Bipolar Disorder Status Research Articles

Lithium-associated transcriptional regulation of CRMP1 in patient-derived olfactory neurons and symptom changes in bipolar disorder

There is growing evidence that lithium used in the treatment of bipolar disorder (BD) affects molecular targets that are involved in neuronal growth, survival, and maturation, but it remains unclear if neuronal alterations in any of these molecules predict specific symptom changes in BD patients undergoing lithium monotherapy. The goals of this study were to (a) determine which molecular changes in the olfactory neurons of symptomatic patients receiving lithium are associated with antimanic or antidepressant response, and (b) uncover novel intraneuronal regulatory mechanisms of lithium therapy. Twenty-two treatment-naïve non-smoking patients, with symptomatic BD underwent nasal biopsies for collection of olfactory tissues, prior to their treatment and following a 6-week course of lithium monotherapy. Sixteen healthy controls were also biopsied. Combining laser capture microdissection with real-time polymerase chain reaction, we investigated baseline and treatment-associated transcriptional changes in candidate molecular targets of lithium action in the olfactory neuroepithelium. Baseline mRNA levels of glycogen synthase kinase 3 beta (GSK3β) and collapsin response mediator protein 1 (CRMP1) genes were significantly associated with BD status and with severity of mood symptoms. Among BD subjects, treatment-associated downregulation of CRMP1 expression was most predictive of decreases in both manic and depressive symptoms. This study provides a novel insight into the relevance of CRMP1, a key molecule in semaphorin-3A signaling during neurodevelopment, in the molecular mechanism of action of lithium, and in the pathophysiology of BD. It supports the use of human-derived olfactory neuronal tissues in the evaluation of treatment response of psychiatric disorders.

Effect of memantine on C-reactive protein and lipid profiles in bipolar disorder

BackgroundBalance in the immune system plays roles in bipolar disorder (BD) and its metabolic co-morbidities. Memantine is an NMDA receptor antagonist with anti-inflammatory effects. However, the effects of memantine adjunct treatment on metabolic status of BD are unclear. MethodsDuring the 12 weeks period, a total of 191 BD patients were enrolled and split into valproate (VPA) + placebo and VPA + memantine (5mg/day) arms. The fasting plasma levels of high-sensitivity C-reactive protein (CRP) and metabolic indices were assessed. BD patients were stratified according to their initial CRP level. ResultsA cut-off value of initial CRP level of 2322ng/mL discriminated the waist circumference in these BD patients after 12-week VPA treatment. In the high CRP (> 2322ng/mL) group, patients in the VPA + memantine arm had a significantly decreased in their CRP (p= 0.009), total cholesterol (p= 0.002), LDL (p= 0.002) levels, BMI (p= 0.001), and waist circumference (p< 0.001), compared to those in the VPA + placebo arm. However, analysis of the low CRP group did not showed the effect. LimitationsWe recruited BD patients in depressed states and the sample size was relative small. The effects of the fixed dose of memantine on metabolic indices were 12-week follow up in BD patients treated with VPA. ConclusionsBD patients with high initial CRP levels receiving memantine adjunct treatment have a reduced risk of inflammation and metabolic imbalance. Prospective studies are needed to confirm the long-term outcome for memantine adjunct therapy in BD patients.

Change in employment status in bipolar disorder: a longitudinal study using national claims data.

To assess change in employment status in patients with bipolar disorder in comparison with non-mentally ill controls from 1 year before bipolar incidence to 10 years after. Sociodemographic factors of change in employment status were also examined for patients with bipolar disorder. A cohort of 502 patients with ICD-9-CM bipolar disorder was identified using claims data from the National Health Insurance Research Database of Taiwan between 1998 and 2001 and compared to non-mentally ill controls through December 31, 2008. The primary outcome measure was the time from bipolar incidence to the time of change in employment status, ie, from earning income to not earning income. The probability of changing to a non-income earner was significantly higher (P < .0001) in patients with bipolar disorder than in controls over time, even before the incidence of bipolar disorder (27% vs 14% for patients with bipolar disorder vs controls, respectively). Risks of occupational deterioration in patients with bipolar disorder were greater in the year before incidence and in the following year, with gradually decreasing risks over the subsequent 2 years, and comparable to controls from the third year onward. The adjusted hazard ratio of changing to a non-income earner was 2.06 (95% CI, 1.82-2.33) in patients with bipolar disorder. Male sex, ages 18 to 25 years, lower payroll bracket (< NT$50,001 [US $1,489]), and living in an urban area and insured area in the Northern region were associated with the risk of changing to a non-income earner in patients with bipolar disorder. Patients with bipolar disorder had poorer employment outcomes than the controls, with greater risks of occupational deterioration before and after the bipolar episodes. Employment status should be incorporated as a measure of functioning and of treatment and intervention effectiveness in clinical practices and research.

Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy.

Objective. To discuss the link between glycogen synthase kinase-3 (GSK3) and the main biological alterations demonstrated in bipolar disorder (BD), with special attention to the redox status and the evidence supporting the efficacy of lithium (a GSK3 inhibitor) in the treatment of BD. Methods. A literature research on the discussed topics, using Pubmed and Google Scholar, has been conducted. Moreover, a manual selection of interesting references from the identified articles has been performed. Results. The main biological alterations of BD, pertaining to inflammation, oxidative stress, membrane ion channels, and circadian system, seem to be intertwined. The dysfunction of the GSK3 signalling pathway is involved in all the aforementioned “biological causes” of BD. In a complex scenario, it can be seen as the common denominator linking them all. Lithium inhibition of GSK3 could, at least in part, explain its positive effect on these biological dysfunctions and its superiority in terms of clinical efficacy. Conclusions. Deepening the knowledge on the molecular bases of BD is fundamental to identifying the biochemical pathways that must be targeted in order to provide patients with increasingly effective therapeutic tools against an invalidating disorder such as BD.

A review on the impact of cognitive dysfunction on social, occupational, and general functional outcomes in bipolar disorder.

Bipolar disorder (BD) is associated with significant impairment in cognitive performance across multiple domains of function that often persist after clinical recovery. It remains unclear, however, as to whether this process is related to the clinical status of BD being depressed, manic/hypomanic, or euthymic. In this review, we examine the literature on the cross-sectional and longitudinal relationships between cognitive function and general function depending on the clinical phase of BD. A systematic review of original research that studied both cognitive function and general function in adults (18-60 years), restricted to BD, was conducted in a total of 18 studies meeting inclusion/exclusion criteria. Results show cross-sectional and prospective relationships between cognitive function and general function in patients with BD in both symptomatic and euthymic patients with BD. While studies using general measures of function (e.g., Global Assessment of Function scale) show more inconsistent associations with cognitive function, those employing assessments of domain specific function, suggest a consistent relationship between social and occupational function and cognitive performance. Executive function is commonly affected by cognitive deficits in these patients, but in addition a variety of domains show associations with functional outcomes (e.g., social function, occupational function). Notably, the emerging evidence suggests that cognitive function may be a better predictor of future general function than affective symptom severity. Despite some inconsistencies, in sum the literature on the relationship between cognitive function and general function in BD implicates both cross-sectional and longitudinal associations, both in symptomatic and euthymic patients with BD. And in terms of capturing these changes functional scales in particular domain-specific measures seem superior to general measures.

Affective temperaments and concomitant alcohol use disorders in bipolar disorder

BackgroundAlcohol misuse (AM) is more common in bipolar disorder (BD) than within the general population but the mechanisms of this association are unclear. We hypothesized that certain affective temperaments (including hyperthymic, cyclothymic, anxious, depressive and/or irritability) might represent ‘fundamental states’ contributing to risk of both AM and BD and we aimed to assess whether extremes of these five affective temperaments were associated with BD and concomitant AM status. MethodsOur sample comprised 1420 individuals with BD who were recruited into a clinical-genetic study conducted by the Bipolar Disorder Research Network. Phenotypic assessments, including evaluation for AM and the 32-item TEMPS-A questionnaire, were conducted. Binary logistic regression was used to determine the effect of TEMPS-A scores on the likelihood of concomitant AM, with adjustment for confounders. ResultsMean scores for four affective temperaments (hyperthymic, cyclothymic, depressive and irritable) were higher in cases (BD+AMs) than controls (BD only) (p<0.001). Hyperthymic and irritable temperaments in particular significantly increased the odds of concomitant AM within the BD sample after adjustment for potential confounders. LimitationsThe definition of AM was not directly based on formal diagnostic classification systems. A retrospective, cross-sectional design was used. Our findings may not generalize to other countries and cultures. ConclusionsHigher scores on measures of hyperthymic and irritable temperament may contribute to the association between AM and BD. Assessing affective temperaments early in the course of BD may help to predict the development of an AM problem in vulnerable individuals.

Openness predicts cognitive functioning in bipolar disorder

ObjectivesOpenness to experience (O) is a well-established personality factor and is associated with cognitive performance. Little is known about the personality-cognitive relationship in bipolar disorder, an illness with significant variability in mood. Cognitive evaluation is essential in psychopathology assessment as it may reflect underlying disease processes and psychosocial functional capacity. Screening using a proxy personality variable may identify those in need of comprehensive cognitive testing. We hypothesized that O and measures of cognition would associate in both the Bipolar Disorder (BD) and healthy control (HC) samples, whereas neuroticism and extraversion would correlate with cognition only in the BD sample. MethodsData from a longitudinal study of BD were used to study the association between personality factors and cognitive measures of attention, executive functioning, memory and fine motor skills. Regression analyses were used to determine the variables that account for the association between personality and cognition. ResultsAspects of O explained significant cognitive variance (~5%) in both groups; this persisted when demographic variables (including BD versus HC status) were considered. Neuroticism and extraversion did not consistently correlate with cognitive performance in either group. LimitationsThere were more females in the HC group who were slightly younger compared to the BD group. We lack direct measures of positive affect, and there is a reliance on a single measure of personality. ConclusionsBD Individuals scoring low on self-reported Openness are potential candidates for more comprehensive cognitive assessments (which represent a limited resource).

Thyroglobulin antibodies and risk of readmission at one year in subjects with bipolar disorder

Thyroid autoimmunity has been proposed as an endophenotype for Bipolar Disorder (BD), although its relationship with clinical outcomes remains unclear. We aimed to determine whether thyroid autoimmune status (thyroperoxidase antibodies [TPO-Abs] and thyroglobulin antibodies [TG-Abs]) in BD is associated with a greater risk for readmission at one year. We studied 77 inpatients with BD admitted for an index manic or mixed episode. Serum thyroid antibodies (TPO-Abs and TG-Abs) were determined at admission. We compared the readmission risk at 1 year, based on patients׳ thyroid autoimmunity profile using survival analyses. Cox regression was used to control covariates. TG-Abs+ but not TPO-Abs+ was associated with a lower risk of relapse. The Kaplan–Meier mean estimated survival times were 341.6 days (CI95% 316.4–366.8) for the TG-Abs+ group and 261.9 days (CI95%: 221.8 to 302.0) for the TG-Abs− group. Cox proportional hazards regression indicated that subjects with TG-Abs+ were 3.7 (1/OR=1/0.27) times less likely to get admitted during the follow-up period than those with TG-Abs−. Our study suggests that an autoimmune biomarker in patients with BD (i.e., the presence of TG-Abs) is associated with a lower risk of psychiatric readmission after an index hospitalization for a manic or mixed episode.

Deficit status in bipolar disorder: Investigation on prevalence rate and description of seven cases

While the Kraepelinian dichotomy explicitly distinguishes between schizophrenia and bipolar disorder, it remains unclear as to whether a deficit form of bipolar disorder exists. We conducted a study to investigate the prevalence rate of the deficit form of bipolar disorder; the criteria of which were basically adopted by the original proposal for schizophrenia that described the predominance of negative symptoms for over a year. Moreover, we presented a series of cases with "deficit" bipolar disorder to characterize its clinical pictures in detail. Consecutive outpatients who visited one psychiatric hospital in Tokyo, Japan in March 2007 were evaluated cross-sectionally. Additionally, medical charts of inpatients who were hospitalized in the same hospital between April 2006 and March 2007 were also thoroughly reviewed. Of 494 patients, 7 patients (1.4%; 10.9% of 64 bipolar cases) fulfilled the criteria for bipolar disorder with deficit syndrome. Seven "deficit" cases had a mean±SD age of 61±5 year-old with the age at onset being 25±8 year-old. In addition to pervasive negative symptoms, they exhibited evidence of cognitive impairments close to the magnitude of what is usually noted in schizophrenia (i.e. a mean±SD total IQ score of 80±9 in the Wechsler Adult Intelligence Scale and 0.4±0.5 in the Wisconsin Card Sorting Test, categories achieved). Although preliminary, the evidence on deficit status in patients with bipolar disorder that we found in this study appears more consistent with recent evidence and challenges the Kraepelinian dichotomy that reserves deficit status solely to schizophrenia patients.

Further understanding of the comorbidity between attention-deficit/hyperactivity disorder and bipolar disorder in adults: An MRI study of cortical thickness

Although Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BPD) frequently co-occur and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this comorbidity is scarce. Our aim was to evaluate cortical thickness in ADHD and BPD, testing the hypothesis that comorbid subjects (ADHD+BPD) would have neuroanatomical correlates of both disorders. Magnetic Resonance Imaging (MRI) findings were compared between 31 adults with ADHD+BPD, 18 with BPD, 26 with ADHD, and 23 healthy controls. Cortical thickness analysis of regions of interest was estimated as a function of ADHD and BPD status, using linear regression models. BPD was associated with significantly thicker cortices in 13 regions, independently of ADHD status and ADHD was associated with significantly thinner neocortical gray matter in 28 regions, independent of BPD. In the comorbid state of ADHD plus BPD, the profile of cortical abnormalities consisted of structures that are altered in both disorders individually. Results support the hypothesis that ADHD and BPD independently contribute to cortical thickness alterations of selective and distinct brain structures, and that the comorbid state represents a combinatory effect of the two. Attention to comorbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

Development and psychometric evaluation of the Bipolar Functional Status Questionnaire (BFSQ)

Persistently impaired psychosocial functioning has been recognized in many individuals with bipolar disorder. However, existing measures of functional disability have been adapted for use in bipolar disorder based mainly on those developed for use in other conditions. The present study involved the development and validation of a new patient self-report measure specific to bipolar disorder, the Bipolar Functional Status Questionnaire (BFSQ). Relevant constructs were identified, evaluated, and refined through an expert advisory panel in conjunction with patient interviews. Questionnaire items were vetted through iterative patient interviews. Psychometric properties were determined based on patient responses from implementation of the proposed 33-item questionnaire in an 11-site study of 596 patients with bipolar disorder across varied phases of illness. Eight constructs were identified as fundamental to functional status in bipolar disorder: cognitive function, sleep, role functioning, emotional functioning, energy/vitality, social functioning, personal management, and sexual functioning. Psychometric validation supported item reduction to a 24-item unidimensional scale, with high internal consistency (coefficient alpha's = 0.93-0.95), high test-retest reliability (intraclass correlation coefficient = 0.86, 95% confidence interval = 0.82-0.89), strong convergent validity with other functional disability measures (r's > 0.70), and highly significant discriminant validity across illness phases, with large effect sizes (Cohen's d > 0.70). The BFSQ is a psychometrically sound self-report measure that can be used to effectively quantify functional status across different clinical states in patients with bipolar disorder.

A prospective study of the impact of comorbid medical disease on bipolar disorder outcomes

Background Several studies suggest that medical comorbidity is associated with worse clinical status in bipolar disorder. It is unclear which aspect of medical comorbidity is responsible: simple disease count, risk for future morbidity, or current physical burden. Methods We analyzed three years of prospective data from a randomized clinical trial of collaborative care in 306 bipolar veterans. We examined the association of clinical outcome with baseline medical comorbidity defined as: (1) simple active disease count, (2) diseases with risk for future morbidity measured with the Charlson Comorbidity Index, and (3) current physical burden measured with the SF-36 Physical Component Summary score (PCS). Bipolar outcomes were weeks in episode, mean depression score, and change in mental health burden measured by the SF-36 Mental Component Summary score (MCS). Results The three medical comorbidity measures were not highly correlated, indicating that each conveyed novel information. Controlling for potential confounders, worse baseline PCS predicted significantly higher mean depression scores ( p = 0.011) and less improvement in MCS scores ( p = 0.0099) over three years. Simple disease count and risk for future risk did not predict worse bipolar outcomes. Limitations Some potential limitations include not accounting for all confounding factors, selection bias for participants, increased the likelihood of Type I error due to multiple comparisons and having a predominantly male population. Conclusions This long-term prospective study extends cross-sectional and retrospective research on the link between medical illness and bipolar outcomes. It is the current experience of burden of physical illness, rather than an unweighted or weighted disease count, that leads to worse bipolar outcomes.

An imbalance in the production of IL‐1β and IL‐6 by monocytes of bipolar patients: restoration by lithium treatment

To study the ex vivo interleukin (IL)-1beta and IL-6 production of monocytes in bipolar disorder (BD) patients in the absence/presence of lithium. Monocytes of outpatients with DSM-IV BD (n=80, of whom 64 were lithium-treated) and of healthy control subjects (n=59) were cultured in vitro and exposed (24 h) or not exposed to lipopolysaccharide (LPS) and/or graded concentrations of lithium chloride (LiCl). IL-1beta and IL-6 production was assessed by enzyme-linked immunosorbent assay (ELISA) (supernatants). Monocytes stimulated by LPS from non-lithium-treated bipolar patients were characterized by an abnormal IL-1beta/IL-6 production ratio, i.e., low IL-1beta and high IL-6 production. Lithium treatment increased IL-1beta and decreased IL-6 production and thus restored the aberrant ratio. In vitro exposure of monocytes to LiCl did not have the same effects as lithium treatment: the procedure decreased IL-1beta production and had minimal effects on IL-6 production. Blood monocytes have an altered proinflammatory status in BD. Lithium treatment restores this altered status. Short-term in vitro exposure of monocytes to lithium has other effects than lithium treatment.

Towards further understanding of the co-morbidity between attention deficit hyperactivity disorder and bipolar disorder: a MRI study of brain volumes

Although attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this co-morbidity is scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI) underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that subjects with this co-morbidity would have neuroanatomical correlates of both disorders. Morphometric MRI findings were compared between 31 adults with ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy controls. The volumes (cm(3)) of our regions of interest (ROIs) were estimated as a function of ADHD status, BPD status, age, sex, and omnibus brain volume using linear regression models. When BPD was associated with a significantly smaller orbital prefrontal cortex and larger right thalamus, this pattern was found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was associated with significantly less neocortical gray matter, less overall frontal lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects. Our results support the hypothesis that ADHD and BPD independently contribute to volumetric alterations of selective and distinct brain structures. In the co-morbid state of ADHD plus BPD, the profile of brain volumetric abnormalities consists of structures that are altered in both disorders individually. Attention to co-morbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins

To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 5' region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case-control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder..

Treatment with Lithium, Alone or in Combination with Olanzapine, Relieves Oxidative Stress but Increases Atherogenic Lipids in Bipolar Disorder

The changes in antioxidant-oxidant balance play important roles in the pathophysiology of neuropsychiatric conditions. Bipolar disorder (BD) is a psychiatric condition with recurrent mood disturbances. This study evaluates the effects of treatment with lithium, alone or in combination with antipsychotic olanzapine, on oxidant-antioxidant status and atherogenic character in patients with BD. The blood samples from 15 patients were tested before the treatment (pre-treatment phase) and at the ends of two consecutive treatment periods: period I, treatment with lithium and an antipsychotic drug, olanzapine (first 6 months) and period II, treatment with only lithium (6 months following period I). We measured serum atherogenic lipids (total cholesterol, triglycerides, and LDL-cholesterol), plasma lipid peroxides (thiobarbituric acid-reactive substances), antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) in neutrophils and lymphocytes, and total antioxidant status in plasma. Compared with pre-treatment phase, the lipid parameters were increased with each treatment; especially, LDL-cholesterol was significantly increased only with lithium treatment. These findings alert to be cautious about use of lithium in patients with atherogenic conditions. Moreover, plasma lipid peroxides were decreased significantly after the combination therapy and further decreased with lithium treatment. Antioxidant enzyme activities in lymphocytes were decreased after both types of treatment. Importantly, plasma total antioxidant status was increased only with lithium treatment. Thus, treatment with lithium alone decreases already up-set oxidant status in BD. In conclusion, the combination therapy with olanzapine is better in terms of atherogenic profile, while lithium alone produces better antioxidant status in patients with BD.

Seasonal changes in clinical status in bipolar disorder: a prospective study in 1000 STEP‐BD patients

To investigate seasonal and regional effects on bipolar I and II patients. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) patients were prospectively examined for monthly change in prevalence rates of depressed and recovered clinical status over the year. General Estimating Equation modeling was used to assess the effect of season on prevalence rates. Additionally, patients were stratified by bipolar subtype and by region. A significantly higher prevalence rate of depression is observed in the northern sites, a significant prevalence by month effect is found only in the bipolar II patients. The prevalence of depression is greater in patients from the northern vs. southern STEP-BD sites. Seasonal peak prevalence rates of depression differ by region. Bipolar II patients were more ill year-round and demonstrated greater monthly fluctuation in prevalence rates of being ill than did bipolar I patients. We conclude that seasonal effects upon bipolar patients vary by region and bipolar subtype.