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.

Weekly links among irritability and suicidal thoughts and behaviors in high-risk youth.

BACKGROUND: Previous studies demonstrate a link between irritability and suicidal thoughts and behaviors (STBs) in youth samples. However, they have mostly assessed irritability in community samples and as a largely dispositional (i.e. trait-like) construct. Thus, it remains unclear to what extent links between irritability and STBs reflect within-person processes of elevated risk in clinically meaningful time periods. METHODS: The present study used clinical data from 689 adolescents aged 12-19 years attending a total of 6,128 visits at a specialty Intensive Outpatient Program for depressed and suicidal youth to examine patterns in weekly assessments of irritability and STBs throughout treatment, including associations among trends and fluctuations departing from these trends via multilevel structural equation modeling. Youth completed self-report measures of irritability, depression, and STBs weekly as part of standard IOP clinical care. RESULTS: Overall, two-thirds of variance in weekly irritable mood was accounted for by between-person differences and the remaining portion by weekly fluctuations. After controlling for depression, during weeks when youth were more irritable they experienced increased STBs. Rates of change in irritability and STBs tended to track together at early stages of treatment, but these effects were generally accounted for by depression severity. CONCLUSIONS: Our results suggest that although changes in STBs are best accounted for by depression, irritability can be understood as a specific, proximal risk factor for youth STBs that exacerbates youth STBs in clinically informative timeframes above and beyond depression.

Sleep influences daily suicidal ideation through affective reactivity to interpersonal events among high-risk adolescents and young adults.

BACKGROUND: Identifying proximal risk factors for suicidal ideation that are modifiable and relevant for adolescents and young adults is critical for suicide prevention. This study used an intensive monitoring approach to examine whether objectively- and subjectively- measured sleep characteristics predict next-day suicidal ideation occurrence and intensity through affective reactivity to interpersonal events in young people at high risk for suicide. METHODS: Participants included 59 (13-23 years; 76% White; 75% female) adolescents and young adults undergoing intensive outpatient program treatment for depression and suicidality. Participants completed daily ratings of suicidal ideation, sleep quality, and affective reactivity to positive and negative interpersonal events for up to 3 months (M = 56 days, SD = 24.13). Actigraphy captured behavioral sleep duration and timing. Multilevel modeling was used to evaluate within-person fluctuations in sleep and affective reactivity as predictors of suicidal ideation, and multilevel mediation tested the indirect effects of sleep on suicidal ideation via affective reactivity to interpersonal events. RESULTS: Results indicate significant indirect effects of objectively measured sleep duration and subjective sleep quality on next-day suicidal ideation via affective reactivity to negative and positive interpersonal events, respectively. Shorter-than-usual sleep predicted the presence and intensity of next-day suicidal ideation via heightened affective reactivity to negative interpersonal events. Worse sleep quality than usual predicted next-day suicidal ideation via reduced affective reactivity to positive interpersonal events. CONCLUSIONS: Affectivity reactivity is a proximal mechanism through which sleep indices may influence risk for suicidal thinking on a daily basis. Findings highlight the utility of targeting sleep and emotion regulation in suicide prevention among adolescents and young adults at high-risk for suicide.

Early indicators of bipolar risk in preschool offspring of parents with bipolar disorder.

BACKGROUND: Offspring of parents with bipolar disorder (BD-I/II) are at increased risk to develop the disorder. Previous work indicates that bipolar spectrum disorder (BPSD) is often preceded by mood/anxiety symptoms. In school-age offspring of parents with BD, we previously built a risk calculator to predict BPSD onset, which generates person-level risk scores. Here, we test whether preschool symptoms predict school-age BPSD risk. METHODS: We assessed 113 offspring of parents with BD 1-3 times during preschool years (2-5 years old) and then approximately every 2 years for a mean of 10.6 years. We used penalized (lasso) regression with linear mixed models to assess relationships between preschool mood, anxiety, and behavioral symptoms (parent-reported) and school-age predictors of BPSD onset (i.e., risk score, subthreshold manic symptoms, and mood lability), adjusting for demographics and parental symptomatology. Finally, we conducted survival analyses to assess associations between preschool symptoms and school-age onset of BPSD and mood disorder. RESULTS: Of 113 preschool offspring, 33 developed new-onset mood disorder, including 19 with new-onset BPSD. Preschool irritability, sleep problems, and parental factors were lasso-selected predictors of school-age risk scores. After accounting for demographic and parental factors, preschool symptoms were no longer significant. Lasso regressions to predict mood lability and subthreshold manic symptoms yielded similar predictors (irritability, sleep problems, and parental affective lability), but preschool symptoms remained predictive even after adjusting for parental factors (ps < .005). Exploratory analyses indicated that preschool irritability univariately predicted new-onset BPSD (p = .02) and mood disorder (p = .02). CONCLUSIONS: These results provide initial prospective evidence that, as early as preschool, youth who will develop elevated risk scores, mood lability, and subthreshold manic symptoms are already showing symptomatology; these preschool symptoms also predict new-onset BPSD. While replication of findings in larger samples is warranted, results point to the need for earlier assessment of risk and development of early interventions.

Age Trends in Actigraphy and Self-Report Sleep Across the Life Span: Findings From the Pittsburgh Lifespan Sleep Databank.

OBJECTIVE: Sleep changes over the human life span, and it does so across multiple dimensions. We used individual-level cross-sectional data to characterize age trends and sex differences in actigraphy and self-report sleep dimensions across the healthy human life span. METHODS: The Pittsburgh Lifespan Sleep Databank consists of harmonized participant-level data from sleep-related studies conducted at the University of Pittsburgh (2003-2019). We included data from 1065 (n = 577 female; 21 studies) Pittsburgh Lifespan Sleep Databank participants aged 10 to 87 years without a major psychiatric, sleep, or medical condition. All participants completed wrist actigraphy and the self-rated Pittsburgh Sleep Quality Index. Main outcomes included actigraphy and self-report sleep duration, efficiency, and onset/offset timing, and actigraphy variability in midsleep timing. RESULTS: We used generalized additive models to examine potentially nonlinear relationships between age and sleep characteristics and to examine sex differences. Actigraphy and self-report sleep onset time shifted later between ages 10 and 18 years (23:03-24:10 [actigraphy]; 21:58-23:53 [self-report]) and then earlier during the 20s (00:08-23:40 [actigraphy]; 23:50-23:34 [self-report]). Actigraphy and self-report wake-up time also shifted earlier during the mid-20s through late 30s (07:48-06:52 [actigraphy]; 07:40-06:41 [self-report]). Self-report, but not actigraphy, sleep duration declined between ages 10 and 20 years (09:09-07:35). Self-report sleep efficiency decreased over the entire life span (96.12-93.28), as did actigraphy variability (01:54-01:31). CONCLUSIONS: Awareness of age trends in multiple sleep dimensions in healthy individuals-and explicating the timing and nature of sex differences in age-related change-can suggest periods of sleep-related risk or resilience and guide intervention efforts.

A risk calculator to predict suicide attempts among individuals with early-onset bipolar disorder.

OBJECTIVES: To build a one-year risk calculator (RC) to predict individualized risk for suicide attempt in early-onset bipolar disorder. METHODS: Youth numbering 394 with bipolar disorder who completed ≥2 follow-up assessments (median follow-up length = 13.1 years) in the longitudinal Course and Outcome of Bipolar Youth (COBY) study were included. Suicide attempt over follow-up was assessed via the A-LIFE Self-Injurious/Suicidal Behavior scale. Predictors from the literature on suicidal behavior in bipolar disorder that are readily assessed in clinical practice were selected and trichotomized as appropriate (presence past 6 months/lifetime history only/no lifetime history). The RC was trained via boosted multinomial classification trees; predictions were calibrated via Platt scaling. Half of the sample was used to train, and the other half to independently test the RC. RESULTS: There were 249 suicide attempts among 106 individuals. Ten predictors accounted for >90% of the cross-validated relative influence in the model (AUC = 0.82; in order of relative influence): (1) age of mood disorder onset; (2) non-suicidal self-injurious behavior (trichotomized); (3) current age; (4) psychosis (trichotomized); (5) socioeconomic status; (6) most severe depressive symptoms in past 6 months (trichotomized none/subthreshold/threshold); (7) history of suicide attempt (trichotomized); (8) family history of suicidal behavior; (9) substance use disorder (trichotomized); (10) lifetime history of physical/sexual abuse. For all trichotomized variables, presence in the past 6 months reliably predicted higher risk than lifetime history. CONCLUSIONS: This RC holds promise as a clinical and research tool for prospective identification of individualized high-risk periods for suicide attempt in early-onset bipolar disorder.

Smartphone-based interventions in bipolar disorder: Systematic review and meta-analyses of efficacy. A position paper from the International Society for Bipolar Disorders (ISBD) Big Data Task Force.

BACKGROUND: The clinical effects of smartphone-based interventions for bipolar disorder (BD) have yet to be established. OBJECTIVES: To examine the efficacy of smartphone-based interventions in BD and how the included studies reported user-engagement indicators. METHODS: We conducted a systematic search on January 24, 2022, in PubMed, Scopus, Embase, APA PsycINFO, and Web of Science. We used random-effects meta-analysis to calculate the standardized difference (Hedges' g) in pre-post change scores between smartphone intervention and control conditions. The study was pre-registered with PROSPERO (CRD42021226668). RESULTS: The literature search identified 6034 studies. Thirteen articles fulfilled the selection criteria. We included seven RCTs and performed meta-analyses comparing the pre-post change in depressive and (hypo)manic symptom severity, functioning, quality of life, and perceived stress between smartphone interventions and control conditions. There was significant heterogeneity among studies and no meta-analysis reached statistical significance. Results were also inconclusive regarding affective relapses and psychiatric readmissions. All studies reported positive user-engagement indicators. CONCLUSION: We did not find evidence to support that smartphone interventions may reduce the severity of depressive or manic symptoms in BD. The high heterogeneity of studies supports the need for expert consensus to establish ideally how studies should be designed and the use of more sensitive outcomes, such as affective relapses and psychiatric hospitalizations, as well as the quantification of mood instability. The ISBD Big Data Task Force provides preliminary recommendations to reduce the heterogeneity and achieve more valid evidence in the field.

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.

Longitudinal course and risk factors associated with psychosis in bipolar youths.

OBJECTIVES: To compare the longitudinal clinical course of youths with bipolar disorder (BD) spectrum with lifetime (past, intake, and/or follow-up) psychosis (BDP+) to youths with BD without lifetime psychosis (BDP-). Also, to identify risk factors associated with increased risk of first onset of psychosis during prospective follow-up. METHOD: Bipolar disorder youths (BDP+ = 137, BDP- = 233), aged 7-17 years old, were followed on average every 7 months for 11.7 years and were evaluated using standardized instruments. Data were analyzed using linear and generalized linear models for the full sample, as well as for youths who developed first period of psychosis (n = 55). RESULTS: After adjusting for confounders, BDP+ youths with one, and in particular ≥2 lifetime psychotic episodes, had higher rates and more severe mood and anxiety symptoms, higher rates of suicidality, psychiatric hospitalizations, and sexual/physical abuse, and poorer psychosocial functioning than BDP- youths. Even before the first onset of psychosis during follow-up, BDP+ youths showed more psychopathology and had more family history of psychiatric illness than those who never developed psychosis. First-onset psychosis was associated with low socioeconomic status (SES), living with one parent, bipolar disorder type one and type two, comorbid anxiety, history of hospitalizations, and family history of mania and suicidality. CONCLUSION: BDP+ is associated with poor prognosis and worse clinical picture, even before the onset of psychosis, indicating the need for prompt identification and treatment of these youths. Studies aimed to treat acute symptoms of psychosis, as well as prevent the onset of psychosis, including risk factors amenable to change, are warranted.

Sleep and Parasympathetic Activity During Rest and Stress in Healthy Adolescents and Adolescents With Bipolar Disorder.

OBJECTIVE: Sleep disruption contributes to the pathophysiology of mental disorders, particularly bipolar illness, but the biobehavioral mechanisms of this relationship are insufficiently understood. This study evaluated sleep duration, timing, and variability as prospective predictors of parasympathetic nervous system activity during rest and social stress in adolescents with bipolar disorder, reflecting sleep-related interference in stress regulatory systems that may confer vulnerability to mood episodes. METHOD: Participants were adolescents with bipolar disorder (n = 22) and healthy adolescents (n = 27). Sleep duration and timing were measured by actigraphy for 1 week before a laboratory social stress task, during which high-frequency heart rate variability (HF-HRV) was indexed using electrocardiography. Multilevel models were used to evaluate group, sleep characteristics, and their interactions as predictors of initial HF-HRV and change in HF-HRV during rest and stress. RESULTS: Associations between group and changes in HF-HRV during stress were moderated by sleep duration mean (z = 2.24, p = .025) and variability (z = -2.78, p = .006). There were also main effects of mean sleep duration on initial HF-HRV during rest (z = -5.37, p < .001) and stress (z = -2.69, p = .007). Follow-up analyses indicated that, in bipolar adolescents during stress, shorter and longer sleep durations were associated with lower initial HF-HRV (z = -5.44, p < .001), and greater variability in sleep duration was associated with less change in HF-HRV (z = -2.18, p = .029). CONCLUSIONS: Sleep durations that are relatively short or long, which are characteristic of mood episodes, are associated with parasympathetic vulnerability to social stress in adolescents with bipolar disorder. Obtaining regular sleep of moderate duration may favorably affect responses to stress in bipolar youth.

Cognitive control under stressful conditions in transitional age youth with bipolar disorder: Diagnostic and sleep-related differences in fronto-limbic activation patterns.

OBJECTIVES: Adults with bipolar disorder (BD) display aberrant activation in fronto-limbic neural circuitry during cognitive control. However, fronto-limbic response to cognitive control, and factors destabilizing this circuitry, remain under-studied during the transition from adolescence to young adulthood in BD. Sleep patterns are disturbed in BD, undergo change in adolescence, and support brain function. Among transitional age youth, BD diagnosis and sleep (duration and variability) were tested as predictors of fronto-limbic response to a stressful cognitive control task. METHODS: Two groups of youth (13-22 years old) participated: 15 with BD type I, II or not otherwise specified (NOS) [BD; age 18.1 ± 2.7 years (mean ± standard deviation, SD); 17 female] and 25 healthy controls [CTL; age 19.4 ± 2.7 years (mean ± SD); 17 female]. Sleep was monitored with actigraphy for at least 1 week prior to an adaptive multi-source interference functional magnetic resonance imaging (fMRI) paradigm (a Stroop-like cognitive interference task). Group status and sleep duration (average and intra-individual variability) were examined as predictors of activation in response to incongruent>congruent trials within the bilateral amygdala, anterior cingulate (ACC), ventrolateral prefrontal and dorsolateral prefrontal cortical regions of interest. RESULTS: The BD group displayed greater right amygdala activation than the CTL group. Average sleep duration and rostroventral ACC (rvACC) activity were negatively associated in the CTL group, but exhibited a quadratic relationship in the BD group such that short and long sleep were related to greater rvACC activation. Sleep duration variability and dorsal ACC activity were negatively associated in the BD group, and unrelated in the CTL group. Findings remained significant after controlling for age, sex, and mood symptoms. CONCLUSIONS: Subjects with BD displayed a hyper-limbic response during cognitive control, and sleep was a source of variability in ACC engagement. Stabilizing sleep may be one avenue for improving cognitive control in BD.

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.

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.

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.