Mats Adler

Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: Cytokine challenge increases production of 3-hydroxykynurenine

Accumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and pathogenesis of bipolar disorder and schizophrenia. The goal of this study was to examine the production of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and the expression of kynurenine pathway enzymes involved in their synthesis and metabolism in cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals. The assessment was performed under basal conditions or following treatment with interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, or their combinations, in cells exposed to exogenous kynurenine. In both groups of patients, the baseline production of KYNA and 3-HK was increased, as compared to control subjects. Case-treatment analyses revealed significant interactions between bipolar case status and IL-1β, IL-6, IFN-γ + TNF-α, or IFN-γ + IL-1β, as well as between schizophrenia case status and IL-1β, IFN-γ + TNF-α, or IFN-γ + IL-1β, in terms of higher 3-HK. Noteworthy, no case-treatment interactions in terms of KYNA production were found. Observed changes did not appear to correlate with the expression of genes encoding kynurenine aminotransferases (KATs), kynureninase (KYNU) or kynurenine-3-monooxygenase (KMO). The single nucleotide polymorphisms (SNPs), rs1053230 and rs2275163, in KMO influenced KYNA levels yet did not explain the case-treatment discrepancies. In conclusion, our present findings indicate the utility of skin-derived fibroblasts for kynurenines research and support the concept of kynurenine pathway alterations in bipolar disorder and schizophrenia. The increase in ratio between neurotoxic 3-HK and neuroinhibitory/neuroprotective KYNA following exposure to cytokines may account for altered neurogenesis and structural abnormalities characteristic for both diseases.

Psychiatric admissions and hospitalization costs in bipolar disorder in Sweden

a Department of Psychiatry, Danderyd University Hospital, Sweden b Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden c Medical Management Centre (MMC), LIME, Karolinska Institutet, Stockholm, Sweden d Bristol-Myers Squibb, Global Epidemiology and Outcomes Research (GEOR;4), Belgium e Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Development and validation of the Affective Self Rating Scale for manic, depressive, and mixed affective states

Most rating scales for affective disorders measure either depressive or hypomanic/manic symptoms and there are few scales for hypomania/mania in a self-rating format. We wanted to develop and validate a self-rating scale for comprehensive assessment of depressive, manic/hypomanic and mixed affective states. We developed an 18-item self-rating scale starting with the DSM-IV criteria for depression and mania, with subscales for depression and mania. The scale was evaluated on 61 patients with a diagnosis of affective disorder, predominantly bipolar disorder type I, using Montgomery–Åsberg Depression Rating Scale (MADRS), Hypomania Interview Guide—Clinical version (HIGH-C) and Clinical Global Impression scale, modified for bipolar patients (CGI-BP) as reference scales. Internal consistency of the scale measured by Cronbachs alpha was 0.89 for the depression subscale and 0.91 for the mania subscale. Spearmans correlation coefficients (two-tailed) between the depression subscale and MADRS was 0.74 (P<0.01) and between mania subscale and HIGH-C 0.80 (P<0.01). A rotated factor analysis of the scale supported the separation of symptoms in the mania and depression subscale. We established that the self-rating scales sensitivity to identify mixed states, with combined cut-offs on the MADRS and HIGH-C as reference, was 0.90 with a specificity of 0.71. The study shows that the Affective Self Rating Scale is highly correlated with ratings of established interview scales for depression and mania and that it may aid the detection of mixed affective states.

A comparison of three methods of assessing differential item functioning (DIF) in the Hospital Anxiety Depression Scale: ordinal logistic regression, Rasch analysis and the Mantel chi-square procedure.

PurposeIt is important for clinical practice and research that measurement scales of well-being and quality of life exhibit only minimal differential item functioning (DIF). DIF occurs where different groups of people endorse items in a scale to different extents after being matched by the intended scale attribute. We investigate the equivalence or otherwise of common methods of assessing DIF.MethodThree methods of measuring age- and sex-related DIF (ordinal logistic regression, Rasch analysis and Mantel χ2 procedure) were applied to Hospital Anxiety Depression Scale (HADS) data pertaining to a sample of 1,068 patients consulting primary care practitioners.ResultsThree items were flagged by all three approaches as having either age- or sex-related DIF with a consistent direction of effect; a further three items identified did not meet stricter criteria for important DIF using at least one method. When applying strict criteria for significant DIF, ordinal logistic regression was slightly less sensitive.ConclusionsOrdinal logistic regression, Rasch analysis and contingency table methods yielded consistent results when identifying DIF in the HADS depression and HADS anxiety scales. Regardless of methods applied, investigators should use a combination of statistical significance, magnitude of the DIF effect and investigator judgement when interpreting the results.

An item response theory evaluation of three depression assessment instruments in a clinical sample

BackgroundThis study investigates whether an analysis, based on Item Response Theory (IRT), can be used for initial evaluations of depression assessment instruments in a limited patient sample from an affective disorder outpatient clinic, with the aim to finding major advantages and deficiencies of the instruments.MethodsThree depression assessment instruments, the depression module from the Patient Health Questionnaire (PHQ9), the depression subscale of Affective Self Rating Scale (AS-18-D) and the Montgomery-Åsberg Depression Rating Scale (MADRS) were evaluated in a sample of 61 patients with affective disorder diagnoses, mainly bipolar disorder. A ‘3- step IRT strategy’ was used.ResultsIn a first step, the Mokken non-parametric analysis showed that PHQ9 and AS-18-D had strong overall scalabilities of 0.510 [C.I. 0.42, 0.61] and 0,513 [C.I. 0.41, 0.63] respectively, while MADRS had a weak scalability of 0.339 [C.I. 0.25, 0.43]. In a second step, a Rasch model analysis indicated large differences concerning the item discriminating capacity and was therefore considered not suitable for the data. In third step, applying a more flexible two parameter model, all three instruments showed large differences in item information and items had a low capacity to reliably measure respondents at low levels of depression severity.ConclusionsWe conclude that a stepwise IRT-approach, as performed in this study, is a suitable tool for studying assessment instruments at early stages of development. Such an analysis can give useful information, even in small samples, in order to construct more precise measurements or to evaluate existing assessment instruments. The study suggests that the PHQ9 and AS-18-D can be useful for measurement of depression severity in an outpatient clinic for affective disorder, while the MADRS shows weak measurement properties for this type of patients.

An IRT validation of the Affective Self Rating Scale

Background: The Affective Self Rating Scale (AS-18) is intended for the use in bipolar outpatients. It includes subscales for the rating of depressive and manic-type symptoms. It has previously been validated using methods from Classical Test Theory. Aims: The aim of this study was to evaluate the psychometric properties of the AS-18 when used at an outpatient clinic for patients with bipolar disorder at routine visits, and to analyze the potential for improvement of the scale. Methods: 231 patients with mainly bipolar I disorder doing ratings on routine visits at an affective disorder outpatient clinic were included. Ratings were analyzed using the Mokken non-parametric and the Rasch parametric model statistical methods. Results: In the Mokken analysis, both subscales of the AS-18 showed a strong ability to rank respondents according to their total score and all items contributed adequately to the measurement. In the Rasch model, there were no indications of disturbing influence from secondary dimensions in the subscales. The depression subscale had the capacity reliably to separate the sample in at most three levels and the mania subscale in two levels. The limited capacity to separate respondents can mainly be explained by a lack of items reflecting lower levels of depressive and manic symptoms. Conclusions: AS-18 has good basic psychometric properties for use of rating of symptoms in bipolar I patients at routine visits, but there is also room for improvement. Item Response Theory (IRT) methods are suitable tools for evaluation and construction of rating scales.

Motor imagery in bipolar depression with slowed movement

Abstract We hypothesized that motor retardation in bipolar depression is mediated by disruption of the pre-executive stages of motor production. We used functional magnetic resonance imaging to investigate neural activity during motor imagery and motor execution to elucidate whether brain regions that mediate planning, preparation, and control of movement are activated differently in subjects with bipolar depression (n = 9) compared with healthy controls (n = 12). We found significant between-group differences. During motor imagery, the patients activated the posterior medial parietal cortex, the posterior cingulate cortex, the premotor cortex, the prefrontal cortex, and the frontal poles more than the controls did. Activation in the brain areas involved in motor selection, planning, and preparation was altered. In addition, limbic and prefrontal regions associated with self-reference and the default mode network were altered during motor imagery in bipolar depression with motor retardation.

Functional and Structural Alterations in the Cingulate Motor Area Relate to Decreased Fronto-Striatal Coupling in Major Depressive Disorder with Psychomotor Disturbances

Psychomotor disturbances are a classic feature of major depressive disorders. These can manifest as lack of facial expressions and decreased speech production, reduced body posture and mobility, and slowed voluntary movement. The neural correlates of psychomotor disturbances in depression are poorly understood but it has been suggested that outputs from the cingulate motor area (CMA) to striatal motor regions, including the putamen, could be involved. We used functional and structural magnetic resonance imaging to conduct a region-of-interest analysis to test the hypotheses that neural activation patterns related to motor production and gray matter volumes in the CMA would be different between depressed subjects displaying psychomotor disturbances (n = 13) and matched healthy controls (n = 13). In addition, we conducted a psychophysiological interaction analysis to assess the functional coupling related to self-paced finger-tapping between the caudal CMA and the posterior putamen in patients compared to controls. We found a cluster of increased neural activation, adjacent to a cluster of decreased gray matter volume in the caudal CMA in patients compared to controls. The functional coupling between the left caudal CMA and the left putamen during finger-tapping task performance was additionally decreased in patients compared to controls. In addition, the strength of the functional coupling between the left caudal CMA and the left putamen was negatively correlated with the severity of psychomotor disturbances in the patient group. In conclusion, we found converging evidence for involvement of the caudal CMA and putamen in the generation of psychomotor disturbances in depression.

The neural correlates of self-paced finger tapping in bipolar depression with motor retardation

Objective Motor retardation is a characteristic feature of bipolar depression, and is also a core feature of Parkinsons disease. Within the framework of the functional deafferentiation theory in Parkinsons disease, we hypothesised that motor retardation in bipolar depression is mediated by disrupted subcortical activation, leading to decreased activation of cortical motor areas during finger tapping. Methods We used functional magnetic resonance imaging to investigate neural activity during self-paced finger tapping to elucidate whether brain regions that mediate preparation, control and execution of movement are activated differently in subjects with bipolar depression (n = 9) compared to healthy controls (n = 12). Results An uncorrected whole-brain analysis revealed significant group differences in dorsolateral and ventromedial prefrontal cortex. Corrected analyses showed non-significant differences in patients compared to controls: decreased and less widespread activation of the left putamen and left pallidum; increased activity in the left thalamus and supplementary motor area; decreased activation in the left lateral pre- and primary motor cortices; absence of activation in the pre-supplementary motor area; activation of the bilateral rostral cingulate motor area. Conclusion Both movement preparation and execution may be affected in motor retardation, and the activity in the whole left-side motor circuit is altered during self-initiated motor performance in bipolar depression.

Symptoms and treatment of bipolar patients in Sweden

Objective. The objective of the study was to investigate affective symptoms and pharmacological treatment in bipolar I disorder patients, and to test whether self-rated symptoms could predict hospital admissions during a 12-month follow-up period. Methods. A total of 231 outpatients with clinical bipolar I disorder were recruited. The clinical diagnoses were reassessed by a semi-structured interview. Twenty-four patients (10%) was reclassified as bipolar disorder type II or schizoaffective disorder (bipolar type). Medication status was recorded and symptoms were assessed with the self-rating scale AS-18. Patients were prospectively followed for 12 months and hospitalizations during that time were recorded. Results. More than half (60%) rated themselves as normothymic. Mixed affective symptoms were more common than either depressive or manic/hypomanic symptoms. The admission rate during 1 year of follow-up was 13% (95% C.I. 8–17%). Patients which at baseline rated themselves high in either mania or in depression had a significantly increased risk for hospitalization (OR = 3.15; 95% C.I. 1.38–7.19). Conclusions. The findings should encourage clinicians to use patient self ratings in order to identify patients with a high risk for hospitalization for targeted interventions.