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Peripheral blood brain-derived neurotrophic factor (BDNF) and inflammatory markers may reflect key pathophysiological mechanisms in bipolar disorder in relation to disease activity and neuroprogression.To investigate whether neutrophins and inflammatory marker vary with mood states and are increased in patients with bipolar disorder type I during euthymia as well as in all affective states as a group, compared to levels in healthy control subjects.In a prospective 6-12 months follow-up study, we investigated state specific, intra-individual alterations in levels of BDNF, hsCRP, IL-1β, IL-6, IL-8, IL-18 and TNF-α in 60 patients with bipolar I disorder with an acute severe manic index episode and in subsequent euthymic and depressive and manic states and compared with repeated measurements in healthy control subjects. Data were analysed with linear mixed effects model and with adjustment for gender, age, BMI, alcohol intake and smoking.From inclusion to end of the 6-12 months follow-up, samples of blood were drawn from the 60 patients during a total of 180 affective states, comprising 57 manic, 11 mixed, 23 depressive and 89 states of euthymia. Further, 69 blood samples were drawn from 35 healthy control subjects with three months apart. In unadjusted mixed-model analysis, levels of IL-6 and IL-8 were increased 64% (b=1.64, 95% CI: 1.31-2.05, p=0.0001) and 24% (b=1.24, 95% CI: 1.05-1.47, p=0.013), respectively in patients with bipolar disorder overall compared with healthy control subjects. However, in adjusted models, no statistically significant differences were found in any measure between patients and control individuals. Levels of hsCRP in depressive states were decreased with 40% (95% CI: 5-62%, p=0.029) compared with euthymia and with 48% (95% CI: 17-66%, p=0.006) when compared with hypomanic/manic states after adjustment. BDNF and the other inflammatory markers did not vary according to affective state in adjusted mixed models.Patients were all medicated, specifically with high doses of atypical antipsychotics during the manic index episodes.In a sample recruited during hospitalization for acute mania, levels of hsCRP varied according to affective state with higher levels during manic states compared with depressive states.

Cognitive deficits are common in patients with bipolar disorder (BD) in remission and may be associated with glycogen synthase kinase-3 (GSK-3) activity, which is inhibited by lithium. GSK-3 may be a relevant treatment target for interventions tailored at cognitive disturbances in BD but the relation between GSK-3 activity, cognition and lithium treatment is unknown. We therefore investigated the possible association between GSK-3 activity and cognition and whether lithium treatment moderates this association in patients with BD. In a prospective 6-12 month follow-up study, GSK- 3β activity in peripheral blood mononuclear cells was measured concurrently with cognitive performance assessed using a comprehensive test battery in 27 patients with BD-I in early and late remission following a manic or mixed episode. The GSK-3β activity, measured as serine-9 phosphorylated GSK-3β (pGSK-3β) and the GSK-3β ratio (serine-9-pGSK-3β /total GSK-3β), was negatively associated with sustained attention (p = 0.009 and p = 0.042, respectively), but not with other cognitive domains or global cognition. A crossover interaction between lithium treatment and the GSK activity was observed, indicating that lower pGSK-3β levels (p = 0.015) and GSK ratio (p = 0.010) were associated with better global cognition in lithium users whereas the opposite association was observed in non-lithium treated patients. Findings were not statistically significant after Bonferroni correction. In conclusion, cognitive functioning may be associated with GSK-3 activity in patients with BD-I and lithium treatment may modulate this relationship. Future studies in larger sample sizes are warranted to confirm these associations.

BackgroundThe 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.MethodA 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.ResultsIntention-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.ConclusionsThese results highlight that electronic self-monitoring, although intuitive and appealing, needs critical consideration and further clarification before it is implemented as a clinical tool.

Low-grade inflammation has been found in patients with bipolar disorder (BD), but rarely assessed using leukocyte counts and findings are limited by lack of control for confounding factors. As a result, it is unclear whether BD per se is associated with peripheral inflammation. We pooled populations from two studies using similar longitudinal designs, including 300 blood samples from a total of 97 patients with BD and 133 blood samples from a total of 72 healthy control individuals (HC). Total leukocyte and neutrophil counts were measured together with interleukin (IL) - 6, IL-8, IL-18, tumor necrosis factor (TNF) - α and high sensitivity C-reactive protein (hsCRP). Adjusted for confounders, leukocyte counts were 23% higher and neutrophil counts were 30% higher in patients with BD compared with HC. There were no state-related differences in leukocyte or neutrophil counts. Lithium use, cigarette smoking as well as levels of IL-6, TNF-α and hsCRP were positively associated with leukocyte and neutrophil counts. Due to confounding issues it cannot be concluded that differences were related to bipolar disorder per se. Future studies are recommended to include leukocytes as markers of low-grade inflammation and to include relevant confounders in statistical analyses.

Objectives The enzyme glycogen synthase kinase-3β (GSK3β) is involved in the mechanisms of action of lithium and may play a role in relation to affective states in bipolar disorder. The objectives of the present study were to compare the activity of GSK-3β (measured as levels of phosphorylated GSK-3β [p-GSK-3β]) between patients with bipolar disorder in the euthymic state and healthy control subjects, and to investigate whether GSK-3β activity varies with affective states in patients with bipolar I disorder. Methods In a prospective 6–12-month follow-up study, we investigated state-specific, intraindividual alterations in the activity of GSK-3β in 60 patients with bipolar I disorder with an acute severe manic index episode and in subsequent euthymic, depressive and manic states and compared this with repeated measurements in healthy control subjects. Data were analyzed using linear mixed-effects models. Results From baseline to the end of follow-up, blood samples were drawn from the 60 patients during 181 affective states, comprising 60 manic, 11 mixed, 23 depressive, and 87 states of euthymia. A total of 69 blood samples were drawn from 35 healthy control subjects, with two samples from the same subject taken three months apart. In mixed-model analysis, p-GSK-3β was decreased in the euthymic state of subjects with bipolar disorder compared with healthy control subjects (b=0.63, 95% confidence interval [CI]: 0.42–0.96, P=.03). In addition, p-GSK-3β varied with affective states, being increased in depressive (b=1.68, 95% CI: 1.08–2.62, P=.02) and mixed (b=2.07, 95% CI: 1.12–3.84, P=.02) states but not in mania compared with euthymia. Conclusions The activity of GSK-3β is altered in euthymic bipolar disorder compared with healthy control subjects and varies with affective states.

Background: Literature reports a genetic component for suicidal behavior, especially of determinant/violent type. One of the candidates has been the polymorphism 5-HTTLPR in the serotonin promoter. Employing a between group design, we wished to test the association between suicidal behavior and serotonin-related polymorphisms. Method: 350 Danish patients with average 14 years' duration of illness and with well researched history of suicidal behavior participated. Three groups were identified: 1. without suicidal behavior, 2. with suicidal behavior of non- determinant/non-violent methods, and 3. suicidal behavior with determinant/violent methods. We used the common alleles S and L as well as the new aspect with allelic subtypes SA, SG, LA.LG to constitute 3 functional genotypes: SS, SL and LL. We also included duration of illness, age at onset and sex in our study as potential covariates. Results: We tested suicidal behavior types 2 and 3 versus type 1 for distribution differences as well as for possible trend. We did not find any statistical significant relations. Conclusions: We could not find support for a relevant relation between the polymorphisms in the serotonin promoter and suicidal behavior in our schizophrenic patient sample.

Evidence indicates a role for glycogen synthase kinase-3β (GSK-3β) in the pathophysiology of mood disorders and in cognitive disturbances; however, the natural variation in GSK-3β activity over time is unknown. We aimed to investigate GSK-3β activity over time and its possible correlation with emotional lability, subjective mood fluctuations and cognitive function in healthy individuals. Thirty-seven healthy subjects were evaluated with neuropsychological tests and blood samples at baseline and 12-week follow-up. Total GSK-3β and serine-9-phosphorylated GSK-3β in peripheral blood mononuclear cells were quantitated using enzyme immunometric assays. The activity of GSK-3β (serine-9-phosphorylated GSK-3β/total GSK-3β) was lower at baseline compared with follow-up. No significant mean change over time was observed in levels of total GSK-3β and serine-9-phosphorylated GSK-3β. Exploratory analysis revealed lower activity of GSK-3β in spring and summer compared with the fall season. No correlation was observed between GSK-3β activity and emotional lability, subjective mood fluctuations or cognitive function. The results suggest that intra- and interindividual variation in GSK-3β activity over time could contribute to the heterogeneity of findings in clinical studies. The stability of GSK-3β activity and the role of potential moderators of GSK-3β activity warrant further investigation. Clinical studies of GSK-3β should consider including repeated measures of both cases and healthy individuals.

The mechanisms underlying bipolar disorder (BD) and the associated medical burden are unclear. Damage generated by oxidation of nucleosides may be implicated in BD pathophysiology; however, evidence from in vivo studies is limited and the extent of state-related alterations is unclear. This prospective study investigated for we believe the first time the damage generated by oxidation of DNA and RNA strictly in patients with type I BD in a manic or mixed state and subsequent episodes and remission compared with healthy control subjects. Urinary excretion of 8-oxo-deoxyguanosine (8-oxodG) and 8-oxo-guanosine (8-oxoGuo), valid markers of whole-body DNA and RNA damage by oxidation, respectively, was measured in 54 patients with BD I and in 35 healthy control subjects using a modified ultraperformance liquid chromatography and mass spectrometry assay. Repeated measurements were evaluated in various affective phases during a 6- to 12-month period and compared with repeated measurements in healthy control subjects. Independent of lifestyle and demographic variables, a 34% (P<0.0001) increase in RNA damage by oxidation across all affective states, including euthymia, was found in patients with BD I compared with healthy control subjects. Increases in DNA and RNA oxidation of 18% (P<0.0001) and 8% (P=0.02), respectively, were found in manic/hypomanic states compared with euthymia, and levels of 8-oxodG decreased 15% (P<0.0001) from a manic or mixed episode to remission. The results indicate a role for DNA and RNA damage by oxidation in BD pathophysiology and a potential for urinary 8-oxodG and 8-oxoGuo to function as biological markers of diagnosis, state and treatment response in BD.

Department of Suicide Prevention, Centre of Psychiatry Amager, Institute of Biological Research, Department of Research, Centre of Psychiatry Frederiksberg, Department O, Centre of Psychiatry Copenhagen, Department of Research, Centre of Psychiatry Hvidovre, Department of Clinical Pharmacology, Copenhagen University Hospital and Laboratory of Neuropsychiatry, Institute for Neuroscience and Pharmacology, Copenhagen University, Copenhagen, Denmark Correspondence to August G. Wang, DMSc, Department of Suicide Prevention, Centre of Psychiatry Amager, Copenhagen University Hospital, Digevej 110, DK-2300 Copenhagen S, Denmark Tel: + 45 386 41765; fax: + 45 386 41804; e-mail: august.g.wang@gmail.com

Bipolar disorder is a great challenge to patients, relatives and clinicians, and there is a need for development of new methods to identify prodromal symptoms of affective episodes in order to provide efficient preventive medical and behavioural intervention. Clinical trials prove that electronic monitoring is a feasible, valid and acceptable method. Hence it is recommended, that controlled trials on the effect of electronic monitoring on patients' course of illness, level of function and quality of life are conducted.