Disturbed sleep as risk factor for the subsequent onset of bipolar disorder – Data from a 10-year prospective-longitudinal study among adolescents and young adults

There is ample data suggesting that individuals with bipolar disorder more frequently suffer from disturbed sleep even when euthymic. Since sleep is a process that is crucial for affective homeostasis, disturbed sleep in healthy individuals may be a risk factor for the subsequent onset of bipolar disorder. Utilizing data from a large cohort of adolescents and young adults, this study tests the hypothesis that disturbed sleep constitutes a risk factor for the later onset of bipolar disorder. A representative community sample of N = 3021 adolescents and young adults (baseline age 14–24) was assessed using the standardized Composite International Diagnostic Interview and followed-up prospectively up to 3 times over up to 10 years. Disturbed sleep at baseline was quantified utilizing the corresponding items from the self-report inventory SCL-90-R. The compound value (insomnia-score) as an ordinal parameter for the severity of sleep disturbances was used to assess associations with the incidence of bipolar disorder among participants free of major mental disorder at baseline (N = 1943) using odds ratios (OR) from logistic regressions. Analyses were adjusted for age, gender, parental mood disorder and lifetime alcohol or cannabis dependence. Poor sleep quality significantly increased the risk for the subsequent development of bipolar disorder (OR = 1.75; p = 0.001). Regarding individual sleep items, trouble falling asleep and early morning awakening were predictive for the subsequent onset of bipolar disorder.Disturbed sleep in persons otherwise free of major mental disorders appears to confer an increased risk for the subsequent onset of bipolar disorder.     

Sleep and circadian alterations in people at risk for bipolar disorder: A systematic review

BackgroundSleep and circadian abnormalities have been mostly demonstrated in bipolar patients. However, it is not clear whether these alterations are present in population at high risk for bipolar disorder (BD), indicating a possible risk factor for this condition.ObjectiveThis systematic review aims to define current evidence about sleep and rhythm alterations in people at risk for BD and to evaluate sleep and circadian disorders as risk factor for BD.MethodsThe systematic review included all articles about the topic until February 2016. Two researchers performed an electronic search of PubMed and Cochrane Library. Keywords used were ‘sleep’ or ‘rhythm’ or ‘circadian’ AND ‘bipolar disorder’ or ‘mania’ or ‘bipolar depression’ AND ‘high-risk’ or ‘risk’.ResultsThirty articles were analyzed (7451 participants at risk for BD). Sleep disturbances are frequent in studies using both subjective measures and actigraphy. High-risk individuals reported irregularity of sleep/wake times, poor sleep and circadian rhythm disruption. Poor sleep quality, nighttime awakenings, and inadequate sleep are possible predictive factors for BD. A unique study suggested that irregular rhythms increase risk of conversion. People at risk for BD showed high cortisol levels in different times of day. Studies about anatomopathology, melatonin levels, inflammatory cytokines and oxidative stress were not identified. The most important limitations were differences in sleep and rhythm measures, heterogeneity of study designs, and lack of consistency in the definition of population at risk.ConclusionSleep and circadian disturbances are common in people at risk for BD. However, the pathophysiology of these alterations and the impact on BD onset are still unclear.     

Actigraphic assessment of circadian activity and sleep patterns in bipolar disorder

OBJECTIVES: Theoretical accounts and psychological interventions for bipolar disorder indicate that disruption of circadian rhythms is important, both in affective episodes and as a vulnerability factor in subsyndromal periods. This study aims at assessing both circadian activity and sleep patterns using actigraphy within a bipolar sample experiencing low levels of subsyndromal symptoms. It is hypothesized that such participants will display circadian activity disruption in spite of low levels of symptoms. METHODS: This study employed a mixed design with cross-sectional assessment of mood and week-long (7-day) recording of actigraphy data. All clinical participants were psychiatric outpatients within a UK NHS Hospital. Nineteen bipolar patients and 19 age- and gender-matched controls wore an actigraph for 7 days to obtain sleep and circadian activity data. SCID was used to confirm DSM-IV diagnostic status. Self-report measures of mood were obtained from both groups. RESULTS: Bipolar patients were found to have less stable and more variable circadian activity patterns than controls. Regression analysis indicated that variability alone was a significant independent predictor of diagnostic group. There was evidence from raw activity data that bipolar patients were also less active than controls. These differences were not associated with levels of subsyndromal symptoms. Bipolar patients did not differ from controls on any of the sleep indices used. CONCLUSIONS: Circadian activity disruption is apparent in bipolar patients even when not acutely ill. This finding is not associated with the presence of sleep disturbance. Should such patterns be replicated interventions to address both circadian instability and individual attributions for the effects of such instability are likely to be relevant to successful psychological interventions.     

Relationship between objective and subjective sleep measures in depressed patients and healthy controls

The purpose of this study was to correlate subjective sleep characteristics based on questionnaire response, and objective sleep EEG features based on polysomnography, in 52 patients with major depressive disorders (MDD) and 49 healthy controls. With the exception of the number of awakenings, subjective and objective sleep measures were strongly correlated in both groups. Patients and controls were able to accurately judge time in bed, total sleep time and sleep latency. However, sleep quality, depth, and how rested participants felt upon awakening were not strongly correlated with objective sleep characteristics, particularly in those with MDD The findings suggest that estimates such as total sleep time and sleep latency, obtained from questionnaire data, bear a strong resemblance to objective polysomnographic characteristics in both those with MDD and healthy controls. Patients with MDD do not show sleep-state misperceptions although depressed women are more accurate in estimating sleep characteristics than depressed men. Depression and Anxiety 5:97–102, 1997. © 1997 Wiley-Liss, Inc.     

The role of circadian clock genes in mental disorders

The study of molecular clock mechanisms in psychiatric disorders is gaining significant interest due to data suggesting that a misalignment between the endogenous circadian system and the sleep-wake cycle might contribute to the clinical status of patients suffering from a variety of psychiatric disorders. Sleep disturbances in major depressive disorder (MDD) are characterized by increased sleep latency, poorer sleep efficiency reduced latency to the first rapid eye movement (REM) sleep episode, and early-morning awakening, but there is little data to indicate a role of circadian clock genes in MDD. There is also relatively little information regarding the role of clock genes in anxiety. In contrast, a significant amount of evidence gathered in bipolar disorder (BPD) patients suggests a circadian rhythm disorder, namely an advanced circadian rhythm and state-dependent alterations of REM sleep latency. Most research on the role of clock genes in BPD has focused on polymorphisms of CLOCK, but the lithium target GSK3 may also play a significant role. A circadian phase shift is also theorized to contribute to the pathophysiology of winter seasonal affective disorder (SAD). Certain allelic combinations of NPAS2, PER3, and BMAL1 appear to contribute to the risk of SAD. In chronic schizophrenia, disturbances of sleep including insomnia and reduced sleep efficiency have been observed. Genetic studies have found associations with CLOCK, PER1, PER3, and TIMELESS. Sleep and circadian changes associated with dementia due to Alzheimer's disease suggest a functional change in the circadian master clock, which is supported by postmortem studies of clock gene expression in the brain.     

Ambulatory sleep-wake patterns and variability in young people with emerging mental disorders

Background

The nature of sleep-wake abnormalities in individuals with mental disorders remains unclear. The present study aimed to examine the differences in objective ambulatory measures of the sleep-wake and activity cycles across young people with anxiety, mood or psychotic disorders.

Methods

Participants underwent several days of actigraphy monitoring. We divided participants into 5 groups (control, anxiety disorder, unipolar depression, bipolar disorder, psychotic disorder) according to primary diagnosis.

Results

We enrolled 342 participants aged 12–35 years in our study: 41 healthy controls, 56 with anxiety disorder, 135 with unipolar depression, 80 with bipolar disorder and 30 with psychotic disorders. Compared with the control group, sleep onset tended to occur later in the anxiety, depression and bipolar groups; sleep offset occurred later in all primary diagnosis groups; the sleep period was longer in the anxiety, bipolar and psychosis groups; total sleep time was longer in the psychosis group; and sleep efficiency was lower in the depression group, with a similar tendency for the anxiety and bipolar groups. Sleep parameters were significantly more variable in patient subgroups than in controls. Cosinor analysis revealed delayed circadian activity profiles in the anxiety and bipolar groups and abnormal circadian curve in the psychosis group.

Limitations

Although statistical analyses controlled for age, the sample included individuals from preadolescence to adulthood. Most participants from the primary diagnosis subgroups were taking psychotropic medications, and a large proportion had other comorbid mental disorders.

Conclusion

Our findings suggest that delayed and disorganized sleep offset times are common in young patients with various mental disorders. However, other sleep-wake cycle disturbances appear to be more prominent in broad diagnostic categories.     

Assessment of circadian function in fibroblasts of patients with bipolar disorder

Previous studies have implicated the circadian system in the pathophysiology of bipolar disorder, but conclusive evidence for altered circadian clocks is lacking. Cultured fibroblasts harbor circadian clocks representative of those in the master clock resident in the suprachiasmatic nuclei, providing a new avenue to investigate the core clock machinery in patients with bipolar illness. We examined the rhythmic expression patterns of core clock genes (BMAL1, PER1, PER2, REV-ERBalpha, DEC2, DBP) in fibroblasts from 12 bipolar patients and 12 healthy controls. Although we did not detect differences in the circadian period between bipolar patients and controls, the amplitude of rhythmic expression for BMAL1, REV-ERBalpha and DBP, as well as the overall mRNA expression level for DEC2 and DBP was reduced in fibroblasts from bipolar patients. Bonferroni's correction for multiple comparisons still resulted in significantly reduced DBP expression level, and trends toward reduced overall expression level of DEC2 and circadian amplitude of BMAL1, in fibroblasts from bipolar patients. We next examined an expanded cohort of 18 bipolar patients and 35 healthy controls for mRNA expression levels of four kinases (CKIdelta, CKIepsilon, GSK3alpha and GSK3beta) and the protein and phosphorylation levels of two of them (GSK3alpha and GSK3beta). We did not detect differences in steady-state mRNA levels or protein levels of these kinases between bipolar patients and controls, but the level of GSK3beta phosphorylation was significantly reduced in bipolar patients within an Old Order Amish bipolar kindred. Our results suggest that the reduced amplitudes and overall expression levels of circadian genes, and the decreased phosphorylation level of GSK3beta may lead to dysregulation of downstream genes, which could explain some pathological features of bipolar disorder.     

Des gènes circadiens à la sémiologie psychiatrique

Psychiatric disorders, such as bipolar disorder and autism spectrum disorders, are highly inherited. Many studies have reported a higher relative risk of developing these disorders than in general population when there is already an affected individual in the family. The heritability of these disorders varies from 70% to 90%. However, the identification of susceptibility genes to these disorders remains difficult, due to their high clinical and etiological heterogeneity. The combination of endophenotypes and environmental factors in genetic studies shed new lights on the biological pathways that are affected in subjects with psychiatric disorders. In particular, sleep disorders and circadian rhythm abnormalities have been frequently reported in these two disorders. Here, we summarize several associations between sleep disorders or circadian rhythm abnormalities and single nucleotide polymorphisms in circadian genes and in genes encoding enzymes of the melatonin synthesis pathway. In particular, we describe studies reporting that polymorphisms in the circadian genes TIMELESS and RORA may increase the risk of developing bipolar disorder by altering circadian rhythms. In addition, we describe studies showing that genetic variations in acetylserotonin methyltransferase (ASMT) identified in patients with psychiatric disorders affect its enzymatic activity. This approach may have therapeutic benefits in bipolar disorders, through the assessment of sleep and circadian rhythms, and a personal management of these alterations.     

Long-lasting sleep patterns of adult patients with minor traumatic brain injury (mTBI) and non-mTBI subjects

BACKGROUND: Sleep disturbance is a common subjective complaint of minor traumatic brain-injured (mTBI) patients, but little is known about the characteristics of sleep disturbance in adults years after the injury. METHODS: Polysomnographic (PSG) and multiple sleep latency test (MSLT) records of 26 mTBI adult patients with normal brain computerized tomography and negative encephalographic studies, no past history of CNS pathology, no premorbid or present major psychiatric diagnosis, and no sleep apnea syndrome were compared to a matched group of apparently healthy individuals (controls). RESULTS: Sleep patterns were disturbed in the mTBI patients. Their sleep architecture was altered, with significantly higher light-sleep non-rapid eye movement (NREM) stage 2 scores compared to controls (54.5+/-13.4% vs. 46.6+/-10.4%, respectively, p=0.03) and significantly lower REM sleep scores (21.2+/-8.4% vs. 25.4+/-4.5%, respectively, p=0.05). The MSLT findings documented significant excessive daytime episodes of falling asleep. CONCLUSIONS: Sleep disturbances of adult patients with chronic mTBI may manifest characteristic alterations in both timing and architecture of their sleep patterns. Sleep lab evaluations may help identify subgroups of mTBI patients who would probably benefit from treatment.     

Evaluating sleep in bipolar disorder: comparison between actigraphy,polysomnography, and sleep diary

Kaplan KA, Talbot LS, Gruber J, Harvey AG. Evaluating sleep in bipolar disorder: comparison between actigraphy, polysomnography, and sleep diary.
Bipolar Disord 2012: 14: 870–879. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Bipolar disorder is an illness characterized by sleep and circadian disturbance, and monitoring sleep in this population may signal an impending mood change. Actigraphy is an important clinical and research tool for examining sleep, but has not yet been systematically compared to polysomnography or sleep diary in bipolar disorder. The present study compares actigraphy, polysomnography, and sleep diary estimates of five standard sleep parameters in individuals with bipolar disorder and matched controls across two nights of assessment. Methods: Twenty‐seven individuals who met diagnostic criteria for bipolar disorder type I or II and were currently between mood episodes, along with 27 matched controls with no history of psychopathology or sleep disturbance, underwent two nights of research laboratory monitoring. Sleep was estimated via polysomnography, actigraphy, and sleep diary. Results: Over the 108 nights available for comparison, sleep parameter estimates from actigraphy and polysomnography were highly correlated and did not differ between the two groups or across the two nights for sleep onset latency, wake after sleep onset, number of awakenings, total sleep time, or sleep efficiency percentage. The medium wake threshold algorithm in the actigraphy software was the most concordant with polysomnography and diaries across the five sleep parameters. Concordance between actigraphy, polysomnography, and sleep diary was largely independent of insomnia presence and medication use. Conclusions: Actigraphy is a valid tool for estimating sleep length and fragmentation in bipolar disorder.     

Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults

Nusslock R, Almeida JRC, Forbes EE, Versace A, Frank E, LaBarbara EJ, Klein CR, Phillips ML. Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. Bipolar Disord 2012: 14: 249–260. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Bipolar disorder may be characterized by a hypersensitivity to reward‐relevant stimuli, potentially underlying the emotional lability and dysregulation that characterizes the illness. In parallel, research highlights the predominant role of striatal and orbitofrontal cortical (OFC) regions in reward‐processing and approach‐related affect. We aimed to examine whether bipolar disorder, relative to healthy, participants displayed elevated activity in these regions during reward processing. Methods: Twenty‐one euthymic bipolar I disorder and 20 healthy control participants with no lifetime history of psychiatric disorder underwent functional magnetic resonance imaging (fMRI) scanning during a card‐guessing paradigm designed to examine reward‐related brain function to anticipation and receipt of monetary reward and loss. Data were collected using a 3T Siemens Trio scanner. Results: Region‐of‐interest analyses revealed that bipolar disorder participants displayed greater ventral striatal and right‐sided orbitofrontal [Brodmann area (BA) 11] activity during anticipation, but not outcome, of monetary reward relative to healthy controls (p < 0.05, corrected). Whole‐brain analyses indicated that bipolar disorder, relative to healthy, participants also displayed elevated left‐lateral OFC (BA 47) activity during reward anticipation (p < 0.05, corrected). Conclusions: Elevated ventral striatal and OFC activity during reward anticipation may represent a neural mechanism for predisposition to expansive mood and hypo/mania in response to reward‐relevant cues that characterizes bipolar disorder. Our findings contrast with research reporting blunted activity in the ventral striatum during reward processing in unipolar depressed individuals, relative to healthy controls. Examination of reward‐related neural activity in bipolar disorder is a promising research focus to facilitate identification of biological markers of the illness.     

The actigraphic documentation of circadian sleep-wake rhythm dysregulation in myotonic dystrophy type 1

Study objectivesThe present study aimed at identifying the sleep-wake rhythm in patients with myotonic dystrophy type 1 (DM1) compared to healthy controls.MethodsPatients with genetic diagnosis of DM1 and healthy controls underwent a 7-day actigraphic recording and filled out a daily sleep diary to evaluate the sleep-wake rhythm. All participants underwent a physical and neurological examination to exclude conditions interfering with the sleep-wake cycle. Daytime activity, nocturnal sleep, and non-parametric circadian rhythm activity (NPCRA) were analysed.ResultsTwenty-nine patients affected by DM1 were included in the present study and were compared to 16 controls. Considering nocturnal actigraphic data, DM1 patients showed a longer time in bed, sleep period time, actual sleep time, and sleep latency compared to controls. Central phase measurement was significantly longer in DM1 patients than controls. At NPCRA analysis patients showed a lower degree of regularity in the activity-rest pattern compared to controls. Moreover, DM1 patients showed reduced motor activity during daytime and a lower synchronization of the rest-activity rhythm than controls.ConclusionsThis study documented that patients with DM1 not only present the impairment of nocturnal sleep, but also show a dysregulation of the sleep-wake circadian rhythm; moreover, reduced amplitude of the circadian rhythmicity was also evident in comparison to controls, probably in relation to the reduced diurnal motor activity of patients. These findings add further evidence to the already documented sleep impairment and excessive daytime sleepiness in DM1 patients.     

The role of disturbed sleep in the early recognition of bipolar disorder: a systematic review

Ritter PS, Marx C, Bauer M, Lepold K, Pfennig A. The role of disturbed sleep in the early recognition of bipolar disorder: a systematic review.
Bipolar Disord 2011: 13: 227–237. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Severely disturbed sleep is known to occur during and shortly prior to the onset of mood episodes in bipolar disorder. Whether alterations in sleep occur parallel and as part of the disease process or whether they represent a trait existent before the onset of the disorder itself remains unclear. Methods: A systematic review evaluating all published data on the occurrence of disordered sleep prior to the onset of the first mood episode was conducted. Results: The evidence cited within this paper suggests that sleep disturbances frequently precede bipolar disorder by several years and convey an elevated long‐term risk for developing any kind of mood disorder. Disordered sleep appears to emerge about the time of puberty and remains persistently elevated in individuals at high risk. Conclusion: Disturbed sleep appears to be an early symptom of bipolar disorder but further research, especially longitudinal studies in individuals at high risk, will be required to characterize the type and patterns more precisely.     

Altered interaction between cardiac vagal influence and delta sleep EEG suggests an altered neuroplasticity in patients suffering from major depressive disorder

Jurysta F, Kempenaers C, Lancini J, Lanquart J‐P, van de Borne P, Linkowski P. Altered interaction between cardiac vagal influence and delta sleep EEG suggests an altered neuroplasticity in patients suffering from major depressive disorder. Objective: Major depressive disorder (MDD), which is associated with altered neuroplasticity and increased relative cardiac sympathic activity, enhances the risk of cardiovascular pathologies. Interaction between cardiac sympatho‐vagal indexes and delta sleep power is probably altered in MDD. Method: Sleep characteristics and cardiac sympatho‐vagal indexes of 10 depressive patients were compared to 10 control men across the first three non‐rapid eye movement (NREM)–REM cycles. Interaction between normalized high frequency (HF) and delta power bands was studied using coherence analysis. Results: Patients showed increased sleep latency, stage 1 and wake durations. No differences in heart rate variabilities were observed: Total power, HF and RR‐interval decreased from NREM to REM sleep and wakefulness in both groups. Gain value was lower in patients while coherence and phase shift were similar between groups. Modifications in HF appear 8 min before modifications in delta. Conclusion: Major depressive disorder is related to an altered link between cardiac vagal influence and delta sleep, suggesting disorders in cardiovascular controls and an altered neuroplasticity.     

The effects of testosterone on sleep and sleep-disordered breathing in men: its bidirectional interaction with erectile function

As a major androgen with a key role in developing and maintaining male sexual characteristics, testosterone exerts a broad range of actions regulating several systems throughout human life. This article reviews data on the role of sleep in modulating endocrine release, as well as data on the effects of testosterone and androgen-replacement therapy on sleep architecture and breathing. This review also discusses the interaction of testosterone and sleep, with a particular emphasis on bilateral effects. Changes in nocturnal testosterone are sleep-related, with levels rising during sleep and falling on waking, whereas circadian effects are apparently marginal. Peak testosterone levels coincide with rapid-eye movement (REM) sleep onset. The decreasing sleep efficiency and numbers of REM sleep episodes with altered REM sleep latency observed in older men are associated with lower concentrations of circulating testosterone. The well-established male preponderance of sleep apnea suggests that sex hormones are involved in the pathogenesis of this breathing disorder. In addition, androgens are most certainly key players in the central and peripheral modulation of erectile function. Among other effects, sleep curtailment has been shown to lead to reduced levels of circulating androgens in healthy men and male rodents, and this highlights the biological significance of sleep homeostasis for endocrine regulation.     

Differential pattern of semantic memory organization between bipolar I and II disorders

Semantic cognition is one of the key factors in psychosocial functioning. The aim of this study was to explore the differences in pattern of semantic memory organization between euthymic patients with bipolar I and II disorders using the category fluency task. Study participants included 23 euthymic subjects with bipolar I disorder, 23 matched euthymic subjects with bipolar II disorder and 23 matched control subjects. All participants were assessed for verbal learning, recall, learning strategies, and fluency. The combined methods of hierarchical clustering and multidimensional scaling were used to compare the pattern of semantic memory organization among the three groups. Quantitative measures of verbal learning, recall, learning strategies, and fluency did not differ between the three groups. A two-cluster structure of semantic memory organization was identified for the three groups. Semantic structure was more disorganized in the bipolar I disorder group compared to the bipolar II disorder. In addition, patients with bipolar II disorder used less elaborate strategies of semantic memory organization than those of controls. Compared to healthy controls, strategies for categorization in semantic memory appear to be less knowledge-based in patients with bipolar disorders. A differential pattern of semantic memory organization between bipolar I and II disorders indicates a higher risk of cognitive abnormalities in patients with bipolar I disorder compared to patients with bipolar II disorder. Exploring qualitative nature of neuropsychological domains may provide an explanatory insight into the characteristic behaviors of patients with bipolar disorders.     

High-sensitivity C-reactive protein levels in patients with major depressive disorder and bipolar mania

The serum high-sensitivity C-reactive protein (hsCRP) levels in patients with major depressive disorder and bipolar I disorder in acute phases were investigated. During a 1-year period, a total of 67 participants including 23 patients with major depressive disorder, 13 patients with bipolar I disorder (manic episode) and 31 healthy controls were recruited in this study. The diagnoses of mental disorders in participants were made by one psychiatrist according to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Both patient groups with major depression and bipolar disorder had higher mean serum hsCRP levels than the healthy control group. Using analysis of covariance with age adjustment, patients with bipolar I disorders still had significantly higher hsCRP levels than healthy controls (P=0.043). However, patients with major depression did not have significantly higher hsCRP levels than healthy controls (P=0.172). These results suggest that patients with bipolar I disorder might have a more severe inflammation reaction than patients without major depression. However, larger samples and adequate statistical methods are needed to prove these results.     

Circadian activity rhythm abnormalities in ill and recovered bipolar I disorder patients

OBJECTIVES: Most physiological indicators of bipolar disorder (BPD) reflect current acute illness, and rarely have proved to be state-independent. Activity rhythms are highly abnormal in acute phases of BPD; we compared circadian activity rhythms in BPD I patients during ill and recovered states to those of normal controls to test the hypothesis that some abnormalities may persist. METHODS: We compared 36 adult DSM-IV BPD I patients during acute mania or mixed states, and during full and sustained clinical recovery, to 32 healthy controls of similar age and sex distribution, using wrist-worn, piezoelectric actigraphic monitoring for 72 h and computed cosinor analysis of circadian activity rhythms. RESULTS: We verified expected major differences between manic or mixed-state BPD I patients and matched normal controls, including phase advances averaging 2.1 h in ill BPD I patients and 1.8 h in recovered patients. Moreover, recovered BPD patients differed highly significantly from controls in several measures, including acrophase advance, higher percentage of nocturnal sleep, and lower average daily activity (mesor). Actigraphic measures among recovered BPD patients were independent of ratings of mania (on the Young Mania Rating Scale), depression (on the Hamilton Depression Rating Scale), or rating-scale scored subjective distress, as well as the type and dose of concurrent psychotropic medication. CONCLUSIONS: These findings suggest that abnormal activity rhythms, including sustained phase advances, may represent enduring (trait) characteristics of BPD patients even during clinical recovery. If verified, such indices may be useful in supporting diagnoses and as an objective phenotype for genetic or other biological studies.     

Lifetime psychopathology in child and adolescent offspring of parents diagnosed with schizophrenia or bipolar disorder: a 2-year follow-up study

Having one parent diagnosed with a severe mental disorder is considered one of the main risk factors for developing that disorder in adulthood, and it also increases the risk of a wide range of mental disorders in the offspring. The aim of this study is to compare the prevalence of several psychopathological diagnoses, the presence of prodromal symptoms, and global functioning in offspring of parents with schizophrenia or bipolar disorder and in offspring of controls at baseline and 2-year follow-up. This study included 41 offspring of parents with schizophrenia, 90 offspring of parents with bipolar disorder, and 107 offspring of controls (mean age 11.7 ± 3.2 at baseline and 13.9 ± 3.2 at follow-up). The prevalence of psychopathology and comorbidity was higher in offspring of parents with schizophrenia and offspring of parents with bipolar disorder than in offspring of controls at baseline and at 2-year follow-up. Interestingly, mood disorders were more prevalent in offspring of parents with bipolar disorder and disruptive disorders were more prevalent in offspring of parents with schizophrenia. Prodromal symptoms were more frequent in offspring of parents with schizophrenia than in offspring of controls, while the offspring of parents with bipolar disorder showed an intermediate pattern. Finally, global functioning was lower in the offspring of parents with schizophrenia than the offspring of parents with bipolar disorder and the offspring of controls. Screening patients’ children is clinically relevant, since, as a group, they have an elevated risk of developing a psychiatric disorder and of experiencing their first symptoms during childhood and adolescence.

     

Circadian Polymorphisms in Night Owls,in Bipolars,and in Non-24-Hour Sleep Cycles

People called night owls habitually have late bedtimes and late times of arising, sometimes suffering a heritable circadian disturbance called delayed sleep phase syndrome (DSPS). Those with DSPS, those with more severe progressively-late non-24-hour sleep-wake cycles, and those with bipolar disorder may share genetic tendencies for slowed or delayed circadian cycles. We searched for polymorphisms associated with DSPS in a case-control study of DSPS research participants and a separate study of Sleep Center patients undergoing polysomnography. In 45 participants, we resequenced portions of 15 circadian genes to identify unknown polymorphisms that might be associated with DSPS, non-24-hour rhythms, or bipolar comorbidities. We then genotyped single nucleotide polymorphisms (SNPs) in both larger samples, using Illumina Golden Gate assays. Associations of SNPs with the DSPS phenotype and with the morningness-eveningness parametric phenotype were computed for both samples, then combined for meta-analyses. Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057). A group of haplotypes overlapping BHLHE40 was associated with non-24-hour sleep-wake cycles, and less robustly, with delayed sleep and bipolar disorder (e.g., rs34883305, rs34870629, rs74439275, and rs3750275 were associated with n=37, p=4.58E-09, Bonferroni p=2.95E-06). Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms. After further replication and identification of the causal polymorphisms, these findings may point to future treatments for DSPS, non-24-hour rhythms, and possibly bipolar disorder or depression.