The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression

Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46;p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52;p=0.01). Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment

a study from the German Algorithm Project

Einleitung: Eine Regeneration des HPA-Systems gilt als Voraussetzung für eine adäquate Response auf Antidepressiva. Das FKBP5-Gen reguliert die Funktion des HPA-Systems durch Modulierung der Sensitivität des GR. Vorarbeiten zeigten, dass Polymorphismen in diesem Gen die Antidepressiva-Response beeinflussen. Insbesondere der Polymorphismus rs1360780 war in zwei vorangegangenen Studien signifikant mit dem Therapieansprechen assoziiert. Die vorliegende Arbeit zielte in einer ersten Fragestellung darauf ab, diese Befunde an einem Sample stationär behandelter Patienten mit unipolarer Depression über einen gesamten komplexen Therapieprozess hinweg zu replizieren. Die Patienten waren randomisiert auf eine standardisierte algorithmusgestützte oder eine naturalistische Therapie. In einer zweiten Fragestellung wurde untersucht, ob der FKBP5-Genotyp einen Einfluss auf den Effekt einer algorithmusgestützten Pharmakotherapie hat. Dies würde bedeuten, dass der Effekt der algorithmusgestützen Behandlung bei einem Genotyp überproportional stark ausgeprägt ist und dieser Genotyp möglicherweise in besonderem Maße von einer standardisierten Behandlung profitiert. Methoden: Zur Beantwortung der ersten Fragestellung wurde die Assoziation von Genotyp und Response bzw. Remission in der gesamten Stichprobe von 298 Patienten untersucht. Hierbei gab es zwei Beobachtungszeiträume, welche sich am Algorithmus orientierten: Der erste betrug bis zu sechs Wochen (Antidepressiva-Monotherapie im Algorithmus), der zweite bis zu 14 Wochen (kompletter Therapieverlauf inklusive pharmakologischer Eskalationsstrategien). Die Stichprobe bestand aus 171 standardisiert und 127 naturalistisch behandelten Patienten. In der zweiten Fragestellung wurde ermittelt, ob eine Interaktion zwischen Genotyp und Behandlungsmodus (standardisiert vs. naturalistisch) vorlag. Als statistisches Hauptverfahren kam die Cox-Regressionsanalyse zum Einsatz. Die Response war definiert als eine Abnahme des HAMD-21 um mindestens 50 %, eine Remission lag vor bei einem HAMD-Wert unter 10. Ergebnisse: In Übereinstimmung mit Vorarbeiten war ein signifikanter Einfluss des Genotyps auf das Therapieansprechen zu konstatieren. T/T-Träger zeigten eine signifikant höhere Responsewahrscheinlichkeit als C-Allel-Träger. Der Unterschied war über den ersten Messzeitraum hinweg bereits signifikant (HR = 1,77; p = 0,032) und wurde tendenziell über den gesamten Beobachtungszeitraum von bis zu 14 Wochen hinweg noch deutlicher (HR = 1,92; p = 0,008). Die Ergebnisse für die Remission waren ähnlich. In Hinblick auf die zweite Fragestellung zeigte sich für die C-Allel-Träger eine signifikante Überlegenheit der standardisierten Behandlung, wohingegen der Behandlungsmodus das Therapieansprechen der T/T-Patienten nicht entscheidend beeinflusste. Konklusion: Die Replikation des Genotyp-Einflusses, welcher über einen langen Therapieprozess hinweg nachweisbar war, spricht für einen prädiktiven Wert des untersuchten Polymorphismus auch in Hinblick auf eine komplexe Antidepressivatherapie. T/T-Patienten zeigten unabhängig vom Behandlungsmodus eine signifikant höhere Ansprechwahrscheinlichkeit. Die Ergebnisse legen nahe, dass insbesondere C -Allel-Träger von einer hochgradig standardisierten Behandlung profitieren und damit ihr „genetische Nachteil“ bzgl. des Therapieansprechens zum Teil kompensiert werden kann.Introduction: Regeneration oft the HPA-system is considered as a prerequisite for appropriate response to antidepressants. The FKBP5-gene regulates the function of the HPA-system by modulating the sensitivity of the GR. Previous studies demonstrated that polymorphisms in this gene are associated with response to different classes of antidepressants. This association has most consistently been shown for the single nucleotide polymorphism rs1360780 in two previous studies. The present study firstly aimed to replicate these findings in a sample of unipolar depressed inpatients during an entire complex treatment process. The patients were randomized to either standardized algorithm-guided treatment or naturalistic treatment. The second objective of the study was to analyse if the FKBP5-genotype exerts an influence on the effect of an algorithm- guided pharmacotherapy. This would mean that the effect of the algorithm is disproportionately high for a specific genotype and that this genotype might benefit notably from standardization of treatment. Methods: For objective 1 we analysed the association of genotype and response respectively remission in the total sample of 298 patients for two different treatment periods which were oriented towards the algorithm: The first period lasted up to 6 weeks (antidepressant monotherapy in the algorithm), the second up to 14 weeks of treatment (complete treatment process including pharmacological augmentation strategies). The sample was composed of 171 algorithm-treated and 127 naturalistically treated patients. For objective 2 we analysed for statistical interactions between genotype and treatment mode (standardized vs. naturalistic). Main statistical method was Cox-regression analysis. Response was defined as a 50% reduction of HAMD-21 and remission was achieved with a HAMD-score < 10\. Results: In accordance with previous studies we found a significant association of the FKBP5-genotype with treatment outcome. T/T-carriers showed a higher chance of responding compared to C-allele carriers. The difference was significant for the first observation period (HR = 1,77; p = 0,032) with an even stronger level of significance for the entire observation period of up to 14 weeks (HR = 1,92; p = 0,008). The results for remission were similar. Regarding the second objective of the study we detected a significantly superior effect of the algorithm-guided treatment in C-allele carriers, whereas the treatment mode did not influence treatment outcome in T/T-carriers. Conclusion: Our findings replicate the association of FKBP5 genotype with response to antidepressant treatment and show the association even for a complex treatment process. Homozygous carriers of the T-allele showed a significantly higher chance to respond independently of the treatment mode. The results suggest that especially C- allele carriers benefit from a highly standardized treatment and thus their “genetic disadvantage” concerning treatment response can partially be compensated

The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression

Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01). Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment

Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study

Background: In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design: This multi-center, prospective controlled study has a two-phase cohort design. Methods: Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD's outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes: Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients' quality of life and evaluation of care; and f) physicians' satisfaction with the innovative care approach. Conclusions: This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease