Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity

Abstract

Background: The treatment of schizophrenia is challenging due to the wide range of symptoms (positive, negative, cognitive) associated with the disease. Typical antipsychotics that antagonize D2 receptors are effective in treating positive symptoms, but extrapyramidal side-effects (EPS) are a common occurrence. Atypical antipsychotics targeting 5-HT2A and D2 receptors are more effective at treating cogni-tive and negative symptoms compared to typical antipsychotics, but these drugs also result in side-effects such as metabolic syndromes.Objective: To identify evidence in the literature that elucidates the pharmacological profile of aripiprazole.Methods: We searched PubMed for peer reviewed articles on aripiprazole and its clinical efficacy, side-effects, pharmacolo-gy, and effects in animal models of schizophrenia symptoms.Results: Aripiprazole is a newer atypical antipsychotic that displays a unique pharmacological profile, including partial D2 agonism and functionally selective properties. Aripiprazole is effective at treating the positive symptoms of schizophrenia and has the potential to treat negative and cognitive symptoms at least as well as other atypical antipsychotics. The drug has a favorable side-effect profile and has a low propensity to result in EPS or metabolic syndromes. Animal models of schizophrenia have been used to determine the efficacy of aripiprazole in symptom management. In these instanc-es, aripiprazole resulted in the reversal of deficits in extinction, pre-pulse inhibition, and social withdrawal. Because aripipra-zole requires a greater than 90% occupancy rate at D2 receptors to be clinically active and does not produce EPS, this suggests a functionally selective effect on intracel-lular signaling pathways.Conclusion: A combination of factors such as dopamine system stabilization via partial agonism, functional selectivity at D2 receptors, and serotonin-dopamine system interaction may contribute to the ability of aripiprazole to successfully manage schizophrenia symptoms. This review examines these mechanisms of action to further clarify the pharmacological actions of aripiprazole.

Effects of aripiprazole on circadian prolactin secretion related to pharmacogenetics in healthy volunteers

“…Additionally, serotoninergic pathways have a stimulatory effect on prolactin release . ARI acts as a partial agonist at DRD2 and 5‐HT1A receptors and as an antagonist at 5‐HT2A . It binds to the D2 receptor with the same affinity than dopamine if it is not present.…”

“…42 ARI acts as a partial agonist at DRD2 and 5-HT1A receptors and as an antagonist at 5-HT2A. 2 It binds to the D2 receptor with the same affinity than dopamine if it is not present. On the contrary, if dopamine is present, it shows functional antagonist activity.…”

“…Aripiprazole (ARI), a quinolinone derivative, is an atypical (second generation) antipsychotic drug indicated for the treatment of adult patients with schizophrenia or schizoaffective disorders. Aripiprazole acts as a partial agonist at dopamine (D2, D3) and 5‐hydroxytryptamine (5‐HT)1A receptors and as an antagonist at 5‐HT2A . Opposite to other antipsychotic agents, ARI is the first approved antipsychotic that reduces dopaminergic neurotransmission through D2 partial agonism, not D2 antagonism .…”

“…Aripiprazole acts as a partial agonist at dopamine (D2, D3) and 5-hydroxytryptamine (5-HT)1A receptors and as an antagonist at 5-HT2A. 2 Opposite to other antipsychotic agents, ARI is the first approved antipsychotic that reduces dopaminergic neurotransmission through D2 partial agonism, not D2 antagonism. 3 ARI is extensively metabolized by cytochrome P450 (CYP) isoforms CYP3A4 and CYP2D6.…”

Caution in Co-administration of Aripiprazole and Lithium in Patients with Learning Disability

“…Aripiprazole was approved by the FDA in 2004 for treatment of bipolar disorder. 7 An important meta-analyses which was designed by Dian-JengLi and co-authors confirmed the efficacy or safety of aripiprazole in manic episodes. 8 There are several studies that show long-term administration of aripiprazole in combination to lithium or valproate in bipolar mania is well tolerated and safe and this improvement in functioning is maintained.…”