title: Intracellular pathways of antipsychotic combined therapies: implication for psychiatric disorders treatment.
abstract: Dysfunctions in the interplay among multiple neurotransmitter systems have been implicated in the wide range of behavioral, emotional and cognitive symptoms displayed by major psychiatric disorders, such as schizophrenia, bipolar disorder or major depression. The complex clinical presentation of these pathologies often needs the use of multiple pharmacological treatments, in particular (1) when monotherapy provides insufficient improvement of the core symptoms; (2) when there are concurrent additional symptoms requiring more than one class of medication and (3) in order to improve tolerability, by using two compounds below their individual dose thresholds to limit side effects. To date, the choice of drug combinations is based on empirical paradigm guided by clinical response. Nonetheless, several preclinical studies have demonstrated that drugs commonly used to treat psychiatric disorders may impact common intracellular target molecules (e.g. Akt/GSK-3 pathway, MAP kinases pathway, postsynaptic density proteins). These findings support the hypothesis that convergence at crucial steps of transductional pathways could be responsible for synergistic effects obtained in clinical practice by the co-administration of those apparently heterogeneous pharmacological compounds. Here we review the most recent evidence on the molecular crossroads in antipsychotic combined therapies with antidepressants, mood stabilizers, and benzodiazepines, as well as with antipsychotics. We first discuss clinical clues and efficacy of such combinations. Then we focus on the pharmacodynamics and on the intracellular pathways underpinning the synergistic, or concurrent, effects of each therapeutic add-on strategy, as well as we also critically appraise how pharmacological research may provide new insights on the putative molecular mechanisms underlying major psychiatric disorders.
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, Reproductive and Odontostomatologic Sciences, Section of Psychiatry, University Medical School of Naples "Federico II", Naples, Italy. Electronic address: adebarto@unina.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: de Bartolomeis
authors.forename: Livia
authors.initials: L
authors.lastname: Avvisati
authors.forename: Felice
authors.initials: F
authors.lastname: Iasevoli
authors.forename: Carmine
authors.initials: C
authors.lastname: Tomasetti
mesh_terms: D000339:Affect / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004338:Drug Combinations; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects*; D001523:Mental Disorders / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D004338:Drug Combinations
keywords: Antidepressant; Benzodiazepine; Bipolar disorder; Mood stabilizer; Postsynaptic density; Schizophrenia