Neurobiological mechanisms of individual response to antidepressive therapy

Why does one patient respond to antidepressant therapy and another not? Why can the success of therapy vary greatly even in the same patient in different episodes of illness? Which molecular mechanisms mediate the change in behavior, i.e. the improvement from the depressive state (i.e. the response to antidepressive therapy)?

To date, the neurobiological mechanisms underlying inter- and intraindividual differences in the response to antidepressant treatment are not known. This means that therapeutic decisions in depression treatment still cannot be made on the basis of scientific, objective criteria. Targeted research on the neurobiological basis of antidepressant efficacy requires a suitable animal model that best reflects the clinical problem. We were able to establish a mouse model that for the first time enables us to map the great heterogeneity in the response to antidepressive therapy and to select extreme groups of mice that respond to treatment with above-average good and below-average bad response. This allows us to compare the extreme groups with respect to differences in local gene expression profiles in brain and blood, with profiles of regulatory microRNAs, in the proteome and in the metabolome. The aim of this approach is to 1) identify and characterize those genes and molecular mechanisms that modulate target behavior, i.e. the response to antidepressant therapy; and based on this, 2) identify antidepressant targets that might mediate a more rapid antidepressant effect with targeted intervention. Furthermore, this model allows the identification of predictive biomarkers for the response to antidepressive therapy.

Key publications

• Weckmann K, Labermaier C, Webhofer C, Asara M, Müller MB, Turck CW (2014).Time-dependent metabolomic profiling of ketamine drug action reveals hippocampal pathway alterations and biomarker candidates. Translational Psychiatry 4, e481; doi:10.1038/tp.2014.119
• Labermaier C, Masana M, Müller MB (2013). Biomarkers Predicting Antidepressant Treatment Response: How Can We Advance the Field? Disease Markers 35, Issue 1, Pages 23–31; dx.doi.org/10.1155/2013/984845
• Ganea K, Menke A, Schmidt MV, Lucae S, Rammes G, Liebl C, Harbich D, Sterlemann V, Storch C, Uhr M, Holsboer F, Binder EB, Sillaber I, Müller MB (2012). Convergent animal and human evidence suggests the activin/inhibin pathway to be involved in antidepressant response. Translational Psychiatry 2, e177; doi:10.1038/tp.2012.104
• Kohli, MA, Lucae S, Sämann PG, Schmidt MV, Demirkan A, Hek K, Roeske D, Alexander M, Salyakina D, Ripke S, Höhn D, Specht M, Menke A, Hennings J, Heck A, Wolf C, Ising M, Schreiber S, Czisch M, Müller MB, Uhr M, Bettecken T, Beckers A, Schramm J, Rietschel M, Maier W, Bradley B, Ressler KJ, Nöthen MM, Cichon S, Craig IW, Breen G, Lewis CM, Hofman A, Tiemeier H, van Duijn CM, Holsboer F, Müller-Myhsok B, Binder EB (2011). The neuronal transporter gene SLC6A15 confers risk to major depression. Neuron 70: 252-265