Indications and Usage

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.^[2] Several double-blind, placebo-controlled trials support this use.^[3][4][5][6] 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.^[7][8] Aripiprazole is at least as effective as haloperidol at reducing manic symptoms,^[9] and is much better tolerated by patients.^[10]

Aripiprazole's use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness^[11][12] (with one finding a reduction in anhedonia symptoms^[13]), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo.^[14] One study reported depression as a side effect of the drug.^[15]

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.^[16][17] 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.^[18][19] Aripiprazole has moderate affinity for histamine and α-adrenergic receptors and for the serotonin transporter, and no appreciable affinity for cholinergic muscarinic receptors.^[20] Aripiprazole also acts as a 5-HT_2C partial agonist, which may underly the minimal weight gain seen in the course of therapy.^[21]

D₂ and D₃ receptor occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.^[22] 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.^[24]

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.^[20]

Patent status

Otsuka's US patent on aripiprazole expires on October 20, 2014;^[25] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[2] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.^[26] This challenge is still in court as of 14 August 2009.

Side effects

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

Uncommon side effects: 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.

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

Tardive dyskinesia (As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.^[27][28][29])

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.

Very rare side effects: 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.

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 Abilify should be aware that their dosage of Abilify 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.

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]

References