Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to ...antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS,
= 529) and the International SSRI Pharmacogenomics Consortium (ISPC,
= 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at
< 0.05 across P
thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near
gene and (b) SSRI remission and neuroticism eight loci near
, and
genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.
Schizophrenia is a common psychiatric disease affecting about 1% of population. One major problem in the treatment is finding the right the drug for the right patients. However, pharmacogenetic ...results in psychiatry can seldom be replicated.
We selected three candidate genes associated with serotonergic neurotransmission for the study: serotonin 2A (5-HT2A) receptor gene, tryptophan hydroxylase 1 (TPH1) gene, and G-protein beta-3 subunit (GNB3) gene. We recruited 94 schizophrenia patients representing extremes in treatment response to typical neuroleptics: 43 were good responders and 51 were poor responders. The control group consisted of 392 healthy blood donors.
We do, in part, replicate the association between 5-HT2A T102C polymorphism and response to typical neuroleptics. In female patients, C/C genotype was significantly more common in non-responders than in responders OR = 6.04 (95% Cl 1.67-21.93), p = 0.005 or in the control population OR = 4.16 (95% CI 1.46-11.84), p = 0.005. TPH1 A779C C/A genotype was inversely associated with good treatment response when compared with non-responders OR = 0.59 (95% Cl 0.36-0.98), p = 0.030 or with the controls OR = 0.44 (95% CI 0.23-0.86, p = 0.016, and GNB3 C825T C/T genotype showed a trend-like positive association among the male patients with a good response compared with non-responders OR = 3.48 (95% Cl 0.92-13.25), p = 0.061, and a clearer association when compared with the controls OR = 4.95 (95% CI 1.56-15.70), p = 0.004.
More findings on the consequences of functional polymorphisms for the role of serotonin in the development of brain and serotonergic neurotransmission are needed before more detailed hypotheses regarding susceptibility and outcome in schizophrenia can be formulated. The present results may highlight some of the biological mechanisms in different courses of schizophrenia between men and women.
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.
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.
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.
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.
Several lines of evidence suggest that catechol-O-methyltransferase (COMT) may be associated with treatment response in depression. We conducted a study on 119 patients with treatment-refractory ...depression admitted consecutively for electroconvulsive therapy (ECT). The COMT high/high genotype leads to a higher enzyme activity and thus lowers dopaminergic activity in the prefrontal cortex. In the present sample, those homozygous to high-active allele of COMT responded significantly more frequently to ECT.
The aims of the study were to investigate the relationship between Apolipoprotein E (APOE) polymorphism, risk of schizophrenia, treatment response to conventional anti-psychotics, and age of onset in ...schizophrenia. The sample comprised 94 Finnish patients with a DSM-IV diagnosis of schizophrenia. Forty-three of the patients were good responders to conventional anti-psychotics and 51 were classified as non-responders. The control group consisted of 98 healthy blood donors. The APOE allele frequencies (epsilon 2, epsilon 3, and epsilon 4) were 4.8, 72.3, and 22.9% in patients and 7.1, 75.0, and 17.9 in controls. None of the differences between groups were statistically significant. No association between treatment response and APOE genotype was found. Patients with APOE epsilon 4/epsilon 4 genotype had a markedly lower age of onset compared with rest of the sample (p=0.0015), which remained significant when controlling for gender (p=0.02). There was an increasing linear trend between the number of epsilon 3 alleles (0, 1, or 2) and age of onset in schizophrenia (p=0.08). An inverse trend was found between the number of epsilon 4 alleles and age of onset (p=0.07). No relationship between APOE polymorphism and risk for schizophrenia was found. APOE epsilon 4/epsilon 4 genotype may be associated with early onset schizophrenia. APOE epsilon 3 allele may function protectively in later onset in this disease.
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.
Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is ...often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different
p
value thresholds (
P
T
) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC,
N
= 865), and in a replication cohort (STAR*D,
N
= 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including
NEGR1, CADM2, PMAIP1, PARK2)
that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (
LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2)
with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.
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 may be associated with MDD. ► No previous studies on association between these SNPs and remission after SSRI or ECT. ► Neither Gln460Arg nor His155Tyr ...was associated with MDD. ► Neither Gln460Arg nor His155Tyr was associated with 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.
Abstract 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.
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