Aripiprazole

Aripiprazole
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:LinkUS FDA:link
Pregnancy cat. C (USA)
Legal status Prescription only
Routes oral (via tablets, orodispersable tablets, and oral solution); intramuscular
Pharmacokinetic data
Bioavailability 87%
Protein binding >99%
Metabolism liver
Half-life 75h (active metabolite : 94h)
Excretion feces and urine
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
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Aripiprazole (play /ˌɛərɨˈpɪprəzl/ air-i-pip-rə-zohl; brand names: Abilify, Aripiprex) is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression. It was approved by the US Food and Drug Administration (FDA) for schizophrenia on November 15, 2002; 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; and to treat irritability in children with autism on 20 November 2009.[1][2] Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Contents

Medical uses

Aripiprazole is used for the treatment of schizophrenia or bipolar disorder.[3]

Bipolar disorder

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.[4] Several double-blind, placebo-controlled trials support this use.[5][6][7][8] In addition, it is often used as maintenance therapy, either on its own or in conjunction with a mood stabilizer such as lithium or valproate. This use is also supported by a handful of studies.[9][10] Aripiprazole is at least as effective as haloperidol at reducing manic symptoms,[11][unreliable source?] and is much better tolerated by patients.[12]

Aripiprazole's use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness[13][14] (with one finding a reduction in anhedonia symptoms[15]), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo.[16] One study reported depression as a side effect of the drug.[17]

Major depression

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[18] It has not been FDA-approved for use as monotherapy in unipolar depression.

Autism

In 2009, the United States FDA approved aripiprazole to treat irritability in persons with autism.[19] It was approved on the basis of two studies that showed it reduced aggression towards others, self-injury, quickly changing moods, and irritability.

Cocaine dependency

Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behaviour in animal models without significantly affecting other rewarding behaviours (such as food self-administration).[20]

Methamphetamine dependency

The book Addiction Medicine mentions studies, suggesting aripiprazole would 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. The author mentions studies that suggest that dopamine agonist treatment would be counter-therapeutic for methamphetamine/amphetamine dependency. [21]

Side effects

Frequent

  • akathisia[22]
  • headache
  • agitation
  • anxiety
  • unusual tiredness or weakness
  • nausea and vomiting
  • an uncomfortable feeling in the stomach
  • constipation
  • increased production of saliva
  • light-headedness
  • insomnia
  • sleepiness
  • shaking
  • blurred vision
  • sexual dysfunction

Infrequent

Discontinuation

Aripiprazole should be discontinued gradually, with careful consideration from the prescribing doctor, to avoid withdrawal symptoms or relapse.

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[26] Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostasis, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics.[27][28] Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.[citation needed]

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.[29]

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

Aripiprazole may change the subjective effects of alcohol. One study[31] found that aripiprazole increased the sedative effect and reduced the sense of euphoria normally associated with alcohol consumption. However, another alcohol study[32] found that there was no difference in subjective effect between a placebo group and a group taking aripiprazole.

Pharmacology

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 (Ki = 0.34 nM).[33][34] Aripiprazole is also a partial agonist at the 5-HT1A receptor (Ki = 1.65 nM), and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor (Ki = 0.8 nM).[35][36] It also antagonizes the 5-HT7 receptor (Ki = 39 nM) and acts as a partial agonist at the 5-HT2C receptor (Ki = 15 nM), both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy.[37] Aripiprazole has moderate affinity for histamine (Ki = 61 nM), α-adrenergic (Ki = 57 nM), and D4 receptors as well as the serotonin transporter, while it has no appreciable affinity for cholinergic muscarinic receptors.[38]

D2 and D3 receptor occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.[39][40] 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.[41]

Recently, it has been demonstrated that in 5-HT7 receptor knockout mice, aripiprazole does not reduce immobility time in the forced swim test (FST), and actually increases it.[42][43] This implicates 5-HT7 antagonism as playing a major role in aripiprazole's antidepressant effects, similarly to amisulpride.[42][43][44]

Aripiprazole produces 2,3-dichlorophenylpiperazine (DCPP) as a metabolite similarly to how trazodone and nefazodone reduce to 3-chlorophenylpiperazine (mCPP) and niaprazine converts to 4-fluorophenylpiperazine (pFPP).[45] It is unknown whether DCPP contributes to aripiprazole's pharmacology in any way, but the possibility cannot be excluded.

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

Patent status

Otsuka's US patent on aripiprazole expires on October 20, 2014;[46] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.[4] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[47] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[1][2]

Dosage forms

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

Aripiprazole synth.png

U.S. Patent 5,006,528

References

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