Rixt F. Riemersma-van der Lek

Relationship between clinical features and inflammation related monocyte gene expression in bipolar disorder - towards a better understanding of psychoimmunological interactions

Existing and previously published datasets were examined for associations between illness and treatment characteristics and monocyte pro‐inflammatory gene expression in patients with bipolar disorder (BD). We hypothesized a priori that increased monocyte pro‐inflammatory gene expression would be found more frequently in patients with a lifetime history of psychotic symptoms.

Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder - A combined magnetic resonance imaging and positron emission tomography study

BACKGROUND The hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning. MATERIALS AND METHODS Twenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [(11)C]-(R)-PK11195 neuroinflammation positron emission tomography scan. RESULTS In contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr)+phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA+NAAG concentration, between alcohol use and NAA+NAAG concentration, between microglial activation and the depression score and a negative relation between Cr+PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally. CONCLUSION Compared to HCs, the decreased NAA+NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.

Can Variation in Hypothalamic-Pituitary-Adrenal (HPA)-Axis Activity Explain the Relationship between Depression and Cognition in Bipolar Patients?

Background Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to be associated with more mood symptoms and worse cognitive functioning. This study examined whether variation in HPA axis activity underlies the association between mood symptoms and cognitive functioning. Methodology/Principal Findings In 65 bipolar patients cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating version. Saliva cortisol measurements were performed to calculate HPA axis indicators: cortisol awakening response, diurnal slope, the evening cortisol level and the cortisol suppression on the dexamethasone suppression test. Regression analyses of depressive symptoms and cognitive functioning on each HPA axis indicator were performed. In addition we calculated percentages explanation of the association between depressive symptoms and cognition by HPA axis indicators. Depressive symptoms were associated with dysfunction in psychomotor speed, attentional switching and the mean score, as well as with attenuation in diurnal slope value. No association was found between HPA axis activity and cognitive functioning and HPA axis activity did not explain the associations between depressive symptoms and cognition. Conclusions/Significance As our study is the first one in this field specific for bipolar patients and changes in HPA-axis activity did not seem to explain the association between severity of depressive symptoms and cognitive functioning in bipolar patients, future studies are needed to evaluate other factors that might explain this relationship.

Diffusion tensor imaging in euthymic bipolar disorder – A tract-based spatial statistics study

BACKGROUND In the current DTI study we compared euthymic bipolar I disorder (BD-I) patients and healthy controls (HC). We subsequently divided the total patient group into lithium-users and non-lithium-users and estimated differences across the three groups. METHODS Twenty-one euthymic BD-I patients and twenty-two HC participants were included in psychiatric interviews and MRI image acquisition (diffusion-weighted (DW) and T1-weighted scans). Fractional anisotropy (FA), radial, mean and axial diffusivity (RD, MD, AD) were estimated from the DW data, using DTI. These measures were then compared between groups using FSL Tract Based Spatial Statistics (TBSS). Correlations with age at onset, number of episodes and depression score were analyzed. RESULTS A difference in FA, MD, RD and AD between the whole sample of euthymic BD-I patients and healthy controls could not be detected. Amongst others, lithium-using patients demonstrated a higher FA and lower RD when compared to non-lithium-using BD-I patients in the corpus callosum and left anterior corona radiata. Widespread clusters demonstrated negative FA associations and positive RD and MD associations with minor depressive symptoms. LIMITATIONS Patients were naturalistically treated. Although the sample size is comparable to several other DTI studies, a larger sample size would have been benificial. TBSS and DTI have their own limitations. CONCLUSION Our findings support the theory that previously described DTI-based microstructural differences between HC and BD patients could be less pronounced in euthymic BD patients. Differences in FA between patients using and not using lithium suggest a counteracting effect of lithium on white matter microstructural disturbances.

Social jetlag and depression status: Results obtained from the Netherlands Study of Depression and Anxiety

ABSTRACT Social jetlag, the misalignment between the internal clock and the socially required timing of activities, is highly prevalent, especially in people with an evening chronotype and is hypothesized to be related to the link between the evening chronotype and major depressive disorder. Although social jetlag has been linked to depressive symptoms in non-clinical samples, it has never been studied in patients with major depressive disorder (MDD). This study is aimed to study social jetlag in patients with major depressive disorder and healthy controls, and to further examine the link between social jetlag and depressive symptomatology. Patients with a diagnosis of MDD (n = 1084) and healthy controls (n = 385), assessed in a clinical interview, were selected from the Netherlands Study of Depression and Anxiety. Social jetlag was derived from the Munich Chronotype Questionnaire, by calculating the absolute difference between the midsleep on free days and midsleep on work days. Depression severity was measured with the Inventory of Depressive Symptomatology. It was found that patients with MDD did not show more social jetlag compared to healthy controls, neither in a model without medication use (β = 0.06, 95% CI: −0.03–0.15, p = 0.17) nor in a model where medication use is accounted for. There was no direct association between the amount of social jetlag and depressive symptoms, neither in the full sample, nor in the patient group or the healthy control group. This first study on social jetlag in a clinical sample showed no differences in social jetlag between patients with MDD and healthy controls.

Feature-expression heat maps - A new visual method to explore complex associations between two variable sets

INTRODUCTION Existing methods such as correlation plots and cluster heat maps are insufficient in the visual exploration of multiple associations between genetics and phenotype, which is of importance to achieve a better understanding of the pathophysiology of psychiatric and other illnesses. The implementation of a combined presentation of effect size and statistical significance in a graphical method, added to the ordering of the variables based on the effect-ordered data display principle was deemed useful by the authors to facilitate in the process of recognizing meaningful patterns in these associations. MATERIALS AND METHODS The requirements, analyses and graphical presentation of the feature-expression heat map are described. The graphs display associations of two sets of ordered variables where a one-way direction is assumed. The associations are depicted as circles representing a combination of effect size (color) and statistical significance (radius). RESULTS An example dataset is presented and relation to other methods, limitations, areas of application and possible future enhancements are discussed. CONCLUSION The feature-expression heat map is a useful graphical instrument to explore associations in complex biological systems where one-way direction is assumed, such as genotype-phenotype pathophysiological models.

The dysregulated brain: Consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis

Increasingly, evidence has been accumulating emphasizing the importance of looking at bipolar disorder (BD) from a neurodevelopmental and transdimensional perspective to better understand its origins and its course. In this overview article, the problems facing pathophysiological psychiatric research in BD are addressed and interpreted in the light of brain complexity. Brain complexity can be split into spatial complexity, which constitutes the physiological levels of the central nervous system (i.e., the genetic, molecular, cellular, neuronal circuit and phenomenological levels), and temporal complexity, that is, neurodevelopment. The consequences of this consideration are discussed and suggestions for clinical practice and pathophysiological psychiatric research are made.

Coping with a life event in bipolar disorder: ambulatory measurement, signalling and early treatment

Disruption of the biological rhythm in patients with bipolar disorder is a known risk factor for a switch in mood. This case study describes how modern techniques using ambulatory assessment of sleep parameters can help in signalling a mood switch and start early treatment. We studied a 40-year-old woman with bipolar disorder experiencing a life event while wearing an actigraph to measure sleep-wake parameters. The night after the life event the woman had sleep later and shorter sleep duration. Adequate response of both the woman and the treating psychiatrist resulted in two normal nights with the use of 1 mg lorazepam, possibly preventing further mood disturbances. Ambulatory assessment of the biological rhythm can function as an add-on to regular signalling plans for prevention of episodes in patients with bipolar disorder. More research should be conducted to validate clinical applicability, proper protocols and to understand underlying mechanisms.

An actigraphy study investigating sleep in bipolar I patients, unaffected siblings and controls

OBJECTIVES Disturbances in sleep and waking patterns are highly prevalent during mood episodes in bipolar disorder. The question remains whether these disturbances persist during phases of euthymia and whether they are heritable traits of bipolar disorder. The current study investigates objective sleep measures in a large sample of bipolar I patients, non-affected siblings and controls. METHODS A total of 107 bipolar disorder I patients, 74 non-affected siblings, and 80 controls were included. Sleep was measured with actigraphy over the course of 14 days. Seven sleep parameters were analyzed for group differences and their relationship with age at onset, number of episodes and psychotic symptoms using linear mixed model analysis to account for family dependencies. RESULTS Patients had a longer sleep duration and later time of sleep offset compared to the non-affected siblings but these differences were entirely attributable to differences in mood symptoms. We found no difference between patients and controls or siblings and controls when the analyses were restricted to euthymic patients. None of the bipolar illness characteristics were associated with sleep. LIMITATIONS Medication use was not taken into account which may have influenced our findings and controls were younger compared to non-affected siblings. CONCLUSIONS In the largest study to date, our findings suggest that recovered bipolar I patients and their siblings do not experience clinically significant sleep disturbances. Sleep disturbances are primarily a reflection of current mood state, but are unrelated to the course of the disorder.

Corrigendum to "Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder - A combined magnetic resonance imaging and positron emission tomography study" [Brain Behav. Immun. (2015)].

While retrieving additional information from patients’ medical files for another study, it became clear that one patient who was actually using valproate and levetiracetam, was previously processed as a lithium user. Below you will find the corrected version of the subjects’ characteristics Table 1, as well as corrected results of the explorative analyses of this study where lithium use was involved and an updated version of Fig. 7, summarizing the explorative analysis results of the left hippocampus. The altered text of the concerned paragraphs are set in boldface. The cited references are as in the original report.