Progression Of Bipolar Disorder Research Articles

Weibull multi-state models with misclassification

ABSTRACTIt is often important to allow multi-state models (MSMs) to accommodate misclassification of states. We introduce Bayesian parametric MSMs with unknown misclassification of states and Weibull distributed waiting times between states. This allows transitions between states to depend on the time spent in the current state, a feature lacking in commonly used exponential waiting times model. To fit the proposed model, a MCMC algorithm was employed. An example on the progression of bipolar disorder is presented along with simulation results. There was evidence that Weibull waiting times are an improvement over exponential in the study of bipolar disorder.

Genetic Influences On Inflammatory Biomarkers In Bipolar Disorder

Background Inflammatory mechanisms have been implicated in the pathophysiology and progression of bipolar disorder. Markers of inflammation circulating in blood are often used in these investigations, but demonstrate little relationship to central nervous system inflammation and related biomarkers in the cerebrospinal fluid (CSF). This study investigates the genetic mediation of inflammation biomarkers in CSF and serum from subjects with bipolar disorder and healthy controls. Methods Subjects were drawn from the St. Goran Bipolar Project which enrolls patients from bipolar disorder clinics in Gothenburg and Stockholm in addition to age and sex-matched healthy controls. For the inflammation-related biomarkers YKL40, MCP1, sCD14, TIMP1, and TIMP2, CSF and serum levels were quantified, as well as CSF levels of IL8 and serum levels of CRP and MMP9. Subjects were genotyped using the Affymetrix 6.0 and Illumina OmniExpress arrays. Genome-wide association studies of these biomarkers were conducted for the 51-57 controls and 101-164 cases with available data using PLINK and included covariates for age, sex, and principle components accounting for population substructure. Results Genome-wide significant associations (p Discussion Levels of inflammatory biomarkers in CSF and serum are both genetically mediated but probably differentially. The associated genetic markers, in conjunction with the biomarker levels previously associated with bipolar disorder, could be used to aid diagnoses and as possible targets for the development of novel therapeutics.

Peripheral blood mRNA expressions of stress biomarkers in manic episode and subsequent remission

Theoretical models of the neuroprogressive nature of bipolar disorder (BD) are based on the hypothesis that it is an accelerated aging disease, with the allostatic load playing a major role. Glucocorticoids, oxidative stress markers, inflammatory cytokines and neurotrophins play important roles in BD. The messenger ribonucleic acid (mRNA) expressions of brain-derived neurotrophic factor (BDNF), tissue plasminogen activator (tPA), glucocorticoid receptor (GR), heat shock protein 70 (HSP70), tumour necrosis factor-alpha (TNF-α) were examined in the peripheral blood of 20 adult male, drug-free BD patients during manic and remission periods and in 20 adult male, healthy controls. mRNA expression was measured using the quantitative real-time polymerase chain reaction (qRT-PCR). Compared to the controls, the expressions of BDNF and tPA mRNA were down-regulated in mania. In remission, BNDF and tPA mRNA levels increased, but they were still lower than those of the controls. Between mania and remission periods, only the change in mRNA levels of BDNF reached statistical significance. The results suggest that BDNF and tPA may be biomarkers of BD and that proteolytic conversion of BDNF may be important in the pathophysiology of BD. The change in BDNF levels between mania and remission could be adaptive and used to follow the progression of BD.

The Adverse Effects of Smoking on Health Outcomes in Bipolar Disorder: A Review and Synthesis of Biological Mechanisms.

Several biological systems are implicated in the neuroprogression of bipolar disorder including but not limited to cytokine levels, oxidative stress markers, monoamine levels, tryptophan catabolite and glutamate-mediated excitotoxicity, microglial activation as well as structural and functional changes. The high rate of smoking behaviour in individuals with bipolar disorder provides the impetus for exploring shared and discrete pathogenetic mechanisms. In addition to contributing to increased mortality, smoking activates several neurobiological effector systems implicated in the progression of bipolar disorder. Here, a narrative review provides evidence and putative mechanisms of comorbid effects of BD, cigarette use, and nicotine dependence, and discusses the clinical implications of these interactions.

Metabolic Syndrome in First Manic Episode: A Comparison between Patients with or without Previous Depressive Episode

Objective: The purpose of this study was to investigate, whether an association between metabolic syndrome (MetS) and clinical features and affective temperaments exists or not in first manic episode of bipolar disorder (BD) with or without previous depressive episode. Methods: Diagnosed with dipolar disorder type I according to DSM-IV criteria fifty four patients who were had a least one previous depressive episode (PDE) and 87 patients who were experiencing their first manic episode (FME) evaluated consecutively for inclusion. Comorbid axis I disorders and alcohol or substance use were excluded. NCEP ATP III formulated an operational definition of MetS based on the presence of three or more of the following characteristics: abdominal obesity (waist circumference), hypertriglyceridemia, low HDL or being on an antilipidemic agent, high blood pressure or being on an antihypertensive agent, and fasting hyperglycemia or being on antiglycemic agent. The patients who had been in remission period for at least 8 weeks were evaluated with SCIP-TURK and TEMPS-A. Remission was defined as YMRS score<5. Results: MetS was found to be more frequent in these patients than the patients who didn’t have a PDE. PDE, negative family history, childhood trauma and seasonality are determined as the predictors of MetS. Anxious temperament scores were higher in MetS (+) FME patients of both groups. Irritable temperament scores were higher only in MetS (+) FME patients without PDE group. Conclusion: The presence of MetS seems to be correlated with the onset and progression of BD. This may also contribute to the discovery of biological markers, increase in our diagnostic tools, development of protective and individual-spesific treatment options.

Memory and brain-derived neurotrophic factor after subchronic or chronic amphetamine treatment in an animal model of mania

Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain-derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH-treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala.

Pharmacological treatment and staging in bipolar disorder: evidence from clinical practice

Staging models for medical diseases are widely used to guide treatment and prognosis. Bipolar disorder (BD) is a chronic condition and it is among the most disabling disorders in medicine. The staging model proposed by Kapczinski in 2009 presents four progressive clinical stages of BD. Our aim was to evaluate pharmacological maintenance treatment across these stages in patients with BD. One hundred and twenty-nine subjects who met DSM-IV criteria for BD were recruited from the Bipolar Disorders Program at Hospital de Clínicas de Porto Alegre, Brazil. All patients were in remission. The subjects were classified according to the staging model: 31 subjects were classified as stage I, 44 as stage II, 31 as stage III, and 23 as stage IV. Patterns of pharmacological treatment differed among the four stages (p = 0.001). Monotherapy was more frequent in stage I, and two-drug combinations in stage II. Patients at stages III and IV needed three or more medications or clozapine. Impairment in functional status (Functioning Assessment Short Test [FAST] scale scores) correlated positively with the number of medications prescribed. This study demonstrated differences in pharmacological treatment in patients with stable BD depending on disease stage. Treatment response can change with progression of BD. Clinical guidelines could consider the staging model to guide treatment effectiveness.

Biomarkers of Neuroprogression in Bipolar Disorder

In bipolar disorder (BD), illness progression has been associated with a higher number of mood episodes and hospitalizations, reduced interepisode intervals, poorer response to treatment, and cognitive/functional impairment. The term ‘neuroprogression” has been proposed to describe the pathological rewiring of the brain that takes place when clinical and cognitive deterioration occurs in the context of the progression of BD. Accordingly, neuroprogression would correspond to the biological underpinnings of illness progression and staging in BD. In some cases of BD it is possible to identify an active process of neuroprogression mediated by immune activation which cincludes: a) inflammation, b) changes in growth factors, c) oxidative stress and d) mitochondrial dysfunction. Recent evidence showing neuroinflammation in BD suggest that it may be associated with neuroprogressive changes such as incremental volume loss in brain, cognitive changes, and a declining likelihood of response to pharmacological and psychosocial treatments. Prompt treatment may be potentially neuroprotective and attenuate the volumetric and neurocognitive changes that emerge with chronicity. Accumulating evidence suggest that the assessment of immune activation in BD may be a means to assess illness progression. Interventions aiming at reducing immune activation in BD are currently being tested.

Biomarkers and staging of bipolar disorder: a systematic review.

A growing body of evidence suggests that bipolar disorder (BD) is a progressive disease according to clinical, biochemical and neuroimaging findings. This study reviewed the literature on the relationship between specific biomarkers and BD stages. A comprehensive literature search of MEDLINE and PubMed was conducted to identify studies in English and Portuguese using the keywords biomarker, neurotrophic factors, inflammation, oxidative stress, neuroprogression and staging models cross-referenced with bipolar disorder. Morphometric studies of patients with BD found neuroanatomic abnormalities, such as ventricular enlargement, grey matter loss in the hippocampus and cerebellum, volume decreases in the prefrontal cortex and variations in the size of the amygdala. Other studies demonstrated that serum concentrations of neurotrophic factors, inflammatory mediators and oxidative stress may be used as BD biomarkers. The analysis of neurobiological changes associated with BD progression and activity may confirm the existence of BD biomarkers, which may be then included in staging models that will lead to improvements in treatment algorithms and more effective, individually tailored treatment regimens. Biomarkers may also be used to define early interventions to control disease progression.

P.2.c.009 Epigenetically-induced modulation of the stress axis associated with the progression of bipolar disorder

Lisdexamfetamine dimesylate is a therapeutically inactive prodrug in which d-amphetamine is covalently bound to l-lysine, a naturally occurring amino acid. Pharmacologically active d-amphetamine is released from lisdexamfetamine following oral ingestion.This phase 2, randomized, double-blind, placebo- and active-controlled crossover study compared the efficacy and safety of lisdexamfetamine (LDX: 30, 50, or 70 mg) with placebo, with mixed amphetamine salts extended-release (MAS XR: 10, 20, or 30 mg) included as a reference arm of the study, in 52 children aged 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD) in an analog classroom setting. The primary efficacy measure was the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale; secondary efficacy measures included the Permanent Product Measure of Performance (PERMP) Derived Measures, and the Clinical Global Impression (CGI) Scale.LDX treatment significantly improved scores on SKAMP-deportment, SKAMP-attention, PERMP-attempted, PERMP-correct, and CGI-improvement from baseline. Adverse events were similar for both active treatments.In a laboratory classroom environment, LDX significantly improved ADHD symptoms versus placebo in school-age children with ADHD.

Verbal episodic memory along the course of schizophrenia and bipolar disorder: A new perspective

Impairment on episodic memory (EM) has been strongly correlated with psychiatric disorders, including schizophrenia (SZ) and bipolar disorder (BD). Morevover, the effects of course and progression of the illness on cognitive functioning have not been well established. The aim of the present study is to assess performance of episodic memory in BD and SZ according to their clinical stages.Subjects who met DSM-IV criteria for bipolar disorder (n=43) and schizophrenia (31), on euthymia or clinical remission, were recruited from the outpatients facilities at Hospital de Clínicas de Porto Alegre (Brazil). They were classified into two clinical stages (early or late for BD, and recent onset or chronic for SZ) and compared to 54 healthy controls. Episodic memory performance was assessed by means the Hopkins Verbal Learning Test-Revised (HVLT-R) that measures verbal learning and episodic memory in both disorders. Our results showed that patients in early stage of BD (EBD) performed better performance on the total immediate free recall (p<0.0001, F=12.060) as well as in delayed free recall (p<0.0001, F=13.914) compared to late stage (LBD) and SZ groups. In the ability to retain words learned, LBD and chronic (CSZ) were more impaired than other groups. Furthermore, the variation of learning (i.e, learning effects) along the 3 trials of immediate free recall was similar between groups.In conclusion, we found a cognitive decline alongside with the progression of BD whereas such impairment was evident in the early of SZ. Despite this, both groups (BD and SZ) seem to maintain the ability to learn. It emphasizes the relevance of studying new therapeutic strategies, in particular, cognitive rehabilitation/remediation techniques as promissory treatment for psychiatric patients, even in those with moderate disabilities.

General medical conditions in 347 bipolar disorder patients: Clinical correlates of metabolic and autoimmune-allergic diseases

BackgroundPatients with bipolar disorder (BD) suffer from greater physical morbidity and mortality than the general population. The aim of the present study is to explore the prevalence and clinical correlates of General Medical Conditions (GMC) in a large consecutive sample of patients with BD. MethodThe study sample comprised of 347 patients who met DSM-IV-TR criteria for BD I (n=207, 59.7%), BD II or Cyclothymic Disorder (n=140, 40.3). Diagnostic information was collected by means of the Structured Clinical Interview for DSM-IV Axis I Disorders– Clinical Version (SCID-I), and information about personal and family history were collected by the Semi-Structured Interview for Mood Disorder-Revised (SIMD-R). Standardized procedure was used to assess the diagnosis of GMC, which was considered present only if a specific therapy to treat the condition was prescribed by a specialist or a general practitioner. In order to explore possible relationships between physical comorbidity and clinical features of BD, we compared patients with (MD) and without (No-MD) Metabolic Diseases (MD) and patients with (AAD) and without (No-AAD) Autoimmune-Allergic Diseases (AAD). ResultsThe most commonly reported GMCs were: Headache, Hypercholesterolemia (>200mg/dl), Chronic Constipation, Obesity, Arterial Hypertension (BP >140/90mmHg), Hypothyroidism, Allergic Rhino-Conjunctivitis, Irritable Bowel Syndrome, Hypertriglyceridemia (>150mg/dl), Metabolic Syndrome, Hiatus Hernia, Dysmenorrhea, Urticaria, Atopic Dermatitis, Psoriasis, Seborrheic Dermatitis, Diabetes Mellitus, Bronchial Asthma, Cardiac Arrhythmias, Biliary Lithiasis, and COPD. In our sample, MD (n=148, 42.7%) and AAD (n=167, 48.1%) were the most common categories of GMCs. Interestingly, the lifetime prevalence of cancer and neoplastic diseases was very low: 1 patient (.3%) reported Lung Adenocarcinoma and 2 (.6%) patients Bowel Cancer. In the group comparisons, length of pharmacological treatment (OR=1.054; 95% CI=1.030–1.078), age at onset of first major episode (OR=1.043; 95% CI=1.019–1.067), length of the current episode (OR=1.025; 95% CI=1.020–1.533) and absence of lifetime comorbid substance abuse (OR=.373; 95% CI=.141–.989) were statistically associated with the presence of comorbid MD; while only AD-induced hypomania (OR=1.62; 95% CI=1.011–2.597), and cyclothymic temperament (OR=1.051; 95% CI=1.016–1.087) were statistically associated with the presence of comorbid AAD. LimitationsPossible referral and selection bias; retrospective, non-blind, cross-sectional evaluation. ConclusionMD and AAD were highly represented in our sample, while cancer and neoplastic diseases were uncommon. The clinical correlates of different sub-groups of GMC suggest different interpretations. The presence of MD seems to be correlated with the progression of BD and the chronic medication exposure, while comorbid AAD seems to correlate with a specific clinical subtype of BD, characterized by mood reactivity and temperamental mood instability. If the link with autoimmune-allergic diathesis will be confirmed, it could provide an interesting new paradigm for the study of the “systemic” nature of mood disorders and a promising target for future treatment options.

EPA-0444 – The role of staging in bipolar disorder - associations with overweight and obesity

Introduction Overweight and obesity are highly prevalent in bipolar disorder (BD), and have been observed to worsen treatment response and outcome. Moreover, a relationship between overweight/obesity and cognitive impairment has been reported previously. Clinical staging includes clinical features, data of biomarkers and cognition, and is related to global functioning in BD. Earlier stages of illness may be associated with a better prognosis and a higher treatment response. Objectives The present study aims to evaluate the relationship between clinical staging and overweight/obesity in euthymic BD individuals. Clinical staging was hypothesized to be associated with overweight/obesity, especially with indicators of abdominal obesity. Methods A cohort of 100 euthymic BD patients was recruited and anthropometric variables (including body mass index and waist/hip circumference) were measured. Body composition was evaluated with lipometry measurement, an exact calculation of the subcutaneous adipose tissue thickness. Clinical staging was done according to the staging model by Kapzinsky et al. For statistical analyses, partial correlations controlled for age were used. Results Findings show a positive correlation between staging and hip circumference r=.265, p Conclusions As clinical outcome parameter, staging enables to unterstand the mechanisms underlying progression of BD and assists in treatment planning and prognosis. Based on the results we might suggest, that abdominal obesity is associated with a higher progression of BD accompanied with negative outcome characteristics. The data provide an updated quantification of the growing public health burden in BD.

Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder

Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA). This astrocyte-derived mediator acts as a neuroprotectant and modulates sensory gating and cognitive function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder. We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high-performance liquid chromatography. Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean [SEM] 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers. The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease. Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disorder.

The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder

The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD.

Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult mice: Prevention by chronic lithium treatment

Objectives Emerging data suggests that omega-3 fatty acid deficiency may be a risk factor for bipolar disorder. In the present study, we determined the effects of chronic dietary-induced omega-3 fatty acid deficiency and/or concomitant chronic lithium chloride (LiCl) treatment on amphetamine (AMPH)-induced behavioral sensitization, a phenomenon that may recruit neuroplastic mechanisms relevant to the pathophysiology of bipolar disorder. Method Adult male C57BL/6J mice were randomly assigned to one four diets: Control (α-linolenic-fortified), Control + LiCl (0.255%), α-linolenic-Deficient, or Deficient + LiCl (0.255%), and behavioral testing initiated 65 days later. Locomotor activity was determined following 3 intermittent (separated by 7 d) injections of amphetamine (AMPH) (1 mg/kg). After behavioral testing, red blood cell (RBC) and regional brain (prefrontal cortex, hippocampus, ventral striatum) fatty acid composition was determined by gas chromatography. Results Each diet group exhibited comparable locomotor activity following acute AMPH treatment. However, the development of sensitization following repeated AMPH treatment was significantly augmented in Deficient mice relative to controls, and this augmented response was prevented by chronic LiCl treatment. Relative to controls, Deficient mice exhibited deficits in RBC and regional brain docosahexaenoic acid (DHA, 22:6 n−3) composition, reciprocal elevations in vaccenic acid (18:1 n−7), arachidonic acid (AA, 20:4 n−6), and docosapentaenoic acid (DPA, 22:5 n−6) compositions, and elevations in AA:DHA, oleic acid:DHA, and DPA:DHA ratios. The fatty acid abnormalities in Deficient mice were not altered by concurrent chronic lithium treatment. Mice fed the Control + LiCl diet exhibited a significant increase in AA composition in RBC and all brain regions, and an elevated AA:DHA ratio in the prefrontal cortex and hippocampus, relative to Controls. Fatty acid composition in RBC and different brain regions were predominantly positively correlated. Within the ventral striatum, DHA composition was inversely correlated, and AA:DHA and oleic acid:DHA ratios positively correlated, with total distance traveled following the final AMPH treatment. Conclusion These data indicate that alterations in fatty acid composition resulting from dietary-induced omega-3 fatty acid deficiency augment the development of AMPH-induced behavioral sensitization in a manner that is prevented by chronic lithium treatment. The implications of these findings for understanding the contribution of omega-3 fatty acid deficiency to the pathophysiology and progression of bipolar disorder are discussed.

The Role of Psychosocial Stress in the Onset and Progression of Bipolar Disorder and its Comorbidities: The Need for Earlier and Alternative Modes of Therapeutic Intervention

Psychosocial stress plays an important role at multiple junctures in the onset and course of bipolar disorder. Childhood adversity may be a risk factor for vulnerability to early onset illness, and an array of stressors may be relevant not only to the onset, recurrence, and progression of affective episodes, but the highly prevalent substance abuse comorbidities as well. A substantial group of controlled studies indicate that various cognitive behavioral psychotherapies and psycho-educational approaches may yield better outcomes in bipolar disorder than treatment as usual. Yet these approaches do not appear to be frequently or systematically employed in clinical practice, and this may contribute to the considerable residual morbidity and mortality associated with conventional treatment. Possible practical approaches to reducing this deficit (in an illness that is already underdiagnosed and undertreated even with routine medications) are offered. Without the mobilization of new clinical and public health a...

The role of psychosocial stress in the onset and progression of bipolar disorder and its comorbidities: The need for earlier and alternative modes of therapeutic intervention

Psychosocial stress plays an important role at multiple junctures in the onset and course of bipolar disorder. Childhood adversity may be a risk factor for vulnerability to early onset illness, and an array of stressors may be relevant not only to the onset, recurrence, and progression of affective episodes, but the highly prevalent substance abuse comorbidities as well. A substantial group of controlled studies indicate that various cognitive behavioral psychotherapies and psychoeducational approaches may yield better outcomes in bipolar disorder than treatment as usual. Yet these approaches do not appear to be frequently or systematically employed in clinical practice, and this may contribute to the considerable residual morbidity and mortality associated with conventional treatment. Possible practical approaches to reducing this deficit (in an illness that is already underdiagnosed and undertreated even with routine medications) are offered. Without the mobilization of new clinical and public health approaches to earlier and more effective treatment and supportive interventions, bipolar illness will continue to have grave implications for many patients' long-term well being.