Serotonin 1A receptor distribution in treatment-resistant depression during psychopharmacotherapy compared to healthy controls

Major depressive disorder (MDD) is associated with a high lifetime prevalence and is a major cause of disability. An additional burden on patients is that up to 60% of the first antidepressant (AD) trials do not provide adequate symptom relief and after two subsequent AD trials, a patient is referred to as treatment-resistant. The serotonin 1A receptor subtype (5-HT1A) has commonly been used to study pathophysiological alteration in MDD. However, PET data on treatment-resistant depression (TRD) populations is still limited. In this cross-sectional study, 5-HT1A receptor binding was assessed in 20 TRD patients (9 female, mean age ± SD, 29.0 ± 5.2) and 20 healthy controls (HC) (10 female, mean age ± SD, 33.2 ± 8.2). Positron emission tomography (PET) scans with the radiotracer [ carbonyl -11C]WAY-100635 were acquired and 5-HT1A non-displaceable binding potential (BPND) was quantified using the multilinear reference tissue model 2, with the cerebellar white matter as reference region. Mean regional BPND in five regions of interest (amygdala, anterior cingulate cortex, hippocampus, insula and orbitofrontal cortex) was compared in a repeated measures analysis of covariance (rmANCOVA) with age, sex and group as covariates. Estimated marginal means showed slightly lower BPND in TRD group (mean ± SD = 5.464 ± 0.247) than in the HC group (mean ± SD = 5.938 ± 0.245). However, the rmANCOVA showed no significant group difference (p = 0.659). Studies on 5-HT1A binding in MDD show heterogeneous results, where the directionality of difference as well as the significance of findings strongly depend on specific outcome measures (BPND, BPF or BPP), reference region or quantification method. Here we showed no significant effect of TRD on BPND, similar to other studies applying the same methodology for MDD cohorts. ### Competing Interest Statement In the past three years S. Kasper has received grant/research support from Lundbeck; he has served as a consultant or on advisory boards for Angelini, Biogen, Esai, Janssen, IQVIA, Lundbeck, Mylan, Recordati, Sage and Schwabe; and he has served on speaker bureaus for Abbott, Angelini, Aspen Farmaceutica S.A., Biogen, Janssen, Lundbeck, Recordati, Sage, Sanofi, Schwabe, Servier, Sun Pharma and Vifor. Without any relevance to this work, R. Lanzenberger received investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR and travel grants and/or conference speaker honoraria from Bruker BioSpin, Shire, AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, Heel and Roche Austria GmbH. in the years before 2020. He is a shareholder of the start-up company BM Health GmbH, Austria since 2019.. M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, Siemens Healthineers. G.S. Kranz declares that he received conference speaker honorarium from Roche, AOP Orphan and Pfizer. The other authors do not report any conflict of interest. ### Clinical Trial ISRCTN30885829; [NCT02810717][1] ### Funding Statement This research was funded in whole, or in part, by the Austrian Science Fund (FWF) [Grant number KLI 551, PI: S. Kasper]. M. Murgaš is funded by the Austrian Science Fund (FWF) [Grant number DOC 33-B27, Supervisor R. Lanzenberger]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of the Medical University of Vienna gave ethical approval for the study (318/2002) Ethics Committee of the Medical University of Vienna gave ethical approval for the study(475/2011) Ethics Committee of the Medical University of Vienna gave ethical approval for the study(1761/2015) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Raw data will not be publicly available due to reasons of data protection. Processed data and custom code can be obtained from the corresponding author with a data-sharing agreement, approved by the departments of legal affairs and data clearing of the Medical University of Vienna. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02810717&atom=%2Fmedrxiv%2Fearly%2F2023%2F10%2F02%2F2023.09.29.23296333.atom