Aripiprazole – Mechanism of Action, Psychopharmacology and Clinical Application

PHARMACOLOGY

Aripiprazole is a partial D2 agonist. Aripiprazole has also been shown to exert greater agonist activity at presynaptic D2 autoreceptors (autoreceptors reduce DA transmission) than at postsynaptic D2 receptors. [Kikuchi et al., 2021]

A partial agonist is a medication that binds to the dopamine receptor but possesses less intrinsic activity than the endogenous full agonist dopamine, i.e. qualitatively acts like DA but quantitatively produces a response that is smaller than that produced by dopamine.

Depending on DA levels, it can act as either a functional antagonist or agonist, which provides benefits in treating schizophrenia. [Kikuchi et al., 2021]

Functional antagonist:

• In the presence of excess DA transmission, it can reduce this transmission to lower levels, levels corresponding to its intrinsic activity.

Functional agonist:

• In the presence of low DA levels, it can increase DA neurotransmission again to the level of its intrinsic activity.

Thus, Aripiprazole is pharmacologically different from other oral atypical antipsychotics that are D2-5HT2A antagonists. It reduces dopaminergic neurotransmission through partial agonism of D2 receptors, mainly in the mesolimbic and mesocortical pathways. [Shapiro et al. 2003]

This unique pharmacological profile has led to it being considered a third-generation antipsychotic.

Because aripiprazole is characterised by its stabilising effect on dopamine neurotransmission and is thus described as a dopamine-system stabiliser (DSS). [Kikuchi et al., 2021]

A partial dopamine agonist can be considered to be a dopamine modulator adjusting dopamine levels depending on whether they are too high or low (the dimmer switch effect or Goldilocks effect)

The Goldilocks effect

The Dimmer Switch Effect 

• Reduces positive symptoms: Aripiprazole has a lower intrinsic effect than dopamine, and therefore, partial agonism of D2 receptors in the mesolimbic pathway is postulated to reduce hyperfunctioning dopaminergic transmission.
• Reduces negative symptoms: Aripiprazole’s partial agonism of D2 receptors in the mesocortical pathway increases dopaminergic activity back to normal levels.

Partial agonists may be particularly useful in managing schizophrenia as concerns have been raised about the long-term administration of D2 antagonists resulting in D2 receptor upregulation and the risk of dopamine supersensitivity psychosis.[Nair et al., 2022]

The potential clinical consequence of dopamine supersensitivity psychosis is that antipsychotic medication may progressively lose effectiveness in treating schizophrenia, necessitating increasingly higher antipsychotic doses over time, with an increased side-effect burden.

There are suggestions that DA supersensitivity psychosis may progress to treatment-resistant schizophrenia (TRS).

Thus medications that minimise the risk of DA supersensitivity psychosis may lead to better long-term clinical outcomes and reduced rates of TRS.

Aripiprazole also exhibits a unique and broad receptor binding profile with the antagonism of serotonin 5-HT2A receptors and the partial agonist of serotonin 5-HT1A receptors. [Tuplin and Holahan 2017]

The antagonism of 5-HT7 receptors may contribute to some pro-cognitive and antidepressant effects.

The 5-HT7 antagonism is an important attribute of vortioxetine, a novel antidepressant.

Aripiprazole also has a high affinity for D3 dopamine receptors and a moderate affinity for D4 dopamine receptors.

COMPARING ARIPIPRAZOLE WITH BREXPIPRAZOLE

Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia) and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.

The lower intrinsic activity of brexpiprazole at D₂ receptors relative to aripiprazole indicates a lower likelihood of inducing side effects such as akathisia, restlessness, insomnia; side effects considered to be associated with aripiprazole-induced stimulating activity at D2 receptors (Activating side effects).

The potency and intrinsic activity of brexpiprazole are much higher and slightly lower than buspirone (5HT1A partial agonist).

In addition, brexpiprazole shows moderate affinities for histamine H1 receptors and adrenaline α1A receptors.

Due to the equally high affinities for the 5-HT1A (partial agonist), 5-HT2A (antagonist) and D2 (partial agonist) receptors, Brexpiprazole is an antipsychotic that belongs to a new category of drugs and is classified as a serotonin-dopamine activity modulator (SDAM). [Kikuchi et al., 2021]

Brexpiprazole also has a high affinity for α1B and α2C receptors and acts as an antagonist at both receptors. The α1B antagonism confers prazosin-like effects and may explain why brexpiprazole blocks PTSD-like memory while promoting normal fear memory in an animal model. A paper on two treatment-resistant cases showed that adjunctive treatment with brexpiprazole improved treatment-resistant complex PTSD in domestic family violence victims. [O’Connor, 2020]

Brexpiprazole had little or no significant effect on blood prolactin levels in schizophrenia, although aripiprazole was associated with decreases in blood prolactin levels. This can possibly be attributed to the lower intrinsic activity of brexpiprazole. [Kikuchi et al., 2021]

COMPARING ARIPIPRAZOLE WITH CARIPRAZINE

PHARMACOKINETICS

• Aripiprazole tablets have a bioavailability of 87% and peak plasma concentrations occur within 3 to 5 hours with steady-state concentrations attained after 14 days.
• Aripiprazole has a half-life of 75 hours and is primarily eliminated by the hepatic enzymes, CYP3A4 and CYP2D6. Hepatic expression levels of these enzymes are known to cause interindividual variability. [Kim et al 2008]

DOSING

• Oral aripiprazole (tablet or solution) is initially dosed at 10 to 15 mg/day in adults and 2 mg/day in adolescents and this dose should be titrated up to the recommended dose of 30 mg/day for both adults and adolescents.
• Dosage increases should not be made before 2 weeks, the time needed to achieve steady-state.
• There is no evidence that doses higher than 15 mg/day are more effective than the recommended starting dose of 10 to 15 mg.
• In patients with bipolar disorder, the recommended target dose is 15 mg/day (although 30 mg/day is permitted) monotherapy or as adjunctive therapy with lithium or valproate.

SIDE EFFECTS

Aripiprazole has been shown to be well tolerated in short- (4 to 8 weeks) and long-term (26 to 52 weeks) clinical trials. [Stip and Tourjman 2010]

It has a lower risk of extrapyramidal symptoms than other antipsychotics such as haloperidol and there is also significantly less weight gain and a clinically reduced risk of metabolic syndrome compared to olanzapine.

The most commonly observed adverse events are nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. [Abilify, prescribing information], [TGA PI].

These adverse events have been reported in ≥10% of patients enrolled in clinical trials.

• Dose reduction may be warranted if the patient is currently being administered known CYP3A4 inhibitors such as erythromycin, ketoconazole, or nefazodone or CYP2D6 inhibitors such as paroxetine, fluoxetine, or duloxetine.
• Dose increase may be warranted if the patient is currently being administered known CYP3A4 inducers such as carbamazepine or phenytoin.

Warnings and precautions on adverse reactions that have been observed in clinical trials include cerebrovascular events, suicidal thoughts and behaviours, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia, seizures, and dysphagia.

CLINICAL APPLICATIONS

• Aripiprazole has good evidence for the management of positive symptoms in patients with schizophrenia. It is also viewed as an important and valid alternative for patients who are currently suffering from persistent motor or metabolic side effects induced by other typical and atypical antipsychotic drugs.
• Switching to aripiprazole or augmentation of olanzapine or clozapine with aripiprazole are possible strategies for antipsychotic-induced weight gain. [Cooper s et al., 2016]
• Switching over to aripiprazole or adjunctive aripiprazole has been advocated for optimal management of antipsychotic-induced hyperprolactinemia. Adjunctive treatment with aripiprazole has been shown to normalize prolactin levels without a relapse of psychotic symptoms. [Meng M et al., 2015]
• Aripiprazole is a low-risk antipsychotic in relation to Qtc interval prolongation in healthy patients. However, baseline and steady-state electrocardiogram is recommended in patients at high risk for torsade due to marked QTc prolongation. [Polcwiartek c et al., 2015]
• Aripiprazole has been shown to provide symptomatic control of acute relapsing schizophrenia as well as significantly increasing the time to relapse in chronic stabilized schizophrenia. Overall, relapse/remission rates favour aripiprazole over haloperidol [Kane et al 2002], however, it has been observed that improvements in positive and negative symptoms were not as great as those reported for olanzapine. [Fleischhacker et al 2009]
• Aripiprazole has also been approved as monotherapy or as adjunctive therapy for the treatment of bipolar disorder (manic and maintenance phases) and as an augmentation option for the treatment of major depressive disorder.
• Aripiprazole is also an evidence-based augmentation strategy in treatment-resistant late-life depression. [Lenze E et al., 2015]
• Aripiprazole augmentation of clozapine is a well-tolerated and efficacious strategy that may allow for the reduction of doses of clozapine. [Muscatello M et al., 2011], [Ashton A, 2005]
• There is some evidence for Aripiprazole improving cognitive symptoms in schizophrenia. [Riedel M et al., 2010]
• Aripiprazole has also been approved by the FDA for the treatment of autistic spectrum disorder with results showing a reduction in irritability and hyperactivity in the short term. [Bartram et al 2019]

Off label use: 

• Off-label use includes patients with Alzheimer’s disease where it has modest levels of evidence for efficacy on dementia-related psychosis; however, there is a class-effect of increased mortality. [De Deyn et al 2013]
• Furthermore, although there have been no RCTs to date, aripiprazole has been shown in two open-label trials to be effective in treating anxiety disorders. [Katzman 2011]

SUMMARY

Aripiprazole is approved for the treatment of schizophrenia and bipolar disorder and has the unique property of partial D2 agonism as well as a class antagonist activity at serotonin 5HT2A receptors.

Aripiprazole is well tolerated within the recommended dose range with lower metabolic risk, lower propensity for weight gain and negligible prolactin increase.

RECOMMENDED BOOKS