Resolvin D1 as a novel anti-inflammatory marker in manic, depressive and euthymic states of bipolar disorder.

Background: Resolvin D1 (RvD1) is a soluble mediator, which is the metabolite of docosahexaenoic acid (DHA), an omega-3 fatty acid. It is thought that RvD1 may contribute to the etiology of bipolar disorder (BD) because of its anti-inflammatory and antidepressant effect. In this study, it was aimed to compare the serum RvD1 levels of patients with BD diagnosed manic-depressive-euthymic episodes with those of healthy subjects. The secondary objective of this study is to investigate the relationship between RvD1 measures and inflammatory markers.Methods: We included 121 male patients with BD type I, 44 in a mania, 35 in depression and 42 in euthymic state, and 41 healthy controls. Serum RvD1 levels and inflammation indicators (CRP, neutrophil, leukocyte, and albumin) were measured.Results: When the RvD1 values of patients were compared, the median (interquartile range) RvD1 value was 11.2 (5.2) for manic patients, 11.2 (6.6) for depressive patients, 9.6 (5.6) for euthymic patients and 8.4 (7.7) for the control group. There were statistically significant differences between the groups in terms of RvD1 values (p < .001). After adjustment for age and current state with ANCOVA, there were statistically significant differences between manic vs. control groups and depression vs. control groups (p < .001, p=.047). Also mean CRP measures (p=.029) and neutrophil counts (p=.009) were significantly correlated with log transformed RvD1 levels.Conclusions: Our results of increased anti-inflammatory RvD1 during manic and depressive states suggest RvD1 may serve as a delayed resolvent possibly improving inflammatory imbalance. Further research is needed to confirm our findings.

MicroRNA dysregulation in manic and euthymic patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BPD) is a major psychiatric disorder with an unclear pathophysiology. Peripheral blood samples are easily drawn, making them are good candidates for diagnosing diseases. MicroRNAs are small non-coding RNA transcripts that regulate gene expression by binding to the 3'- UTR of mRNAs and directing their degradation. The aim of this study was to use blood plasma to investigate microRNA dysregulations in bipolar manic and euthymic patients. SUBJECTS AND METHODS: Blood samples were collected from 58 patients with bipolar I disorder (19 manic, 39 euthymic) and 51 healthy controls. RESULTS: Four microRNAs (miR-29a-3p, p = 0.035; miR-106b-5p, p = 0.014; miR-107, p = 0.011; and miR-125a-3p, p = 0.014) were upregulated in the entire bipolar group, compared to the healthy controls. Seven microRNAs (miR-9-5p, p = 0.032; miR-29a-3p, p = 0.001; miR-106a-5p, p = 0.034; miR-106b-5p, p = 0.003; miR-107, p < 0.001; miR-125a-3p, p = 0.016; and miR-125b-5p, p = 0.004) were more upregulated in bipolar manic patients compared to the healthy controls, and two microRNAs (miR-106a-5p, p = 0.013, and miR-107, p = 0.021) showed statistically significant upregulation in the manic patients compared to the euthymic patients. CONCLUSIONS: Our results showed greater miRNA dysregulation in the manic patients than in the euthymic patients. Two microRNAs could be more selective for bipolar manic episodes. Future studies should include depressive patients along with euthymic and manic patients.

Dysregulation of cytokine coding genes in peripheral blood of bipolar patients.

BACKGROUND: The role of immune response dysregulation has been previously noticed in the pathogenesis of bipolar disorder (BD). METHODS: In the current investigation, we compared expression levels of eight cytokines and a chemokine (CXCL8) in the peripheral blood of BD patients and healthy subjects. All BD patients were in euthymic phase. RESULTS: We found higher expression of IL-1B, IL-10, IFN-G, TNF-a, TGF-B and IL-2 in male patients compared with male controls (ExR=3.44, P<0.0001, ExR=2.54, P<0.0001; ExR=2.39, P<0.0001; ExR=2.74, P<0.0001; ExR=2.32, P<0.0001; ExR=1.87, P = 0.04 respectively). For these cytokines, no significant differences were found between female patients and female controls. While expression of IL-6 was higher in male patients compared with male controls (ExR=2.07, P = 0.006), in female subjects the opposite trend was detected (ExR=0.44, P = 0.02). However, no significant difference was detected between female subjects. Expression levels of IL-17 were not different between patients and controls or between any subgroups of them. We found significant correlations between expression of IFN-G and age at disease onset (R = 0.25, P = 0.04) as well as expression of CXCL8 and both age of patients and age at disease onset (R = 0.26, P = 0.03; R = 0.25, P = 0.04). Moreover, inverse correlation was detected between expression of TNF-a and age in control group (R=-0.34, P = 0.008). CONCLUSION: Combination of transcript levels of six genes could differentiate BD patients from healthy subjects with diagnostic power of 0.85 (Sensitivity=78%, Specificity=80% and P<0.0001). The current investigation highlights the role of cytokine coding genes in the pathogenesis of BD and potentiates them as diagnostic biomarkers.

Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes.

The present study aims to investigate the oxidative stress parameters in isolated mitochondria, as well as looking at mitochondrial complex activity in patients with Bipolar Disorder (BD) during depressive or euthymic episodes. This study evaluated the levels of mitochondrial complex (I, II, II-III and IV) activity in lymphocytes from BD patients. We evaluated the following oxidative stress parameters: superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl levels in submitochondrial particles of lymphocytes from bipolar patients. 51 bipolar patients were recruited into this study: 34 in the euthymic phase, and 17 in the depressive phase. Our results indicated that the depressive phase could increase the levels of mitochondrial superoxide, carbonyl and TBARS, and superoxide dismutase, and could decrease the levels of mitochondrial complex II activity in the lymphocytes of bipolar patients. It was also observed that there was a negative correlation between the Hamilton Depression Rating Scale (HDRS) and complex II activity in the lymphocytes of depressive bipolar patients. In addition, there was a positive correlation between HDRS and superoxide, superoxide dismutase, TBARS and carbonyl. Additionally, there was a negative correlation between complex II activity and oxidative stress parameters. In conclusion, our results suggest that mitochondrial oxidative stress and mitochondrial complex II dysfunction play important roles in the depressive phase of BD.

Homocysteine as a peripheral biomarker in bipolar disorder: A meta-analysis.

BACKGROUND: Bipolar disorder (BD) is a psychiatric disorder with an uncertain aetiology. Recently, special attention has been given to homocysteine (Hcy), as it has been suggested that alterations in 1-carbon metabolism might be implicated in diverse psychiatric disorders. However, there is uncertainty regarding possible alterations in peripheral Hcy levels in BD. METHODS: This study comprises a meta-analysis comparing serum and plasma Hcy levels in persons with BD and healthy controls. We conducted a systematic search for all eligible English and non-English peer-reviewed articles. RESULTS: Nine cross-sectional studies were included in the meta-analyses, providing data on 1547 participants. Random-effects meta-analysis showed that serum and plasma levels of Hcy were increased in subjects with BD in either mania or euthymia when compared to healthy controls, with a large effect size in the mania group (g=0.98, 95% CI: 0.8-1.17, P<0.001, n=495) and a small effect in the euthymia group (g=0.3, 95% CI: 0.11-0.48, P=0.002, n=1052). CONCLUSIONS: Our meta-analysis provides evidence that Hcy levels are elevated in persons with BD during mania and euthymia. Peripheral Hcy could be considered as a potential biomarker in BD, both of trait (since it is increased in euthymia), and also of state (since its increase is more accentuated in mania). Longitudinal studies are needed to clarify the relationship between bipolar disorder and Hcy, as well as the usefulness of peripheral Hcy as both a trait and state biomarker in BD.

Divalproex sodium reduces overall aggression in youth at high risk for bipolar disorder.

INTRODUCTION: The psychopharmacology of aggression in youth is relatively unexplored, even though such maladaptive aggression manifests across many different diagnoses. METHODS: This study was a 12-week, open-label trial with divalproex sodium (DVPX) in 24 bipolar offspring 6-18 years of age (mean age = 11.3 years; 17 boys) with mixed diagnoses of major depression, cyclothymia, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). The Overt Aggression Scale (OAS) was used to measure aggression in 4-week intervals. We measured serum gamma-butyric acid (GABA) and glutamate levels at baseline and week 12. RESULTS: Seventy-one percent of evaluable subjects were considered responders to DVPX treatment by the OAS. There was a significant correlation between the Young Mania Rating Scale (YMRS) and OAS scores at week 0 (p = 0.036) and week 12 (p = 0.025). Serum DVPX level did not correlate with treatment response. CONCLUSIONS: These youths who are at high risk for bipolar disorder experienced an overall decrease in aggressive behavior in response to DVPX. Age or gender did not predict a positive response to DVPX. This study is the first report of treatment efficacy of a mood stabilizer for aggression in youth at high risk for bipolar disorder.

Leptin in bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Bipolar disorder (BD) is a psychiatric disorder associated with increased rates of obesity and inflammation. Leptin is an adipokine that is mainly produced by the white adipose tissue in response to insulin. It stimulates the immune system, increasing the production of pro-inflammatory cytokines. There is currently uncertainty regarding possible alterations in peripheral leptin levels across the mood states in BD. METHODS: This study comprises a between-group meta-analysis comparing serum and plasma leptin levels in people with BD in mania, depression or euthymia and healthy controls. We conducted a systematic search for all possibly eligible-English and non-English peer-reviewed articles. We calculated the effect size (ES) utilizing Hedges' adjusted g using random effects. RESULTS: Eleven studies were included in the meta-analyses, providing data on 1118 participants. Serum and plasma leptin levels were not altered in subjects with BD when compared to healthy controls in mania (g=-0.99, 95% CI -2.43 to 0.43, P=0.171), in depression (g=0.17, 95% CI -0.45 to 0.79, P=0.584), or in euthymia (g=0.03, 95% CI -0.39 to 0.46, P=0.882). However, we did observe a stronger association between leptin levels and both age and BMI in patients with BD in euthymia compared to healthy controls, such that the greater the age of the individuals, the greater the difference in leptin levels between BD and controls; and the higher the BMI, the greater the difference in leptin levels between BD and controls. CONCLUSIONS: Our meta-analysis provides evidence that leptin levels are not altered in BD across the mood spectrum compared to healthy controls. The disproportionate increase of leptin levels with increase in BMI in BD speaks in favour of a potential inflammatory role of white adipose tissue in BD and a disproportionate increase of leptin levels with increase in age.

Increased uric acid levels in bipolar disorder subjects during different phases of illness.

BACKGROUND: Recent evidence indicates the possible involvement of adenosine and the purinergic system in the pathophysiology of bipolar disorder (BD). The aim of this study is to compare serum uric acid (UA) levels in a large group of BD patients (in mania, depression and euthymia) vs. a control group of patients with different psychiatric disorders. METHODS: 150 BD (SCID-I; DSM-IV) patients were compared to 150 age- and gender-matched subjects with MDD, OCD, or Schizophrenia. Mean serum UA values were compared with the ANOVA, with Bonferroni's post-hoc tests. RESULTS: Mean serum UA levels (5.06 ± 1.45 vs. 4.17 ± 1.05 mg/dL) and rates of hyperuricaemia (30.7% vs. 6.7%) were significantly higher in the bipolar than in the control group. No differences were detected between bipolars in different phases of illness, with all three groups (manic, depressive and euthymic bipolars) showing significantly higher UA levels as compared to controls. No correlations were found between UA levels and YMRS or HAM-D scores. Mean UA levels were also higher in bipolars never exposed to mood stabilizers vs. controls (5.08 ± 1.43 vs. 4.17 ± 1.05 mg/dL), with no differences compared to other bipolars. LIMITATIONS: Our study suffers from the lack of a healthy comparison group; moreover, longitudinal data are missing. CONCLUSIONS: Our study provides further evidence of a purinergic dysfunction associated with BD, in all phases of the illness. It is possible that increased UA levels are a trait marker of higher vulnerability to bipolar disorder, and are even more increased during mania (mostly in the first manic episode of drug-naïve patients).

Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder--Gender and obesity effects.

INTRODUCTION: Oxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS). METHODS: Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m(2)], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS. RESULTS: The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28). CONCLUSION: Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD.

The behavioral high-risk paradigm and bipolar affective disorder, VIII: Serum free cortisol in nonpatient cyclothymic subjects selected by the General Behavior Inventory.

The degree of biologic concordance between bipolar affective disorder and cyclothymia was assessed within a 3-hour protocol of cortisol functioning. Cyclothymic subjects, selected by the General Behavior Inventory, showed cortisol hypersecretion approaching that of subjects with major affective disorders; they also showed poor modulation of cortisol levels over time, the degree of which was related to increased current level of depression and to a chronic, intermittent depressive course. These results not only support the validity of the General Behavior Inventory but also suggest that cyclothymic subjects with a chronic depressive course may experience persistent biologic disturbance similar to that found during episodes of major depression.

The lithium loading dose method in a clinical setting.

The lithium loading dose method developed by Cooper and associates resulted in achievement of therapeutic concentrations in 29 of 30 psychiatric inpatients. Fewer lithium determinations were required than in 30 other inpatients treated with the traditional trial-and-error technique.

[Lithium in erythrocytes--model value and clinical relevance]. / Lithium in Erythrozyten--Modellwert und klinische Relevanz.

The additional determination of lithium in erythrocytes may serve to estimate the course of treatment individually more detailed than by serum values only, but not as a predictor of clinical response.

Cortisol changes in long-term lithium therapy.

a.m. and p.m. serum cortisol levels were investigated in a group of 53 patients before the start of long-term lithium therapy (I) and again after 4 months (II) and 12 months (III) on lithium. The patients were assessed by means of the CPRS and scores for 28 depression items were calculated. When 5 patients with manic/hypomanic scores were excluded the remainder (n = 48) showed a significant decrease in a.m. serum cortisol levels after 1 year on lithium. Those patients with the greatest differences between the CPRS scores before lithium and after 12 months on lithium also displayed significant differences between a.m. and p.m. cortisol levels before the start of lithium and after 12 months of lithium therapy.

[Lithium carbonate (Contemnol--Spofa). A clinical study]. / Carbonatul de litiu (Contemnol--Spofa). Studiu clinic.

The estimation of the present day stage in the therapy with lithium salts allowed the authors some considerations on the mechanisms of action and pharmacodynamics of lithium ion, as well as on the indications and counterindications, side effects and therapeutical management. Thus, the authors have analysed the findings of a simple-blind clinical study on lithium carbonate (Contemnol--Spofa) in a series of 15 inpatients. The research methodology included the thorough examination of the patients, blood lithium screening, psychological investigations and laboratory tests on the basis of an itemized investigation card. The analysis of the results confirmed the efficacy of this substance in bipolar hyperthymic psychosyndromes, depressions and hyperthymic psychosyndromes with dissociative elements, its tolerance and low incidence of side effects. The selection of the cases, the clinical and paraclinical examinations, the observance of the indications and counterindications permit the administration of this substance as a curative and prophylactic treatment, providing the blood lithium is screened and clinical control and biological investigations are carried out.