Using structural MRI to identify individuals at genetic risk for bipolar disorders: a 2-cohort,machine learning study

Background

Brain imaging is of limited diagnostic use in psychiatry owing to clinical heterogeneity and low sensitivity/specificity of between-group neuroimaging differences. Machine learning (ML) may better translate neuroimaging to the level of individual participants. Studying unaffected offspring of parents with bipolar disorders (BD) decreases clinical heterogeneity and thus increases sensitivity for detection of biomarkers. The present study used ML to identify individuals at genetic high risk (HR) for BD based on brain structure.

Methods

We studied unaffected and affected relatives of BD probands recruited from 2 sites (Halifax, Canada, and Prague, Czech Republic). Each participant was individually matched by age and sex to controls without personal or family history of psychiatric disorders. We applied support vector machines (SVM) and Gaussian process classifiers (GPC) to structural MRI.

Results

We included 45 unaffected and 36 affected relatives of BD probands matched by age and sex on an individual basis to healthy controls. The SVM of white matter distinguished unaffected HR from control participants (accuracy = 68.9%, p = 0.001), with similar accuracy for the GPC (65.6%, p = 0.002) or when analyzing data from each site separately. Differentiation of the more clinically heterogeneous affected familiar group from healthy controls was less accurate (accuracy = 59.7%, p = 0.05). Machine learning applied to grey matter did not distinguish either the unaffected HR or affected familial groups from controls. The regions that most contributed to between-group discrimination included white matter of the inferior/middle frontal gyrus, inferior/middle temporal gyrus and precuneus.

Limitations

Although we recruited 126 participants, ML benefits from even larger samples.

Conclusions

Machine learning applied to white but not grey matter distinguished unaffected participants at high and low genetic risk for BD based on regions previously implicated in the pathophysiology of BD.     

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

Background

Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples.

Methods

The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting.

Results

Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples.

Limitations

Oligodendrocytes were identified using morphological criteria.

Conclusion

This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons.     

Subjective Cognitive Complaints and Functional Disability in Patients With Borderline Personality Disorder and Their Nonaffected First-Degree Relatives

Objective:

To examine the contributions of subjective cognitive complaints to functional disability in patients with borderline personality disorder (BPD) and their nonaffected relatives.

Method:

Patients with BPD (n = 26), their first-degree biological relatives (n = 17), and nonpsychiatric control subjects (n = 31) completed a self-report measure of cognitive difficulties and rated the severity of their functional disability on the World Health Organization Disability Assessment Schedule 2.0.

Results:

After accounting for group differences in age and severity of depressive symptoms, patients and relatives endorsed more inattention and memory problems than control subjects. Whereas probands reported greater disability than relatives and control subjects across all functional domains, relatives described more difficulties than control subjects in managing multiple life activities, including domestic activities and occupational and academic functioning, and participating in society. For both probands and relatives, inattention and memory problems were linked primarily to difficulties with life activities, independent of depression and other comorbid psychiatric disorders.

Conclusions:

Problems with inattention and forgetfulness may lead to difficulties carrying out activities of daily living and occupational or academic problems in patients with BPD, as well as their nonaffected first-degree relatives.     

Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders

Background

Brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (trkB-TK+) and glutamic acid decarboxylase (GAD₆₇) mRNA levels have previously been found to be reduced in the prefrontal cortex of patients with schizophrenia. To determine whether this reduction extends to other brain regions, we measured the expression levels of BDNF, trkB-TK+ and GAD₆₇ mRNA in regions of the hippocampus, including the dentate gyrus (DG), cornu ammonis subfields (CA1–4), subiculum and entorhinal cortex (EC) of individuals with schizophrenia, bipolar disorder, major depression and unaffected controls.

Methods

In situ hybridization was performed on postmortem brain tissue obtained from the Stanley Foundation Consortium and analyzed using film-based quantification.

Results

Analyses of covariance comparing the expression of mRNA among all groups revealed a significant decrease in BDNF mRNA in CA4 in the bipolar disorder group compared with controls (33%). We found trkB-TK+ mRNA levels to be significantly reduced in CA4 in the schizophrenia group (36%) and in layer II of the EC in the bipolar disorder and major depression groups (28%, 21%, respectively) compared with controls. In addition, GAD₆₇ mRNA levels were reduced in patients with schizophrenia in both the DG (23%) and CA4 (60%) compared with controls. Individuals with major depression also expressed significantly less GAD₆₇ mRNA (44%) compared with controls in CA4 of the hippocampus.

Limitations

It is necessary to account for factors that influence the molecular preservation in postmortem brain tissue, including pH, postmortem interval and tissue storage time. Moreover, there are limitations to the sensitivity of the film-based method of quantification.

Conclusion

Our findings show abnormal BDNF, trkB-TK+ and GAD₆₇ mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders, indicating that fundamental properties of hippocampal signalling transmission, plasticity and circuitry may be affected in individuals with these major mental illnesses.     

Verbal and Visual Memory Impairments in Bipolar I and II Disorder

Objective

To compare verbal and visual memory performances between patients with bipolar I disorder (BD I) and patients with bipolar II disorder (BD II) and to determine whether memory deficits were mediated by impaired organizational strategies.

Methods

Performances on the Korean-California Verbal Learning Test (K-CVLT) and the Rey-Osterrieth Complex Figure Test (ROCF) in 37 patients with BD I, 46 patients with BD II and 42 healthy subjects were compared. Mediating effects of impaired organization strategies on poor delayed recall was tested by comparing direct and mediated models using multiple regression analysis.

Results

Both patients groups recalled fewer words and figure components and showed lower Semantic Clustering compared to controls. Verbal memory impairment was partly mediated by difficulties in Semantic Clustering in both subtypes, whereas the mediating effect of Organization deficit on the visual memory impairment was present only in BD I. In all mediated models, group differences in delayed recall remained significant.

Conclusion

Our findings suggest that memory impairment may be one of the fundamental cognitive deficits in bipolar disorders and that executive dysfunctions can exert an additional influence on memory impairments.     

ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype

Background

Apolipoprotein E (apoE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between apoE and cholesterol levels and the APOE genotype.

Methods

We obtained dorsolateral prefrontal grey and white matter from the Stanley Medical Research Institute Brain Collection (schizophrenia n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were quantified using high-pressure liquid chromatography, whereas apoE was measured by enzyme-linked immunosorbent assay.

Results

We found no significant differences in cholesterol or apoE levels among the groups. ApoE levels were higher in grey matter than in white matter in all groups; conversely, levels of cholesterol were higher in white matter than in grey matter. We observed a significant inverse correlation between apoE and cholesterol levels in both grey and white matter. Furthermore, in grey matter, apoE levels were significantly higher in APOE ɛ2 carriers compared with APOE ɛ3 or APOE ɛ4 carriers, with cholesterol levels following the opposite trend.

Limitations

Limitations of our study include our inability to control for potential confounding variables and the small numbers of APOE ɛ2 and ɛ4 carriers in each group.

Conclusion

Although large amounts of cholesterol are present in white matter, apoE expression is limited. The APOE genotype may play a role in the regulation of both cholesterol and apoE levels in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people with psychiatric disorders warrants further investigation.     

Association between the BDNF Val66Met Polymorphism and Chronicity of Depression

Objective

Both clinical and biological factors influence the course of depressive disorders. This study tested for associations between the brain-derived neurotrophic factor (BDNF) gene at the Val66Met locus and the course of major depressive disorder (MDD).

Methods

Three hundred ten Korean subjects (209 patients, 101 controls) were genotyped for rs6265 at nucleotide 196 (G/A), which produces an amino acid substitution at codon 66 (Val66Met) of the gene for BDNF. Course of illness was evaluated both by chronicity of current episode (episode duration >24 months) and by the lifetime history of recurrences.

Results

Patients with the Met/Met BDNF genotype had a significantly higher rate of chronic depression than all others. There was a significant dose effect of the Met allele on chronicity. Compared with the Val/Val genotype, the relative risk of chronicity was 1.67 for the Val/Met genotype, and 2.58 for the Met/Met genotype. Lifetime history of recurrent episodes was not related to BDNF genotypes but was significantly associated with younger age of onset and with a history of depression in first degree relatives.

Conclusion

BDNF genotyping may be informative for anticipating chronicity in major depression.     

Corpus callosum area in patients with bipolar disorder with and without psychotic features: an international multicentre study

Background

Previous studies have reported MRI abnormalities of the corpus callosum (CC) in patients with bipolar disorder (BD), although only a few studies have directly compared callosal areas in psychotic versus nonpsychotic patients with this disorder. We sought to compare regional callosal areas in a large international multicentre sample of patients with BD and healthy controls.

Methods

We analyzed anatomic T₁ MRI data of patients with BD-I and healthy controls recruited from 4 sites (France, Germany, Ireland and the United States). We obtained the mid-sagittal areas of 7 CC subregions using an automatic CC delineation. Differences in regional callosal areas between patients and controls were compared using linear mixed models (adjusting for age, sex, handedness, brain volume, history of alcohol abuse/dependence, lithium or antipsychotic medication status, symptomatic status and site) and multiple comparisons correction. We also compared regional areas of the CC between patients with BD with and without a history of psychotic features.

Results

We included 172 patients and 146 controls in our study. Patients with BD had smaller adjusted mid-sagittal CC areas than controls along the posterior body, the isthmus and the splenium of the CC. Patients with a positive history of psychotic features had greater adjusted area of the rostral CC region than those without a history of psychotic features.

Limitations

We found small to medium effect sizes, and there was no calibration technique among the sites.

Conclusion

Our results suggest that BD with psychosis is associated with a different pattern of interhemispheric connectivity than BD without psychosis and could be considered a relevant neuroimaging subtype of BD.     

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

Background

In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its patho-physiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed.

Methods

We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar disorder type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system.

Results

The mean interleukin (IL)-1β level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respectively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10).

Limitations

All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out.

Conclusion

Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1β in bipolar disorder.     

Osteoprotegerin levels in patients with severe mental disorders

Background

Severe mental disorders are associated with elevated levels of inflammatory markers. In the present study, we investigated whether osteoprotegerin (OPG), a member of the tumour necrosis factor receptor family involved in calcification and inflammation, is elevated in patients with severe mental disorders.

Methods

We measured the plasma levels of OPG in patients with severe mental disorders (n = 312; 125 with bipolar disorder and 187 with schizophrenia) and healthy volunteers (n = 239).

Results

The mean plasma levels of OPG were significantly higher in patients than in controls (t₅₃₁ = 2.6, p = 0.01), with the same pattern in bipolar disorder and schizophrenia. The increase was significant after adjustment for possible confounding variables, including age, sex, ethnic background, alcohol consumption, liver and kidney function, diabetes, cardiovascular disease, autoimmune diseases and levels of cholesterol, glucose and C-reactive protein.

Limitations

Owing to the cross-sectional design, it is difficult to determine causality.

Conclusion

Our results indicate that elevated OPG levels are associated with severe mental disorders and suggest that mechanisms related to calcification and inflammation may play a role in disease development.     

A comparison of affected and unaffected relatives of patients with bipolar disorder using proton magnetic resonance spectroscopy

Objective

Bipolar disorders have a strong genetic underpinning. Little is known about biological predispositions that convey vulnerability for the illness. We searched for biological vulnerability markers using proton magnetic resonance spectroscopy (MRS) in both affected and unaffected participants at high genetic risk for bipolar disorder.

Methods

We recruited high-risk participants aged 15–30 years from families in which multiple members were affected with bipolar disorder. Our primary sample included 14 affected and 15 unaffected relatives of probands with bipolar I disorder. Our extended sample comprised 19 affected and 21 unaffected participants with a family history of either bipolar I or bipolar II disorders. We matched both samples by age and sex with 31 control participants without a personal or family history of psychiatric disorders. We performed single voxel proton MRS at 1.5 T in bilateral dorsal and ventral medial prefrontal cortices with correction for grey matter proportion.

Results

We found comparable levels of choline, creatine, myo-inositol and N-acetylaspartate among the groups in both samples. There were no differences between regions of the medial prefrontal cortex or between hemispheres for any of the metabolites in any of the samples. The exclusion of 5 participants taking medication did not change our results.

Conclusion

Neurochemical changes in the medial prefrontal cortex that are measurable using proton MRS do not appear to be antecedent to the onset of mood disorders in genetically susceptible individuals.Medical subject headings: magnetic resonance spectroscopy, bipolar disorders     

Microstructural Changes of Anterior Corona Radiata in Bipolar Depression

Objective

In bipolar disorder, dysregulation of mood may result from white matter abnormalities that change fiber tract length and fiber density. There are few studies evaluating the white matter microstructural changes in bipolar I patients (BD) with depressive episodes. The present study aimed to evaluate anterior corona radiata in BD patients with depressive episode using Diffusion Tensor Imaging (DTI).

Methods

Twenty-one patients with bipolar depression and 19 healthy controls were investigated and groups were matched for age and gender. Diffusion-weighted echoplanar brain images (DW-EPI) were obtained using a 1.5 T MRI scanner. Regions of interest (ROIs) were manually placed on directional maps based on principal anisotropy. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of white matter were measured in the anterior corona radiata (ACR) bilaterally by diffusion tensor imaging.

Results

There was not a significant difference between groups of age and gender (p>0.05). Significantly lower FA was observed in bilateral ACR in bipolar patients with depression compared with healthy individuals. And there is significantly higher ADC values in the left frontal corona radiate in bipolar patients.

Conclusion

White matter abnormalities can be detected in patients with BD using DTI. The neuropathology of these abnormalities is unclear, but neuronal and axonal loss, myelin abnormalities and reduced white matter fiber density are likely to be relevant.     

Serum brain-derived neurotrophic factor and peripheral indicators of the serotonin system in underweight and weight-recovered adolescent girls and women with anorexia nervosa

Background

Brain-derived neurotrophic factor (BDNF) mutant mice show hyperphagia and hyperleptinemia. Animal and cell-culture experiments suggest multiple interrelations between BDNF and the serotonin (5-HT) system. We studied serum BDNF in patients with anorexia nervosa and its associations with peripheral indicators of the 5-HT system. To control for secondary effects of acute malnutrition, we assessed acutely underweight patients with anorexia nervosa (acAN) in comparison to long-term weight-recovered patients with the disorder (recAN) and healthy controls.

Methods

We determined serum BDNF, platelet 5-HT content and platelet 5-HT uptake in 33 patients in the acAN group, 20 patients in the recAN group and 33 controls. Plasma leptin served as an indicator of malnutrition.

Results

Patients in the acAN group were aged 14–29 years and had a mean body mass index (BMI) of 14.9 (standard deviation [SD] 1.4) kg/m². Those in the recAN group were aged 15–29 years and had a mean BMI of 20.5 (SD 1.3) kg/m² and the controls were aged 15–26 years and had a BMI of 21.4 (SD 2.1) kg/m². The mean serum BDNF levels were significantly increased in the recAN group compared with the acAN group (8820, SD 3074 v. 6161, SD 2885 pg/mL, U = 154.5, p = 0.001). There were no significant associations between BDNF and either platelet 5-HT content or platelet 5-HT uptake. Among patients with anorexia nervosa, we found significant positive linear relations between BDNF and BMI (r = 0.312, p = 0.023) and between BDNF and leptin (r = 0.365, p = 0.016).

Limitations

We measured the signal proteins under study in peripheral blood.

Conclusion

Serum BDNF levels in patients with anorexia nervosa depend on the state of illness and the degree of hypoleptinemia. Upregulation of BDNF in weight-recovered patients with anorexia nervosa could be part of a regenerative process after biochemical and molecular neuronal injury due to prolonged malnutrition. Associations between the BDNF and the 5-HT system in humans remain to be established.     

A Longitudinal Study of BDNF Promoter Methylation and Depression in Breast Cancer

Objective

Brain-derived neurotrophic factor (BDNF) is investigated in depression related to medical disorders and its secretion is influenced by epigenetic factors. We investigated the association between BDNF promoter methylation and depression following mastectomy for breast cancer.

Methods

In total, 309 patients with breast cancer were evaluated 1 week after mastectomy, and 244 (79%) were followed up 1 year later. Depression was diagnosed (major or minor depressive disorder) according to DSM-IV criteria and depression severity was estimated by Montgomery-Asberg Depression Rating Scale (MADRS). We assessed BDNF promoter methylation using leukocyte DNA. The effects of BDNF methylation on depression diagnosis and severity were investigated using multivariate logistic and linear regression models, respectively. The two-way interaction between BDNF methylation and the val66met polymorphism on depression was also evaluated using multivariate logistic regression models.

Results

Higher BDNF methylation was independently associated with depression diagnosis and with more severe symptoms at both 1 week and 1 year after mastectomy. No significant methylation-genotype interactions were found.

Conclusion

A role for BDNF in depression related to breast cancer was supported. Indeed, the association between depression and BDNF methylation may be useful for identifying patients who are at high risk for depression and for suggesting directions for promising drug research.     

Epigenetic Regulation in the Brain after Spinal Cord Injury : A Comparative Study

Objective

After spinal cord injury (SCI), functional and structural reorganization occurs at multiple levels of brain including motor cortex. However, the underlying mechanism still remains unclear. The current study was performed to investigate the alterations in the expression of the main regulators of neuronal development, survival and death, in the brain following thoracic contusive SCI in a mouse model.

Methods

Eight-week-old female imprinting control region mice (n=60; 30-35 g) were used in this study. We analyzed the expression levels of regulators such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and histone deacetylase (HDAC) 1 in the brain following thoracic contusive SCI.

Results

The expression of BDNF levels were elevated significantly compared with control group at 2 weeks after injury (p<0.05). The expression of NGF levels were elevated at 2, 4 weeks compared with control group, but these difference were not significant (p>0.05). The GDNF levels were elevated at 2 week compared with control group, but these differences were not significant (p>0.05). The difference of HDAC1 levels were not significant at 2, 4 and 8 weeks compared with control group (p>0.05).

Conclusion

These results demonstrate that the upregulation of BDNF may play on important role in brain reorganization after SCI.     

Decreased Serum Brain-Derived Neurotrophic Factor Levels in Elderly Korean with Dementia

Objective

The primary purpose of this study was to investigate the differences in the serum brain-derived neurotrophic factor (BDNF) level between elderly Korean people over 65 years with and without dementia.

Methods

171 individuals over 65 years were enrolled in this study. Screening for cognitive impairments was carried out using the Mini-Mental Status Examination-Korean version (MMSE-KC). One hundred thirty-two subjects scored below 1.5 standard deviations (SD) of the mean MMSE-KC score, and these were evaluated using the Consortium to Establish a Registry for Alzheimer''s Disease, Korean version (CERAD-K) and the Geriatric Depression Scale (GDS). The Clinical Dementia Rating Scale (CDRS) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria were used for further evaluation. Subjects with a CDRS score of 1 or higher were classified as having Alzheimer''s disease (AD), and subjects with a CDRS score of 0.5 were classified as having a mild cognitive impairment (MCI). Subjects with a CDRS score of 0 were classified as having aging-associated cognitive decline (AACD). Serum BDNF levels were analyzed using the enzyme-linked immunosorbent assay (ELISA) method.

Results

The serum BDNF levels were significantly lower in the subjects with MCI and AD compared with the healthy controls (p<0.01). A significant correlation was found between the total MMSE-KC score and serum BDNF level (r=0.295; p<0.01). However, no significant correlation was observed between the severity of MMSE-KC and the total GDS score. A significant difference was found in the total score of GDS between the AACD group and subjects with AD (p<0.05).

Conclusion

This study suggested that BDNF might be involved in the pathophysiology of cognitive decline in elderly people.     

Prevalence of Bipolar I and II Disorder in Canada

Objective:

Current epidemiologic knowledge about bipolar disorder (BD) in Canada is inadequate. To date, only 3 prevalence studies have been conducted: only 1 was based on a national sample, and none distinguished between BD I and II. The objective of this study was to estimate the prevalence of BD I and II in Canada in 2012.

Method:

Data were obtained from the 2012 Canadian Community Health Survey: Mental Health and Well-being, a cross-sectional survey of a nationally representative sample of household residents ages 15 years and older (n = 25 113). The survey response rate was 68.9%. Interviews were based on the World Health Organization Composite International Diagnostic Interview (CIDI). Prevalence was estimated using generalized linear modelling. Prevalence of self-reported diagnosis of BD and use of lithium were also estimated.

Results:

The estimated lifetime prevalence of BD I and II (based on the CIDI) in Canada in 2012 was 0.87% (95% CI 0.67% to 1.07%) and 0.57% (95% CI 0.44% to 0.71%), respectively. Prevalence did not differ by sex. The estimated prevalence of self-reported BD was 0.87% (95% CI 0.65% to 1.07%). There was a lack of congruence between CIDI-defined and self-reported BD, and few people taking lithium were positive for BD on the CIDI, which raises some concerns about the validity of the CIDI’s assessment of BD.

Conclusions:

These prevalence estimates align with those reported in prior literature. However, caution should be exercised when interpreting general population studies that use CIDI-defined BD owing to the possibility of misclassification.     

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia

Background

Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized.

Methods

Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls.

Results

We found increased oxidation of DAT-immunoreactive regions in patients with BD (F_3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of TH-immunoreactive regions in both patients with BD (F_3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F_3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F_3,46 = 1.75; p = 0.17).

Limitations

Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem interval and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis.

Conclusion

These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD.     

Toward a Comprehensive Clinical Staging Model for Bipolar Disorder: Integrating the Evidence

Objectives

To describe key findings relating to the natural history and heterogeneity of bipolar disorder (BD) relevant to the development of a unitary clinical staging model. Currently proposed staging models are briefly discussed, highlighting complementary findings, and a comprehensive staging model of BD is proposed integrating the relevant evidence.

Method:

A selective review of key published findings addressing the natural history, heterogeneity, and clinical staging models of BD are discussed.

Results:

The concept of BD has broadened, resulting in an increased spectrum of disorders subsumed under this diagnostic category. Different staging models for BD have been proposed based on the early psychosis literature, studies of patients with established BD, and prospective studies of the offspring of parents with BD. The overarching finding is that there are identifiable sequential clinical phases in the development of BD that differ in important ways between classical episodic and psychotic spectrum subtypes. In addition, in the context of familial risk, early risk syndromes add important predictive value and inform the staging model for BD.

Conclusions:

A comprehensive clinical staging model of BD can be derived from the available evidence and should consider the natural history of BD and the heterogeneity of subtypes. This model will advance both early intervention efforts and neurobiological research.