T. Brückl

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

The stress hormone–regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor–regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant–dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Heterogeneity of DSM-IV Major Depressive Disorder as a Consequence of Subthreshold Bipolarity

CONTEXT There is growing evidence that major depressive disorder (MDD) might be overdiagnosed at the expense of bipolar disorder (BPD). OBJECTIVES To identify a subgroup of subthreshold BPD among DSM-IV MDD, which is distinct from pure MDD regarding a range of validators of bipolarity, and to examine the pattern of these validators among different groups with affective disorders. DESIGN Ten-year prospective longitudinal and family study including 3 follow-up waves. Data were assessed with the DSM-IV Munich Composite International Diagnostic Interview. SETTING Community sample in Munich, Germany. PARTICIPANTS A total of 2210 subjects (aged 14-24 years at baseline) who completed the third follow-up. MAIN OUTCOME MEASURES Cumulative incidence of pure MDD, BPD, and subthreshold BPD (defined as fulfilling criteria for MDD plus having manic symptoms but never having met criteria for [hypo]mania). RESULTS Among 488 respondents with MDD, 286 (58.6%) had pure MDD and 202 (41.4%) had subthreshold BPD (cumulative incidence, 9.3%). Compared with respondents who had pure MDD, respondents with subthreshold BPD were found to have a significantly increased family history of mania, considerably higher rates of nicotine dependence and alcohol use disorders, rates of panic disorder that were twice as high, and a tendency toward higher rates of criminal acts. Prospective analyses showed that subthreshold BPD converted more often into BPD during follow-up, with DSM-IV criterion D (symptoms observable by others) being of critical predictive relevance. With increasing severity of the manic component, rates for diverse validators accordingly increased (eg, alcohol use disorders, parental mania) or decreased (harm avoidance). CONCLUSIONS Data suggest that MDD is a heterogeneous concept including a large group with subthreshold BPD, which is clinically significant and shares similarities with BPD. Findings might support the need for a broader concept and a more comprehensive screening of bipolarity, which could be substantial for future research and adequate treatment of patients with bipolarity.

Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study.

OBJECTIVE The binding protein FKBP5 is an important modulator of the function of the glucocorticoid receptor, the main receptor of the stress hormone system. This turns the FKBP5 gene into a key candidate for gene-environment interactions, which are considered critical for pathogenesis of stress-related disorders. The authors explored gene-environment interactions between FKBP5 gene variants and adverse life events in predicting the first occurrence of a major depressive episode. METHOD The analyses were based on 884 Caucasians in a 10-year prospective community study. At baseline, they were 14-24 years old and did not fulfill criteria for a major depressive episode. The DSM-IV-based Munich Composite International Diagnostic Interview was used to assess adverse life events preceding baseline and major depressive episodes during follow-up. On the basis of previous findings, five single-nucleotide polymorphisms (SNPs) within the FKBP5 gene were selected for genotyping. RESULTS While the authors did not observe genetic main effects, they found interactions between the five SNPs and traumatic (but not separation) events, with the strongest effect for severe trauma. The effect of trauma on incident major depressive episodes was evident among subjects homozygous for the minor alleles but not subjects with other genotypes. The findings were replicated in the U.K. Environmental Risk Longitudinal Twin Study. CONCLUSIONS These hypothesis-driven results suggest that an interaction between FKBP5 genotype and trauma is involved in the onset of depression. Subjects homozygous for the minor alleles of the investigated FKBP5 SNPs seem to be particularly sensitive to effects of trauma exposure in terms of triggering depression onset.

Childhood Separation Anxiety and the Risk of Subsequent Psychopathology: Results from a Community Study

Objective: To examine the association between separation anxiety disorder (SAD) and mental disorders in a community sample and to evaluate whether separation anxiety is specifically related to panic disorder with and without agoraphobia. Method: The data come from a 4-year, prospective longitudinal study of a representative cohort of adolescents and young adults aged 14–24 years at baseline in Munich, Germany. The present analyses are based on a subsample of the younger cohort that completed baseline and two follow-up investigations (n = 1,090). DSM-IV diagnoses were made using the Munich Composite International Diagnostic Interview. Cox regressions with time-dependent covariates were used to examine whether prior SAD is associated with an increased risk for subsequent mental disorders. Results: Participants meeting DSM-IV criteria for SAD were at an increased risk of developing subsequent panic disorder with agoraphobia (PDAG) (HR = 18.1, 95% CI = 5.6–58.7), specific phobia (HR = 2.7, 95% CI = 1.001–7.6), generalized anxiety disorder (HR = 9.4, 95% CI = 1.8–48.7), obsessive-compulsive disorder (HR = 10.7, 95% CI = 1.7–66.1), bipolar disorder (HR = 7.7, 95% CI = 2.8–20.8), pain disorder (HR = 3.5, 95% CI = 1.3–9.1), and alcohol dependence (HR = 4.7, 95% CI = 1.7–12.4). Increased hazard rates for PDAG (HR = 4.2, 95% CI = 1.4–12.1), bipolar disorder type II (HR = 8.1, 95% CI = 2.3–27.4), pain disorder (HR = 1.9, 95% CI = 1.01–3.5), and alcohol dependence (HR = 2.1, 95% CI = 1.1–4.) were also found for subjects fulfilling subthreshold SAD. Conclusions: Although revealing a strong association between SAD and PDAG, our results argue against a specific SAD-PDAG relationship. PDAG was neither a specific outcome nor a complete mediator variable of SAD.

Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression

The FK506 binding protein 51 or FKBP5 has been implicated in the regulation of glucocorticoid receptor (GR) sensitivity, and genetic variants in this gene have been associated with mood and anxiety disorders. GR resistance and associated stress hormone dysregulation are among the most robust biological findings in major depression, the extent of which may be moderated by FKBP5 polymorphisms. FKBP5 mRNA expression in peripheral blood cells (baseline and following in vivo GR stimulation with 1.5 mg dexamethasone p.o.) was analyzed together with plasma cortisol, ACTH, dexamethasone levels and the FKBP5 polymorphism rs1360780 in 68 depressed patients and 87 healthy controls. We observed a significant (P = 0.02) interaction between disease status and FKBP5 risk allele carrier status (minor allele T) on GR-stimulated FKBP5 mRNA expression. Patients carrying the risk T allele, but not the CC genotype, showed a reduced induction of FKBP5 mRNA. This FKBP5 polymorphism by disease status interaction was paralleled by the extent of plasma cortisol and ACTH suppression following dexamethasone administration, with a reduced suppression only observed in depressed patients carrying the T allele. Only depressed patients carrying the FKBP5 rs1360780 risk allele showed significant GR resistance compared with healthy controls, as measured by dexamethasone-induced FKBP5 mRNA induction in peripheral blood cells and suppression of plasma cortisol and ACTH concentrations. This finding suggests that endocrine alterations in depressed patients are determined by genetic variants and may allow identification of specific subgroups.

The interplay of familial depression liability and adverse events in predicting the first onset of depression during a 10-year follow-up

BACKGROUND The aim of the present article is to explore interaction and correlation effects between familial depression liability and selected adverse (separation and traumatic) events in predicting the first onset of a major depressive episode (MDE) in a 10-year prospective longitudinal community survey. METHODS Analyses are based on 1982 subjects (14 to 24 years at baseline) without baseline MDE who participated during the whole study period and for whom diagnostic information about psychopathology in both parents was available. The offsprings familial depression liability was determined by aggregating information on parental depressive symptoms obtained from family history data and direct interviews with parents. Data were assessed with the Munich-Composite International Diagnostic Interview according to its DSM-IV algorithms. RESULTS Adverse events predicted a substantially increased incidence of MDE among respondents with familial liability but not in those without familial liability. There was a significant interaction between familial liability and traumatic events with the strongest effect for the number of severe traumatic events (risk difference = 11.3%; 95% confidence interval = 3.55-19.15). Associations with familial liability were most pronounced for separation events. CONCLUSIONS Adverse events are particularly pathogenic in individuals with familial liability. The involvement of interactions and correlations between familial liability and adversity might depend on type, severity, and number of events. Both processes are suggested to be concomitant rather than exclusive.

FKBP5 Genotype-Dependent DNA Methylation and mRNA Regulation After Psychosocial Stress in Remitted Depression and Healthy Controls

Background: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress. Methods: A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells. Results: Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression. Conclusions: The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.

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.

ABCB1 gene variants and antidepressant treatment outcome: A meta-analysis

The efflux pump P‐glycoprotein (P‐gp), a gene product of the ABCB1 gene, plays a pivotal role in the transfer of various molecules across the blood–brain barrier. P‐gp protects the brain by selectively extruding its substrates, including certain antidepressive drugs, thereby limiting their uptake into the brain. Uhr et al. [2008] first showed that ABCB1 variants predicted the remission to antidepressants with P‐gp substrate properties in patients suffering from major depression (MD). Other studies investigating the influence of ABCB1 polymorphisms on antidepressant treatment response produced inconclusive results. In this meta‐analysis, we systematically summarized 16 pharmacogenetic studies focused on the association of ABCB1 variants and antidepressant treatment outcome in patients with MD (overall n = 2695). We investigated the association of treatment outcome and six ABCB1 single nucleotide polymorphisms (SNPs): rs2032583, rs2235015, rs2235040, rs1045642, rs2032582, rs1128503. We stratified for admission status, ethnicity, and prescription of concomitant medication. SNP rs2032583 showed a nominally significant association across all studies (P = 0.035, SNP was studied in a total of 2,037 patients) and a significant Bonferroni‐corrected association among inpatients (P = 1.5 × 10−05, n = 485). Also SNP rs2235015 was significantly associated with antidepressant treatment outcome withstanding Bonferroni correction (P = 3.0 × 10−04) among inpatients in a smaller subsample (n = 195). There were no significant associations of the other SNPs tested with antidepressant treatment outcome. Future pharmacogenetic association studies should focus on the role of the ABCB1 SNP rs2032583 in antidepressant outcome prediction.

Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels.

Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.