Prediction of Antidepressant Treatment Response and Remission Using an Ensemble Machine Learning Framework.

In the wake of recent advances in machine learning research, the study of pharmacogenomics using predictive algorithms serves as a new paradigmatic application. In this work, our goal was to explore an ensemble machine learning approach which aims to predict probable antidepressant treatment response and remission in major depressive disorder (MDD). To discover the status of antidepressant treatments, we established an ensemble predictive model with a feature selection algorithm resulting from the analysis of genetic variants and clinical variables of 421 patients who were treated with selective serotonin reuptake inhibitors. We also compared our ensemble machine learning framework with other state-of-the-art models including multi-layer feedforward neural networks (MFNNs), logistic regression, support vector machine, C4.5 decision tree, naïve Bayes, and random forests. Our data revealed that the ensemble predictive algorithm with feature selection (using fewer biomarkers) performed comparably to other predictive algorithms (such as MFNNs and logistic regression) to derive the perplexing relationship between biomarkers and the status of antidepressant treatments. Our study demonstrates that the ensemble machine learning framework may present a useful technique to create bioinformatics tools for discriminating non-responders from responders prior to antidepressant treatments.

Gene-Based Association Analysis Suggests Association of HTR2A With Antidepressant Treatment Response in Depressed Patients.

The serotonin [5-hydroxytryptamine (5-HT)] system has been implicated in the pathogenesis of major depressive disorder (MDD). Among the 5-HT receptor subtypes, 5-HT2 is one of the major pharmacological therapeutic targets for MDD. There have been inconsistent findings in previous pharmacogenetic studies investigating the antidepressant therapeutic response using one or several 5-HT2A (HTR2A) genetic polymorphisms. By using gene-based association analysis, we hope to identify genetic variants of HTR2A which are related to MDD susceptibility and its antidepressant therapeutic response. 288 HTR2A single nucleotide polymorphisms in MDD susceptibility have been investigated through a case-control (455 MDD patients and 2, 998 healthy controls) study, as well as in antidepressant efficacy (n = 455) in our current research. The 21-item Hamilton Rating Scale for Depression was used to evaluate measures of antidepressant therapeutic efficacy. From two MDD groups in the antidepressant therapeutic response, by using gene-based analyses, we have identified 14 polymorphisms as suggestive markers for therapeutic response (13 for remission and 1 for response) in both meta- and mega-analyses. All of these HTR2A reported polymorphisms did not reach statistical significance in the case-control association study. This current investigation supported the link between HTR2A variants and antidepressant therapeutic response in MDD but not with MDD susceptibility.

A Deep Learning Approach for Predicting Antidepressant Response in Major Depression Using Clinical and Genetic Biomarkers.

In the wake of recent advances in scientific research, personalized medicine using deep learning techniques represents a new paradigm. In this work, our goal was to establish deep learning models which distinguish responders from non-responders, and also to predict possible antidepressant treatment outcomes in major depressive disorder (MDD). To uncover relationships between the responsiveness of antidepressant treatment and biomarkers, we developed a deep learning prediction approach resulting from the analysis of genetic and clinical factors such as single nucleotide polymorphisms (SNPs), age, sex, baseline Hamilton Rating Scale for Depression score, depressive episodes, marital status, and suicide attempt status of MDD patients. The cohort consisted of 455 patients who were treated with selective serotonin reuptake inhibitors (treatment-response rate = 61.0%; remission rate = 33.0%). By using the SNP dataset that was original to a genome-wide association study, we selected 10 SNPs (including ABCA13 rs4917029, BNIP3 rs9419139, CACNA1E rs704329, EXOC4 rs6978272, GRIN2B rs7954376, LHFPL3 rs4352778, NELL1 rs2139423, NUAK1 rs2956406, PREX1 rs4810894, and SLIT3 rs139863958) which were associated with antidepressant treatment response. Furthermore, we pinpointed 10 SNPs (including ARNTL rs11022778, CAMK1D rs2724812, GABRB3 rs12904459, GRM8 rs35864549, NAALADL2 rs9878985, NCALD rs483986, PLA2G4A rs12046378, PROK2 rs73103153, RBFOX1 rs17134927, and ZNF536 rs77554113) in relation to remission. Then, we employed multilayer feedforward neural networks (MFNNs) containing 1-3 hidden layers and compared MFNN models with logistic regression models. Our analysis results revealed that the MFNN model with 2 hidden layers (area under the receiver operating characteristic curve (AUC) = 0.8228 ± 0.0571; sensitivity = 0.7546 ± 0.0619; specificity = 0.6922 ± 0.0765) performed maximally among predictive models to infer the complex relationship between antidepressant treatment response and biomarkers. In addition, the MFNN model with 3 hidden layers (AUC = 0.8060 ± 0.0722; sensitivity = 0.7732 ± 0.0583; specificity = 0.6623 ± 0.0853) achieved best among predictive models to predict remission. Our study indicates that the deep MFNN framework may provide a suitable method to establish a tool for distinguishing treatment responders from non-responders prior to antidepressant therapy.

Gene-based analysis of genes related to neurotrophic pathway suggests association of BDNF and VEGFA with antidepressant treatment-response in depressed patients.

It is well established that brain-derived neurotrophic factor (BDNF) signaling pathway plays a key role in the pathophysiology of major depressive disorder (MDD) and in therapeutic mechanisms of antidepressants. We aim to identify genetic vairiants related to MDD susceptibility and antidepressant therapeutic response by using gene-based association analysis with genes related to the neurotrophic pathway. The present study investigated the role of genetic variants in the 10 neurotrophic-related genes (BDNF, NGFR, NTRK2, MTOR, VEGFA, S100A10, SERPINE1, ARHGAP33, GSK3B, CREB1) in MDD susceptibility through a case-control (455 MDD patients and 2,998 healthy controls) study and in antidepressant efficacy (n = 455). Measures of antidepressant therapeutic efficacy were evaluated using the 21-item Hamilton Rating Scale for Depression. Our single-marker and gene-based analyses with ten genes related to the neurotrophic pathway identified 6 polymorphisms that reached a significant level (p-value < 5.0 × 10-3) in both meta- and mega-analyses in antidepressant therapeutic response. One polymorphism was mapped to BDNF and 5 other polymorphisms were mapped to VEGFA. For case-control association study, we found that all of these reported polymorphisms and genes did not reach a suggestive level. The present study supported a role of BDNF and VEGFA variants in MDD therapeutic response.

Convergent evidence from mouse and human studies suggests the involvement of zinc finger protein 326 gene in antidepressant treatment response.

OBJECTIVES: The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. METHODS: FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498). RESULTS: One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028). CONCLUSIONS: The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response.

The influence of apolipoprotein E Epsilon4 polymorphism on qEEG profiles in healthy young females: a resting EEG study.

The epsilon4 allele of the Apolipoprotein E (ApoE) gene has been linked to various neurological conditions and the aging process in the elderly. However, evidence has suggested that the influence of ApoE epsilon4 may commence in early life. This study examined the modulatory effects of ApoE epsilon4 on regional neural activity as well as inter-regional neural interactions in a young population aged 19-21. Blood samples and resting state eyes-closed EEG signals were collected from 265 healthy females, and stratified into two groups: epsilon4 carriers and non-carriers. The values of the log-transformed mean power of 18 electrodes and the mutual information of 20 channel pairs across delta, theta, alpha and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group statistics were performed by independent t-test. We notice a consistent trend across the brain, in which ApoE epsilon4 carriers possess lower regional power at the alpha band. The epsilon4 allele is also associated with lower regional power at the theta frequency in the left frontal and posterior brain regions. Functional connectivity analyses reveal a right-lateralized network that differentiates epsilon4 carriers and non-carriers, with lower connectivity strengths for the former. Our tonic EEG analyses complement those of previous reports in that the ApoE epsilon4 allele has a negative impact on regional neural synchronization and inter-regional neural interaction.

The influence of dopamine receptor d4 polymorphism on resting EEG in healthy young females.

The polymorphism of variable number of tandem repeat (VNTR) in dopamine receptor D4 (DRD4) gene exon III has been linked to various neuro-psychiatric conditions with disinhibition/impulsivity as one of the core features. This study examined the modulatory effects of long-allele variant of DRD4 VNTR on the regional neural activity as well as inter-regional neural interactions in a young female population. Blood sample and resting state eyes-closed EEG signals were collected in 233 healthy females, stratified into two groups by polymerase chain reaction: long-allele carriers (>4- repeat) and non-carriers (<=4-repeat/<=4-repeat). The values of mean power of 18 electrodes and mutual information of 38 channel pairs across theta, alpha, and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group differences of regional power and connectivity strength were quantified by independent t-test, while between-group differences in global trends were examined by non-parametric analyses. We noticed that DRD4 VNTR long-allele was associated with decreased global connectivity strength (from non-parametric analysis), especially over bi-frontal, biparietal and right fronto-parietal and right fronto-temporal connections (from independent t-tests). The between-group differences in regional power were not robust. Our findings fit with the networks of response inhibition, providing evidence bridging DRD4 long-allele and disinhibition/impulsivity in neuropsychiatric disorders. We suggest future DRD4 studies of imaging genetics incorporate connectivity analysis to unveil its impact on cerebral network.

The implication of functional connectivity strength in predicting treatment response of major depressive disorder: a resting EEG study.

Predicting treatment response in major depressive disorder (MDD) has been an important clinical issue given that the initial intent-to-treat response rate is only 50 to 60%. This study was designed to examine whether functional connectivity strengths of resting EEG could be potential biomarkers in predicting treatment response at 8 weeks of treatment. Resting state 3-min eyes-closed EEG activity was recorded at baseline and compared in 108 depressed patients. All patients were being treated with selective serotonin-reuptake inhibitors. Baseline coherence and power series correlation were compared between responders and non-responders evaluated at the 8th week by Hamilton Depression Rating Scale. Pearson correlation and receiver operating characteristic (ROC) analyses were applied to evaluate the performance of connectivity strengths in predicting/classifying treatment responses. The connectivity strengths of right fronto-temporal network at delta/theta frequencies differentiated responders and non-responders at the 8th week of treatment, such that the stronger the connectivity strengths, the poorer the treatment response. ROC analyses supported the value of these measures in classifying responders/non-responders. Our results suggest that fronto-temporal connectivity strengths could be potential biomarkers to differentiate responders and slow responders or non-responders in MDD.

Do resting brain dynamics predict oddball evoked-potential?

BACKGROUND: The oddball paradigm is widely applied to the investigation of cognitive function in neuroscience and in neuropsychiatry. Whether cortical oscillation in the resting state can predict the elicited oddball event-related potential (ERP) is still not clear. This study explored the relationship between resting electroencephalography (EEG) and oddball ERPs. The regional powers of 18 electrodes across delta, theta, alpha and beta frequencies were correlated with the amplitude and latency of N1, P2, N2 and P3 components of oddball ERPs. A multivariate analysis based on partial least squares (PLS) was applied to further examine the spatial pattern revealed by multiple correlations. RESULTS: Higher synchronization in the resting state, especially at the alpha spectrum, is associated with higher neural responsiveness and faster neural propagation, as indicated by the higher amplitude change of N1/N2 and shorter latency of P2. None of the resting quantitative EEG indices predict P3 latency and amplitude. The PLS analysis confirms that the resting cortical dynamics which explains N1/N2 amplitude and P2 latency does not show regional specificity, indicating a global property of the brain. CONCLUSIONS: This study differs from previous approaches by relating dynamics in the resting state to neural responsiveness in the activation state. Our analyses suggest that the neural characteristics carried by resting brain dynamics modulate the earlier/automatic stage of target detection.

The influence of serotonin transporter polymorphisms on cortical activity: a resting EEG study.

BACKGROUND: The serotonin transporter gene (5-HTT) is a key regulator of serotonergic neurotransmission and has been linked to various psychiatric disorders. Among the genetic variants, polymorphisms in the 5-HTT gene-linked polymorphic region (5-HTTLPR) and variable-number-of-tandem-repeat in the second intron (5-HTTVNTR) have functional consequences. However, their genetic impact on cortical oscillation remains unclear. This study examined the modulatory effects of 5-HTTLPR (L-allele carriers vs. non-carriers) and 5-HTTVNTR (10-repeat allele carriers vs. non-carriers) polymorphism on regional neural activity in a young female population. METHODS: Blood samples and resting state eyes-closed electroencephalography (EEG) signals were collected from 195 healthy women and stratified into 2 sets of comparisons of 2 groups each: L-allele carriers (N=91) vs. non-carriers for 5-HTTLPR and 10-repeat allele carriers (N=25) vs. non-carriers for 5-HTTVNTR. The mean power of 18 electrodes across theta, alpha, beta, gamma, gamma1, and gamma2 frequencies was analyzed. Between-group statistics were performed by an independent t-test, and global trends of regional power were quantified by non-parametric analyses. RESULTS: Among 5-HTTVNTR genotypes, 10-repeat allele carriers showed significantly low regional power at gamma frequencies across the brain. We noticed a consistent global trend that carriers with low transcription efficiency of 5-HTT possessed low regional powers, regardless of frequency bands. The non-parametric analyses confirmed this observation, with P values of 3.071×10-8 and 1.459×10-12 for 5-HTTLPR and 5-HTTVNTR, respectively. CONCLUSIONS AND LIMITATIONS: Our analyses showed that genotypes with low 5-HTT activity are associated with less local neural synchronization during relaxation. The implication with respect to genetic vulnerability of 5-HTT across a broad range of psychiatric disorders is discussed. Given the low frequency of 10-repeat allele of 5-HTTVNTR in our research sample, the possibility of false positive findings should also be considered.

Cortical mechanisms of the symptomatology in major depressive disorder: a resting EEG study.

BACKGROUND: Diagnosis and treatment rely on symptom criteria in modern psychiatry. However, the cortical mechanisms of symptomatology in major depressive disorder (MDD) are still not clear. This study examined neural correlates of symptom clusters of MDD by electroencephalography (EEG). METHODS: Resting state eye-closed EEG signals were recorded in 196 depressive patients. Quantitative EEG (qEEG) of regional power, coherence and power series correlation across delta, theta, alpha and beta frequencies were used to correlate with overall depression severity evaluated by the Hamilton Depression Rating Scale (HDRS). Further, statistical comparisons between patients with high vs. low qEEG indices (median-split) were undertaken regarding symptom severity of core depression, sleep, activity, psychic anxiety, somatic anxiety, and delusion. RESULTS: None of the qEEG indices significantly correlated with overall depression severity or differentiated symptom severity of core depression, sleep, activity and psychic anxiety. A higher symptom severity of somatic anxiety was associated with higher regional power over widespread cortical regions and lower strengths at bi-temporal, temporo-parietal and fronto-parietal connections. A higher symptom severity of delusion was associated with higher regional power in the frontal and temporal regions, and lower strengths at inter-hemispheric (frontal, temporal and parietal) and fronto-temporo-parietal connections. LIMITATIONS: Our EEG recording with sampling rate of 128Hz and 20 electrodes may provide restricted spatial and temporal precision. CONCLUSIONS: Our results suggest that cortical mechanisms play important roles in the symptom manifestation of cognitive distortion (sub-score of delusion) and somatic anxiety in MDD. Our findings further imply that psychic anxiety and somatic anxiety are distinct entities.

The effects of catechol-O-methyl-transferase polymorphism Val158Met on functional connectivity in healthy young females: a resting EEG study.

The catechol-O-methyl-transferase (COMT) gene has been linked to a wide spectrum of human phenotypes, including cognition, affective response, pain sensitivity, anxiety and psychosis. This study examined the modulatory effects of COMT Val158Met on neural interactions, indicated by connectivity strengths. Blood samples and resting state eyes-closed EEG signals were collected in 254 healthy young females. The COMT Val158Met polymorphism was decoded into 3 groups: Val/Val, Val/Met and Met/Met. The values of mutual information of 20 frontal-related channel pairs across delta, theta, alpha and beta frequencies were analyzed based on the time-frequency mutual information method. Our one-way ANOVA analyses revealed that the significant connection-frequency pairs were relatively left lateralized (P<0.01) and included F7-T3 and F7-C3 at delta frequency, and F3-F4, F7-T3, F7-C3, F7-P3, F3-C3, F3-F7 and F4-F8 at theta frequency. The F-test at F7-T3 and F7-C3 theta surpassed the statistical threshold of P<0.003 (after Bonferroni correction). For all the above connection-frequency pairs, there was a dose-dependent trend in the connectivity strengths of the alleles as follows: Val/Val>Val/Met>Met/Met. Our analyses complemented previous literature regarding neural modulation by the COMT Val158Met polymorphism. The implication to the pathogenesis in schizophrenia was also discussed. Further studies are needed to clarify whether there is gender difference on this gene-brain interaction.

Evidence of involvement of the human Par-4 (PAWR) gene in major depressive disorder.

UNLABELLED: QBJECTIVES: The aim of the study was to examine the associations between genetic variations in the human PAWR gene and major depressive disorder (MDD) as well as the response to antidepressant treatment. METHODS: Six-hundred and two patients with MDD and 543 controls were included in the study; among the MDD patients, 268 were followed-up for a further 8 weeks in order to assess their response to treatment with selective serotonin reuptake inhibitors (SSRIs). Six polymorphisms (rs17005769, rs4842318, rs7305141, rs2307223, rs8176874 and rs2307220) of the PAWR gene were investigated with regard to their association with MDD and antidepressant treatment efficacy. RESULTS: One polymorphism, rs8176874, was in genotypic (uncorrected P=0.005) and allelic (uncorrected P=0.0015) association with MDD. Several haplotypes spanning rs7305141-rs2307223-rs8176874 were also significantly associated with MDD after correction for multiple testing (corrected P<0.05). However, neither single-marker nor haplotype-based analyses suggested an association between the studied markers and SSRI treatment response. CONCLUSIONS: Genetic variations in the PAWR gene are related to susceptibility to MDD but not to SSRI treatment response.

Support for the involvement of the KCNK2 gene in major depressive disorder and response to antidepressant treatment.

OBJECTIVE: The aim of this study was to examine the associations between genetic variations in the human KCNK2 gene and major depressive disorder (MDD) and response to antidepressant treatment. METHOD: Four hundred and forty-nine patients with MDD and 421 normal controls were included in the study; among the MDD patients, 158 were further followed-up for 8 weeks to assess their response to antidepressant treatment. Five polymorphisms (rs12131478, rs6667764, rs10494994, rs11583745 and rs6686529) of the KCNK2 gene were investigated in terms of their association with MDD and antidepressant treatment efficacy. RESULTS: The genotype frequency of rs6686529 differed significantly between the MDD patients and controls (uncorrected P = 0.00052) and remained statistically significant after correction for multiple comparisons. Individuals with homozygous genotypes (CC or GG) showed greater susceptibility to MDD than those with heterozygous genotypes, indicating a possible heterosis effect of the polymorphism on MDD. In addition, this polymorphism also affected the efficacy of antidepressant treatment: the CC carriers had a greater probability of achieving remission after 8 weeks of treatment than the G-allele carriers [odds ratio = 2.55 (95% confidence interval = 1.11-5.88)]. CONCLUSION: Our findings are in line with those of animal studies, and show that KCNK2 is related to the susceptibility to MDD, and involved in antidepressant treatment response. However, the finding of heterosis association of rs6686529 and MDD may be mechanistic, and further replication studies will be essential.

Haplotype analysis of single nucleotide polymorphisms in the vascular endothelial growth factor (VEGFA) gene and antidepressant treatment response in major depressive disorder.

Vascular endothelial growth factor (VEGF) has been implicated in neurotrophy and neurogenesis, which play a pivotal role in brain development and may be involved in antidepressant therapeutic mechanisms. Recent animal studies demonstrate that VEGF levels are increased by several antidepressants, including selective serotonin reuptake inhibitors, and that VEGF signalling is required for antidepressant-induced behavioural response. We hypothesized that common genetic variants in the VEGF gene (official gene name: VEGFA) may be associated with the therapeutic response to antidepressants in major depressive disorders (MDD). Seven VEGFA polymorphisms were genotyped in 351 patients with MDD who were treated with selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressants and who were were studied in a therapeutic evaluation for at least 4 weeks. Of the 351 patients, 158 completed an 8-week therapeutic evaluation. No significant association with either 4-week or 8-week antidepressant therapeutic effect was shown in the alleles and genotypes of single loci, or haplotypes from two blocks constructed from these polymorphisms. Our findings suggested that VEGFA genetic variants do not play a major role in the response to selective serotonin reuptake inhibitors.

Tryptophan hydroxylase 2 gene is associated with major depression and antidepressant treatment response.

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and has been implicated in the pathogenesis of major depressive disorder (MDD) and in the mechanism of antidepressant action. This study aimed to investigate whether common genetic variation in the TPH2 gene is associated with MDD and therapeutic response to antidepressants in a Chinese population. A total of 508 MDD patients and 463 unrelated controls were recruited. Among the MDD patients, 187 accepted selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressant treatment for 8 weeks with therapeutic evaluation before and after treatment. Five TPH2 polymorphisms were genotyped and their association with MDD or treatment response was assessed by haplotype and single-marker analysis. In single-marker-based analysis, the rs17110747-G homozygote polymorphism was found to be more frequent in the MDD patients than in the controls (P=0.002). Genotype analysis in responders (defined as those with a 50% reduction in baseline Hamilton score) and non-responders after 8 weeks of antidepressant treatment showed that the proportion of rs2171363 heterozygote carriers was higher in the responders than the non-responders (P=0.009). No significant association with MDD or antidepressant therapeutic response was discovered in haplotype analyses. Our findings show that TPH2 genetic variants may play a role in MDD susceptibility and in acute therapeutic response to selective serotonin reuptake inhibitors.

Sexually dimorphic effect of catechol-O-methyltransferase val158met polymorphism on clinical response to fluoxetine in major depressive patients.

BACKGROUND: Essential in dopamine degradation, it was suggested that catechol-O-methyltransferase (COMT) might be involved in the action of antidepressants and may therefore be a promising candidate for antidepressant pharmacogenetic studies. METHODS: COMT Val158met polymorphism was genotyped in 334 Chinese major depressive disorder (MDD) patients who were treated with fluoxetine for at least 4 weeks. Clinical response was evaluated using the 21-item Hamilton Rating Scale for Depression (HAM-D(21)). In the analysis of association, response was defined as >or=50% decrease in HAM-D(21) score after treatment and then further clarified by intra-individual changes in HAM-D(21) score. RESULTS: We found that the COMT val158met polymorphism was not associated with 4-week fluoxetine therapeutic response; however, association analysis showed that patients with the COMT(Val/Val) genotype had poorer responses in the eighth week (CLUMP T1 P=0.020) and consistently showed significantly smaller reductions in HAM-D(21) scores in the eighth week (P=0.027). Further stratification based on gender revealed an isolated effect of the COMT genotype in males (P=0.035) but not in females (P=0.650) in percent reduction in HAM-D(21) scores in the eighth week. LIMITATIONS: There was a lack of placebo control and the serum fluoxetine concentration was not taken into account. CONCLUSIONS: This identified association between the COMT genetic variation and antidepressant response may be useful either as a clinical predictor in the future.

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.

Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response.

OBJECTIVE: Evidence suggests that plasminogen activator inhibitor type 1 gene (SERPINE1) is a stress-related gene and serum plasminogen activator inhibitor type 1 levels are increased in patients with major depressive disorders (MDD). METHODS: To investigate whether common genetic variation in the SERPINE1 gene is associated with MDD and the therapeutic response to antidepressants, six polymorphisms (rs2227631, rs1799889, rs6092, rs6090, rs2227684 and rs7242) of the SERPINE1 gene were genotyped in 188 Chinese MDD patients and 346 controls. Among the MDD patients, 140 accepted selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressant treatment for 4 weeks with therapeutic evaluation before and after. RESULTS: In single-marker-based analysis, the rs2227684-G and rs7242-T alleles were more frequent in MDD patients than in controls (P=0.010 and 0.010, respectively). The haplotype derived from the rs6090-G, rs2227684-G and rs7242-T polymorphisms was 1.19-fold higher in patients with MDD than in controls (P=0.0038). Haplotype analysis in responders (defined as a 50% reduction of the initial Hamilton score) and nonresponders after 4 weeks of antidepressant treatment showed that the haplotype derived from the rs2227631-G and rs1799889-4G polymorphisms was lower in responders than nonresponders (11.4 vs. 22.4%, P=0.014). CONCLUSION: Our findings show, for the first time, that SERPINE1 genetic variants may play a role in MDD susceptibility and in the acute therapeutic response to selective serotonin reuptake inhibitors.

Evidence for association between genetic variants of p75 neurotrophin receptor (p75NTR) gene and antidepressant treatment response in Chinese major depressive disorder.

The p75 neurotrophin receptor (p75(NTR)) is an essential component of neurotrophin system, and has been implicated in the pathogenesis of major depressive disorder (MDD) and in the mechanism of antidepressant action. This study aimed to delineate the association between phenotype (MDD susceptibility and antidepressant response) and genotype (p75(NTR) common genetic variants) in a Chinese population. A total of 228 MDD patients and 402 unrelated controls were recruited. Subjects took selective serotonin reuptake inhibitors (SSRIs) and responders were defined as those with at least a 50% decrease in score of the Hamilton Rating Scale for Depression (HAM-D) from baseline. Five p75(NTR) polymorphisms were genotyped and their association with MDD or treatment response was assessed by haplotype and single marker analysis. No significant association with MDD was discovered in single locus or haplotype analyses. With regard to the therapeutic outcome, however, one missense polymorphism (S250L) showed association in both genotype distribution (P = 0.039) and allele frequency (P = 0.012). Haplotype analysis also revealed that p75(NTR) TCT carriers had a more unfavorable response to therapy (P = 0.010). Our exploratory study has demonstrated the association between p75(NTR) and SSRI response for the first time, which may assist in individualized therapy for MDD patients in the future.