Inserm UMR-S 1144

Response Variability to Psychotropics

The research projects developed by the Research Unit have been conceived keeping in mind the major clinical issues facing our field today: the failure of treatment and its prevention in drug abusers, as well as the mood disorders to which the latter are subject, two leading causes of chronic disability, mortality and cost. This failure of therapy, in its extreme forms, is manifested as overdoses and/or suicide attempts.

Our objective is to improve the therapeutic monitoring of patients exposed to psychotropic drugs either due to drug abuse or as part of their treatment for mood disorders or pain management, by the identification of different markers - clinical, humoral, genetic or imaging-based - that will allow us to predict the response to therapy and prevent toxic side effects. This project thus aims to help establish personalized treatment in psychiatry and drug abuse.

The principal objectives of our project can be summarized as follows:

  • To identify molecular signatures predicting treatment failure or relapse in addicts and patients with bipolar disorders. In accordance with the recruitment of patients, we will focus our study on those treated for opiate or cocaine dependency, in whom relapses are frequent, and those treated with lithium, a major mood-regulator, and for which 60% of patients are considered "poor responders". 
  • To characterize the mechanisms of toxicity of psychotropic drugs, including new psychoactive substances (“party drugs”), alone or in combination, and to identify factors of individual vulnerability.
  • To characterize the structure and molecular changes induced in the blood-brain barrier (BBB) by chronic exposure to psychotropic drugs, including at toxic doses or in the context of mental disorders. New regulatory mechanisms for the exchange or transport of substances across the BBB could be discovered, explaining response variability and leading to therapeutic or diagnostic applications.

The Unit (Prof. Jean-Louis Laplanche, Director, PharmD, PhD) is organized into three teams to encourage their multidisciplinary nature and interactions within and between them:

Team 1: "Biomarkers of relapse and therapeutic response in addiction and mood disorders" (headed by Prof. Frank Bellivier, MD, PhD, psychiatrist, Paris Diderot University and Dr. Cynthia Marie-Claire, Senior Researcher from the Centre National de la Recherche Scientifique (CNRS) develops research programs on biomarkers (central or peripheral, using molecular or imaging investigations) that could predict the psychotropic drugs response and relapse prediction in addictions (opiates, cocaine) and bipolar disorders. Patients are recruited patients through its specialized centers for drug addiction and bipolar disorder at Fernand Widal Hospital.

Team 2: "Mechanisms of toxicity and therapeutic optimization of psychotropic drugs", (headed by Prof. Bruno Mégarbane, MD, PhD, clinical toxicologist, Paris Diderot University), aims to identify the predictive factors of response variability to psychoactive drugs (including illegal drugs, and central analgesics), in situations of poisoning (aiming to better understand mechanisms of toxicity) and prescription (aiming to optimize strategies of patient treatment). Identification of factors of response variability is conditioned by transversal investigations including pharmacogenetics, pharmacokinetics (PK) and pharmacodynamics (PD) of psychotropic drugs as well as mechanisms of drug-drug interactions which may explain this variability in patients with highly prevalent polypharmacy.

Team 3: "Pathophysiology and therapeutic targets of the blood-brain barrier", headed by Prof. Xavier Declèves, PharmD, PhD, Pharmacokinetician, Paris Descartes University) conducts fundamental research into the BBB. Its objective is to study and identify the mechanisms involved in the regulation of molecular exchanges across the BBB, under pathological conditions or in models of exposure to psychoactive substances (drugs of abuse or therapeutic drugs used in the context of addiction or bipolar disorder). In the long term, this project aspires to improve, on the one hand, the treatment of psychiatric disorders and addiction, and on the other, our understanding of the mechanisms brought into play in these pathological situations. This new knowledge will allow us to define biomarkers of interest to the clinic, and to designate new therapeutic targets.

The Research Unit is member of the "Fondation FondaMental" and is affiliated to the "Ecole des Neurosciences de Paris (ENP)"