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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/05/27 06:28:09」(JST)
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| Pronunciation | /ˌeɪrᵻˈpɪprəzoʊl/ AIR-i-PIP-rə-zohl |
| Trade names | Abilify |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a603012 |
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By mouth (tablets, dissolving tablets, solution); IM (including a depot) |
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| Bioavailability | 87%[1][2][3][4] |
| Protein binding | >99%[1][2][3][4] |
| Metabolism | Liver (mostly via CYP3A4 and 2D6[1][2][3][4]) |
| Biological half-life | 75 hours (active metabolite is 94 hours)[1][2][3][4] |
| Excretion | Renal (27%; <1% unchanged), Faecal (60%; 18% unchanged)[1][2][3][4] |
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| ECHA InfoCard | 100.112.532 |
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| Formula | C23H27Cl2N3O2 |
| Molar mass | 448.385 g/mol |
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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.[5] Other uses include as an add-on treatment in major depressive disorder, tic disorders, and irritability associated with autism.[6] According to a Cochrane review, evidence for the oral form in schizophrenia is not sufficient to determine effects on general functioning.[7] Additionally, because many people dropped out of the medication trials before they were completed, the overall strength of the conclusions is low.[7]
Side effects include neuroleptic malignant syndrome, a movement disorder known as tardive dyskinesia, and high blood sugar in those with diabetes.[5] In the elderly there is an increased risk of death.[5] It is thus not recommended for use in those with psychosis due to dementia.[5] It is pregnancy category C in the United States and category C in Australia, meaning there is possible evidence of harm to the fetus.[5][8] It is not recommended for women who are breastfeeding.[5] It is unclear whether it is safe or effective in people less than 18 years old.[5]
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.[9]
Contents
- 1 Medical uses
- 1.1 Schizophrenia
- 1.2 Bipolar disorder
- 1.3 Major depression
- 1.4 Autism
- 1.5 Obsessive-compulsive disorder
- 2 Side effects
- 2.1 Discontinuation
- 2.2 Overdosage
- 2.3 Drug interactions
- 3 Pharmacology
- 3.1 Binding profile
- 4 Pharmacokinetics
- 5 History
- 6 Society and culture
- 6.1 Regulatory status
- 6.2 Patent status
- 6.3 Sales
- 7 Dosage forms
- 8 Research
- 9 See also
- 10 References
- 11 External links
Medical uses
Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.[5]
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.[10] 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.[11] Health Canada approved aripiprazole for the acute and maintenance treatment of schizophrenia in 2009.[12]
A Cochrane review concluded that aripiprazole is similar to other typical and atypical antipsychotics with respect to benefit.[13][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 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).[17]
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.[7] The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.[17] 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]
Bipolar disorder
Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents.[21][22] Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression.[23][24] 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.[25]
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.[26][27][28][29] The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning.[27] 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.[1]
Autism
Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours.[30] Adverse effects include weight gain, sleepiness, drooling and tremors.[30] 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.[30]
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.[31]
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.[1][2][3][4][32] Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose.[1] A strong desire to gamble, binge eat, shop, and have sex may also occur.[33]
Uncontrolled movement such as restlessness, tremors, and muscle stiffness have been reported in children and adults, but they are rare.[1][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 agonist[50] |
| 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.[51][52] 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.[53][54] 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.[55] 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.[56][57] 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.[58]
Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be the cause of positive schizophrenia symptoms. 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.[59]
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]
History
Aripiprazole was discovered in 1988 and Otsuka developed it independently.[60][third-party source 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;[61] and to treat irritability in children with autism on 20 November 2009.[62] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.[1]
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.[63]
In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[64] It has not been FDA-approved for use as monotherapy in unipolar depression.
| Regulatory administration (country)[65][66][67] | 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;[68] however, due to a pediatric extension, a generic did not become available until April 20, 2015.[63] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[69] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[70]
Otsuka's European patent EP0367141,[71] which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014.[72] The UK Intellectual Property Office decided[73] 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.[74][75]
Sales
As of 2013, Abilify had annual sales of US$7 billion.[76]
Dosage forms
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Abilify 2 mg tablets (US)
- Intramuscular injection (solution)
- Long-acting intramuscular injection (lyophilized powder for reconstitution)
- Long-acting intramuscular injection (single-use pre-filled syringe) [77]
- Solution, oral [contains propylene glycol, sucrose, and fructose ; orange cream flavor]
- Tablet
- Tablet, orally disintegrating [contains phenylalanine; 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).[78] 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.[79]
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.[80]
See also
- Aripiprazole lauroxil (extended-release prodrug form)
- Brexpiprazole (obvious structural similarity)
- Phenylpiperazine (list of compounds that use the -piprazole suffix)
- Cariprazine (structural similarity)
References
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- ^ Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR (December 2005). "Intrinsic Efficacy of Antipsychotics at Human D2, D3, and D4 Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D2/D3 Partial Agonist". J Pharmacol Exp Ther. 315 (3): 1278–87. doi:10.1124/jpet.105.092155. PMID 16135699.
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External links
- Abilify website
- Abilify Full Prescribing Information (for Health Care Professionals)
- U.S. National Library of Medicine: Drug Information Portal - Aripiprazole
- Abilify adverse events reported to the FDA
- Mechanism of Action Of Aripiprazole
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UpToDate Contents
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- 1. Pediatric bipolar disorder: Overview of choosing treatment
- 2. 成人における単極性うつ病：第2世代抗精神病薬による治療 unipolar depression in adults treatment with second generation antipsychotics
- 3. 成人における双極性障害：維持療法の選択 bipolar disorder in adults choosing maintenance treatment
- 4. Pediatric mania and second-generation antipsychotics: Efficacy, administration, and side effects
- 5. 第二世代抗精神病薬：薬理学、用法および副作用 second generation antipsychotic medications pharmacology administration and side effects
English Journal
- Two-year effectiveness of risperidone and aripiprazole in the maintenance treatment of patients with recent-onset or chronic schizophrenia and related psychotic disorders: a retrospective multicenter study.
- Yoshimura Y1,2, Takeda T1, Kishi Y3, Harada T4, Nomura A5, Washida K1,2, Yoshimura B3, Sato K3, Yada Y3, Aoki S2.
- International clinical psychopharmacology.Int Clin Psychopharmacol.2018 May;33(3):147-154. doi: 10.1097/YIC.0000000000000209.
- PMID 29406406
- Switching antipsychotic treatment to aripiprazole in psychotic patients with neuroleptic-induced tardive dyskinesia: a 24-week follow-up study.
- Chan CH1,2, Chan HY1,3, Chen YC4,5.
- International clinical psychopharmacology.Int Clin Psychopharmacol.2018 May;33(3):155-162. doi: 10.1097/YIC.0000000000000208.
- PMID 29324468
- DNA methylation of ANKK1 and response to aripiprazole in patients with acute schizophrenia: A preliminary study.
- Miura I1, Kunii Y2, Hino M2, Hoshino H2, Matsumoto J2, Kanno-Nozaki K2, Horikoshi S2, Kaneko H2, Bundo M3, Iwamoto K3, Yabe H2.
- Journal of psychiatric research.J Psychiatr Res.2018 May;100:84-87. doi: 10.1016/j.jpsychires.2018.02.018. Epub 2018 Feb 23.
- PMID 29499474
Japanese Journal
- 私が歩んだ向精神薬開発の道 : 秘話でつづる向精神薬開発の歴史(第64回)第二世代抗精神病薬の持効性筋注製剤の開発物語(その3)Aripiprazole持続性筋注製剤(Abilify持続性水懸筋注用)
- 臨床精神薬理 19(11), 1633-1655, 2016-11
- NAID 40020991665
- Development of Gummi Drugs of Aripiprazole as Hospital Formulations
- Chemical and Pharmaceutical Bulletin 63(5), 354-360, 2015
- NAID 130005067247
- 統合失調症治療薬アリピプラゾール(エビリファイ^【○!R】)
- 日本薬理学雑誌 : FOLIA PHARMACOLOGICA JAPONICA 128(5), 331-345, 2006-11-01
- NAID 10018553699
Related Links
- Learn about ABILIFY (aripiprazole) for Bipolar I Disorder, Schizophrenia, or Depression in adults. View Important Safety Information and Boxed WARNINGS.
- 2011年2月18日 ... 米国において「ABILIFY」は、単剤での双極I型障害による躁症状または混合型症状の 急性期治療、ならびに双極I型障害の維持療法の効能・効果をすでに取得しています。 また、双極I型障害の躁症状および混合型症状の急性期治療における、 ...
Related Pictures
★リンクテーブル★
| リンク元 | 「アリピプラゾール」 |
「アリピプラゾール」
- 向精神薬
- 抗精神病薬
- 非定型抗精神病薬
作用機序
- ドパミンD2受容体の部分作動薬。
- シナプス間隙のドパミン濃度が高い場合にドパミン神経伝達を減弱させる薬物。