A Candidate Pathway Strategy for Integration of Pharmacogenomic Components of Variability in Antipsychotic Treatment Outcomes: A Focus on Aripiprazole

Christopher      Reist; Lawrence   J.   Albers; Stephen   R.   Marder; Bryn      Williams-Jones; Joseph   C.   Wu; Steven      Mee; Kazutaka      Shimoda; Toshiyuki      Someya; Vural      Ozdemir

Abstract

Aripiprazole is the first atypical antipsychotic introduced to medical practice with partial dopamine-serotonin agonist properties. Other new molecular entities such as bifeprunox, a partial agonist at the dopamine D2 and serotonin 5- HT1A receptors, are currently being evaluated in early stage drug development as potential antipsychotic agents. As a partial agonist, whether aripiprazole displays an agonist effect or attenuates dopaminergic neurotransmission may depend on regional variations in endogenous dopamine tone. Hence, aripiprazole offers a therapeutic advantage to differentially modulate dopaminergic activity in brain regions in a graded fashion. This mechanism of action is intriguing when considered in the context of the dopamine hypothesis of schizophrenia whereby positive symptoms (e.g. hallucinations and delusions) are associated with increased mesolimbic dopaminergic activity while reduced activity in mesocortical dopaminergic pathways underlies negative symptoms (e.g. avolition and anhedonia) and cognitive deficits. Despite its therapeutic promise, antipsychotic response to aripiprazole is highly variable, and some patients do not respond at all to drug therapy. Treatment-emergent adverse events associated with aripiprazole include insomnia, anxiety, akathisia or worsening of psychosis in some patients. These observations suggest that the underlying mechanism of action of aripiprazole in psychotic disorders is more complex than what would be anticipated solely by simple partial agonist effects at the dopamine D2 receptor. For example, while aripiprazole attenuates dopaminergic hyperactivity it does not increase locomotor activity in reserpinized (hypodopaminergic) rats, which is not fully consistent with a partial agonist mode of action. Aripiprazole can induce a diverse range of effects at dopamine D2 receptors (agonism, antagonism, partial agonism) depending on the cellular milieu defined by promiscuous interactions with a host of signaling partners and variability in local G protein complement and concentration. This diversity provides an opportunity to illustrate the importance of integrating data on genetic variation in pharmacokinetic pathways and molecular targets for antipsychotics including biogenic amine receptors and their downstream signaling partners. Theragnostics, a new subspecialty of molecular medicine formed by combination of therapeutics with diagnostics, offers the potential to synthesize different types of biomarkers (DNA and protein-based) in the context of antipsychotic treatment outcomes. Because the dopamine receptor genetic variation is extensively reviewed elsewhere, we discuss the pharmacogenomic significance of variability in genes encoding for the 5-HT1A (HTR1A) and 5-HT2A (HTR2A) receptors and CYP2D6- and CYP3A4-mediated aripiprazole metabolism. As the field moves toward predictive genetic testing for newer antipsychotics, we emphasize the need for collaboration among pharmacogeneticists, bioethicists and specialists in science and technology studies.

Keywords: Aripiprazole, OPC-14597, pharmacogenomics, atypical antipsychotics, genetic biomarkers, personalized, therapeutics, CYP2D6, CYP3A4, HTR1A, HTR2A