Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

, and irritability associated with

autism spectrum disorder Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...

; other uses include as an add-on treatment for

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

and tic disorders. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of its effectiveness at treating schizophrenia. Common side effects include restlessness,

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, transient weight gain,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, and mild sedation. Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia, and

anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...

. It is not recommended for older people with

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

-related psychosis due to an increased risk of death. In

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, there is evidence of possible harm to the fetus. It is not recommended in women who are

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

. It has not been very well studied in people younger than 18 years old. Aripiprazole was approved for medical use in the United States in 2002. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2022, it was the 106th most commonly prescribed medication in the United States, with more than 6million prescriptions. It is on the World Health Organization's List of Essential Medicines.

Medical uses

Aripiprazole is primarily used for the treatment of

Schizophrenia

The 2016

National Institute for Health and Care Excellence The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care (United Kingdom), Department of Health and Social Care. As the national health technolog ...

(NICE) guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second-line treatment after

risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...

for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia. A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second-generation antipsychotics for people who have trouble taking medication as directed or who prefer it. A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor. A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behavior, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse. A Cochrane review found only low-quality evidence of effectiveness in treating schizophrenia. Accordingly, part of its methodology on quality of evidence is based on the quantity of qualified studies. A 2013 review placed aripiprazole in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone,

chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...

, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for reducing weight gain, 5th best for reducing

extrapyramidal symptoms Extrapyramidal symptoms (EPS) are signs and symptoms, symptoms that are wikt:archetypical, archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they ...

, best for reducing

prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...

levels, 2nd best for prolongated QTc interval, and 5th best for sedative symptoms). The authors concluded that for acute psychotic episodes, aripiprazole results in benefits in some aspects of the condition. In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A. The British Association for Psychopharmacology similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic and that such treatment should continue for at least 1–2 years, as "There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period". The guideline further notes that "Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)". The British Association for Psychopharmacology and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in the prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person's preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics.

Bipolar disorder

Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents. Used as maintenance therapy, it is useful for the prevention of manic episodes but is not useful for bipolar depression. Thus, it is often used in combination with an additional mood stabilizer; however, co-administration with a mood stabilizer increases the risk of extrapyramidal side effects. In September 2014, aripiprazole had a UK marketing authorization for up to twelve weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged thirteen and older. Aripiprazole in low doses of 2.5 mg can cause mania in those with Bipolar disorder.

Depression

Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and movement disorders. The overall benefit is small to moderate and its use appears to neither improve

quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

nor functioning. Aripiprazole may interact with some antidepressants, especially

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs) that are metabolized by CYP2D6. There are known interactions with fluoxetine and paroxetine and it appears lesser interactions with

sertraline Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...

escitalopram Escitalopram ( ), sold under the brand names Lexapro and Cipralex, among others, is an antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class. It is mainly used to treat major depressive disorder, generalized ...

citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soci ...

and fluvoxamine. CYP2D6 inhibitors increase aripiprazole concentrations to 2–3 times their normal level. When strong CYP2D6

SSRI Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by ...

s (such as fluoxetine, paroxetine) are co-administered, the FDA recommends dose monitoring, although it is not clear the SSRI dose should be lowered.

Autism

Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours. Adverse effects include weight gain, sleepiness, drooling, and tremors. It is suggested that children and adolescents need to be monitored regularly while taking this medication to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long-term use.

Tic disorders

Aripiprazole is approved for the treatment of

Tourette syndrome Tourette syndrome (TS), or simply Tourette's, is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) tic. Common tics are blinkin ...

and other tic disorders. It is effective, safe, and well-tolerated for this use per

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

s and

meta-analyses Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

Obsessive-compulsive disorder

A 2014

and

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

concluded that add-on therapy with low-dose aripiprazole is an effective treatment for obsessive-compulsive disorder (OCD) that does not improve with

s (SSRIs) alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms. However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD. Aripiprazole is not currently approved for the treatment of OCD and is instead used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

for this indication. Depending on the dose, aripiprazole can increase impulse control issues in a small percentage of people. The FDA Drug Safety Communication warned about this side effect.

Available forms

Aripiprazole is available in the form of

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets, orally disintegrating tablets, oral solutions, oral films, and as injectables for intramuscular administration. It is also available in the form of aripiprazole lauroxil, a

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

prodrug of aripiprazole for use as a long-acting injectable.

Contraindications

Contraindications to aripiprazole include known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

to aripiprazole, among others.

Adverse effects

A 2024 study indicated it was found to have the highest hazard ratio among antipsychotics associated with dementia risk: with a hazard ratio of 4.42 (95% confidence interval 1.99-9.81) for all cause dementia; the risk appeared to be elevated when the medication was administered in long-acting injectable form compared to oral administration. This elevated risk may be due to the high rate of oral medication non-adherence in schizophrenia patients. In the elderly with dementia, there is an increased risk of death. In children, adolescents, and young adults, there is an increased risk of

suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...

. In adults, side effects with greater than 10% incidence include weight gain, mania, headache, akathisia, insomnia, delirium, and gastrointestinal effects like nausea, constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur rarely. These urges can be uncontrollable. Uncontrolled movement such as restlessness, tremors, and muscle rigidity may occur.

Discontinuation

The

British National Formulary The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medicin ...

recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time. There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a part of a withdrawal syndrome. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Overdose

Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3–4 fold over normal therapeutic levels; as of 2008, no deaths had been recorded.

Interactions

Aripiprazole is a substrate of CYP2D6 and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole. Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose. Antipsychotics like aripiprazole and stimulant medications, such as

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

, are traditionally thought to have opposing effects because both drugs affect dopaminergic neurons. However, both stimulants and antipsychotics lead to increases in synaptic dopamine levels. In antipsychotics, this is caused by the inhibition of dopamine autoreceptors as well as the effects of antipsychotics on non-

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

receptors, while in amphetamine this is caused by non-competitive inhibition of dopamine reuptake and agonism of intracellular TAAR1. Therefore, aripiprazole may interact with amphetamine to synergistically increase postsynaptic levels of dopamine. This interaction frequently occurs in the setting of comorbid

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD) (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.

Pharmacology

Pharmacodynamics

Aripiprazole's

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and

). It shows differential engagement at the dopamine receptor (D₂). Aripiprazole is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

at dopamine D₂ receptors, a partial agonist at 5-HT_1A receptors, and an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT_2A receptors. It appears to show predominantly partial agonistic activity on postsynaptic D₂ receptors and partial agonist activity on presynaptic D₂ receptors, D₃, and partially D₄ and is a partial activator of

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

( 5-HT_1A, 5-HT_2A, 5-HT_2B, 5-HT₆, and 5-HT₇). It also shows lower effect on

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

( H₁), as well as the serotonin transporter. Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms. As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D₂ partial agonist (with an intrinsic activity of ~50%) as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown,

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

, to bind to and/or induce receptor conformations (i.e., facilitate receptor shapes) in such a way as to not only prevent receptor internalization (and, thus, lower receptor density) but even to lower the rate of receptor internalization below that of neurons not in the presence of agonists (including dopamine) or antagonists. It is often the nature of partial agonists, including aripiprazole, to display a stabilizing effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole's partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D₂ receptor occupancy (approximately 31%, 44%, 75%, 80%, and 95% at daily dosages of 0.5 mg, 2 mg, 10 mg, 30 mg and 40 mg respectively) Aripiprazole has been characterized as possessing predominantly partial agonist activity on postsynaptic D₂ receptors and partial agonist activity on presynaptic D₂ receptors; however, while this explanation intuitively explains the drug's efficacy as an antipsychotic, as the degree of agonism is a function of more than a drug's inherent properties as well as in vitro demonstration of aripiprazole's partial agonism in cells expressing postsynaptic (D_2L) receptors, it was noted that "It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D₂ receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5–1 pmol/mg). Instead, the current data are most parsimoniously explained by the "functional selectivity" hypothesis of Lawler et al. (1999)". Aripiprazole is also a partial agonist of the D₃ receptor. In healthy human volunteers, D₂ and D₃ receptor occupancy levels are high, with average levels ranging between approximately 75% at 2 mg/day to approximately 95% at 40 mg/day. Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain. Aripiprazole is also a partial agonist of the postsynaptic

5-HT_1A receptor (intrinsic activity = 68%). a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found 5-HT_1A receptor occupancy to be only 16% compared to ~90% for D₂. It is a very weak partial agonist of the Postsynaptic 5-HT_2A receptor ( intrinsic activity = 12.7%). The drug differs from other atypical antipsychotics in having higher

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the D₂ receptor than for the 5-HT_2A receptor. At the 5-HT_2B receptor, aripiprazole has both great binding affinity and acts as a potent

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

, "Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC₅₀ of 11 nM". Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the postsynaptic 5-HT_2C receptor (intrinsic activity = 82%) this property may underlie the minimal weight gain seen in the course of therapy, however if used while taking antidepressants it will become a functional antagonist and increase weight gain. At the presynaptic 5-HT₇ receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor. Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites such as the serotonin transporter, while it has negligible affinity for the

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g., at 5-HT₆), sometimes an inverse agonist (e.g., 5-HT_2B), sometimes a partial agonist (e.g., D_2S, D_3S, D_4S, D_2L). Aripiprazole was frequently found to be a partial agonist or full agonist, with an intrinsic activity that could be low (5-HT_2A, 5-HT₇), intermediate (D_2L, 5-HT1A), or high (5-HT_2C). This mixture of

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has "functionally selective" actions. The "functional-selectivity" hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially "sensed" by the local complement of

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

s to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D₂-dopamine receptors are clearly cell-type specific (e.g., agonism, antagonism, partial agonism), and are most parsimoniously explained by the "functional selectivity" hypothesis. Since 5-HT_2C receptors have been implicated in the control of depression, obsessive–compulsive disorder (OCD), and appetite, postsynaptic partial agonism at the 5-HT_2C receptor might be associated with therapeutic potential in obsessive-compulsive disorder,

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

, and depression. 5-HT_2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of postsynaptic 5-HT_2C receptors; it is conceivable that the 5-HT_2C partial agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an antiobsessional agent, it is worthwhile noting that a variety of 5-HT_2A/5-HT_2C agonists have shown promise as antiobsessional agents, yet many of these compounds are hallucinogenic. Aripiprazole has a favorable pharmacological profile in being a 5-HT_2C partial agonist. Based on this profile, one can predict that aripiprazole may have antiobsessional and anorectic actions in humans. Wood and Reavill's (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D₂ receptor without significantly affecting the majority of serotonin receptors. A

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D₂ receptor in various brain areas (

putamen The putamen (; from Latin, meaning "nutshell") is a subcortical nucleus (neuroanatomy), nucleus with a rounded structure, in the basal ganglia nuclear group. It is located at the base of the forebrain and above the midbrain. The putamen and c ...

, caudate,

ventral striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamater ...

) versus 54 to 60% occupancy of the 5-HT_2A receptor and only 16% occupancy of the 5-HT_1A receptor. It has been suggested that the low occupancy of the 5-HT_1A receptor by aripiprazole may have been an erroneous measurement however. Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic

mesolimbic pathway The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The v ...

, which is thought to be a cause of positive schizophrenia symptoms. Due to its partial agonist activity on D_2L receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduced.

Pharmacokinetics

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. C_max (maximum plasma concentration) is achieved 3–5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and ''N''-dealkylation), principally by the enzymes CYP2D6 and

. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.

Chemistry

Aripiprazole belongs to the chemical class of drugs called 2,3-dichlorophenylpiperazines and is chemically related to cariprazine, nefazodone, etoperidone, and trazodone. It is unusual in having twelve known crystalline polymorphs.

History

Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical and was called OPC-14597. It was first published in 1995. Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole. It was approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) for schizophrenia in November 2002, and by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 1 October 2004; as an adjunct for

on 20 November 2007; and to treat irritability in children with autism on 20 November 2009. Likewise it was approved for use as a treatment for schizophrenia by the Therapeutic Goods Administration (TGA) of Australia in May 2003. Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years. In 2006, the FDA required manufacturers to add a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death. In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS's off-label marketing of aripiprazole for children and older people with dementia. In 2011 Otsuka and

Lundbeck H. Lundbeck A/S, commonly referred to as Lundbeck, is a Denmark, Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products ar ...

signed a collaboration to develop a depot formulation of aripiprazole. As of 2013, Abilify had annual sales of . In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug. Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole. Otsuka's US patent on aripiprazole expired on 20 October 2014, but due to a pediatric extension, a generic did not become available until 20 April 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. On 15 November 2010, this challenge was rejected by the U.S. District Court in New Jersey. Otsuka's European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014., The UK Intellectual Property Office decided on 4 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015. From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion. In April 2015, the FDA announced the first generic versions. In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA. In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million. In November 2017, the FDA approved Abilify Mycite, a digital pill containing a sensor intended to record when its consumer takes their medication. A long-acting injectable version of aripiprazole was approved by the FDA for the treatment of bipolar disorder 1 and

in April 2023. In 2024, the European Commission approved the 2 month long-acting injectable formulation of aripiprazole for the maintenance treatment of schizophrenia. This came after the 1 month long-acting injectable formulation lost drug exclusivity status in the US and Europe (the market is now open to generics).

Society and culture

Legal status

Classification

Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like haloperidol and second-generation (atypical) antipsychotics like clozapine. It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists. The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.

Brand names

Brand names of aripiprazole include Abilify, Aristada (as aripiprazole lauroxil), Arip MT, Explemed, and Arivitae, among others.

Research

Attention deficit hyperactivity disorder

Aripiprazole was under development for the treatment of attention-deficit hyperactivity disorder (ADHD), but development for this indication was discontinued. A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD. A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition. Although all 6 non-controlled open-label studies in the review reported effectiveness, two small

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

s found that aripiprazole did not significantly decrease ADHD symptoms. A high rate of adverse effects with aripiprazole such as weight gain, sedation, and

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

was noted. Most research on aripiprazole for ADHD is in children and adolescents. Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrenc ...

Substance dependence

Aripiprazole has been studied for the treatment of amphetamine dependence and other

substance use disorder Substance use disorder (SUD) is the persistent use of drugs despite substantial harm and adverse consequences to self and others. Related terms include ''substance use problems'' and ''problematic drug or alcohol use''. Along with substance-ind ...

s, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed. Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole. As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.

References

External links

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