Deep phenotyping as a contribution to personalized depression therapy: the GEParD and DaCFail protocols

Abstract

Depressive patients suffer from a complex of symptoms of varying intensity compromising their mood, emotions, self-concept, neurocognition, and somatic function. Due to a mosaic of aetiologies involved in developing depression, such as somatic, neurobiological, (epi-)genetic factors, or adverse life events, patients often experience recurrent depressive episodes. About 20-30% of these patients develop difficult-to-treat depression. Here, we describe the design of the GEParD (Genetics and Epigenetics of Pharmaco- and Psychotherapy in acute and recurrent Depression) cohort and the DaCFail (Depression-associated Cardiac Failure) case-control protocol. Both protocols intended to investigate the incremental utility of multimodal biomarkers including cardiovascular and (epi-)genetic markers, functional brain and heart imaging when evaluating the response to antidepressive therapy using comprehensive psychometry. From 2012 to 2020, 346 depressed patients (mean age 45 years) were recruited to the prospective, observational GEParD cohort protocol. Between 2016 and 2020, the DaCFail case-control protocol was initiated integrating four study subgroups to focus on heart-brain interactions and stress systems in patients > 50 years with depression and heart failure, respectively. For DaCFail, 120 depressed patients (mean age 60 years, group 1 + 2), of which 115 also completed GEParD, and 95 non-depressed controls (mean age 66 years) were recruited. The latter comprised 47 patients with heart failure (group 3) and 48 healthy subjects (group 4) of a population-based control group derived from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study. Our hypothesis-driven, exploratory study design may serve as an exemplary roadmap for a standardized, reproducible investigation of personalized antidepressant therapy in an inpatient setting with focus on heart comorbidities in future multicentre studies.

Keywords: Affective disorders; Biomarkers; Brain–heart interaction; Major depressive disorder; Predictive markers.

Fig. 1

Study designs. After study enrolment, patients were scheduled for weekly blood sample collection in both study protocols. Psychometry was carried out within the clinical routine, with exemptions. In selected study weeks, patients were scheduled for cardiac assessment, modified dexamethasone-suppression test (mDST), and blood sample collection for (epi-)genetic analyses. Patients of DaCFail group 1 and 3 underwent MIBG scintigraphy. Abbreviations: diff = differential, MIBG = ¹²³I-meta-iodobenzylguanidine, RR = blood pressure, TDM = therapeutic drug monitoring, TTE = transthoracic echocardiography, w = week, w/ = with. For psychometry and multimodal biomarkers including functional imaging in detail, please see Tables 2 and 3

Fig. 2

Consort chart for the GEParD and DaCFail protocols (2012–2020). Overview of screening and enrolment process in the GEParD and DaCFail study protocols