Aripiprazole

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Aripiprazole
Aripiprazole2D1.svg
Aripiprazole3DanBall.gif
Systematic (IUPAC) name
7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Clinical data
Trade names Abilify
AHFS/Drugs.com monograph
MedlinePlus a603012
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a depot)
Pharmacokinetic data
Bioavailability 87%[1][2][3][4]
Protein binding >99%[1][2][3][4]
Metabolism Hepatic (liver; mostly via CYP3A4 and CYP2D6[1][2][3][4])
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]
Identifiers
CAS number 129722-12-9 YesY
ATC code N05AX12
PubChem CID 60795
IUPHAR ligand 34
DrugBank DB01238
ChemSpider 54790 YesY
UNII 82VFR53I78 YesY
KEGG D01164 YesY
ChEBI CHEBI:31236 YesY
ChEMBL CHEMBL1112 YesY
Chemical data
Formula C23H27Cl2N3O2 
Mol. mass 448.385
 N (what is this?)  (verify)

Aripiprazole (/ˌɛərɨˈpɪprəzl/ AIR-i-PIP-rə-zohl; brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation (or atypical antipsychotic) class of antipsychotics that is primarily used in the treatment of schizophrenia, bipolar disorder, major depressive disorder (as an add on to other treatment), tic disorders, and irritability associated with autism.[5]

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;[6] and to treat irritability in children with autism on 20 November 2009.[7] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.[1]

Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Medical uses[edit]

Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.[8]

Schizophrenia[edit]

There is evidence aripiprazole may be useful in schizophrenia with it decreasing relapse in up to the medium term and helping those who are given it follow treatment better.[9] Definitive conclusions are difficult to draw though as there was a high rate of drop out during trials and there is a lack of outcome data regarding general functioning, behavior, mortality, economic outcomes, or cognitive functioning.[9] For acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.[10] 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.[11]

A Cochrane review concluded that it is similar to other typical and atypical antipsychotics with respect to benefit.[12][13] Compared to typical antipsychotics, there are fewer extrapyramidal side effects, but higher rates of dizziness.[14] With respect to other atypicals, it is difficult to determine differences in adverse effects as data quality is poor.[15] 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).[10] Reviews from the National Institute of Health and Clinical Excellence,[16] the British Association for Psychopharmacology[17] 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[edit]

When used by itself for bipolar disorder, aripiprazole does not appear to improve symptoms of depression,[19] although it may be useful in preventing mania.[20] 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.[21]

Major depression[edit]

Aripiprazole is an effective adjunct treatment for major depressive disorder. However, there is a greater rate of side effects as an adjunctive therapy (such as weight gain and akathisia).[22][23] Aripiprazole is the most efficacious antipsychotic to alleviate symptoms of treatment-resistant major depressive disorder (although not significantly).[23] Likewise, in a few earlier meta-analyses, similar results were obtained.[24][25] Aripiprazole may pharmacokinetically interact with some antidepressants, especially SSRIs. There are significant 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 raise aripiprazole concentrations 2-3 times their level.[1]

Autism[edit]

Short-term data (8 weeks) shows reduced irritability, hyperactivity, and stereotypy.[26] Adverse effects included weight gain, sleepiness, drooling and tremors.[26] Long-term outcomes are not clear.[26]

Regulatory approval status[edit]

Regulatory administration (country)[27][28][29] 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

Side effects[edit]

Adverse effect incidences
In Adults[1][2][3][4][30]

Very Common (>10% incidence) adverse effects
  • Weight gain
  • Headache
  • Agitation
  • Insomnia
  • Anxiety
  • Nausea & vomiting
  • Akathisia — a sense of unease and restlessness that presents itself with anxiety
  • Lightheadedness
  • Constipation
Common (1-10% incidence) adverse effects
  • Dizziness
  • Dyspepsia — indigestion
  • Somnolence — which is usually mild and transient and less severe than that seen with most antipsychotics.[31]
  • Fatigue
  • Restlessness
  • Dry mouth
  • Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.)
  • Orthostatic hypotension
  • Musculoskeletal stiffness
  • Abdominal discomfort
  • Blurred vision
  • Cough
  • Pain
  • Myalgia
  • Rash
  • Rhinitis
Uncommon (0.1-1% incidence) adverse effects
  • Leukopenia
  • Neutropenia
  • Thrombocytopenia
  • Bradycardia (low heart rate)
  • Palpitations
  • Orthostatic hypotension
  • Dry eye
  • Photophobia
  • Diplopia
  • Eyelid oedema
  • Photopsia
  • Diarrhoea
  • Gastritis
  • Dysphagia
  • Gastroesophageal reflux disease
  • Swollen tongue
  • Oesophagitis
  • Hypoaesthesia oral
  • Face oedema
  • Gait disturbance
  • Chills
  • Discomfort
  • Feeling abnormal
  • Mobility decreased
  • Self-mutilation
  • Heart rate increased
  • Blood glucose increased
  • Pyrexia
  • Blood prolactin increased
  • Blood urea increased
  • Electrocardiogram QT prolonged
  • Blood bilirubin increased
  • Hepatic enzyme increased
  • Increased appetite
  • Nocturia
  • Polyuria
  • Pollakiuria
  • Incontinence
  • Urinary retention
  • Sexual dysfunction
  • Amenorrhoea
  • Pruritus (itchiness)
  • Photosensitivity reaction
  • Urticaria
Rare (<0.1%) adverse effects include

Sudden unexplained death has been reported, however the frequency is unknown.[35]

Common in children
  • Feeling sleepy
  • Headache
  • Vomiting
  • Fatigue
  • Increased appetite
  • Insomnia
  • Nausea
  • Stuffy nose
  • Weight gain
  • Uncontrolled movement such as restlessness, tremor muscle stiffness [36]

Discontinuation[edit]

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[37] 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.[38]

Overdosage[edit]

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.[39]

Drug interactions[edit]

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

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.[41] Patients with risk factors for diabetes mellitus (eg, 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.[42]

Pharmacology[edit]

Binding profile[edit]

Aripiprazole acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:[43][44][45][46][47][48][49][50]

Receptor Ki (nM) Efficacy
5-HT1A 5.6  partial agonist
5-HT1B 832   
5-HT1D 65.5
5-HT2A 8.7
5-HT2B 0.4
5-HT2C 22.4 partial agonist
5-HT3 628   
5-HT5A 1240   
5-HT6 642    
5-HT7 10     weak partial agonist
D1 1170    
D2 1.6  partial agonist
D3 5.4  partial agonist
D4 514    partial agonist
D5 2130   
α1A-adrenergic 25.9
α1B-adrenergic 34.4
α2A-adrenergic 74.1
α2B-adrenergic 102   
α2C-adrenergic 37.6
β1-adrenergic 141   
β2-adrenergic 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.[44]

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]

Pharmacokinetics[edit]

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.[44] 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[edit]

Regulator status[edit]

In the United States, the FDA has approved aripiprazole for the treatment of schizophrenia in adults and adolescents (aged 13–17), of manic and mixed episodes associated with Bipolar I (One) Disorder with or without psychotic features in adults, children and adolescents (aged 10–17),[59] of irritability associated with autism in pediatric patients (aged 6–17),[60] and of depression when used along with antidepressants in adults.[61]

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.[62]

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[63] It has not been FDA-approved for use as monotherapy in unipolar depression.

Patent status[edit]

Otsuka's US patent on aripiprazole expires on October 20, 2014;[64] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.[62] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[65] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[1][2]

Dosage forms[edit]

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]

Synthesis[edit]

Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amine:[66]

Aripiprazole synth.png

Research[edit]

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).[67] 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.[68]

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