Aripiprazole

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File:Aribit (Aripiprazole) tablets.jpg

Aribit (Aripiprazole) tablets

Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder;<ref name="AHFS2019" /> other uses include as an add-on treatment for major depressive disorder and tic disorders.<ref name=AHFS2019 /> Aripiprazole is taken by mouth or via injection into a muscle.<ref name=AHFS2019 /> A Cochrane review found low-quality evidence of its effectiveness at treating schizophrenia.<ref name=Coch2011>Template:Cite journal</ref>

Common side effects include restlessness, insomnia, transient weight gain, nausea, vomiting, constipation, dizziness, and mild sedation.<ref name="AHFS2019" /> Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia, and anaphylaxis.<ref name="AHFS2019" /> It is not recommended for older people with dementia-related psychosis due to an increased risk of death.<ref name="AHFS2019" /> In pregnancy, there is evidence of possible harm to the fetus.<ref name="AHFS2019" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is not recommended in women who are breastfeeding.<ref name="AHFS2019" /> It has not been very well studied in people younger than 18 years old.<ref name="AHFS2019" />

Aripiprazole was approved for medical use in the United States in 2002.<ref name=AHFS2019 /> It is available as a generic medication.<ref name=BNF76>Template:Cite book</ref> In 2022, it was the 106th most commonly prescribed medication in the United States, with more than 6Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref>

Medical uses

Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.<ref name = EMA /><ref name= AHFS2019 /><ref name="Abilify FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor.<ref>Template:Cite journal</ref> 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.<ref name=Coch2011 /> A Cochrane review found only low-quality evidence of effectiveness in treating schizophrenia.<ref name=Coch2011 /> Accordingly, part of its methodology on quality of evidence is based on the quantity of qualified studies.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A 2013 review placed aripiprazole in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine<ref>Template:Cite journal</ref> and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for reducing weight gain, 5th best for reducing extrapyramidal symptoms, 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.<ref name= "Lancet2013">Template:Cite journal</ref>

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.<ref name="Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ 2013 2–44">Template:Cite journal</ref>

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)".<ref name="Barnes TR 2011 567–620">Template:Cite journal</ref>

The British Association for Psychopharmacology<ref name="Barnes TR 2011 567–620" /> 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.<ref name="Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ 2013 2–44" />

Bipolar disorder

Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Used as maintenance therapy, it is useful for the prevention of manic episodes but is not useful for bipolar depression.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name="NICE2014B">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

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.<ref name= "Spielmans_2013">Template:Cite journal</ref><ref name= "pmid19687129">Template:Cite journal</ref><ref name= "pmid21154393">Template:Cite journal</ref> The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning.<ref name= "Spielmans_2013" /> Aripiprazole may interact with some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) that are metabolized by CYP2D6. There are known interactions with fluoxetine and paroxetine<ref>Template:Cite journal</ref> and it appears lesser interactions with sertraline, escitalopram, citalopram and fluvoxamine. CYP2D6 inhibitors increase aripiprazole concentrations to 2–3 times their normal level.<ref name = Abilify /> When strong CYP2D6 SSRIs (such as fluoxetine, paroxetine) are co-administered, the FDA recommends dose monitoring, although it is not clear the SSRI dose should be lowered.<ref name="Abilify FDA label" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Autism

Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours.<ref name =Hirsch2016>Template:Cite journal</ref> Adverse effects include weight gain, sleepiness, drooling, and tremors.<ref name=Hirsch2016 /> 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.<ref name=Hirsch2016 />

Tic disorders

Aripiprazole is approved for the treatment of Tourette syndrome and other tic disorders.<ref name="AdisInsight">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid29154107">Template:Cite journal</ref><ref name="Müller-Vahl_2022">Template:Cite journal</ref> It is effective, safe, and well-tolerated for this use per systematic reviews and meta-analyses.<ref name= "pmid28441584">Template:Cite journal</ref><ref name= "pmid29388585">Template:Cite journal</ref><ref name="pmid26310194">Template:Cite journal</ref><ref name="pmid26220447">Template:Cite journal</ref>

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.<ref name="pmid25432131">Template:Cite journal</ref> The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms.<ref name="pmid25432131" /><ref>Template:Cite journal</ref><ref name= "pmid17849776">Template:Cite journal</ref><ref>Template:Cite journal</ref> However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD.<ref name= "Pignon et al Review">Template:Cite journal</ref> Aripiprazole is not currently approved for the treatment of OCD and is instead used off-label for this indication.<ref name="AdisInsight" /> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Available forms

Aripiprazole is available in the form of oral tablets, orally disintegrating tablets, oral solutions, oral films, and as injectables for intramuscular administration.<ref name="Drugs@FDA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Failed verification It is also available in the form of aripiprazole lauroxil, a lipophilic ester prodrug of aripiprazole for use as a long-acting injectable.<ref name="Drugs@FDA" />Template:Failed verification

Contraindications

Contraindications to aripiprazole include known hypersensitivity to aripiprazole, among others.<ref name="AHFS2019" />

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;<ref name = "Ma_2024">Template:Cite journal</ref> the risk appeared to be elevated when the medication was administered in long-acting injectable form compared to oral administration.<ref name = "Ma_2024" /> This elevated risk may be due to the high rate of oral medication non-adherence<ref>Template:Cite journal</ref> in schizophrenia patients.

In the elderly with dementia, there is an increased risk of death.<ref name="MedlinePlus">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In children, adolescents, and young adults, there is an increased risk of suicide.<ref name="Abilify FDA label" />

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.<ref name="Abilify FDA label" /><ref name = EMC /><ref name = EMA /><ref name = Abilify /><ref name="WebMD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose.<ref name = Abilify /> A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur rarely.<ref name="FDA impulse control">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid26658263">Template:Cite journal</ref> These urges can be uncontrollable.<ref name="FDA impulse control" />

Uncontrolled movement such as restlessness, tremors, and muscle rigidity may occur.<ref name = Abilify />

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.<ref>Template:Cite book</ref> Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.<ref name=Had2004>Template:Cite book</ref> Other symptoms may include restlessness, increased sweating, and trouble sleeping.<ref name=Had2004 /> Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.<ref name=Had2004 /> Symptoms generally resolve after a short period of time.<ref name=Had2004 />

There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a part of a withdrawal syndrome.<ref>Template:Cite journal</ref> It may also result in reoccurrence of the condition that is being treated.<ref>Template:Cite book</ref> Rarely tardive dyskinesia can occur when the medication is stopped.<ref name=Had2004 />

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.<ref>Template:Cite book</ref><ref name="Skov 2015 41-44">Template:Cite journal</ref>

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.<ref name="drugLabelWP">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Abilify FDA label" />

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.<ref name=AHFS2019 />

Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, 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.<ref>Template:Cite journal</ref> In antipsychotics, this is caused by the inhibition of dopamine autoreceptors as well as the effects of antipsychotics on non-dopaminergic 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 (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.<ref name="Yanofski review">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

citation

CitationClass=web }}</ref><ref name="pmid12784105">Template:Cite journal</ref><ref>Template:Cite journal</ref>
Site	Ki (nM)	IA (%)	Action	Ref
Template:Abbrlink	900 – 1260		Reuptake inhibitor	<ref name="pmid12665420" /><ref name="pmid12784105" />
Template:Abbrlink	1340 – 2840		Reuptake inhibitor	<ref name="pmid12784105" />
Template:Abbrlink	2560 – 3880		Reuptake inhibitor	<ref name="pmid12784105" />
5-HT1AL	1.7 – 6.4	68%	Partial agonist / functional full agonist	<ref name="pmid12784105" /><ref name="pmid12629531">Template:Cite journal</ref><ref name="pmid12665420">Template:Cite journal</ref>
5-HT1B	570 – 1090		Template:Abbr	<ref name="pmid12784105" />
5-HT1D	57 – 79		Template:Abbr	<ref name="pmid12784105" />
5-HT1E	3000 – >10,000		Template:Abbr	<ref name="pmid12784105" />
5-HT2AL	6.7 – 39	0–52%	Partial agonist / functional full agonist	<ref name="GaitondeAvetdelaFuenteRevenga2024">Template:Cite journal</ref><ref name="pmid12665420" /><ref name="pmid12784105" /><ref name="pmid12629531" />
5-HT2B	0.25 – 0.47		Inverse agonist	<ref name="pmid12784105" />
5-HT2CL	11 – 197	82%	Partial agonist / functional full agonist	<ref name="pmid12665420" /><ref name="pmid12784105" /><ref name="pmid12629531" />
5-HT3	520 – 740		Template:Abbr	<ref name="pmid12784105" />
5-HT5A	960 – 1520	87%	Near-full Agonist	<ref name="pmid12784105" />
5-HT6	475 – 665		Antagonist	<ref name="pmid12665420" /><ref name="pmid12784105" /><ref name="pmid12629531" />
5-HT7L	6.6 – 14	58%	Partial agonist / functional full agonist	<ref name="pmid12784105" /><ref name="pmid12629531" /><ref name="pmid12665420" />
α1A	25.7		Antagonist	<ref name="pmid12784105" /><ref name="pmid12629531" />
α1B	35		Antagonist	<ref name="pmid12784105" />
α2A	74.3		Antagonist	<ref name="pmid12784105" /><ref name="pmid12629531" />
α2B	103		Template:Abbr	<ref name="pmid12784105" /><ref name="pmid12629531" />
α2C	38		Antagonist	<ref name="pmid12784105" /><ref name="pmid12629531" />
β1	141		Agonist	<ref name="pmid12784105" />
β2	163		Agonist	<ref name="pmid12784105" />
D1L	1290 – 2630		Agonist	<ref name="pmid12665420" /><ref name="pmid12784105" />
D2S	2.2 – 4.4	~60%	Partial agonist / functional antagonist	<ref name="pmid12784105" />
D2L	0.65 – 0.83	~58%	Partial agonist / functional full agonist
D3S	4.3 – 15.1	~40%	Partial agonist / functional antagonist	<ref name="pmid12665420" /><ref name="pmid12784105" />
D4L	417 – 603	~30%	Partial agonist / functional full agonist	<ref name="pmid12665420" /><ref name="pmid12784105" />
D5L	1240 – 3940		Agonist	<ref name="pmid12665420" /><ref name="pmid12784105" />
H1	22.5 – 27.7		Neutral Antagonist	<ref name="pmid12784105" /><ref name="pmid12629531" /><ref name="pmid12665420" />
H2	>10,000		Template:Abbr	<ref name="pmid12784105" />
H3	60 – 388		Template:Abbr	<ref name="pmid12784105" />
H4	>10,000		Template:Abbr	<ref name="pmid12784105" />
M1	6,780		Template:Abbr	<ref name="pmid12784105" />
M2	3,510		Template:Abbr	<ref name="pmid12784105" />
M3	4,680		Template:Abbr	<ref name="pmid12784105" /><ref name="pmid12629531" />
M4	1,520		Template:Abbr	<ref name="pmid12784105" />
M5	2,330		Template:Abbr	<ref name="pmid12784105" />
GABAA-ρ			Orthostatic Negative allosteric modulator
[[NMDA receptor|Template:Abbr (Template:Abbr)]]	1.824		Uncompetitive channel blocker / Antagonist	<ref name="pmid12784105" />
[[NMDA receptor|Template:Abbr (Template:Abbr)]]	1.824		Uncompetitive channel blocker / Antagonist	<ref name="pmid12784105" />
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat), D4 (human/rat), H3 (guinea pig), and NMDA/PCP (rat).<ref name="pmid12784105" /> IA = Intrinsic Activity

Aripiprazole's mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone).<ref name="Starrenburga 2009 164–170">Template:Cite journal</ref><ref name="drugLabelPC" /><ref name=Goodman>Template:Cite book</ref><ref name="Davies_2004">Template:Cite journal</ref> It shows differential engagement at the dopamine receptor (D₂<ref name="pmid12784105" />). Aripiprazole is a partial agonist at dopamine D₂ receptors, a partial agonist at 5-HT_1A receptors, and an antagonist or very weak partial agonist at 5-HT_2A receptors.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

It appears to show predominantly partial agonistic activity on postsynaptic D₂ receptors and partial agonist activity on presynaptic D₂ receptors,<ref name="pmid17501690">Template:Cite journal</ref> D₃,<ref name="pmid12784105" /><ref name="kegeles">Template:Cite journal</ref><ref name="pmid12093598">Template:Cite journal</ref> and partially D₄<ref name="pmid12784105" /><ref name="drugLabelPC" /> and is a partial activator of serotonin (5-HT_1A,<ref name="pmid12784105" /><ref name="pmid12063084">Template:Cite journal</ref><ref name="pmid17728427" /> 5-HT_2A,<ref name="pmid12784105" /> 5-HT_2B,<ref name="pmid12784105" /> 5-HT₆, and 5-HT₇).<ref name="pmid12784105" /><ref name="Davies_2004" /> It also shows lower effect on histamine (H₁), as well as the serotonin transporter.<ref name="pmid12784105" /><ref name="drugLabelPC" /> Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.<ref name="pmid19909227">Template:Cite journal</ref>

As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D₂ partial agonist (with an intrinsic activity of ~50%)<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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)<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Aripiprazole has been characterized as possessing predominantly partial agonist activity on postsynaptic D₂ receptors and partial agonist activity on presynaptic D₂ receptors;<ref name="pmid17501690" /> 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)".<ref>Template:Cite journal</ref> Aripiprazole is also a partial agonist of the D₃ receptor.<ref name="pmid12784105" /> 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.<ref name="kegeles" /><ref name="pmid12093598" /> 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.<ref name="editorial1">Template:Cite journal</ref>

Aripiprazole is also a partial agonist of the postsynaptic serotonin 5-HT_1A receptor (intrinsic activity = 68%).<ref name="pmid12784105" /><ref name="pmid12063084" /><ref name="pmid17728427" /> 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.<ref name="pmid17728427" /> It is a very weak partial agonist of the Postsynaptic 5-HT_2A receptor (intrinsic activity = 12.7%).<ref name="pmid12784105" /> The drug differs from other atypical antipsychotics in having higher affinity for the D₂ receptor than for the 5-HT_2A receptor.<ref name="pmid17728427" /> At the 5-HT_2B receptor, aripiprazole has both great binding affinity and acts as a potent inverse agonist, "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".<ref name="pmid12784105" /> 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.<ref name="pmid16336943">Template:Cite journal</ref> 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.<ref name="pmid12784105" /><ref name="Davies_2004" /> 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 receptors<ref name="pmid12784105" /><ref name="drugLabelPC" />

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 actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has "functionally selective" actions.<ref>Template:Cite journal</ref> 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 D₂-dopamine receptors are clearly cell-type specific (e.g., agonism, antagonism, partial agonism), and are most parsimoniously explained by the "functional selectivity" hypothesis.<ref name="pmid12784105" />

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, 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.<ref name="pmid12784105" />

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.<ref name="pmid17501690" /> A positron emission tomography 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, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT_2A receptor and only 16% occupancy of the 5-HT_1A receptor.<ref name="pmid26417330">Template:Cite journal</ref><ref name="pmid17728427">Template:Cite journal</ref> It has been suggested that the low occupancy of the 5-HT_1A receptor by aripiprazole may have been an erroneous measurement however.<ref name="pmid17728411">Template:Cite journal</ref>

Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms.<ref name="pmid19909227" /> 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.<ref name="pmid19909227" />

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 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.<ref name="drugLabelPC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Abilify FDA label" />

Chemistry

Aripiprazole belongs to the chemical class of drugs called 2,3-dichlorophenylpiperazines and is chemically related to cariprazine, nefazodone, etoperidone, and trazodone.<ref>Template:Cite book</ref><ref>Template:Cite book</ref> It is unusual in having twelve known crystalline polymorphs.<ref>Template:Cite journal</ref><ref name=Warren>Template:Cite journal</ref>

History

File:Abilify 10mg.jpg

Abilify (aripiprazole) 10 mg tablets (TR)

Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical and was called OPC-14597.<ref name="AdisInsight" /><ref name=NatDD>Template:Cite journal</ref><ref>Template:Cite book</ref><ref name="Update on the Mechanism of Action o">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> It was first published in 1995.<ref name=NatDD /><ref>Template:Cite journal</ref> Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.<ref>Template:Cite news</ref>

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;<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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;<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and to treat irritability in children with autism on 20 November 2009.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Likewise it was approved for use as a treatment for schizophrenia by the Therapeutic Goods Administration (TGA) of Australia in May 2003.<ref name = Abilify>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.<ref name="orangeBook" />

In 2006, the FDA required manufacturers to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.<ref name=Settle>Template:Cite news</ref>

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.<ref name="Abilify FDA label" /> 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.<ref>Template:Cite news</ref>

In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of aripiprazole.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

As of 2013, Abilify had annual sales of Template:US$.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug.<ref>Template:Cite news</ref> Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.<ref>Template:Cite news</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="orangeBook">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.<ref>Template:Cite press release</ref> On 15 November 2010, this challenge was rejected by the U.S. District Court in New Jersey.<ref>Template:Cite news</ref>

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.,<ref name="EP0367141">Template:Cite patent</ref> The UK Intellectual Property Office decided<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="thedailybeast.com">Template:Cite news</ref>

In April 2015, the FDA announced the first generic versions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="pmid26573020">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name=Settle /><ref>Template:Cite news</ref>

In November 2017, the FDA approved Abilify Mycite, a digital pill containing a sensor intended to record when its consumer takes their medication.<ref name=FDAdigital>Template:Cite press release</ref><ref>Template:Cite news</ref>

A long-acting injectable version of aripiprazole was approved by the FDA for the treatment of bipolar disorder 1 and schizophrenia in April 2023.<ref name="Abilify Asimtufii FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In 2024, the European Commission approved the 2 month long-acting injectable formulation of aripiprazole for the maintenance treatment of schizophrenia.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Society and culture

Legal status

citation	CitationClass=web }}</ref><ref>Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Jun 25]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref> !! Schizophrenia !! Acute mania !! Bipolar maintenance !! Major depressive disorder (as an adjunct) !! Irritability in autism
Food and Drug Administration (US)<ref name="Abilify FDA label" />	Yes	Yes	Yes (as an adjunct to lithium/valproate)	Yes	Yes (children and adolescents)
Therapeutic Goods Administration (AU)	Yes	Yes (as an adjunct to lithium/valproate)	Yes	No	No
Medicines and Healthcare products Regulatory Agency (UK)	Yes	Yes	Yes (to prevent mania)	No	No
European Medicines Agency (EU)<ref name="Abilify EPAR" />	Yes	No	Yes	No	No

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.<ref name="pmid28368577">Template:Cite journal</ref> 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.<ref name="pmid28368577" /> 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.<ref name="pmid28368577" /><ref name="Update on the Mechanism of Action o"/>

Brand names

Brand names of aripiprazole include Abilify, Aristada (as aripiprazole lauroxil), Arip MT, Explemed, and Arivitae, among others.<ref name="Drugs.com-International">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="AdisInsight" /> A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD.<ref name="pmid27993933">Template:Cite journal</ref> 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.<ref name="pmid24141455">Template:Cite journal</ref> 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.<ref name="pmid24141455" /> A high rate of adverse effects with aripiprazole such as weight gain, sedation, and headache was noted.<ref name="pmid24141455" /> Most research on aripiprazole for ADHD is in children and adolescents.<ref name="pmid24141455" /><ref name="pmid27993933" /> Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single case report.<ref name="pmid26693882">Template:Cite journal</ref><ref name="pmid18208634">Template:Cite journal</ref>

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.<ref name="pmid22095579">Template:Cite journal</ref><ref name="pmid23104650">Template:Cite journal</ref><ref name="pmid20565449">Template:Cite journal</ref><ref name="pmid19042205">Template:Cite journal</ref> Available evidence of aripiprazole for amphetamine dependence is mixed.<ref name="pmid22095579" /><ref name="pmid23104650" /><ref name="pmid20565449" /><ref name="pmid19042205" /> 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.<ref name="pmid22095579" /><ref name="pmid23104650" /><ref name="pmid20565449" /><ref name="pmid19042205" /> 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.<ref name="pmid22095579" /><ref name="pmid23104650" /><ref name="pmid20565449" /><ref name="pmid19042205" />

Further reading

• Template:Cite book

External links

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