Influence of eight ABCB1 polymorphisms on antidepressant response in a prospective cohort of treatment-free Russian patients with moderate or severe depression: An explorative psychopharmacological study with naturalistic design.

BACKGROUND: Many antidepressants are substrates of P-glycoprotein, an efflux transporter in the blood-brain-barrier encoded by the ABCB1 gene. Genetic variations might influence the transport rate of antidepressants and hence their pharmacological effects. This study investigates the influence of eight polymorphisms in the ABCB1 gene on antidepressant treatment response. METHOD: 152 patients were included from psychiatric departments of the Mental Health Research Institute in Tomsk. The difference in Hamilton-Depression-Rating-Scale (HAMD-17)-scores between baseline and week two, week two and four, and baseline and week four was used to estimate timing of improvement of depression. Associations between the ABCB1 gene-polymorphisms and reduction in HAMD-17 score were assessed using independent t-test and multiple linear regression. RESULTS: Tricyclic antidepressants were associated with a higher reduction of HAMD-17 score when compared to SSRIs. The SNP rs2235040 A-allele had a significant positive influence on the ΔHAMD-17(0→2W) score but a significant negative influence on the ΔHAMD-17(2→4W) score. The rs4148739 G-allele had a significant negative influence on the ΔHAMD-17(0→2W) score but a significant positive influence on the ΔHAMD-17(2→4W) score. The SNP rs2235015 T-allele is significant negatively related to the ΔHAMD-17(2→4W) score. CONCLUSION: ABCB1 Genetic variations appear to affect speed but not magnitude of antidepressant drug response.

Beta-Endorphin and Oxytocin in Patients with Alcohol Use Disorder and Comorbid Depression.

BACKGROUND: The neuropeptides ß-endorphin and oxytocin are released into the bloodstream as hormones from the pituitary gland but also have an important function as neuroregulators in the forebrain. The blood levels of both polypeptides have been shown to reflect depressive symptoms. ß-Endorphin, in particular, is also involved in abstinence from alcohol. METHODS: The serum levels of ß-endorphin and oxytocin were measured during the early withdrawal phase in patients with alcohol use disorder (AUD) with (N = 35) or without (N = 45) depressive comorbidity and compared with those in healthy volunteers (N = 23). In addition to comparing the groups, the study examined whether serum levels correlated with various psychometric measures of dependence, depression and aggression, as well as with clinical characteristics of dependence. RESULTS: Both serum levels of beta-endorphin and oxytocin were significantly lower in patients than those in healthy controls (p = 0.011 for ß-endorphin and p = 0.005 for oxytocin, Kruskal-Wallis test). In patients with depressive comorbidity, the significance was greatest (p = 0.005 for ß-endorphin and p = 0.004 for oxytocin, U-test). There was no correlation with clinical or psychometric parameters (p > 0.05, Spearman test), but beta-endorphin levels did correlate significantly with physical aggression (p = 0.026, Spearman test). CONCLUSIONS: Serum levels of ß-endorphin and oxytocin are lower in patients with AUD, particularly in those with depressive comorbidity. ß-Endorphin levels correlated with physical aggression according to the Buss-Durkee (BDHI) estimates.

Preliminary Pharmacogenetic Study to Explore Putative Dopaminergic Mechanisms of Antidepressant Action.

BACKGROUND: There is sufficient evidence that interference of dopaminergic neurotransmission contributes to the therapeutic effects of antidepressants in unipolar and bipolar depression. METHODS: Hamilton depression rating scale (HAMD 17) scores of 163 at least moderately ill patients with major depressive disorders were used to establish treatment response. HAMD 17 score status was measured before initiation, after two weeks, and after four weeks of treatment with various antidepressants. The possible association between response and genotype in a total of 14 variants of dopamine neurotransmission-related proteins was investigated. RESULTS: DRD4 rs11246226 CA heterozygous patients were found with a greater improvement of HAMD 17 score when compared to homozygous C patients during 0-2 weeks and 0-4 weeks. Patients with MAOB rs1799836 heterozygous GA and homozygous A also demonstrated improved scores during 2-4 weeks and 0-4 weeks. CONCLUSIONS: The results are preliminary due to the limited population size and the small number of variants. Further research into the involvement of habenular dopamine D4 receptors in the antidepressant response is desirable.

Exploring Brain Derived Neurotrophic Factor and Cell Adhesion Molecules as Biomarkers for the Transdiagnostic Symptom Anhedonia in Alcohol Use Disorder and Comorbid Depression.

BACKGROUND: Alcohol Use Disorder (AUD) and depressive disorder often co-exist and have a shared heritability. This study aimed to investigate Brain-Derived Neurotrophic Factor (BDNF) and three Cell Adhesion Molecules (CAMs) as transdiagnostic biomarkers in AUD and depression co-morbidity. METHODS: In a cross-sectional study, patients with AUD (n=22), AUD and depression (n=19), and healthy controls (n=20) were examined. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale. Anhedonia, alcohol use and dependence, craving, and social adaptation were assessed through self-report questionnaires. BDNF and CAM concentrations in peripheral serum were measured after overnight fasting using a Luminex assay. After controlling for age and gender, biomarker levels were compared across groups. The association between biomarker concentrations and symptom severity scales were explored using correlation and multiple regression analyses. RESULTS: BDNF and Neuronal CAM were lower in patients with AUD with and without depression compared to healthy controls. No differences were observed for Vascular CAM-1 and Interstitial CAM-1. BDNF correlated negatively with anhedonia levels. BDNF, age and gender together explained 21% of variability in anhedonia levels. CONCLUSION: This pilot study suggests that peripheral levels of BDNF and NCAM might be reduced in AUD with and without comorbid mood disorder. Since low BDNF levels were associated with self- reported anhedonia across these conditions, BDNF and anhedonia might reflect transdiagnostic aspects involved in AUD and depression.

Association Between BDNF Gene Variant Rs6265 and the Severity of Depression in Antidepressant Treatment-Free Depressed Patients.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, and its dysregulation has been associated with the pathogenesis of mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone which is also produced as a cytokine by immune cells and could be a neurotrophic factor regulating the functional activity of stress-related mechanisms. AIM: To investigate the possible relationship between depressive state and BDNF and PRL genotypes or levels with special reference to severity of depression. METHODS: Participants of 18-70 years with a clinical diagnosis of depressive disorder of at least moderate severity were included. These patients had not been treated with antidepressant drugs before admission to hospital during the preceding period of the last 6 months, and 54.5% had never been treated with antidepressant drugs during their entire life. The DNA was genotyped for rs1341239 within the prolactin and for rs6265, rs7124442, and rs11030104 within the BDNF gene. Rs11030104 violated the Hardy-Weinberg equilibrium distribution and was excluded from further analyses. BDNF and prolactin concentration was measured in serum by MAGPIX multiplex analyzer (Luminex, USA) using MILLIPLEX® MAP kit (Merck, Germany). Genetic associations were determined by sequentially regressing prolactin, BDNF, 17-items Hamilton's Depression (HAMD-17) and Clinical Global Impression scale, Severity (CGI-S) ratings, and depression (absent/present) on the available SNPs. Genetic associations were evaluated assuming an additive model. RESULTS: A total of 186 depressed patients (of which 169 were women) and 94 healthy controls (67 women) were genotyped. After excluding subjects without genetic information on all three study SNPs, 217 remained of whom 138 suffered from depression. Within depressed patients we observed an association of rs6265 with HAMD-17: mean difference (MD) 2.33 (95%CI 0.49; 4.16; p = 0.014) and CGI-S: MD 0.38 (95%CI 0.09; 0.66; p = 0.011). No significant association was observed between the prolactin SNP rs1341239 and prolactin levels. Similarly the mean differences of BDNF SNPs did not show an association with BDNF: rs6265 -0.042 ln(pg/ml) (95%CI -0.198; 0.113), and rs7124442 0.006 ln(pg/ml) (95%CI -0.117; 0.130). No other association reached statistical significance. CONCLUSION: We observed a significant association between BDNF gene variant rs6265 and the severity of depression in newly admitted, antidepressant treatment-free, depressed patients. Actual PRL and BDNF levels were not elevated sufficiently in depressed patients to reach statistical significance and were not associated with the studied genotypes.

Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients: A prospective inception cohort study in treatment-free patients.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response. OBJECTIVES: To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response. METHODS: Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (∆HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and ∆HAM-D. RESULTS: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in post-menopausal women found a similar comparison between alleles. LIMITATIONS: Study lasted four weeks, which may be considered short to associate genuine antidepressant effects. CONCLUSIONS: Patients taking tricylic antidepressants were noted to have a significant improvement in ∆HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment.

Limited Associations Between 5-HT Receptor Gene Polymorphisms and Treatment Response in Antidepressant Treatment-Free Patients With Depression.

Major depressive disorder has become a prominent cause of disability, as lifetime prevalence has increased to ~15% in the Western world. Pharmacological effects of serotonin (5-hydroxytryptamine, 5-HT) are mediated through 5-hydroxytryptamine receptor (5-HTR) binding. Serotonin regulation of amygdala activity is attained through activation of three 5-HT2 family receptor subtypes, 5-HT2A, 5-HT2B, and 5-HT2C. Specifically, HT2A and the HT2C receptors have similar gross cerebral distribution and function, with higher constitutive activity found in HT2C than in HT2A. We investigated the possible association of 5-HTR gene polymorphisms to specific and non-specific antidepressant treatment responses in treatment-free patients in Siberia. 156 patients, aged between 18-70 years and clinically diagnosed with depressive disorders, were treated with antidepressants for 4 weeks. Patients were genotyped for a subset of 29 SNPs from the following 5-HT Receptor genes: HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B and HTR6. Primary outcome was measured by differences in Hamilton Depression Rating Scale (ΔHAM-D 17) scores between baseline/week two, week two/week four and baseline/week four. Univariate linear regression was initially conducted to determine the 5-HTR SNPs to be studied within the multiple linear regression. Multiple linear regression analyses over the three time periods were conducted for ΔHAM-D 17 with independent factors including: age, gender, depression diagnosis, antidepressant treatment and selected 5-HTR SNPs. We found improved ∆HAM-D 17 in patients taking tricyclic antidepressants (0-4 weeks: B = 4.85, p = 0.0002; 0-2 weeks: B = 3.58, p = 0.002) compared to patients taking SSRIs. Over the course of study, significant associations between 5-HT receptors SNPs and antidepressant response were not identified.

The functional variant rs334558 of GSK3B is associated with remission in patients with depressive disorders.

PURPOSE: GSK3B and AKT1 genes have been implicated in the pathogenesis of a number of psychiatric and neurological disorders. Furthermore, their genetic variants are associated with response to antidepressant pharmacotherapy. As the evidence is still incomplete and inconsistent, continuing efforts to investigate the role of these two genes in the pathogenesis and treatment of brain disorders is necessary. The aim of our study was thus to evaluate the association of variants of these two genes with depressive disorders and drug treatment response. PATIENTS AND METHODS: In the present study, 222 patients with a depressive disorder who underwent pharmacological antidepressant treatment were divided into remitters and non-remitters following a 28-day course of pharmacotherapy. The association of a depressive disorder and remission rates with polymorphisms rs334558 in the GSK3B gene and rs1130214 and rs3730358 in the AKT1 gene was evaluated with a chi-square test. RESULTS: Neither of the studied genetic variants was associated with a depressive disorder. Furthermore, frequencies of alleles and genotypes for rs1130214 and rs3730358 were not different in the groups of remitters and non-remitters. However, the activating allele T of the functional polymorphism rs334558 was significantly associated with remission, when all types of antidepressant drugs were included. This association continued as a trend when only patients taking selective serotonin reuptake inhibitors were considered. CONCLUSION: The present study provides support that the functional polymorphism rs334558 of GSK3B may play a role as a useful genetic and pharmacogenetic biomarker in the framework of personalized medicine approach.

An association of AKT1 gene polymorphism with antidepressant treatment response.

OBJECTIVES: Nowadays it is considered that protein kinase Akt1 could be involved in pathogenesis of affective disorders. We have examined whether AKT1 gene polymorphisms are associated with antidepressant treatment response. METHODS: The study included 106 Caucasian patients with depressive disorders from Siberia and 103 healthy control donors. The frequencies of single nucleotide polymorphisms rs1130214 and rs3730358 of AKT1 gene were examined. RESULTS: A comparison of genotypic or allelic frequencies between the groups of healthy donors and depressive patients showed no statistically significant difference. No association between the polymorphisms under study and the scores according to Hamilton Depression Rating Scale 17 was found. However, an association between treatment response assessed by the Clinical Global Impression - Improvement scale and rs1130214 polymorphism was observed. CONCLUSIONS: AKT1 gene polymorphism rs1130214 is associated with antidepressant treatment response in patients with depressive disorders.