Symptoms Of Bipolar Disorder Research Articles

Association of anhedonia and suicidal ideation in patients with treatment-refractory depression after intravenous ketamine infusions

Objectives Accumulating evidence suggests that the effects of ketamine administered intravenously at subanaesthetic doses on both anhedonic symptoms and suicidal ideation occur independently of depressive symptoms in major depressive disorder (MDD) and bipolar disorder (BD). This study sought to determine the relationship between anhedonia and suicidal ideation after serial ketamine infusions. Methods A total of 79 subjects with either treatment-refractory MDD (n = 60) or BD (n = 19) were included in a clinical ketamine study. The Montgomery–Åsberg Depression Rating Scale (MADRS) anhedonia factor and the first five items of the Scale for Suicidal Ideations (SSI-Part I) were used to assess anhedonia symptoms and suicidal ideation, respectively. Results At baseline, anhedonia, as measured by the MADRS, was not significantly associated with suicidal ideation or specific suicide-related ideation as measured by SSI-Part I (all p’s > 0.05). Only the ‘wish to die’ and ‘desire to make a suicide attempt’ items were positively associated with anhedonia at two weeks after the sixth ketamine infusion, which was independent of the reductions in depressive symptoms (all p’s < 0.05). Conclusion Anhedonia as measured by the MADRS appeared to not be positively related to suicidal ideation after serial ketamine infusions. KEY POINTS Serial ketamine (0.5 mg/kg) infusions have shown quick and dramatic antisuicidal and antianhedonic effects in patients with depression. The association between anhedonia and suicidal ideation after serial ketamine infusions is unclear. Anhedonia appeared to not be positively related to suicidal ideation after serial ketamine infusions.

Matrixmetalloproteinase-9 gene polymorphism (rs 17576) increases the risk of depressive symptoms in bipolar disorder.

Plasticity of neural synapses is known to be involved in the complications in bipolar disorder (BD) patients. Matrix metalloproteinases (MMPs) play a role in synaptic plasticity and memory. Even though elevated MMP-9 levels are reported in neuropsychiatric disorders, there is limited data about MMP-9 gene polymorphism in BD. The objectives of the study was to investigate genotype frequency and allele frequency of MMP-9 genetic variant (rs 17576) in BD and its association with disease severity. Eighty BD cases and 80 controls were recruited in the study. MMP-9 genotyping and allele frequency and plasma MMP-9 levels were analyzed in both the groups. Hamilton depression rating scale and Young's Mania Rating Scale (YMRS) were used to evaluate severity of BD. The genotype and minor allele (G allele) frequency were not significant between BD and controls. MMP-9 levels were significantly increased in BD patients with AG (P < 0.001) and GG (P = 0.022) genotypes compared to controls. BD patients with GG genotype (P = 0.038, OR: 3.26 (1.16-9.09), and G (mutant) allele (P = 0.013, OR 2.03(1.18-3.48) confer increased risk of depressive symptoms. MMP-9 was positively correlated with YMRS scale (r = 0.227, P = 0.043) in BD. MMP-9 gene polymorphism (rs 17576) is linked with depressive symptoms in BD.

A longitudinal study of the association between pro-inflammatory cytokines and mood symptoms in bipolar disorder.

Because of a relative dearth of longitudinal studies, the directionality of the relationship between mood and inflammation among patients with bipolar disorder (BD) is still unclear. We aimed to investigate the longitudinal associations of pro-inflammatory markers with mood symptom severity in BD. Hundred and thirty-two adult patients with BD were enrolled. At the baseline and 1-year follow-up visit, all participants received mood assessment with Montgomery Åsberg depression rating scale (MADRS) and Young mania rating scale, and underwent blood draws to quantify metabolic profile and serum levels of the pro-inflammatory markers, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), monocyte chemoattractant protein-1, and C-reactive protein. A four-factor model of MADRS, consisting of sadness, negative thoughts, detachment, and neurovegetative symptoms, were applied. At baseline, 65 patients with BD were in depressed state, and 67 patients with BD were in euthymic state. Among patients in depressed state, baseline MADRS total score positively correlated with sTNF-αR1 level at follow-up. While baseline sTNF-αR1 level positively predicted sadness symptom in euthymic patients with BD who later developed depression (n=22), sadness in patients with bipolar depression predicted later increase in serum sTNF-αR1 level even after remission (n=17). Moreover, lithium had a stronger effect of lowering peripheral sTNF-αR1 level as compared with other mood stabilizers. Our results indicate the bidirectional inflammation-depression relationship in BD.

Segregation, integration and balance in resting-state brain functional networks associated with bipolar disorder symptoms.

Bipolar disorder (BD) is a serious mental disorder involving widespread abnormal interactions between brain regions, and it is believed to be associated with imbalanced functions in the brain. However, how this brain imbalance underlies distinct BD symptoms remains poorly understood. Here, we used a nested-spectral partition (NSP) method to study the segregation, integration, and balance in resting-state brain functional networks in BD patients and healthy controls (HCs). We first confirmed that there was a high deviation in the brain functional network toward more segregation in BD patients than in HCs and that the limbic system had the largest alteration. Second, we demonstrated a network balance of segregation and integration that corresponded to lower anxiety in BD patients but was not related to other symptoms. Subsequently, based on a machine-learning approach, we identified different system-level mechanisms underlying distinct BD symptoms and found that the features related to the brain network balance could predict BD symptoms better than graph theory analyses. Finally, we studied attention-deficit/hyperactivity disorder (ADHD) symptoms in BD patients and identified specific patterns that distinctly predicted ADHD and BD scores, as well as their shared common domains. Our findings supported an association of brain imbalance with anxiety symptom in BD patients and provided a potential network signature for diagnosing BD. These results contribute to further understanding the neuropathology of BD and to screening ADHD in BD patients.

Psychotic symptoms in bipolar disorder and their impact on the illness: A systematic review.

BACKGROUNDLifetime psychotic symptoms are present in over half of the patients with bipolar disorder (BD) and can have an adverse effect on its course, outcome, and treatment. However, despite a considerable amount of research, the impact of psychotic symptoms on BD remains unclear, and there are very few systematic reviews on the subject.AIMTo examine the extent of psychotic symptoms in BD and their impact on several aspects of the illness.METHODSThe Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. An electronic literature search of six English-language databases and a manual search was undertaken to identify published articles on psychotic symptoms in BD from January 1940 to December 2021. Combinations of the relevant Medical Subject Headings terms were used to search for these studies. Articles were selected after a screening phase, followed by a review of the full texts of the articles. Assessment of the methodological quality of the studies and the risk of bias was conducted using standard tools.RESULTSThis systematic review included 339 studies of patients with BD. Lifetime psychosis was found in more than a half to two-thirds of the patients, while current psychosis was found in a little less than half of them. Delusions were more common than hallucinations in all phases of BD. About a third of the patients reported first-rank symptoms or mood-incongruent psychotic symptoms, particularly during manic episodes. Psychotic symptoms were more frequent in bipolar type I compared to bipolar type II disorder and in mania or mixed episodes compared to bipolar depression. Although psychotic symptoms were not more severe in BD, the severity of the illness in psychotic BD was consistently greater. Psychosis was usually associated with poor insight and a higher frequency of agitation, anxiety, and hostility but not with psychiatric comorbidity. Psychosis was consistently linked with increased rates and the duration of hospitalizations, switching among patients with depression, and poorer outcomes with mood-incongruent symptoms. In contrast, psychosis was less likely to be accompanied by a rapid-cycling course, longer illness duration, and heightened suicidal risk. There was no significant impact of psychosis on the other parameters of course and outcome.CONCLUSIONThough psychotic symptoms are very common in BD, they are not always associated with an adverse impact on BD and its course and outcome.

Shared and distinct functional connectivity of hippocampal subregions in schizophrenia, bipolar disorder, and major depressive disorder.

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) share etiological and pathophysiological characteristics. Although neuroimaging studies have reported hippocampal alterations in SZ, BD, and MDD, little is known about how different hippocampal subregions are affected in these conditions because such subregions, namely, the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB), have different structural foundations and perform different functions. Here, we hypothesize that different hippocampal subregions may reflect some intrinsic features among the major psychiatric disorders, such as SZ, BD, and MDD. By investigating resting functional connectivity (FC) of each hippocampal subregion among 117 SZ, 103 BD, 96 MDD, and 159 healthy controls, we found similarly and distinctly changed FC of hippocampal subregions in the three disorders. The abnormal functions of middle frontal gyrus might be the core feature of the psychopathological mechanisms of SZ, BD, and MDD. Anterior cingulate cortex and inferior orbital frontal gyrus might be the shared abnormalities of SZ and BD, and inferior orbital frontal gyrus is also positively correlated with depression and anxiety symptoms in SZ and BD. Caudate might be the unique feature of SZ and showed a positive correlation with the cognitive function in SZ. Middle temporal gyrus and supplemental motor area are the differentiating features of BD. Our study provides evidence for the different functions of different hippocampal subregions in psychiatric pathology.

A cumulative Bayesian network meta-analysis on the comparative efficacy of pharmacotherapies for mania over the last 40years.

Mania (or manic episodes) is a common symptom of bipolar disorder and is frequently accompanied by hyperactivity and delusions; given the cost and resources available, there is a paucity of evidence for direct comparison of different drugs. We aimed to provide evidence-based recommendations on the efficacy of overall currently used pharmacological treatments for patients with acute bipolar mania. We conducted a systematic review and network meta-analysis (NMA) using a Bayesian network frame. We searched the primary literature databases without language restrictions until Dec 18, 2021, for reports of randomized controlled trials (RCTs) of suspected antimanic drugs used as monotherapy for patients with acute bipolar mania, with the primary outcomes being efficacy (mean difference (MD), standardized mean difference (SMD) in the change of mania score). Eighty-seven studies were included in which 18,724 manic participants (mean age = 34.6years, with 50.36% males) were allocated at random to one of 25 active medication drug therapies or placebo, resulting in 87 direct comparisons on 192 data points. Tamoxifen (- 22·00 [- 26·00 to - 18·00]) had the best efficacy over the placebo. Meanwhile, risperidone (- 6·60 [- 8·40 to - 4·90]) was substantially more effective than placebo in treating acute mania. Carbamazepine, haloperidol, ziprasidone, cariprazine, olanzapine, quetiapine, aripiprazole, lithium, paliperidone, asenapine, and divalproex were noticeably more effective than placebo. Overall, tamoxifen appears to be the most effective of the currently known pharmaceutical therapy available to treat acute mania or manic episodes; however, this conclusion is restricted by the scale of RCTs conducted, and risperidone was found to be the most effective medication among antipsychotics. Carbamazepine, haloperidol, ziprasidone, cariprazine, olanzapine, quetiapine, aripiprazole, lithium, paliperidone, asenapine, and divalproex were noticeably effective in treating acute mania or manic episodes.

Genetic Liabilities Differentiating Bipolar Disorder, Schizophrenia, and Major Depressive Disorder, and Phenotypic Heterogeneity in Bipolar Disorder

Understanding the origins of clinical heterogeneity in bipolar disorder (BD) will inform new approaches to stratification and studies of underlying mechanisms. To identify components of genetic liability that are shared between BD, schizophrenia, and major depressive disorder (MDD) and those that differentiate each disorder from the others and to examine associations between heterogeneity for key BD symptoms and each component. Using data from the Bipolar Disorder Research Network in the United Kingdom, components of liability were identified by applying genomic structural equation modeling to genome-wide association studies of schizophrenia, BD, and MDD. Polygenic risk scores (PRS) representing each component were tested for association with symptoms in an independent BD data set. Adults with DSM-IV BD or schizoaffective disorder, bipolar type, were included. Data were collected from January 2000 to December 2013, and data were analyzed from June 2020 to February 2022. PRS representing the components of liability were tested for association with mania and depression, psychosis, and mood incongruence of psychosis in participants with BD, measured using the Bipolar Affective Disorder Dimensional Scale. Of 4429 included participants, 3012 (68.0%) were female, and the mean (SD) age was 46.2 (12.3) years. Mania and psychosis were associated with the shared liability component (mania β = 0.29; 95% CI, 0.23-0.34; P = 3.04 × 10-25; psychosis β = 0.05; 95% CI, 0.04-0.07; P = 2.33 × 10-13) and the components that differentiate each of schizophrenia (mania β = 0.08; 95% CI, 0.03-0.14; P = .002; psychosis β = 0.03; 95% CI, 0.01-0.04; P = 1.0 × 10-4) and BD (mania β = 0.14; 95% CI, 0.09-0.20; P = 1.99 × 10-7; psychosis β = 0.02; 95% CI, 0.01-0.03; P = .006) from the other disorders. The BD differentiating component was associated with mania independently of effects on psychosis (β = 0.14; 95% CI, 0.08-0.20; P = 4.32 × 10-6) but not with psychosis independently of mania. Conversely, the schizophrenia differentiating component was associated with psychosis independently of effects on mania (β = 0.01; 95% CI, 0.003-0.03; P = .02), but not with mania independently of psychosis. Mood incongruence of psychosis was associated only with the schizophrenia differentiating component (β = 0.03; 95% CI, 0.01-0.05; P = .005). Depression was associated with higher MDD differentiating component (β = 0.07; 95% CI, 0.01-0.12; P = .01) but lower BD differentiating component (β = -0.11; 95% CI, -0.17 to -0.06; P = 7.06 × 10-5). In this study of BD, clinical heterogeneity reflected the burden of liability to BD and the contribution of alleles that have differentiating effects on risk for other disorders; mania, psychosis, and depression were associated with the components of genetic liability differentiating BD, MDD, and schizophrenia, respectively. Understanding the basis of this etiological heterogeneity will be critical for identifying the different pathophysiological processes underlying BD, stratifying patients, and developing precision therapeutics.

Social Media Use and Well-being With Bipolar Disorder During the COVID-19 Pandemic: Path Analysis.

BackgroundReliable and consistent social support is associated with the mental health and well-being of persons with severe mental illness, including bipolar disorder (BD). Yet the COVID-19 pandemic and associated social distancing measures (eg, shelter in place) reduced access to regular social contacts, while social media use (SMU) increased concomitantly. Little is currently known about associations between the well-being of adults with BD and different types of SMU (eg, passive and active).ObjectiveFor this study, we had two goals. First, we report descriptive information regarding SMU by persons with BD during COVID-19 (all platforms). Specific to Facebook, we next developed and tested a hypothesized model to identify direct and indirect associations between BD symptoms, social support, loneliness, life satisfaction, and SMU. Responses were collected during the global spread of the Delta variant and prior/concurrent with the Omicron variant, 20 months after the World Health Organization declared COVID-19 a global pandemic.MethodsOver 8 weeks, we obtained responses from an international sample of 102 adults with BD using the Qualtrics online platform. Most had previously participated in the BADAS (Bipolar Affective Disorders and older Adults) Study (n=89, 87.3%); the remainder were recruited specifically for this research (n=13, 2.7%). The subsamples did not differ in age (t100=1.64; P=.10), gender (χ22=0.2; P=.90), socioeconomic status (χ26=9.9; P=.13), or time since BD diagnosis (t97=1.27; P=.21). Both were recruited using social media advertising micro-targeted to adults with BD. On average, participants were 53.96 (SD 13.22, range 20-77) years of age, they had completed 15.4 (SD 4.28) years of education, and were diagnosed with BD 19.6 (SD 10.31) years ago. Path analyses were performed to develop and test our hypothesized model.ResultsAlmost all participants (n=95, 93.1%) reported having both Facebook and LinkedIn accounts; 91.2% (n=93) reported regular use of either or both. During the pandemic, most (n=62, 60.8%) reported accessing social media several times a day; 36.3% (n=37) reported using social media more often since the emergence of COVID-19. Specific to Facebook, the model we hypothesized differed somewhat from what emerged. The resulting model suggests that symptoms of depression predict loneliness and, inversely, social support and life satisfaction. Social support predicts social Facebook use, whereas passive Facebook use predicts life satisfaction. Symptoms of depression emerged as indirect predictors of SMU via social support.ConclusionsOur findings suggest that the operational definition of passive-active SMU requires further analysis and refinement. In contrast to theory, passive Facebook use appears positively associated with well-being among certain populations. Longitudinal data collection over multiple points is required to identify associations between BD symptoms, SMU, and well-being over time.

Limited time-specific and longitudinal effects of depressive and manic symptoms on cognition in bipolar spectrum disorders.

Previous research suggests that cognitive performance worsens during manic and depressed states in bipolar disorder (BD). However, studies have often relied upon between-subject, cross-sectional analyses and smaller sample sizes. The current study examined the relationship between mood symptoms and cognition in a within-subject, longitudinal study with a large sample. Seven hundred and seventy-three individuals with BD completed a neuropsychological battery and mood assessments at baseline and 1-year follow-up. The battery captured eight domains of cognition: fine motor dexterity, visual memory, auditory memory, emotion processing, and four aspects of executive functioning: verbal fluency and processing speed; conceptual reasoning and set shifting; processing speed with influence resolution; and inhibitory control. Structural equation modeling was conducted to examine the cross-sectional and longitudinal relationships between depressive symptoms, manic symptoms, and cognitive performance. Age and education were included as covariates. Eight models were run with the respective cognitive domains. Baseline mood positively predicted 1-year mood, and baseline cognition positively predicted 1-year cognition. Mood and cognition were generally not related for the eight cognitive domains. Baseline mania was predictive in one of eight baseline domains (conceptual reasoning and set shifting); baseline cognition predicted 1-year symptoms (inhibitory control-depression symptoms, visual memory-manic symptoms). In a large community sample of patients with bipolar spectrum disorder, cognitive performance appears to be largely unrelated to depressive and manic symptoms, suggesting that cognitive dysfunction is stable in BD and is not dependent on mood state in BD. Future work could examine how treatment affects relationship between cognition and mood. Cognitive dysfunction appears to be largely independent of mood symptoms in bipolar disorder. The sample was generally highly educated (M= 15.22), the majority of the subsample with elevated manic symptoms generally presented with concurrent depressive elevated symptoms, and the study did not stratify recruitment based on mood state.

Smartphone-based interventions in bipolar disorder: Systematic review and meta-analyses of efficacy. A position paper from the International Society for Bipolar Disorders (ISBD) Big Data Task Force.

The clinical effects of smartphone-based interventions for bipolar disorder (BD) have yet to be established. To examine the efficacy of smartphone-based interventions in BD and how the included studies reported user-engagement indicators. We conducted a systematic search on January 24, 2022, in PubMed, Scopus, Embase, APA PsycINFO, and Web of Science. We used random-effects meta-analysis to calculate the standardized difference (Hedges' g) in pre-post change scores between smartphone intervention and control conditions. The study was pre-registered with PROSPERO (CRD42021226668). The literature search identified 6034 studies. Thirteen articles fulfilled the selection criteria. We included seven RCTs and performed meta-analyses comparing the pre-post change in depressive and (hypo)manic symptom severity, functioning, quality of life, and perceived stress between smartphone interventions and control conditions. There was significant heterogeneity among studies and no meta-analysis reached statistical significance. Results were also inconclusive regarding affective relapses and psychiatric readmissions. All studies reported positive user-engagement indicators. We did not find evidence to support that smartphone interventions may reduce the severity of depressive or manic symptoms in BD. The high heterogeneity of studies supports the need for expert consensus to establish ideally how studies should be designed and the use of more sensitive outcomes, such as affective relapses and psychiatric hospitalizations, as well as the quantification of mood instability. The ISBD Big Data Task Force provides preliminary recommendations to reduce the heterogeneity and achieve more valid evidence in the field.

Evaluation of mood disorder questionnaire positivity and associated factors in a population-based screening study

The Mood Disorders Questionnaire (MDQ) is a 3-item scale that is frequently used in bipolar disorders (BD) screening and questions the symptoms of BD, its effect on functionality, and the coexistence of symptoms. The aim of this study is to evaluate the prevalence of positive screening of the MDQ among general population and to investigate the associated risk factors.In this cross-sectional study, the sample was randomly selected from household data to represent the city population. A total of 432 participants were asked to fill in MDQ, CAGE (cutting down, annoyance by criticism, guilty feeling, and eye-openers) questionnaire, which consists of four clinical interview questions proven to aid in the diagnosis of alcoholism, and clinical and sociodemographic data form.The Cronbach’s alpha value of our current study was 0.813 for MDQ. The prevalence of MDQ positivity was found 7.6%. The estimated prevalence rate of bipolar disorders varied between 0.3 and 13.4% according to different cut-off values. Multivariate logistic regression models showed that the presence of possible alcohol addiction, shift work history, and body mass index (BMI) were statistically significant predictors of MDQ positivity.The prevalence of MDQ positivity found is similar to studies in literature. Keeping in mind that psychometric properties of the MDQ, positive screen results should be cautiously interpreted due to the presence of other risk factors and comorbidities.

The Effects of Yoga on Bipolar Disorder: A Systematic Review.

Bipolar disorder (BD) is a mood disorder characterized by severe mood swings and or periods of depression. This study examined the role that practicing yoga has on the symptoms of BD. One of the main goals was to identify if patients with BD believe that yoga is a viable treatment option. Six research databases were searched using the keywords "yoga" AND "therapy" AND "BD" AND "bipolar depression." Articles published in 2005 and later were included in the search. After duplicates were removed, and inclusion and exclusion criteria were applied, five articles were analyzed and included in this literature review. Results of this review indicate that yoga has been shown to be associated with both benefits and risks for the treatment of BD. Studies have shown that yoga might relieve some symptoms of BD and depression. However, due to the lack of research on the impact of yoga on BD and the small number of studies included in this review, results should be approached with caution. Overall, yoga was well-tolerated in the studies reviewed in this article. Yoga may relieve the symptoms of depression. Future research should analyze the long-term impact of yoga on bipolar depression. Yoga instructional standards should also be considered.

Mindfulness based cognitive therapy (MBCT) reduces depression-related self-referential processing in patients with bipolar disorder: an exploratory task-based study

ABSTRACT Negative self-referential processing has fruitfully been studied in unipolar depressed patients, but remarkably less in patients with bipolar disorder (BD). This exploratory study examines the relation between task-based self-referential processing and depressive symptoms in BD and their possible importance to the working mechanism of mindfulness-based cognitive therapy (MBCT) for BD. The study population consisted of a subsample of patients with BD (n = 49) participating in an RCT of MBCT for BD, who were assigned to MBCT + TAU (n = 23) or treatment as usual (TAU) (n = 26). Patients performed the self-referential encoding task (SRET), which measures (1) positive and (2) negative attributions to oneself as well as (3) negative self-referential memory bias, before and after MBCT + TAU or TAU. At baseline, all three SRET measures were significantly related to depressive symptoms in patients with BD. Moreover, repeated measures analyses of variance revealed that negative self-referential memory bias diminished over time in the MBCT + TAU group, compared with the TAU group. Given the preliminary nature of our findings, future research should explore the possibly mediating role of reducing negative self-referential memory bias in preventing and treating depressive symptoms in BD through MBCT.

Chronic Stress in Bipolar Disorders Across the Different Clinical States: Roles of HPA Axis and Personality.

IntroductionChronic stress has been linked to the pathophysiology of bipolar disorder (BD); however, the underlying mechanism remains unclear. In BD patients, hypothalamic-pituitary-adrenal (HPA) axis activity is associated with stress. This study aimed to examine the relationship between HPA axis activity and BD symptoms in various clinical states, as well as how personality influences the process.MethodsThis study investigated the differences in HPA axis activity among four BD states. We enrolled 813 BD patients in an 8-week longitudinal study to examine the relationship between HPA axis activity and symptom trajectories using dynamic temporal warping (DTW) analysis and an unsupervised machine learning technique. Furthermore, using mediation analyses, the relationship between the HPA axis, personality, and BD symptoms was investigated.ResultsAnalysis of variance (ANOVA) analysis showed that glucocorticoid cortisol (CORT) and adrenocorticotropin (ACTH) did not differ significantly among the four clinical states of BD. The DTW integrating clustering analysis revealed that the two clusters were optimal, with cluster 1 characterized by severe manic symptoms, which then improved, and cluster 2, characterized by milder manic severity, which also improved. The two clusters showed different ACTH levels (t = 2.289, p = 0.022), and logistic regression analysis revealed a slight positive association between ACTH levels and cluster 1. Furthermore, the mediation analysis indicated that ACTH influences curative efficacy via conscientiousness (βc =0.103, p=0.001).DiscussionIn conclusion, we found that a higher level of ACTH is associated with severe manic symptoms, indicating a chronic stress response in BD patients. Additionally, the ACTH levels affect short-term BD curative efficacy via the mediation of conscientiousness, providing a psychotherapeutic strategy direction for BD.

Internal clock variability, mood swings and working memory in bipolar disorder

BackgroundDistortions in time processing may be regarded as an endophenotypic marker of neuropsychiatric diseases; however, investigations addressing Bipolar Disorder (BD) are still scarce. MethodsThe present study compared timing abilities in 30 BD patients and 30 healthy controls (HC), and explored the relationship between time processing and affective-cognitive symptoms in BD, with the aim to determine whether timing difficulties are primary in bipolar patients or due to comorbid cognitive impairment. Four tasks measuring external timing were administered: a temporal and spatial orienting of attention task and a temporal and colour discrimination task, for assessing the ability to evaluate temporal properties of external events; two other tasks assessed the speed of the internal clock (i.e. temporal bisection and temporal production tasks). Attentional, executive and working memory (WM) demands were equated for controlling additional cognitive processes. ResultsBD patients did not show differences in external timing accuracy compared to HC; conversely, we found increased variability of the internal clock in BD and this performance was related to Major Depressive Episodes recurrence and WM functioning. Hence, variability of the internal clock is influenced by the progressive course of BD and impacted by variations in WM. LimitationsFuture studies including BD patients stratified by mood episode will further specify timing alterations conditional to the current affective state. ConclusionsOur results shed new light on the clinical phenotypes of BD, suggesting that timing might be used as a model system of the ongoing pathophysiological process.

Linkage of Young Mania Rating Scale to Clinical Global Impression Scale to Enhance Utility in Clinical Practice and Research Trials.

The Young Mania Rating Scale (YMRS) is the gold standard to assess manic symptoms of bipolar disorder, yet the clinical meaning of scores is unknown. To clinically understand and interpret YMRS scores, we examined linkages between the total and change scores of YMRS with the Clinical Global Impression (CGI) ratings. Individual participant data (N=2,988) from eight randomized, double-blind, placebo-controlled trials were included. Data were collected at baseline and subsequent visits. Spearman's correlation coefficients ρ were computed, and equipercentile linking was implemented. A YMRS score of 6 points corresponded approximately to 'borderline mentally ill,' 12 points to 'mildly ill,' 20 points to 'moderately ill,' 30 points to 'markedly ill,' 40 points to 'severely ill,' and 52 points to 'among the most extremely ill' patients on the CGI-S. A reduction of CGI-S by one point as well as 'minimally improved' on the CGI-I corresponded approximately to an absolute decrease of 4 to 8 YMRS points or a 21% to 29% reduction of YMRS baseline score whereas a reduction of CGI-S by two points and 'much improved' on the CGI-I corresponded to an absolute decrease of 10 to 15 points or a 42% to 53% reduction of YMRS baseline score. The current study findings offer clinicians meaningful cutoff values to interpret YMRS scores. Moreover, these values contribute to the definition of treatment targets, response, remission, and entry criteria in mania trials.

Chronobiological aspects of bipolar disorder

Numerous symptoms of bipolar disorder are regulated by the circadian rhythm. Because of this association it is assumed that disruption of the circadian rhythm may be part of the pathomechanism of bipolar disorder. Acomparison and subsequent critical discussion of the current data situation on chronobiological aspects of bipolar disorder are presented. Anarrative literature search was carried out and the main findings are presented in a summarized form. There are alarge number of animal and human studies investigating the connection between disorders of the circadian rhythm and bipolar disorder. Especially chronotype, the environmental factor light and sleep disorders seem to be associated with the development of bipolar disorder. The neurobiology of bipolar disorder shows numerous chronobiological aspects. There is evidence for adirect connection of disruption of the circadian rhythm and development and progression of bipolar disorder; however, at present there is no proof for the specificity of these findings for bipolar disorder. Future studies should consolidate the evidence on the impact of disorders of the circadian rhythm on the pathomechanism of bipolar disorder.

Depressive-like behavior accompanies neuroinflammation in an animal model of bipolar disorder symptoms induced by ouabain

IntroductionA previous study from our Laboratory showed no alteration in inflammatory parameters seven days after ouabain (OUA) administration, a Na+K+ATPase inhibitor, which was previously considered only a mania model. However, the administration of OUA in rats was recently validated as a model of bipolar disorder (BD) symptoms, demonstrating that 14 days after single intracerebroventricular (ICV) administration, OUA also induces depressive-like behavior. Therefore, it is important to investigate the long-term effect of OUA on inflammatory parameters since this mechanism seems to play a key role in BD physiopathology. MethodsAdult male Wistar rats received a single ICV administration of OUA or artificial cerebrospinal fluid (aCSF). From the fourth day after the ICV infusion, the rats received saline or Lithium (Li) for 14 days. The open-field test was performed on the 7th day after OUA. On the 14th day, locomotion was re-evaluated, and the forced swimming test (FST) was used to evaluate depressive-like behavior. Inflammatory parameters were assessed in the frontal cortex and hippocampus. ResultsOUA increased the locomotion of rats after seven days, considered a mania-like behavior. In the FST, OUA increased the time of immobility on the 14th day, considered a depressive-like behavior. Li reversed the mania-like behavior and partially reversed the depressive-like behavior. Furthermore, OUA increased the levels of interleukin (IL)-1β, IL-6, IL-10, TNF-α, and CINC-1 in the frontal cortex and hippocampus. Li treatment reverses all these inflammatory alterations. ConclusionThis study suggests that the long-term Na+K+ATPase inhibition effects induce depressive-like behavior, which was accompanied by inflammation in the BD symptoms model.

Metabolomic biomarkers related to non-suicidal self-injury in patients with bipolar disorder

BackgroundNon-suicidal self-injury (NSSI) is an important symptom of bipolar disorder (BD) and other mental disorders and has attracted the attention of researchers lately. It is of great significance to study the characteristic markers of NSSI. Metabolomics is a relatively new field that can provide complementary insights into data obtained from genomic, transcriptomic, and proteomic analyses of psychiatric disorders. The aim of this study was to identify the metabolic pathways associated with BD with NSSI and assess important diagnostic and predictive indices of NSSI in BD.MethodNuclear magnetic resonance spectrometry was performed to evaluate the serum metabolic profiles of patients with BD with NSSI (n = 31), patients with BD without NSSI (n = 46), and healthy controls (n = 10). Data were analyzed using an Orthogonal Partial Least Square Discriminant Analysis and a t-test. Differential metabolites were identified (VIP > 1 and p < 0.05), and further analyzed using Metabo Analyst 3.0 to identify associated metabolic pathways.ResultsEight metabolites in the serum and two important metabolic pathways, the urea and glutamate metabolism cycles, were found to distinguish patients with BD with NSSI from healthy controls. Eight metabolites in the serum, glycine and serine metabolism pathway, and the glucose-alanine cycle were found to distinguish patients with BD without NSSI from healthy controls. Five metabolites in the serum and the purine metabolism pathway were found to distinguish patients with BD with NSSI from those with BD without NSSI.ConclusionsAbnormalities in the urea cycle, glutamate metabolism, and purine metabolism played important roles in the pathogenesis of BD with NSSI.