Cerebrospinal fluid proteomic study of two bipolar disorder cohorts

The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total of 204 patients and 144 controls. We used three Olink Multiplex panels, whereof one specifically targets immune biomarkers, to assess a broad set of CSF protein concentrations. After quality control and removal of proteins with a low detection rate, 105 proteins remained for analyses in relation to case-control status and clinical variables. Only case-control differences that replicated across cohorts were considered. Results adjusted for potential confounders showed that CSF concentrations of growth hormone were lower in bipolar disorder compared with controls in both cohorts. The effect size was larger when the analysis was restricted to bipolar disorder type 1 and controls. We found no indications of immune activation or other aberrations. Growth hormone exerts many effects in the central nervous system and our findings suggest that growth hormone might be implicated in the pathophysiology of bipolar disorder

On cognition and personality in bipolar disorder

Even though the hallmark of bipolar disorder is recurrent episodes of elevated or depressed mood, mounting evidence suggests that cognitive impairment is a prominent characteristic of bipolar disorder. The heterogeneity and longitudinal trajectory of cognitive functioning are, however, poorly understood. Additionally, certain personality traits may play a role in psychopathological processes along with cognitive impairments. This thesis is based on six studies. Data were collected within the framework of St. Göran bipolar project, which is a longitudinal study of patients with bipolar disorder. Study I examined the clinical relevance of cognitive impairments and examined if cognitive abilities differ between bipolar disorder subtypes and healthy controls. Study II examined whether the correlation structure between various cognitive abilities differs between individuals with bipolar disorder and healthy controls. Study III examined if cognitive abilities differ between individuals with bipolar disorder with and without attention-deficit hyperactivity disorder (ADHD). Study IV examined if long-term changes in cognitive functioning in individuals with bipolar disorder differ from normal aging. Study V examined if personality traits differ between individuals with bipolar disorder and healthy controls, as well as the association between personality traits and illness course. Study VI examined if the cognition/personality interface is altered in bipolar disorder, and if combining cognitive predictors with personality measures would enhance the understanding of the illness course. Results showed that cognitive impairments approached clinical significance for substantial minority of the patients on certain cognitive tests measuring, e.g., set shifting and inhibition (I). While the majority of bipolar disorder patients performed on par with healthy controls, a subgroup (30%) showed impairments concerning memory (II). Comorbid ADHD in bipolar disorder could not explain the cognitive heterogeneity in bipolar disorder (III). The cognitive trajectory over a 6-year period did not differ between individuals with bipolar disorder patients and healthy controls (IV). The personality profile differed between patients and healthy controls but had no prognostic value (V). However, differences in personality traits explained some of the variation in cognitive performance in individuals with bipolar disorder (VI)

Personality traits in bipolar disorder and influence on outcome

Abstract Background The aim was to investigate the personality profile of bipolar disorder I and II, and healthy controls, and to study whether personality influences the course of bipolar disorder. Methods One hundred ten patients with bipolar disorder I, 85 patients with bipolar disorder II, and 86 healthy individuals had their personality profile assessed using the Swedish universities Scales of Personality (SSP), an instrument developed to explore personality-related vulnerabilities and correlates of psychiatric disorders. Patients were followed prospectively for 2 years. To assess the impact of Neuroticism, Aggressiveness, and Disinhibition on illness course, we performed logistic regressions with the outcome variables mood episodes (depressive, hypo/manic, mixed), suicide attempts, violence, and the number of sick leave days. Results Bipolar disorder I and II demonstrated higher global measures of Neuroticism, Aggressiveness, and Disinhibition as compared with healthy controls. A third of the patients scored ≥1 SD above the population-based normative mean on the global neuroticism measure. The two subtypes of bipolar disorder were, however, undistinguishable on all of the personality traits. In the unadjusted model, higher neuroticism at baseline predicted future depressive episodes and suicide attempts/violent behavior, but this association disappeared when adjusting for baseline depressive symptoms as assessed with MADRS. Conclusions A significant minority of the patients scored ≥1 SD above the population mean on the global measures of Neuroticism, Aggressiveness and Disinhibition; scores this high are usually evident clinically. Yet, the personality profile does not seem to have prognostic value over a 2-year period

Psychoeducation for bipolar disorder and risk of recurrence and hospitalization - a within-individual analysis using registry data

Background: The efficacy of psychoeducation for bipolar disorder has been demonstrated in clinical trials, but it is not known if the results translate into effectiveness in routine clinical practice. The aim was to determine the effectiveness of psychoeducation for bipolar disorder in a routine clinical setting. Method: We identified 2819 patients with at least three registrations in the Swedish Quality Assurance Register for Bipolar Disorder. Among those, 402 had not been exposed to psychoeducation at the first visit, but received psychoeducation during any of the following registrations. Using within-individual analyses, the risk of recurrence after having received psychoeducation was compared with the risk prior to psychoeducation. Results: In adjusted within-individuals comparisons, periods after psychoeducation was associated with decreased risks of any recurrence [odds ratio (OR) 0.57, 95% CI 0.42-0.78], (hypo-)manic or mixed episodes (OR 0.54, 95% CI 0.39-0.76), depressive episodes (OR 0.63, 95% CI 0.47-0.86), and inpatient care (OR 0.54, 95% CI 0.33-0.86) relative to periods prior to psychoeducation. There was no association with rates of involuntary sectioning or suicide attempts. Conclusions: The results suggest that psychoeducation for bipolar disorder reduces the risk of mood episodes and inpatient care also when implemented in routine clinical practice

OPLS-DA score plot showing a partial separation between patients with bipolar disorder I (top panel), bipolar disorder II (middle panel) and healthy controls (lower panel).

<p>Each participant’s score is represented by a circle. The scores were t[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115562#pone.0115562.ref001" target="_blank">1</a>] values on the component predictive of diagnostic group. The vast majority (97%) of the participants were within a ±2 standard deviation limit according to Hotelling’s T². Positive values represent better overall performance.</p

Performance of euthymic patients with bipolar disorder I (BD I), bipolar disorder II (BD II), and healthy controls (C) on a neuropsychological test battery.

<p>The neuropsychological measures are arranged according to the size of the OPLS-DA loadings. Results are expressed as means, 95% confidence intervals (CIs) and effect sizes (<i>η</i>²). Percentage was calculated of patients scoring ≤ the 1.25 s.d. of the control group.</p><p><i>Note.</i></p><p>^a Pålsson et al, 2012,</p><p>^b loading on predictive component,</p><p>^c Games Howell otherwise Scheffé.</p><p>Performance of euthymic patients with bipolar disorder I (BD I), bipolar disorder II (BD II), and healthy controls (C) on a neuropsychological test battery.</p

Summary of demographic and clinical characteristics in patients with bipolar disorder I (n = 64) and bipolar disorder II (n = 44).

<p>The controls (n = 86) were matched for age and sex (X% female). No differences were found regarding education level between the bipolar disorder groups and the control group.</p><p>^a data from 47–64 patients</p><p>^b data from 36–44 patients</p><p>Summary of demographic and clinical characteristics in patients with bipolar disorder I (n = 64) and bipolar disorder II (n = 44).</p

Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia.

Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology