Synapse & Trauma

Targeting novel synaptic pathways in trauma-related psychiatric disorder: a Clinical Research Priority Program 2019-2021 funded by University of Zurich

In today’s turbulent world, psychological trauma and early-life adversity have emerged as major risk factors for various psychiatric disorders. Across the entire spectrum of trauma-related disorders, cognitive-behavioural psychotherapy, which seeks to modify aversive memories (Milad and Quirk, 2012), is currently the recommended treatment by national and international guidelines. Yet, in clinical practice the majority of patients remain symptomatic (Loerinc et al., 2015; Yehuda et al., 2015). This has led to high-profile calls for developing adjunct pharmacological therapies (Krystal et al., 2017). During the same time, our understanding of synaptic biology has increased exponentially, yielding a wide range of compounds that modify synapses themselves, the surrounding extracellular matrix that shapes their properties (Huntley, 2012), and the daily rhythms of sleep and wake that govern their strength (Chen et al., 2013).

This CRPP connects these disparate strands and delivers a novel approach to alter aversive memories with pharmacological agents. The conceptual idea, already established in pre-clinical (Lee et al., 2017) and clinical models (Brunet et al., 2018), is to activate synapses through psychotherapeutic intervention, and then modify them pharmacologically. While previous models for pharmacological intervention targeted synapses indirectly via neurotransmitters, this CRPP focuses on directly targeting molecular pathways involved in degrading old, and shaping new, synaptic connections. In humans, the CRPP will use several candidate drugs already approved for other indications, one of which has already been shown to impact on human fear memory (Bach et al., 2017). The CRPP will further strive to identify new mechanisms of action in non-human models.

Contact

Mrs Karolina Wicki
Department of Psychiatry, Psychotherapy, and Psychosomatics
Psychiatric Hospital, University of Zurich
Lenggstrasse 31
8032 Zurich
Switzerland

Principal Investigators

Dominik Bach, Assistant Professor for Clinical Psychiatry Research, Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Zurich

Birgit Kleim, Professor for Experimental Psychopathology and Psychotherapy, Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Zurich

Steven Brown, Professor for Chronobiology and Sleep Research, Institute of Pharmacology and Toxicology, University of Zurich

Shiva Tyagarajan, Assistant Professor for Neurodevelopmental Pharmacology, Institute of Pharmacology and Toxicology, University of Zurich

Co-Investigator

Erich Seifritz, Professor for Psychiatry and Director of the Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Zurich

Scientific Advisory Board

Emily Holmes, Karolinska Institute Stockholm

Kai Kaila, University of Helsinki

Rafael Kalisch, University of Mainz

Andreas Maercker, University of Zurich

References

Bach DR, Tzovara A, Vunder J (2017) Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline. Molecular psychiatry.

Brunet A, Saumier D, Liu A, Streiner DL, Tremblay J, Pitman RK (2018) Reduction of PTSD Symptoms With Pre-Reactivation Propranolol Therapy: A Randomized Controlled Trial. Am J Psychiatry:appiajp201717050481.

Chen Z, Yoo SH, Takahashi JS (2013) Small molecule modifiers of circadian clocks. Cell Mol Life Sci 70:2985-2998.

Huntley GW (2012) Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13:743-757.

Krystal JH, Davis LL, Neylan TC, M AR, Schnurr PP, Stein MB, Vessicchio J, Shiner B, Gleason TD, Huang GD (2017) It Is Time to Address the Crisis in the Pharmacotherapy of Posttraumatic Stress Disorder: A Consensus Statement of the PTSD Psychopharmacology Working Group. Biological psychiatry 82:e51-e59.

Lee JLC, Nader K, Schiller D (2017) An Update on Memory Reconsolidation Updating. Trends in cognitive sciences 21:531-545.

Loerinc AG, Meuret AE, Twohig MP, Rosenfield D, Bluett EJ, Craske MG (2015) Response rates for CBT for anxiety disorders: Need for standardized criteria. Clin Psychol Rev 42:72-82.

Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129-151.

Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, Hobfoll SE, Koenen KC, Neylan TC, Hyman SE (2015) Post-traumatic stress disorder. Nat Rev Dis Primers 1:15057.