BDNF and NRG1 polymorphisms and temperament in selective serotonin reuptake inhibitor-treated patients with major depression.

OBJECTIVE: We investigated the separate effects of and possible interactions between the functional polymorphisms of brain-derived neurotrophic factor (BDNF) rs11030101, BDNF rs61888800, and neuregulin-1 (NRG1) rs3924999 and NRG1 rs6994992 on change of temperament scores in a clinical sample of subjects with major depression (MDD), who received selective serotonin reuptake inhibitor treatment for a period of 6 weeks. METHODS: The study population consisted of 98 Finnish individuals with MDD. They were assessed by the 107-item Temperament and Character Inventory temperament questionnaire (version IX) and the Montgomery-Åsberg Depression Rating Scale (MADRS). In general linear univariate models (GLM) for novelty seeking (NS) or reward dependence (RD) change age, gender, MADRS score change and BDNF and NRG1 genotypes were used as explaining explanatory variables. RESULTS: Mean comparisons between corresponding temperament dimensions and genotypes showed significant differences between NS change and BDNF rs61888800 T-carrying status (mean difference: GG 0.30, GT/TT 2.47, p=0.022, t-test) and between RD change and NRG1 rs3924999 A-carrying status (mean difference: GG 1.21, GA/AA -0.33, p=0.003). In GLM models for NS change the significant predictors comprised BDNF rs61888800 T-carrying status, age and MADRS score change (model 1), and additionally NRG1 rs6994992 T-carrying status (model 2). For RD change the predictors included NRG1 rs3924999 A-carrying status, age and MADRS score change (model 1) and additionally gender (model 2). CONCLUSION: According to the current results both BDNF and NRG1 are associated with temperament traits during depression. These results warrant further studies regarding the impact of this association on depression recovery.

SERT and NET polymorphisms, temperament and antidepressant response.

BACKGROUND: The genetic variations in norepinephrine transporter (NET) and serotonin transporter (SERT) genes have been associated with personality traits, several psychiatric disorders and the efficacy of antidepressant treatment. AIMS: We investigated the separate effects and possible interactions between NET T-182C (rs2242446) and SERT 5-HTTLPR (rs4795541) polymorphisms on selective serotonin reuptake inhibitors (SSRI) treatment response and temperamental traits assessed by the Temperament and Character Inventory (TCI) in a clinical sample of subjects with major depressive disorder (MDD). METHODS: Our sample of 97 patients with major depression completed the 107-item TCI temperament questionnaire (version IX) at the initial assessment of the study and after 6 weeks of follow-up. All subjects received selective SSRI medications. Temperament dimension scores at baseline ( 1 ) and endpoint ( 2 ) during antidepressant treatment were analyzed between NET and SERT genotypes. RESULTS: SS-genotype of 5-HTTLPR was associated with higher baseline Persistence scores than SL- or LL-genotype. A corresponding but weaker association was found at endpoint. No differences were found between 5-HTTLPR genotypes and other temperament dimensions and 5-HTTLPR genotypes had no effect on treatment response. CONCLUSIONS: Our results suggest that the SS-genotype of 5-HTTLPR is associated with Persistence scores in patients with MDD. Higher Persistence could be viewed as a negative trait when recovering from stress and its association with short and "weaker" S-allele may be related to less efficient serotonin neurotransmission, possibly resulting in less effective coping strategies on a behavioral level.

TPH1 A218C polymorphism and temperament in major depression.

BACKGROUND: In major depression, one of the candidate genes possibly affecting the risk and severity of symptoms has been found to be tryptophan hydroxylase (TPH1). Variation in treatment response to antidepressive agents according to TPH1 genotype has also been found in several studies. However, the relationship between temperament and TPH1 genotype in major depression is poorly understood, as only one study has been published so far. There are no earlier studies on the interaction between temperament traits, antidepressive medication response and TPH1 genotype. This interaction was studied in 97 subjects with major depression treated for six weeks with selective serotonine reuptake inhibitors. METHODS: Temperament dimensions Harm Avoidance (HA), Novelty Seeking (NS), Reward Dependence (RD) and Persistence (P) scores at baseline (1) and endpoint (2) were rated with the Temperament and Character Inventory (TCI) and compared between TPH1 A218C genotypes. Multivariate analysis of co-variance (MANCOVA) was used to analyze the interaction between the TPH1 genotype, treatment response and the different temperament dimensions at baseline and endpoint. In the analysis model, treatment response was used as a covariate and TPH1 genotype as a factor. A post hoc analysis for an interaction between remission status and TPH1 A218C genotype at endpoint HA level was also performed. RESULTS: The number of TPH1 A-alleles was associated with increasing levels in NS1 and NS2 scores and decreasing levels in HA1 and HA2 scores between TPH1 A218C genotypes. In the MANCOVA model, TPH1 genotype and treatment response had an interactive effect on both HA1 and HA2 scores, and to a lesser degree on NS2 scores. Additionally, an interaction between remission status and TPH1 A218C genotype was found to be associated with endpoint HA score, with a more marked effect of the interaction between CC genotype and remission status compared to A-allele carriers. CONCLUSIONS: Our results suggest that in acute depression TPH1 A218C polymorphism and specifically the CC genotype together with the information on remission or treatment response differentiates between different temperament profiles and their changes.

Is 5-HTTLPR linked to the response of selective serotonin reuptake inhibitors in MDD?

The role of a functional polymorphism in the transcriptional control region of serotonin transporter gene (5-HTTLPR, SERTPR) has been studied intensively in major depression and in the response to selective serotonin inhibitors (SSRIs) in major depression. The findings have been contradictory, although majority of the studies indicate that the short allele is associated with poor response to SSRIs in major depression. In the present study, we evaluated the association of 5-HTTLPR with treatment response to SSRI medication in Finnish Caucasian MDD patients. A secondary purpose was to study the possible association of this particular polymorphism with major depressive disorder. The aim of the study was to replicate the previous findings in this area. Primary outcomes of the treatment were remission, defined by an exit score of seven or less, and response, defined by a reduction of at least 50% on the MADRS. We had also a control population of 375 healthy blood donors, as a secondary objective was to evaluate the possible association of this particular polymorphism with major depressive disorder. Twenty-nine of the 85 (34.1%) patients reached the remission and 58.8% achieved the predefined response criteria. The l/l genotype of 5-HTTLPR was presented in 51.7% of those patients who achieved remission vs. 25.0% in the non-remitters (P = 0.03). The result remained statistically significant after adjusting for age, gender, medication and MADRS points at the study entry. However, the small sample size limits the reliability of this result.

Temperament profiles, 5-HT2A genotype, and response to treatment with SSRIs in major depression.

Variation in antidepressive medication response according to 5-HT2A genotype has been reported in several studies. Temperament has been proposed to be one of the vulnerability factors in mood and anxiety disorders. We studied temperament profiles of 98 patients with major depression and explored the interaction between Temperament and Character Inventory (TCI) temperament dimensions, 5-HT2A genotype (SNPs rs6311, rs6313 and rs7997012) and treatment response. No interactive effects for TCI temperament dimensions and 5-HT2A genotypes on antidepressive treatment response were found.

Catechol-O-methyltransferase val108/158met genotype, major depressive disorder and response to selective serotonin reuptake inhibitors in major depressive disorder.

The functional val108/158met polymorphism of the COMT gene (rs4680) was evaluated in major depressive disorder (MDD), and in the treatment response to antidepressants in MDD. We could not demonstrate any significant difference in the distribution of this COMT single-nucleotide polymorphism (SNP) in the treatment response to selective serotonin reuptake inhibitors or between patients with MDD and control subjects.

A cluster model of temperament as an indicator of antidepressant response and symptom severity in major depression.

OBJECTIVE: Not enough is known about which patients suffering from major depressive disorder benefit from antidepressant drug treatment. Individual temperament is relatively stable over a person's lifespan and is thought to be largely biologically predefined. We assessed how temperament profiles are related to depression and predict the efficacy of antidepressant treatment. METHODS: We recruited one hundred Finnish outpatients (aged 19 to 72) suffering from major depressive disorder, of whom 86 completed the 6-week study. We assessed their temperament features with the Temperament and Character Inventory and used cluster analysis to determine the patient's temperament profile. We also categorized the patients according to the vegetative symptoms of major depressive disorder. RESULTS: There was an association between skewed temperament profile and severity of major depressive disorder, but the temperament profiles alone did not predict antidepressant treatment response. Those with higher baseline vegetative symptoms score had modest treatment response. Our model with baseline Montgomery Åsberg Depression Rating Scale (MADRS) vegetative symptoms, age and temperament clusters as explanatory variables explained 20% of the variance in the endpoint MADRS scores. CONCLUSION: The temperament clusters were associated both with severity of depression and antidepressive treatment response of depression. The effect of the temperament profile alone was modest but, combined with vegetative symptoms of depression, their explanatory power was more marked suggesting that there could be an association of these two in the biological basis of MDD.

No support for a role for BDNF gene polymorphisms rs11030101 and rs61888800 in major depressive disorder or antidepressant response in patients of Finnish origin.

Brain-derived neurotrophic factor (BDNF) is suggested to play a role in the aetiology of major depression and in the antidepressant response in patients with major depression. Several BDNF gene polymorphisms have been investigated in the above-mentioned context. The aim of the present study was to examine the role of two BDNF gene polymorphisms (rs11030101 and rs61888800) in relation to the response to selective serotonin reuptake inhibitor medication in 106 patients of Finnish origin suffering from major depression. The secondary objective was to evaluate the association of these two BDNF polymorphisms in major depression, as we also had a control population of 386 healthy individuals. We did not find any significant differences in the distribution of these two BDNF gene polymorphisms in our patient population in relation to remission or response to treatment with selective serotonin reuptake inhibitor. Also, there were no significant differences between the patients and the controls.

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.

Interaction between two HTR2A polymorphisms and gender is associated with treatment response in MDD.

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.

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 Asberg Depression Rating Scale (MADRS). Patients scoring <8 in post-treatment MADRS were considered remitters. There was a trend that CC genotype of VEGF 2578C/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.

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.

5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression.

Genes that regulate the serotonin signalling system are potential targets for research in the aetiology of mood disorders and also in the treatment response of serotonin reuptake inhibitors. In this study, we evaluated the association of seven serotonin signal transduction-linked single nucleotide polymorphisms [HTR1A (rs6295), HTR2A (rs6313, rs6311 and rs7997012), HTR6 (rs1805054), TPH1 (rs1800532) and TPH2 (rs1386494)] with major depressive disorder and/or treatment outcome with serotonin reuptake inhibitors. Patients who met the criteria for major depressive disorder were treated for 6 weeks with fluoxetine, paroxetine or citalopram. The treatment response was evaluated with the Montgomery-Asberg Depression Rating Scale, and according to predefined response criteria, the patients were divided into responders, nonresponders, remitters and nonremitters. Altogether, 86 patients completed the entire study according to the study protocol. We had also a control population (N = 395) of healthy blood donors. None of the seven single nucleotide polymorphisms was associated with major depressive disorder or with treatment response in our study population of Finnish individuals.