Trait Marker For Bipolar Disorder Research Articles

The influence of chronic inflammation on the illnesscourse of bipolar disorder: A longitudinal study

IntroductionC-reactive protein (CRP) is a systemic inflammatory marker, which indicates systemic inflammatory processes It is involved in different inflammatory processes of the body and is a reliable marker for the general inflammatory state of the body. High sensitive CRP seems to play a key role as a state and trait marker of bipolar disorder (BD). In the current study, we tried to determine the long-term effect of CRP levels on clinical symptoms and illness course of bipolar disorder. MethodsFor the current study, we examined 106 patients with BD for a period of four years. Participants underwent a clinical screening for depressive and manic episodes with the Hamilton Depression Scale (HAMD) and the Young Mania Rating Score (YMRS) and a serological diagnostic for inflammatory parameters every six months, thus leading to 8 measurement times in total. Patients with the presence of severe medical or neurological comorbidities such as active cancer, chronic obstructive lung disease, rheumatoid arthritis, systemic lupus erythematosus, Alzheimer's disease, Parkinson's disease, Huntington's disease or multiple sclerosis and acute infections were not included in the study. ResultsIn our sample, 26% showed a mean hsCRP above 5 mg/dl. Those patients showed a significantly higher mean YMRS score than those with a mean hsCRP under 5 mg/dl during our observation period. Regarding HAMD there was no significant difference in hsCRP values. The existence of lithium treatment showed no significant influence on mean hsCRP levels between the start and endpoint. ConclusionIndividuals who were exposed to a higher level of inflammation over time suffered from more manic symptoms in this period. These findings underline the hypothesis that inflammatory processes have an accumulative influence on the illness course of BD, especially concerning manic symptoms and episodes.

Altered brain dopamine metabolism is a trait marker for bipolar disorder

Pharmacological treatment, imaging, and neurochemistry studies identify altered dopamine signaling in bipolar disorder. Our previous work has shown higher concentration of homovanillic acid (HVA), the end metabolite of dopamine, in cerebrospinal fluid (CSF) from individuals with bipolar disorder compared to healthy controls. Here, we analyzed HVA concentrations from a follow-up visit in 103 adults with bipolar disorder and 57 controls from our first cohort. Further, we analyzed CSF monoamine metabolite concentrations in a second cohort of 152 adults with bipolar disorder and 55 controls. At the follow-up visit for the first cohort, HVA was higher in individuals with bipolar disorder (278 ± 102 nmol/L, p = 0.003) compared with controls (232 ± 83 nmol/L). In the second cohort, individuals with bipolar disorder had higher HVA (272 ± 97 nmol/L, p = 0.001) and lower 3-methoxy-4-hydroxyphenylglycol (MHPG, 40 ± 9 nmol/L, p = 0.002) concentrations than controls (HVA, 231 ± 71 nmol/L and MHPG, 45 ± 9 nmol/L). Baseline and follow-up measures of monoamine metabolites showed medium to high correlation to each other but did not predict course of illness. We failed to replicate the association of HVA concentration and psychotic symptoms but confirmed lower 5-hydroxyindoleacetic acid (5-HIAA) concentration in individuals treated with antidepressants. In conclusion, we confirmed high HVA concentration in CSF in patients with bipolar disorder compared to a control group. Previous work suggest that this is a feature shared with ADHD but distinct from schizophrenia and major depressive disorder. The role of increased HVA concentration in the course of illness in bipolar disorder remains unclear.

Bipolar Disorder, Circadian Rhythm and Clock Genes.

Sleep disturbance and abnormal circadian rhythm might be closely related to bipolar disorder. Several studies involving disturbed sleep/wake cycle, changes in rhythms such as melatonin and cortisol, clock genes, and circadian preference have shown the relationship between bipolar disorder and circadian rhythm. The results differed across different studies. In some studies, a delay in the circadian rhythm was observed in the depressive episode and advanced circadian rhythm was observed during the manic episode. In other studies, a delay in circadian rhythm was observed independent of mood episodes. Accordingly, circadian rhythm disorder was proposed as a trait marker for bipolar disorder. The altered circadian rhythm may represent a pathological mechanism that contributes to the mood episodes. However, a prospective cohort study is needed for further clarification.

Different oxytocin and corticotropin-releasing hormone system changes in bipolar disorder and major depressive disorder patients.

SummaryBackgroundOxytocin (OXT) and corticotropin-releasing hormone (CRH) are both produced in hypothalamic paraventricular nucleus (PVN). Central CRH may cause depression-like symptoms, while peripheral higher OXT plasma levels were proposed to be a trait marker for bipolar disorder (BD). We aimed to investigate differential OXT and CRH expression in the PVN and their receptors in prefrontal cortex of major depressive disorder (MDD) and BD patients. In addition, we investigated mood-related changes by stimulating PVN-OXT in mice.MethodsQuantitative immunocytochemistry and in situ hybridization were performed in the PVN for OXT and CRH on 6 BD and 6 BD-controls, 9 MDD and 9 MDD-controls. mRNA expressions of their receptors (OXTR, CRHR1 and CRHR2) were determined in anterior cingulate cortex and dorsolateral prefrontal cortex (DLPFC) of 30 BD and 34 BD-controls, and 24 MDD and 12 MDD-controls. PVN of 41 OXT-cre mice was short- or long-term activated by chemogenetics, and mood-related behavior was compared with 26 controls.FindingsSignificantly increased OXT-immunoreactivity (ir), OXT-mRNA in PVN and increased OXTR-mRNA in DLPFC, together with increased ratios of OXT-ir/CRH-ir and OXTR-mRNA/CRHR-mRNA were observed in BD, at least in male BD patients, but not in MDD patients. PVN-OXT stimulation induced depression-like behaviors in male mice, and mixed depression/mania-like behaviors in female mice in a time-dependent way.InterpretationIncreased PVN-OXT and DLPFC-OXTR expression are characteristic for BD, at least for male BD patients. Stimulation of PVN-OXT neurons induced mood changes in mice, in a pattern different from BD.Funding10.13039/501100001809National Natural Science Foundation of China (81971268, 82101592).

A review: Circadian Rhythm Dysfunction and Bipolar Disorder

IntroductionCircadian rhythm (CR) dysfunction is a prominent feature in bipolar disorder (BD) and sleep disturbances are characteristic, although not essential to the diagnosis.ObjectivesTo review the literature regarding the CR dysfunction and its impact on the onset and clinical course of BD.MethodsWe conducted a MEDLINE search using bipolar disorder, circadian rhythm and sleep as keywords, selecting studies written in English.ResultsCR dysfunction is a trait marker of BD. It’s known that during depressive episodes insomnia is present, with difficulty falling asleep/ maintaining sleep and early awakening. Regarding mania, decreased need for sleep is a critical marker. During the euthymic period significant alterations in sleep pattern have been described. It’s also known that changes in the sleep pattern occur prior to those in mood patterns, indicating that sleep dysregulation may trigger the onset of mood episodes or relapses. Therefore, CR disruption may be associated with the pathophysiology of BD and some factors have already been identified: irregularity of the sleep-wake rhythm, eveningness chronotype, abnormality of melatonin secretion, vulnerability of clock genes and the irregularity of social zeitgeber.ConclusionsDisturbances of sleep are pervasive, and an essential feature of BD, worse during mood episodes, but still present during euthymic periods. It remains to determine whether circadian rhythm dysfunction is a trait marker or mood state dependent. Further studies are warranted to clarify this association.DisclosureNo significant relationships.

Uric acid levels among Tunisian patients with bipolar disorder during different phases of illness

IntroductionBipolar disorder is a recurrent chronic disorder characterised by fluctuation of mood state. Recent studies focused on the involvement of adenosine and the purinergic system in the pathophysiology of bipolar disorder.ObjectivesWe aimed to investigate the difference in (SUA) levels between different phases of relapse and remission period.MethodsFor this aim a prospective study was conducted during six months at Razi psychiatric Hospital in Tunisia with patients diagnosed with BD The socio-demographic, clinical data were gathered from patient and a psychometric assessment using YMRS and Beck scale was employed. Uric acid level was studied during relapse and remission period.ResultsAmong 30 consentent patients included in the study : 65.7% were women, The age of the participants varied between 22 and 65 years old. Uric acid level at the relapse varied between 328 and 499 mmol/L and level of controlled value at the remission period which is eight weeks under treatment varied between 137 and 307 mmol/L. Patients under antipsychotic treatment were 55.9% the other were under lithium or mood stabilizer. There is no significant difference between patients with bipolar disorder type I or II neither for the molecule chosen for treatment (p<0.05).ConclusionsBipolar disorder is a chronic psychiatric disease which needs to be regulary controlled. Uric acid levels were higher in manic or depressive phases as compared with euthymia phase. Uric acid could be used as a trait marker in bipolar disorder and help psychiatrist to monitor patients and to adjust treatment in order to avoid relapsing.DisclosureNo significant relationships.

Peripheral levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability

ImportanceIt is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls. ObjectiveTo run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity. Data sourcesSystematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020. Study selectionCase-control studies reporting inflammatory mediators' levels in BD and controls. Data extraction and synthesisSummary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g). Main outcomes and measuresCo-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls. ResultsOut of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31–1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46–1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19–0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI −0.68–0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels. Conclusions and relevancePeripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.

A comparison of inflammatory markers in manic and euthymic states of bipolar disorder

Objectives The number of studies investigating inflammatory biomarkers in bipolar disorder has increased significantly in recent years. The neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) are inexpensive and easy to obtain values used to measure the level of inflammation. This study compared the NLR, PLR, and MLR values in the manic and euthymic phases of the same patients. Methods Patients who met the inclusion criteria and were hospitalized due to bipolar affective disorder manic episodes at the Ondokuz Mayis University Faculty of Medicine inpatient psychiatry clinic between 01.01.2013 and 01.01.2019 were enrolled in the study. One hundred thirteen patients undergoing manic episodes were included. White blood cells, neutrophil, lymphocyte, platelet, and monocyte counts were retrospectively recorded from complete blood count data collected during the hospital stay, and NLR, PLR, and MLR values were calculated from these. Results Neutrophil, platelet, and monocyte counts, as well as NLR, PLR, and MLR values were higher in the manic episodes of bipolar disorder compared to the control group. Decreased neutrophil and lymphocyte counts, and decreased NLR, PLR, and MLR were observed in the remission period after-treatment of the manic bipolar disorder episodes. In the euthymic phase of bipolar disorder, however, platelet and monocyte counts and MLR were higher than in the control group. Conclusions The study indicates that NLR and PLR may be used as state markers and that MLR may be used as a trait marker in bipolar disorder.

Mood instability in patients with newly diagnosed bipolar disorder, unaffected relatives, and healthy control individuals measured daily using smartphones

ObjectivesTo investigate whether mood instability (MI) qualify as a trait marker for bipolar disorder (BD) we investigated: 1) differences in smartphone-based self-reported MI between three groups: patients with newly diagnosed BD, unaffected first-degree relatives (UR), and healthy control individuals (HC); 2) the correlation between MI and functioning, stress, and duration of illness, respectively; and 3) the validity of smartphone-based self-evaluated mood ratings as compared to observer-based ratings of depressed and manic mood. Methods203 patients with newly diagnosed BD, 54 UR and 109 HC were included as part of the longitudinal Bipolar Illness Onset study. Participants completed daily smartphone-based mood ratings for a period of up to two years and were clinically assessed with ratings of depression, mania and functioning. ResultsMood instability scores were statistically significantly higher in patients with BD compared with HC (mean=1.18, 95%CI: 1.12;1.24 vs 1.05, 95%CI: 0.98;1.13, p = 0.007) and did not differ between patients with BD and UR (mean=1.17, 95%CI: 1.07;1.28, p = 0.91). For patients, increased MI scores correlated positively with impaired functioning (p<0.001), increased stress level (p<0.001) and increasing number of prior mood episodes (p<0.001). Smartphone-based mood ratings correlated with ratings of mood according to sub-item 1 on the Hamilton Depression Rating Scale 17-items and the Young Mania Rating Scale, respectively (p´s<0.001). LimitationThe study had a smaller number of UR than planned. ConclusionMood instability is increased in patients with newly diagnosed BD and unaffected relatives and associated with decreased functioning. The findings highlight MI as a potential trait marker for BD.

C-reactive protein concentration in bipolar disorder: association with genetic variants

BackgroundSeveral recent studies have investigated the role of C-reactive protein (CRP) in bipolar disorder (BD), but few studies have directly investigated the interaction between CRP genetic variants and peripheral CRP concentration across different phases of BD. In this study, we aimed to replicate previous findings that demonstrated altered CRP levels in BD, and to investigate whether there is an association of peripheral protein expression with genetic variants in the CRP gene.Methods221 patients were included in the study, of which 183 (all episodes, 46 not medicated, 174 medicated) were genotyped for CRP single-nucleotide polymorphisms (SNPs) shown to influence peripheral CRP protein expression (rs1800947, rs2808630, rs1417938, rs1205).ResultsThere were no differences in CRP levels associated with the genotypes, only regarding the rs1205 SNP there were significantly different CRP protein expression between the genotypes when taking body mass index, age, BD polarity, subtype and leukocyte number into account. However, we could show significantly elevated CRP protein expression in manic patients compared to euthymic and depressed patients, independent from genotype. Medication was found to have no effect on CRP protein expression.ConclusionsThese results indicate that low grade inflammation might play a role in mania and might be rather a state than a trait marker of bipolar disorder.

Neuropsychological Functioning and Temperament Traits in a Czech Sample of Children and Adolescents at Familial Risk of Bipolar Disorder.

Background: Although a positive family history is the strongest predictor for bipolar disorder (BD), most offspring of BD parents (BO) will not develop the disorder. Identification of vulnerability markers for BD is essential for specific individual risk estimation. Impairments in cognitive functioning and the presence of specific temperament traits are considered promising candidates.Methods: Sixty-three BO (48% female; 11.8 ± 3.3 years) and 54 control offspring (CO; 44% female; 12.3 ± 3.2 years) comparable in sex (p = 0.4) and age (p = 0.4) were enrolled. Detection of current sub/threshold mood symptoms by the Kiddie Schedule for Affective Disorders and Schizophrenia and General Behavior Inventory was applied to separate BO into ultrahigh-risk (UHR) and high-risk (HR) subgroups. Cognitive functions were tested by the Developmental Neuropsychological Assessment II test battery, d2 Test of Attention, and Amsterdam Neuropsychological Tasks. Temperament was assessed by the Temperament in Middle Childhood and Early Adolescent Temperament Questionnaires.Results: The BO sample consisted of 5 BD, 17 UHR, and 41 HR participants. We did not observe any significant differences between the BO and CO groups or between the UHR, HR, and CO subgroups (Hedges' g = 0.21–0.39) in cognitive functioning. The BO differed significantly in some temperament traits from the CO (g = 0.42–0.61), while the UHR subgroup exhibited lower effortful control and attention focusing than both HR and CO participants (g = 0.92–1.19).Limitations: The cross-sectional design and wide age range of the sample limited our findings.Conclusions: Neuropsychological impairment does not seem to be a trait marker of BD in the premorbid stage. Temperament with low effortful control and low attention focusing might be associated with the development of mood disorders in BO.

Theory of mind abilities and its relationship with clinical features in euthymic bipolar patients

Purpose: The term of ‘Theory of mind’ (ToM), is the ability to understand one’s own others’ mental states, is an important capacity for social cognition and there is increasing data that theory of mind is compromised in bipolar patients even in euthymic periods. The aim of this study was to investigate theory of mind deficits in euthymic bipolar disorder patients and its relation to the clinical features. Materials and method:Fifty two euthymic patients with bipolar I disorder according to DSM IV-TR and 60 matched healthy control subjects were involved in this study. ToM was assessed by Reading the Mind in the Eyes test and the Dokuz Eylül Theory of Mind Scale. Results: The patient group had significantly lower performance on both of the ToM tests. We observed significant correlation between age of onset, the number of hospitalizations, the number of manic/mixed episodes and theory of mind performance. Conclusion: The result we showed is that ToM is impaired in euthymic bipolar I patients, which is consistent with the studies suggesting that ToM might be a trait marker for bipolar disorder.

Aberrant Brain Structural-Functional Connectivity Coupling in Euthymic Bipolar Disorder

Aberrant structural (diffusion tensor imaging, DTI) and resting-state functional (rsfMRI) connectivity are core features of bipolar disorder (BD). However, few studies have explored the integrity agreement between structural and functional connectivity in BD (SC-FC coupling). Such SC-FC coupling index could potentially provide additional clinical predictive value for BD spectrum disorders besides the intra-modality network measures. Thus, we examined the structural (DTI) and resting-state functional network properties, as well as their coupling index, among 57 euthymic BD patients (age 13-28 years, 18 females) and 42 age- and gender-matched healthy controls (age 13-28 years, 16 females). We found that compared to controls, BD patients showed increased structural rich club connectivity as well as decreased functional modularity. Importantly, the coupling strength between structural and functional connectome was decreased in BD patients compared to controls, which emerged as the most powerful feature discriminating the two groups. Our findings suggest that structural-functional coupling strength could serve as a valuable biological trait marker for bipolar disorder over and above the intra-modality network measures. Such measure can have important clinical implications for early identification of BD individuals, and inform strategies for prevention of BD onset and relapse. Funding: This study was funded by the National Natural Science Foundation of China (NSFC: 81471375,81671347), Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders (201805010009), and Guangzhou Municipal Psychiatric Disease Clinical Transformation Laboratory (201805010009), which had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. Declaration of Interest: We declare no competing interests. Ethical Approval: This study was approved by the Institutional Review Board of the Guangzhou Brain Hospital.

Circadian rhythm in bipolar disorder: A review of the literature.

Sleep disturbances and circadian rhythm dysfunction have been widely demonstrated in patients with bipolar disorder (BD). Irregularity of the sleep-wake rhythm, eveningness chronotype, abnormality of melatonin secretion, vulnerability of clock genes, and the irregularity of social time cues have also been well-documented in BD. Circadian rhythm dysfunction is prominent in BD compared with that in major depressive disorders, implying that circadian rhythm dysfunction is a trait marker of BD. In the clinical course of BD, the circadian rhythm dysfunctions may act as predictors for the first onset of BD and the relapse of mood episodes. Treatments focusing on sleep disturbances and circadian rhythm dysfunction in combination with pharmacological, psychosocial, and chronobiological treatments are believed to be useful for relapse prevention. Further studies are therefore warranted to clarify the relation between circadian rhythm dysfunction and the pathophysiology of BD to develop treatment strategies for achieving recovery in BD patients.

Cognitive Functioning in Euthymic Bipolar Patients on Monotherapy with Novel Antipsychotics or Mood Stabilizers.

Bipolar disorder is associated with cognitive dysfunction in several domains. Medication effect is a potential confounder that can only be statistically controlled in many studies. The cognitive profile in bipolar disorder during remission on maintenance antipsychotics or mood stabilizers medication has not been compared before. We compared the cognitive profile of bipolar disorder patients euthymic for 2 month or more on monotherapy with novel antipsychotics (AP) (n=16), lithium carbonate (Li) (n=25) or valproic acid (VPA; n=26). Forty-two individuals were assessed as controls. The cognitive battery included Wechsler Adult Intelligence Scale-Revised (WAIS-R) subtests, the Wechsler Memory Scale (WMS), and Wisconsin Card Sorting Test (WCST). All three patient groups compared to controls performed poorly on the working memory and verbal memory tasks (F=3.59, df=3, p=0.02 for WAIS-R Arithmetic and F=123.64, df=3, p<0.01 for WMS Logical Memory). The differences remained significant after controlling for age. Across patients, the only significant difference was between the Li and AP groups in terms of working memory. The Li group performed better (F=3.59, df=2, p=0.02) and the difference survived correction for age and clinical features. The findings of this study suggest that working memory impairment in bipolar patients on monotherapy with atypical AP, whereas verbal memory impairment might be related to bipolar disorder itself. Working memory might be a state marker, whereas verbal memory could be a trait marker of bipolar disorder. Atypical AP might have an adverse effect on cognition in bipolar disorder. These findings cannot be generalized to all bipolar patients, particularly the poor responders to monotherapy.

Patterns of impairment in executive functions within unipolar and bipolar depression

IntroductionThe majority of studies revealed that cognitive deficits are an important aspect in many psychiatric illnesses, such as bipolar disorder and major depressive disorder. In the past, cognitive impairment was considered part of depression and it was expected to diminish as other mood symptoms improved with treatment.MethodThis study is based on the review of recent literature, performed in order to understand the dimension of executive impairment in unipolar and bipolar depression.ResultsBoth unipolar and bipolar depressed patients display cognitive deficits in several cognitive domains within executive functions. Different subcomponents of executive functions are altered in both types of patients, but impairments in sustained attention appear specific in bipolar depression while dysfunctional divided attention is reported in unipolar disorder. Studies describe deficits in planning strategies and monitoring processes that are characteristically impaired in unipolar depressed patients. Also these subjects tend to make more perseverative responses suggesting set shifting deficits and moreover they require longer time and more cognitive effort in order to accomplish tasks involving inhibitory control or cognitive flexibility. Other findings suggest that bipolar I depressed patients perform worse than bipolar II depressed patients and unipolar depressed patients across all executive functions especially in the decision making process that is considered to be a trait marker for bipolar disorder with no differences between the two types of bipolar subjects.ConclusionsExecutive functions represent a term that includes a higher order of cognitive abilities with deficits that are present in both disorders but display slightly different patterns of impairment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Abnormal brain oscillations persist after recovery from bipolar depression

When directly perturbed in healthy subjects, premotor cortical areas generate electrical oscillations in the beta range (20–40Hz). In schizophrenia, major depressive disorder and bipolar disorder (BD), these oscillations are markedly reduced, in terms of amplitude and frequency. However, it still remains unclear whether these abnormalities can be modulated over time, or if they can be still observed after treatment. Here, we employed transcranial magnetic stimulation (TMS) combined with EEG to assess the frontal oscillatory activity in eighteen BD patients before/after antidepressant treatments (sleep deprivation and light therapy), relative to nine healthy controls. In order to detect dominant frequencies, event related spectral perturbations (ERSP) were computed for each TMS/EEG session in all participants, using wavelet decomposition. The natural frequency at which the cortical circuit oscillates was calculated as the frequency value with the largest power across 300ms post-stimulus time interval. Severity of depression markedly decreased after treatment with 12 patients achieving response and nine patients achieving remission. TMS/EEG resulted in a significant activation of the beta/gamma band response (21–50Hz) in healthy controls. In patients, the main frequencies of premotor EEG responses to TMS did not significantly change before/after treatment and were always significantly lower than those of controls (11–27Hz) and comparable in patients achieving remission and in those not responding to treatment. These results suggest that the reduction of natural frequencies is a trait marker of BD, independent from the clinical status of the patients. The present findings shed light on the neurobiological underpinning of severe psychiatric disorders and demonstrate that TMS/EEG represents a unique tool to develop biomarkers in psychiatry.

P.2.d.008 - Are theory of mind impairments a trait marker of bipolar disorder?

To perform a systematic review and meta-analysis of studies investigating neurocognition in euthymic youths with bipolar disorder (BD) compared to healthy controls (HCs).A systematic literature search was conducted in the PubMed/MEDLINE, PsycINFO, and EMBASE databases from inception up until March 23, 2016, for original peer-reviewed articles that investigated neurocognition in euthymic youths with BD compared to HCs. Effect sizes (ES) for individual tests were extracted. In addition, results were grouped according to cognitive domain. This review complied with the PRISMA statement guidelines.A total of 24 studies met inclusion criteria (N = 1,146; 510 with BD). Overall, euthymic youths with BD were significantly impaired in verbal learning, verbal memory, working memory, visual learning, and visual memory, with moderate to large ESs (Hedge’s g 0.76−0.99); significant impairments were not observed for attention/vigilance, reasoning and problem solving, and/or processing speed. Heterogeneity was moderate to large (I2 ≥ 50%) for most ES estimates. Differences in the definition of euthymia across studies explained the heterogeneity in the ES estimate for verbal learning and memory. We also found evidence for other potential sources of heterogeneity in several ES estimates including co-occurring attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders, and the use of medications. In addition, the use of different neuropsychological tests appeared to contribute to heterogeneity of some estimates (e.g., attention/vigilance domain).Euthymic youths with BD exhibit significant cognitive dysfunction encompassing verbal learning and memory, working memory, and/or visual learning and memory domains. These data indicate that for a subset of individuals with BD, neurodevelopmental factors may contribute to cognitive dysfunction.

Associations of Serum Cytokine Receptor Levels with Melancholia, Staging of Illness, Depressive and Manic Phases, and Severity of Depression in Bipolar Disorder.

To examine cytokine receptor biomarkers in bipolar disorder (BD), we recruited 133 well-phenotyped BD patients and 50 normal controls and measured serum levels of soluble interleukin 1 receptor antagonist (sIL-1RA), soluble interleukin-2 receptor (sIL-2R), sIL-6R, and tumor necrosis factor receptor 60 and 80kDa (sTNFR60/80). sIL-1RA and sTNFR80 are significantly higher in BD than in controls and sTNFR80 and higher in melancholic than in non-melancholic patients and controls. Kapczinski's stages 3 + 4 are characterized by lowered sIL-2R and increased sTNFR80 levels. Acute phase depression is characterized by increased sTNFR80 levels as compared with controls, manic, and euthymic patients. Both sTNFR60 and sTNFR80 levels are significantly and positively related with severity of depression but not mania. Logistic regression analysis showed that the significant predictors for BD are increased sIL-1RA levels, nicotine dependence and a family history of depression and alcoholism. The risk factors for stages 3 + 4 are lowered sIL-2R levels and nicotine dependence. Melancholia is predicted by higher sTNFR80 levels and female sex. Severity of depression is predicted by female sex, nicotine dependence, and increased sTNFR60 and sTNFR80 levels. Cell-mediated immunity is activated during a current episode of depression but not (hypo)mania or the euthymic state. There are no associations between the biomarkers and age at onset, duration of illness, severity of mania, bipolar (BP)2 or BP1 subtypes, rapid cycling, atypical depression, psychotic or suicidal symptoms, and a family history of psychiatric disease. The results show that increased sIL-1RA may be a trait marker of BD, increased sTNFR80 a state marker of the depressive phase, especially melancholia, while lower sIL-2R but higher sTNFR80 may be staging biomarkers.

Assessment of executive functions in bipolar depression

Introduction Cognitive functions in bipolar disorder have been assessed during acute mood episodes but also during remission. While other cognitive functions, such as verbal and working memory, attention, verbal fluency and psychomotor speed seem to recover after the acute episode, executive functions impairment remains also during remission; this aspect led to the assumption that executive functions may be a trait marker for bipolar disorder. Objective The purpose of this study was to assess the executive functions, such as cognitive flexibility, set shifting, problem solving and abstract thinking in bipolar depression compared to healthy subjects. Method Forty patients diagnosed with Bipolar Disorder and Major Depressive Episode according to DSM IV-TR were included into the study. Executive functions were investigated using Wisconsin Card Sorting Test (WCST). Results obtained by patients were compared with those of 30 healthy who underwent the same cognitive evaluation. Results Depressed bipolar patients scored significantly worse on the majority of WCST measures. Thus, for total trials, total errors, preservative errors and preservative responses (raw scores and percents) and failure to maintain set scores, the differences between the two groups were significant at the 1% threshold ( P =0.000). The patients and controls displayed similar behavior for total correct ( P =0.215) and conceptual levels scores ( P =0.421). Conclusions Patients with bipolar disorder show during a depressive episode difficulties in most cognitive tasks involving executive functions. Results obtained by patients at failure to maintain set score suggest frontal dysfunctions for this category of patients.