Sleep and circadian rhythms as possible trait markers of suicide attempt in bipolar disorders: An actigraphy study.

BACKGROUND: The poor prognostic of Bipolar disorders (BD) is closely linked to deaths by suicide. Sleep and circadian abnormalities are observed during all phases of BD and are also associated with suicide attempt (SA). In this context, this study sought to identify specific sleep and circadian rhythms markers associated with suicidal attempt in euthymic patients with BD. METHODS: The sample (N = 236) comprised 3 groups: 147 patients with BD including 57 with a history of SA and 90 without (NoSA), and 89 healthy controls (HC). All participants were recorded during 21 days with actigraphy. RESULTS: SA was associated with women gender (p = 0.03), familial history of SA (p = 0.03), mixed episodes (p = 0.001), and benzodiazepines (p = 0.019). SA, compared to noSA, had a morning phase preference (p = 0.04), and were more vigorous on the circadian type inventory (p = 0.04), and tended to suffer more from insomnia (45% versus 25% respectively, p = 0.10). SA was also associated with an earlier onset of daily activity assessed with actigraphy (M10 onset: p = 0.01). Backward stepwise linear regression indicated that a combination of four variables (Gender, vigour, insomnia, M10onset) significantly differentiated patients with SA from NoSA (p = 0.03). LIMITATIONS: Cross-sectional design, and no examination of suicidal behaviors' subgroups such as first attempters or repeaters, or violent suicide attempt. CONCLUSIONS: Woman gender, vigorous circadian type, insomnia and an earlier daily activity appeared independently associated with SA in BD. If these biomarkers are confirmed in prospective studies, they should be screened and used to prevent suicide, with the development of personal and targeted chronobiological treatments.

Metabolic syndrome and actigraphy measures of sleep and circadian rhythms in bipolar disorders during remission.

OBJECTIVE: This study explored the correlations between sleep and circadian rhythm measures and the metabolic syndrome (MetS) components in remitted patients with bipolar disorder (BD). METHOD: Euthymic patients with BD (n = 67) were recorded by 3 weeks with actigraphy. We used nonparametric correlations to study the links between the MetS parameters, atherogenic index of plasma (AIP), sleep efficacy, sleep latency, fragmentation index, and phase and amplitude of rhythms. We performed multivariable analyses to take into account potential confounding factors such as sleep apnea risk, antipsychotics use, and smoker status. RESULTS: We found correlations between lower sleep efficiency and higher triglyceride levels (P = 0.002), lower M10 onset (beginning of the 10 most active hours during the 24-h cycle) and higher systolic blood pressure (P = 0.03), higher fragmentation index and higher systolic blood pressure (P = 0.009), lower sleep efficiency, higher fragmentation index, and higher AIP (respectively P = 0.02 and P = 0.04). These correlations mostly remained significant when adjusting for confounders, with the exception of M10 onset and systolic blood pressure. CONCLUSION: Sleep efficiency and fragmentation index might contribute to the cardiovascular risk of patients with BD independently of major confounding factors. Although these associations did not imply causality, proposing interventions on sleep quality and circadian rhythm regularity might contribute to reduce cardiovascular risk in patients with BD.

A study of the real-world effectiveness of group psychoeducation for bipolar disorders: Is change in illness perception a key mediator of benefit?

BACKGROUND: Findings from efficacy trials of group psychoeducation (PE) for bipolar disorders (BD) led to its inclusion in evidence-based guidelines as a first-line mandatory treatment. However, pragmatic trials and observational studies are needed to determine its real-world effectiveness, impact on outcomes deemed important to patients and to clarify potential mediators of any benefits. METHODS: Individuals with BD were offered the opportunity to participate in 20h of PE and asked to complete pre- and post-intervention ratings of symptoms, knowledge about BD, medication adherence, and illness perception. A priori, two key patient outcomes were identified (social functioning and self-esteem); sample attrition due to dropout or relapse was recorded. RESULTS: Of 156 individuals who completed the pre-PE assessments, 103 completed the program and post-PE assessments. Only 4 of 53 dropouts were associated with BD relapse. Post-intervention, the PE completers demonstrated a statistically significant improvement in social functioning (p = 0.003, Effect Size (ES) = 0.26) and a trend towards improved self-esteem (ES = 0.14). Whilst there were significant changes in medication adherence (p = 0.002, ES = 0.28), knowledge of BD (p < 0.001, ES = 1.20), and illness perception (p < 0.001, ES = -0.37), mediational analysis demonstrated that only change in illness perception was associated to change in functioning (p=0.03) with no contribution from changes in knowledge of BD or medication adherence. CONCLUSIONS: In real-world settings, over 60% individuals completed 10-session course of PE. After controlling for demography and baseline clinical state, change in illness perception, rather than change in knowledge or medication adherence, emerged as a potential mediator of some benefits of PE.

Sleep quality and emotional reactivity cluster in bipolar disorders and impact on functioning.

OBJECTIVE: Bipolar disorders (BD) are characterized by sleep disturbances and emotional dysregulation both during acute episodes and remission periods. We hypothesized that sleep quality (SQ) and emotional reactivity (ER) defined clusters of patients with no or abnormal SQ and ER and we studied the association with functioning. METHOD: We performed a bi-dimensional cluster analysis using SQ and ER measures in a sample of 533 outpatients patients with BD (in remission or with subsyndromal mood symptoms). Clusters were compared for mood symptoms, sleep profile and functioning. RESULTS: We identified three clusters of patients: C1 (normal ER and SQ, 54%), C2 (hypo-ER and low SQ, 22%) and C3 (hyper-ER and low SQ, 24%). C1 was characterized by minimal mood symptoms, better sleep profile and higher functioning than other clusters. Although highly different for ER, C2 and C3 had similar levels of subsyndromal mood symptoms as assessed using classical mood scales. When exploring sleep domains, C2 showed poor sleep efficiency and a trend for longer sleep latency as compared to C3. Interestingly, alterations in functioning were similar in C2 and C3, with no difference in any of the sub-domains. CONCLUSION: Abnormalities in ER and SQ delineated three clusters of patients with BD and significantly impacted on functioning.

[Antibiomania: Think of the manic syndrome secondary to antibiotic therapy]. / Antibiomania : penser au syndrome maniaque secondaire à une antibiothérapie.

INTRODUCTION: Antibiomania is characterized by the emergence of a manic episode in reaction to antibiotics. Although relatively uncommon, this kind of side effect is observed in a growing number of cases and mostly occurs in patients who do not have a history of bipolar disorder. Several dozen cases have been reported showing the onset of manic symptoms after taking antibiotics. The antibiotic most frequently involved is clarithromycin. CLINICAL CASE: We report the case of a 61-year-old patient who presented a manic episode after taking an antibiotic combination to treat Helicobacter pylori. Five days after the start of highly active antiretroviral therapy (HAART), behavioral problems appeared (aggressiveness, irritability, talkativeness, insomnia). At the time of hospitalization, she had an acute delusional symptomatology, with a theme of persecution, associated with intuitive, interpretive and imaginative mechanisms. Manic symptoms were obvious: psychomotor excitement, aggressiveness and irritability, flight of ideas, verbal disinhibition and a denial of problems. There was no toxic cause. Brain magnetic resonance imaging (MRI) was normal. Her condition improved very quickly and delusions disappeared in four days. Mrs. H. could critic her delirium and recovered a euthymic state. During hospitalization, treatment divalproate sodium was introduced (250mg, 3 times a day), was maintained following hospital discharge for 2 years for prevention, and then decreased to the stop. There are currently no further behavioral problems or sleep disorders two years after this episode. DISCUSSION: Facing this clinical case, several questions arise: Which drug therapy is the most suitable for this type of mental disorder? Are there predictors of antibiomania? Is there a risk of recurrence of mood episodes following an antibiomania that occurs spontaneously? What are the pathophysiological mechanisms that could explain this reaction? In all cases identified, stopping the antibiotics was decisive. However, the introduction of a psychotropic and the duration of this treatment remain unclear. First, longitudinal follow-up would assess this variable. Second, it is unclear whether the presence of personal psychiatric history is a predictor of antibiomania. Finally, there are several hypotheses to explain antibiomania: the competitive effect of GABAergic inhibitory receptors, seizure-like phenomena that mimic psychiatric symptoms, and disruption of the intestinal microbiota by antibiotics leading to a modification of the functioning of the central nervous system. The explanatory model of antibiomania is not yet known and requires further research.

[Metabolic syndrome and bipolar disorder: Is sleep the missing link?] / Syndrome métabolique et troubles bipolaires : le sommeil est-il le chaînon manquant ?

OBJECTIVE: To examine the pathophysiologic mechanisms that may link circadian disorder and metabolic syndrome in bipolar disorder (BP). METHOD: A systematic review of the literature was conducted from January 2013 to January 2015, using the Medline and Cochrane databases, using the keywords "metabolic syndrome", "obesity", "leptin" and "circadian disorders", "sleeping disorders" and cross-referencing them with "bipolar disorder". The following types of publications were candidates for review: (i) clinical trials; (ii) studies involving patients diagnosed with bipolar disorder; (iii) studies involving patients with sleeping disorder; or (iv) data about metabolic syndrome. RESULTS: Forty articles were selected. The prevalence of metabolic syndrome in BP was significantly higher compared to the general population (from 36 to 49% in the USA [Vancampfort, 2013]), and could be explained by several factors including reduced exercise and poor diet, genetic vulnerability, frequent depressive episodes, psychiatric comorbidity and psychotropic treatment. This high frequency of metabolic syndrome worsens the prognosis of these patients, increasing morbidity and mortality. Secondly, patients with BP experienced circadian and sleep disturbance, including modification in melatonin secretion. These perturbations are known to persist in periods of mood stabilization and are found in patients' relatives. Circadian disturbances are factors of relapse in bipolar patients, and they may also have a role in the metabolic comorbidities of these patients. Recent studies show that in populations of patients with bipolar disorder, a correlation between circadian disturbance and metabolic parameters are found. To identify the pathophysiological pathway connecting both could lead to a better comprehension of the disease and new therapeutics. In the overall population, mechanisms have been identified linking circadian and metabolic disorder involving hormones like leptin and ghrelin. These hormones are keys to regulation of energy balance in the organism, via their action on the hypothalamus, and are also regulated by sleep. We have hypothesized that these pathways could be implicated in the vulnerability of bipolar patients to metabolic syndrome. This hypothesis is supported by several studies showing dysregulation in leptin and ghrelin secretion in multiple psychiatric disorders, including bipolar disorder, as well as genetic variations of leptin and ghrelin genes in these diseases. We also assume that other mechanisms may be at stake to explain this link, such as melatonin dysregulation and inflammation. CONCLUSIONS: Circadian and sleeping disorder may have a role in the prevalence of metabolic syndrome in BP. Hormones like leptin and ghrelin could be the link between these perturbations. Prevention and treatment of circadian disorder in BP may greatly reduce the occurrence of MetS in these patients. Being aware of this statement and taking care of these troubles should be a big step forward for treatment of BP.

[Bright light therapy in seasonal bipolar depressions]. / Luminothérapie et épisodes dépressifs saisonniers du trouble bipolaire.

INTRODUCTION: Bipolar disorders (BD) are frequent mood disorders associated with a poor prognosis mainly due to a high relapse rate. Depressive relapses may follow a seasonal cyclicality, and bright-light therapy (BLT) has been established as the treatment of choice for seasonal affective disorder (SAD). The use of BLT for seasonal unipolar depression is well known, but the scientific literature is much poorer on the management of seasonal depressive episodes in BD. In addition, some specificities related to BD must be taken into account. METHODS: We conducted a comprehensive review using Medline and Google Scholar databases up to August 2014 using the following keywords combination: "bipolar disorder" and "light therapy" or "phototherapy". Papers were included in the review if (a) they were published in an English or French-language peer-reviewed journal; (b) the study enrolled patients with BD and SAD; and (c) the diagnosis was made according to the DSM or ICD criteria. RESULTS: BLT was considered among the first-line treatments for SAD with a size effect similar to antidepressants. Most of the studies did not distinguish between patients with unipolar and bipolar disorders. However, it has been demonstrated that the most significant risk of BLT in patients with BD is the mood shift. Thus, the most important therapeutic adaptation corresponds to the use of an effective mood stabilizer, as with any antidepressant. Another therapeutic adaptation in first intention is that the times of exposure to light should be shifted from morning to midday. This review also includes therapeutic guidelines regarding the management of BLT in seasonal bipolar depressive episodes. DISCUSSION: There are very few specific data on seasonal bipolar depressive episodes. This literature review has highlighted that BLT should be handled as a regular antidepressant treatment in patients suffering from seasonal bipolar depressive episodes.

Sleep in patients with remitted bipolar disorders: a meta-analysis of actigraphy studies.

OBJECTIVE: Sleep dysregulation is highly prevalent in bipolar disorders (BDs), with previous actigraphic studies demonstrating sleep abnormalities during depressive, manic, and interepisode periods. We undertook a meta-analysis of published actigraphy studies to identify whether any abnormalities in the reported sleep profiles of remitted BD cases differ from controls. METHOD: A systematic review identified independent studies that were eligible for inclusion in a random effects meta-analysis. Effect sizes for actigraphy parameters were expressed as standardized mean differences (SMD) with 95% confidence intervals (95% CI). RESULTS: Nine of 248 identified studies met eligibility criteria. Compared with controls (N=210), remitted BD cases (N=202) showed significant differences in SMD for sleep latency (0.51 [0.28-0.73]), sleep duration (0.57 [0.30-0.84]), wake after sleep onset (WASO) (0.28 [0.06-0.50]) and sleep efficiency (-0.38 [-0.70-0.07]). Moderate heterogeneity was identified for sleep duration (I2=44%) and sleep efficiency (I2=44%). Post hoc meta-regression analyses demonstrated that larger SMD for sleep duration were identified for studies with a greater age difference between BD cases and controls (ß=0.22; P=0.03) and non-significantly lower levels of residual depressive symptoms in BD cases (ß=-0.13; P=0.07). CONCLUSION: This meta-analysis of sleep in remitted bipolar disorder highlights disturbances in several sleep parameters. Future actigraphy studies should pay attention to age matching and levels of residual depressive symptoms.

[Circadian markers and genes in bipolar disorder]. / Biomarqueurs et gènes circadiens dans le trouble bipolaire.

INTRODUCTION: Bipolar disorder is a severe and complex multifactorial disease, characterized by alternance of acute episodes of depression and mania/hypomania, interspaced by euthymic periods. The etiological determinants of bipolar disorder yet, are still poorly understood. For the last 30 years, chronobiology is an important field of investigation to better understand the pathophysiology of bipolar disorder. METHODS: We conducted a review using Medline, ISI Database, EMBase, PsyInfo up to January 2015, using the following keywords combinations: "mood disorder", "bipolar disorder", "depression", "unipolar disorder", "major depressive disorder", "affective disorder", for psychiatric conditions; and "circadian rhythms", "circadian markers", "circadian gene", "clock gene", "melatonin" for circadian rhythms. The search critera was presence of word in any field of the article. RESULTS: Quantitative and qualitative circadian abnormalities are associated with bipolar disorders both during acute episodes and euthymic periods, suggesting that these altered circadian rhythms may represent biological trait markers of the disorder. These circadian dysfunctions were assessed by various validated tools including polysomnography, actigraphy, sleep diaries, chronotype assessments and blood melatonin/cortisol measures. Other altered endogenous circadian activities have also been reported in bipolar patients, such as hormones secretion, core body temperature or fibroblasts activity. Moreover, these markers were also altered in healthy relatives of bipolar patients, suggesting a degree of heritability. Several genetic association studies have also showed associations between multiple circadian genes and bipolar disorder, such as CLOCK, ARTNL1, GSK3ß, PER3, NPAS2, NR1D1, TIMELESS, RORA, RORB, and CSNK1ε. Thus, these circadian gene variants may contribute to the genetic susceptibility of the disease. Furthermore, the study of the clock system may help to better understand some phenotypic aspects like the mechanisms of pharmacological treatments used in bipolar disorder, in particular lithium carbonate. CONCLUSION: Several clinical, physiological and genetic data suggest that circadian rhythms dysregulations are involved in the pathophysiology of bipolar disorder. The circadian model has led to the development of new therapeutic strategies such as chronotherapeutics or Inter Personal Social and Rhythms Therapies. Further studies are needed in this promising research field to keep exploring the relationship between these circadian markers, genes and the clinical aspects of the disease.

Links between sleep and body mass index in bipolar disorders: an exploratory study.

STUDY OBJECTIVES: Obesity and excess bodyweight are highly prevalent in individuals with bipolar disorders (BD) and are associated with adverse consequences. Multiple factors may explain increased bodyweight in BD including side effects of psychotropic medications, and reduced physical activity. Research in the general population demonstrates that sleep disturbances may also contribute to metabolic burden. We present a cross-sectional study of the associations between body mass index (BMI) and sleep parameters in patients with BD as compared with healthy controls (HC). METHODS: Twenty-six French outpatients with remitted BD and 29 HC with a similar BMI completed a 21-day study of sleep parameters using objective (actigraphy) and subjective (PSQI: Pittsburgh Sleep Quality Index) assessments. RESULTS: In BD cases, but not in HC, higher BMI was significantly correlated with lower sleep efficiency (P=0.009) and with several other sleep parameters: shorter total sleep time (P=0.01), longer sleep onset latency (P=0.05), higher fragmentation index (P=0.008), higher inter-day variability (P=0.05) and higher PSQI total score (P=0.004). CONCLUSIONS: The findings suggest a link between a high BMI and several sleep disturbances in BD, including lower sleep efficiency. Physiological mechanisms in BD cases may include an exaggeration of phenomena observed in non-clinical populations. However, larger scale studies are required to clarify the links between metabolic and sleep-wake cycle disturbances in BD.

The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders.

Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35-46%) of patients), as well as the deficit in melatonin (51% (45-57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41-54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS-melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS-melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.

Association between circadian genes, bipolar disorders and chronotypes.

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR = 1.49 95%CI[1.18-1.88]; p = 0.0008) and rs782931 in RORA (OR = 1.31 95%CI[1.12-1.54]; p = 0.0006) and BD. Then we used a "reverse phenotyping approach" to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p = 0.04) and languid circadian type (p = 0.01), whereas rs782931 was associated with rigid circadian type (p = 0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.

An ASMT variant associated with bipolar disorder influences sleep and circadian rhythms: a pilot study.

Patients with bipolar disorder (BD) experience persistent circadian rhythm and sleep abnormalities during periods of remission, and biological studies have shown that these patients have abnormal melatonin secretion profiles or reactivity to light. We previously reported the association with BD of a common polymorphism (rs4446909) of the promoter of the acetylserotonin O-methyltransferase (ASMT) gene, encoding one of the two enzymes involved in melatonin biosynthesis. This variant was associated with weaker transcription and lower levels of ASMT activity in lymphoblastoid cell lines. Actigraphy, based on the use of a mobile portable device for the analysis of sleep/wake cycles in natural conditions, may be useful for studies of carriers of the at-risk allele. We studied the association between the ASMT rs4446909 variant and sleep/activity, as assessed with the Pittsburgh Sleep Quality Index (PSQI) and by actigraphy, in 53 subjects (25 patients with BD in remission and 28 healthy controls). The two groups were similar for age, sex ratio, current mood symptoms, body mass index and risk of sleep apnea syndrome. In the total sample, the GG at-risk genotype was associated with longer sleep duration (P = 0.03), greater activity in active periods of sleep (P = 0.015) and greater interday stability (P = 0.003). These associations remained significant when disease status was included in the model. Only the association with interday stability remained significant after correction for multiple testing. This pilot study thus shows that a BD-associated functional variant involved in the melatonin synthesis pathway influences sleep and circadian rhythms in bipolar patients in remission and controls.

Chronotypes of bipolar patients in remission: validation of the French version of the circadian type inventory in the FACE-BD sample.

Circadian rhythm disturbances have been associated with bipolar disorder (BD) during both the mood episodes and the periods of remission. Circadian phase preferences for the evening have been reported for remitted patients, whereas the amplitude and stability of their rhythms have never been assessed using questionnaires. The primary aim of our study was the validation of a French version of the Circadian Type Inventory (CTI), whereas its secondary aim was the comparison between remitted patients with BD and healthy controls for rhythm stability and amplitude and for phase preference. For this purpose, we used the CTI and the Composite Scale of Morningness (CSM) that assesses phase preference ("morning" or "evening" type). First, we report here on the validation of the French version of the 11-item Circadian Type Inventory in a sample of 140 remitted patients with BD and 156 healthy controls. Principal components analysis revealed a two-factor structure (FR: flexibility/rigidity scale corresponding to rhythm stability; LV: languid/vigorous scale corresponding to rhythm amplitude) explaining 52% of the variance in the control group and 47% in the bipolar group. Cronbach's alpha was 0.75 for FR and 0.73 for LV. The test-retest reliability was 0.74 for FR and 0.86 for LV (3 wks) and 0.62 for FR and 0.72 for LV (6 mos). LV and FR scores correlated with the Composite Scale of Morningness score (p < 0.00001 and p = 0.0002, respectively). Second, as compared with controls, patients with BD were more languid (p < 0.00001) and showed an evening preference (p = 0.0003), but they did not differ from the controls with regard to flexibility/rigidity. The French version of the CTI appeared to have satisfactory psychometrics characteristics. Bipolar patients exhibited not only abnormalities in phase preference but also in amplitude as measured by languidity. Since circadian rhythm dysfunction has been shown to predict poor functioning and mood relapses in interepisodic patients with BD, this tool would appear to be a promising, easy-to-use, measure of the amplitude and flexibility of circadian rhythms that could enrich the arsenal of assessments used in clinical settings.