Aripiprazole

Aripiprazole

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Systematic (IUPAC) name
7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: Abilify US FDA: Aripiprazole
Pregnancy category	C (USA)
Routes of administration	oral (via tablets, orodispersable tablets, and oral solution); intramuscular
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	87%
Protein binding	>99%
Metabolism	liver
Biological half-life	75h (active metabolite : 94h)
Excretion	feces and urine
Identifiers
CAS Number	129722-12-9
ATC code	N05AX12 (WHO)
PubChem	CID 60795
IUPHAR/BPS	34
DrugBank	APRD00638
ChemSpider	54790
Chemical data
Formula	C23H27Cl2N3O2
Molar mass	448.385[[]]
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Aripiprazole (pronounced AR-i-PIP-ra-zole; brand names: Abilify, Abilify Discmelt, 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, and as an adjunct for major depressive disorder on November 20, 2007. Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Indications and usage

Schizophrenia

Aripiprazole has been approved by the FDA for the treatment of schizophrenia.

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. Several double-blind, placebo-controlled trials support this use. 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. Aripiprazole is at least as effective as haloperidol at reducing manic symptoms, and is much better tolerated by patients.

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

Major depression (Unipolar depression)

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

Autism

In 2009, the United States FDA approved Abilify to treat irritability in persons with autism. It was approved on the basis of two studies that showed it reduced aggression towards others, self-injury, quickly changing moods, irritability, and temper tantrums in autistic males and females 6–17 years of age.

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).

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. Aripiprazole is also a partial agonist at the 5-HT_1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT_2A receptor. It also antagonizes the 5-HT₇ receptor and acts as a partial agonist at the 5-HT_2C receptor, both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy. Aripiprazole has moderate affinity for histamine and α-adrenergic receptors and for the serotonin transporter, and no appreciable affinity for cholinergic muscarinic receptors.

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

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. This implicates 5-HT₇ antagonism as playing a major role in aripiprazole's antidepressant effects, similarly to amisulpride.

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). 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. C_max (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. When dosed daily, brain concentrations of aripiprazole will increase for a period of 10-14 days, before reaching stable constant levels. This phenomenon is due to the long half life of aripiprazole, and is responsible for many of the adverse side effects that appear after multiple days of dosing (whereas the first dose normally does not cause these side effects). Aripiprazole possesses very high binding affinity for D2 receptors throughout the brain. Although aripiprazole is described as a partial agonist, its intrinisic affinity is lower than most other partial agonists, thus functioning as an antagonist in most physiological instances. This is due to the normal presence of dopamine throughout the brain, which possesses a much higher intrinsic activity for dopamine receptors. Single low doses of ariprazole will only occupy small amounts of dopamine D2 receptors, which does not cause extrapyramidial symptoms, akathisia, or parkinsonism. However, even if the dose is low, consecutive daily administration will result in accumulation of brain concentrations, thereby causing undesirable side effects in many patients, such as Akathisia, anxiety, restless leg syndrome, and other side effects typical of traditional and atypical antipsychotic medications. An even higher risk for unwanted side effects, is present in situations of high-dose daily dosing (10mg and above/per day). Such dosing results in brain concentrations occupying up to 80% of dopamine D2 receptors in most areas of the brain. Common medical knowledge assumes that due to the partial agonist properties of aripiprazole, typical D2-blocking side effects will not be significant. This assumption is incorrect: a partial agonist will always produce agonist effects weaker than the endogenous full agonist (dopamine), specifically, aripiprazole's intrinsic agonist activity is so weak, that in nearly all real-life cases, aripiprazole will function solely as an antagonist at dopamine D2 receptors throughout the brain.

Patent status

Otsuka's US patent on aripiprazole expires on October 20, 2014; however, due to a pediatric extension, a generic will not become available until at least April 20, 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. As of 14 August 2009 (2009 -08-14), this challenge is still in court.

Side effects

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Akathisia, headache, unusual tiredness or weakness, nausea, vomiting, an uncomfortable feeling in the stomach, constipation, light-headedness, insomnia, sleepiness, shaking, and blurred vision.

Uncontrollable twitching or jerking movements, tremors, seizure, and weight gain. Some people may feel dizzy, especially when getting up from a lying or sitting position, or may experience a fast heart rate.

Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate.)

Aripiprazole also causes sexual dysfunction.

Tardive dyskinesia (As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.)

Stroke (While taking aripiprazole some elderly patients with dementia have suffered from stroke or 'mini' stroke.)

Other elderly patients may experience high blood sugar or the onset or worsening of diabetes.

Allergic reaction (such as swelling in the mouth or throat, itching, rash), increased production of saliva, speech disorder, nervousness, agitation, fainting, reports of abnormal liver test values, inflammation of the pancreas, muscle pain, weakness, stiffness, or cramps.

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 no deaths have yet been recorded.

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. As such, anyone taking Abilify should be aware that their dosage of Abilify may need to be decreased.

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

Dosage forms

• Intramuscular injection, solution: 7.5 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

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U.S. Patent 5,006,528

External links

• Abilify website
• Abilify Full Prescribing Information (for Health Care Professionals)
• U.S. National Library of Medicine: Drug Information Portal - Aripiprazole

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