Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Associations between oxidative stress and perceived stress in patients with bipolar disorder and healthy control individuals.

OBJECTIVE: Patients with neurodegenerative disorders, schizophrenia, and bipolar disorder present with increased oxidative stress markers. Not only is oxidative stress associated with development of disease, but also with increased disease progression and mortality. Oxidative stress reflects an increase in pro-oxidants, which subsequently leads to oxidative modifications of cellular components, such as RNA and DNA. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the valid marker of whole-body RNA and DNA damage, respectively. Recently, cerebrospinal fluid (CSF) oxidative stress markers of RNA damage (8-oxoGuo) have showed both state and trait dependence in patients with bipolar disorder. However, the relation to subjective measures of stress and quality of life (QoL) is unknown. MATERIALS AND METHODS: This prospective, longitudinal 1-year follow-up case-control study investigated the association between the oxidative stress markers, 8-oxoGuo and 8-oxodG and, perceived stress and QoL in patients with bipolar disorder (n = 86, 51% female) and gender-and-age-matched healthy control (HC) individuals (n = 44, 44% female). Oxidative stress markers obtained in CSF and urine were analysed using ultra-performance liquid chromatography-tandem mass spectrometry. The subjective perception of stress was assessed using the Perceived Stress Scale. Subjective evaluation of QoL was assessed using the World Health Organization Quality of Life questionnaire. RESULTS AND CONCLUSION: We found that markers of oxidative stress in CSF and urine were not associated with perceived stress and QoL quality in patients with bipolar disorder. However, a putative association between urinary 8-oxoGuo oxidative stress marker for RNA damage and perceived stress in HC encourages further investigations.

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 .

A randomized placebo-controlled trial examining the effects of escitalopram on neuroticism and state anxiety in a nonclinical sample.

OBJECTIVE: This study reanalyzed data from a randomized placebo-controlled trial that failed to find an effect of the selective serotonin reuptake inhibitor escitalopram on neuroticism and state anxiety in a nonclinical sample. The purpose was to test for unique effects on two neuroticism factors, trait anxiety and mood instability, and to explore whether neuroticism moderated the effect of escitalopram on state anxiety. METHODS: The sample included 80 adults who had a first-degree relative with major depression but without any psychiatric disorders themselves. Participants were randomized to escitalopram 10 mg/day or placebo for 4 weeks. Neuroticism was assessed with the Eysenck Personality Questionnaire (EPQ) and state anxiety with the Hamilton Anxiety Rating Scale (HAM-A). RESULTS: The main effects on the neuroticism factors were not statistically significant, although there was a significant interaction such that the effect of escitalopram compared with placebo on HAM-A scores was statistically significant in participants with higher levels of EPQ trait anxiety, even after controlling for baseline HAM-A scores. A similar interaction with EPQ mood instability was nonsignificant. CONCLUSION: A potential beneficial effect of escitalopram on neuroticism may be driven by reductions in anxiety.

The relationship between self-reported childhood adversities, adulthood psychopathology and psychological stress markers in patients with schizophrenia.

BACKGROUND: Childhood adversity is a well-established risk factor for the development of schizophrenia. In particular, there is evidence that childhood adversity increases the occurrence of positive symptoms, possibly through glucocorticoid influences on dopaminergic neurotransmission. AIMS: To compare levels of childhood trauma in schizophrenia patients vs. healthy control persons, and to study the association between childhood adversity and the symptomatology of adulthood schizophrenia, as well as subjective and biological markers of psychological stress. METHODS: Thirty-seven patients fulfilling ICD-10 criteria for schizophrenia and 39 healthy control persons filled out the comprehensive Childhood Abuse and Trauma Scale (CATS). Data were analyzed after a data-driven dichotomization into two groups of either high or low CATS score in patients and controls, respectively. The psychopathology of the patients was measured by the Positive and Negative Syndrome Scale (PANSS) and analyzed by a five-factor PANSS model. Measures of perceived stress (Perceived Stress Scale) and hypothalamic-pituitary-adrenal (HPA)-axis activity (9AM plasma cortisol and daytime salivary cortisol output) were recorded. RESULTS: As expected, patients had significantly higher total CATS scores than the control persons (>3-fold, P<0.001), reflecting significantly higher scores across all subscales of the CATS. In patients, the total PANSS score did not significantly differ between the high and the low CATS score group (P=0.2). However, there was a statistically significant higher level of positive symptoms in the high CATS group (P=0.014), and no difference in other psychopathological domains. Correspondingly, when using the CATS score as a continuous variable, a strong association with positive PANSS scores was found (P=0.009). The high CATS score group showed higher levels of perceived stress (P=0.02), but there was no difference between the high vs. low CATS group in HPA-axis activity. CONCLUSION: Although causal inferences cannot be made from this cross-sectional study, the study adds support to the suggestion that childhood adversity specifically increases the occurrence of positive symptoms in adulthood schizophrenia in a manner that appears to leave HPA-axis activity unaltered.

Effect of escitalopram versus placebo on GRα messenger RNA expression in peripheral blood cells of healthy individuals with a family history of depression - a secondary outcome analysis from the randomized AGENDA trial.

Background Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed as first-line drugs for the treatment of depression. However, the mechanisms of action for SSRIs are unclear and besides neurotransmitter modulation may depend on modulation of the hypothalamic-pituitary-adrenal (HPA) system. The glucocorticoid receptor (GR) isoform α plays an important role in the negative feedback regulation of the HPA axis and reduced GRα messenger RNA (mRNA) expression has been shown in mood disorder patients and first-degree relatives compared to healthy individuals with no family history of psychiatric disorders. Aim Based on the AGENDA trial dataset, we analysed whether an intervention with SSRI versus placebo decreases the GRα mRNA expression in peripheral blood cells in healthy first-degree relatives of patients with major depression. Methods The participants (N = 80) were randomly allocated to receive daily tablets of escitalopram 10 mg versus placebo for 4 weeks. GRα mRNA expression levels in peripheral blood were measured using reverse transcription polymerase chain reaction. Results Four weeks of intervention with escitalopram decreased the relative change from baseline in the expression of GRα mRNA compared with placebo (p = 0.002). Conclusion These findings from a randomized trial suggest that a 4-week escitalopram administration to healthy participants results in a decrease in GRα mRNA expression levels in peripheral blood compared with inert placebo. The decrease in GRα mRNA expression levels may reflect a decrease in the HPA axis activity.

No effect of escitalopram versus placebo on brain-derived neurotrophic factor in healthy individuals: a randomised trial.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) seems to play an important role in the course of depression including the response to antidepressants in patients with depression. We aimed to study the effect of an antidepressant intervention on peripheral BDNF in healthy individuals with a family history of depression. METHODS: We measured changes in BDNF messenger RNA (mRNA) expression and whole-blood BDNF levels in 80 healthy first-degree relatives of patients with depression randomly allocated to receive daily tablets of escitalopram 10 mg versus placebo for 4 weeks. RESULTS: We found no statistically significant difference between the escitalopram and the placebo group in the change in BDNF mRNA expression and whole-blood BDNF levels. Post hoc analyses showed a statistically significant negative correlation between plasma escitalopram concentration and change in whole-blood BDNF levels in the escitalopram-treated group. CONCLUSION: The results of this randomised trial suggest that escitalopram 10 mg has no effect on peripheral BDNF levels in healthy individuals.

Asymmetric dimethylarginine in somatically healthy schizophrenia patients treated with atypical antipsychotics: a case-control study.

BACKGROUND: Schizophrenia is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, and the L-arginine:ADMA ratio are markers of endothelial dysfunction that predict mortality and adverse outcome in a range of cardiovascular disorders. Increased ADMA levels may also lead to increased oxidative stress. We hypothesized that ADMA and the L-arginine:ADMA ratio are increased in somatically healthy schizophrenia patients treated with atypical antipsychotics (AAP), and that the ADMA and the L-arginine: ADMA ratio are positively correlated to measures of oxidative stress. METHODS: We included 40 schizophrenia patients treated with AAP, but without somatic disease or drug abuse, and 40 healthy controls. Plasma concentrations of ADMA and L-arginine were determined by high-performance liquid chromatography. Data were related to markers of systemic oxidative stress on DNA, RNA and lipids, as well as measures of medication load, duration of disease and current symptomatology. RESULTS: Plasma ADMA and the L-arginine:ADMA ratio did not differ between schizophrenia patients and controls. Furthermore, ADMA and the L-arginine:ADMA ratio showed no correlations with oxidative stress markers, medication load, or Positive and Negative Syndrome Scale scores. CONCLUSIONS: Schizophrenia and treatment with AAP was not associated with increased levels of plasma ADMA or the L-arginine:ADMA ratio. Furthermore, plasma levels of ADMA were not associated with levels of systemic oxidative stress in vivo.

Electronic monitoring of psychomotor activity as a supplementary objective measure of depression severity.

BACKGROUND: Rating scales used to assess the severity of depression e.g. the Hamilton Depression Rating Scale 17-item (HDRS-17) partly rely on the patient's subjective experience and reporting. Such subjective measures tend to have low reliability and adding objective measures to complement the assessment of depression severity would be a major step forward. AIMS: To investigate correlations between electronic monitoring of psychomotor activity and severity of depression according to HDRS-17. METHODS: A total of 36 patients with unipolar disorder (n = 18) or bipolar disorder (n = 18) and 31 healthy control persons aged 18-60 years were included. Psychomotor activity was measured using a combined heart rate and movement sensor device (Actiheart) for 3 consecutive days, 24 h a day. RESULTS: We found that sleeping heart rate (beats/min) correlated with HDRS-17 in both patients with unipolar disorder and bipolar disorder (unadjusted model: B = 0.46, 95% CI 0.037-0.89, P = 0.034). In contrast, correlations between activity energy expenditure (kJ/kg/day), cardio-respiratory fitness (mlO2/min/kg) and HDRS-17 were non-significant. CONCLUSIONS: These results suggest that measuring sleeping heart rate in non-experimental daily life could be an objective supplementary method to measure the severity of depression and perhaps indicate presence of insomnia.

Familial risk for major depression is associated with lower striatal 5-HT4 receptor binding.

BACKGROUND: The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. METHODS: We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first-degree relatives treated for MDD. RESULTS: We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a "risk-dose effect" on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). CONCLUSIONS: Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT4 receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment.

Biomarkers for neurodegeneration impact cognitive function: a longitudinal 1-year case-control study of patients with bipolar disorder and healthy control individuals.

BACKGROUND: Abnormalities in cerebrospinal fluid (CSF)-amyloid-beta (Aß)42, CSF-Aß40, CSF-Aß38, CSF-soluble amyloid precursor proteins α and ß, CSF-total-tau, CSF-phosphorylated-tau, CSF-neurofilament light protein (NF-L), CSF-neurogranin, plasma-Aß42, plasma-Aß40, plasma-total-tau, plasma-NF-L and, serum-S100B during affective episodes may reflect brain changes that could impact cognitive function in patients with bipolar disorder (BD). The study aimed to investigate the association between these biomarkers indicative of Alzheimer's disease and those reflecting neurodegeneration alongside their impact on cognitive function in patients with BD and healthy control individuals (HC). The primary hypothesis was that GL and VL would increase with increasing levels of CSF-Aß42 based on data from T0 and T3 in BD and HC jointly. METHODS: In a prospective, longitudinal case-control study euthymic patients with BD (N = 85) and HC (N = 44) were evaluated with clinical assessment and neuropsychological testing at baseline (T0) and during euthymia after a year (T3). Patients' affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. If an episode occurred during follow-up, the patient was also assessed in post-episode euthymia. Cognitive performance was measured as a global cognitive score (GL) for four cognitive domains including verbal learning and memory (VL). RESULTS: Estimated in a linear mixed model GL increased with 0.001 for each increase of 1 pg/ml of CSF-Aß42 (97.5%, CI 0.00043-0.0018, adjusted-p = 0.0005) while VL increased by 0.00089 (97.5%, CI 0.00015-0.0018, adjusted-p = 0.045) in BD and HC jointly. The association was weak, however stronger in patients with BD compared to HC. Associations between other biomarkers including CSF-neurogranin, and cognitive domains were overall weak, and none remained significant after adjustment for multiple testing. LIMITATIONS: Modest sample size. A complete data set regarding both CSF-AB-42 and cognitive test scores was obtained from merely 61 patients with BD and 38 HC individuals. CONCLUSION: CSF-Aß42 may be associated with cognitive dysfunction in patients with BD and HC individuals. The association appeared to be stronger in BD but with overlapping confidence intervals. Hence it remains uncertain whether the association is a general phenomenon or driven by BD.

Cerebrospinal fluid synaptic biomarker changes in bipolar disorder - A longitudinal case-control study.

BACKGROUND: This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections. METHODS: Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14-3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes. RESULTS: The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up. LIMITATION: It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect. CONCLUSION: This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.

An algorithm for pharmacological treatment of mania during hospitalisation.

Current evidence for pharmacological treatment of mania during hospitalisation is insufficient as there are no larger well-designed randomised trials of comparative medical treatments of mania during inpatient stays. Moreover, there is considerable variation in pharmacological medication in clinical practice during hospitalisation for mania. Based on a hospital data overview, a systematic search of the literature and a three-day consensus meeting, this narrative review proposed an algorithm for optimised pharmacological treatment of mania during hospitalisation and its subsequent scientific evaluation.

Cerebrospinal fluid erythropoietin, oxidative stress, and cognitive functions in patients with bipolar disorder and healthy control participants: A longitudinal case-control study.

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients' cognitive outcomes.

Circadian Reinforcement Therapy in Combination With Electronic Self-Monitoring to Facilitate a Safe Postdischarge Period for Patients With Major Depression: Randomized Controlled Trial.

BACKGROUND: Patients with major depression exhibit circadian disturbance of sleep and mood, and when they are discharged from inpatient wards, this disturbance poses a risk of relapse. We developed a circadian reinforcement therapy (CRT) intervention to facilitate the transition from the inpatient ward to the home for these patients. CRT focuses on increasing the zeitgeber strength for the circadian clock through social contact, physical activity, diet, daylight exposure, and sleep timing. OBJECTIVE: In this study, we aimed to prevent the worsening of depression after discharge by using CRT, supported by an electronic self-monitoring system, to advance and stabilize sleep and improve mood. The primary outcome, which was assessed by a blinded rater, was the change in the Hamilton Depression Rating Scale scores from baseline to the end point. METHODS: Participants were contacted while in the inpatient ward and randomized 1:1 to the CRT or the treatment-as-usual (TAU) group. For 4 weeks, participants in both groups electronically self-monitored their daily mood, physical activity, sleep, and medication using the Monsenso Daybuilder (MDB) system. The MDB allowed investigators and participants to simultaneously view a graphical display of registrations. An investigator phoned all participants weekly to coinspect data entry. In the CRT group, participants were additionally phoned between the scheduled calls if specific predefined trigger points for mood and sleep were observed during the daily inspection. Participants in the CRT group were provided with specialized CRT psychoeducation sessions immediately after inclusion, focusing on increasing the zeitgeber input to the circadian system; a PowerPoint presentation was presented; paper-based informative materials and leaflets were reviewed with the participants; and the CRT principles were used during all telephone consultations. In the TAU group, phone calls focused on data entry in the MDB system. When discharged, all patients were treated at a specialized affective disorders service. RESULTS: Overall, 103 participants were included. Participants in the CRT group had a significantly larger reduction in Hamilton Depression Scale score (P=.04) than those in the TAU group. The self-monitored MDB data showed significantly improved evening mood (P=.02) and sleep quality (P=.04), earlier sleep onset (P=.009), and longer sleep duration (P=.005) in the CRT group than in the TAU group. The day-to-day variability of the daily and evening mood, sleep offset, sleep onset, and sleep quality were significantly lower in the CRT group (all P<.001) than in the TAU group. The user evaluation was positive for the CRT method and the MDB system. CONCLUSIONS: We found significantly lower depression levels and improved sleep quality in the CRT group than in the TAU group. We also found significantly lower day-to-day variability in daily sleep, mood parameters, and activity parameters in the CRT group than in the TAU group. The delivery of the CRT intervention should be further refined and tested. TRIAL REGISTRATION: ClinicalTrials.gov NCT02679768; https://clinicaltrials.gov/study/NCT02679768. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-019-2101-z.

The effect of smartphone-based monitoring and treatment including clinical feedback versus smartphone-based monitoring without clinical feedback in bipolar disorder: the SmartBipolar trial-a study protocol for a randomized controlled parallel-group trial.

INTRODUCTION: A substantial proportion of patients with bipolar disorder experience daily subsyndromal mood swings, and the term "mood instability" reflecting the variability in mood seems associated with poor prognostic factors, including impaired functioning, and increased risk of hospitalization and relapse. During the last decade, we have developed and tested a smartphone-based system for monitoring bipolar disorder. The present SmartBipolar randomized controlled trial (RCT) aims to investigate whether (1) daily smartphone-based outpatient monitoring and treatment including clinical feedback versus (2) daily smartphone-based monitoring without clinical feedback or (3) daily smartphone-based mood monitoring only improves mood instability and other clinically relevant patient-related outcomes in patients with bipolar disorder. METHODS AND ANALYSIS: The SmartBipolar trial is a pragmatic randomized controlled parallel-group trial. Patients with bipolar disorder are invited to participate as part of their specialized outpatient treatment for patients with bipolar disorder in Mental Health Services in the Capital Region of Denmark. The included patients will be randomized to (1) daily smartphone-based monitoring and treatment including a clinical feedback loop (intervention group) or (2) daily smartphone-based monitoring without a clinical feedback loop (control group) or (3) daily smartphone-based mood monitoring only (control group). All patients receive specialized outpatient treatment for bipolar disorder in the Mental Health Services in the Capital Region of Denmark. The trial started in March 2021 and has currently included 150 patients. The outcomes are (1) mood instability (primary), (2) quality of life, self-rated depressive symptoms, self-rated manic symptoms, perceived stress, satisfaction with care, cumulated number and duration of psychiatric hospitalizations, and medication (secondary), and (3) smartphone-based measures per month of stress, anxiety, irritability, activity, and sleep as well as the percentage of days with presence of mixed mood, days with adherence to medication and adherence to smartphone-based self-monitoring. A total of 201 patients with bipolar disorder will be included in the SmartBipolar trial. ETHICS AND DISSEMINATION: The SmartBipolar trial is funded by the Capital Region of Denmark and the Independent Research Fund Denmark. Ethical approval has been obtained from the Regional Ethical Committee in The Capital Region of Denmark (H-19067248) as well as data permission (journal number: P-2019-809). The results will be published in peer-reviewed academic journals, presented at scientific meetings, and disseminated to patients' organizations and media outlets. TRIAL REGISTRATION: Trial registration number: NCT04230421. Date March 1, 2021. Version 1.

Alzheimer's disease related biomarkers in bipolar disorder - A longitudinal one-year case-control study.

INTRODUCTION: Bipolar disorder (BD) is a heterogeneous mental disorder characterized by recurrent relapses of affective episodes: Subgroups of patients with BD have cognitive deficits, and an increased risk of dementia. METHODS: This prospective, longitudinal, one-year follow-up, case-control study investigated biomarkers for AD and neurodegenerative diseases, namely: cerebrospinal fluid (CSF) amyloid beta (Aß) isoforms and ratios (Aß42, Aß40, Aß38), CSF soluble amyloid precursor protein (sAPP) α and ß, CSF total (t-tau) and phosphorylated tau (p-tau), CSF neurofilament-light (NF-L), CSF neurogranin (NG), plasma-isoforms Aß42 and Aß40, plasma-tau, plasma-NF-L, and serum S100B, in patients with BD (N = 62, aged 18-60) and gender-and-age-matched healthy control individuals (N = 40). CSF and plasma/serum samples were collected at baseline, during and after an affective episode, if it occurred, and after a year. Data were analyzed in mixed models. RESULTS: Levels of CSF Aß42 decreased in patients with BD who had an episode during follow-up (BD-E) (N = 22) compared to patients without an episode (BD-NE) (N = 25) during follow-up (P = 0.002). Stable levels were seen for all other markers in BD-E compared to BD-NE during the one-year follow-up. We found no statistically significant differences between patients with BD and HC at T0 and T3 for Aß42, Aß40, Aß38, Aß42/38, Aß42/40, sAPPα, sAPPß, t-tau, p-tau, p-tau /t-tau, NF-L, NG in CSF and further Aß40, Aß42, Aß42/40, t-tau, NF-L in plasma, S100B in serum, and APOE-status. Furthermore, all 18 biomarkers were stable in HC during the one-year follow-up from T0 to T3. CONCLUSION: A panel of biomarkers of Alzheimer's and neurodegeneration show no differences between patients with BD and HC. There were abnormalities of amyloid production/clearance during an acute BD episode. The abnormalities mimic the pattern seen in AD namely decreasing CSF Aß42 and may suggest an association with brain amyloidosis.

The impact of the trajectory of bipolar disorder on global cognitive function: A one-year clinical prospective case-control study.

BACKGROUND: The relationship between cognitive function and relapse of affective episodes in bipolar disorder (BD) is rarely studied. The aim of this prospective, longitudinal, case-control study was to assess the trajectory of cognitive function and mood occilations within a one-year period in patients with BD relative to healthy control (HC) individuals. METHODS: The sample included 86 outpatients with BD in euthymia, and 44 gender-and-age-matched HC. All participants were evaluated with clinical assessement and neuropsychological testing at baseline and during euthymia after a year. Further patients with BD were reevaluated if they developed a new affective episode during follow-up. The patients´ affective states were recorded on a weekly basis as asymptomatic, subthreshold level, major depression or (hypo)mania. Cognitive changes over time were measured for a global cognitive score and for the four cognitive domains: 'working memory and executive skills', 'psychomotor speed', 'sustained attention', and 'verbal learning and memory' in patients and HC. RESULTS: The study showed that cognitive performance in patients with BD was unaltered compared to baseline when they stabilised in euthymia following an affective episode and, at the one-year follow-up. Cognitive performance showed practice effect, thus improved within a year across patients with BD and HC. Furthermore, cognitive functions were not related to clinical subtypes BDI/II, prior psychosis, the polarity of the relapse and week-to-week mood fluctuations during follow-up. Functioning correlated weakly to moderately with week-to-week mood fluctuations. LIMITATIONS: Modest sample size. CONCLUSION: A one-year trajectory of BD seems to have no direct negative impact on cognitive function.

Melanopsin-mediated pupillary responses in bipolar disorder-a cross-sectional pupillometric investigation.

BACKGROUND: Visible light, predominantly in the blue range, affects mood and circadian rhythm partly by activation of the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). The light-induced responses of these ganglion cells can be evaluated by pupillometry. The study aimed to assess the blue light induced pupil constriction in patients with bipolar disorder (BD). METHODS: We investigated the pupillary responses to blue light by chromatic pupillometry in 31 patients with newly diagnosed bipolar disorder, 22 of their unaffected relatives and 35 healthy controls. Mood state was evaluated by interview-based ratings of depressive symptoms (Hamilton Depression Rating Scale) and (hypo-)manic symptoms (Young Mania Rating Scale). RESULTS: The ipRGC-mediated pupillary responses did not differ across the three groups, but subgroup analyses showed that patients in remission had reduced ipRGC-mediated responses compared with controls (9%, p = 0.04). Longer illness duration was associated with more pronounced ipRGC-responses (7% increase/10-year illness duration, p = 0.02). CONCLUSIONS: The ipRGC-mediated pupil response to blue light was reduced in euthymic patients compared with controls and increased with longer disease duration. Longitudinal studies are needed to corroborate these potential associations with illness state and/or progression.