A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives.

AIMS: Substantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. METHODS: In a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. RESULTS: Compared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12-1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09-1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04-1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02-1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC. Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75-0.77) CONCLUSIONS: Higher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD.

Association between lifetime and recent stressful life events and the early course and psychopathology in patients with newly diagnosed bipolar disorder, first-degree unaffected relatives and healthy controls: Cross-sectional results from a prospective study.

OBJECTIVE: There is an accumulation of stressful life events prior to the first mood episode, but the impact of previous severe life events on psychopathology in patients with bipolar disorder (BD) is not well studied. We aimed to examine the number of recent and lifetime life events in patients with newly diagnosed BD, their unaffected relatives (UR), and healthy controls (HC) as well as the impact of severe lifetime life events on the early course of BD. METHODS: We compared the number of recent and lifetime life events in 398 patients with newly diagnosed BD, 109 UR, and 214 HC. We subsequently dichotomized the patients with BD by >2 lifetime life events to investigate the associations of severe lifetime life events with clinical characteristics and affective symptoms. RESULTS: Patients with newly diagnosed BD reported significantly more life events in the last 12 months and lifetime before compared with UR and HC. Patients who reported >2 lifetime life events (n = 160) compared with patients with 0-2 life events (n = 238) had a significantly longer diagnostic delay (9.5 years ± 8.2 vs. 6.2 years ± 6.9), presented with more anxiety and depressive symptoms and had at least one previous suicide attempt (30.6% vs. 15.6%) and one previous admission (51.3% vs. 36.6%). CONCLUSION: The experience of severe lifetime life events seems to impact the early course in BD in terms of longer diagnostic delay, more severe psychopathology including more admissions and a more than doubled risk for previous suicide attempts.

A nationwide population-based longitudinal study mapping psychiatric disorders during lifetime in siblings to patients with bipolar disorder.

OBJECTIVE: The aim was to map rates and cumulative incidences of psychiatric disorders during lifetime for siblings to patients with a diagnosis of bipolar disorder compared with the general population. METHODS: Danish nationwide population-based longitudinal register linkage study including 13,923 unaffected siblings to 19,955 patients with bipolar disorder and 278,460 unaffected control individuals from the general population matched according to year of birth and sex. Follow-up covered 22 years from 1995 to 2017. RESULTS: Rates of 'any psychiatric disorder' among siblings compared with control individuals were constantly around twofold increased throughout lifespan whereas there was a bimodal age distribution of hazard ratios of bipolar disorder, unipolar disorder and use of alcohol or psychoactive drugs with the highest hazard ratios up to age 20 and above 60 years of age. Cumulative incidences from age 15 years of any psychiatric disorder were 44.2% at age 80 years for siblings versus 27.6% for control individuals and the corresponding numbers for bipolar disorder was 8.7% for siblings compared with 1.6% for control individuals. CONCLUSION: Strategies to prevent onset of psychiatric illness in individuals with a first-generation family history of bipolar disorder should not be limited to adolescence and early adulthood but should be lifetime, likely with differentiated age-specific strategies.

Circadian reinforcement therapy in combination with electronic self-monitoring to facilitate a safe post-discharge period of patients with depression by stabilizing sleep: protocol of a randomized controlled trial.

BACKGROUND: The transition phase from inpatient to outpatient care for patients suffering from Major Depressive Disorder represents a vulnerable period associated with a risk of depression worsening and suicide. Our group has recently found that the sleep-wake cycle in discharged depressive patients became irregular and exhibited a drift towards later hours, associated with worsening of depression. In contrast, an advancement of sleep phase has earlier been shown to have an antidepressant effect. Thus, methods to prevent drift of the sleep-wake cycle may be promising interventions to prevent or reduce worsening of depression after discharge. METHODS: In this trial, we apply a new treatment intervention, named Circadian Reinforcement Therapy (CRT), to patients discharged from inpatient psychiatric wards. CRT consists of a specialized psychoeducation on the use of regular time signals (zeitgebers): daylight exposure, exercise, meals, and social contact. The aim is to supply stronger and correctly timed zeitgebers to the circadian system to prevent sleep drift and worsening of depression. The CRT is used in combination with an electronic self-monitoring system, the Monsenso Daybuilder System (MDB). By use of the MDB system, all patients self-monitor their sleep, depression level, and activity (from a Fitbit bracelet) daily. Participants can inspect all their data graphically on the MDB interface and will have clinician contact. The aim is to motivate patients to keep a stable sleep-wake cycle. In all, 130 patients referred to an outpatient service will be included. Depression rating is blinded. Patients will be randomized 1:1 to a Standard group or a CRT group. The intervention period is 4 weeks covering the transition phase from inpatient to outpatient care. The primary outcome is score change in interviewer rated levels of depression on the Hamilton Depression Rating Scale. A subset of patients will be assessed with salivary Dim Light Melatonin Onset (DLMO) as a validator of circadian timing. The trial was initiated in 2016 and will end in 2020. DISCUSSION: If the described intervention is beneficial it could be incorporated into usual care algorithms for depressed patients to facilitate a better and safer transition to outpatient treatment. TRIAL REGISTRATION: Posted prospectively at ClinicalTrials.gov at February 10, 2016 with identifier NCT02679768 .

Lithium induced hypercalcemia: an expert opinion and management algorithm.

BACKGROUND: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. METHODS: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. RESULTS: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. CONCLUSIONS: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment.

Forecasting Mood in Bipolar Disorder From Smartphone Self-assessments: Hierarchical Bayesian Approach.

BACKGROUND: Bipolar disorder is a prevalent mental health condition that is imposing significant burden on society. Accurate forecasting of symptom scores can be used to improve disease monitoring, enable early intervention, and eventually help prevent costly hospitalizations. Although several studies have examined the use of smartphone data to detect mood, only few studies deal with forecasting mood for one or more days. OBJECTIVE: This study aimed to examine the feasibility of forecasting daily subjective mood scores based on daily self-assessments collected from patients with bipolar disorder via a smartphone-based system in a randomized clinical trial. METHODS: We applied hierarchical Bayesian regression models, a multi-task learning method, to account for individual differences and forecast mood for up to seven days based on 15,975 smartphone self-assessments from 84 patients with bipolar disorder participating in a randomized clinical trial. We reported the results of two time-series cross-validation 1-day forecast experiments corresponding to two different real-world scenarios and compared the outcomes with commonly used baseline methods. We then applied the best model to evaluate a 7-day forecast. RESULTS: The best performing model used a history of 4 days of self-assessment to predict future mood scores with historical mood being the most important predictor variable. The proposed hierarchical Bayesian regression model outperformed pooled and separate models in a 1-day forecast time-series cross-validation experiment and achieved the predicted metrics, R2=0.51 and root mean squared error of 0.32, for mood scores on a scale of -3 to 3. When increasing the forecast horizon, forecast errors also increased and the forecast regressed toward the mean of data distribution. CONCLUSIONS: Our proposed method can forecast mood for several days with low error compared with common baseline methods. The applicability of a mood forecast in the clinical treatment of bipolar disorder has also been discussed.

Reporting guidelines on remotely collected electronic mood data in mood disorder (eMOOD)-recommendations.

Prospective monitoring of mood was started by Kraepelin who made and recorded frequent observations of his patients. During the last decade, the number of research studies using remotely collected electronic mood data has increased markedly. However, standardized measures and methods to collect, analyze and report electronic mood data are lacking. To get better understanding of the nature, correlates and implications of mood and mood instability, and to standardize this process, we propose guidelines for reporting of electronic mood data (eMOOD). This paper provides an overview of remotely collected electronic mood data in mood disorders and discusses why standardized reporting is necessary to evaluate and inform mood research in Psychiatry. Adherence to these guidelines will improve interpretation, reproducibility and future meta-analyses of mood monitoring in mood disorder research.

Areas of uncertainties and unmet needs in bipolar disorders: clinical and research perspectives.

This Review discusses crucial areas related to the identification, clinical presentation, course, and therapeutic management of bipolar disorder, a major psychiatric illness. Bipolar disorder is often misdiagnosed, leading to inappropriate, inadequate, or delayed treatment. Even when bipolar disorder is successfully diagnosed, its clinical management presents several major challenges, including how best to optimise treatment for an individual patient, and how to balance the benefits and risks of polypharmacy. We discuss the major unmet needs in the diagnosis and management of bipolar disorder in this Review, including improvement of adequate recognition and intervention in at-risk and early-disease stages, identification of reliable warning signs and prevention of relapses in unstable and rapid cycling patients, treatment of refractory depression, and prevention of suicide. Taken together, there are several promising opportunities for improving treatment of bipolar disorder to deliver medical care that is more personalised.

Parkinson's disease and antidepressant drug treatment: a case-register study.

UNLABELLED: We estimated the nationwide prevalence rate of antidepressant drug treatment in Parkinson's disease (PD) patients. BACKGROUND: Very few studies exist on the frequency of antidepressant drug treatment in patients with PD. METHOD: Patients with a PD diagnosis at first hospital contact were identified and followed for up to 6 years. The subsequent probability of antidepressant drug treatment was estimated and compared to a control group of patients with osteoarthritis. RESULTS: The probability of antidepressant drug treatment was 3.98 [95% CI: 3.23-4.91) times higher for PD patients than for controls. CONCLUSION: Patients with PD have higher rates of actual antidepressant drug treatment than a control group with osteoarthritis. Still, however, undertreatment of depressive states may be the case.

Diagnostic stability in pediatric bipolar disorder.

BACKGROUND: The diagnostic stability of pediatric bipolar disorder has not been investigated previously. The aim was to investigate the diagnostic stability of the ICD-10 diagnosis of pediatric mania/bipolar disorder. METHODS: All patients below 19 years of age who got a diagnosis of mania/bipolar disorder at least once in a period from 1994 to 2012 at psychiatric inpatient or outpatient contact in Denmark were identified in a nationwide register. RESULTS: Totally, 354 children and adolescents got a diagnosis of mania/bipolar disorder at least once; a minority, 144 patients (40.7%) got the diagnosis at the first contact whereas the remaining patients (210; 59.3%) got the diagnosis at later contacts before age 19. For the latter patients, the median time elapsed from first treatment contact with the psychiatric service system to the first diagnosis with a manic episode/bipolar disorder was nearly 1 year and for 25% of those patients it took more than 2½ years before the diagnosis was made. The most prevalent other diagnoses than bipolar disorder at first contact were depressive disorder (21.4%), acute and transient psychotic disorders or other non-organic psychosis (19.2%), reaction to stress or adjustment disorder (14.8%) and behavioral and emotional disorders with onset during childhood or adolescents (10.9%). Prevalence rates of schizophrenia, personality disorders, anxiety disorder or hyperkinetic disorders (ADHD) were low. LIMITATIONS: Data concern patients who get contact to hospital psychiatry only. CONCLUSIONS: Clinicians should be more observant on manic symptoms in children and adolescents who at first glance present with transient psychosis, reaction to stress/adjustment disorder or with behavioral and emotional disorders with onset during childhood or adolescents (F90-98) and follow these patients more closely over time identifying putable hypomanic and manic symptoms as early as possible.

Cytokines in bipolar disorder: a systematic review and meta-analysis.

BACKGROUND: Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according to affective state. METHODS: We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement. RESULTS: Thirteen studies were included, comprising 556 bipolar disorder patients and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared with healthy control subjects (p<0.01 for each). Levels of sTNF-R1 and TNF-α were elevated in manic patients compared to euthymic patients (p=0.01 and p=0.04, respectively). sTNF-R1 levels were elevated in euthymic patients compared with healthy control subjects (p<0.01). There were no significant findings for other comparisons, including intra-individual alterations of cytokine levels. LIMITATIONS: Stratification according to mood state resulted in small study numbers for some cytokines. Findings were limited by heterogeneity, small sample sizes and a lack of control for confounding factors in individual studies. CONCLUSIONS: This meta-analysis found some support for immune dysregulation in bipolar disorder. Future research is warranted to elucidate the role of endogenous cytokine alterations in bipolar disorder. Clinical studies examining longitudinal changes within individuals are recommended.

Interaction between genetic polymorphisms and stressful life events in first episode depression.

BACKGROUND: A polymorphism in the serotonin transporter (5-HTT) gene seems to moderate the influence of stressful life events on depression. However, the results from previous studies of gene-environment interactions in depression are inconsistent and might be confounded by the history of depression among participants. METHOD: We applied a case-only design, including 290 ethnically homogeneous patients suffering exclusively from first episode depression. Psychiatric mo-morbidity, personality traits and disorders and stressful life events in a six months period preceding onset of depression were evaluated by means of interviews and questionnaires. Additionally, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophane hydroxylase, and the serotonin receptors 1A, 2A, and 2C. RESULTS: The low activity variants of the 5-HTT-linked polymorphic region in the serotonin transporter gene and the Met-allele of a single nucleotide polymorphism (Val66Met) in the gene encoding brain derived neurotrophic factor were independently associated with the presence of stressful life events prior to onset of depression, also when corrected for the effect of age, gender, marital status, personality disorder, neuroticism, and severity of depressive symptoms at the time of interview. CONCLUSION: Polymorphisms in the genes encoding the serotonin transporter and the brain derived neurotrophic factor interact with recent stressful life events on depression among patients with no history of previous depressive episodes.