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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/ˌɛər[invalid input: 'ɨ']ˈpɪprəzoʊl/ AIR-i-PIP-rə-zohl
Trade namesAbilify
AHFS/Drugs.comMonograph
MedlinePlusa603012
License data
Pregnancy
category
  • AU: B3
Routes of
administration		Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a depot)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability87%[2][3][4][5]
Protein binding>99%[2][3][4][5]
MetabolismHepatic (liver; mostly via CYP3A4 and CYP2D6[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 United States Food and Drug Administration 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.[14][15] Compared to typical antipsychotics, there are fewer extrapyramidal side effects, but higher rates of dizziness.[16][needs update] With respect to other atypicals, it is difficult to determine differences in adverse effects as data quality is poor.[17][needs update] A Lancet review found it is in the middle range of 15 antipsychotics for effectiveness, 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).[18]

A Cochrane review 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 authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.[18] 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.[19]

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.[20]

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)" [21]

The National Institute of Health and Clinical Excellence,[20] the British Association for Psychopharmacology[21] 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.[19]

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, and stereotypy.[31] Adverse effects included weight gain, sleepiness, drooling and tremors.[31] Long-term outcomes are not clear.[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]

Side effects

See also: List of side 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][33]

Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose.[2]

Uncontrolled movement such as restlessness, tremors, and muscle stiffness have been reported in children and adults, but they are rare.[2][34]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[35] Joanne Moncrieff has suggested that the withdrawal process might itself be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics, but the limited evidence was found to support this hypothesis for antipsychotics other than clozapine.[36]

Overdosage

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 patients were elevated by up to 3-4 fold over normal therapeutic levels, yet to date no deaths have been recorded.[37][38]

Drug 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.[39] As such, anyone taking aripiprazole should be aware that their dosage of aripiprazole may need to be adjusted.

For the purpose of D2 blockage, aripiprazole, a partial agonist on D2 receptor site, should not be used with a full antagonist.[medical citation needed]

Precautions should be taken in patients 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.[40] Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia (excessive thirst), polyuria (excessive urination), polyphagia (increased appetite), and weakness.[41]

Pharmacology

Binding profile

Aripiprazole acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:[42][43][44][45][46][47][48][49]

Receptor Ki (nM) Pharmacodynamic action
5-HT1A 5.6 Partial agonism
5-HT1B 832
5-HT1D 65.5
5-HT2A 8.7
5-HT2B 0.4
5-HT2C 22.4 Partial agonism
5-HT3 628
5-HT5A 1240
5-HT6 642
5-HT7 10 Weak partial agonism
D1 1170
D2 1.6 Partial agonism
D3 5.4 Partial agonism
D4 514 Partial agonism
D5 2130
α1A 25.9
α1B 34.4
α2A 74.1
α2B 102
α2C 37.6
β1 141
β2 163
H1 27.9
M1 6780
M2 3510
M3 4680
M4 1520
M5 2330
SERT 1080
NET 2090
DAT 3220

Aripiprazole's mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). Rather than antagonizing the D2 receptor, aripiprazole acts as a D2 partial agonist.[50][51] Aripiprazole is also a partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor.[52][53] It also antagonizes the 5-HT7 receptor and acts as a partial agonist at the 5-HT2C receptor, both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy.[54] Aripiprazole has moderate affinity for histamine, α-adrenergic, and D4 receptors as well as the serotonin transporter, while it has no appreciable affinity for cholinergic muscarinic receptors.[43]

D2 and D3 receptor occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.[55][56] 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.[57]

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

Society and culture

Regulatory status

It was approved by the U.S. Food and Drug Administration (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;[58] and to treat irritability in children with autism on 20 November 2009.[59] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.[2]

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.[60]

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[61] It has not been FDA-approved for use as monotherapy in unipolar depression.

Regulatory administration (country)[62][63][64] 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

Patent status

Otsuka's US patent on aripiprazole expired on October 20, 2014;[65] however, due to a pediatric extension, a generic did not become available until April 20, 2015.[60] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[66] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[67]

Otsuka's European patent EP0367141,[68] which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014.[69] The UK Intellectual Property Office decided[70] 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.

On April 28, 2015, the U.S. Food and Drug Administration (FDA) released a press announcement which approved the first generic versions.[71][72]

Sales

As of 2013, Abilify had annual sales of US$7 billion.[73]

Dosage forms

File:Abilify bottle.jpg
Abilify 2mg tablets (US)
  • Intramuscular injection, solution: 9.75 mg/mL (1.3 mL)
  • Solution, oral: 1 mg/mL (150 mL) [contains propylene glycol, sucrose 400 mg/mL, and fructose 200 mg/mL; orange cream flavor]
  • Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
  • Tablet, orally disintegrating: 10 mg [contains phenylalanine 1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]

Research

Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behavior in animal models without significantly affecting other rewarding behaviors (such as food self-administration).[74] 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.[75]

See also

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