FKBP5 Gene Expression Predicts Antidepressant Treatment Outcome in Depression.

Adverse experiences and chronic stress are well-known risk factors for the development of major depression, and an impaired stress response regulation is frequently observed in acute depression. Impaired glucocorticoid receptor (GR) signalling plays an important role in these alterations, and a restoration of GR signalling appears to be a prerequisite of successful antidepressant treatment. Variants in genes of the stress response regulation contribute to the vulnerability to depression in traumatized subjects. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), which is a strong inhibitor of the GR, and thus, an important regulator of the stress response. We investigated the role of FKBP5 and FKB51 expression with respect to stress response regulation and antidepressant treatment outcome in depressed patients. This study included 297 inpatients, who participated in the Munich Antidepressant Response Signature (MARS) project and were treated for acute depression. In this open-label study, patients received antidepressant treatment according to the attending doctor's choice. In addition to the FKBP5 genotype, changes in blood FKBP51 expression during antidepressant treatment were analyzed using RT-PCR and ZeptoMARKTM reverse phase protein microarray (RPPM). Stress response regulation was evaluated in a subgroup of patients using the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. As expected, increased FKBP51 expression was associated with an impaired stress response regulation at baseline and after six weeks was accompanied by an elevated cortisol response to the combined dex/CRH test. Further, we demonstrated an active involvement of FKBP51 in antidepressant treatment outcome. While patients responding to antidepressant treatment had a pronounced reduction of FKBP5 gene and FKBP51 protein expression, increasing expression levels were observed in nonresponders. This effect was moderated by the genotype of the FKBP5 single nucleotide polymorphism (SNP) rs1360780, with carriers of the minor allele showing the most pronounced association. Our findings demonstrate that FKBP5 and, specifically, its expression product FKBP51 are important modulators of antidepressant treatment outcome, pointing to a new, promising target for future antidepressant drug development.

Analyzing pathways from childhood maltreatment to internalizing symptoms and disorders in children and adolescents (AMIS): a study protocol.

BACKGROUND: Effective interventions for maltreated children are impeded by gaps in our knowledge of the etiopathogenic mechanisms leading from maltreatment to mental disorders. Although some studies have already identified individual risk factors, there is a lack of large-scale multilevel research on how psychosocial, neurobiological, and genetic factors act in concert to modulate risk of internalizing psychopathology in childhood following maltreatment. To help close this gap, we aim to delineate gender-specific pathways from maltreatment to psychological disorder/resilience. To this end, we examine the interplay of specific maltreatment characteristics and psychological, endocrine, metabolomic, and (epi-)genomic stress response patterns as well as cognitive-emotional/social processes as determinants of developmental outcome. Specifically, we will explore endocrine, metabolomic, and epigenetic mechanisms leading from maltreatment to a higher risk of depression and anxiety disorders. METHODS/DESIGN: Four large samples amounting to a total of N = 920 children aged 4-16 years will be assessed: Two cohorts with prior internalizing psychopathology and controls will be checked for maltreatment and two cohorts with substantiated maltreatment will be checked for internalizing (and externalizing) psychopathology. We will apply a multi-source (interview, questionnaires, official records), multi-informant strategy (parents, children, teachers) to assess maltreatment characteristics (e.g., subtypes, developmental timing, chronicity) and psychopathological symptoms, supplemented with multiple measurements of risk and protective factors and cutting-edge laboratory analyses of endocrine, steroid metabolomic and epigenetic factors. As previous assessments in the two largest samples are already available, longitudinal data will be generated within the three year study period. DISCUSSION: Our results will lay the empirical foundation for (a) detection of early biopsychosocial markers, (b) development of screening measures, and

The clinical application of ABCB1 genotyping in antidepressant treatment: a pilot study.

BACKGROUND: The gene product of the ABCB1 gene, the P-glycoprotein, functions as a custodian molecule in the blood-brain barrier and regulates the access of most antidepressants into the brain. Previous studies showed that ABCB1 polymorphisms predicted the response to antidepressants that are substrates of the P-gp, while the response to nonsubstrates was not influenced by ABCB1 polymorphisms. The aim of the present study was to evaluate the clinical application of ABCB1 genotyping in antidepressant pharmacotherapy. METHODS: Data came from 58 depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project, whose ABCB1 gene test results were implemented into the clinical decision making process. Hamilton Depression Rating Scale (HAM-D) scores, remission rates, and duration of hospital stay were documented with dose and kind of antidepressant treatment. RESULTS: Patients who received ABCB1 genotyping had higher remission rates [χ2(1) = 6.596, p = 0.005, 1-sided] and lower Hamilton sores [t(111) = 2.091, p = 0.0195, 1-sided] at the time of discharge from hospital as compared to patients without ABCB1 testing. Among major allele homozygotes for ABCB1 single nucleotide polymorphisms (SNPs) rs2032583 and rs2235015 (TT/GG genotype), an increase in dose was associated with a shorter duration of hospital stay [rho(28) = -0.441, p = 0.009, 1-sided], whereas other treatment strategies (eg, switching to a nonsubstrate) showed no significant associations with better treatment outcome. Discussion The implementation of ABCB1 genotyping as a diagnostic tool influenced clinical decisions and led to an improvement of treatment outcome. Patients carrying the TT/GG genotype seemed to benefit from an increase in P-gp substrate dose. CONCLUSION: Results suggest that antidepressant treatment of depression can be optimized by the clinical application of ABCB1 genotyping.

Childhood abuse and depression in adulthood: The mediating role of allostatic load.

BACKGROUND: Traumatic experiences during childhood are considered a major risk factor for depression in adulthood. Childhood trauma may induce physiological dysregulation with long-term effects of increased allostatic load until adulthood, which may lead to depression. Thus, our aim was to investigate whether allostatic load - which represents a multi-system measure of physiological dysregulation - mediates the association between childhood trauma and adult depression. METHODS: The study sample consisted of 324 depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project and 261 mentally healthy control participants. The mediation analysis using a case-control approach included childhood trauma, i.e., physical and sexual abuse, as predictor variables and an allostatic load index comprised of 12 stress-related biomarkers as mediator. Age and sex were included as covariates. RESULTS: Mediation analyses revealed that the influence of physical abuse, but not sexual abuse, during childhood on depression in adulthood was mediated by allostatic load. This effect was moderated by age: particularly young (18-42 years) and middle-aged (43-54 years) adults with a history of physical abuse during childhood exhibited high allostatic load, which in turn was associated with increased rates of depression, but this was not the case for older participants (55-81 years). CONCLUSIONS: Results support the theoretical assumption of allostatic load mediating the effect of physical abuse during childhood on depression in adulthood. This predominantly holds for younger participants, while depression in older participants was independent of physical abuse and allostatic load. The effect of sexual abuse on depression, however, was not mediated by allostatic load. Identifying allostatic load biomarkers prospectively in the developmental course of depression is an important target for future research.

FKBP5 polymorphisms moderate the influence of adverse life events on the risk of anxiety and depressive disorders in preschool children.

FKBP5 is thought to be involved in the pathogenesis of stress-related disorders. Studies have shown that FKBP5 genotypes moderate the risk of post-traumatic stress disorder and depression in traumatized adults. We aimed to replicate this finding in a sample of preschool children. Parents of preschoolers (N = 186) were interviewed using the Preschool Age Psychiatric Assessment (PAPA) to evaluate the presence of anxiety and depressive disorders and to quantify the child's exposure to adverse events. All FKBP5 polymorphisms showed significant interactions with mild to moderate life events, but not with severe life events, in predicting the risk of anxiety and/or depressive disorders (p = 0.003-0.019). Children who experienced a high number of mild to moderate life events had a higher risk of developing an anxiety and/or depressive disorder if they were carriers of the minor allele compared to major allele homozygotes. Results indicate that genetic variation in FKBP5 influences the risk of anxiety and/or depressive disorders in preschool age by altering the sensitivity to the deleterious effects of mild to moderate adverse events. In case of severe life events, the FKBP5 genotype does not seem to play a role, suggesting that severe life events might influence directly the risk of anxiety and/or depressive disorders independent of an FKBP5 genotype-dependent vulnerability.

Association of ABCB1 gene variants, plasma antidepressant concentration, and treatment response: Results from a randomized clinical study.

P-glycoprotein, encoded by the ABCB1 gene, functions as an ATP-driven efflux pump in the blood-brain barrier, extruding its substrates and thereby limiting their passage into the brain. ABCB1 polymorphisms predicted antidepressant drug response: Minor allele carriers of SNPs rs2032583 and rs2235015 had higher remission rates than major allele homozygotes. The aim of the current study was to evaluate an ABCB1 genotype-dependent efficacy of a quick dose escalation strategy. Depressed inpatients (n = 73) treated with antidepressants that are P-glycoprotein substrates were randomly assigned to a standard or high dose condition for 28 days. HAM-D scores, adverse effects and plasma antidepressant concentration were measured weekly and tested among two intronic SNPs rs2032583 and rs2235015. A treatment as usual control sample (n = 128) was retrospectively matched to the study group by gender, age, and diagnosis. There was a significant interaction of genotype x plasma antidepressant concentration: Minor allele carriers of rs2032583 [F(1,65) = 7.221, p = 0.009] and rs2235015 [F(1,65) = 4.939, p = 0.030] whose plasma drug concentration were within recommended range had a greater symptom reduction at study endpoint which exceeded the therapeutic benefit of the treatment as usual group [for rs2032583: F(1,163) = 4.366, p = 0.038]. Minor allele carriers of rs2032583 with high plasma drug levels had more sleep-related side effects than major allele homozygotes with high plasma drug levels. The treatment of MDD can be optimized by ABCB1 genotyping combined with monitoring of plasma drug concentrations: For minor allele carriers of rs2032583 and rs2235015, plasma antidepressant levels should not exceed the recommended range in order to obtain optimal treatment outcome.

Are there meaningful biomarkers of treatment response for depression?

During the past decades, the prevalence of affective disorders has been on the rise globally, with only one out of three patients achieving remission in acute treatment with antidepressants. The identification of physiological markers that predict treatment course proves useful in increasing therapeutic success. On the basis of well-documented, recent findings in depression research, we highlight and discuss the most promising biomarkers for antidepressant therapy response. These include genetic variants and gene expression profiles, proteomic and metabolomic markers, neuroendocrine function tests, electrophysiology and imaging techniques. Ultimately, this review proposes an integrative use of biomarkers for antidepressant treatment outcome.