The dynamic interplay between sleep and mood: an intensive longitudinal study of individuals with bipolar disorder.

BACKGROUND: Sleep disturbances are important symptoms to monitor in people with bipolar disorder (BD) but the precise longitudinal relationships between sleep and mood remain unclear. We aimed to examine associations between stable and dynamic aspects of sleep and mood in people with BD, and assess individual differences in the strength of these associations. METHODS: Participants (N = 649) with BD-I (N = 400) and BD-II (N = 249) provided weekly self-reports of insomnia, depression and (hypo)mania symptoms using the True Colours online monitoring tool for 21 months. Dynamic structural equation models were used to examine the interplay between weekly reports of insomnia and mood. The effects of clinical and demographic characteristics on associations were also assessed. RESULTS: Increased variability in insomnia symptoms was associated with increased mood variability. In the sample as a whole, we found strong evidence of bidirectional relationships between insomnia and depressive symptoms but only weak support for bidirectional relationships between insomnia and (hypo)manic symptoms. We found substantial variability between participants in the strength of prospective associations between insomnia and mood, which depended on age, gender, bipolar subtype, and a history of rapid cycling. CONCLUSIONS: Our results highlight the importance of monitoring sleep in people with BD. However, researchers and clinicians investigating the association between sleep and mood should consider subgroup differences in this relationship. Advances in digital technology mean that intensive longitudinal data on sleep and mood are becoming increasingly available. Novel methods to analyse these data present an exciting opportunity for furthering our understanding of BD.

Actigraphic patterns, impulsivity and mood instability in bipolar disorder, borderline personality disorder and healthy controls.

OBJECTIVES: To differentiate the relation between the structure and timing of rest-activity patterns and symptoms of impulsivity and mood instability in bipolar disorder (BD), borderline personality disorder (BPD) and healthy controls (HC). METHODS: Eighty-seven participants (31 BD, 21 BPD and 35 HC) underwent actigraph monitoring for 28 days as part of the Automated Monitoring of Symptom Severity (AMoSS) study. Impulsivity was assessed at study entry using the BIS-11. Mood instability was subsequently longitudinally monitored using the digital Mood Zoom questionnaire. RESULTS: BPD participants show several robust and significant correlations between non-parametric circadian rest-activity variables and worsened symptoms. Impulsivity was associated with low interdaily stability (r = -0.663) and weak amplitude (r = -0.616). Mood instability was associated with low interdaily stability (r = -0.773), greater rhythm fragmentation (r = 0.662), weak amplitude (r = -0.694) and later onset of daily activity (r = 0.553). These associations were not present for BD or HCs. Classification analysis using actigraphic measures determined that later L5 onset reliably distinguished BPD from BD and HC but did not sufficiently discriminate between BD and HC. CONCLUSIONS: Rest-activity pattern disturbance indicative of perturbed sleep and circadian function is an important predictor of symptom severity in BPD. This appears to validate the greater subjective complaints of BPD individuals that are sometimes regarded as exaggerated by clinicians. We suggest that treatment strategies directed towards improving sleep and circadian entrainment may in the future be investigated in BPD.

Mood instability: significance, definition and measurement.

Mood instability is common, and an important feature of several psychiatric disorders. We discuss the definition and measurement of mood instability, and review its prevalence, characteristics, neurobiological correlates and clinical implications. We suggest that mood instability has underappreciated transdiagnostic potential as an investigational and therapeutic target.

Borderline personality disorder, but not euthymic bipolar disorder, is associated with a failure to sustain reciprocal cooperative behaviour: implications for spectrum models of mood disorders.

BACKGROUND: Borderline personality disorder (BPD) and bipolar disorder (BD) have overlapping clinical presentations and symptoms - sources of persistent clinical confusion. Game-theory can characterize how social function might be sub-optimal in the two disorders and move the field beyond the anecdotal description of clinical history. Here, we tested the hypothesis that BPD and BD can be distinguished on the basis of diminished reciprocal altruism in iterated Prisoner's Dilemma (PD) games. METHOD: Twenty females with BPD, 20 females with euthymic BD and 20 healthy (non-clinical) females, matched for age and cognitive ability, were assessed for Axis-I and personality disorders, and completed psychometric measures of state affect, impulsivity and hostility. Participants completed two iterated PD games and a test of gaze-cueing. RESULTS: In the PD games, BPD participants failed to show statistically stable preferences to cooperate with social partners (playing tit-for-tat) and made significantly fewer cooperative responses compared to BD or controls (ANOVA main effect p = 0.03, post-hoc Tukey p < 0.05 for both comparisons). BPD participants were also less likely to sustain cooperation following experiences involving mutual cooperation than the other groups. Neither BPD nor BD participants demonstrated impairments in shifting visual attention on the basis of other peoples' gaze. CONCLUSIONS: These data indicate that BPD is (selectively) associated with difficulties in establishing, and then maintaining, reciprocal cooperation, involving altruism. These difficulties are not seen in euthymic BD. Our data support the differentiation of BPD from BD and offer fresh insights into the social difficulties experienced by individuals with diagnoses of BPD.

Mental health and academic outcomes over the first year at university in international compared to domestic Canadian students.

OBJECTIVE: To compare risk factors and associated mental health and academic outcomes between international and domestic students. PARTICIPANTS: Canadian university undergraduate students. METHODS: Electronic surveys were completed at university entry and the end of first year. Surveys assessed demographics, risk factors, symptoms of mental disorders, and access to support. Academic outcomes were obtained from university databases. RESULTS: International students had comparable or lower rates of clinically significant anxiety, depression, and insomnia. Domestic female students reported the highest screening rates for common mental disorders. However, international students were more likely to report having attempted suicide. International students felt less connected to the university community and had lower academic performance. Psychosocial risk factor profiles and proportions accessing mental health services were similar. CONCLUSIONS: The scope of mental health need appears more similar than different between international and domestic students; however, international students may benefit from targeted academic and social support initiatives.

Efficacy of digital cognitive behavioural therapy for symptoms of generalised anxiety disorder: a study protocol for a randomised controlled trial.

BACKGROUND: Generalised anxiety disorder (GAD) is a chronic and disabling condition with considerable personal and economic impact. Cognitive behavioural therapy (CBT) is a recommended psychological therapy for GAD; however, there are substantial barriers to accessing treatment. Digital CBT, in particular smartphone-delivered CBT, has the potential to improve accessibility and increase dissemination of CBT. Despite the emerging evidence of smartphone-based psychological interventions for reducing anxiety, effect size scores are typically smaller than in-person interventions, and there is a lack of research assessing the efficacy of smartphone-delivered digital interventions specifically for GAD. METHODS: In the DeLTA trial (DigitaL Therapy for Anxiety), we plan to conduct a parallel-group superiority randomised controlled trial examining the efficacy of a novel smartphone-based digital CBT intervention for GAD compared to a waitlist control. We aim to recruit 242 adults (aged 18 years or above) with moderate-to-severe symptoms of GAD. This trial will be conducted entirely online and will involve assessments at baseline (week 0; immediately preceding randomisation), mid-intervention (week 3), post-intervention (week 6; primary end point) and follow-up (week 10). The primary objective is to evaluate the efficacy of the intervention on GAD symptom severity compared to a waitlist control at post-intervention. Secondary objectives are to examine between-group effects on GAD at follow-up, and to examine the following secondary outcomes at both post-intervention and follow-up: 1) worry; 2) depressive symptoms; 3) wellbeing; 4) quality of life; and 5) sleep difficulty. DISCUSSION: This trial will report findings on the initial efficacy of a novel digital CBT intervention for GAD. Results have the potential to contribute towards the evidence base for digital CBT for GAD and increase the dissemination of CBT. TRIAL REGISTRATION: ISRCTN, ISRCTN12765810. Registered on 11 January 2019.

Predictors of mental health and academic outcomes in first-year university students: Identifying prevention and early-intervention targets.

BACKGROUND: Although there is growing interest in mental health problems in university students there is limited understanding of the scope of need and determinants to inform intervention efforts. AIMS: To longitudinally examine the extent and persistence of mental health symptoms and the importance of psychosocial and lifestyle factors for student mental health and academic outcomes. METHOD: Undergraduates at a Canadian university were invited to complete electronic surveys at entry and completion of their first year. The baseline survey measured important distal and proximal risk factors and the follow-up assessed mental health and well-being. Surveys were linked to academic grades. Multivariable models of risk factors and mental health and academic outcomes were fit and adjusted for confounders. RESULTS: In 1530 students surveyed at entry to university 28% and 33% screened positive for clinically significant depressive and anxiety symptoms respectively, which increased to 36% and 39% at the completion of first year. Over the academic year, 14% of students reported suicidal thoughts and 1.6% suicide attempts. Moreover, there was persistence and overlap in these mental health outcomes. Modifiable psychosocial and lifestyle factors at entry were associated with positive screens for mental health outcomes at completion of first year, while anxiety and depressive symptoms were associated with lower grades and university well-being. CONCLUSIONS: Clinically significant mental health symptoms are common and persistent among first-year university students and have a negative impact on academic performance and well-being. A comprehensive mental health strategy that includes a whole university approach to prevention and targeted early-intervention measures and associated research is justified.

Variability in phase and amplitude of diurnal rhythms is related to variation of mood in bipolar and borderline personality disorder.

Variable mood is an important feature of psychiatric disorders. However, its measurement and relationship to objective measureas of physiology and behaviour have rarely been studied. Smart-phones facilitate continuous personalized prospective monitoring of subjective experience and behavioural and physiological signals can be measured through wearable devices. Such passive data streams allow novel estimates of diurnal variability. Phase and amplitude of diurnal rhythms were quantified using new techniques that fitted sinusoids to heart rate (HR) and acceleration signals. We investigated mood and diurnal variation for four days in 20 outpatients with bipolar disorder (BD), 14 with borderline personality disorder (BPD) and 20 healthy controls (HC) using a smart-phone app, portable electrocardiogram (ECG), and actigraphy. Variability in negative affect, positive affect, and irritability was elevated in patient groups compared with HC. The study demonstrated convincing associations between variability in subjective mood and objective variability in diurnal physiology. For BPD there was a pattern of positive correlations between mood variability and variation in activity, sleep and HR. The findings suggest BPD is linked more than currently believed with a disorder of diurnal rhythm; in both BPD and BD reducing the variability of sleep phase may be a way to reduce variability of subjective mood.

Experiences of remote mood and activity monitoring in bipolar disorder: A qualitative study.

BACKGROUND: Mobile technology enables high frequency mood monitoring and automated passive collection of data (e.g. actigraphy) from patients more efficiently and less intrusively than has previously been possible. Such techniques are increasingly being deployed in research and clinical settings however little is known about how such approaches are experienced by patients. Here, we explored the experiences of individuals with bipolar disorder engaging in a study involving mood and activity monitoring with a range of portable and wearable technologies. METHOD: Patients were recruited from a wider sample of 50 individuals with Bipolar Disorder taking part in the Automated Monitoring of Symptom Severity (AMoSS) study in Oxford. A sub-set of 21 patients participated in a qualitative interview that followed a semi-structured approach. RESULTS: Monitoring was associated with benefits including increased illness insight, behavioural change. Concerns were raised about the potential preoccupation with, and paranoia about, monitoring. Patients emphasized the need for personalization, flexibility, and the importance of context, when monitoring mood. CONCLUSIONS: Mobile and electronic health approaches have potential to lend new insights into mental health and transform healthcare. Capitalizing on the perceived utility of these approaches from the patients' perspective, while addressing their concerns, will be essential for the promise of new technologies to be realised.

Detecting Bipolar Depression From Geographic Location Data.

OBJECTIVE: This paper aims to identify periods of depression using geolocation movements recorded from mobile phones in a prospective community study of individuals with bipolar disorder (BD). METHODS: Anonymized geographic location recordings from 22 BD participants and 14 healthy controls (HC) were collected over 3 months. Participants reported their depressive symptomatology using a weekly questionnaire (QIDS-SR16). Recorded location data were preprocessed by detecting and removing imprecise data points and features were extracted to assess the level and regularity of geographic movements of the participant. A subset of features were selected using a wrapper feature selection method and presented to 1) a linear regression model and a quadratic generalized linear model with a logistic link function for questionnaire score estimation; and 2) a quadratic discriminant analysis classifier for depression detection in BD participants based on their questionnaire responses. R esults: HC participants did not report depressive symptoms and their features showed similar distributions to nondepressed BD participants. Questionnaire score estimation using geolocation-derived features from BD participants demonstrated an optimal mean absolute error rate of 3.73, while depression detection demonstrated an optimal (median ± IQR) [Formula: see text] score of 0.857 ± 0.022 using five features (classification accuracy: 0.849 ± 0.016; sensitivity: 0.839 ± 0.014; specificity: 0.872 ± 0.047). CONCLUSION: These results demonstrate a strong link between geographic movements and depression in bipolar disorder. S ignificance: To our knowledge, this is the first community study of passively recorded objective markers of depression in bipolar disorder of this scale. The techniques could help individuals monitor their depression and enable healthcare providers to detect those in need of care or treatment.

Daily longitudinal self-monitoring of mood variability in bipolar disorder and borderline personality disorder.

BACKGROUND: Traditionally, assessment of psychiatric symptoms has been relying on their retrospective report to a trained interviewer. The emergence of smartphones facilitates passive sensor-based monitoring and active real-time monitoring through time-stamped prompts; however there are few validated self-report measures designed for this purpose. METHODS: We introduce a novel, compact questionnaire, Mood Zoom (MZ), embedded in a customised smart-phone application. MZ asks participants to rate anxiety, elation, sadness, anger, irritability and energy on a 7-point Likert scale. For comparison, we used four standard clinical questionnaires administered to participants weekly to quantify mania (ASRM), depression (QIDS), anxiety (GAD-7), and quality of life (EQ-5D). We monitored 48 Bipolar Disorder (BD), 31 Borderline Personality Disorders (BPD) and 51 Healthy control (HC) participants to study longitudinal (median±iqr: 313±194 days) variation and differences of mood traits by exploring the data using diverse time-series tools. RESULTS: MZ correlated well (|R|>0.5,p<0.0001) with QIDS, GAD-7, and EQ-5D. We found statistically strong (|R|>0.3,p<0.0001) differences in variability in all questionnaires for the three cohorts. Compared to HC, BD and BPD participants exhibit different trends and variability, and on average had higher self-reported scores in mania, depression, and anxiety, and lower quality of life. In particular, analysis of MZ variability can differentiate BD and BPD which was not hitherto possible using the weekly questionnaires. LIMITATIONS: All reported scores rely on self-assessment; there is a lack of ongoing clinical assessment by experts to validate the findings. CONCLUSIONS: MZ could be used for efficient, long-term, effective daily monitoring of mood instability in clinical psychiatric practice.

Distinguishing bipolar disorder from borderline personality disorder: A study of current clinical practice.

BACKGROUND: Diagnosing mental illness is a central role for psychiatrists. Correct diagnosis informs both treatment and prognosis, and facilitates accurate communication. We sought to explore how psychiatrists distinguished two common psychiatric diagnoses: bipolar disorder (BD) and borderline personality disorder (BPD). METHODS: We conducted a qualitative study of psychiatrists to explore their practical experience. We then sought to validate these results by conducting a questionnaire study testing the theoretical knowledge and practical experience of a large number of UK psychiatrists. Finally we studied the assessment process in NHS psychiatric teams by analysing GP letters, assessments by psychiatrists, and assessment letters. RESULTS: There was broad agreement in both the qualitative and questionnaire studies that the two diagnoses can be difficult to distinguish. The majority of psychiatrists demonstrated in survey responses a comprehensive understanding DSM-IV-TR criteria although many felt that these criteria did not necessarily assist diagnostic differentiation. This scepticism about diagnostic criteria appeared to strongly influence clinical practice in the sample of clinicians we observed. In only a minority of assessments were symptoms of mania or BPD sufficiently assessed to establish the presence or absence of each diagnosis. CONCLUSION: Clinical diagnostic practice was not adequate to differentiate reliably BD and BPD. The absence of reliable diagnostic practice has widespread implications for patient care, service provision and the reliability of clinical case registries.

Accelerated growth without prepubertal obesity in nutritionally programmed microswine offspring.

Poor fetal growth and associated prepubertal growth acceleration are linked to increased risk of cardiometabolic dysfunction in later life, but whether obesity is integral to 'catch-up' growth and its ensuing risks are unknown. In microswine offspring exposed to perinatal maternal protein restriction (MPR), we measured body and organ sizes (during MPR); linear growth and weight gain (birth to 5 months of age); feed intake and utilization efficiency (5-14 weeks); and body composition at 6 and 11 weeks of age (by dual-energy X-ray absorptiometry, DEXA). During MPR, low protein offspring (LPO) showed asymmetric growth restriction with reduced body weight (Wt):length (Lth) at birth and elevated heart Wt:liver Wt ratio by 2 weeks of age. In LPO, after slow early postnatal growth (0-5 weeks), subsequent linear growth on ad libitum normal feed was absolutely accelerated (cm/week; P < 0.001) over 6-11 weeks but normal thereafter, whereas absolute weight gain (kg/week) was similar to controls but accelerated relative to lower LPO nadir weights. Concurrently, rates of fat and lean tissue accrual in LPO over 6-11 weeks were similar to normal protein offspring in absolute terms (g/5 weeks) but increased relative to lower mass at 6 weeks, yielding normal lean:Lth but reduced fat:Lth ratios at 11 weeks. LPO had higher relative feed intake (g/kg/meal) in both sexes and higher feed efficiency in females over 5-11 weeks of age. Findings suggest that postnatal linear growth acceleration preserved thinness in juvenile LPO. Given separately reported abnormalities of vascular (Bagby et al., 2011) and adipocyte function in juvenile LPO, (DuPriest et al., 2011) findings demonstrate that perinatal MPR programs catch-up growth and cardiovascular abnormalities independently of obesity.

Altered adipocyte structure and function in nutritionally programmed microswine offspring.

Adipose tissue (AT) dysfunction links obesity of any cause with cardiometabolic disease, but whether early-life nutritional deficiency can program adipocyte dysfunction independently of obesity is untested. In 3-5-month-old juvenile microswine offspring exposed to isocaloric perinatal maternal protein restriction (MPR) and exhibiting accelerated prepubertal fat accrual without obesity, we assessed markers of acquired obesity: adiponectin and tumor necrosis factor (TNF)-α messenger ribonucleic acid (mRNA) levels and adipocyte size in intra-abdominal (ABD-AT) and subcutaneous (SC-AT) adipose tissues. Plasma cortisol, leptin and insulin levels were measured in fetal, neonatal and juvenile offspring. In juvenile low-protein offspring (LPO), adipocyte size in ABD-AT was reduced 22% (P = 0.011 v. controls), whereas adipocyte size in SC-AT was increased in female LPO (P = 0.05) and normal in male LPO; yet, adiponectin mRNA in LPO was low in both sexes and in both depots (P < 0.001). Plasma leptin (P = 0.004) and cortisol (P < 0.05) were reduced only in neonatal LPO during MPR. In juveniles, correlations between % body fat and adiponectin mRNA, TNF-α mRNA or plasma leptin were significant in normal-protein offspring (NPO) but absent in LPO. Plasma glucose in juvenile LPO was increased in males but decreased in females (interaction, P = 0.023); plasma insulin levels and insulin sensitivity were unaffected. Findings support nutritional programming of adipocyte size and gene expression and subtly altered glucose homeostasis. Reduced adiponectin mRNA and adipokine dysregulation in juvenile LPO following accelerated growth occurred independently of obesity, adipocyte hypertrophy or inflammatory markers; thus, perinatal MPR and/or growth acceleration can alter adipocyte structure and disturb adipokine homeostasis in metabolically adverse patterns predictive of enhanced disease risk.

A probable case of the homozygous condition of the aniridia gene.

A non-consanguineous union between two people with congenital aniridia is described which resulted in the stillbirth of a female fetus with complete absence of eyes, nose, and adrenal glands.

Use of pulsed-field gel electrophoresis to determine genomic diversity in strains of Helicobacter hepaticus from geographically distant locations.

In 1992 a helical microorganism associated with chronic active hepatitis and a high incidence of hepatocellular tumors was identified in the hepatic parenchyma of A/JCr mice. By using biochemical tests, phenotypic characterization, and 16S rRNA gene sequence analysis, the organism was classified as a novel Helicobacter species and named Helicobacter hepaticus. Recent surveys completed in our laboratory indicate that H. hepaticus is widespread in academic and commercial mouse colonies. The aim of this study was to examine the H. hepaticus genome by pulsed-field gel electrophoresis (PFGE) to determine the degree of genomic variation and genomic size. This technique has been used to identify significant genomic diversity among strains of Helicobacter pylori and to demonstrate only slight genomic diversity among strains of Helicobacter mustelae. Genomic DNAs from 11 isolates of H. hepaticus from the United States, Germany, France, and The Netherlands were subjected to PFGE after digestion with SmaI. Isolates from three independent sources within the United States had very similar PFGE patterns, suggesting that the genomic DNAs of these isolates are conserved. Genomic DNA isolated from a fourth source within the United States had a PFGE pattern different from those of the other U.S. isolates. Isolates obtained from Germany, France, and The Netherlands had PFGE patterns that differed markedly from those of the U.S. isolates and from one another. The use of DNA fingerprinting may be useful in subsequent epidemiological studies of H. hepaticus when the source and method of spread of this murine pathogen need to be ascertained. By PFGE, the genomic size of H. hepaticus is estimated to be roughly 1.3 Mb, which compares to 1.67 Mb for H. pylori and 1.7 Mb for H. mustelae.

Novel intestinal Helicobacter species isolated from cotton-top tamarins (Saguinus oedipus) with chronic colitis.

A disease similar to ulcerative colitis in humans has been identified in cotton-top tamarins (CTTs) in captivity. The clinical signs include weight loss, diarrhea, and rectal bleeding with the pathological features and biochemical abnormalities of ulcerative colitis. Approximately 25 to 40% of these animals develop colon cancer after 2 to 5 years of captivity. An infectious etiology has been proposed; however, no microbial agent to date has been identified. Helicobacter spp. have been associated with enterocolitis and inflammatory bowel disease (IBD) in humans and animals. Infection with Helicobacter pylori or Helicobacter mustelae is associated with an increased risk of gastric adenocarcinoma and lymphoma of the mucosa-associated lymphoid tissue. Helicobacter hepaticus causes hepatitis, hepatic adenomas, and hepatocellular carcinomas in susceptible strains of mice. The aim of this study was to assess a colony of CTTs with a high incidence of IBD and colon cancer for the presence of colonic Helicobacter spp. A fusiform, gram-negative bacterium with bipolar flagella and periplasmic fibers was isolated from the feces of CTTs. The bacterium grew under microaerobic conditions at 37 and 42 degrees C but not at 25 degrees C, did not hydrolyze urea, was positive for catalase and oxidase, did not reduce nitrate to nitrite, did not hydrolyze indoxyl acetate or alkaline phosphatase, and was resistant to nalidixic acid, cephalothin, and trimethoprim-sulfamethoxazole. On the basis of 16S rRNA gene sequence analysis, the organism was classified as a novel Helicobacter species. This is the first Helicobacter isolated from CTTs. Further studies are needed to elucidate the role of this novel Helicobacter sp. in the pathogenesis of ulcerative colitis and colonic adenocarcinoma in CTTs.