State-related functional specialization of visual regions in bipolar disorder across different mood states.

Bipolar disorder is a common condition diagnosed by the occurrence of pathological mood elevation but most often dominated by dysphoria states. Over the past 10 years, understanding of bipolar disorder and the number of evidence-based treatments have increased dramatically. This article offers strategies for improving diagnostic confidence and simple benchmarks that facilitate integrating principles of evidence-based medicine into the management of patients with bipolar disorder. Simple systematic assessment techniques such as focusing the evaluation to assess the most extreme episode of mood elevation and longitudinal factors such as age of onset and course of illness can avoid errors of omission and raise diagnostic confidence. An iterative measurement-based treatment model that aims to bring patients and their supports into the collaborative care process for progressively better outcomes is recommended.

Bipolar Disorder: Imaging State Versus Trait

Clinical Characteristics and Health Service Use of Veterans With Comorbid Bipolar Disorder and PTSD

Brain functional specialization in obsessive-compulsive disorder associated with neurotransmitter profiles

The empathic abilities have never been examined in bipolar disorder patients, despite frequent observations of impaired social behavior. To examine the neuropsychological processes that underlie the affective and cognitive empathic ability in bipolar disorder, the authors compared affective and cognitive empathic abilities, as well as theory of mind and executive functions, of euthymic bipolar disorder patients and healthy comparison subjects. Significant deficits in cognitive empathy and theory of mind were observed, while affective empathy was elevated in bipolar disorder. Patients showed impaired cognitive flexibility (shifting and reversal learning) but intact planning behavior. Impaired cognitive empathy was related with performance in neurocognitive tasks of cognitive flexibility, suggesting that prefrontal cortical dysfunction may account for impaired cognitive empathy in bipolar disorder.

Repetitive transcranial magnetic stimulation (rTMS) represents a potential clinical tool in treating bipolar disorder (BD). However, the intervention of rTMS combined with pharmacotherapy on the plasma fatty acids (FAs) in patients with bipolar depression has not been reported yet. In this study, we assessed the clinical symptoms and evaluated plasma FAs from 30 inpatients with bipolar depression at baseline phase (BD group), after 2 weeks of treatment with rTMS combined with quetiapine and mood stabilizer (BD-2w group), and 32 healthy controls (HCs). We found that acetic acid, propionic acid, isovaleric acid, isobutyric acid, and valeric acid, as well as levels of total short-chain fatty acids (SCFAs), were decreased in both BD and BD-2w groups, and levels of several medium- and long-chain fatty acids (MLCFAs) were altered in BD when compared with HC. Moreover, 2 weeks of treatment increased the levels of various MLCFAs. Finally, we developed combinational FAs panels that could distinguish BD from HC (area under the curve [AUC] = 0.961), BD-2w from HC (AUC = 0.978), and BD from BD-2w (AUC = 0.891) effectively. These findings might provide a basis for developing diagnostic methods and reveal the potential relationship between bipolar depression and plasma FAs.

Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3-nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation [lipid hydroperoxides (LPH), 8-isoprostane (8-Iso), 4-hydroxy-2-nonenal (4-HNE)] were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3-nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8-Iso was found increased in the BD group while 4-HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins. Oxidative stress has been shown to be higher in the brain of patients with bipolar disorder (BD). Here, we demonstrated increased levels of protein oxidation in synaptosomes from postmortem prefrontal cortex from patients from BD group, while 3-nitrotyrosine was increased in mitochondria from BD and schizophrenia (SCZ) groups. Moreover, lipid peroxidation was found increased in the BD when compared with controls; suggesting that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.

Decreased left brain specialization in bipolar disorder patients and its association with neurotransmitter and genetic profiles: A longitudinal study.

Depression in the context of bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatment and poor clinical outcomes. However, little is known about the similarities and differences in interhemispheric functional connectivity between BD and UD. Patients with bipolar II disorder (n=36) and UD (n=32) during a depressive episode as well as 40 healthy controls underwent resting-state functional magnetic resonance imaging. The functional connectivity between any pair of symmetric interhemispheric voxels (i.e., functional homotopy) was measured by voxel-mirrored homotopic connectivity (VMHC). The three groups showed significant VMHC differences in the posterior cingulate cortex (PCC), fusiform and lingual gyrus, anterior lobe of the cerebellum (CeAL), and posterior lobe of the cerebellum (CePL). In the BD group, the VMHC decreases in the fusiform/lingual gyrus, CeAL, and CePL were shown relative to controls. In the UD group, the VMHC decreases in the PCC, fusiform/lingual gyrus, and CePL were shown relative to controls. No regions of increased VMHC were detected in either patient group. There was no significant difference in the VMHC values in any brain region between the BD group and the UD group. Depressive episodes in BD and UD have similar impairments of interhemispheric coordination, which might imply an overlap in the neuropathology of depression.

Omega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids. This observational, parallel group study compared biomarkers between HCs (n = 31) and symptomatic subjects with BD (n = 27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis. UE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d = 0.86, p < 0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p < 0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p < 0.0001). At follow-up in the BD group, UE, E DHA:ALA, and UE EPA:ALA were decreased (p < 0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class. A large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake.

Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder

Positron Emission Tomography Quantification of Serotonin-1A Receptor Binding in Medication-Free Bipolar Depression

Daily mood monitoring of symptoms using smartphones in bipolar disorder: A pilot study assessing the feasibility of ecological momentary assessment

BackgroundStriatum is a key node in reward circuit and aberrant striatal functional connectivity (FC) underlies the pathophysiology of bipolar disorder (BD) (Dandash et al., 2018, Karcher et al., 2019) (Teng et al., 2013) (Altinay et al., 2016). However, it is unknown how striatal FC abnormalities are related to the disorder itself (trait effects) or to manic/hypomanic and depressive states (state effects), and whether dimensional functional abnormalities of the striatum would be a critical mechanism underlying the symptomatology of BD across mood states, particularly both emotional symptoms and cognitive performance.Aims & ObjectivesWe primarily aimed to investigate striatal FC abnormalities in BD in different mood states, with secondary analyses examining associations among striatal connectivity, emotional symptoms and cognitive performance.MethodNinety-three bipolar subjects: 31 manic/hypomanic (BDM), 31 depressed (BDD) and 31 euthymic (BDE) and 32 healthy controls (HCs) underwent structural and resting-state functional MRI and completed the Wisconsin card sorting test (WCST) and continuous performance test (CPT). Bipolar subjects were assessed using the 17-item Hamilton Rating Scale for Depression, Young Mania Rating Scale and Positive and Negative Affect Schedule. First, striatal subregion FC was compared between patients with BD in different mood states and HCs. Second, a multivariate data-driven approach, partial least squares (PLS) analysis, was used to explore dimensional associations between striatal connectivity and the symptomatology (i.e., emotional and cognitive profile) in bipolar subjects. Finally, a post-hoc analysis was conducted to compare the striatal FC scores and behavioral scores (which represent the association between FC and the symptomatology) among subjects in different mood states.ResultsThe inferior and superior ventral striatum and ventral rostral putamen (VRP) seed showed significant FC with dorsolateral frontal cortex, caudate, angular and thalamus among four groups. Compared to HCs, the FC between the bilateral VRP and the right ventrolateral thalamus was increased in all bipolar subgroups. Compared to BDD and BDE subjects, BDM subjects showed higher FC in bilateral VSs-dorsolateral prefrontal cortex, left VSs-right caudate, and right VRP-left angular. A distinctive striatal connectivity pattern was found in BD, which was positively associated with manic symptom, positive affect, percentage of error, perseverative and non-perseverative error responses in WCST, and total error responses in CPT. Post hoc analysis revealed that BDM had the highest scores and BDD had the lowest scores in both striatal FC and behavioral scores.Discussion & ConclusionTrait- and state- related striatal FC changes are present in BD. A dimensional FC abnormality in striatal subregions was found to be scaled with symptomatology across mood states, and a categorical difference was found among bipolar subgroups in composite variables that represent the association between FC and the symptomatology. These findings lay an emphasis on the dominated role of the striatum in the psychopathology of BD and provide evidence that mood instability and cognitive deficits in BD may be associated with aberrant striatal functional connectivity (Pacifico and Davis, 2017, Ashok et al., 2017).ReferencesDANDASH, O., YUCEL, M., DAGLAS, R., PANTELIS, C., MCGORRY, P., BERK, M. &FORNITO, A. 2018. Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania. Transl Psychiatry, 8, 59.KARCHER, N. R., ROGERS, B. P. &WOODWARD, N. D. 2019. Functional Connectivity of the Striatum in Schizophrenia and Psychotic Bipolar Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging, 4, 956-965.TENG, S., LU, C. F., WANG, P. S., HUNG, C. I., LI, C. T., TU, P. C., SU, T. P. &WU, Y. T. 2013. Classification of bipolar disorder using basal-ganglia-related functional connectivity in the resting state. Annu Int Conf IEEE Eng Med Biol Soc, 2013, 1057-60.ALTINAY, M. I., HULVERSHORN, L. A., KARNE, H., BEALL, E. B. &ANAND, A. 2016. Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania. Brain Connect, 6, 255-65.PACIFICO, R. &DAVIS, R. L. 2017. Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Mol Psychiatry, 22, 441-449.ASHOK, A. H., MARQUES, T. R., JAUHAR, S., NOUR, M. M., GOODWIN, G. M., YOUNG, A. H. &HOWES, O. D. 2017. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Molecular psychiatry, 22, 666-679.

Activity of the paraoxonase 1 (PON1) enzyme varies prominently according to the PON1 Q192R genotype. The arginine (R) genotype hydrolyzes peroxided lipids more quickly and efficiently than the glutamine (Q) genotype. The Q phenotype suggests greater liability to neurodegenerative processes, cardiovascular and malignancy risks than the R phenotype. Stimulated PON/ARES ratio is associated with the PON1 Q192R polymorphism. This study aimes to assess the Q192R phenotype in schizophrenia, bipolar disorder and depression. Patients with schizophrenia (37), bipolar disorder (n=50), depression (n=43) and healthy volunteers (n=43) were enrolled. Serum PON1, stimulated paraoxonase (sPON) and aryl esterase (ARES) levels were assessed with an automatic analyzer. Clusters of sPON/ARES ratio were detected with frequency analysis in PON1. QQ, QR and RR variant groups. There were significant differences between the bipolar disorder, depression, schizophrenia and healthy volunteer groups in terms of phenotype frequencies in groups (Fisher's Exact Coefficient=18.96, p=0.003). A higher prevalence of the PON1 RR variant was found in bipolar disorder whereas the PON1 QQ variant had a higher prevalence in depression and schizophrenia as compared to others. Serum PON1 activity correlated with number of episodes in the bipolar disorder group and with SANS, SAPS scores in the schizophrenia group. Difference between bipolar disorder, schizophrenia and depression in PON1 activity and PON1 phenotype might be suggestive of different liability to lipid peroxidation and neurodegeneration between the diagnostic groups. Longitudinal studies may identify long term differences between PON1 Q192R polymorphisms in clinical outcomes and neuropathology.