S. Horstmann

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.

Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment.

Single-nucleotide polymorphisms (SNPs) in the FKBP5, GRIK4, and HTR2A genes have been shown to be associated with response to citalopram treatment in the STAR*D sample, but only associations with FKBP5 have so far been tested in the Munich Antidepressant Response Signature (MARS) project. Response and remission of depressive symptoms after 5 weeks of antidepressant treatment were tested against 82 GRIK4 and 37 HTR2A SNPs. Association analysis was conducted in about 300 depressed patients from the MARS project, 10% of whom had bipolar disorder. The most predictive SNPs from these two genes and rs1360780 in FKBP5 were then genotyped in a total of 387 German depressed in-patients to analyze potential additive and interactive effects of these variants. We could not replicate previous findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study in our sample. Although not statistically significant, the effect for the best GRIK4 SNP of STAR*D (rs1954787, p=0.076, pcorrected=0.98) seemed to be in the same direction. On the other hand, the nominally significant association with the top HTR2A SNPs of STAR*D (rs7997012, allelic, p=0.043, pcorrected=0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p=0.0019, pcorrected=0.12) and the HTR2A SNP (rs17288723, genotypic, p=0.0011, pcorrected=0.02), which showed the strongest association with remission in our sample, had not been reported previously. Associations across all genetic markers within the GRIK4 (genotypic, p=0.022) or HTR2A (genotypic, p=0.012) locus using the Fishers product method (FPM) were also significant. In all 374 patients, the best predictive model included a main effect for GRIK4 rs12800734 and two significant interactions between GRIK4 rs12800734 and FKBP5 rs1360780, and GRIK4 rs12800734 and HTR2A rs17288723. This three SNP model explained 13.1% of the variance for remission after 5 weeks (p=0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p=0.002) and cortisol (p=0.021) responses of rs12800734 GG (GRIK4) carriers, who also showed favorable treatment response, were significantly lower in the second combined dexamethasone (dex)/corticotrophin-releasing hormone (CRH) test before discharge compared with the other two genotype groups. Despite large differences in ethnicity and design compared with the STAR*D study, our results from the MARS study further support both independent and interactive involvement of GRIK4, HTR2A and FKBP5 in antidepressant treatment response.

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients – Findings from the Munich Antidepressant Response Signature (MARS) project

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.

Overweight and Obesity Affect Treatment Response in Major Depression

BACKGROUND Epidemiologic and clinical studies suggest comorbidity between major depressive disorder (MDD) and obesity. To elucidate the impact of weight on the course of depression beyond comorbidity, we investigated psychopathology, attention, neuroendocrinology, weight change, and treatment response in MDD patients, depending on their weight. METHODS Four hundred eight inpatients with MDD participated in the Munich Antidepressant Response Signature Study, designed to discover biomarkers and genotypes that are predictive for clinical outcome. Psychopathology and anthropometric parameters were monitored weekly in 230 patients. In subsamples, combined dexamethasone-corticotropin-releasing hormone and attention tests were conducted at admission and discharge. One thousand twenty-nine diagnosed matched controls served for morphometric comparisons. RESULTS Patients with MDD had a significantly higher body mass index (BMI) compared with healthy controls. Patients with high BMI (> or =25) showed a significantly slower clinical response, less improvement in neuroendocrinology and attention, and less weight gain than did patients with normal BMI (18.5 < or = BMI < 25) during antidepressant treatment. CONCLUSIONS Our findings suggest that overweight and obesity characterize a subgroup of MDD patients with unfavorable treatment outcome.

Pharmacogenomics of antidepressant drugs

While antidepressant pharmacotherapy is an effective treatment of depression, it is still hampered by the slow onset of appreciable clinical improvement and a series of side effects. Moreover, a substantial group of patients does not achieve remission or fails to respond at all. One possible source accounting for these variations in treatment outcome are genetic differences. In recent years a number of pharmacogenetic studies on antidepressant drugs have been published. This manuscript summarizes findings related to the pharmacogenetics of genes involved in the pharmacokinetics as well as pharmacodynamics of antidepressants to date. Illustrated by examples from current candidate gene- and whole genome association studies, this manuscript critically discusses aspects of pharmacogenetic studies in antidepressant response related to study design and clinical relevance.

Persistent cognitive impairment in depression: the role of psychopathology and altered hypothalamic-pituitary-adrenocortical (HPA) system regulation

BACKGROUND Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system and cognitive impairment are consistent findings in depression. This study examines the associations between HPA system regulation, cognitive functioning, and psychopathology in depressed inpatients on admission and at discharge. METHODS The HPA system dysregulation was evaluated with the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. Cognitive assessment included speed of information processing, divided and selective attention, as well as short-term and working memory. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Data from 75 depressed inpatients are reported, 51 (68%) of them achieved remission. RESULTS Despite a significant reduction of depressive symptoms between admission and discharge, a high rate of patients remained cognitively impaired. Selective attention improved significantly in remitters and nonremitters, while speed of information processing increased only in remitters. The cortisol response to the DEX/CRH test decreased significantly only in remitters, which was uncorrelated with cognitive performance. In nonremitters, severity of depression was significantly correlated with information processing time while improvement in short-term memory was negatively associated with the cortisol response at discharge. CONCLUSIONS Our data support the assumption that psychopathological symptoms and the HPA system dysregulation can be dissociated in their impact on cognitive functioning in depressed patients.

Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.

CONTEXT A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported. OBJECTIVE To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci. DESIGN Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a case-control association design. SETTING Inpatients and screened control subjects. PARTICIPANTS The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively. INTERVENTIONS Blood or saliva samples were collected from each participant for DNA extraction and genotyping. MAIN OUTCOME MEASURES Associations of SNPs in BDNF and NTRK2 with SA and MDD. RESULTS Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7 x 10(-7) for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes. CONCLUSIONS Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide.

HTR2A gene variation is involved in antidepressant treatment response

Two serotonin 2A receptor (HTR2A) SNPs recently reported to be associated with antidepressant treatment response in STARD (rs7997012; rs1928040) were analyzed for association with treatment response in two independent Caucasian samples of patients with a Major Depressive Episode. In the combined sample (n=637) SNP rs7997012 was significantly associated with remission after five weeks providing first replicative support for the initial finding, with, however, an inverse allelic association as compared to the STARD sample.

Genetic markers within glutamate receptors associated with antidepressant treatment-emergent suicidal ideation.

ajp.psychiatryonline.org cause of space limitations, we were unable to include several key aspects of clinical care. As educators as well as clinicians, we consistently remind those who we teach about the importance of close communication with school personnel regarding the functioning of our patients, wherever they may be on the spectrum of risk to others. In hindsight, including content that stressed the importance of close communication between the clinician and school personnel could have strengthened our article. We agree that the use of a systematic assessment of violence risk is essential. However, it is our opinion that a reductionistic tendency of systems to rely on only one approach of risk assessment—as we have frequently seen in our own clinical practices—often does not lead to optimal placements for young, school-age patients.