Classics in Chemical Neuroscience: Aripiprazole

Abstract

Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D2 receptor binding kinetics, have significantly lower risk of movement side effects, but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole’s polypharmacology—characterized by its unique agonist activity at dopamine D2, D3 and serotonin 5-HT1A receptors as well as antagonist activity at serotonin 5-HT2A receptors—translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole’s neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.

Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure

“…Aripiprazole has unique receptor-binding properties acting as a partial agonist at dopaminergic D 2 and serotonergic 5-HT 1A receptors, and as an antagonist at 5-HT 2A receptors [8,9,12]. It has advantages, such as lower risk of extrapyramidal symptoms, hyperprolactinemia, bodyweight gain, diabetes mellitus and sedation; however, the treatment discontinuation rate associated with aripiprazole inefficacy seems to be higher than that of olanzapine or haloperidol [10,[13][14][15].…”

Embedding neuroscience in psychiatry training

“…Such a stance neglects significant clinical domains where diagnosis and treatment are clearly informed by neuroscientific developments: psychiatrists who work with people with intellectual disabilities, with new-onset psychosis or with dementia routinely rely on imaging, electroencephalogram (EEG) studies or immunological testing to guide management strategies. Likewise, the development of aripiprazole as a widely used first-line treatment for psychosis hinged on the requirements of finding a medication that reduces dopamine D 2 receptor function without the wider side-effects of previous treatments (Casey 2017).…”

Synthesis and Biological Evaluation of Five‐Atom‐Linker‐Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile

“…However, this strategy seems to be unsuitable for complex psychiatric diseases such as schizophrenia. [9][10][11] Besides dopamine D 2 receptors, various serotonin receptors are also important targets for schizophrenia. [5] Patients often take several single drugs with different bioavailability, pharmacokinetics, and metabolism profiles.…”