An association of AKT1 gene polymorphism with antidepressant treatment response

Objectives: Nowadays it is considered that protein kinase Akt1 could be involved in pathogenesis of affective disorders. We have examined whether AKT1 gene polymorphisms are associated with antidepressant treatment response. Methods: The study included 106 Caucasian patients with depressive disorders from Siberia and 103 healthy control donors. The frequencies of single nucleotide polymorphisms rs1130214 and rs3730358 of AKT1 gene were examined. Results: A comparison of genotypic or allelic frequencies between the groups of healthy donors and depressive patients showed no statistically significant difference. No association between the polymorphisms under study and the scores according to Hamilton Depression Rating Scale 17 was found. However, an association between treatment response assessed by the Clinical Global Impression – Improvement scale and rs1130214 polymorphism was observed. Conclusions: AKT1 gene polymorphism rs1130214 is associated with antidepressant treatment response in patients with depressive disorders.     

Effects of IL1B single nucleotide polymorphisms on depressive and anxiety symptoms are determined by severity and type of life stress

Interleukin-1β is one of the main mediators in the cross-talk between the immune system and the central nervous system. Higher interleukin-1β levels are found in mood spectrum disorders, and the stress-induced expression rate of the interleukin-1β gene (IL1B) is altered by polymorphisms in the region.Therefore we examined the effects of rs16944 and rs1143643 single nucleotide polymorphisms (SNPs) within the IL1B gene on depressive and anxiety symptoms, as measured by the Brief Symptom Inventory, in a Hungarian population sample of 1053 persons. Distal and proximal environmental stress factors were also included in our analysis, namely childhood adversity and recent negative life-events.We found that rs16944 minor (A) allele specifically interacted with childhood adversity increasing depressive and anxiety symptoms, while rs1143643’s minor (A) allele showed protective effect against depressive symptoms after recent life stress. The genetic main effects of the two SNPs were not significant in the main analysis, but the interaction effects remained significant after correction for multiple testing. In addition, the effect of rs16944 A allele was reversed in a subsample with low-exposure to life stress, suggesting a protective effect against depressive symptoms, in the post hoc analysis.In summary, both of the two IL1B SNPs showed specific environmental stressor-dependent effects on mood disorder symptoms. We also demonstrated that the presence of exposure to childhood adversity changed the direction of the rs16944 effect on depression phenotype. Therefore our results suggest that it is advisable to include environmental factors in genetic association studies when examining the effect of the IL1B gene.     

促肾上腺皮质激素释放激素受体1基因多态与抗抑郁药物疗效的关联研究

目的探讨促肾上腺皮质激素释放激素受体1(corticotropin-releasing hormone receptor1,CRHR1)基因多态性与选择性5-羟色胺再摄取抑制剂(Selective Serotonin Reuptake Inhibitors,SSRIs)、5-羟色胺和去甲肾上腺素再摄取抑制剂(Serotonin and Norepinephrine Reuptake Inhibitors,SNRIs)抗抑郁疗效差异的相关性。方法对符合美国精神障碍诊断与统计手册第4版(Diagnostic and Statistical Manual of Mental Disorders,Fourth Edi-tion,DSM-Ⅳ)抑郁症诊断标准的271例抑郁症患者予以单一新型抗抑郁药(SSRIs或SNRIs)常规剂量治疗至少6周,以治疗前后17项汉密尔顿抑郁量表(Hamilton Depression Scale,HAMD)总分减分率作为评估疗效的指标。采用TaqMan探针法检测CRHR1基因上4个单核苷酸多态性(Single Nucleotide Polymorphism,SNP)的基因型,比较有效组(HAMD-17减分率≥50%)和无效组(HAMD-17减分率<50%)之间4个位点基因型及多位点组成单倍型的不同。结果治疗4周末:CRHR1基因rs17689966位点A等位基因及AA基因型携带者在治疗无效组的频率均显著高于有效组(88.0%vs.77.0%,P=0.004;75.8%vs.59.0%,P=0.004)。有3种单倍型在有效组和无效组之间的分布差异有统计学意义,分别是T-A/T-G(rs242924-rs17689966:86.6%vs.74.7%,P=0.002;8.1%vs.15.5%,P=0.018),G-T-G(rs4458044-rs rs242924-rs17689966:8.2%vs.15.5%,P=0.019)。治疗6周末:CRHR1基因4个SNPs的基因型、等位基因频率及单倍型分析在不同疗效患者组间分布差异均无统计学意义(均P>0.05)。结论CRHR1基因多态性可能与SSRIs、SNRIs类药物的早期疗效相关。     

The RS685012 Polymorphism of ACCN2, the Human Ortholog of Murine Acid-Sensing Ion Channel (ASIC1) Gene,is Highly Represented in Patients with Panic Disorder

Panic disorder (PD) is a disabling anxiety disorder that is characterized by unexpected, recurrent panic attacks, associated with fear of dying and worrying about possible future attacks or other behavioral changes as a consequence of the attacks. The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of behaviors including fear, anxiety, pain, depression, learning, and memory. The human analog of ASIC1a is the amiloride-sensitive cation channel 2 (ACCN2). Adenosine A2A receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. In this work we aimed to evaluate the distribution of ACCN2 rs685012 and ADORA2A rs2298383 polymorphisms in PD patients compared with healthy subjects. We found no association between ADORA2A polymorphism and PD. Instead, the C mutated allele for ACCN2 rs685012 polymorphism was significantly more frequent in patients than in controls. On the contrary, the TT homozygous wild-type genotype and also the ACCN2 TT/ADORA2A CT diplotype were significantly more represented in controls. These results are suggestive for a role of ACCN2 rs685012 polymorphism in PD development in Caucasian people.     

No association between a polymorphism of the adenylate cyclase type IX gene and major depressive disorder in the Chinese Han population

Previous studies have demonstrated that a missense single-nucleotide polymorphism variant (2316A>G;rs2230739)of the adenylate cyclase type IX gene was associated with bipolar disorder and affective disorder.We determined genotype and allele frequencies using a ligase detection reaction method in 315 patients with major depressive disorder and 278 unrelated, sex-matched healthy control subjects.We did not detect any statistically significant differences in genotype and allele frequencies between patients and healthy control subjects.Furthermore,we found no significant difference between genders in major depressive disorder,nor between patients and controls in the same gender.These results suggest that 2316A>G(rs2230739)may not be a risk factor for increasing susceptibility to major depressive disorder in the Chinese Han population.     

重性抑郁障碍患者多药耐药基因多态性与帕罗西汀疗效及不良反应的关联研究

目的 探索中国汉族重性抑郁障碍(MDD)患者多药耐药基因(MDR1)多态性与帕罗西汀疗效及药物不良反应的关联.方法 对116例MDD患者给予帕罗西汀治疗,剂量范围20～50mg/d,疗程8周.采用限制性片段长度多态性技术及DNA测序方法检测MDR1基因上5个单核苷酸多态性的基因型,分析各位点基因型及多位点组成的单体型与帕罗西汀临床效应的关系.结果 携带rs1128503位点CC基因型患者的临床缓解率低于其他基因型携带者(TT基因型86.0%,CT基因型72.4%,CC基因型50.0%,P<0.05),且焦虑/躯体化因子减分率较低(P<0.05).携带单体型C-A(rs1128503-rs1202169)患者的临床痊愈率(69.7%)低于非携带者(86.0%),P<0.05.而携带单体型T-A/T-T-G(rs1045642-rs2032582-rs1128503-rs1202169)的患者药物不良反应发生率(29.0%)低于非携带者(49.0%),P<0.05.结论 MDR1基因多态性可能与中国汉族MDD患者帕罗西汀的疗效及不良反应关联.     

Apolipoprotein E epsilon 4 allele and Japanese late-onset depressive disorders.

BACKGROUND: Several studies have suggested that late-onset depressive disorder (LOD) and the apolipoprotein E (Apo E) epsilon 4 allele are associated with dementia, respectively. The Apo E polymorphism is significantly heterogeneous among races. We hypothesized that the Apo E epsilon 4 allele frequency is elevated in Japanese LOD. METHODS: The Apo E genotype was studied in 134 patients (male, 53; female, 81) with early-/late-onset depressive disorder and 105 healthy normal controls (male, 41; female, 64). The patients were subdivided into those with early onset and late onset using 45 and 50 years as the cutoff ages. All the subjects were Japanese. RESULTS: There was statistically no difference between normal control subjects and patients with depressive disorders in Apo E genotype or allele frequency. There was statistically no difference in the age of onset of depressive disorders according to the Apo E genotype. There was no relation between the age of onset of depressive disorder and the number of epsilon 4 alleles the patient had. There was also no association between early-/late-onset depressive disorder and the Apo E genotype or allele frequency. CONCLUSIONS: Our results suggest that there is no association between the Apo E epsilon 4 allele and Japanese LOD.     

The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder.Consequently,the norepinephrine transporter gene is an attractive candidate in major depressive disorder research.In the present study,we evaluated the depression symptoms of subjects with major depressive disorder,who were all from the North of China and of Han Chinese origin,using the Hamilton Depression Scale.We examined the rela-tionship between two single nucleotide polymorphisms in the norepinephrine transporter,rs2242446 and rs5569,and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program.rs5569 was associated with depressed mood,and the GG genotype may be a risk factor for this;rs2242446 was associated with work and interest,and the TT genotype may be a risk factor for loss of interest.Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Han Chinese population.     

Association between T-182C,G1287A polymorphism in NET gene and suicidality in major depressive disorder in Chinese patients

Abstract

Objective: Previous studies have implicated norepinephrine transporter gene (NET) polymorphisms in the etiology of major depressive disorder (MDD). A functional NET T-182C polymorphism (rs2242446) in the promoter region and a synonymous polymorphisms G1287A in the exon 9 (rs5569) were associated with MDD in different populations. However, few studies have focused on the relationship between these polymorphisms and MDD patients with suicidality. The objective of the present study was to examine whether the two polymorphisms are associated with MDD patients with suicidality in the Han Chinese population.

Methods: Two hundred and sixty-three suicidal depressed patients and 241 non-suicidal depressed patients who met DSM-IV criteria for MDD were recruited from our hospital. Three hundred and three unrelated, age- and sex-matched healthy control subjects participated in this case-control study. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton rating scale for depression (HAMD). Genotypes of T-182C polymorphism (rs2242446) and G1287A (rs5569) were screened by polymerase chain reaction.

Results: No statistical significant differences between patients and controls were found for any of the analysed polymorphisms, either in the genotype or allele distribution.

Conclusions: Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of MDD with suicidality. However, the results must be verified in larger samples and different ethnicities.     

Presenilin-1 in late-onset depressive disorder

Late-onset depressive disorder (LOD) is thought to be associated with dementia. Allele 1 in the presenilin-1 (PS-1) gene is a risk factor for Alzheimer's disease. An association study on this polymorphism was performed in depressive patients and control subjects. The patients were subdivided into those with early onset and late onset, using 50 years as the cut-off age. There was no statistically significant difference in the age of onset of depressive disorders according to the PS-1 genotype. There was also no association between early/late-onset depressive disorders and the PS-1 genotype. Our results suggest there is no association between the PS-1 allele and LOD.     

Distress and functioning in mixed anxiety and depressive disorder

The aim of the present study was to evaluate the validity of mixed anxiety and depressive disorder (MADD) with reference to functional characteristics and symptomatic characteristics in comparison with anxiety disorders, depressive disorders, and groups showing subthreshold symptoms (exclusively depressive or anxiety related). The present study was carried out in the following three medical settings: two psychiatric and one primary care. Patients seeking care in psychiatric institutions due to anxiety and depressive symptoms and attending primary medical settings for any reason were taken into account. A total of 104 patients (65 women and 39 men, mean age 41.1 years) were given a General Health Questionnaire (GHQ-30), Global Assessment of Functioning (GAF) and Present State Examination questionnaire, a part of Schedules for Clinical Assessment in Neuropsychiatry, Version 2.0. There were no statistically relevant differences between MADD and anxiety disorders in median GHQ score (19 vs 16) and median GAF score (median 68.5 vs 65). When considering depressive disorders the median GHQ score (28) was higher, and median GAF score (59) was lower than that in MADD. In groups with separated subthreshold anxiety or depressive symptoms, median GHQ scores (12) were lower and median GAF scores (75) were higher than that in MADD. The most frequent symptoms of MADD are symptoms of generalized anxiety disorder (GAD) and depression. Mixed anxiety and depressive disorder differs significantly from GAD only in higher rates of depressed mood and lower rates of somatic anxiety symptoms. Distinction from depression was clearer; six of 10 depressive symptoms are more minor in severity in MADD than in the case of depression. Distress and interference with personal functions in MADD are similar to that of other anxiety disorders. A pattern of MADD symptoms locates this disorder between depression and GAD.     

General health and well-being in outpatients with depressive and bipolar disorders

Prior studies have found contradictory results regarding the association between course of illness and quality of life among patients with depressive disorder or bipolar disorder. Questionnaires about quality of life and affective symptoms (the EQ-5D, EQ-5D-VAS, WHO (Five) well-being index and the BDI-42) were mailed to a large population of outpatients with depressive or bipolar disorder representative of patients treated in hospital settings in Denmark. Among the 1005 recipients, 49.9% responded to the letter. Depressive disorder was associated with poorer general health (EQ-5D, EQ-5D-VAS) and well-being (WHO (Five) well-being index) and more depressive and anxiety symptoms compared with bipolar disorder. Similarly, more psychiatric admissions were associated with poorer general health and well-being and more depressive and anxiety symptoms. However, when adjusting for the effect of depressive symptoms, the associations between number of admissions and general health, and between numbers of admissions and well-being, lost significance. Thus, depressive symptoms seem to be the strongest predictor of general health and well-being in both disorders. As the response rate to the questionnaire was relatively low, the findings should be interpreted with caution.     

Serotonin-related gene pathways associated with undifferentiated somatoform disorder

It has been suggested that serotonergic hypofunction and serotonergic pathway genes underlie the somatic symptoms of somatoform disorders. We examined a variety of serotonin-related gene polymorphisms to determine whether undifferentiated somatoform disorder is associated with specific serotonin-related gene pathways. Serotonin-related polymorphic markers were assessed using single nucleotide polymorphism (SNP) genotyping. One hundred and two patients with undifferentiated somatoform disorder and 133 healthy subjects were enrolled. The genotype and allele frequencies of tryptophan hydroxylase (TPH)1 A218C, TPH2 rs1386494, serotonin receptor 2A-T102C (5-HTR 2A-T102C), 5-HTR 2A-G1438A and serotonin transporter (5HTTLPR) gene were compared between the groups. The Hamilton Rating Scale for Depression and the somatization subscale of the Symptom Checklist-90-Revised (SCL-90-R) were used for psychological assessment. Patients with undifferentiated somatoform disorder had higher frequencies of the TPH1 C allele than healthy controls (p = 0.02) but the difference was not significant after Bonferroni correction. The frequency of TPH1 genotype also did not differ significantly between the patients and the healthy controls, nor did TPH2 rs1386494, 5-HTR 2A-T102C, 5-HTR 2A-G1438A or 5HTTLPR allele and genotype frequencies differ significantly between the two groups. These findings suggest that a variety of serotonin-related gene pathways are unlikely to be definite genetic risk factors for undifferentiated somatoform disorder. Therefore, the pathogenesis of the disorder may be related to epigenetic factors, including psychosocial and cultural factors. Nonetheless, future studies need to include a larger sample of subjects and polymorphisms of more serotonin-related gene variants.     

Association between the 5-HT6 receptor C267T polymorphism and response to antidepressant treatment in major depressive disorder

The purpose of the present study was to determine if a 5-HT6 receptor polymorphism is associated with antidepressant treatment response in major depressive disorder (MDD). Ninety-one patients with MDD, compared with 127 normal control subjects, were evaluated after an 8-week treatment period. An association analysis revealed no differences in genotype and allele distribution between patients with MDD and normal control subjects. However, there were significant differences in the treatment response in some Hamilton Depression Rating Scale (HAM-D) scores (sleep, activity, somatic anxiety, and total) between genotypes. Moreover, the heterozygote group (CT genotype) had significantly better treatment response than the homozygote group (CC + TT genotypes), especially in the somatic-anxiety subcategory and the total score of HAM-D. These findings imply that a 5-HT6 receptor polymorphism (C267T) is associated with treatment response in MDD.     

A major single nucleotide polymorphism of the PDLIM5 gene associated with recurrent major depressive disorder

OBJECTIVE: The PDLIM5 gene is known to interact specifically with the N-type calcium channel alpha-1B subunit and protein kinase C epsilon and is critical for rapid, efficient potentiation of the calcium channel activation by protein kinase C in neurons. Increasing amounts of data suggested that PDLIM5 might be involved in the pathophysiology of major depressive disorder (MDD). The aim of this study was to examine whether genetic variations in the human PDLIM5 gene might contribute to the liability to develop MDD. METHOD: We undertook a gene-based association analysis of single nucleotide polymorphisms (SNPs). Three SNPs (rs10008257, rs2433320 and rs2452600) were identified in the PDLIM5 gene and genotyped in patients diagnosed with recurrent MDD and in matched control subjects. RESULTS: We observed significant allele (p = 0.007) and genotype (p = 0.007) association with rs2433320, and the G allele of rs2433320 was significantly overrepresented in control subjects in comparison with MDD patients. CONCLUSION: These results support the hypothesis of a protective effect for the G allele of rs2433320 in the PDLIM5 gene in recurrent MDD.     

Depressive symptoms and signs that differentiate major and atypical depression from dysthymic disorder in elderly finns

Symptoms and signs that in terms of severity differentiate major and atypical depression from dysthymic disorder were investigated in depressed Finns aged 60 years or over. The overall symptomatology of major depression was not significantly more severe than that of dysthymic disorder, although some symptoms, viz. sadness, paranoid symptoms, loss of interest in work and activities, loss of weight and depersonalization, were more severe in major depressive patients than in dysthymic patients. The overall symptomatology of atypical depression was less severe than that of dysthymic disorder. Sadness, psychic anxiety, loss of interest in work and activities, somatic anxiety, general somatic symptoms, strength of diurnal variation of symptoms, gastrointestinal symptoms and suicidal ideas were less severe in atypical depressive patients than in dysthymic patients but loss of insight was more severe in atypical depressive patients. Of objective signs, loss of weight was more common in major depressive patients than in dysthymic patients. Sad expression and crying were less common in atypical depressive patients than in dysthymic patients.     

Protective effect of the apo epsilon2 allele in major depressive disorder in Taiwanese

OBJECTIVE: Major depression is an important comorbidity in Alzheimer's disease, which is definitely associated with the apolipoprotein E (apo E) polymorphism. The aim of this study was to explore the role of the different apo E polymorphisms in major depressive disorder (MDD) in a Taiwanese population. METHOD: We examined apo E genotypes in 273 Taiwanese patients with MDD and 429 healthy community controls, and compared their polymorphism distribution. RESULTS: The allelic frequency of apo epsilon2 was significantly lower in patients with MDD than in the controls, whereas no significant difference in apo epsilon4 allelic frequency between these two groups was found. CONCLUSION: The apo epsilon4 allele was not associated with MDD in this study. However, the finding of a lower frequency of the apo epsilon2 allele in MDD could lead to the conclusion that the apo epsilon2 allele likely provides a protective effect against MDD in the Taiwanese population.     

抑郁障碍的眼动指标研究

背景：认知受损是抑郁障碍常见的核心症状之一,眼动（eye movement）检查主要反映患者的认识、记忆、注意及再认、回忆比较等方面的认知功能,对研究抑郁发作的认知功能有一定的理论和实践意义。目的：探究从未服药抑郁障碍患者眼动指标是否异常以及这些指标与精神症状的关系。方法：纳入60例抑郁障碍患者和性别、年龄及教育年限匹配的60例健康志愿者进行注视稳定性、跳视、自由视图三个任务的眼球运动测试,应用EyeLink桌面式眼动仪收集眼动信息,分析比较两组三个任务的眼动指标。结果：（1）注视稳定性任务中,相对于健康对照,抑郁障碍患者在无干扰任务和有干扰任务中都呈现注视次数增加、注视时间缩短、跳视次数增加、跳视路径增加;（2）跳视任务中,抑郁障碍患者反向跳视潜伏期延长,反向跳视峰速度减小;（3）自由视图任务中,抑郁障碍患者扫视次数减少、平均注视时间延长;（4）相关分析显示：朝向跳视幅度与焦虑症状呈负相关,反向跳视潜伏期与焦虑症状呈正相关,自由视图任务的注视次数、跳视次数、扫视路径与抑郁障碍症状呈负相关,而平均注视时间与抑郁障碍症状呈正相关。结论：抑郁障碍患者较健康对照眼动指标存在明显异常,且患者的焦虑、抑郁症状与眼动指标有相关性,其病理生理学意义值得进一步探究。     

Lack of association between alpha1-antichymotrypsin polymorphism and late-onset depressive disorder

Late-onset depressive disorder (LOD) has been thought to be associated with dementia. Recently, it was reported that the position-15 (alanine) polymorphism of the alpha1-antichymotrypsin gene (ACT*A) was a risk factor for Alzheimer's disease. We wondered whether the ACT*A allele frequency might be elevated in LOD. ACT genotyping was performed as described by Kamboh et al. (Kamboh, M.I., Sanghera D.K., Ferrell R.E., DeKosky, S.T., 1995. APO* E4-associated Alzheimer's disease risk is modified by alpha1-antichymotrypsin polymorphism. Nature Genetics 10, 486-488) in 153 patients with depressive disorders and 107 healthy controls. The patients were subdivided into those with early-onset and late-onset, using 50 years as the cut-off age. There was no statistically significant difference in the age of onset of depressive disorders according to the ACT genotype. There was also no significant association between early-/late-onset depressive disorders and the ACT genotype. In addition, there was no association between the apolipoprotein E epsilon 4 allele and the ACT genotype in LOD. Our results suggest that there is no association between the ACT*A allele and LOD.     

首发精神分裂症与双相障碍及抑郁障碍认知功能比较

目的探讨首发精神分裂症、双相障碍及抑郁障碍患者认知功能差异。方法纳入首发精神分裂症患者61例,双相障碍患者57例,抑郁障碍患者48例,另设正常对照59名。所有研究对象采用重复性神经心理测查系统(Repeatable Battery for the Assessment of Neuropsychological Status,RBANS)评估认知功能,首发精神分裂症组采用阳性和阴性症状量表(positive and negative syndrome scale,PANSS)评定精神病性症状,双相障碍组、抑郁障碍组采用汉密尔顿抑郁量表(Hamilton depression scale,HAMD)、汉密尔顿焦虑量表(Hamilton anxiety scale,HAMA)评估抑郁和焦虑症状,贝克—拉范森躁狂(Bech-Rafaelsen mania scale,BRMS)量表评估躁狂症状。结果 4组对象的RBANS总分(F=5.18,P0.01)、即刻记忆(F=4.09,P0.01)、言语功能(F=9.53,P0.01)、注意(F=3.87,P=0.01)、延时记忆(F=9.86,P0.01)因子得分差异具有统计学意义,其中首发精神分裂症、双相障碍组RBANS总分低于对照组(P0.01),首发精神分裂症、双相障碍、抑郁障碍组即刻记忆、言语功能、延时记忆得分低于对照组(P0.05),双相障碍组言语功能得分低于首发精神分裂症组(P0.01),首发精神分裂症组注意得分低于抑郁障碍及对照组(P0.01)。结论首发精神分裂症、双相障碍、抑郁障碍患者均存在认知功能损伤,首发精神分裂症认知功能缺陷重于抑郁障碍,轻于双相障碍。