Ellen Margrethe Christensen

Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials

Background  Glucocorticosteroids versus placebo or no intervention for patients with alcoholic hepatitis have been evaluated for more than 35 years. However, the results of randomized trials and meta‐analyses differ substantially.

Treatment in a specialised out-patient mood disorder clinic v. standard out-patient treatment in the early course of bipolar disorder: randomised clinical trial

BACKGROUND Little is known about whether treatment in a specialised out-patient mood disorder clinic improves long-term prognosis for patients discharged from initial psychiatric hospital admissions for bipolar disorder. AIMS To assess the effect of treatment in a specialised out-patient mood disorder clinic v. standard decentralised psychiatric treatment among patients discharged from one of their first three psychiatric hospital admissions for bipolar disorder. METHOD Patients discharged from their first, second or third hospital admission with a single manic episode or bipolar disorder were randomised to treatment in a specialised out-patient mood disorder clinic or standard care (ClinicalTrials.gov: NCT00253071). The primary outcome measure was readmission to hospital, which was obtained from the Danish Psychiatric Central Register. RESULTS A total of 158 patients with mania/bipolar disorder were included. The rate of readmission to hospital was significantly decreased for patients treated in the mood disorder clinic compared with standard treatment (unadjusted hazard ratio 0.60, 95% CI 0.37-0.97, P = 0.034). Patients treated in the mood disorder clinic more often used a mood stabiliser or an antipsychotic and satisfaction with treatment was more prevalent than among patients who received standard care. CONCLUSIONS Treatment in a specialised mood disorder clinic early in the course of bipolar disorder substantially reduces readmission to a psychiatric hospital and increases satisfaction with care.

Daily electronic self-monitoring of subjective and objective symptoms in bipolar disorder--the MONARCA trial protocol (MONitoring, treAtment and pRediCtion of bipolAr disorder episodes): a randomised controlled single-blind trial.

Introduction Electronic self-monitoring of affective symptoms using cell phones is suggested as a practical and inexpensive way to monitor illness activity and identify early signs of affective symptoms. It has never been tested in a randomised clinical trial whether electronic self-monitoring improves outcomes in bipolar disorder. We are conducting a trial testing the effect of using a Smartphone for self-monitoring in bipolar disorder. Methods We developed the MONARCA application for Android-based Smartphones, allowing patients suffering from bipolar disorder to do daily self-monitoring—including an interactive feedback loop between patients and clinicians through a web-based interface. The effect of the application was tested in a parallel-group, single-blind randomised controlled trial so far including 78 patients suffering from bipolar disorder in the age group 18–60 years who were given the use of a Smartphone with the MONARCA application (intervention group) or to the use of a cell phone without the application (placebo group) during a 6-month study period. The study was carried out from September 2011. The outcomes were changes in affective symptoms (primary), social functioning, perceived stress, self-rated depressive and manic symptoms, quality of life, adherence to medication, stress and cognitive functioning (secondary and tertiary). Analysis Recruitment is ongoing. Ethics Ethical permission has been obtained. Dissemination Positive, neutral and negative findings of the study will be published. Registration details The trial is approved by the Regional Ethics Committee in The Capital Region of Denmark (H-2-2011-056) and The Danish Data Protection Agency (2013-41-1710). The trial is registered at ClinicalTrials.gov as NCT01446406.

Blood-brain barrier transport of amino acids in healthy controls and in patients with phenylketonuria

SummaryBlood-brain barrier permeability to phenylalanine and leucine in four patients with phenylketonuria and in four volunteers was measured five times by the double-indicator method at increasing plasma concentrations of phenylalanine. Based on the permeability-surface area product (PS) from blood to brain (PS1) and on plasma phenylalanine levels, Vmax and the apparentKm for phenylalanine were determined.Statistically significant relationships between plasma phenylalanine and PS1 were established in three out of four volunteers, the averageVmax value being 46.7 nmol/g per min and the apparentKm 0.328 mmol/L. Owing to saturation of the carrier, such a relationship could not be established in the patients.In phenylketonuria, PS1 for phenylalanine and leucine decreased significantly by 55% and 46%, respectively. Transport from brain back to blood, PS2, decreased significantly and cerebral large neutral amino acid net uptake was generally decreased in patients with phenylketonuria.In conclusion, the transport ofl-phenylalanine across the human blood-brain barrier follows Michaelis-Menten kinetics. In phenylketonuria, brain permeability to large neutral amino acids is reduced by about 50% and net uptake appears decreased.

Recombinant Human Erythropoietin for Treating Treatment-Resistant Depression: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Trial

Pharmacological treatments for depression have insufficient efficacy in 30–40% of patients and fail to reverse cognitive deficits. Erythropoietin (EPO) has neurotrophic actions and aids neurocognitive function. The aim of this exploratory study was to determine whether recombinant human EPO improves mood and memory in treatment-resistant depression. Forty treatment-resistant depressed unipolar patients with Hamilton Depression Rating Scale-17 (HDRS-17) score ⩾17 were randomized to eight weekly EPO (Eprex; 40 000 IU) or saline infusions in a double-blind, placebo-controlled, parallel-group design. Patients were assessed at baseline and at weeks 5, 9, and 14. Primary outcome was reduction in HDRS-17 score. Global assessment of function (GAF) was reported in addition. Secondary outcome was remission rate, and tertiary outcomes were changes in Rey Auditory Verbal Learning Test (RAVLT), Beck Depression Inventory-21 (BDI-21), and World Health Organization Quality of life-BREF (WHOQOL-BREF). Exploratory outcomes were depression and cognition composite scores. HDRS-17, GAF, and remission rates showed no effects of EPO over saline at week 9 (P-value ⩾0.09). However, EPO improved BDI (P=0.02) and WHOQOL-BREF (P=0.01), and this was maintained at follow-up week 14 (P-values ⩽0.04). EPO enhanced verbal recall (P=0.02) and recognition (P=0.03), which was sustained at follow-up (P-values ⩽0.04). Exploratory analysis in patients fulfilling depression severity criteria at trial start revealed ameliorated HDRS-17 in EPO (N=14) vs saline groups (N=17), which was sustained at week 14 (P-values ⩽0.05). Exploratory analysis in the complete cohort showed that EPO reduced depression composite at weeks 9 and 14 (P-values=0.02). The findings of this exploratory study highlight EPO as an interesting compound for treatment-resistant depression, which deserves further investigation.

Smartphone Data as an Electronic Biomarker of Illness Activity in Bipolar Disorder

Objective methods are lacking for continuous monitoring of illness activity in bipolar disorder. Smartphones offer unique opportunities for continuous monitoring and automatic collection of real‐time data. The objectives of the paper were to test the hypotheses that (i) daily electronic self‐monitored data and (ii) automatically generated objective data collected using smartphones correlate with clinical ratings of depressive and manic symptoms in patients with bipolar disorder.

Differences in psychomotor activity in patients suffering from unipolar and bipolar affective disorder in the remitted or mild/moderate depressive state.

BACKGROUND Abnormalities in psychomotor activity are a central and essential feature of affective disorder. Studies measuring differences in psychomotor activity between unipolar and bipolar disorder show divergent results and none have used a combined heart rate and movement monitor for measuring activity during free-living conditions. OBJECTIVE To compare objectively measured psychomotor activity in patients with unipolar and bipolar disorder in a remitted or mild/moderate depressive state. Further, both groups were compared to a healthy control group. METHODS A cross-sectional study of outpatients suffering from unipolar (n=20) and bipolar (n=18) disorder and healthy controls (n=31), aged 18-60 years. For three consecutive days a combined acceleration (m/s(2)) and heart rate (beats per minute) monitoring was used in conjunction with a step test to estimate activity energy expenditure (J/min/kg) as measures of psychomotor activity and physical fitness. RESULTS Overall score on Hamilton-17 items ranged between 0 and 22. Patients had higher sleeping heart rate (p<0.001), lower fitness (p=0.02), lower acceleration (p=0.004), and lower activity energy expenditure (p=0.004) compared to controls. Comparing unipolar and bipolar patients and adjusting for differences in Hamilton-17 revealed lower acceleration (p=0.01) and activity energy expenditure in bipolar patients (p=0.02); the difference was most prominent in the morning. CONCLUSIONS Electronic monitoring of psychomotor activity may be a promising additional tool in the distinction between unipolar and bipolar affective disorder when patients present in a remitted or depressive state.

Daily electronic self-monitoring in bipolar disorder using smartphones - the MONARCA I trial: a randomized, placebo-controlled, single-blind, parallel group trial.

BACKGROUND The number of studies on electronic self-monitoring in affective disorder and other psychiatric disorders is increasing and indicates high patient acceptance and adherence. Nevertheless, the effect of electronic self-monitoring in patients with bipolar disorder has never been investigated in a randomized controlled trial (RCT). The objective of this trial was to investigate in a RCT whether the use of daily electronic self-monitoring using smartphones reduces depressive and manic symptoms in patients with bipolar disorder. METHOD A total of 78 patients with bipolar disorder according to ICD-10 criteria, aged 18-60 years, and with 17-item Hamilton Depression Rating Scale (HAMD-17) and Young Mania Rating Scale (YMRS) scores ≤17 were randomized to the use of a smartphone for daily self-monitoring including a clinical feedback loop (the intervention group) or to the use of a smartphone for normal communicative purposes (the control group) for 6 months. The primary outcomes were differences in depressive and manic symptoms measured using HAMD-17 and YMRS, respectively, between the intervention and control groups. RESULTS Intention-to-treat analyses using linear mixed models showed no significant effects of daily self-monitoring using smartphones on depressive as well as manic symptoms. There was a tendency towards more sustained depressive symptoms in the intervention group (B = 2.02, 95% confidence interval -0.13 to 4.17, p = 0.066). Sub-group analysis among patients without mixed symptoms and patients with presence of depressive and manic symptoms showed significantly more depressive symptoms and fewer manic symptoms during the trial period in the intervention group. CONCLUSIONS These results highlight that electronic self-monitoring, although intuitive and appealing, needs critical consideration and further clarification before it is implemented as a clinical tool.

Do young adults with bipolar disorder benefit from early intervention

BACKGROUND It is unknown whether young adults with bipolar disorder are able to benefit from early intervention combining optimised pharmacological treatment and group psychoeducation. The aim of the present report was to compare the effects of early intervention among patients with bipolar disorder aged 18-25 years to that of patients aged 26 years or older. METHODS Patients were randomised to early treatment in a specialised outpatient mood disorder clinic versus standard care. The primary outcome was risk of psychiatric re-hospitalisation. RESULTS A total of 158 patients with mania/bipolar disorder were included among whom 29 (18.4%) were between 18 and 25 years and 129 patients were 26 years or older. For both age groups, the point estimate of the hazard ratio of re-hospitalisation was insignificantly decreased for patients treated in the mood disorder clinic versus standard treatment but more so for patients between 18 and 25 years (HR 0.33, 95% CI 0.10-1.07; p=0.064) than for patients 26 years or older (HR 0.68, 95% CI 0.40-1.14, p=0.14). Younger adults treated in the mood disorder clinic used mood stabilisers and antipsychotics more in contrast to those treated in standard care. The differences between the estimates of effects did not reach significance in tests of interactions (p>0.2). LIMITATIONS The study was based on a post hoc subgroup analysis and due to the small number of patients aged 18-25 years, type II errors cannot be excluded. CONCLUSIONS Although not statistically different, the observed differences of the point estimates was surprisingly larger for young adults suggesting that young adults with bipolar disorder may benefit even more than older adults from early intervention combining pharmacological treatment and group psychoeducation.

From items to syndromes in the Hypomania Checklist (HCL-32): Psychometric validation and clinical validity analysis

BACKGROUND The Hypomania Checklist (HCL-32) was developed to identify subthreshold bipolarity in patients with major depression. An HCL-32 version with fewer items has been suggested. METHODS Principal component analysis (PCA) without rotation was used to identify active/elevated mood versus risk-taking/irritable behaviour in the HCL-32. Using the Bech-Rafaelsen Mania Scale as index of clinical validity a shorter version was developed. Item response theory analysis was used to evaluate whether the total score of the HCL-32 was sufficient to measure subthreshold bipolarity. The short 13-item Mood Disorder Questionnaire (MDQ) was used for comparison. RESULTS In accordance with the SCID-II criteria, we included 59 bipolar I and 63 unipolar (depressed) outpatients who had recently been discharged from inpatient treatment. In the HCL-32, PCA identified the two contrasting factors: active/elevated mood versus risk-taking/irritable behaviour. The clinical validation analysis focussed on 20 HCL items as the most acceptable (HCL-20). Item response analysis accepted that the total scores of the HCL-32/HCL-20 were a sufficient statistic, as was the total score of the MDQ. Among the unipolar (depressed) patients not responding to their antidepressive medication, subtreshold bipolarity was identified in 55% of patients using the HCL-20, 36% using the HCL-32, but only 18% using the MDQ. LIMITATIONS Only outpatients recently discharged from inpatient treatment were studied. A further limitation is that 9.5% of the unipolar patients had only suffered from one episode, which, however had led to hospitalisation. CONCLUSION The HCL-20 was found to identify subthreshold bipolarity in up to 55% of inpatients with major depressive disorder not responding to antidepressive medication.