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Aripiprazole

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Aripiprazole
Structural formula of aripiprazole
Ball-and-stick model of the aripiprazole molecule
Clinical data
Pronunciation/ˌeɪrɪˈpɪprəzoʊl/
AIR-i-PIP-rə-zohl
Abilify ə-BIL-i-fy
Trade namesAbilify
AHFS/Drugs.comMonograph
MedlinePlusa603012
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth (tablets, dissolving tablets, solution); IM (including a depot)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability87%[2][3][4][5]
Protein binding>99%[2][3][4][5]
MetabolismLiver (mostly via CYP3A4 and 2D6[2][3][4][5])
Elimination half-life75 hours (active metabolite is 94 hours)[2][3][4][5]
ExcretionRenal (27%; <1% unchanged), Faecal (60%; 18% unchanged)[2][3][4][5]
Identifiers
  • 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.112.532 Edit this at Wikidata
Chemical and physical data
FormulaC23H27Cl2N3O2
Molar mass448.385 g/mol g·mol−1
3D model (JSmol)
  • Clc4cccc(N3CCN(CCCCOc2ccc1c(NC(=O)CC1)c2)CC3)c4Cl
  • InChI=1S/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29) checkY
  • Key:CEUORZQYGODEFX-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Aripiprazole, sold under the brand name Abilify among others, is an atypical antipsychotic. It is recommended and primarily used in the treatment of schizophrenia and bipolar disorder.[6] Other uses include as an add-on treatment in major depressive disorder, tic disorders, and irritability associated with autism.[7] According to a Cochrane review, evidence for the oral form in schizophrenia is not sufficient to determine effects on general functioning.[8] Additionally, because many people dropped out of the medication trials before they were completed, the overall strength of the conclusions is low.[8]

Side effects include neuroleptic malignant syndrome, a movement disorder known as tardive dyskinesia, and high blood sugar in those with diabetes.[6] In the elderly there is an increased risk of death.[6] It is thus not recommended for use in those with psychosis due to dementia.[6] It is pregnancy category C in the United States and category C in Australia, meaning there is possible evidence of harm to the fetus.[6][9] It is not recommended for women who are breastfeeding.[6] It is unclear whether it is safe or effective in people less than 18 years old.[6]

It is a partial dopamine agonist. Aripiprazole was developed by Otsuka in Japan. In the United States, Otsuka America markets it jointly with Bristol-Myers Squibb. From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.[10]

Medical uses

Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.[6]

Schizophrenia

The FDA approved the oral form of aripiprazole for the treatment of acute exacerbations of schizophrenia and for maintenance treatment (relapse prevention) in 2002. The approval was based on efficacy demonstrated in 5 "adequate and well-controlled" clinical trials, including 4 short-term studies (4 or 6 weeks) showing a reduction in psychotic symptoms in the acute setting and 1 longer-term study (26 weeks) demonstrating reduced relapse compared to placebo.[11] Marketing approval was granted by the European Medicines Agency based on the results of these same studies, plus an additional long-term study demonstrating non-inferiority to haloperidol in the prevention of relapse.[12] Health Canada approved aripiprazole for the acute and maintenance treatment of schizophrenia in 2009.[13]

A Cochrane review concluded that aripiprazole is similar to other typical and atypical antipsychotics with respect to benefit.[8][14] Compared to typical antipsychotics, there are fewer extrapyramidal side effects, but higher rates of dizziness.[15] With respect to other atypicals, it is difficult to determine differences in adverse effects as data quality is poor.[16]

A Lancet review found that it is in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for weight gain, 5th best for extrapyramidal symptoms, best for prolactin elevation, 2nd best for QTc prolongation, and 5th best for sedation). The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.[17]

A 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.[8] The World Federation of Societies for Biological Psychiatry recommends aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.[18]

The National Institute for Health and Care Excellence offers the following recommendations with respect to pharmacological treatment of those presenting with an acute episode of psychosis:

  • Offer an oral antipsychotic medication.
  • Inform those who want to try psychological interventions alone that these are more effective when performed in conjunction with treatment with an antipsychotic medication
  • In the early post-acute period, warn the person of a high risk of relapse if antipsychotic medication is discontinued in the first 1–2 years after the acute episode
  • If a decision is made to discontinue medication, reduce the dose gradually and monitor for relapse for at least 2 years.[19]

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)".[20]

The National Institute of Health and Clinical Excellence,[19] the British Association for Psychopharmacology[20] and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on persons preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics.[18]

Aripiprazole versus risperidone[21][needs update]
Information is of limited quality, incomplete, and problematic to apply. Long-term data is few and quality of evidence is all low or very low. Aripiprazole also has important side effects.[21]

Bipolar disorder

Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents.[22][23] Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression.[24][25] 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.[26]

Major 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.[27][28][29][30] The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning.[28] Aripiprazole may interact with some antidepressants, especially SSRIs. There are interactions with fluoxetine and paroxetine and lesser interactions with sertraline, escitalopram, citalopram and fluvoxamine, which inhibit CYP2D6, for which aripiprazole is a substrate. CYP2D6 inhibitors increase aripiprazole concentrations to 2-3 times their normal level.[2]

Autism

Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours.[31] Adverse effects include weight gain, sleepiness, drooling and tremors.[31] 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.[31]

Obsessive–compulsive disorder

A 2014 systematic review concluded that add-on therapy with low dose aripiprazole is an effective treatment for obsessive-compulsive disorder that does not improve with SSRIs alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms.[32] Risperidone (another second-generation antipsychotic) appears to be superior to aripiprazole for this indication, and is recommended by the 2007 American Psychiatric Association guidelines, though aripiprazole is cautiously recommended by a 2017 review by Pignon and colleagues.[33]

Adverse effects

See also: List of adverse effects of aripiprazole

In adults side effects with greater than 10% incidence include weight gain, headache, agitation or anxiety, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness.[2][3][4][5][34] Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose.[2] A strong desire to gamble, binge eat, shop, and have sex may also occur.[35] Cases of pathological gambling have been reported.[36]

Uncontrolled movement such as restlessness, tremors, and muscle stiffness have been reported in children and adults, but they are rare.[2][37]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[38] Joanne Moncrieff has suggested that the withdrawal process might itself be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy people, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of people currently and previously treated with antipsychotics, but the limited evidence was found to support this hypothesis for antipsychotics other than clozapine.[39]

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.[40][41]

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.[42] As such, anyone taking aripiprazole should be aware that their dosage of aripiprazole may need to be adjusted.

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.[6]

Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects to their effects on dopamine receptors: stimulants are thought to increase dopamine in the synaptic cleft, whereas antipsychotics are thought to decrease dopamine. However, it is an oversimplification to state the interaction as such, due to the differing actions of antipsychotics and stimulants in different parts of the brain, as well as the effects of antipsychotics on non-dopaminergic receptors. This interaction frequently occurs in the setting of comorbid ADHD (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has shown 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.[43]

Pharmacology

Pharmacodynamics

See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Aripiprazole[44][45]
Site Ki (nM) Action Ref
5-HT1A 1.7–5.6 Partial agonist [45][46][47]
5-HT1B 830 ND [45]
5-HT1D 68 ND [45]
5-HT1E 8,000 ND [45]
5-HT2A 3.4–35 Antagonist [47][45][46]
5-HT2B 0.11-0.36 Inverse agonist [45]
5-HT2C 15–180 Partial agonist [47][45][46]
5-HT3 628 ND [45]
5-HT5A 1,240 ND [45]
5-HT6 214–786 Antagonist [47][45][46]
5-HT7 9.6–39 Antagonist [45][46][47]
D1 265–1,170 ND [45]
D2 0.45–3.3 Partial agonist [48][46][45]
D2L 0.74–0.9 Partial agonist [45]
D3 0.8–9.7 Partial agonist [47][45]
D4 44–514 Partial agonist [47][45]
D5 95–2,590 ND [47][45]
α1A 25.9 ND [45][46]
α1B 34.4 ND [45]
α2A 74.3 ND [45][46]
α2B 102 ND [45][46]
α2C 37.9 ND [45][46]
β1 141 ND [45]
β2 163 ND [45]
H1 27.9–61 ND [45][46][47]
H2 >10,000 ND [45]
H3 224 ND [45]
H4 >10,000 ND [45]
M1 6,780 ND [45]
M2 3,510 ND [45]
M3 4,680 ND [45][46]
M4 1,520 ND [45]
M5 2,330 ND [45]
SERTTooltip Serotonin transporter 98–1,080 Blocker [47][45]
NETTooltip Norepinephrine transporter 2,090 Blocker [45]
DATTooltip Dopamine transporter 3,220 Blocker [45]
NMDA
(PCP)		 4,001 Antagonist [45]
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).[45]

Aripiprazole's mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone).[45][49][50][51][52][53][54][55] Rather than acting as a pure antagonist of the dopamine D2 receptor, aripiprazole shows functional selectivity at the D2 receptor, acting as a silent antagonist of some subpopulations of D2 receptors but as a high-efficacy partial agonist (intrinsic activity = 75%) of other D2-receptor subpopulations.[45] It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors.[56] Aripiprazole is also a partial agonist of the D3 receptor.[45] In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day.[57][58] 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.[59]

Aripiprazole is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%).[45][60][61] It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%),[45] and like other atypical antipsychotics, displays a functional antagonist profile at this receptor.[45] The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor.[61] At the 5-HT2B receptor, aripiprazole acts as a potent inverse agonist.[45] Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity;[45] this property may underlie the minimal weight gain seen in the course of therapy.[62] At the 5-HT7 receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor.[45][55] Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors.[45][50]

Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (eg at 5-HT6 and D2L), sometimes an inverse agonist (eg 5-HT2B), sometimes a partial agonist (eg D2L), and sometimes a full agonist (D3, D4). Aripiprazole was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has ‘functionally selective’ actions.[63] 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 (eg agonism, antagonism, partial agonism), and are most parsimoniously explained by the ‘functional selectivity’ hypothesis.[45]

Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C 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-HT2A/5-HT2C agonists have shown promise as antiobsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation. Aripiprazole has a favorable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that aripiprazole may have antiobsessional and anorectic actions in humans.[45]

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.[56] A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 93% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor.[64][61] It has been suggested that the low occupancy of the 5-HT1A receptor by aripiprazole may have been an erroneous measurement however.[65]

Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms.[66] Due to its agonist activity on D2 receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduced.[66]

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. Cmax (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.[50] When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels.[citation needed]

Chemistry

Aripiprazole is a phenylpiperazine and is chemically related to nefazodone, etoperidone, and trazodone.[67][68]

History

Aripiprazole was discovered by scientists at Otsuka Pharmaceutical and was called OPC-14597.[69][70] It was first published in 1995.[70][71] Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.[72]

It was approved by the FDA for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007;[73] and to treat irritability in children with autism on 20 November 2009.[74] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.[2]

Abilify (aripiprazole) 10 mg tablets (TR)

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both people older than 10 years.[75]

In 2006, the FDA required the companies 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.[76]

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[77] That same year, BMS settled a case with the U.S. 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.[78]

In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of apripiprazole.[79]

As of 2013, Abilify had annual sales of US$7 billion.[80] In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug.[81] Also in 2013, Otsuka and Lundbeck received U.S. and European marketing approval for an injectable depot formulation of aripiprazole.[82][83]

Otsuka's U.S. patent on aripiprazole expired on October 20, 2014 but due to a pediatric extension, a generic did not become available until April 20, 2015.[75] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[84] On November 15, 2010, this challenge was rejected by the U.S. District Court in New Jersey.[85]

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.,[86] The UK Intellectual Property Office decided[87] 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.

In April 2015, the FDA announced the first generic versions.[88][89] 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.[90][91]

In 2016, BMS settled cases with 42 U.S. states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.[76][92]

In November 2017, the FDA approved Abilify MyCite, a digital pill containing a sensor intended to record when its consumer takes their medication.[93][94]

Society and culture

Regulatory status

Regulatory administration (country)[95][96][97] Schizophrenia Acute mania Bipolar maintenance Major depressive disorder (as an adjunct) Autism
Food and Drug Administration (US) Yes Yes Yes (as an adjunct to lithium/valproate) Yes Yes
Therapeutic Goods Administration (AU) Yes Yes (as an adjunct to lithium/valproate) Yes No No
Medicines and Healthcare products Regulatory Agency (UK) Yes No Yes (to prevent mania) No No

Research

Aripiprazole may be counter-therapeutic as treatment for methamphetamine dependency because it increased methamphetamine's stimulant and euphoric effects, and increased the baseline level of desire for methamphetamine.[98]

Urine drug screens are used to test for recreational drug use. There are case reports of 2 children accidentally ingesting large quantities of aripiprazole and subsequently testing positive for amphetamines on urine drug screens; both children then had gas chromatography-mass spectrometry analysis sent on their blood and urine that were negative for amphetamines.[99]

See also

References

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