Abelson Helper Integration Site-1 Gene Variants on Major Depressive Disorder and Bipolar Disorder

Objective

The present study aimed to explore whether 4 single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with major depressive disorder (MD) and bipolar disorder (BD), and whether they could predict clinical outcomes in mood disorders.

Methods

One hundred and eighty-four (184) patients with MD, 170 patients with BD and 170 healthy controls were genotyped for 4 AHI1 SNPs (rs11154801, rs7750586, rs9647635 and rs9321501). Baseline and final clinical measures for MD patients were assessed through the Hamilton Rating Scale for Depression (HAM-D). Allelic and genotypic frequencies in MD and BD subjects were compared with those of each disorder and healthy group using the χ² statistics. Repeated measures ANOVA was used to test possible influences of SNPs on treatment efficacy.

Results

The rs9647635 A/A was more represented in subjects with BD as compared with MD and healthy subjects together. The rs9647635 A/A was also more presented in patients with MD than in healthy subjects. With regard to the allelic analysis, rs9647635 A allele was more represented in subjects with BD compared with healthy subjects, while it was not observed between patients with MD and healthy subjects.

Conclusion

Our findings provide potential evidence of an association between some variants of AHI1 and mood disorders susceptibility but not with clinical outcomes. However, we will need to do more adequately-powered and advanced association studies to draw any conclusion due to clear limitations.     

Metabotropic Glutamate Receptor 2 and 3 Gene Expression in The Human Prefrontal Cortex and Mesencephalon in Schizophrenia

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in schizophrenia. We characterized mGluR2 and 3 mRNA in the human prefrontal cortex (PFC) and mesencephalon, and then compared cases with schizophrenia to matched controls. In the human brain, both receptors were expressed in the PFC and, unlike the rodent, in dopaminergic (DA) cell groups. In schizophrenia, we found significantly higher levels of mGluR2 mRNA in the PFC white matter. The expression of mGluR2, 3 in DA cells provide a mechanism for glutamate to modulate dopamine release in the human brain and this species-specific difference may be critical to understanding rodent models in schizophrenia.     

Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication-free individuals with bipolar disorder: an in vivo1H MRS study

Objectives:  While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy (¹H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N -acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr).
Methods:  Thirty-two medication-free BD subjects (33.8 ± 10.2 years) and 32 matched controls (33.8 ± 9.0 years) underwent a short echo-time (TE = 30 ms) ¹H MRS. An 8-cm³ single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo -inositol, and glutamate were obtained, using the water signal as an internal reference.
Results:  BD subjects had lower Cr + PCr [ F _(1,62) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [ F _(1,62) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites.
Conclusions:  These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.     

Bipolar disorder and polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1)

Glutathione S-transferases are ubiquitous multifunctional enzymes, which play a key role in cellular detoxification. The present case-control study was performed in Shiraz, Iran to investigate the association between polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) and susceptibility to bipolar disorder (BPD). A total of 228 BPD patients participated in the study. In addition, 236 healthy blood donors, who frequency matched with the patients according to age and gender, were also studied as a control group. Statistical analysis revealed that polymorphisms of neither GSTM1 (OR = 0.73, 95% CI: 0.50-1.05) nor GSTT1 (OR = 0.98, 95% CI: 0.65-1.47) were associated with risk of BPD. Patients were stratified according to their age of onset into early onset (below 19 years old) and late onset (more than 19 years old) groups. Among the early onset group, the GSTM1 null genotype decreases the risk of BPD (OR = 0.43, 95% CI: 0.24-0.79). Further analysis showed that a combination of “GSTM1 positive genotype and GSTT1 null genotype” versus “positive genotypes of GSTM1 and GSTT1” increased the risk of BPD (OR = 2.28, 95% CI: 1.07-4.85). However, there was no significant association between the study polymorphisms and risk of BPD among the late onset group. The present finding indicated that GSTM1 and GSTT1 are candidate polymorphisms for susceptibility to BDP among adolescents.     

A near-infrared spectroscopy study of prefrontal cortex activation during a verbal fluency task and carbon dioxide inhalation in individuals with bipolar disorder

OBJECTIVES: There is evidence of prefrontal cortex (PFC) dysfunction in patients with bipolar disorder (BP). Magnetic resonance and neuropathological studies show abnormalities of the brain microvasculature in patients with BP. However, the underlying biological mechanisms are not well understood. We investigated the relationship between activation of the PFC during a cognitive task and the vascular function in response to a physiological task in patients with BP. METHODS: Fourteen euthymic patients with BP and 14 control subjects matched for age, sex, and education were recruited. We examined the response of the PFC during a verbal fluency task and during 5% CO(2) inhalation using a 24-channel near-infrared spectroscopy imaging system to measure alteration of oxygenated and deoxygenated hemoglobin. RESULTS: The BP patients showed a significantly lower level of PFC activation during the cognitive task compared to the healthy controls, but the task-performance of the BP patients was not significantly different from that of the controls. The vascular response of the BP patients to CO(2) was not significantly different from that of controls. CONCLUSIONS: This study suggests functional hypoactivation of the PFC during a cognitive load in patients with BP while they are in a euthymic state. The mechanism of this hypoactivation is different from that of vascular regulation in response to a physiological stimulus.     

The Quality of Life in Bipolar Disorder (QoL.BD) Scale: Validation of a French Cross-Cultural Adaptation

Objective:The goal of this study was to validate the French version of the Quality of Life in Bipolar Disorder (QoL.BD) scale, a condition-specific measure for bipolar disorder (BD).Method:The QoL.BD scale was translated into French in accordance with the recommendations for transcultural adaptation. It was administered to 125 participants with BD living in Quebec, Canada. Construct validity was evaluated through correlations with other measures of self-reported quality of life (QoL), functioning, and symptoms. Factorial structure was examined through an exploratory factor analysis.Results:Internal reliability and test–retest reliability standards were met. Correlations in expected directions with other QoL, functioning, and depressive symptom scales supported convergent validity. The item loadings structure of the French QoL.BD largely replicated the original English version, with some modifications.Conclusion:The French version of the QoL.BD (full and brief) is comparable in its psychometric properties to the English version. It is a valid and sound measure for the evaluation of the QoL of French-speaking patients with BD.     

Demographic and diagnostic characteristics of the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

OBJECTIVES: Bipolar disorder is a severe, recurrent, and often highly impairing psychiatric disorder. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is a large-scale multicenter study funded by the National Institute of Mental Health (NIMH) to examine the longitudinal course of the disorder and the effectiveness of current treatments. The current report provides a context for interpreting studies resulting from STEP-BD by summarizing the baseline demographic and diagnostic characteristics of the first 1000 enrolled. METHODS: The majority of the sample met DSM-IV criteria for bipolar I disorder (71%). Mean age of patients was 40.6 (+/-12.7) years and mean duration of bipolar illness was 23.1 (+/-12.9) years. Among the first 1000 subjects enrolled, 58.6% are females and 92.6% Caucasian. This report compares the STEP-BD sample with other large cohorts of bipolar patients (treatment and community samples). RESULTS: Compared with US population and community studies, the first 1000 STEP-BD patients were less racially diverse, more educated, had lower income, and a higher unemployment rate. Results are discussed in terms of the contributions of STEP-BD (and other large-scale treatment studies) in understanding the nature, treatments, and outcomes of bipolar disorder for patients seeking care at academic treatment centers. CONCLUSIONS: The current report provides a context for interpreting future studies resulting from STEP-BD. The comparison of demographic and clinical characteristics between the samples across clinic-based studies suggests broad similarities despite the substantial differences in geography, payer mix, and clinical entry point.     

Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder

Objective Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD. Methods We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway. Results Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality. Conclusion This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.