Early warning signals observed in motor activity preceding mood state change in bipolar disorder.

INTRODUCTION: Alterations in motor activity are well-established symptoms of bipolar disorder, and time series of motor activity can be considered complex dynamical systems. In such systems, early warning signals (EWS) occur in a critical transition period preceding a sudden shift (tipping point) in the system. EWS are statistical observations occurring due to a system's declining ability to maintain homeostasis when approaching a tipping point. The aim was to identify critical transition periods preceding bipolar mood state changes. METHODS: Participants with a validated bipolar diagnosis were included to a one-year follow-up study, with repeated assessments of the participants' mood. Motor activity was recorded continuously by a wrist-worn actigraph. Participants assessed to have relapsed during follow-up were analyzed. Recognized EWS features were extracted from the motor activity data and analyzed by an unsupervised change point detection algorithm, capable of processing multi-dimensional data and developed to identify when the statistical property of a time series changes. RESULTS: Of 49 participants, four depressive and four hypomanic/manic relapses among six individuals occurred, recording actigraphy for 23.8 ± 0.2 h/day, for 39.8 ± 4.6 days. The algorithm detected change points in the time series and identified critical transition periods spanning 13.5 ± 7.2 days. For depressions 11.4 ± 1.8, and hypomania/mania 15.6 ± 10.2 days. CONCLUSION: The change point detection algorithm seems capable of recognizing impending mood episodes in continuous flowing data streams. Hence, we present an innovative method for forecasting approaching relapses to improve the clinical management of bipolar disorder.

Struggling with Fitting in: Clients Mixed Experiences of Receiving Job Support and Getting a Job When Participating in Individual Placement and Support in Norway.

PURPOSE: To explore clients' experiences of receiving job support from employment specialists (ESs) working with individual placement and support (IPS) in Norway. IPS is developed to help people with severe mental illness (SMI) into competitive employment as an integral component of mental health services. METHODS: Using a hermeneutic phenomenological methodology, this study comprises individual semi-structured interviews with ten participants engaged in IPS at two districts psychiatric centers. Data analysis was conducted according to systematic text condensation. RESULTS: Three themes emerged: (1) ES-a door opener? (2) Striving to sidestep a "spider web" of triggers at and away from work; and (3) Calling for a safer route. CONCLUSION: This study highlights the importance of ESs offering IPS clients' opportunities to try out diverse jobs and focusing more on assessing the work environment in the jobs they place people into. Our findings imply that ESs should spend more time on building a good working alliance with both clients and employers, and pay more attention on understanding individuals' vocational capacities and support needs at the worksite. The ES training should focus not simply on the technical processes of job development and placement, but more directly on empowering clients to stay focused on their vocational ambitions and prospects. The salutogenic model of health can help ESs to analyze whether clients experience workplaces as meaningful, manageable, and comprehensible.

Exploring New Electroencephalogram Parameters in Electroconvulsive Therapy.

OBJECTIVE: This pilot study aims to evaluate a novel metric based on the power spectrum of the EEG recordings from ECT-induced seizures-its association to volume changes in the hippocampus after ECT and improvement in depression rating scores. METHODS: Depressed patients treated with ECT underwent brain magnetic resonance imaging before and after treatment and the EEG from each seizure was recorded (N = 29). Hippocampal volume changes and EEG parameters were recorded in addition to clinician-rated and self-reported measures of depressive symptoms. The slope of the power law in the power spectral density of the EEG was calculated. Multivariate linear models relating seizure parameters to volume change or clinical outcome were systematically and successively simplified. The best models were selected according to Akaike information criterion. RESULTS: The slope of the power law was steeper in the right than the left hemisphere (P < 0.001). Electroencephalogram measures were included in the best models of volume change for both hippocampi as well as in the models explaining clinical outcome ( P = 0.014, P = 0.004). CONCLUSIONS: In this pilot study, novel EEG measures were explored and contributed in models explaining the variation in volume change in the hippocampus and in clinical outcome after ECT.

Objective assessment of motor activity in a clinical sample of adults with attention-deficit/hyperactivity disorder and/or cyclothymic temperament.

BACKGROUND: Most research on patterns of motor activity has been conducted on adults with mood disorders, but few studies have investigated comorbid attention-deficit/hyperactivity disorder (ADHD) or temperamental factors that may influence the clinical course and symptoms. Cyclothymic temperament (CT) is particularly associated with functional impairment. Clinical features define both disorders, but objective, biological markers for these disorders could give important insights with regard to pathophysiology and classification. METHODS: Seventy-six patients, requiring diagnostic evaluation of ADHD, mood or anxiety disorders were recruited. A comprehensive diagnostic evaluation, including the CT scale of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego - Auto-questionnaire (TEMPS-A), neuropsychological tests and actigraphy, was performed. ADHD was diagnosed according to the DSM-IV criteria. There was a range of different conditions in this clinical sample, but here we report on the presence of CT and ADHD in relation to motor activity. Twenty-nine healthy controls were recruited. We analyzed motor activity time series using linear and nonlinear mathematical methods, with a special focus on active and inactive periods in the actigraphic recordings. RESULTS: Forty patients fulfilled the criteria for ADHD, with the remainder receiving other psychiatric diagnoses (clinical controls). Forty-two patients fulfilled the criteria for CT. Twenty-two patients fulfilled the criteria for ADHD and CT, 18 patients met the criteria for ADHD without CT, and 15 patients had neither. The ratio duration of active/inactive periods was significantly lower in patients with CT than in patients without CT, in both the total sample, and in the ADHD subsample. CONCLUSIONS: CT is associated with objectively assessed changes in motor activity, implying that the systems regulating motor behavior in these patients are different from both healthy controls and clinical controls without CT. Findings suggest that actigraphy may supplement clinical assessments of CT and ADHD, and may provide an objective marker for CT.

Elevated body weight modulates subcortical volume change and associated clinical response following electroconvulsive therapy.

Background: Obesity is a frequent somatic comorbidity of major depression, and it has been associated with worse clinical outcomes and brain structural abnormalities. Converging evidence suggests that electroconvulsive therapy (ECT) induces both clinical improvements and increased subcortical grey matter volume in patients with depression. However, it remains unknown whether increased body weight modulates the clinical response and structural neuroplasticity that occur with ECT. Methods: To address this question, we conducted a longitudinal investigation of structural MRI data from the Global ECT-MRI Research Collaboration (GEMRIC) in 223 patients who were experiencing a major depressive episode (10 scanning sites). Structural MRI data were acquired before and after ECT, and we assessed change in subcortical grey matter volume using FreeSurfer and Quarc. Results: Higher body mass index (BMI) was associated with a significantly lower increase in subcortical grey matter volume following ECT. We observed significant negative associations between BMI and change in subcortical grey matter volume, with pronounced effects in the thalamus and putamen, where obese participants showed increases in grey matter volume that were 43.3% and 49.6%, respectively, of the increases found in participants with normal weight. As well, BMI significantly moderated the association between subcortical grey matter volume change and clinical response to ECT. We observed no significant association between BMI and clinical response to ECT. Limitations: Because only baseline BMI values were available, we were unable to study BMI changes during ECT and their potential association with clinical and grey matter volume change. Conclusion: Future studies should take into account the relevance of body weight as a modulator of structural neuroplasticity during ECT treatment and aim to further explore the functional relevance of this novel finding.

Supported accommodation for people with schizophrenia.

Background: As a result of deinstitutionalization of psychiatric treatment and care, many people with severe mental illness have been offered supported accommodation. However, research on this costly intervention in Norway has been scarce. Aims: The aim of this study was to prospectively investigate the clinical and demographic factors associated with allocation to supported accommodation for people with schizophrenia. Methods: The study was a prospective cohort study of 334 people with schizophrenia acutely admitted to Haukeland University Hospital between 2005 and 2010. Information concerning allocation to supported accommodation in their residential municipalities was collected retrospectively. Univariate and multivariate statistical methods were used to assess the association of clinical and demographical variables with allocation to supported accommodation. Results: Supported accommodation was allocated to 29.6% of the participants during the study period. Age, gender, implementation of compulsory mental health care, substance abuse, symptom burden and suicidality were not associated with allocation to supported accommodation. Functional impairment, especially difficulties with activities of daily living, experiencing exacerbation in the course of chronic disease, being medicated and of Norwegian origin, favoured supported accommodation. Conclusions: Our results supported the hypothesis that people with severe mental illness presenting the greatest need for supported accommodation, based on functional difficulties and exacerbation of chronic disease were allocated supported accommodation. Symptom burden was not associated with allocation. Clinical implications: Further research is needed to examine the impact of supported accommodation on the outcomes for people with schizophrenia.

Prevalence and clinical features associated to bipolar disorder-migraine comorbidity: a systematic review.

BACKGROUND: The prevalence and clinical features associated with bipolar disorders (BDs)-migraine comorbidity have been reported inconsistently across different studies, therefore warranting a systematic review on the matter. METHODS: A systematic review was conducted in accordance with the PRISMA statement searching major electronic databases for documents indexed between January, 2000 and July, 2014. Eligible studies were those including quantitative data on prevalence rates and clinical features associated to BD-migraine comorbidity; case reports excluded. Three authors independently conducted searches, quality assessment of the studies and data extraction. RESULTS: Several cross-sectional studies, and a handful of retrospective follow-up studies or non-systematic reviews assessed the prevalence and/or the clinical correlates of migraine-BD comorbidity. High prevalence rates and a significant burden of BD-migraine comorbidity were common findings, particularly in case of BD-II women (point-prevalence rates up to 77%), migraine with aura (up to 53%) and/or cyclothymic temperament (up to 45% of the cases). LIMITATIONS: Some of the biases encountered in a few studies accounted by the present review may nonetheless have hampered the generalizability of the overall conclusions drawn herein. CONCLUSIONS: BD-migraine comorbidity may comprise of a sub-phenotype of BDs requiring patient-tailored therapeutic interventions to achieve an optimal outcome. Specifically, additional studies including longitudinal follow-up studies are aimed in order to shed further light on the actual prevalence rates and clinical features associated to BD-migraine comorbidity, with a special emphasis towards the clinically suggestive potential connection between mixed features, bipolar depression, migraine, and increased risk for suicidality. PROSPERO registration number: CRD42014009335.

Does diabetes have a protective effect on migraine?

BACKGROUND: Diabetes is associated with an increased risk of several other chronic diseases. In contrast, a previous study found an inverse relation between diabetes and migraine, whereas another large population-based study showed that the prevalence of migraine among patients with diabetes varied strongly depending on age. We aimed to investigate how the prevalence of medically treated migraine in patients with diabetes varied depending on diabetic drug treatment, sex, and age in the complete Norwegian population. METHODS: Data on all persons in Norway being prescribed medication for diabetes (n =124,649) or migraine (n = 81,225) in 2006 were obtained from the National Register of Prescriptions and analyzed in a cross-sectional design. RESULTS: Persons using diabetic drugs had an overall reduced prevalence of medically treated migraine when compared with the nondiabetic population (odds ratio [OR] = 0.72 [95% confidence interval = 0.68-0.75]). The OR was strongly associated with age. Although young persons receiving oral diabetic medication had, in fact, an increased prevalence of medically treated migraine, the prevalence declined with increasing age to about the same reduced prevalence (OR = 0.4-0.6) for all types of diabetes treatment in patients 60 to 69 years of age. The prevalence was equally decreased between men and women. CONCLUSIONS: The results suggest a markedly reduced prevalence of migraine among older patients with diabetes, when compared with the general population. One may speculate that the seemingly protective effect of diabetes on migraine could be a result of neuropathy.

Complexity and variability analyses of motor activity distinguish mood states in bipolar disorder.

Changes in motor activity are core symptoms of mood episodes in bipolar disorder. The manic state is characterized by increased variance, augmented complexity and irregular circadian rhythmicity when compared to healthy controls. No previous studies have compared mania to euthymia intra-individually in motor activity. The aim of this study was to characterize differences in motor activity when comparing manic patients to their euthymic selves. Motor activity was collected from 16 bipolar inpatients in mania and remission. 24-h recordings and 2-h time series in the morning and evening were analyzed for mean activity, variability and complexity. Lastly, the recordings were analyzed with the similarity graph algorithm and graph theory concepts such as edges, bridges, connected components and cliques. The similarity graph measures fluctuations in activity reasonably comparable to both variability and complexity measures. However, direct comparisons are difficult as most graph measures reveal variability in constricted time windows. Compared to sample entropy, the similarity graph is less sensitive to outliers. The little-understood estimate Bridges is possibly revealing underlying dynamics in the time series. When compared to euthymia, over the duration of approximately one circadian cycle, the manic state presented reduced variability, displayed by decreased standard deviation (p = 0.013) and augmented complexity shown by increased sample entropy (p = 0.025). During mania there were also fewer edges (p = 0.039) and more bridges (p = 0.026). Similar significant changes in variability and complexity were observed in the 2-h morning and evening sequences, mainly in the estimates of the similarity graph algorithm. Finally, augmented complexity was present in morning samples during mania, displayed by increased sample entropy (p = 0.015). In conclusion, the motor activity of mania is characterized by altered complexity and variability when compared within-subject to euthymia.

Adult attention deficit hyperactivity disorder is associated with migraine headaches.

Attention deficit hyperactivity disorder (ADHD) is now recognized as a common disorder both in child and adult psychiatry. Adult patients with a diagnosis of ADHD (n = 572) and community controls (n = 675) responded to auto-questionnaires rating past and present symptoms of ADHD, co-morbid conditions, including migraine, treatment history and work status. The prevalence of migraine was significantly higher in the patient group compared to the controls (28.3% vs. 19.2%, P < 0.001, OR = 1.67, CI 1.28-2.17). The difference from controls was particularly marked for men (22.5% vs. 10.7%, P < 0.001, OR = 2.43, CI 1.51-3.90) but was also significant for women (34.4% vs. 24.9%, P = 0.008, OR = 1.58, CI 1.13-2.21). In both patients and controls, migraine was associated with symptoms of mood and anxiety disorders. These findings point to a co-morbidity of migraine with ADHD, and it is possible that these patients represent a clinical and biological subgroup of adult patients with ADHD.

Adult attention deficit hyperactivity disorder is associated with asthma.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is increasingly recognized as a common disorder not only in children, but also in the adult population. Similarly, asthma also has a substantial prevalence among adults. Previous studies concerning a potential relationship between ADHD and asthma have not presented consistent results. METHODS: A cross-sectional study of 594 adult patients diagnosed with ADHD, compared with 719 persons from the general population. Information was collected between 1997 and 2005 using auto-questionnaires rating past and present symptoms of ADHD, co-morbid conditions, including asthma, and work status. RESULTS: The prevalence of asthma was significantly higher in the ADHD patient group compared to the controls, 24.4% vs. 11.3% respectively (OR = 2.54, 95% CI 1.89-3.44), and controls with asthma scored higher on ratings of both past and present symptoms of ADHD. Female ADHD patients had a significantly higher prevalence of asthma compared to male ADHD patients (30.9% vs. 18.2%, OR = 2.01, CI 1.36-2.95), but in controls a slight female preponderance was not statistically significant. In both ADHD patients and controls, having asthma was associated with an increased prevalence of symptoms of mood- and anxiety disorders. CONCLUSIONS: The present findings point to a co-morbidity of ADHD and asthma, and these patients may represent a clinical and biological subgroup of adult patients with ADHD.

Short and long-term effects of single and multiple sessions of electroconvulsive therapy on brain gray matter volumes.

BACKGROUND: Electroconvulsive therapy (ECT) has been shown to induce broadly distributed cortical and subcortical volume increases, more prominently in the amygdala and the hippocampus. Structural changes after one ECT session and in the long-term have been understudied. OBJECTIVE: The aim of this study was to describe short-term and long-term volume changes induced in cortical and subcortical regions by ECT. METHODS: Structural brain data were acquired from depressed patients before and 2 h after their first ECT session, 7-14 days after the end of the ECT series and at 6 months follow up (N = 34). Healthy, age and gender matched volunteers were scanned according to the same schedule (N = 18) and patients affected by atrial fibrillation were scanned 1-2 h before and after undergoing electrical cardioversion (N = 16). Images were parcelled using FreeSurfer and estimates of cortical gray matter volume and subcortical volume changes were obtained using Quarc. RESULTS: Volume increase was observable in most of gray matter regions after 2 h from the first ECT session, with significant results in brain stem, bilateral hippocampi, right putamen and left thalamus, temporal and occipital regions in the right hemisphere. At the end of treatment series, widespread significant volume changes were observed. After six months, the right amygdala volume was still significantly increased. No significant changes were observed in the comparison groups. CONCLUSIONS: Volume increases in gray matter areas can be detected 2 h after a single ECT session. Further studies are warranted to explore the underlying molecular mechanisms.

Enduring cognitive dysfunction in unipolar major depression: a test-retest study using the Stroop paradigm.

The aim of the study was to investigate automatic and effortful information processing with the Stroop paradigm in a long term perspective in patients with major depressive disorder (MDD). Patients were tested at two test occasions: at inclusion with a Hamilton Depression Rating Scale (HDRS) score >18, and after 6 months, when most patients had experienced symptom reduction. The Stroop paradigm is considered to measure aspects of attention and executive functioning and consists of three conditions/cards: naming the color of the patches (Color), reading of the color-words (Word) and naming the ink color of color-words (Color-Word). The Color-Word condition is proved to be the most cognitive demanding task and requires the proband to actively suppress interference and is therefore considered to require more effortful information processing, whereas naming the color of the patches and reading the color-words are expected to be more automatic and less cognitive demanding. A homogenous group of 19 patients with unipolar recurrent MDD according to DSM-IV and a HDRS score of >18 were included in the study. A control group was individually matched for age, gender and level of education. Depressed patients performed equal to the control group on the Color and Word cards at both test occasions. However, the patients were impaired compared with the control group on the Color-Word card task at both test occasions. Thus, the depressed patients showed no improvement of effortful attention/executive performance as a function of symptom reduction. The results indicate that the depressed patients showed impaired cognitive performance on cognitive demanding tasks when symptomatic and that this impairment prevailed after 6 months, despite significant improvement in their depressive symptoms.

A Longitudinal 5-Year Follow-Up Study of Cognitive Function After First Episode Major Depressive Disorder: Exploring State, Scar and Trait Effects.

Major depression (MDD) is associated with cognitive deficits in processing speed and executive function (EF) following first episode (FE). It is unclear whether deficits are state or trait related. Studies following FE MDD over longer periods are lacking, making it uncertain how cognition and symptoms develop after the initial episode. The present study assessed cognitive function and symptoms 5 years following FE MDD. In addition, the study explored relationships between MDD symptoms, rumination, and cognitive deficits with regards to the trait, state, and scar perspective. Twenty-three participants with previous FE MDD, and 20 matched control participants were compared on Delis-Kaplan Executive Function System measures of processing speed and EF, in a 5-year longitudinal follow-up study. Correlations between current symptoms- and history of MDD, rumination, cognition were investigated. Findings indicated that cognitive deficits persisted with no clear signs of exacerbation after initial episode. Inhibition appeared independent of current and previous symptoms of depression. Processing speed was related to depressive- symptoms and rumination. In conclusion, results indicated persisting, stable deficits in both EFs and processing speed. Findings further suggest that depressive symptoms could be related to deficits in processing speed, indicating state effects. There was limited support for worsening of cognition after initial episode. Some aspects of EF like Inhibition could show persistent deficits independent of depressive symptoms indicating trait effects.

Applying machine learning in motor activity time series of depressed bipolar and unipolar patients compared to healthy controls.

Current practice of assessing mood episodes in affective disorders largely depends on subjective observations combined with semi-structured clinical rating scales. Motor activity is an objective observation of the inner physiological state expressed in behavior patterns. Alterations of motor activity are essential features of bipolar and unipolar depression. The aim was to investigate if objective measures of motor activity can aid existing diagnostic practice, by applying machine-learning techniques to analyze activity patterns in depressed patients and healthy controls. Random Forrest, Deep Neural Network and Convolutional Neural Network algorithms were used to analyze 14 days of actigraph recorded motor activity from 23 depressed patients and 32 healthy controls. Statistical features analyzed in the dataset were mean activity, standard deviation of mean activity and proportion of zero activity. Various techniques to handle data imbalance were applied, and to ensure generalizability and avoid overfitting a Leave-One-User-Out validation strategy was utilized. All outcomes reports as measures of accuracy for binary tests. A Deep Neural Network combined with SMOTE class balancing technique performed a cut above the rest with a true positive rate of 0.82 (sensitivity) and a true negative rate of 0.84 (specificity). Accuracy was 0.84 and the Matthews Correlation Coefficient 0.65. Misclassifications appear related to data overlapping among the classes, so an appropriate future approach will be to compare mood states intra-individualistically. In summary, machine-learning techniques present promising abilities in discriminating between depressed patients and healthy controls in motor activity time series.

Cyclothymic temperament: Associations with ADHD, other psychopathology, and medical morbidity in the general population.

BACKGROUND: Cyclothymic temperament (CT) is an affective disposition often preceding bipolar disorder (BD), and is the most common affective temperament in patients with BD. In depressed patients, CT is a predictor for developing a bipolar course. In a clinical sample of adults with BD and attention deficit hyperactivity disorder (ADHD), CT was associated with higher loads of psychiatric symptoms, somatic comorbidity, impairment, and higher morbidity among first-degree relatives. We aimed to investigate the morbidity and occupational functioning of persons with CT in the general population. METHODS: Randomly recruited Norwegian adults (n = 721) were assessed with a 21-item cyclothymic subscale from the TEMPS Autoquestionnaire. Self-reported data were collected on psychiatric symptoms, comorbidity, educational and occupational level, and known family morbidity. RESULTS: Thirteen percent had CT associated with an increased prevalence of ADHD, BD, high scores on the Mood Disorder Questionnaire (MDQ), and childhood and adulthood ADHD symptoms. CT was found in 75% (p < .001) of the bipolar participants, and in 68% (p < .001) of those with a positive MDQ score. CT was associated with more anxiety/depression, substance and alcohol problems, lower educational and occupational levels, and having a first-degree relative with anxiety/depression, alcohol problems, ADHD, and BD. LIMITATIONS: The CT subscale alone might include overlapping features with cyclothymic, anxious, irritable, and depressed temperaments, thus increasing the prevalence estimate of CT. CONCLUSIONS: CT is a strong predictor of occupational failure and associated with more psychiatric impairment in the participants and their families. CT should be assessed in both mood disorder and ADHD patients.

Elderly patients with no previous psychiatric history: suicidality and other factors relating to psychiatric acute admissions.

BACKGROUND: The common recommendation that adults with onset of mental illness after the age of 65 should receive specialised psychogeriatric treatment is based on limited evidence. AIMS: To compare factors related to psychiatric acute admission in older adults who have no previous psychiatric history (NPH) with that of those who have a previous psychiatric history (PPH). METHOD: Cross-sectional cohort study of 918 patients aged ≥65 years consecutively admitted to a general adult psychiatric acute unit from 2005 to 2014. RESULTS: Patients in the NPH group (n = 526) were significantly older than those in the PPH group (n = 391) (77.6 v. 70.9 years P < 0.001), more likely to be men, married or widowed and admitted involuntarily. Diagnostic prevalence in the NPH and PPH groups were 49.0% v. 8.4% (P < 0.001) for organic mental disorders, 14.6% v. 30.4% (P < 0.001) for psychotic disorders, 30.2% v. 55.5% (P < 0.001) for affective disorders and 20.7% v. 13.3% (P = 0.003) for somatic disorders. The NPH group scored significantly higher on the Health of the Nation Outcome Scale (HoNOS) items agitated behaviour; cognitive problems; physical illness or disability and problems with activities of daily living, whereas those in the PPH group scored significantly higher on depressed mood. Although the PPH group were more likely to report suicidal ideation, those in the NPH group were more likely to have made a suicide attempt before the admission. CONCLUSIONS: Among psychiatric patients >65 years, the subgroup with NPH were characterised by more physical frailty, somatic comorbidity and functional and cognitive impairment as well as higher rates of preadmission suicide attempts. Admitting facilities should be appropriately suited to manage their needs.

The effect of electroconvulsive therapy (ECT) on serum tryptophan metabolites.

BACKGROUND: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. OBJECTIVE: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. METHODS: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5'-phosphat (PLP), riboflavin, neopterin and cotinine were measured. RESULTS: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. CONCLUSION: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway.

Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative.

BACKGROUND: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. STRUCTURE: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. CONCLUSIONS: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Non-right-handedness is associated with migraine and soft bipolarity in patients with mood disorders.

BACKGROUND: There is a substantial body of data showing differences in the functioning of the two hemispheres in unipolar depressive and bipolar disorders. Migraine is a frequent co-morbid disorder in these patients, and it has been proposed that migraine may be associated with left-handedness. It would therefore be interesting to study migraine and handedness in a population of patients with mood disorders. METHODS: A total of 201 patients with an index episode of either major depression or mania were interviewed with a semi-structured interview based partly on DSM-IV criteria and partly on TEMPS-I for affective temperaments. The criteria of the Headache Classification Committee of the International Headache Society were used to establish the diagnosis of migraine. Hand preference was assessed using the Edinburgh inventory, and the patients were classified as having right-, left-, or mixed-handedness. RESULTS: In the whole group 117 patients had migraine (58%) and 59 (29%) were classified as having non-right hand preference. There was a significant increased prevalence of non-right-handedness in the migraine group (37% vs. 19%, p=0.021, Chi-square test; OR 2.5; 95% CI 1.3 -4.8, p=0.007). In patients with cyclothymic, hyperthymic or irritable temperaments the prevalence of non-right-handedness (42%) was significantly higher (p=0.013, Chi-square test; OR 2.2, 95% CI 1.2-4.3) compared to patients with a depressive or no affective temperament (24%). The prevalence of non-right-handedness was also significantly higher both in patients with co-morbid eating disorders (48% vs. 26%, p=0.008 Chi-square test; OR 2.7, 95% CI 1.3-5.9, p=0.01) and asthma (45% vs. 26%, p=0.026 Chi-square test; OR 2.3, 95% CI 1.1-5.1, p=0.029). LIMITATIONS: Non-blind evaluation of affective diagnosis, migraine and handedness. CONCLUSIONS: Our main finding supports the hypothesis that non-right-handedness is associated with migraine and bipolar affective temperaments ("soft bipolarity") in a sample of patients with major affective disorders.