Pharmacological Modulation of the Psychiatric Risk Factor FKBP51 Alters Efficiency of Common Antidepressant Drugs.

Max L Pöhlmann,Daniela Harbich,Georgia Balsevich,Clara Engelhardt,Michaela Breitsamer,Gerhard Winter,Alexander S Häusl,Felix Hausch,Xixi Feng,Mathias V Schmidt

doi:10.3389/fnbeh.2018.00262

Abstract

Despite a growing body of research over the last few decades, mental disorders, including anxiety disorders or depression, are still one of the most prevalent and hardest to treat health burdens worldwide. Since pharmacological treatment with a single drug is often rather ineffective, approaches such as co-medication with functionally diverse antidepressants (ADs) have been discussed and tried more recently. Besides classical ADs, there is a growing number of candidate targets identified as potential starting points for new treatment methods. One of these candidates, the FK506 binding protein 51 (FKBP51) is linked to a number of psychiatric disorders in humans. In this study, we used SAFit2—a newly developed modulator of FKBP51, which has shown promising results in rodent models for stress-related disorders delivered in a depot formulation. We combined SAFit2 with the commonly prescribed selective serotonin reuptake inhibitor (SSRI) escitalopram and performed basic behavioral characterization in a mouse model. Remarkably, co-application of SAFit2 lowered the efficacy of escitalopram in anxiety-related tests but improved stress coping behavior. Given the fact that mental diseases such as anxiety disorders or depression can be divided into different sub-categories, some of which more or less prone to stress, SAFit2 could indeed be a highly beneficial co-medication in very specific cases. This study could be a first, promising step towards the use of FKBP51 modulators as potent and specific enhancers of AD efficiency for subclasses of patients in the future.

Highlights

In recent years, our understanding and perception of mental disorders, like anxiety disorders or depression, as a major burden for our society, has increased tremendously
For the total distance traveled (Figure 2A), ANOVA revealed no main effect of SAFit2 treatment (F(1,36) = 3.567, p < 0.1), but a main effect of escitalopram (F(1,36) = 56.03, p < 0.001) as well as an interaction effect (F(1,36) = 3.196, p < 0.1)
When the data were split up in three 5-min time bins (Figure 2B), it becomes clear that the moderating effect of SAFit2 treatment on the escitalopram effect is mainly evident in the 2nd (p < 0.05) and 3rd (p < 0.05) time bin

Summary

Introduction

Our understanding and perception of mental disorders, like anxiety disorders or depression, as a major burden for our society, has increased tremendously. The majority of the widely prescribed antidepressants (ADs), like paroxetine or escitalopram, alter the availability of monoamines like serotonin in the synaptic cleft These so-called selective serotonin reuptake inhibitors (SSRIs) prove to be effective in patients with anxiety disorders as well as major depression, the effect size is modest and there is a high non-responder rate (Jakobsen et al, 2017). The lack of a mechanistically broader drug spectrum makes it hard to treat non-responsive patients, and so-called ‘‘treatmentresistant’’ patients often lack a real chance of recovery For this reason, focus has shifted towards a broad cluster of cellular mechanisms and pathways linked to mental disorders as well as approaches that combine different methods and treatments to achieve more reliable results. For example, is often treated with common SSRIs alone; AD response can be enhanced by psychotherapy (Strawn et al, 2018)

Methods

Results

Conclusion