CNS Drugs (2015) 29:773–799 DOI 10.1007/s40263-015-0278-3 REVIEW ARTICLE Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism 1 1 1 Andrea de Bartolomeis • Carmine Tomasetti • Felice Iasevoli Published online: 7 September 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Dopamine partial agonism and functional selec- novel and future biased ligand compounds. This review aims tivity have been innovative strategies in the pharmacological to recapitulate the main neurobiological effects of aripipra- treatment of schizophrenia and mood disorders and have zole and discuss the potential implications for upcoming shifted the concept of dopamine modulation beyond the improvements in schizophrenia therapy based on dopamine established approach of dopamine D2 receptor (D2R) antag- modulation beyond D2R antagonism. onism. Despite the fact that aripiprazole was introduced in therapy more than 12 years ago, many questions are still unresolved regarding the complexity of the effects of this Key Points agent on signal transduction and intracellular pathways, in part linked to its pleiotropic receptor profile. The complexity The atypical antipsychotic aripiprazole has a unique of the mechanism of action has progressively shifted the pharmacological profile that provides ‘adaptive’ conceptualization of this agent from partial agonism to pharmacological activity. functional selectivity. From the induction of early genes to Depending on endogenous dopamine levels and modulation of scaffolding proteins and activation of tran- signaling status, aripiprazole may act as a full scription factors, aripiprazole has been shown to affect mul- antagonist, a moderate antagonist, or a partial agonist tiple cellular pathways and several cortical and subcortical at dopamine D2 receptors (D2Rs), consistent with neurotransmitter circuitries. Growing evidence shows that, purported biased ligand pharmacology. beyond the consequences of D2R occupancy, aripiprazole has a unique neurobiology among available antipsychotics. The The efficacy of aripiprazole can be mainly attributed effect of chronic administration of aripiprazole on D2R to this combination of partial agonism/antagonism at affinity state and number has been especially highlighted, with D2Rs and serotonin 5-HT1A receptors, together with relevant translational implications for long-term treatment of antagonism at serotonin 5-HT2A receptors. psychosis. The hypothesized effects of aripiprazole on cell- However, the receptor profile of the compound is protective mechanisms and neurite growth, as well as the much more complex, and animal models have shown differential effects on intracellular pathways [i.e. extracellular that aripiprazole affects multiple cellular pathways signal-regulated kinase (ERK)] compared with full D2R and several cortical and subcortical neurotransmitter antagonists, suggest further exploration of these targets by circuitries and has an impact on gene expression distinct from other antipsychotics. & Andrea de Bartolomeis Based on the pharmacological and functional [email protected] characteristics of aripiprazole, a number of new 1 Unit of Treatment Resistant Psychosis, Laboratory of dopaminergic biased ligands are emerging as Molecular and Translational Psychiatry, Department of potential candidates for the treatment of psychosis, Neuroscience, University School of Medicine of Napoli potentially improving the ‘dopamine modulation’ ‘‘Federico II’’, Via Pansini, 5, Edificio n.18, 3rd floor, 80131 Naples, Italy features of the prototypical compound. 774 A. de Bartolomeis et al. 1 Introduction forms from full D2R antagonist antipsychotic agents. Furthermore, these effects could be of relevant interest in the onset of secondary antipsychotic treatment resistance, More than 40 years since its first enunciation, the dopa- i.e. the onset of treatment resistance after a successful mine dysregulation hypothesis of schizophrenia is still response to an antipsychotic drug. The purpose of this considered pivotal for the pathophysiology of the disorder, review is to provide a depiction and critical appraisal of the even if preclinical and clinical research has emphasized the molecular pharmacology of aripiprazole and its effects on contribution of signaling of other neurotransmitters, pri- neurobiology as a mainstay for future studies on novel marily the glutamatergic and the serotonergic neurotrans- molecular targets for antipsychotic effect. mitters [1]. In its simplest form, the dopaminergic For the literature search, we conducted multiple sear- hypothesis states that an increase in dopamine release in ches using the PubMed database, with no date constraints the striatum (possibly as a final consequence of multiple but limited to English language articles. receptor aberrant interactions) is associated with a reduced The overall strategy can be summarized in three main dopaminergic tone in the dorsal prefrontal cortex [2]. This sections corresponding to the aim of the review. An initial mechanistic interpretation is probably too reductionist, data search was conducted using the key terms ‘aripipra- particularly considering the complexity of the molecular zole’ AND ‘receptor’, ‘pharmacokinetics’, ‘D2 receptor’, neurobiology of schizophrenia, which has been recently ‘partial agonism’, ‘functional selectivity’, ‘PET’, ‘gene’, conceptualized as a disorder of synaptic plasticity [3–5] ‘dopamine partial agonists’, ‘rat’. A second search was and of aberrant connectomics [6]; however, dopamine conducted focusing on the following key words: ‘arip- aberrant function represents a major landmark for iprazole’ AND ‘immediate early genes’, ‘transcription schizophrenia, both for pathophysiology and for pharma- factors’, ‘c-fos’, ‘Arc’, ‘Homer’, ‘Zif’. A third search cological treatment. included ‘aripiprazole derivatives’, ‘quinolinone deriva- Multiple lines of evidence, from preclinical models to tives’ AND ‘dopamine partial agonism’, ‘ergot derivatives’ in vivo neuroimaging studies in humans, demonstrate an AND ‘dopamine partial agonism’, ‘dopamine partial ago- aberrant release of dopamine in the striatum of nists’ AND ‘clinical studies’, ‘dopamine partial agonists’ schizophrenia patients [7]. In this regard, dynamic studies AND ‘preclinical studies’. measuring the binding of 11C-raclopride to striatal dopa- A final PubMed search was conducted in March 2015 mine D2 receptors (D2Rs) and dopamine D3 receptors immediately before the latest version of this review, with (D3Rs) in schizophrenia patients and in normal controls no restriction except, again, the English language, using the after an acute amphetamine challenge have robustly term ‘aripiprazole’. The new preclinical articles that fitted demonstrated that schizophrenia is associated with higher the subject of the article were selected and included. dopamine release in the striatum, and that this aberrant The articles found were initially reviewed by title and release may correlate with positive symptoms [8]. abstract then examined for relevance; after irrelevant arti- In the context of the dopamine hypothesis, the com- cles were discarded, the reference lists of selected articles plexity of dopamine receptor function deserves special were used to identify additional studies. emphasis, considering that, until the introduction of arip- iprazole, all available antipsychotics were characterized by D2R blockade (albeit to different degrees), and compounds 2 Pharmacokinetic Properties of Aripiprazole devoid of D2R blockade were not found to have an effi- cacious antipsychotic action [9]. Aripiprazole has changed 2.1 Absorption and Distribution this view of antipsychotic action on dopamine signaling, introducing for the first time in the treatment of psychosis a The mean elimination half-life of aripiprazole is about 75 h clinically relevant mechanism based on D2R occupancy after oral administration and reaches 94 h for dehy- without D2R blockade. Beyond its peculiar action on droaripiprazole, its active metabolite. Steady-state con- D2Rs, preclinical and in vivo studies in humans have centrations are attained within 14 days of dosing. After demonstrated the differential effects of aripiprazole on tablet administration, peak plasma concentrations are dopamine signaling and on multiple transcriptional effec- reached within 3–5 h. Tablet bioavailability is 87 %, while tors compared with the action of antipsychotics with full plasma concentrations are higher for the oral solution for- antagonist action at D2Rs. These effects range from the mulation [10, 11]. Administration with food, particularly a selective induction of early genes to the modulation of high-fat meal, does not affect mean peak plasma concen- distinct scaffolding proteins and transcription factors and tration (Cmax) or the area under the plasma concentration– imply that the compound targets multiple cellular pathways time curve, while it delays mean time at maximum serum and affects several neurobiological functions in different concentration (Tmax) by approximately 3 h for aripiprazole. Update on the Mechanism of Action of Aripiprazole 775 Steady-state volume of distribution is high, indicating Japanese subjects was found to reduce the systemic clear- extensive extravascular distribution. At therapeutic con- ance of the antipsychotic by 30 and 50 % in CYP2D6 centrations, both aripiprazole and dehydroaripiprazole are extensive and intermediate metabolizers, respectively