Dopamine 2 receptor C957T and catechol-o-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy

Alterations in dopamine levels and dopamine receptors in brain are suggested to be associated with treatment response in electroconvulsive therapy (ECT). Dopamine 2 receptor gene (DRD2) polymorphism C957T (rs6277) and cathechol-o-methyltransferase (COMT) polymorphism Val158Met (rs4680) interaction was studied in 118 patients suffering from major depressive disorder (MDD) treated with ECT and 383 healthy controls. It was found that the combination of COMT Met allele and DRD2 T allele predicted more severe depression in those already affected but did not predict the risk of depression when compared to normal population. The genotype modified the response to ECT. The patients with TT genotype of D2 receptor gene C957T polymorphism combined with COMT gene polymorphism Met/Met genotype did not achieve remission as often as those with CC genotype of DRD2 C957T combined with COMT Val/Val genotype. Thus the interaction of these polymorphisms may be associated with response to ECT.     

Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression

Antidepressive medication and electroconvulsive therapy (ECT) increase hippocampal neurogenesis by promoting expression of trophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The aims were to test for an association between the VEGF 2578 C/A polymorphism and major depressive disorder (MDD) in two patient populations compared to controls, and the association between this polymorphism and response to serotonin selective reuptake inhibitors (SSRI) and to ECT. The first patient sample consisted of 119 subjects with treatment resistant major depressive disorder who were treated with ECT and the second of 98 depressive patients treated with SSRI. Treatment response was assessed by the Montgomery and Åsberg Depression Rating Scale (MADRS). Patients scoring <8 in post-treatment MADRS were considered remitters. There was a trend that CC genotype of VEGF 2578 C/A polymorphism was more common in ECT-treated and SSRI-treated patients than in controls (31.1%, 25.5% and 18.7% respectively; p = 0.056). The VEGF 2578 C/A polymorphism was associated with treatment resistant MDD. CC genotype was more common in ECT patients than in controls (31.1% and 18.7% respectively; p = 0.015). The VEGF 2578 C/A polymorphism was not associated with treatment response to SSRI or to ECT. The finding suggests an association between VEGF 2578 C/A polymorphism and treatment resistant depression which is reported for the first time. Further studies with larger samples will be required to confirm the results.     

P2RX7 polymorphisms Gln460Arg and His155Tyr are not associated with major depressive disorder or remission after SSRI or ECT

Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) gene polymorphism, has been suggested to be associated with major depressive disorder (MDD). The association between P2RX7 gene polymorphism and remission after serotonin selective reuptake inhibitors (SSRI) or electroconvulsive therapy (ECT) has not previously been studied. The aims of the present study were to test for an association between P2RX7 polymorphisms Gln460Arg (rs2230912) and His155Tyr (rs208294) and MDD in two patient populations compared to controls. The first patient sample consisted of 119 subjects with treatment-resistant major depressive disorder, who were treated with ECT and the second of 99 depressive outpatients treated with SSRI. Genotype frequencies were also compared between remitters (Montgomery and Åsberg Depression Rating Scale (MADRS) < 8) and non-remitters (defined as MADRS ≥ 8) to SSRI or ECT treatment. There were no differences in allele or genotype frequencies of either rs2230912 or rs208294 between patient groups and controls. Neither rs2230912 nor rs208294 was associated with MDD or remission after SSRI or ECT. The results suggest that P2RX7 gene polymorphisms Gln460Arg (rs2230912) and His155Tyr (rs208294) are not associated with MDD or remission after SSRI or ECT.     

TPH1 218A/C polymorphism is associated with major depressive disorder and its treatment response

The association between the tryptophan hydroxylase 1 (TPH1) 218A/C polymorphism and (1) severity of major depressive disorder (MDD) and (2) response to treatment was studied. There were three study populations, the first consisting of 119 treatment-resistant MDD inpatients treated with electro-convulsive therapy (ECT), and the second of 98 MDD open care patients treated with selective serotonin reuptake inhibitors (SSRI). In addition, there was a control population of 395 healthy blood donors. The first aim of the study was to compare the genotypes of the patient with those of the healthy controls and between patient populations. The second aim was to compare the genotypes of MDD patients achieving remission with basic SSRI treatment (MADRS < 8) with the genotypes of non-responders to ECT (defined as MADRS > 15). TPH1 218A/C polymorphism was associated with the risk of MDD. CC genotype was significantly more common in patients (including both ECT and SSRI treated patients) than in controls (38.2% and 26.8% respectively; p = 0.008), and its frequency was significantly higher in more severe forms of depression, i.e. in ECT treated patients compared with SSRI treated patients (42.0% and 33.7%, p = 0.026). CC genotype was also associated with lower probability of achieving remission. It was significantly more frequent among ECT non-responders than among SSRI remitters (53.1% and 23.3%, p = 0.049). In this Finnish population TPH1 218A/C polymorphism was associated with the risk of MDD and treatment response; CC genotype was associated with the increased risk of MDD and lower probability of responding treatment. Further studies with larger samples will be required to confirm the results.     

ACE polymorphism and response to electroconvulsive therapy in major depression

The angiotensin I-converting enzyme gene (ACE) has been repeatedly suggested as a major gene affecting affective disorders and their treatment, but the study results have been ambiguous so far. The primary purpose of this study was to compare the effects of the ACE genotype distributions and treatment response to electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). The association in ACE genotypes and the age at onset of depression was also analyzed and these gene distributions were also compared between patients and healthy controls. The study included 119 treatment-resistant MDD patients who were referred to ECT treatment, and 392 voluntary blood donors as controls. All participants were tested for their ACE genotype, and all study patients were evaluated both before and after treatment. The Montgomery–Åsberg Depression Scale (MADRS) was used as a primary efficacy evaluating method. The ACE genotype was not associated in treatment results for MDD. However, younger onset age of primary depression was associated with the I/D genotype in the whole patient group. The finding was partly gender dependent; in male patients the I allele carried a higher risk of earlier depression onset age, while in female patients the higher risk was seen only in the heterozygous I/D allele carriers. Distributions of these genotypes or alleles did not differ between patients and controls. The studied ACE genotype was not associated with ECT results but may be associated with age of onset of the illness in patients with MDD.     

α₁-Noradrenegic receptor antagonism disrupts female songbird responses to male song

The 5HT2A receptor gene (HTR2A) polymorphisms rs7997012 and rs6311 have in some earlier studies been associated with serotonin selective reuptake inhibitor (SSRI) treatment response in major depressive disorder (MDD), but the findings are inconsistent. The aim of the present study was to test for an association between two HTR2A polymorphisms (rs7997012 and rs6311), their interaction and the Montgomery and Åsberg Depression Rating Scale (MADRS) score change after ECT or SSRI treatment. The total number of patients was 218. All were treated in outpatient care. Of these, 119 subjects had treatment-resistant MDD and were treated with ECT and 99 were depressive patients treated with SSRI. Treatment response was assessed by MADRS. Patients scoring <8 on post-treatment MADRS were considered remitters. Neither rs7997012 nor rs6311 HTR2A polymorphism was significantly associated with MADRS score change alone, but the interaction between them and gender explained 14% of the variance in MADRS score change. The finding suggests an association between MADRS score change and interaction of HTR2A polymorphisms, rs7997012 and rs6311 and gender.     

The importance of Axis II in patients with major depression. A controlled study

Using a naturalistic study design, we compared 76 depressed patients having a DSM-III personality disorder (PD) to a control group of 152 depressed patients with no personality disorder. The patients with major depressive disorder (MDD) and a PD were more likely to have had a younger age of onset, to have had prior hospitalizations, to have a longer duration of episode, to have reported more suicidal thoughts, and to have had more suicide attempts both before and after discharge. Patients with MDD and PD were also more likely to have a family history of alcoholism or antisocial personality and less likely to have dexamethasone nonsuppression, although the latter was not statistically significant. Patients with MDD and PD were less likely to receive electroconvulsive therapy (ECT), equally likely to have received antidepressants, and more likely to receive neither ECT nor antidepressants. Patients with MDD and PD had a poorer response to 'adequate' antidepressants, but a similar response to ECT and 'inadequate' antidepressants. Overall, 91 (60%) of MDD patients and 32 (42%) of MDD plus PD patients were recovered at hospital discharge (X2 = 6.43, P less than 0.025). We conclude that the presence of PD in patients with MDD is associated with a different clinical presentation, family history, and poor recovery at hospital discharge.     

Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment‐resistant depression; disorder severity and unfavorable treatment outcomes are shown to be influenced by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment and response/nonresponse are associated with an increased genetic burden for major depression (MD) using polygenic risk score (PRS), which summarize the contribution of disease‐related common risk variants. Fifty‐one psychiatric inpatients suffering from a major depressive episode underwent ECT. MD‐PRS were calculated for these inpatients and a separate population‐based sample (n = 3,547 healthy; n = 426 self‐reported depression) based on summary statistics from the Psychiatric Genomics Consortium MDD‐working group (Cases: n = 59,851; Controls: n = 113,154). MD‐PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = .022, R² = 1.173%); patients showed higher MD‐PRS. MD‐PRS in population‐based depression self‐reporters were intermediate between ECT patients and controls (n.s.). Significant associations between MD‐PRS and ECT response (50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate that ECT cohorts show an increased genetic burden for MD and are consistent with the hypothesis that treatment‐resistant MD patients represent a subgroup with an increased genetic risk for MD. Larger samples are needed to better substantiate these findings.     

TPH2 polymorphisms may modify clinical picture in treatment-resistant depression

The association of two tryptophan hydroxylase 2 (TPH2) polymorphisms and treatment response in electroconvulsive therapy (ECT) and the risk of depression was studied. The patient sample consisted of 119 subjects with treatment-resistant major depressive disorder who were treated with ECT. Treatment response was assessed by the Montgomery and Åsberg Depression Rating Scale (MADRS) scores. Patients who had <8 scores in post-treatment MADRS were considered remitters; scores >15 indicated non-response. The polymorphisms studied (rs1386494 and rs1843809) were not associated with treatment response to ECT. However, TPH2 rs1386494 A/A genotype carrying patients had significantly higher MADRS scores before ECT than A/G + G/G genotype carriers (p < 0.001). A/A genotype carriers also had a greater decline in MADRS scores than A/G + G/G genotype carriers during the course of ECT treatment (p = 0.03). This polymorphism may be associated with the severity of treatment-resistant depression. ECT may able to counteract a putative genetically driven worse depressive phenotype.     

No association between the tryptophan hydroxylase gene polymorphism and major depressive disorders and antidepressant response in a Korean population

The serotonergic neurotransmitter system has been implicated in major depressive disorder (MDD) and appears to be the target of a variety of antidepressants. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis, and selective serotonin re-uptake inhibitors exert their activity enhancing the general serotonergic tone. The goal of this study was to investigate whether the A218C polymorphism of the TPH gene is associated with MDD or antidepressant response. All patients were evaluated at the start and in the eighth week of using the 21-item Hamilton Depression Rating Scale. Genotyping was analyzed with polymerase chain reaction. There were no significant differences in genotypes and allele frequencies between the MDD patients (n = 93) and the control group (n = 127) and in the antidepressant response among TPH gene variants. Results suggest that the A218C polymorphism of the TPH gene does not play a major role in pathogenesis in MDD and does not serve as a modulator of antidepressant activity.     

Sensitivity to cholecystokinin-tetrapeptide in major depression

Background: Sensitivity to the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) is enhanced in panic disorder patients relative to normal controls (NC). In the present study, we determined whether sensitivity to CCK-4 is enhanced in patients with major depressive disorder (MDD) with no history of panic attacks. We also determined whether CCK-4 would exacerbate depressive symptoms. Methods: The study used a double-blind, randomized, placebo-controlled design. Behavioral and cardiovascular response to a submaximal dose (20 μg) of CCK-4 was studied in seven patients with MDD and 12 NC subjects. Results: None of the subjects panicked with placebo, whereas 29% of MDD and 17% of NC subjects panicked with CCK-4. There was no significant difference between groups on the frequency of CCK-4-induced panic or the number and intensity of panic symptoms. No significant difference was detected for cardiovascular response to the CCK-4 challenge. CCK-4 did not worsen depressive symptoms in MDD patients. Limitations: Small number of study subjects. Conclusions: These data indicate that MDD patients show a response to CCK-4 that is comparable to NC. The lack of effect of CCK-4 on depressive symptoms suggest that central CCK receptors may not play an important role in the pathophysiology of MDD.     

三等位基因5-HTTLPR与青少年重性抑郁障碍的关联研究

目的:探讨三等位基因5-羟色胺转运体基因连锁多态区多态性(5-HTTLPR+rs25531)与青少年重性抑郁障碍之间有无关联。方法:404名研究对象(病例187人,正常对照217人)使用SNaPshot系统进行基因分型。结果:三等位基因5-HTTLPR与青少年抑郁症是否患病、抑郁严重程度、是否共病焦虑、是否出现自杀观念/行为/企图均无关。结论:尚不能认为三等位基因5-HTTLPR与青少年重性抑郁障碍有关。     

Serious life events among resistant and non-resistant MDD patients

BACKGROUND: Over 60% of patients with major depressive disorder (MDD) do not respond fully to therapy. Half of them eventually will not respond at all and will be referred to as treatment resistant depression (TRD) patients. Stressful life events were found to be associated with MDD and were also found to affect the course of the disease. We hypothesize that negative life events might be an independent risk factor for TRD. METHODS: One hundred and seven unipolar MDD patients, all treated for at least 4 weeks, were enrolled in the study. Patients were assessed on their psychiatric and medical history, and seven categories of stressful life events. RESULTS: 39.3% of participants were defined as TRD patients and 60.7% as non-TRD. TRD patients had more severe depression, more past suicide attempts, more hospitalizations, longer episodes, and received more benzodiazepines, antipsychotics, and ECT. Job loss and financial stress were more prevalent among the TRD group. Overall, the TRD patients had more negative life events than responders. LIMITATIONS: This is a retrospective study. In addition, the definition of TRD was done dichotomically, therefore the association between number of stressful life events and the degree of resistance was not tested. CONCLUSIONS: Job loss and financial distress were found to predict TRD. The loss of a parent and severe health conditions were not associated with TRD, suggesting that events affecting the development of MDD, do not necessarily affect the treatment outcome.     

Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling

Disrupted-in-schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and bipolar disorder. Although there are a number of patients with major depressive disorder (MDD) in the family members with the chromosome translocation, the possible association with MDD has not yet been studied. We therefore performed an association study of the DISC1 gene with MDD and schizophrenia. We found that Cys704 allele of the Ser704Cys single-nucleotide polymorphism (SNP) was associated with an increased risk of developing MDD (P=0.005, odds ratio=1.46) and stronger evidence for association in a multi-marker haplotype analysis containing this SNP (P=0.002). We also explored possible impact of Ser704Cys on brain morphology in healthy volunteers using MR imaging. We found a reduction in gray matter volume in cingulate cortex and a decreased fractional anisotropy in prefrontal white matter of individuals carrying the Cys704 allele compared with Ser/Ser704 subjects. In primary neuronal culture, knockdown of endogenous DISC1 protein by small interfering RNA resulted in the suppression of phosphorylation of ERK and Akt, whose signaling pathways are implicated in MDD. When effects of sDISC1 (Ser704) and cDISC1 (Cys704) proteins were examined separately, phosphorylation of ERK was greater in sDISC1 compared with cDISC1. A possible biological mechanism of MDD might be implicated by these convergent data that Cys704 DISC1 is associated with the lower biological activity on ERK signaling, reduced brain gray matter volume and an increased risk for MDD.     

Major depressive disorder with anger: a bipolar spectrum disorder?

BACKGROUND: Depression with anger may be more common in bipolar disorders. The aim of the study was to assess whether major depressive disorder (MDD) with anger could be included in the bipolar spectrum, by comparing it to MDD without anger and to bipolar II disorder. METHODS: Consecutive outpatients (281 bipolar II disorder and 202 MDD) presenting for major depressive episode (MDE) treatment were interviewed with the DSM-IV structured clinical interview. Clinical variables used to support the inclusion of MDD with anger in the bipolar spectrum were age of onset, many MDE recurrences, atypical features of depression, depressive mixed state (an MDE plus some concurrent hypomanic symptoms), and bipolar family history. RESULTS: Frequency of MDE with anger was 50.5% [61.2% in bipolar II, and 35.6% in MDD (z = 5.5, p = 0.0000, 95% CI 16.8-43.3%)]. Logistic regression of MDE with anger (dependent variable) versus bipolar variables showed that MDE with anger was significantly associated with all bipolar variables, apart from recurrences. MDD with anger, compared with MDD without anger, had significantly lower age of onset, more marked depressive mixed state, a bipolar family history with more cases, but comparable atypical features and Global Assessment of Functioning scores. MDD with anger, compared with bipolar II disorder, had significantly higher age of onset, less atypical features, and a bipolar family history with less cases. CONCLUSIONS: MDE with anger was common in outpatients (more in bipolar II disorder). MDD with anger may be midway between MDD without anger and bipolar II disorder, and might be included into the bipolar spectrum. However, MDD with anger does not appear to be associated with the often reported negative response to monotherapy with antidepressants.     

Association study of p11 gene with major depressive disorder, suicidal behaviors and treatment response

The p11 protein (also called S100A10), which plays a pivotal role in the dynamic modulation of serotonergic 1B receptor function, has been implicated in the pathogenesis of major depressive disorder (MDD) and the therapeutic mechanisms of antidepressant action. Humans and mice with depression have lower central p11 levels, and treatment with antidepressant agents raises p11 levels in animals. Furthermore, brain p11 mRNA expression is lower in post mortem brains from patients who were suffering from depression and had committed suicide compared with control subjects who had died from other causes. From the above findings, the p11 gene may be considered a candidate gene for the investigation of MDD susceptibility, response to antidepressants or the likelihood of attempting suicide. Three p11 polymorphisms were genotyped in 470 patients with MDD and 447 normal controls. No significant association with MDD was discovered in single locus or haplotype analyses. The analysis for genotypic effects showed no significant association between any of the three p11 single nucleotide polymorphisms (SNPs) and MDD therapeutic response. With regard to the risk of suicide attempt, 51 of the 470 MDD patients were found to have attempted suicide in the depressive episode during which they were monitored. No significant association with suicide attempt was shown in both the alleles and genotypes of single loci or of haplotypes constructed from these three p11 polymorphisms. Our findings suggest that p11 genetic variants do not play a major role in the MDD susceptibility, antidepressant therapeutic response or the risk of suicide attempt in MDD.     

Association between the so-called “activation syndrome” and bipolar II disorder,a related disorder,and bipolar suggestive features in outpatients with depression

Background

Activation syndrome (AS) is a cluster of symptoms listed by the US Food and Drug Administration as possible suicidality precursors during antidepressant treatment. We aimed to clarify whether AS is associated with bipolar II disorder (BP-II) and its related disorder, i.e., bipolar disorder not otherwise specified (BP-NOS), which are often mistreated as major depressive disorder (MDD), as well as bipolar suggestive features in outpatients with depression.

Methods

The frequency of AS, bipolar suggestive features, and background variables in consecutive outpatients with a major depressive episode (MDE) due to BP-II/BP-NOS or MDD, who were naturalistically treated with antidepressants, were investigated and analyzed retrospectively.

Results

Of 157 evaluable patients (46 BP-II/BP-NOS, 111 MDD), 39 (24.8%) experienced AS. Patients with BP-II/BP-NOS experienced AS significantly more frequently than patients with MDD (52.2% of BP-II/BP-NOS vs. 13.5% of MDD, p<0.01). Univariate analysis revealed that BP-II/BP-NOS diagnosis, cyclothymic temperament, early age at onset of first MDE, psychiatric comorbidities, and depressive mixed state (DMX) were significantly associated with AS development in the entire sample. Multivariate analysis revealed that BP-II/BP-NOS diagnosis and DMX were independent risk factors for AS.

Limitations

This is a retrospective and naturalistic study; therefore, patient selection bias could have occurred.

Conclusions

Cautious monitoring of AS is needed during antidepressant trials in patients with BP-II/BP-NOS. Clinicians should re-evaluate underlying bipolarity when they confront AS. Antidepressants should be avoided for treating a current DMX beyond the unipolar–bipolar dichotomy. Prospective studies are needed to confirm these results.     

Influence of episode duration of major depressive disorder on response to electroconvulsive therapy

BACKGROUND: Longer duration of major depressive episode is supposed to decrease response to electroconvulsive therapy (ECT). Most studies on the subject are dated and their population differs from ours, therefore their results may not be applicable to our population of severely depressed inpatients. METHODS: We reviewed the records of 56 consecutive inpatients with major depressive disorder according to DSM-III-R criteria and assessed each patient's episode duration. We examined whether episode duration has an effect on response to ECT. RESULTS: Episode duration has no significant effect on response to ECT, according to both a reduction on the Hamilton Rating Scale for Depression (HRSD) of at least 50% and a post-treatment HRSD score 相似文献   

Are treatment emergent suicidality and decreased response to antidepressants in younger patients due to bipolar disorder being misdiagnosed as unipolar depression?

While antidepressants have been demonstrated to be a safe and effective treatment for unipolar major depressive disorder (MDD) in adults, the use of antidepressants to treat children and adolescents is controversial. There is a paucity of evidence to suggest that antidepressants are effective when used to treat children and adolescents and some recent placebo-controlled evidence has suggested that antidepressant treatment increases suicidality in this population. MDD is a very broad construct, and includes many clinical subtypes. Bipolar Disorder (BD) has an earlier age of onset than MDD. The initial polarity of illness in bipolar disorder is frequently depression. Patients are more likely to first present for treatment during the depressive phase of the illness than during manic or hypomanic phases. It is probable that a substantial portion of depressed children and adolescents may not suffer from unipolar MDD but may have a bipolar spectrum disorder. There are few trials supporting the efficacy of antidepressants in bipolar disorder, and some evidence that they may induce rapid cycling, switching and mania. Antidepressant induced mania is often mixed, with admixtures of manic and depressive features. An increased suicide risk is a particular feature of mixed states, potentially explaining why suicidal ideation can emerge with antidepressant treatment. Antidepressants are unlikely to somehow act differently in children than they do in adults. A more plausible explanation is that incipient bipolar disorder is often not diagnosed early in children and adolescents and the differential effects of antidepressants in this group is a result of differing diagnostic casemixes.     

缓解期重性抑郁与心境恶劣患者人格特征及人格障碍研究

目的：研究重性抑郁症(MDD)和心境恶劣障碍(DD)患者在人格维度、人格特质水平及人格模型及人格障碍倾向性方面的特征。方法：采用NEO-PI-R个性调查表及人格诊断问卷(PDQ^ 4)对58例MDD和57例DD患者及115例正常人进行测试。结果：MDD和DD在NEO-PI-R的五因素人格模型的外向性、严谨性得分均低于正常组，DD患者的神经质分高于MDD患者，MDD患者的顺同性分高于正常组；在30个特质层面上，MDD和DD与正常组之间有显著性差异，DD患者的N1(焦虑)、N4(自我意识)分明显高于MDD患者，E4(热情性)、A1(信任感)分明显低于MDD患者；MDD和DD在PDQ^ 4的边缘型(BDL)、回避型(AVD)、抑郁型(DEP)、分裂性(SZD)、偏执型(PND)、强迫型(OBC)人格障碍得分明显高于正常组，DD患者在分裂型得分明显高于MDD患者，在表演型(HST)分明显高于正常组。结论：MDD和DD的人格特征既有共同的之处，也存在差异。两者均伴有人格障碍，但DD患者比MDD患者人格障碍更明显。