Aripiprazole, a Novel Atypical Antipsychotic Drug

Tami R. Argo, Pharm.D.; Ryan M. Carnahan, Pharm.D.; Paul J. Perry, Ph.D.


Pharmacotherapy. 2004;24(2) 

In This Article

Clinical Pharmacology

Aripiprazole (Abilify; Bristol-Myers Squibb, Princeton, NJ) is chemically characterized as a quinolinone derivative (Figure 1).[9] Drug therapies developed to treat schizophrenia traditionally have targeted positive symptoms of the disease -- hallucinations and delusions. Dopamine neurotransmission appears to be important in psychosis; the D2 receptor plays the clearest role. All previously available antipsy-chotics are antagonists at D2 receptors.[10,11] Aripiprazole is a partial agonist at these receptors.[12] Under conditions of dopamine excess, aripiprazole acts as a D2 receptor antagonist, since its intrinsic activity at the receptor is less than that of endogenous dopamine. This is its likely action at postsynaptic D2 receptors in patients with schizophrenia.

Chemical structure of aripiprazole.

Autoreceptors are receptors present on neurons that regulate the synthesis and release of ligands by positive and negative feedback processes. Generally, they provide negative feedback and thus downregulate neurotransmission. The intrinsic activity of partial dopamine agonists at presynaptic D2 autoreceptors is thought to reduce the synthesis and release of dopamine at the synapse.[13] The slight measure of agonist activity at autoreceptors lowers the tendency of the partial agonist to upregulate the receptors as a true antagonist would.[13] Aripiprazole has an affinity about 100 times higher for D2 than D1 receptors in rat striatum in vitro,[11] and has a high affinity for the D2 receptor.[14,15] However, it caused minimal upregulation of D2 receptors in contrast to other high-affinity compounds, such as haloperidol.[11] High-affinity blockade of D2 receptors and increases in D2 receptor density are thought to be associated not only with untoward extrapyramidal symptoms but also with the development of tardive dyskinesia.[16]

In animal models, under hyperdopaminergic conditions, binding of aripiprazole resulted in decreased activation of D2 receptors, whereas in hypodopaminergic states, administration resulted in activation of D2 receptors.[15] Several models have been postulated regarding treatment of negative symptoms and focus on the dysregulation of dopamine in the prefrontal cortex. Improvement of negative symptoms through alleviating hypodopaminergic function in the prefrontal cortex with dopamine agonists or partial agonists has been hypothesized.[17,18] The clinical benefits of aripiprazole in treating schizophrenia could be attributed in part to the drug's unique mechanism of action on dopamine and serotonergic receptors.

Aripiprazole is also an antagonist at the serotonin 5-HT2A receptors, a common trait of all atypical antipsychotics. The 5-HT2A antagonism is one potential mechanism by which atypical antipsychotic agents help alleviate negative symptoms associated with schizophrenia -- flattened affect, alogia, anhedonia, avolition, and emotional and social withdrawal.[19,20] Therapy with agents that inhibit serotonergic function may increase dopaminergic transmission in the prefrontal cortex, and may result in improvement of negative symptoms.[19] It has also been asserted that 5-HT2A blockade may offer limited protection from the extrapyramidal symptomatology associated with extensive D2 blockade.[19]

Aripiprazole is also an agonist at 5-HT1A receptors.[21] The 5-HT1A agonists and their actions on somatodendritic autoreceptors may offer extra help in mediating extrapyramidal effects when D2 blockade is complete. This is accomplished through their inhibitory actions on serotonergic neurons, which leads to an increase in dopaminergic transmission in the striatum, thus decreasing EPS.[21] The pharmacologic actions of aripiprazole on these receptor types have led some specialists to describe the drug as the first of a new class of atypical antipsychotic agents, termed dopamine-serotonin system stabilizers.[22]

In addition to the actions mentioned above, aripiprazole is an antagonist at α1-adrenergic receptors. It also exhibits high affinity for D3 receptors, moderate affinity for D4, 5-HT2C and 5-HT7, histamine H1 receptors, and the presynaptic serotonin transporter site. However, the functionality of aripiprazole on these neuroreceptor subtypes is unclear.[23]


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