Bcl-2 rs956572 Polymorphism is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder

B-cell lymphoma 2 (Bcl-2) is an important regulator of cellular plasticity and resilience. In bipolar disorder (BD), studies have shown a key role for a Bcl-2 gene single-nucleotide polymorphism (SNP) rs956572 in the regulation of intracellular calcium (Ca²⁺) dynamics, Bcl-2 expression/levels, and vulnerability to cellular apoptosis. At the same time, Bcl-2 decreases glutamate (Glu) toxicity in neural cells. Abnormalities in Glu function have been implicated in BD. In magnetic resonance spectroscopy (MRS) studies, anterior cingulated cortex (ACC) Glu levels have been reported to be increased in bipolar depression and mania, but no study specifically evaluated ACC Glu levels in BD-euthymia. Here, we compared ACC Glu levels in BD-euthymia compared with healthy subjects using ¹H-MRS and also evaluated the selective role of the rs956572 Bcl-2 SNP in modulating ACC Glu and Glx (sum of Glu and glutamine) in euthymic-BD. Forty euthymic subjects with BD type I and forty healthy controls aged 18–40 were evaluated. All participants were genotyped for Bcl-2 rs956572 and underwent a 3-Tesla brain magnetic resonance imaging examination including the acquisition of an in vivo PRESS single voxel (2 cm³) ¹H-MRS sequence to obtain metabolite levels from the ACC. Euthymic-BD subjects had higher Glu/Cre (creatine) and Glx/Cre compared with healthy controls. The Bcl-2 SNP AA genotype was associated with elevated ACC Glu/Cre and Glx/Cre ratio in the BD group but not in controls. The present study reports for the first time an increase in ACC Glu/Cre and Glx/Cre ratios in BD-euthymia. Also, Bcl-2 AA genotype, previously associated with lower Bcl-2 expression and increase intracellular Ca²⁺, showed to be associated with increased ACC Glu and Glx levels in euthymic-BD subjects. The present findings reinforce a key role for glutamatergic system dysfunction in the pathophysiology of BD, potentially involving modulatory effects by Bcl-2 in the ACC.     

Antidepressant-Induced Mania with Concomitant Mood Stabilizer in Patients with Comorbid Substance Abuse and Bipolar Disorder

ABSTRACT

Antidepressant use in the treatment of bipolar disorder is controversial due the risks of affective switching and cycle acceleration. Studies of non-comorbid samples suggest that the risk can be mitigated with the use of a concomitant mood stabilizer. However, the majority of patients with bipolar disorder will experience a comorbid substance use disorder and little is known about these individuals because they are typically excluded from clinical trials. Patients entering a substance abuse treatment program who had a history of bipolar disorder were interviewed to evaluate antidepressant-induced affective switching with and without concomitant mood stabilizer. Among 41 comorbid participants, the total lifetime antidepressant-induced switch rate was 76%. The switch rate was 56% for patients taking a mood stabilizer and an antidepressant concomitantly. There was no difference between patients with bipolar I and bipolar II disorders.     

Impulsivity in Patients with Bipolar Disorder and Cocaine or Amphetamine Dependence Given Lamotrigine

ABSTRACT

Objective: Impulsivity is a component of bipolar disorder, substance-related disorders, and antisocial personality disorder.

Method: Barratt Impulsiveness Scale nonplanning subscale (BIS-11-NP) scores were assessed from 2001–2003 in 37 outpatients in Dallas, Texas with bipolar disorder and cocaine or amphetamine dependence during therapy with lamotrigine.

Results: Baseline BIS-11-NP scores correlated positively with baseline suicidality. BIS-11-NP scores decreased significantly from baseline to exit. Baseline to exit change on the BIS-11-NP correlated with change in some psychiatric symptom measures, drug craving, and days of drug use. A limitation of the study is the small sample size.

Conclusion: The results suggest that lamotrigine is associated with decreased impulsivity.     

The MATRICS Consensus Cognitive Battery in Patients with Bipolar I Disorder

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was devised to identify a neurocognitive battery to be used in clinical trials targeting cognition in schizophrenia, a process, which resulted in the MATRICS Consensus Cognitive Battery (MCCB). The MCCB has been selected by the United States Food and Drug Administration to be used as the primary outcome measure in registry trials for cognitive agents in schizophrenia. Given the clinical and cognitive overlap between schizophrenia and bipolar disorder (BPD), it is likely that any compound shown to have cognitive benefits in schizophrenia will subsequently be tested in BPD. Unlike the MCCB for schizophrenia, there remains no consensus regarding outcome measures if cognitive trials were to be undertaken in BPD. The utility of the MCCB in BPD has not yet been systematically investigated. We administered the MCCB to 80 bipolar I patients; 37 were strictly euthymic and 43 were symptomatic. We compared their performance with a demographically matched healthy sample (n=148) on seven MCCB domains, and the composite. BPD patients were statistically significantly impaired on five of seven MCCB domains at levels consistent with meta-analytic studies of cognition in BPD. In contrast, patients'' performance was less impaired on the Reasoning and Problem-solving and Social Cognition domains, differences that did not survive statistical correction for multiple testing. Symptomatic status only modestly influenced performance. These data suggest that the MCCB, devised for use in schizophrenia, may also represent a useful outcome measure in cognitive trials for BPD. Additional studies should address important psychometric features such as repeatability and potential practice and/or ceiling effects.     

Mitochondrial DNA Copy Number Is Associated With Treatment Response and Cognitive Function in Euthymic Bipolar Patients Receiving Valproate

BackgroundBipolar disorder (BD) is associated with cognitive impairment and mitochondrial dysfunction. However, the associations among mitochondrial DNA copy number (MCN), treatment response, and cognitive function remain elusive in BD patients.MethodsSixty euthymic BD patients receiving valproate (VPA) and 66 healthy controls from the community were recruited. The indices of metabolic syndrome (MetS) were measured. Quantitative polymerase chain reaction analysis of blood leukocytes was used to measure the MCN. Cognitive function was measured by calculating perseverative errors and completed categories on the Wisconsin Card Sorting Test (WCST). The VPA treatment response was measured using the Alda scale.ResultsBD patients had significantly higher MCN, triglyceride, and C-reactive protein (CRP) levels, waist circumference, and worse performance on the WCST than the controls. Regression models showed that BD itself and the VPA concentration exerted significant effects on increased MCN levels. Moreover, the receiver operating characteristic curve analysis showed that an MCN of 2.05 distinguished VPA responders from nonresponders, with an area under the curve of 0.705 and a sensitivity and specificity of 0.529 and 0.816, respectively. An MCN level ≥2.05 was associated with 5.39 higher odds of being a VPA responder (P = .006). BD patients who were stratified into the high-MCN group had a higher VPA response rate, better WCST performance, lower CRP level, and less MetS.ConclusionsThe study suggests a link between the peripheral MCN and cognitive function in BD patients. As an inflammatory status, MetS might modulate this association.     

Dopamine Transporter Gene Variant Affecting Expression in Human Brain is Associated with Bipolar Disorder

The gene encoding the dopamine transporter (DAT) has been implicated in CNS disorders, but the responsible polymorphisms remain uncertain. To search for regulatory polymorphisms, we measured allelic DAT mRNA expression in substantia nigra of human autopsy brain tissues, using two marker SNPs (rs6347 in exon 9 and rs27072 in the 3′-UTR). Allelic mRNA expression imbalance (AEI), an indicator of cis-acting regulatory polymorphisms, was observed in all tissues heterozygous for either of the two marker SNPs. SNP scanning of the DAT locus with AEI ratios as the phenotype, followed by in vitro molecular genetics studies, demonstrated that rs27072 C>T affects mRNA expression and translation. Expression of the minor T allele was dynamically regulated in transfected cell cultures, possibly involving microRNA interactions. Both rs6347 and rs3836790 (intron8 5/6 VNTR) also seemed to affect DAT expression, but not the commonly tested 9/10 VNTR in the 3′UTR (rs28363170). All four polymorphisms (rs6347, intron8 5/6 VNTR, rs27072 and 3′UTR 9/10 VNTR) were genotyped in clinical cohorts, representing schizophrenia, bipolar disorder, depression, and controls. Only rs27072 was significantly associated with bipolar disorder (OR=2.1, p=0.03). This result was replicated in a second bipolar/control population (OR=1.65, p=0.01), supporting a critical role for DAT regulation in bipolar disorder.     

Bipolar Disorder in a Population of Adolescents with Alcohol Use Disorders

ABSTRACT

Objectives: The objective of this paper is to present the prevalence of Bipolar Disorder (BPD) in a population of adolescents and young adults with alcohol use disorders (AUD) and to compare salient alcohol use, mood, and diagnostic variables between adolescents with BPD, those with Major Depressive Disorder (MDD), and those with AUD without a mood disorder.

Methods: The subjects were 452 adolescents and young adults, age 12.9 to 28.3 years, who met DSM-IV criteria for a lifetime history of either alcohol abuse or alcohol dependence. DSM-IV psychiatric and AUD diagnoses were obtained by semi-structure interviews (K-SADS and SCID) to discern the possible effect of comorbid BPD on alcohol and other drug variables, we compared adolescents or young adults who met DSM-IV criteria for concurrent BPD and AUD with adolescents with MDD plus AUD and those with AUD and no mood disorder. Following one-way ANOVA comparing across the 3 groups, we proceeded with post hoc analysis comparing the BPD+AUD group with either the MDD + AUD or AUD only group.

Results: 6.4% of the subjects met criteria for BPD. While there were no differences between groups on the alcohol consumption variables, subjects with BPD had a significantly earlier onset of an AUD diagnosis than either the MDD group or the AUD only group. The BPD + AUD group had a significantly greater percentage of subjects meeting criteria for alcohol dependence than the AUD only group.

Conclusions: Comorbid mood disorders, particularly Bipolar Disorder, may have an important effect on alcohol and substance use variables and diagnosis. More research is needed to determine the effect of treatments for mood disorder on both mood and substance use variables.     

Neurostructural Correlates of Cannabis Use in Adolescent Bipolar Disorder

BackgroundLittle is known regarding the association of cannabis use with brain structure in adolescents with bipolar disorder (BD). This subject is timely, given expanded availability of cannabis contemporaneously with increased social acceptance and diminished societal constraints to access. Therefore, we set out to examine this topic in a sample of adolescents with BD and healthy control (HC) adolescents.MethodsParticipants included 144 adolescents (47 BD with cannabis use [BD_CB+; including 13 with cannabis use disorder], 34 BD without cannabis use [BD_CB−], 63 HC without cannabis use) ages 13–20 years. FreeSurfer-processed 3T MRI with T1-weighted contrast yielded measures of cortical thickness, surface area (SA), and volume. Region of interest (amygdala, hippocampus, ventrolateral prefrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) analyses and exploratory vertex-wise analysis were undertaken. A general linear model tested for between-group differences, accounting for age, sex, and intracranial volume.ResultsVertex-wise analysis revealed significant group effects in frontal and parietal regions. In post-hoc analyses, BD_CB+ exhibited larger volume and SA in parietal regions, and smaller thickness in frontal regions, relative to HC and BD_CB−. BD_CB− had smaller volume, SA, and thickness in parietal and frontal regions relative to HC. There were no significant region of interest findings after correcting for multiple comparisons.ConclusionThis study found that cannabis use is associated with differences in regional brain structure among adolescents with BD. Future prospective studies are necessary to determine the direction of the observed association and to assess for dose effects.     

Dopaminergic drug-induced modulation of the expression of the dopamine transporter in peripheral blood lymphocytes in Parkinson's disease

The modulation of expression of the dopamine transporter by dopaminergic drugs was investigated by flow cytometry in peripheral blood lymphocytes from patients suffering Parkinson's disease. An 8-week in vivo exposure to pramipexole (0.7 mg free base, 3 times a day) or ropinirole (12 mg, once daily), but not levodopa/carbidopa (100/25 mg, 3 times a day), significantly reduced the mean fluorescence intensity of the dopamine transporter in peripheral blood lymphocytes. These results demonstrate that levodopa differs from dopamine agonists in its regulation of dopamine transporter expression in peripheral blood lymphocytes.     

新疆地区双相情感障碍患儿拉莫三嗪血药浓度的影响因素

目的:探讨新疆地区双相情感障碍患儿拉莫三嗪(LTG)血药浓度的影响因素,为临床个体化用药提供参考。 方法:采用超高效液相色谱法测定 LTG 血药浓度,分析年龄、性别、剂量及联合用药等对患儿 LTG 血药浓度的影响。 结果:150 例患儿服用LTG 后血药浓度为(4. 20±2. 57)μg / mL。 患儿年龄 11~18 岁,11 ~ <14 岁组和 14 ~ 18 岁组的给药剂量、血药浓度、浓度剂量比(CDR)比较差异均无统计学意义(P 均>0. 05);女性患儿的给药剂量、血药浓度和 CDR 均高于男性患儿(P 均<0. 05);维吾尔族和汉族患儿的给药剂量、血药浓度、CDR 比较差异均无统计学意义(P >0. 05);无联合用药组患儿的 LTG 给药剂量和血药浓度均高于 LTG+卡马西平组(P 均<0. 05)。 LTG 血药浓度与给药剂量呈正相关(P<0. 05),但相关性较差(r<0. 5)。 结论:临床使用 LTG 控制和治     

Comparison of the Internal State Scale to Clinician-Administered Assessments in Patients with Bipolar Disorder and Alcohol Abuse or Dependence

Abstract

Objectives: Self-report measures require less clinician time to administer than clinician-rated assessments. The Internal State Scale (ISS) is a well-validated self-report measure that assesses symptoms of mania and depression in patients with bipolar disorder (BPD). However, the ISS has never been specifically evaluated in patients with BPD and comorbid substance misuse. Substances can induce mood symptoms complicating diagnosis and mood state assessment.

Methods: The ISS was compared with the Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS) in 21 patients with BPD and alcohol abuse/dependence at baseline and for up to 16 weeks postbaseline. In addition, ISS-determined mood state was compared to mood state from a structured diagnostic interview.

Results: Significant baseline correlations were observed between the ISS depression subscale and HRSD, ISS activation subscale and YMRS, and ISS perceived conflict subscale and BPRS. Significant correlations of baseline to exit change scores were found between the ISS activation and YMRS, but not ISS depression and HRSD, or ISS perceived conflict and BPRS. All participants had a mixed mood state by structured diagnostic interview. The ISS diagnosed the manic/hypomanic portion of this mood state in 76% of participants but found depression in only 38%.

Conclusions: As in BPD patients without substance abuse, the ISS generally showed correlations with clinician-rated scales at baseline, with less strong correlations observed on change scores. The ISS diagnosis of mania or hypomania appeared to correspond more highly than depression with the findings from a structured diagnostic interview.     

Transition to Mania During Treatment of Bipolar Depression

Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients.     

Psychosocial Functioning of People with Substance Abuse and Bipolar Disorders

This study assessed whether a secondary diagnosis of a substance use disorder in hospitalized people with bipolar disorder was associated with poorer outcomes on self-reported measures of mood (Profile of Mood States), subjective distress (Behavior and Symptom Identification Scale), and coping resources (Coping Resources Inventory), and with specific patient characteristics. Sixty-two patients with bipolar disorder and a secondary diagnosis of a substance use disorder and 60 patients with only a bipolar disorder diagnosis participated. Patients with bipolar disorder and a secondary diagnosis of a substance use disorder perceived significantly more impairment on all three measures than did patients without the secondary diagnosis. Moreover, the background characteristics of a history of violence, past or current involvement with the criminal justice system, and not having an antipsychotic medication prescribed during hospitalization had the strongest association with having a secondary diagnosis of a substance use disorder among the characteristics examined. These findings suggest the existence of a subgroup of patients with substance abuse and bipolar disorders who have substantial psychosocial impairment and probably require more intense treatment.     

Hypothalamic-Pituitary-Adrenal Axis Dysfunction and Illness Progression in Bipolar Disorder

Background:

Impaired stress resilience and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients.

Methods:

Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR).

Results:

Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels.

Conclusions:

Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness.     

Monocyte and Lymphocyte Activation in Bipolar Disorder: A New Piece in the Puzzle of Immune Dysfunction in Mood Disorders

Background:

This study tested the hypothesis that the low-grade inflammation presented in patients with bipolar disorder (BD) is associated with expansion of activated T cells, and this activated state may be due to a lack of peripheral regulatory cells.

Methods:

Specifically, we investigated the distribution of monocytes and lymphocyte subsets, and investigated Th1/Th2/Th17 cytokines in plasma by flow cytometry. Twenty-one BD type I patients and 21 age- and sex-matched controls were recruited for this study.

Results:

BD patients had increased proportions of monocytes (CD14+). Regarding lymphocyte populations, BD patients presented reduced proportions of T cells (CD3+) and cytotoxic T cells (CD3+CD8+). BD patients also exhibited a higher percentage of activated T CD4+CD25+ cells, and a lower percentage of IL-10 expressing Treg cells.

Conclusions:

Our data shed some light into the underlying mechanisms involved with the chronic low-grade inflammatory profile described in BD patients.     

Bimodal Effect of Lithium Plasma Levels on Hippocampal Glutamate Concentrations in Bipolar II Depression: A Pilot Study

Background:

The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium.

Methods:

Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction.

Results:

At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with “standard” lithium levels (≥0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time.

Conclusions:

These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.     

Differentiating Between the Course of Illness in Bipolar 1 and Chronic-Psychotic Heroin-Dependent Patients at Their First Agonist Opioid Treatment

In an effort to inquiry the “self-medication hypothesis” in heroin-dependent patients suffering from chronic psychosis and bipolar disorder, a naturalistic comparative cohort study was designed with the aim of comparing, according to the presence of dual diagnosis, the clinical characteristics of heroin-dependent patients presenting for their first agonist opioid treatment. The main finding was that addictive (heroin) illness was more severe in bipolar 1 patients and less severe in chronic psychotic patients when compared with heroin-dependent patients without dual diagnoses. In the case of chronic psychotic patients, these differences do not allow us to exclude a therapeutic heroin use, at least at the beginning of their toxicomanic career, with limited progression of their addictive disease. This occurrence seems to be excluded for bipolar 1 heroin-dependent patients, who come to their first agonist opioid treatment with a more severe addictive disease.