alt=A box of aripiprazole 15 mg tablets.|thumb|Aripiprazole 15 mg tablets<!-- Medical uses -->
Aripiprazole, sold under the brand name Abilify, among others, is a unique atypical antipsychotic primarily used in the treatment of schizophrenia, mania in bipolar disorder, and irritability associated with autism spectrum disorder; It is not recommended in women who are breastfeeding. In 2023, it was the 95th most commonly prescribed medication in the U.S., with more than 7million prescriptions. It is on the World Health Organization's List of Essential Medicines.
Medical uses
Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.
Schizophrenia
The 2016 National Institute for Health and Care Excellence (NICE) guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second-line treatment after risperidone 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 may 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 it 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 in preventing relapse. This review found only low-quality evidence of effectiveness in treating schizophrenia. and slightly more effective than ziprasidone, chlorpromazine, or asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for reducing weight gain, 5th best for reducing extrapyramidal symptoms, the best for reducing prolactin 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. It lowers prolactin levels. In cases of hyperprolactinaemia caused by other antipsychotics, the addition of or switch to aripiprazole is used to lower prolactin levels.
Aripiprazole is recommended as the initial treatment for schizophrenia according to the INTEGRATE consensus international guidelines.
In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for 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)".
thumb|250x250px|Abilify Maintena 400mg Intramuscular Syringe
The British Association for Psychopharmacology Used as maintenance therapy, it is useful for the prevention of manic episodes but is not 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 12 weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged 13 and older. Aripiprazole in 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 but increases the risk of side effects such as weight gain and movement disorders. The overall benefit is small to moderate and its use appears to improve neither quality of life nor functioning. and lesser interactions with sertraline, escitalopram, citalopram and fluvoxamine. CYP2D6 inhibitors increase aripiprazole concentrations by 2–3 times.
Autism
Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviors. Adverse effects include weight gain, sleepiness, drooling, and tremors. There is evidence supporting that it is effective, safe, and well-tolerated for this use per systematic reviews and meta-analyses.
Obsessive–compulsive disorder
A 2014 systematic review and meta-analysis concluded that add-on therapy with low-dose aripiprazole is an effective treatment for obsessive–compulsive disorder (OCD) that does not improve with selective serotonin reuptake inhibitors (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 for this indication.
Available forms
alt=Two tablets of aripiprazole 15 mg.|thumb|Aripiprazole 15 mg tablets
Aripiprazole is available in the form of oral tablets, oral films, oral disintegrating tablets, oral solution, digital pills with sensors, and as a short-acting injectable for intramuscular administration. It is also available as a long-acting injectable, aripiprazole lauroxil, a lipophilic ester prodrug of aripiprazole designed to be given once per month, and as a once every two months long-acting injectable, under the brand name Abilify Asimtufii.
Contraindications
Contraindications to aripiprazole include known hypersensitivity to aripiprazole, among others. <!--
NB: It carries a boxed warning that states, "Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. " Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. The impulse control problems include a strong desire to gamble, binge eat, shop, and engage in sexual activity. These urges can be uncontrollable. The uncontrollable urges were reported to stop when the dose of aripiprazole was lowered or the medication was discontinued. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Interactions
Aripiprazole is a substrate of CYP2D6 and CYP3A4. 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. In antipsychotics, this is caused by the inhibition of dopamine autoreceptors as well as the effects of antipsychotics on non-dopaminergic receptors; 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 (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
{| class="wikitable floatright" style="font-size:small;"
|+ Aripiprazole
|-
! Site !! K<sub>i</sub> (nM)
! IA (%) !! Action !! Ref
|-
| || 900–1260
| || Reuptake inhibitor ||
|-
| 5-HT<sub>1B</sub> || 570–1090
| || || It shows differential engagement at the dopamine receptor (D<sub>2</sub>
It appears to show predominantly partial agonistic activity on postsynaptic dopamine D<sub>2</sub> receptors and partial agonist activity on presynaptic dopamine D<sub>2</sub> receptors, D<sub>3</sub>, and partially D<sub>4</sub>
As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D<sub>2</sub> 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, 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 D<sub>2</sub> 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 D<sub>2</sub> receptors and partial agonist activity on presynaptic D<sub>2</sub> receptors; Aripiprazole is also a partial agonist of the D<sub>3</sub> receptor.
Aripiprazole is also a partial agonist of the postsynaptic serotonin 5-HT<sub>1A</sub> receptor (intrinsic activity = 68%). At the presynaptic 5-HT<sub>7</sub> receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor.
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 proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D<sub>2</sub>-dopamine receptors are clearly cell-type specific (e.g., agonism, antagonism, partial agonism), and are most parsimoniously explained by the "functional selectivity" hypothesis. It has been suggested that the low occupancy of the 5-HT<sub>1A</sub> receptor by aripiprazole may have been an erroneous measurement however.
Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms.
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<sub>max</sub> (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 CYP3A4. 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. It is unusual in having twelve known crystalline polymorphs. Analogues of aripiprazole with higher-efficacy serotonin 5-HT<sub>2A</sub> receptor partial agonism and with psychedelic- and antidepressant-like effects have been developed. A procedure using ethanol as the solvent is shown below. Tetrahydroquinoline derivative 2 undergoes an S<sub>N</sub>2 reaction with dihalide 1 to give ether 3. This undergoes a further S<sub>N</sub>2 reaction with piperazine derivative 4 giving ariprazole.
center|thumb|892x892px|Flow synthesis of aripiprazole.
History
thumb|Abilify (aripiprazole) 10 mg tablets ([[Turkey|TR)|alt=]]
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 (FDA) for schizophrenia in November 2002, and by the European Medicines Agency in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 1 October 2004; as an adjunct for major depressive disorder 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 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.
In 2011 Otsuka and Lundbeck 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 schizophrenia 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
{| class="wikitable"
|-
! Regulatory administration (country) !! Schizophrenia !! Acute mania !! Bipolar maintenance !! Major depressive disorder (as an adjunct) !! Irritability in autism
|-
| Food and Drug Administration (US) 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.
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 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 trials found that aripiprazole did not significantly decrease ADHD symptoms.
Substance dependence
Aripiprazole has been studied for the treatment of amphetamine dependence and other substance use disorders, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed.