Aripiprazole - Mechanism of Action, Clinical Efficacy and Side Effects

3/7/23, 4:08 PM Aripiprazole - Mechanism of Action, Clinical Efficacy and Side Effects
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Aripiprazole – Mechanism of Action,

Psychopharmacology and Clinical
Application
Posted on:October 23, 2020
Last Updated: August 30, 2022
Time to read: 9 minutes
Aripiprazole is a partial dopamine (D2) agonist with a high affinity for the D2 receptor but
lower intrinsic activity at the D2 receptor than dopamine (DA). It is classified as a
Dopamine System Stabiliser (DSS) due to its ability to modulate DA levels in key brain
pathways.
Aripiprazole is an achiral quinolinone derivative and a second-generation antipsychotic

approved for treating schizophrenia in 2002.
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Aripiprazole is marketed as Abilify and comes in oral tablets (2, 5, 10, 15, 20, and 30 mg
doses), orally disintegrating tablets (10 and 15 mg doses), an oral solution (1 mg/mL), and
as an intramuscular injection (7.5 mg/mL).
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.
https://psychscenehub.com/psychinsights/aripiprazole-mechanism-of-action-psychopharmacology-and-clinical-application/ 1/13
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]
Click here to zoom image
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]
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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.
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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.
In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34
nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding
affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) 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]
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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

When cariprazine was compared with aripiprazole for binding to dopamine D2 and D3
receptors, similar D2 and higher D3 antagonist-partial agonist affinity and a 3- to 10-fold
greater D3 vs D2 selectivity was observed for cariprazine.
The higher D3 selectivity may contribute to pro-cognitive effects. [Citrome L., 2018]
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.
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References
Aripiprazole, A Novel Atypical Antipsychotic Drug With A Unique And Robust
Pharmacology 
Discovery Research And Development History Of The Dopamine D2 Receptor Partial
Agonists, Aripiprazole And Brexpiprazole. 
Trace Amine-Associated Receptor 1 (TAAR1): Molecular And Clinical Insights For The
Treatment Of Schizophrenia And Related Comorbidities. 
Aripiprazole, A Drug That Displays Partial Agonism And Functional Selectivity 
Adjunctive Therapy With Brexpiprazole Improves Treatment Resistant Complex Post
Traumatic Stress Disorder In Domestic Family Violence Victims 
Population Pharmacokinetic Modelling Of Aripiprazole And Its Active Metabolite,

Dehydroaripiprazole, In Psychiatric Patients 
Efficacy And Safety Of Aripiprazole And Haloperidol Versus Placebo In Patients With
Schizophrenia And Schizoaffective Disorder 
A Double-Blind, Randomized Comparative Study Of Aripiprazole And Olanzapine In
Patients With Schizophrenia 
Efficacy, Safety, And Tolerability Of Augmentation Pharmacotherapy With
Aripiprazole For Treatment-Resistant Depression In Late Life: A Randomised, Double-
Blind, Placebo-Controlled Trial 
Effect Of Aripiprazole Augmentation Of Clozapine In Schizophrenia: A Double-Blind,
Placebo-Controlled Study 
Aripiprazole Augmentation Of Clozapine In Refractory Schizophrenia 

Effect Of Aripiprazole On Cognition In The Treatment Of Patients With Schizophrenia

Aripiprazole In Schizophrenia And Schizoaffective Disorder: A Review 
Abilify, Prescribing Information 
BAP Guidelines On The Management Of Weight Gain, Metabolic Disturbances And

Cardiovascular Risk Associated With Psychosis And Antipsychotic Drug Treatment. 
Using Aripiprazole To Reduce Antipsychotic-Induced Hyperprolactinemia: Meta-
Analysis Of Currently Available Randomized Controlled Trials 
The Cardiac Safety Of Aripiprazole Treatment In Patients At High Risk For Torsade: A
Systematic Review With A Meta-Analytic Approach 
Aripiprazole For Treating Irritability Associated With Autism Spectrum Disorders 
Aripiprazole In The Treatment Of Alzheimer's Disease 
Aripiprazole: A Clinical Review Of Its Use For The Treatment Of Anxiety Disorders And
Anxiety As A Comorbidity In Mental Illness 
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3/7/23, 4:08 PM Aripiprazole - Mechanism of Action, Clinical Efficacy and Side Effects

AUTHORS LIST CONTACT US PSYCHIATRY CONVERSATIONS

PSYCH INSIGHTS VIDEO GALLERY PSYCH PEDIA

Aripiprazole – Mechanism of Action,

Aripiprazole is an achiral quinolinone derivative and a second-generation antipsychotic

CrowdStrike® We'll try Ads

Stop seeing this ad Why this ad?

Depending on DA levels, it can act as either a functional antagonist or agonist, which

In the presence of excess DA transmission, it can reduce this transmission to lower

In the presence of low DA levels, it can increase DA neurotransmission again to the

Thus, Aripiprazole is pharmacologically different from other oral atypical antipsychotics

Click here to zoom image

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

Because aripiprazole is characterised by its stabilising effect on dopamine

CrowdStrike® We'll try Ads

Stop seeing this ad Why this ad?

2023 Global Threat

The Goldilocks effect

Click here to zoom image

The Dimmer Switch Effect

Click here to zoom image

Partial agonists may be particularly useful in managing schizophrenia as concerns have

The potential clinical consequence of dopamine supersensitivity psychosis is that

2023 Global Threat

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

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

COMPARING ARIPIPRAZOLE WITH BREXPIPRAZOLE

The lower intrinsic activity of brexpiprazole at D2 receptors relative to aripiprazole

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

2023 Global Threat

Brexpiprazole had little or no significant effect on blood prolactin levels in schizophrenia,

COMPARING ARIPIPRAZOLE WITH CARIPRAZINE

Click here to zoom image

In patients with bipolar disorder, the recommended target dose is 15 mg/day

It has a lower risk of extrapyramidal symptoms than other antipsychotics such as

Click here to zoom image

Dose reduction may be warranted if the patient is currently being administered

Off label use:

Handbook of Prescriber's Stahl's

Shop now Shop now Shop now

Population Pharmacokinetic Modelling Of Aripiprazole And Its Active Metabolite,

Aripiprazole Augmentation Of Clozapine In Refractory Schizophrenia 

BAP Guidelines On The Management Of Weight Gain, Metabolic Disturbances And

Demystifying Chronic Melancholic and Neurobiology of

2 years ago • 2 comments 3 years ago • 3 comments a year ago • 4 comments

Most beautiful women in the world 2021

30 Brutal Hells Angels Rules That Are Mandatory

What do you think?

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These Are The Most Beautiful Women In The World

30 Brutal Hells Angels Rules That Are Mandatory

20 Actors Who Have Serious Martial Arts Skills In Real Life

ABOUT THE AUTHOR

 Number of Views: 43,657

Search this website SEARCH

Referral Pathway For Esketamine

Completing A GP Mental Health

Shared Decision Making In

Psychotic Disorder Spectrum