disturbance may be involved in symptom progression across multiple domains of psychopathology and could represent a target for treatment development in youth. Our objective was to identify sleep patterns that longitudinally change in conjunction with psychiatric symptom severity in at-risk youth. METHOD: The study included 484 Pittsburgh Bipolar Offspring Study (BIOS) youth with at least 2 sleep assessments occurring between 10 and 18 years of age: 267 offspring of parents with bipolar I or II disorder and 217 community comparison offspring. Assessments occurred approximately every 2 years (mean number of assessments, 2.8 ± 0.8; mean follow-up duration, 3.8 ± 1.6 years). Offspring had a range of psychiatric diagnoses at baseline. Multivariate lasso regression was implemented to select offspring-reported sleep patterns associated with changes in five psychiatric symptom measures from baseline through last follow-up (mania, depression, mood lability, anxiety, inattention/externalizing). Analyses accounted for parent psychiatric diagnoses and offspring demographics, psychiatric diagnoses, and medications. RESULTS: Follow-up duration, baseline socioeconomic status, parental history of bipolar disorder, offspring attention-deficit/hyperactivity disorder, and disruptive behavior disorder, and five sleep patterns were identified as predictors of change in all five psychiatric symptom measures. Decreasing sleep duration, later sleep timing preference, longer sleep latency, increasing nighttime awakenings, and greater sleepiness over follow-up were associated with increasing severity the five psychiatric symptom outcomes over follow-up. These 10 predictors explained 16% of the variance in longitudinal psychiatric symptom change, 33% of which was accounted for by sleep predictors. CONCLUSION: A constellation of sleep features were associated with psychiatric symptom changes in youth, and may represent viable targets for future interventions.

A Longitudinal Study of Family Functioning in Offspring of Parents Diagnosed With Bipolar Disorder.

OBJECTIVE: To compare the longitudinal course of family functioning in offspring of parents with bipolar disorder (BD), offspring of parents with non-BD psychopathology, and offspring of healthy control (HC) parents. METHOD: Offspring of parents with BD (256 parents and 481 offspring), parents without BD (82 parents and 162 offspring), and HC parents (88 parents and 175 offspring) 7 to 18 years of age at intake, from the Bipolar Offspring Study (BIOS), were followed for an average of 4.3 years. Family functioning was evaluated using the child- and parent-reported Family Adaptability and Cohesion Scale-II and the Conflict Behavior Questionnaire. The data were analyzed using multivariate multilevel regression, generalized linear estimating equation models, and path analysis. RESULTS: Families of parents with BD and parents with non-BD psychopathology showed lower cohesion and adaptability and higher conflict compared with HC families. There were no significant differences in cohesion and adaptability between families of parents with psychopathology. The effect of parental psychopathology on family functioning was mediated by parental psychosocial functioning and, to a lesser extent, offspring disorders. In all 3 groups, parent-reported family conflict was significantly higher than child-reported conflict. Across groups, family cohesion decreased over follow-up, whereas conflict increased. CONCLUSION: Any parental psychopathology predicted family impairment. These results were influenced by the offspring's age and were mediated by parental psychosocial functioning and, to a lesser degree, by offspring psychopathology. These findings emphasize the need to routinely assess family functioning in addition to psychopathology and provide appropriate interventions to parents and offspring.

Psychotic-Like Experiences in Offspring of Parents With Bipolar Disorder and Community Controls: A Longitudinal Study.

OBJECTIVE: To compare the prevalence and risk factors associated with psychotic-like experiences (PLE) in offspring of parents with bipolar disorder (BP) and offspring of community control parents. METHOD: Delusional and hallucinatory subclinical psychotic experiences were evaluated at intake and longitudinally in a cohort study of 390 offspring of BP parents and 247 offspring of control parents; all offspring were between 6 and 18 years of age. The sample was followed up every 2.5 years on average for 8.3 years. Of the sample, 91.7% completed at least one follow-up. Risk factors at intake and at each assessment until the onset of PLE were analyzed using survival models. RESULTS: In all, 95 offspring (14.9%) reported PLE at some point of the study, 16.9% of BP parents and 11.7% of controls, without statistically significant differences. Psychotic disorders were less frequent, with 16 (2.5%) in both groups. During follow-up, three variables remained as the most significant associated with PLE in the multivariate models: (1) presence of any psychiatric disorder (hazard ratio [HR] = 3.1; p = .01); (2) low psychosocial functioning (HR = 2.94; p < .0001); and (3) current or past history of physical or sexual abuse (HR = 1.85; p = .04). There were no effects of any subtype of BP, IQ, history of medical illnesses, exposure to medications, or perinatal complications. CONCLUSION: In line with previous studies, PLE in our sample were relatively common, and were associated with higher morbidity during the follow-up. Contrary to the literature, neither family risk for bipolar nor early neurodevelopmental insults were associated with PLE.

Intrinsic functional connectivity correlates of person-level risk for bipolar disorder in offspring of affected parents.

Offspring of parents with bipolar disorder (OBP) are at increased risk to develop bipolar disorder (BD). Alterations in resting-state functional connectivity (rsFC) have been identified in OBP; however, replication has been limited and correlation with person-level risk is unknown. A recent study found reduced rsFC between left inferior frontal gyrus (IFG) and clusters in the left insula (LINS), lentiform nucleus (LENT), and midcingulate cortex (MCING) in OBP (Roberts et al. 2017); here, we aim to extend these findings to at-risk youth. We scanned a subset of the Pittsburgh Bipolar Offspring Study, a longitudinal study of OBP and community controls. Twenty-four OBP, 20 offspring of control parents with non-bipolar psychopathology (OCP), and 27 healthy controls (HC) had acceptable rsFC data. After preprocessing steps, we assessed group differences in seed-based rsFC between the IFG and target clusters (LINS, LENT, MCING) using multivariate regression. Next, we tested whether rsFC correlated with person-level risk score and with other dimensional measures. We did not find group differences in rsFC between IFG and target regions. Within OBP, risk score negatively correlated with IFG-LINS rsFC (p = 0.002). Across groups, mood lability correlated negatively with rsFC between IFG and target regions (p = 0.0002), due to negative correlation with IFG-LINS (p = 0.0003) and IFG-MCING (p = 0.001) rsFC. While group-level differences were not replicated, IFG-LINS rsFC was negatively correlated with a person-level risk score in OBP and with mood lability (a predictor of BD) across the sample. Thus, IFG-LINS rsFC might constitute a risk marker, within OBP, for the development of BD.

Assessment of a Person-Level Risk Calculator to Predict New-Onset Bipolar Spectrum Disorder in Youth at Familial Risk.

Importance: Early identification of individuals at high risk for the onset of bipolar spectrum disorder (BPSD) is key from both a clinical and research perspective. While previous work has identified the presence of a bipolar prodrome, the predictive implications for the individual have not been assessed, to date. Objective: To build a risk calculator to predict the 5-year onset of BPSD in youth at familial risk for BPSD. Design, Setting, and Participants: The Pittsburgh Bipolar Offspring Study is an ongoing community-based longitudinal cohort investigation of offspring of parents with bipolar I or II (and community controls), recruited between November 2001 and July 2007, with a median follow-up period of more than 9 years. Recruitment has ended, but follow-up is ongoing. The present analysis included offspring of parents with bipolar I or II (aged 6-17 years) who had not yet developed BPSD at baseline. Main Outcomes and Measures: This study tested the degree to which a time-to-event model, including measures of mood and anxiety, general psychosocial functioning, age at mood disorder onset in the bipolar parent, and age at each visit, predicted new-onset BPSD. To fully use longitudinal data, the study assessed each visit separately, clustering within individuals. Discrimination was measured using the time-dependent area under the curve (AUC), predicting 5-year risk; internal validation was performed using 1000 bootstrapped resamples. Calibration was assessed by comparing observed vs predicted probability of new-onset BPSD. Results: There were 412 at-risk offspring (202 [49.0%] female), with a mean (SD) visit age of 12.0 (3.5) years and a mean (SD) age at new-onset BPSD of 14.2 (4.5) years. Among them, 54 (13.1%) developed BPSD during follow-up (18 with BD I or II); these participants contributed a total of 1058 visits, 67 (6.3%) of which preceded new-onset BPSD within the next 5 years. Using internal validation to account for overfitting, the model provided good discrimination between converting vs nonconverting visits (AUC, 0.76; bootstrapped 95% CI, 0.71-0.82). Important univariate predictors of outcome (AUC range, 0.66-0.70) were dimensional measures of mania, depression, anxiety, and mood lability; psychosocial functioning; and parental age at mood disorder. Conclusions and Relevance: This risk calculator provides a practical tool for assessing the probability that a youth at familial risk for BPSD will develop new-onset BPSD within the next 5 years. Such a tool may be used by clinicians to inform frequency of monitoring and treatment options and for research studies to better identify potential participants at ultra high risk of conversion.

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 sleep phenotypes among offspring of bipolar parents and community controls.

BACKGROUND: Sleep disturbances are a prominent feature of bipolar disorder (BP). However, it remains unclear how sleep phenotypes may evolve among at-risk youth, and their relevance to BP onset. METHODS: Pittsburgh Bipolar Offspring Study (BIOS) offspring (ages 10-18) and their parents completed assessments approximately every two years pertaining to current psychopathology and offspring sleep habits. A latent transition analysis (LTA) identified latent sleep groups within offspring based on their ratings of six sleep domains using the School Sleep Habits Survey. Demographic and clinical characteristics were compared between sleep groups. Logistic regression tested links between sleep group and BP onset at the subsequent assessment. RESULTS: The LTA model identified latent groups of good, poor, and variable sleepers. We observed an overall trend of good sleep becoming variable, and then poor, as youth age. Offspring in the poor sleep group were more likely to have psychopathology. Adjusting for age and depression, poor sleepers had nearly twice the odds of developing BP relative to good (OR=1.99, CI=0.45-8.91) or variable (OR=2.03, CI=0.72-5.72) sleepers. LIMITATIONS: Limitations include the use of proximal sleep phenotypes to predict BP onset, and a self-report measure of sleep CONCLUSIONS: We found three non-overlapping sleep phenotype groups in a large sample of offspring of bipolar probands and offspring of demographically-matched community control parents. Clinicians should consider that youth will likely experience variable and/or poor sleep as they age, and that at-risk youth with poor sleep may be at increased risk of developing MDD and BP at their next assessment.

Psychometrics of the screen for adult anxiety related disorders (SCAARED)- A new scale for the assessment of DSM-5 anxiety disorders.

OBJECTIVE: To examine the psychometrics of the Screen for Adult Anxiety Related Disorders (SCAARED). METHODS: The SCAARED was adapted from the Screen for Child Anxiety Related Emotional Disorders. Participants (N=336) ages 18-27 years old were evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID). The SCAARED was completed at or within two-weeks before the SCID. The psychometrics of the SCAARED were analyzed using standard statistical analyses including principal components, and Receiver Operant Curve analyses. A replication was performed in an age/sex matched independent sample (N=158). RESULTS: The SCAARED showed four factors: somatic/panic/agoraphobia, generalized anxiety, separation anxiety, and social anxiety. The total and each factor scores demonstrated good internal consistency (α=0.86-0.97) and good discriminant validity between anxiety and other disorders and within anxiety disorders for generalized and social anxiety. Area Under the Curve for the total and each of the factor scores ranged between 0.72 and 0.84 (p<0.0001). These results were replicated in the independent sample. CONCLUSIONS: The SCAARED showed excellent psychometric properties supporting its use to screen adults for anxiety disorders, longitudinal studies following youth into adulthood and studies comparing child and adult populations. Further replication studies in larger community and clinical samples are indicated.

Categorical and dimensional psychopathology in Dutch and US offspring of parents with bipolar disorder: A preliminary cross-national comparison.

OBJECTIVE: Accumulating evidence suggests cross-national differences in adults with bipolar disorder (BD), but also in the susceptibility of their offspring (bipolar offspring). This study aims to explore and clarify cross-national variation in the prevalence of categorical and dimensional psychopathology between bipolar offspring in the US and The Netherlands. METHODS: We compared levels of psychopathology in offspring of the Pittsburgh Bipolar Offspring Study (n=224) and the Dutch Bipolar Offspring Study (n=136) (age 10-18). Categorical psychopathology was ascertained through interviews using the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS-PL), dimensional psychopathology by parental reports using the Child Behavior Checklist (CBCL). RESULTS: Higher rates of categorical psychopathology were observed in the US versus the Dutch samples (66% versus 44%). We found no differences in the overall prevalence of mood disorders, including BD-I or -II, but more comorbidity in mood disorders in US versus Dutch offspring (80% versus 34%). The strongest predictors of categorical psychopathology were maternal BD (OR: 1.72, p<.05), older age of the offspring (OR: 1.19, p<.05), and country of origin (US; OR: 2.17, p<.001). Regarding comorbidity, only country of origin (OR: 7.84, p<.001) was a significant predictor. In general, we found no differences in dimensional psychopathology based on CBCL reports. LIMITATIONS: Preliminary measure of inter-site reliability. CONCLUSIONS: We found cross-national differences in prevalence of categorical diagnoses of non-mood disorders in bipolar offspring, but not in mood disorder diagnoses nor in parent-reported dimensional psychopathology. Cross-national variation was only partially explained by between-sample differences. Cultural and methodological explanations for these findings warrant further study.

Preliminary investigation of the relationships between sleep duration, reward circuitry function, and mood dysregulation in youth offspring of parents with bipolar disorder.

BACKGROUND: Altered reward circuitry function is observed in individuals with bipolar disorder (BD) and their unaffected offspring (OBP). While OBP are at elevated risk for BD, modifiable risk factors that may exacerbate neural vulnerabilities in OBP remain under-characterized. As sleep loss is strongly linked to mania in BD, this study tested associations between sleep duration, reward circuitry function, and mood dysregulation in OBP. METHODS: Two groups of youth unaffected with BD (9-17yr) completed a number-guessing fMRI reward paradigm: 25 OBP and 21 age-sex-IQ-matched offspring of control parents with non-BD psychopathology (OCP), to differentiate risk for BD from risk for psychopathology more broadly. Regressions tested effects of group status, self-reported past-week sleep duration, and their interaction on neural activity and bilateral ventral striatum (VS) functional connectivity to win>control. Correlations with parent-reported mood dysregulation were assessed. RESULTS: Group effects were observed for right posterior insula activity (OCP>OBP) and VS-left posterior insula connectivity (OBP>OCP). Group⁎sleep duration interactions were observed for left dorsal anterior-mid-cingulate (daMCC) activity and VS-left anterior insula/ventrolateral prefrontal cortex (VLPFC) connectivity. Specifically, sleep duration and daMCC activity were positively related in OBP, but negatively related in OCP and sleep duration and VS-left anterior insula/VLPFC connectivity were negatively related in OBP, but positively in OCP. Additionally, increased VS-left posterior insula connectivity and VS-left anterior insula/VLPFC connectivity were associated with greater mood dysregulation in OBP only. LIMITATIONS: Cross-sectional design and small sample size. CONCLUSIONS: Altered reward-related VS-insula connectivity could represent a neural pathway underpinning mood dysregulation in OBP, and may be modulated by shortened sleep duration.

Toward the Definition of a Bipolar Prodrome: Dimensional Predictors of Bipolar Spectrum Disorders in At-Risk Youths.

OBJECTIVE: The authors sought to assess dimensional symptomatic predictors of new-onset bipolar spectrum disorders in youths at familial risk of bipolar disorder ("at-risk" youths). METHOD: Offspring 6-18 years old of parents with bipolar I or II disorder (N=359) and community comparison offspring (N=220) were recruited. At baseline, 8.4% of the offspring of bipolar parents had a bipolar spectrum disorder. Over 8 years, 14.7% of offspring for whom follow-up data were available (44/299) developed a new-onset bipolar spectrum disorder (15 with bipolar I or II disorder). Measures collected at baseline and follow-up were reduced using factor analyses, and factors (both at baseline and at the visit prior to conversion or last contact) were assessed as predictors of new-onset bipolar spectrum disorders. RESULTS: Relative to comparison offspring, at-risk and bipolar offspring had higher baseline levels of anxiety/depression, inattention/disinhibition, externalizing, subsyndromal manic, and affective lability symptoms. The strongest predictors of new-onset bipolar spectrum disorders were baseline anxiety/depression, baseline and proximal affective lability, and proximal subsyndromal manic symptoms (p<0.05). While affective lability and anxiety/depression were elevated throughout follow-up in those who later developed a bipolar spectrum disorder, manic symptoms increased up to the point of conversion. A path analysis supported the hypothesis that affective lability at baseline predicts a new-onset bipolar spectrum disorder in part through increased manic symptoms at the visit prior to conversion; earlier parental age at mood disorder onset was also significantly associated with an increased risk of conversion. While youths without anxiety/depression, affective lability, and mania (and with a parent with older age at mood disorder onset) had a 2% predicted chance of conversion to a bipolar spectrum disorder, those with all risk factors had a 49% predicted chance of conversion. CONCLUSIONS: Dimensional measures of anxiety/depression, affective lability, and mania are important predictors of new-onset bipolar spectrum disorders in at-risk youths. These symptoms emerged from among numerous other candidates, underscoring the potential clinical and research utility of these findings.

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.

Longitudinal trajectories of ADHD symptomatology in offspring of parents with bipolar disorder and community controls.

OBJECTIVE: To compare the psychopathology and longitudinal course of attention-deficit/hyperactivity disorder (ADHD) symptomatology and global functioning between the offspring with ADHD of parents with bipolar disorder and the offspring with ADHD of community control parents. METHOD: One hundred twenty-two offspring with ADHD of parents with bipolar disorder and 48 offspring with ADHD of control parents from the Pittsburgh Bipolar Offspring Study (BIOS) were included. DSM-IV lifetime psychiatric disorders were ascertained through the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). The outcome measures of ADHD symptoms were ascertained at intake and every other year for a period of 6 years using the ADHD section of the K-SADS-PL and the Disruptive Behavior Disorder rating scale (DBD). Global functioning was assessed using the Children's Global Assessment Scale (CGAS). RESULTS: The offspring with ADHD of parents with bipolar disorder showed higher lifetime prevalence of mood and anxiety disorders relative to the offspring with ADHD of control parents (P values ≤ .03). For both groups of offspring with ADHD, the hyperactivity, impulsivity, and total K-SADS-PL ADHD scores decreased over time (P values < .001) without differences between the 2 groups. There were no between- or within-group differences in the inattention scores over time. The DBD ADHD scores decreased with age in both groups (P values < .002) without differences between the 2 groups. For both groups of offspring with ADHD, the global functioning did not improve over time. CONCLUSIONS: Offspring with ADHD of parents with bipolar disorder have more psychopathology relative to offspring with ADHD of control parents. However, there were no differences in the developmental courses of ADHD symptomatology between these 2 groups of ADHD youth.

Altered amygdala-prefrontal response to facial emotion in offspring of parents with bipolar disorder.

This study aimed to identify neuroimaging measures associated with risk for, or protection against, bipolar disorder by comparing youth offspring of parents with bipolar disorder versus youth offspring of non-bipolar parents versus offspring of healthy parents in (i) the magnitude of activation within emotional face processing circuitry; and (ii) functional connectivity between this circuitry and frontal emotion regulation regions. The study was conducted at the University of Pittsburgh Medical Centre. Participants included 29 offspring of parents with bipolar disorder (mean age = 13.8 years; 14 females), 29 offspring of non-bipolar parents (mean age = 13.8 years; 12 females) and 23 healthy controls (mean age = 13.7 years; 11 females). Participants were scanned during implicit processing of emerging happy, sad, fearful and angry faces and shapes. The activation analyses revealed greater right amygdala activation to emotional faces versus shapes in offspring of parents with bipolar disorder and offspring of non-bipolar parents than healthy controls. Given that abnormally increased amygdala activation during emotion processing characterized offspring of both patient groups, and that abnormally increased amygdala activation has often been reported in individuals with already developed bipolar disorder and those with major depressive disorder, these neuroimaging findings may represent markers of increased risk for affective disorders in general. The analysis of psychophysiological interaction revealed that offspring of parents with bipolar disorder showed significantly more negative right amygdala-anterior cingulate cortex functional connectivity to emotional faces versus shapes, but significantly more positive right amygdala-left ventrolateral prefrontal cortex functional connectivity to happy faces (all P-values corrected for multiple tests) than offspring of non-bipolar parents and healthy controls. Taken together with findings of increased amygdala-ventrolateral prefrontal cortex functional connectivity, and decreased amygdala-anterior cingulate cortex functional connectivity previously shown in individuals with bipolar disorder, these connectivity patterns in offspring of parents with bipolar disorder may be risk markers for, rather than markers conferring protection against, bipolar disorder in youth. The patterns of activation and functional connectivity remained unchanged after removing medicated participants and those with current psychopathology from analyses. This is the first study to demonstrate that abnormal functional connectivity patterns within face emotion processing circuitry distinguish offspring of parents with bipolar disorder from those of non-bipolar parents and healthy controls.

Diagnostic Precursors to Bipolar Disorder in Offspring of Parents With Bipolar Disorder: A Longitudinal Study.

OBJECTIVE: The authors sought to identify diagnostic risk factors of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder ("high-risk offspring"). METHOD: High-risk offspring 6-18 years old (N=391) and demographically matched offspring (N=248) of community parents without bipolar disorder were assessed longitudinally with standardized diagnostic instruments by staff blind to parental diagnoses. Follow-up assessments were completed in 91% of the offspring (mean follow-up interval, 2.5 years; mean follow-up duration, 6.8 years). RESULTS: Compared with community offspring, high-risk offspring had significantly higher rates of subthreshold mania or hypomania (13.3% compared with 1.2%), manic, mixed, or hypomanic episodes (9.2% compared with 0.8%), and major depressive episodes (32.0% compared with 14.9%). They also had higher rates of attention deficit hyperactivity disorder (30.7% compared with 18.1%), disruptive behavior disorders (27.4% compared with 15.3%), anxiety disorders (39.9% compared with 21.8%), and substance use disorders (19.9% compared with 10.1%), but not unipolar major depressive disorder (major depression with no bipolarity; 18.9% compared with 13.7%). Multivariate Cox regressions showed that in the high-risk offspring, subthreshold manic or hypomanic episodes (hazard ratio=2.29), major depressive episodes (hazard ratio=1.99), and disruptive behavior disorders (hazard ratio=2.12) were associated with subsequent manic, mixed, or hypomanic episodes. Only subthreshold manic or hypomanic episodes (hazard ratio=7.57) were associated when analyses were restricted to prospective data. CONCLUSIONS: Subthreshold manic or hypomanic episodes were a diagnostic risk factor for the development of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder and should be a target for clinical assessment and treatment research. Major depressive episodes and disruptive behavior disorders are also indications for close clinical monitoring of emergent bipolarity in high-risk offspring.