The association between mixed symptoms, irritability and functioning measured using smartphones in bipolar disorder.

OBJECTIVE: To (i) validate patient-evaluated mixed symptoms and irritability measured using smartphones against clinical evaluations; (ii) investigate associations between mixed symptoms and irritability with stress, quality of life and functioning, respectively, in patients with bipolar disorder. METHODS: A total of 84 patients with bipolar disorder used a smartphone-based system for daily evaluation of mixed symptoms and irritability for nine months. Clinically evaluated symptoms, stress, quality of life and clinically rated functioning were collected multiple times during follow-up. RESULTS: Patients presented mild affective symptoms. Patient-reported mixed symptoms and irritability correlated with clinical evaluations. In analyses including confounding factors there was a statistically significant association between both mixed symptoms and irritability and stress (P < 0.0001) and between irritability and both quality of life and functioning (P < 0.0001) respectively. There was no association between mixed mood and both quality of life and functioning. CONCLUSION: Mixed symptoms and irritability can be validly self-reported using smartphones in patients with bipolar disorder. Mixed symptoms and irritability are associated with increased stress even during full or partial remission. Irritability is associated with decreased quality of life and functioning. The findings emphasize the clinical importance of identifying inter-episodic symptoms including irritability pointing towards smartphones as a valid tool.

Voice analysis as an objective state marker in bipolar disorder.

Changes in speech have been suggested as sensitive and valid measures of depression and mania in bipolar disorder. The present study aimed at investigating (1) voice features collected during phone calls as objective markers of affective states in bipolar disorder and (2) if combining voice features with automatically generated objective smartphone data on behavioral activities (for example, number of text messages and phone calls per day) and electronic self-monitored data (mood) on illness activity would increase the accuracy as a marker of affective states. Using smartphones, voice features, automatically generated objective smartphone data on behavioral activities and electronic self-monitored data were collected from 28 outpatients with bipolar disorder in naturalistic settings on a daily basis during a period of 12 weeks. Depressive and manic symptoms were assessed using the Hamilton Depression Rating Scale 17-item and the Young Mania Rating Scale, respectively, by a researcher blinded to smartphone data. Data were analyzed using random forest algorithms. Affective states were classified using voice features extracted during everyday life phone calls. Voice features were found to be more accurate, sensitive and specific in the classification of manic or mixed states with an area under the curve (AUC)=0.89 compared with an AUC=0.78 for the classification of depressive states. Combining voice features with automatically generated objective smartphone data on behavioral activities and electronic self-monitored data increased the accuracy, sensitivity and specificity of classification of affective states slightly. Voice features collected in naturalistic settings using smartphones may be used as objective state markers in patients with bipolar disorder.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

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.

The G-protein coupled estrogen receptor, GPER: The inside and inside-out story.

GPER possesses structural and functional characteristics shared by members of the G-protein-coupled receptor (GPCR) superfamily, the largest class of plasma membrane receptors. This newly appreciated estrogen receptor is localized predominately within intracellular membranes in most, but not all, cell types and its surface expression is modulated by steroid hormones and during tissue injury. An intracellular staining pattern is not unique among GPCRs, which employ a diverse array of molecular mechanisms that restrict cell surface expression and effectively regulating receptor binding and activation. The finding that GPER displays an intracellular predisposition has created some confusion as the estrogen-inducible transcription factors, ERα and ERß, also reside intracellularly, and has led to complex suggestions of receptor interaction. GPER undergoes constitutive retrograde trafficking from the plasma membrane to the endoplasmic reticulum and recent studies indicate its interaction with PDZ binding proteins that sort transmembrane receptors to synaptosomes and endosomes. Genetic targeting and selective ligand approaches as well as cell models that express GPER in the absence of ERs clearly supports GPER as a bonafide "stand alone" receptor. Here, the molecular details that regulate GPER action, its cell biological activities and its implicated roles in physiological and pathological processes are reviewed.

Psychometric validation and clinical validity of the Minor Melancholia Mood Checklist (MMCL-32).

BACKGROUND: The Minor Melancholia Mood Checklist (MMCL-32) was developed to identify sub-threshold states of major depression. The MMCL-32 can be considered as the counterpole to the Hypomanic Check List (HCL-32). METHODS: Principal component analysis (PCA) without rotation was used to identify a bidirectorial principal component. To evaluate the clinical validity of the bidirectorial factors, with reference to brief recurrent depression, the Bech-Rafaelsen Melancholia Scale was used. RESULTS: We included 59 patients with bipolar I disorder (SCID criteria) and 57 patients with unipolar depression (more than one major depressive episode without hypomanic or manic episodes). They were all outpatients, but had recently been discharged from inpatient treatment. The PCA identified two contrasting factors: 17 items with negative loadings (psychasthenic depression factor) and 15 items with positive loadings (cognitive depression factor). When PCA was applied exclusively to the bipolar patients, 5 items within the cognitive factor were identified. When applied exclusively to the unipolar patients, 5 items within the psychasthenic factor were identified. The non-remitted bipolar patients scored higher on the cognitive factor (P=0.01) than the remitted. On the psychasthenic factor (P=0.06), the non-remitted unipolar patients scored higher than the remitted patients. CONCLUSION: The MMCL-32 was found psychometrically valid in measuring sub-threshold states of major depression with rather specific factors for bipolar and unipolar depression. Focusing on these factors could be a clinical aid to distinguish patients at risk of developing a bipolar course.

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.

Relationship between mood and TSH response to TRH stimulation in bipolar affective disorder.

Moderate to severe depression and mania are associated with a reduced thyroid stimulating hormone (TSH) response to TSH releasing hormone (TRH). Continued reduction of this response after clinical recovery seems indicative of early relapse. The aim of the present study was to test the relationship between mild changes in mood and the TSH response to TRH stimulation in patients with bipolar affective disorder. Nineteen outpatients with bipolar affective disorder were followed prospectively for three years. Every third month, mood symptoms were rated using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Bech-Rafaelsen Mania Scale (BRMS). A TRH test was performed in connection with each rating session (IV injection of 200 microg TRH), and serum TSH was measured at 0, 20, and 60 min. The maximum TSH response (D-max TSH) and the temporal change in D-max TSH between succeeding rating sessions (DD-max TSH) were determined. Psychometric rating and TRH data were obtained for a total of 198 examinations. The temporal change in mood symptom rating score was negatively correlated with the temporal change in D-max TSH, thus suggesting that increasing severity of mood symptoms was related to a reduced TSH response to TRH stimulation. The temporal change in TSH response to TRH stimulation correlated with the actual score on an overall index of symptom severity. In conclusion, milder fluctuations in mood in bipolar affective disorder seem to correlate with the TSH response to TRH stimulation: Increasing severity of mood symptoms seems to be associated with reduced TSH response.

The biological functions of glutathione revisited in arabidopsis transgenic plants with altered glutathione levels.

A functional analysis of the role of glutathione in protecting plants from environmental stress was undertaken by studying Arabidopsis that had been genetically modified to have altered glutathione levels. The steady-state glutathione concentration in Arabidopsis plants was modified by expressing the cDNA for gamma-glutamyl-cysteine synthetase (GSH1) in both the sense and antisense orientation. The resulting plants had glutathione levels that ranged between 3% and 200% of the level in wild-type plants. Arabidopsis plants with low glutathione levels were hypersensitive to Cd due to the limited capacity of these plants to make phytochelatins. Plants with the lowest levels of reduced glutathione (10% of wild type) were sensitive to as little as 5 microM Cd, whereas those with 50% wild-type levels required higher Cd concentrations to inhibit growth. Elevating glutathione levels did not increase metal resistance. It is interesting that the plants with low glutathione levels were also less able to accumulate anthocyanins supporting a role for glutathione S-transferases for anthocyanin formation or for the vacuolar localization and therefore accumulation of these compounds. Plants with less than 5% of wild-type glutathione levels were smaller and more sensitive to environmental stress but otherwise grew normally.

[Bipolar affective disorder. A retrospective study of 158 patients in a well-defined geographical region]. / Bipolaer affektiv lidelse. En retrospektiv undersøgelse af 158 patienter i en geografisk velafgroenset region.

A cohort of 158 patients was identified from 723 patients admitted in 1990 or treated as outpatients in 1991 for affective disorders in three university hospitals in Copenhagen, covering a well-defined catchment area. The cohort was subclassified for seasonal pattern according to DSM-III-R. Meteorological data of temperature, hours of sunshine, rainfall and wind-velocity expressed as mean values/month were obtained from the Institute of Meteorology in Copenhagen. There was no relationship between the annual dis- tribution of affective episodes and meteorological data, neither in the total cohort nor in the subgroup of patients with seasonal patterns The present study does not support the hypothesis that a relation exists between start of a new episode and the season or climatic condition.

[Seasonal affective disorders]. / Saesonrelaterede affektive lidelser.

In 1984 Rosenthal described for the first time the syndrome "Seasonal Affective Disorder", SAD, characterized by annual recurrent depressive episodes in the autumn and winter months possibly followed by mania/hypomania in the summer months. The depressive phases showed atypical symptoms such as hypersomnia, carbohydrate-craving, and weight gain. Melatonin seems to be an indicator of disturbed circadian rhythm rather than the cause of SAD. The importance of other circadian and annual biological rhythm in relation to SAD and other depressive syndromes is quite unknown. SAD differs from classical manic-depressive disorders by frequency, severity, symptomatology, and the typical seasonal variations, and is probably not a subgroup of the classical affective disorders, but an extreme variation of the normal seasonal affective variations seen in the general population. Light therapy can be used successfully in depressive states in SAD.

Urinary excretion of albumin and retinol-binding protein in lithium-treated patients: a longitudinal study.

The urinary excretion of albumin and retinol-binding protein was determined by means of sensitive immunochemical methods in a 2-year longitudinal study of 22 lithium-treated patients. During lithium treatment, there were no significant changes in the median albumin:creatinine ratios or retinol-binding protein:creatinine ratios. However, the median albumin:creatinine ratios were significantly higher in lithium-treated patients than in 22 normal subjects, which indicates that glomerular permeability is increased; no correlation with serum lithium level or duration of lithium treatment could be shown. In patients treated with slow-release tablets, the urinary excretion of albumin was significantly higher after 2 years than in patients given lithium carbonate. The median retinol-binding protein:creatinine ratios did not differ significantly between lithium-treated patients and normal subjects, suggesting that lithium does not affect the catabolism of low-molecular-weight proteins in the proximal tubules. In conclusion, the study supports the hypothesis that lithium treatment produces a small but significant and nonprogressive elevation of the urinary excretion of albumin.

Moclobemide in depression: a randomized, multicentre trial against isocarboxazide and clomipramine emphasizing atypical depression.

Moclobemide was compared with isocarboxazide and clomipramine in patients with depression. A total of 167 outpatients were allocated to daily treatment with 300 mg moclobemide, 30 mg isocarboxazide or 150 mg clomipramine for 6 weeks. Moclobemide was slightly inferior to clomipramine, whereas isocarboxazide had an intermediate position. There was no interaction between treatment and atypical or nonatypical depression. Anticholinergic symptoms and orthostatic hypotension were most pronounced in the clomipramine group.

Quantifying depressive symptomatology: inter-rater reliability and inter-item correlations.

In this study an evaluation of the inter-rater reliability of the Hamilton Depression Rating Scale, the Melancholia Scale and the Montgomery-Asberg Depression Rating Scale has been carried out. Furthermore, the inter-item correlations of these scales have been investigated in relation to diagnostic ratings. It was found that the quantitative scales had satisfactory inter-rater relationship. Only low agreement was found between the quantitative and diagnostic scales, as expected, while there was high agreement between the quantitative scales. The relevance of introducing new scales and the definition of major depression are discussed.

Prospective study of EDTA clearance among patients in long-term lithium treatment.

EDTA clearance as a measure of the glomerular filtration rate was followed up to 10 years in 14 patients in long-term lithium treatment. The results in the lithium-treated patients were identical to the results in a standard population.

Surveyor v: lunar surface mechanical properties.

The mechanical properties of the lunar soil at the Surveyor V landing site seem to be generally consistent with values determined for soils at the landing sites of Surveyor I and III. These three maria sites are hundreds of kilometers apart. However, the static bearing capability may be somewhat lower than that at the previous landing sites (2 x 10(5) to 6 x 10(5) dynes per square centimeter or 3 to 8 pounds per square inch). The results of the erosion experiment, the spacecraft landing effects, and other observations indicate that the soil has significant amounts of fine-grained material and a measurable cohesion.