Manfred Uhr

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.

Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: a prospective study

The development and course of depression is causally linked to impairment of central regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Previous research documented that the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test identifies HPA dysfunction with high sensitivity. We evaluated the predictive validity for medium-term outcome of the cortisol response in the combined DEX/CRH test in 74 remitted patients previously suffering from major depressive disorder. Of the 74 patients, 61 remained in stable remission and 13 relapsed during the first 6 months after discharge from the hospital. Although the cortisol and ACTH responses in the DEX/CRH test did not differ between the two groups of patients on admission, the responses differed significantly just before discharge (P< 0.05). We defined two dichotomous variables as prediction rules indicating (1) the change between admission and discharge in the cortisol response to the DEX/CRH test, and (2) the effect of the CRH infusion on cortisol as compared to the baseline level in the DEX/CRH test prior to discharge only. An elevated cortisol response in the DEX/CRH test was correlated with a four- to six-fold higher risk for relapse than in individuals with a normal cortisol response. The two proposed rules for predicting relapse within the first 6 months after discharge could be optimized by including age and gender. Hence, an exaggerated cortisol response in the combined DEX/CRH test predicts the recurrence of depressive psychopathology. The test performance can be further optimized if gender and age are taken into account.

Polymorphisms in the Drug Transporter Gene ABCB1 Predict Antidepressant Treatment Response in Depression

The clinical efficacy of a systemically administered drug acting on the central nervous system depends on its ability to pass the blood-brain barrier, which is regulated by transporter molecules such as ABCB1 (MDR1). Here we report that polymorphisms in the ABCB1 gene predict the response to antidepressant treatment in those depressed patients receiving drugs that have been identified as substrates of ABCB1 using abcb1ab double-knockout mice. Our results indicate that the combined consideration of both the medications capacity to act as an ABCB1-transporter substrate and the patients ABCB1 genotype are strong predictors for achieving a remission. This finding can be viewed as a further step into personalized antidepressant treatment.

Combined Dexamethasone/Corticotropin Releasing hormone test predicts treatment response in major depression--a potential biomarker?

BACKGROUND Exaggerated corticotropin (ACTH) and cortisol response to the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test, indicating impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system, is frequently observed in depression. In the present study, we examined whether change in HPA system function during the first weeks of hospitalization predicts response to antidepressant treatment in major depression and thus constitutes a potential biomarker. METHODS We conducted the DEX/CRH test in 50 inpatients suffering from severe major depression, once after study inclusion and a second time 2 to 3 weeks later while under continuous antidepressant treatment. RESULTS We found increased ACTH and cortisol responses to the first DEX/CRH test compared with healthy control subjects. In the second DEX/CRH test 2 to 3 weeks later, 36 of the 50 patients showed an attenuated cortisol response, while 14 patients did not display improvement or exhibited even aggravation of the altered HPA system function. Improved HPA system regulation in the second DEX/CRH test was associated with beneficial treatment response after 5 weeks and a higher remission rate at the end of hospitalization. CONCLUSIONS The results suggest that change in HPA system regulation assessed with repeated DEX/CRH tests is a potential biomarker that may predict clinical outcome at follow-up. There is consensus that the drug development process could be improved, once reliable biomarkers become available that help to allow a judgement regarding the efficacy of a novel drug candidate. The combined DEX/CRH test seems to be a promising candidate for such a biomarker.

Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls

Mood and anxiety disorders are considered stress‐related diseases characterized by an impaired function of mineralocorticoid and glucocorticoid receptors (MR and GR, respectively), the major regulatory elements of the hypothalamus–pituitary–adrenocortical (HPA) axis. A number of so‐called chaperone proteins moderate the function of these receptors. Genetic variations in one of these chaperones, FKBP5, were associated with antidepressant treatment response in depression and with a major risk‐factor for the development of posttraumatic stress disorder. To further investigate the effect of FKPB5 polymorphisms on corticosteroid receptor‐mediated HPA axis regulation we conducted the Trier Social Stress test, a standardized procedure to evaluate psychosocial stress response, in 64 healthy volunteers. We genotyped rs4713916, rs1360780 and rs3800737, the three single nucleotide polymorphisms (SNPs) in the FKBP5 region which had shown the strongest effect in previous studies. In addition, we evaluated the effects of the GR polymorphisms Bcl1 and N363S as well as the MR polymorphism I180V. Subjects homozygous for any of the FKBP5 variants displayed an incomplete normalization of the stress‐elicited cortisol secretion. This was also observed following a second test additionally accompanied by an increased self‐reported anxiety. Regarding GR and MR, only carriers of the Bcl1 variant displayed an altered cortisol response in the prognosticated direction. While Bcl1 was predominantly associated with anticipatory cortisol, homozygous carriers of the FKBP5 minor allele showed insufficient cortisol recovery and increased self‐reported anxiety after psychosocial stress. This reaction pattern suggests that subjects carrying these variants are at risk of displaying chronically elevated cortisol levels after repeated stress constituting a risk factor for stress‐related diseases.

Penetration of Amitriptyline, but Not of Fluoxetine, into Brain is Enhanced in Mice with Blood-Brain Barrier Deficiency Due to Mdr1a P-Glycoprotein Gene Disruption

Mice with a genetic disruption (knockout) of the multiple drug resistance (Mdr1a) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein at the blood-brain barrier on the uptake of amitriptyline (AMI) and fluoxetine (FLU) and their metabolites into the brain. One hour after intraperitoneal injection of AMI or FLU, knockout (−/−) and wild-type (+/+) mice were sacrificed and drug concentrations of brain, kidney, liver, testis, and plasma were measured. The plasma concentrations of the AMI metabolites and the brain:spleen ratios of AMI, nortriptyline (NOR), 10-OH-AMI and 10-OH-NOR were significantly higher in the −/− mice, demonstrating that AMI and its metabolites are substrates of the P-glycoprotein and that mdr1a activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, tissue distributions of FLU and its metabolites among the various tissues tested were indistinguishable between groups. The herein reported differences in brain penetration of antidepressant drugs depending on the presence of the mdr1a gene may offer an explanation for differences in the treatment response at a given plasma concentration. Moreover, individual differences in mdr1 gene activity may account for variable response patterns at different episodes and development of therapy resistance.

Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b P-glycoproteins.

Numerous investigations have confirmed an important role for multidrug‐resistance gene 1‐type P‐glycoproteins (MDR1‐type P‐gps) in the blood–brain barrier, protecting the brain against the accumulation of a wide range of toxic xenobiotics and drugs. Several studies have provided evidence in vitro that certain steroid hormones are transported by MDR1‐type P‐gps; however, the question of whether this might also apply to the situation in vivo still remained to be determined. We used mice deficient for both murine mdr1a and mdr1b P‐gps [mdr1a/1b(−/−)] to determine the uptake of [3H]‐cortisol, [3H]‐corticosterone, [3H]‐aldosterone and [3H]‐progesterone into the plasma, brain, testes, liver, spleen, pituitary and adrenal glands. We provide evidence that the access of the endogenous steroid hormones corticosterone, cortisol and aldosterone is regulated by MDR1‐type P‐gps in vivo. As peripherally administered steroid hormones accumulate in the brain of mice deficient for MDR1‐type P‐gps, mdr1a/1b proteins are likely to transport these hormones out of the brain, providing a kinetic barrier to their entry. Intracerebral progesterone concentrations are influenced by MDR1‐type P‐gp function as well; however, the effects are only small. In addition, all four endogenous glucocorticoid hormones accumulated in the testes of mdr1a/1b(−/−) mice. Our findings underline the importance of MDR1‐type P‐gps as an endogenous barrier system controlling the access of endogenous steroid hormones at the blood–brain barrier to maintain homeostatic control and to protect central nervous system neurones.

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.

Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption.

BACKGROUND Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood-brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain. METHODS One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured. RESULTS The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, brain distribution of mirtazapine was indistinguishable between the groups. CONCLUSIONS The differences reported here in brain penetration of antidepressant drugs that depend on the presence of the abcb1ab gene may offer an explanation for poor or nonresponse to antidepressant treatment. Furthermore, they may be able to explain in part the discrepancies between plasma levels of an antidepressant and its clinical effects and side effects.

Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence

Chronic stress is widely regarded as a key risk factor for a variety of diseases. A large number of paradigms have been used to induce chronic stress in rodents. However, many of these paradigms do not consider the etiology of human stress-associated disorders, where the stressors involved are mostly of social nature and the effects of the stress exposure persist even if the stressor is discontinued. In addition, many chronic stress paradigms are problematic with regard to stress adaptation, continuity, duration and applicability. Here we describe and validate a novel chronic social stress paradigm in male mice during adolescence. We demonstrate persistent effects of chronic social stress after 1 week of rest, including altered adrenal sensitivity, decreased expression of corticosteroid receptors in the hippocampus and increased anxiety. In addition, pharmacological treatments with the antidepressant paroxetine (SSRI) or with the corticotropin-releasing hormone receptor 1 antagonist DMP696 were able to prevent aversive long-term consequences of chronic social stress. In conclusion, this novel chronic stress paradigm results in persistent alterations of hypothalamus-pituitary-adrenal axis function and behavior, which are reversible by pharmacological treatment. Moreover, this paradigm allows to investigate the interaction of genetic susceptibility and environmental risk factors.