Disruption Of Biological Rhythms Research Articles

The Integrated Stress Response Regulates Diurnal Rhythms in Liver Metabolism

Disruptions in biological rhythms are associated with the development of metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insuffciency and activator of the integrated stress response (ISR), plays an integral role in liver metabolism. The objective of this work was to examine the impact of feeding a low protein quality (LPQ) diet on diurnal rhythms in liver metabolism. We hypothesized that activation of the ISR by GCN2 maintains metabolic rhythms within the liver during LPQ feeding. To address our objective, wild type (WT) and whole body Gcn2 knockout (GCN2KO) mice were housed in total darkness and provided free access to either a Control or a LPQ diet (devoid of leucine) for 8-days and then killed at 2 circadian time (CT) points 12-hours apart (CT3, CT15). WT mice fed a Control diet showed oscillations in hepatic ISR activation that were lost in the livers of GCN2KO mice. Diurnal patterns in the liver transcriptome including genes regulating triglyceride metabolism were also dampened in GCN2KO mice. WT mice fed LPQ showed increased hepatic ISR activation and greater abundance of ISR target genes relative to Control only at CT15 (p<0.05 by two factor ANOVA). GCN2KO mice fed LPQ failed to show oscillations in ISR activation and instead displayed reductions in liver intracellular amino acids alongside significant upregulation of genes encoding gluconeogenesis and amino acid catabolism at CT15 (q<0.05, Log2FC>1). In conclusion, GCN2 is required for diurnal ISR activation and execution in the liver. LPQ feeding increases hepatic ISR activation in a time dependent manner. Sensing of LPQ by GCN2 is necessary for the maintenance of rhythms in liver macronutrient metabolism. NIH DK109714, Pilot award from the NJ IFNH Center for Human Nutrition, Exercise, and Metabolism (NExT). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The relationship between anxiety symptoms and disturbances in biological rhythms in patients with depression

BackgroundBiological rhythms denote the cyclical patterns of life activities anchored to a 24-hour cycle. Research shows that depression exhibits disturbances in biological rhythms. Yet, the relationship between these biological rhythms and concomitant anxiety symptoms is insufficiently investigated in structured clinical assessments. MethodsThis multicenter study, carried out in four Chinese hospitals, comprehensively examined the relationship between anxiety and disruptions in biological rhythms among patients with depression. The study encompassed 218 patients diagnosed with depression and 205 matched healthy controls. The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry was utilized to evaluate the participants' biological rhythms, focusing on four dimensions: sleep, activity, social, and diet. ResultsIn patients with depression, there is a significant positive correlation between the severity of anxiety symptoms and the disturbances in biological rhythms. The severity of anxiety and depression, along with the quality of life, are independently associated with disruptions in biological rhythms. The mediation model reveals that anxiety symptoms mediate the relationship between depressive symptoms and biological rhythms. ConclusionThis research highlights the role of anxiety within the spectrum of depressive disorders and the associated disturbances in biological rhythms. Our findings shed light on potential pathways towards more targeted preventive strategies and therapeutic interventions for individuals battling depression and anxiety.

The relationship between biological rhythm and perceived social support, coping styles and medication adherence in patients with bipolar disorder in Türkiye

IntroductionThe disruption of biological rhythm (sleep, eating patterns, hormonal secretions, activities, and social life etc.) in individuals diagnosed with bipolar disorder makes it challenging to balance the mood of the patient and facilitates recurrence. Although social support, coping with stress, and medication adherence are known to affect prognosis, no study has been found to investigate the relationship between these factors and biological rhythm. AimThis descriptive and correlational design study investigated the relationship between perceived social support, coping styles and medication adherence, and biological rhythm in individuals diagnosed with bipolar disorder. MethodThis study was conducted with 111 patients receiving treatment in the outpatient clinics of the psychiatry department of two public hospitals in Ankara, Turkey. Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN), Multidimensional Scale of Perceived Social Support (MSPSS), Coping Style Inventory (CSI), and Morisky Medication Adherence Scale (MMAS) were used for data collection. ResultsThe biological rhythm total and subscales scores were significantly and negatively related to perceived social support total, and subscales scores (p < 0.005). The biological rhythm total and most of its subscales scores were significantly and negatively related to medication adherence (p < 0.005). The biological rhythm total and domain scores were significantly and negatively related to seeking social support, self-confident, and optimistic subscales of CSI while significantly and positively related to helpless and submissive (p < 0.005). DiscussionIn this study, a positive relationship was found between increased perceived social support, effective coping with stress, and adherence to medication. This study highlights that these factors may be helpful for the regulation of biological rhythm.

МЕТОДОЛОГИЧЕСКИЕ ПРИНЦИПЫ ЛЕЧЕНИЯ ХЕЙЛИТОВ НА КРАЙНЕМ СЕВЕРЕ

When studying exogenous factors of the Far North that negatively affect human health, it was established: the impact of not only low temperatures, traumatic aerodynamic conditions, and a deficiency of ultraviolet radiation, but also geomagnetic field tension, microelement shifts in the composition of soil and water, and fluctuations in atmospheric pressure levels. A special role for carrying out therapeutic and diagnostic measures is played by the fact that the entire territory located beyond the Arctic Circle belongs to zones with a significant deficiency of the biologically active part of the solar spectrum of ultraviolet radiation. This leads to disruption of photoperiodicity due to the change of polar day and polar night, disruption of biological rhythms, and a decrease in reserve capabilities for regulating homeostasis. The fact that a person lives in a long-term deficiency of ultraviolet radiation affects all biological processes occurring in the body; it plays a special role in the occurrence and development of some forms of cheilitis. The study involved 37 patients aged 18 to 55 years with a diagnosis of chronic recurrent fissure of the lip, meteorological cheilitis, dry form of exfoliative cheilitis, symptomatic atopic cheilitis. After a thorough history, review of patient medical records, and dental examination, serum vitamin D and E levels were measured in all patients before treatment. The best results in treatment were achieved by prescribing combined ointments based on glucocorticoids and antibacterial/antifungal components in combination with physiotherapeutic procedures.

Relationship Between Biological Rhythm and Food Addiction in Obesity

Objective: Obesity is a common, multifactorial, and epigenetic disease. Emotional eating and food addiction are common eating behaviors in obese people. Biological rhythm helps the body adapt to the light-dark cycle and relates to eating behavior, including obesity. Thus, the study aims to reveal whether food addiction, an important factor in obesity, is affected by biological rhythm.Methods: A total of 130 participants (obese=76, nonobese=54) participated in the study. All participant’s anthropometrics were recorded. Beck Depression and Anxiety Inventories (BDI and BAI) were obtained. Afterward, the Yale Food Addiction Scale (YFAS) form was filled out to evaluate food addiction. Finally, they were asked to fill in the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) form to assess biological rhythm.Results: Obese and nonobese subjects had a significant positive correlation with body mass index (BMI), fat mass, fat-free mass, body fat percentage, and YFAS between weight (p&lt;0.001). BRIAN chronotype score and BMI were negatively correlated between obese subjects (p&lt;0.05) but not in nonobese subjects. BDI and BAI were significantly positively correlated (p&lt;0.05, p&lt;0.001) with BRIAN subscales except for chronotype in obese patients. Thus, higher scores in BRIAN imply greater disturbances in biological rhythms. YFAS results were positively correlated with weight, BDI, BAI, and BRIAN subtype parameters in the obese group. In the nonobese group, there was a positive correlation between YFAS and BDI and no correlation between the YFAS and BRIAN subtype parameters.Conclusion: As a result, if the person is both obese and has been diagnosed with food addiction, obesity may have emerged as a continuation of depression, anxiety, and biological rhythm disruptions.

Alignment between glioblastoma internal clock and environmental cues ameliorates survival in Drosophila

Virtually every single living organism on Earth shows a circadian (i.e. “approximately a day”) internal rhythm that is coordinated with planet rotation (i.e. 24 hours). External cues synchronize the central clock of the organism. Consequences of biological rhythm disruptions have been extensively studied on cancer. Still, mechanisms underlying these alterations, and how they favor tumor development remain largely unknown. Here, we show that glioblastoma-induced neurodegeneration also causes circadian alterations in Drosophila. Preventing neurodegeneration in all neurons by genetic means reestablishes normal biological rhythms. Interestingly, in early stages of tumor development, the central pacemaker lengthens its period, whereas in later stages this is severely disrupted. The re-adjustment of the external light:dark period to longer glioblastoma-induced internal rhythms delays glioblastoma progression and ameliorates associated deleterious effects, even after the tumor onset.

Impact of Shift Work on Health: A Review

In modern society, more and more people work during ‘non-standard’ working hours, including shift and night work, which are recognized risk factors for health, safety and social well-being. Unfortunately, humans are physiologically unsuited to inverted schedules, leading to negative consequences for shift workers, employers, and society. The circadian and homeostatic processes which govern sleepiness and alertness are improperly aligned for night workers. Shiftwork, in particular night work, causes disruption of biological rhythms, perturbation of social and family life, with a negative influence on performance efficiency and health. Deterioration of health can manifest in the short-term as sleep disorders and accidents; in the long term there is an increased risk of gastrointestinal, psychoneurotic and cardiovascular diseases, and impairment of the female reproductive function. Night work and rotating shift work disrupt the circadian timing system. This disruption may produce significant deleterious symptoms ¡n some workers. Shift-work scheduling may aggravate certain medical conditions. Vulnerable individuals may develop clinical depression when working shifts.

Influence of maternal bipolar disorder on the biological rhythms of their offspring

This study aimed to assess the association between maternal diagnosis of Bipolar Disorder (BD) and the biological rhythms of their offspring, and describe the synchronization of biological rhythms among mothers and their offspring. This study included 59 mothers with a diagnosis of BD and 59 mothers who have not been diagnosed with BD at the first stage of the study, as well as their offspring aged 9–11 years. The mothers' biological rhythms were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) and the offspring's biological rhythms were evaluated using the same assessment tool in the kids' version. The offspring of mothers with BD showed a significantly higher disruption of overall biological rhythm when compared to the offspring of mothers without BD. The mothers with BD and their offspring showed a higher disruption of biological rhythms in all the BRIAN/BRIAN-k domains when compared to the mothers without BD and their offspring. Additionally, we identified a positive correlation between the disruption of biological rhythms in mothers and the disruption of biological rhythms in their offspring. It is likely that they synced their own rhythm with the disrupted rhythm of their mothers. • Mothers with BD and their offspring have difficulties in the biological rhythm pattern. • Offspring synced their own biological rhythm with the biological rhythm of their mothers. • It is important to assess biological rhythms in offspring of mothers with BD.

Investigating biological rhythms disruptions across the menstrual cycle in women with comorbid bipolar disorder and premenstrual dysphoric disorder.

We investigated whether women diagnosed with comorbid bipolar disorder (BD) and premenstrual dysphoric disorder (PMDD) experience higher disruptions in biological rhythms in two independent study samples. The first study has a population-based sample of 727 women, including 104 women with PMDD only, 43 women with BD only, 24 women with comorbid PMDD and BD, and 556 women without BD or PMDD (controls). Biological rhythm disruptions were cross-sectionally evaluated using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). The second study enrolled 77 outpatient women who completed prospective assessments at two timepoints: during the mid-follicular and the late-luteal phases of their menstrual cycles, using the BRIAN, and included 19 women with PMDD, 16 with BD, 17 with comorbid PMDD and BD, and 25 controls. In the population-based sample, all the diagnostic groups (BD, PMDD, BDPMDD) presented greater biological rhythm disruption than controls. In addition, women with BD presented greater overall biological rhythms disruption, and greater disruption in sleep, activity, and eating patterns, than women with PMDD. In the outpatient sample study, women with BDPMDD showed greater disruption in the social domain than women with PMDD. In the outpatient sample, women with BDPMDD reported significantly higher disruptions in biological rhythms across both the follicular and the luteal phases of the menstrual cycle. The comorbidity between BD and PMDD may affect biological rhythms beyond the luteal phase of the menstrual cycle. These results support previous literature on the increased illness burden of women diagnosed with comorbidBD and PMDD.

Effect of nighttime light exposure on glucose metabolism in protein-restricted mice.

Disruption of biological rhythms due to exposure to artificial light at night (ALAN) has emerged as a new risk factor for metabolic diseases. However, the effects of ALAN exposure on energy metabolism with concomitant misalignment in the circadian system caused by nutritional imbalance remain largely unexplored. Here, we evaluate whether a low-protein (LP) diet could enhance the effects induced by exposure to ALAN on the energy metabolism and consequently predispose to metabolic disorders. Male C57BL6/J mice were weaned on a normal protein (NP) or a LP diet and housed on 12 h light:12 h darkness (LD) cycle. After 6 weeks, mice maintained on their respective diets were subdivided into normal light/darkness cycle (NP/LD; LP/LD) or exposed to ALAN (NP/LL; LP/LL) for 8 weeks. We observed that exposure to ALAN concomitant to LP diet disrupts the behavioral rhythms, without shifting the timing of food intake. Furthermore, exposure to ALAN leads to increased body and fat pad weights, higher levels of fast and fed glycemia and glucose intolerance independent of the diet consumed. Importantly, the effects of ALAN on circadian regulation of insulin sensitivity were diet-dependent with LP/LL mice showing insulin resistance in an opposite time of day than NP/LL. At the molecular level, exposure to ALAN concurrent with LP diet increased the expression of phosphoenolpyruvate carboxykinase 1 in both periods analyzed and inverted the pattern of fibroblast growth factor 21 (Fgf21) expression in the liver. Our data suggest that dietary protein restriction modulates the effects induced by nighttime light exposure on glucose metabolism, which could be partially related with the dysregulation of hepatic Fgf21 expression.

The role of circadian genes in the pathogenesis of colorectal cancer.

Colorectal cancer (CRC) is the third most frequent cancer in human beings and is also the major cause of death among the other gastrointestinal cancers. The exact mechanisms of CRC development in most patients remains unclear. So far, several genetically, environmental and epigenetically risk factors have been identified for CRC development. The circadian rhythm is a 24-h rhythm that drives several biologic processes. The circadian system is guided by a central pacemaker which is located in the suprachiasmatic nucleus (SCN) in the hypothalamus. Circadian rhythm is regulated by circadian clock genes, cytokines and hormones like melatonin. Disruptions in biological rhythms are known to be strongly associated with several diseases, including cancer. The role of the different circadian genes has been verified in various cancers, however, the pathways of different circadian genes in the pathogenesis of CRC are less investigated. Identification of the details of the pathways in CRC helps researchers to explore new therapies for the malignancy.

Altered Biological Rhythm and Alzheimer's Disease: A Bidirectional Relationship.

Biological rhythms have become the research focus in recent years. Biological rhythm disruption is a common symptom of Alzheimer's disease (AD) patients, which is usually considered as the late consequence of AD. Recent studies have shown that biological rhythm disruption even occurs before the onset of clinical symptoms of AD. The causal relationship between AD and biological rhythm disruption is not clear. Delineating their relationship can help understand the disease mechanisms and make the early diagnosis of AD possible. This review integrates the research on the abnormal changes of the biological rhythm-related parameters in the clinical manifestations of AD patients and the roles of the biological rhythm disorders in AD. We will discuss the links between biological rhythms and AD, with the focus on the bidirectionality between biological rhythms and AD processes. Collectively, these updated research findings may provide the basis for further exploring the significance of rhythm in the diagnosis and treatment of AD.

Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder.

Objective Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD. Methods We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway. Results Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality. Conclusion This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Chronotype and biological rhythms in bipolar disorders

IntroductionBiological rhythms play an important role in the etiology of mood disorders. Several lines of evidence established a link between circadian rhythm disruption and mood episodes. Chronotypes are the behavioral manifestations of circadian rhythms and eveningness appears to be more frequent in bipolar disorder (BD). The influence of chronotype on mood symptoms needs yet to be clarified.Objectives-Identifying the predominant chronotype in a Tunisian sample of patients with BD -Assessing the association between chronotype and biological rhythm disruptions in the sampleMethodsFor this study, a total of 80 euthymic outpatients with bipolar disorder and 80 control subjects were recruited. Biological rhythms disruptions were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). Predominant chronotype was identified using the composite scale of morningness (CSM).ResultsBRIAN scores showed greater biological rhythms disruptions in bipolar patients than the control subjects (mean scores 35.26±9.21 vs 25.84±2.68). Low CSM scores in the patients’ group indicated a predominant evening chronotype whereas an intermediate chronotype was more frequent within the control group. The correlation analysis revealed a statistically significant negative correlation between the 2 scales (r=-0.716, p&lt;0.001): the CSM scores decreased as the BRIAN scores increased.ConclusionsThis study indicates that eveningness is more common in BD. This chronotype is more likely to disturb biological rhythms which may increase the risk of mood symptoms and lead to a poor prognosis for BD, thus the relevance of treating rhythm alterations, especially in evening-type patients, in order to improve their quality of life and prevent mood episodes.DisclosureNo significant relationships.

Social rhythms and occupational functioning disturbance in remitted bipolar patients

IntroductionBiological rhythm disturbance is etiologically involved in mood disorders. Previous literature focused on studying sleep disruption in bipolar disorders (BD). However, only a few studies addressed the influence of social rhythms and occupational functioning as they may affect circadian regularity and consequently be a critical pathway to mood symptoms.ObjectivesThe main aim of this study was to assess biological rhythms in remitted bipolar patients and to evaluate their social rhythms and occupational functioning.MethodsWe recruited a total of 80 euthymic outpatients with BD and 80 control subjects. Biological rhythm disruptions were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity.ResultsPatients with BD experienced greater biological rhythm alterations than the control group (BRIAN total scores 35.26±9.21 vs. 25.84±2.68). In addition to their sleep-wake rhythm (mean scores 11.1±3.95 vs. 7.41±1.41), patients were particularly more impaired than the control group with regards to social rhythms (7.31 ± 2.57 vs. 5.24 ± 1.06) and general activity (8.9 ± 3.35 vs. 7.01 ± 1.4).ConclusionsOur study indicated that patients with BD experience major disruptions in their social rhythms and occupational functioning. These alterations may lead to unstable biological rhythms and to a higher risk of mood episodes. Therefore, consolidating social rhythms and functioning appears to be a crucial step for preventing relapses in patients with BD.DisclosureNo significant relationships.

Clinical evaluation of biological rhythm domains in patients with major depression.

Objective:Sleep, physical activity, and social domains of biological rhythm disruptions may have specific effects on the symptom cluster and severity of depression. However, there is a lack of structured clinical evaluation to specify the domains of biological rhythms in patients with depression.Methods:Ninety drug-naïve subjects with depression and 91 matched healthy controls were recruited for the study. The severity of depression was examined with the Hamilton Rating Scale for Depression (HRSD), while biological rhythm was evaluated using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN).Results:Patients with depression showed significantly greater biological rhythm disturbances than healthy controls in all domains of BRIAN (sleep, activity, social, and eating). BRIAN-Total correlated positively with HRSD-Total and HRSD-Total without sleep cluster. The sleep and activity domains correlated significantly with HRSD-Total score. Additionally, the sleep, activity, and social domains correlated significantly with HRSD-Total without the sleep cluster score. Regression analysis revealed the activity (β = 0.476, t = 5.07, p<0.001) and sleep (β = 0.209, t = 2.056, p = 0.043) domains may predict HRSD-Total score.Conclusion:Consideration of biological rhythm domains in clinical examination and focusing on the sleep and activity domains may hold promise for the management of depression.

Association between emotional functioning and biological rhythm disruptions in patients with schizophrenia

Objective: Dysregulation of biological rhythm is associated with reduced executive functioning and potentiating psychosis, which are essential for the Theory of Mind (ToM) among patients with schiz...

The effects of artificial light at night on Eurasian tree sparrow (Passer montanus): Behavioral rhythm disruption, melatonin suppression and intestinal microbiota alterations

Abstract Artificial light at night (ALAN) or light pollution is rapidly widespread with fast urbanization and becomes an obvious environmental disturbance. Recent studies showed ALAN has multiple negative impacts on a wide range of species including bird biological rhythm disruption, behavioral and physiological disturbance and hormone secretion disorder. However, its effects on bird gut microbiota are scarcely studied. In this study, we used Eurasian tree sparrow (Passer montanus), a widely distributed and locally abundant bird species in both urban and rural areas of China to examine the effects of ALAN on locomotor activity rhythm and melatonin secretion, and species diversity and community structure of intestinal microbiota by simulating urban and rural night light environment. Our results showed ALAN strongly affected circadian rhythm of locomotor activity with earlier start of activity before light-on and later rest after light-off. Moreover, ALAN significantly suppressed melatonin release. Last but not least, ALAN profoundly affected taxonomic compositions, species diversity and community structure of intestinal microbiota of birds. We concluded that ALAN may cause bird health damage by disrupting circadian rhythm, inhibiting melatonin release and altering intestinal microbiota. Melatonin hormone level and intestinal microbiota diversity may be important bioindicators for light pollution.

Sleep-Wake Disturbance Related to Ocular Disease: A Systematic Review of Phase-Shifting Pharmaceutical Therapies.

PurposeLight input, via the eyes, is essential for regulating circadian rhythms. Eye diseases can cause disruption of vital biological rhythms. Of totally blind people, 87% report sleep problems. There are no UK guidelines for visual disturbance–related circadian rhythm disruption. Our objective was to systematically review the literature to determine the effectiveness of pharmacological agents on the sleep quality of patients with sleep disturbance related to ocular disease.MethodsWe searched CENTRAL, MEDLINE, EMBASE, PsycINFO, and CINAHL alongside protocol registries and citation searches. We assessed the risk of bias using the Cochrane Risk of Bias Assessment Tool and assessed the strength of overall evidence using GRADE criteria.ResultsFour studies (n=116) met the inclusion criteria. Low-quality evidence showed that melatonin can cause entrainment (1 study), increases in total sleep time (all 3 studies), and reduction in sleep latency (1 study). Low-to-moderate quality evidence showed tasimelteon causes a significant improvement in entrainment, midpoint of sleep timing, lower-quartile of night-time sleep, and upper-quartile of daytime sleep.ConclusionsResults should be treated with caution as the melatonin studies had risks of bias due to inadequate reporting of randomization and masking procedures. The tasimelteon trial had a risk of reporting bias due to changing the outcomes after enrolling participants. Despite the paucity of trials, melatonin and tasimelteon may cause entrainment and improve subjective sleep measures with limited side effects.Translational RelevanceGiven the relative cost melatonin may be a viable choice for treatment of circadian rhythm sleep disorders in the blind and warrants further research.

T97. Predicting Functioning and Quality of Life Using Objective and Subjective Measures of Sleep and Biological Rhythms in Major Depressive and Bipolar Disorder

Disruptions in biological rhythms and sleep are a core aspect of mood disorders; sleep and rhythm changes frequently occur prior to and during mood episodes.