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Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: the result of two pooled RCTs.

ABSTRACT: Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper, we investigated early partial improvement (EPI) defined as 20% or more improvement by rating scales 2 ?weeks after treatment, in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder. Two randomized controlled trials with 168 Japanese depressed patients were used. A stepwise multiple linear regression model with HAM-D score change at week 6 as the dependent variable and genotypes, EPI, baseline HAM-D score, age and sex as independent variables was performed in paroxetine, fluvoxamine and milnacipran, respectively, to estimate the prediction of HAM-D change at week 6. In the paroxetine sample, only EPI (P<0.001) was significantly associated with HAM-D change (n=81, R(2)=0.25, P<0.001). In the fluvoxamine sample, 5-HTTLPR La/Lg, S (P=0.029), FGF2 rs1449683C/T (P=0.013) and EPI (P=0.003) were associated with HAM-D change (n=42, R(2)=0.43, P<0.001). In the milnacipran sample, HTR-1A-1019C/G (P=0.001), ADRA2A-1297C/G (P=0.028) and EPI (P<0.001) were associated with outcome (n=45, R(2)=0.71, P<0.001). EPI in combination with genetic variants could be a useful predictor of treatment outcome and could strengthen the practical use of pharmacogenetic data in clinical practice.

SUBMITTER: Kato M

PROVIDER: S-EPMC4445755 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: the result of two pooled RCTs.

Kato M M Serretti A A Nonen S S Takekita Y Y Wakeno M M Azuma J J Kinoshita T T

Translational psychiatry 20150224

Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper, we investigated early partial improvement (EPI) defined as 20% or more improvement by rating scales 2 weeks after treatment, in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder. Two randomized controlled trials with 168 Japanese depressed patients were used. A ...[more]

PMID: 25710119

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:BackgroundWe previously reported higher serotonin 1A receptor (5-HT1A) binding in subjects with major depressive disorder (MDD) during a major depressive episode using positron emission tomography imaging with [(11)C]WAY-100635. 5-HT1A receptor binding is also associated with treatment outcome after nonstandardized antidepressant treatment. We examined whether pretreatment 5-HT1A binding is associated with treatment outcome following standardized escitalopram treatment in MDD. We also compared 5-HT1A binding between all MDD subjects in this cohort and a sample of healthy control subjects.MethodsTwenty-four MDD subjects in a current major depressive episode and 51 previously studied healthy control subjects underwent positron emission tomography scanning with [(11)C]WAY-100635, acquiring a metabolite-corrected arterial input function and free-fraction measurement to estimate 5-HT1A binding potential (BPF = Bmax/KD, where Bmax = available receptors and KD = dissociation constant). Major depressive disorder subjects then received 8 weeks of treatment with escitalopram; remission was defined as a posttreatment 24-item Hamilton Depression Rating Scale <10 and ≥ 50% reduction in Hamilton Depression Rating Scale.ResultsRemitters to escitalopram had 33% higher baseline 5-HT1A binding in the raphe nuclei than nonremitters (p = .047). Across 12 cortical and subcortical regions, 5-HT1A binding did not differ between remitters and nonremitters (p = .86). Serotonin 1A receptor binding was higher in MDD than control subjects across all regions (p = .0003). Remitters did not differ from nonremitters in several relevant clinical measures.ConclusionsElevated 5-HT1A binding in raphe nuclei is associated with subsequent remission with the selective serotonin reuptake inhibitor escitalopram; this is consistent with data from a separate cohort receiving naturalistic antidepressant treatment. We confirmed our previous findings of higher 5-HT1A binding in current MDD compared with control subjects.

Dataset Information

Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: the result of two pooled RCTs.

Publications

Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: the result of two pooled RCTs.

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