Assoc.Prof. Priv.Doz. Dr. Julia Schwarzenberg
Post-traumatic stress disorder (PTSD) in adolescents is a debilitating disorder. Biological factors are increasingly being recognized as indicators of onset, intensity and chronicity of symptoms. Numerous biological systems are impacted by PTSD, often in a supposedly bidirectional way. Hence, there's a growing focus on identifying variables that account for individual variations in stress reactions and their responses to interventions. Results of previous studies conclude that adolescent PTSD displays unique neurodevelopmental substrates which could diminish recovery or represent a focus in the context of adolescent neuroplasticity to enhance outcomes. Whether and how current treatments address these targets remains an open question. Thus, it is of importance to understand PTSD neurobiology to a more profound extent and extend biological research on intervention strategies. Our lab aims to address these topics by means of linking clinical care with biomarker research. This should help to inform the creation of algorithms to improve treatment stratification, with the future goal of improving treatment outcomes by personalized treatment choices.
Focal points of interest
Preliminary data gathered in our lab reveals that two GABA metabolites, i.e. 4-aminobutanamide and 2-pyrollidinone, were found more than two-fold decreased in metabolomic samples of PTSD patients (FDR<0.2). Importantly, we have identified significantly increased values of the gut microbiome-derived metabolites, 3-phenyllactic acid and hydroxyphenyllactic acid in finger sweat samples of PTSD pa)ents (FDR< 0.001), indica)ng a pro-inflammatory microbial imbalance, as already described in previous studies. Thus, the first focal point of interest of the suggested research aims at extending our findings to a larger sample of PTSD patients in the framework of a longitudinal study, encompassing the course of psychotherapy as well as nutrition-associated interventions. This should help to elucidate mechanisms underlying PTSD as systemic disease. One of the main characteristics of PTSD is the overgeneralization of fear to unimportant circumstances. Nevertheless, little is known about the mechanisms by which fear spreads.
In a recent preclinical study (PMID: 38484078), fear generalization was described to be initiated by a neurotransmitter switch in GABA in a population of serotoninergic neurons of the lateral wings of the dorsal raphe induced by the modulation of the glucocorticoid receptor. Mice that had their transmitter switch overridden were unable to develop widespread fear. Prompt antidepressant treatment prevented the cotransmitter switch. The second focal point of interest intends to build on this preclinical research, aiming at translating the mentioned findings into a clinical study of adolescent PTSD patients, benefitting from the unique interplay of preclinical and clinical researchers in the present CoE.
Technical proficiency and instrumentation
The suggested research is embedded in a specialized outpatient clinic for trauma related disorders. The clinic’s team combines members with track records in multimodal biological procedures assessing the impact of stress, psychotherapists and teaching therapists, who will contribute to implementation and supervision of psychotherapeutic treatment procedures. Members of the clinic have undergone training in evidence-based psychotherapeutic interventions and have a long-standing track record in treating children and adolescents by psychopharmacological interventions. In addition, an existing collaboration with the Department of Analytical Chemistry, University of Vienna, will provide expertise in the field of metabolomic and proteomic research. Metabolic phenotyping will be performed using finger sweat analysis based on mass spectrometry, as published previously. The projection of the metabolic profiles on metabolic networks allows to identify biochemical processes specifically affected in the corresponding patient. Additional hypotheses will benefit from collaborations with preclinical research groups.
Aspirations for the next 5 years
The suggested research aims at increasing a mechanistic understanding of the pathology and pathogenesis of PTSD which is currently hampered by extensive heterogeneity within diagnostic categories that are subjectively defined. An aspiration for the next 5 years concerns the translation of potential future findings into the improvement of clinical interventions, both in terms of psychotherapy as well as psychopharmacological treatment.
References
- Post-traumatic Stress Disorder and the Developing Adolescent Brain. Cisler JM, Herringa RJ. Biol Psychiatry. 2021 Jan 15;89(2):144-151. doi: 10.1016/j.biopsych.2020.06.001.
- Using fMRI connectivity to define a treatment-resistant form of post-trauma)c stress disorder. Etkin A, Maron-Katz A, Wu W, Fonzo GA, Huemer J (=Schwarzenberg J, contributed equally as first author), Vértes PE, Patenaude B, Richiardi J, Goodkind MS, Keller CJ, Ramos-Cejudo J, Zaiko YV, Peng KK, Shpigel E, Longwell P, Toll RT, Thompson A, Zack S, Gonzalez B, Edelstein R, Chen J, Akingbade I, Weiss E, Hart R, Mann S, Durkin K, Baete SH, Boada FE, Genfi A, Autea J, Newman J, Oathes DJ, Lindley SE, Abu-Amara D, Arnow BA, Crossley N, Hallmayer J, Fossa) S, Rothbaum BO, Marmar CR, Bullmore ET, O'Hara R. Sci Transl Med. 2019 Apr 3;11(486):eaal3236. doi: 10.1126/scitranslmed.aal3236.
- Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Ressler KJ, Berre$a S, Bolshakov VY, Rosso IM, Meloni EG, Rauch SL, Carlezon WA Jr. Nat Rev Neurol. 2022 May;18(5):273-288. doi: 10.1038/s41582-022-00635-8
