title: A multivariate approach linking reported side effects of clinical antidepressant and antipsychotic trials to in vitro binding affinities.
abstract: The vast majority of approved antidepressants and antipsychotics exhibit a complex pharmacology. The mechanistic understanding of how these psychotropic medications are related to adverse drug reactions (ADRs) is crucial for the development of novel drug candidates and patient adherence. This study aims to associate in vitro assessed binding affinity profiles (39 compounds, 24 molecular drug targets) and ADRs (n=22) reported in clinical trials of antidepressants and antipsychotics (n>59.000 patients) by the use of robust multivariate statistics. Orthogonal projection to latent structures (O-PLS) regression models with reasonable predictability were found for several frequent ADRs such as nausea, diarrhea, hypotension, dizziness, headache, insomnia, sedation, sleepiness, increased sweating, and weight gain. Results of the present study support many well-known pharmacological principles such as the association of hypotension and dizziness with α1-receptor or sedation with H1-receptor antagonism. Moreover, the analyses revealed novel or hardly investigated mechanisms for common ADRs including the potential involvement of 5-HT6-antagonism in weight gain, muscarinic receptor antagonism in dizziness, or 5-HT7-antagonism in sedation. To summarize, the presented study underlines the feasibility and value of a multivariate data mining approach in psychopharmacological development of antidepressants and antipsychotics.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Johanna
authors.initials: J
authors.lastname: Michl
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Scharinger
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
authors.forename: Miriam
authors.initials: M
authors.lastname: Zauner
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Department of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.affiliation: Department of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. Electronic address: gerhard.f.ecker@univie.ac.at.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Pezawas
mesh_terms: D000928:Antidepressive Agents / Q000009:adverse effects*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D002986:Clinical Trials as Topic / Q000009:adverse effects / Q000706:statistics & numerical data; D016208:Databases, Factual / Q000706:statistics & numerical data; D004244:Dizziness / Q000139:chemically induced*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced*; D066298:In Vitro Techniques; D008297:Male; D015999:Multivariate Analysis; D011485:Protein Binding
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents
keywords: Adverse effects; Antidepressive agents; Antipsychotic agents; Clinical pharmacology; Depressive disorder; Schizophrenia