|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Routes||Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a depot)|
|Metabolism||Hepatic (liver; mostly via CYP3A4 and CYP2D6)|
|Half-life||75 hours (active metabolite is 94 hours)|
|Excretion||Renal (27%; <1% unchanged), Faecal (60%; 18% unchanged)|
|(what is this?)|
Aripiprazole (// AIR-i-PIP-rə-zohl; brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation (or atypical) class of antipsychotics that is primarily used in the treatment of schizophrenia, bipolar disorder, major depressive disorder (as an adjunct), tic disorders, and irritability associated with autism. 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; and to treat irritability in children with autism on 20 November 2009. Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003. Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb. Some doctors say that, because of promotion by the pharmaceutical industry, second-generation drugs like aripiprazole, which are appropriate for a few serious psychiatric disorders, are prescribed inappropriately for conditions it may not treat effectively, such as anxiety.
- 1 Medical uses
- 2 Side effects
- 3 Pharmacology
- 4 Pharmacokinetics
- 5 Society and culture
- 6 Dosage forms
- 7 Synthesis
- 8 Research
- 9 References
- 10 External links
There is tentative evidence aripiprazole may be useful in schizophrenia; however, definitive conclusions are difficult to draw as there was a high rate of attrition during trials and there is a lack of outcome data regarding general functioning, behavior, mortality, economic outcomes, or cognitive functioning. It is similar to other typical and atypical antipsychotics with respect to benefit. Compared to typical antipsychotics, there is less extrapyramidal side effects, but higher rates of dizziness. With respect to other atypicals, it is difficult to determine differences in adverse effects as data quality is poor. The efficacy and tolerability of aripiprazole was in the middle range of 15 antipsychotics for efficacy, but had superior tolerability when compared to the other antipsychotic drugs (4th lowest SMD for weight gain, 5th lowest OR for extrapyramidal symptoms, lowest SMD for prolactin elevation, 2nd lowest OR for QTc prolongation, 5th lowest OR for sedation). In a large (N=361) 12-week open-label (hence, no definitive conclusions can be drawn from this study alone) clinical trial, significant improvements in verbal memory and fluency were seen in patients with schizophrenia treated with aripiprazole.
When used by itself for bipolar disorder, aripiprazole does not appear to improve symptoms of depression, although it may be useful in preventing mania. 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.
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). Aripiprazole is the most efficacious antipsychotic to alleviate symptoms of treatment-resistant major depressive disorder (although not significantly). Likewise, in a few earlier meta-analyses, similar results were obtained. 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.
Short-term data (8 weeks) shows reduced irritability, hyperactivity, and stereotypy. Adverse effects included weight gain, sleepiness, drooling and tremors. Long-term outcomes are not clear.
Regulatory Approval Status
|Regulatory Administration (Country)||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|
- Very Common (>10% incidence) adverse effects
- Weight gain
- Nausea & vomiting
- Akathisia — a sense of inner restlessness that presents itself with the inability to stay still
- Common (1-10% incidence) adverse effects
- Dyspepsia — indigestion
- Somnolence — which is usually mild and transient and less severe than that seen with most antipsychotics.
- Dry mouth
- Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.)
- Orthostatic hypotension
- Musculoskeletal stiffness
- Abdominal discomfort
- Blurred vision
- Uncommon (0.1-1% incidence) adverse effects
- Bradycardia (low heart rate)
- Orthostatic hypotension
- Dry eye
- Eyelid oedema
- Gastroesophageal reflux disease
- Swollen tongue
- Hypoaesthesia oral
- Face oedema
- Gait disturbance
- Feeling abnormal
- Mobility decreased
- Heart rate increased
- Blood glucose increased
- Blood prolactin increased
- Blood urea increased
- Electrocardiogram QT prolonged
- Blood bilirubin increased
- Hepatic enzyme increased
- Increased appetite
- Urinary retention
- Sexual dysfunction
- Pruritus (itchiness)
- Photosensitivity reaction
- Rare (<0.1%) adverse effects include
- Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate)
- Suicidal ideation and behaviour
- Painful and/or sustained erection (Priapism)
- Cardiopulmonary failure
- Myocardial infarction (heart attack)
- Atrial flutter
- Supraventricular tachycardia
- Ventricular tachycardia
- Cardio-respiratory arrest
- Atrioventricular block
- Sinus tachycardia
- Atrial fibrillation
- Angina pectoris
- Myocardial ischaemia
- Diabetic ketoacidosis
- Prolonged QT interval (less common than with most other atypical antipsychotic drugs)
- Speech disorder
- Electrolyte abnormalities including hyponatraemia, hypokalaemia, hypocalcaemia, etc.
- Oropharyngeal spasm
- Chest pain
- Urinary retention or incontinence
- Alopecia (hair loss)
- Photosensitivity reaction
- Xerostomia (when given by injection)
- Tardive dyskinesia (As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.)
- Transient Ischaemic Attack
- Increased body temperature
- Cardiorespiratory arrest
- Cardiorespiratory failure
Sudden unexplained death has been reported, however the frequency is unknown.
- Common in children
- Feeling sleepy
- Increased appetite
- Stuffy nose
- Weight gain
- Uncontrolled movement such as restlessness, tremor muscle stiffness 
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. 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, orthostatic hypotension, tachycardia, rhabdomyolysis, nervousness, dizziness, headache, excessive non-stop crying, and anxiety. Some have argued that additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics. This has led some to suggest 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. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well the public.
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.
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 aripiprazole should be aware that their dosage of aripiprazole 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.
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]
- 5-HT1A receptor (Ki = 5.6 nM) (partial agonist)
- 5-HT1B receptor (Ki = 832 nM)
- 5-HT1D receptor (Ki = 65.5 nM)
- 5-HT2A receptor (Ki = 8.7 nM)
- 5-HT2B receptor (Ki = 0.36 nM)
- 5-HT2C receptor (Ki = 22.4 nM) (partial agonist)
- 5-HT3 receptor (Ki = 628 nM)
- 5-HT5A receptor (Ki = 1240 nM)
- 5-HT6 receptor (Ki = 642 nM)
- 5-HT7 receptor (Ki = 10 nM) (weak partial agonist)
- D1 receptor (Ki = 1170 nM)
- D2 receptor (Ki = 1.6 nM) (partial agonist)
- D3 receptor (Ki = 5.4 nM) (partial agonist)
- D4 receptor (Ki = 514 nM) (partial agonist)
- D5 receptor (Ki = 2130 nM)
- α1A-adrenergic receptor (Ki = 25.9 nM)
- α1B-adrenergic receptor (Ki = 34.4 nM)
- α2A-adrenergic receptor (Ki= 74.1 nM)
- α2B-adrenergic receptor (Ki= 102 nM)
- α2C-adrenergic receptor (Ki= 37.6 nM)
- β1-adrenergic receptor (Ki = 141 nM)
- β2-adrenergic receptor (Ki = 163 nM)
- H1 receptor (Ki = 27.9 nM)
- M1 receptor (Ki = 6780 nM)
- M2 receptor (Ki = 3510 nM)
- M3 receptor (Ki = 4680 nM)
- M4 receptor (Ki = 1520 nM)
- M5 receptor (Ki = 2330 nM)
- SERT (Ki = 1080 nM)
- NET (Ki = 2090 nM)
- DAT (Ki = 3220 nM)
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-HT1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor. 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. 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.
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. Note, however, humans possess a splice variant not found in other mammals (the "d" isoform), while mice possess one not found in humans (the "c"). The significantly altered c-terminus observed in 5-HT7(d) results in a similar binding affinity to the other forms of this receptor, however, the "c" variant found in other mammals differs in affinity. This difference in expression means the receptor's function in modulating thalamic and hypothalamic output, and corresponding effect on fatigue perception and alertness may not be homologous in mice and humans.
Aripiprazole produces 2,3-dichlorophenylpiperazine (DCPP) as a metabolite in a similar fashion to the reactions of trazodone and nefazodone to give 3-chlorophenylpiperazine (mCPP) and the conversion of niaprazine to 4-fluorophenylpiperazine (pFPP). It is unknown whether DCPP contributes to aripiprazole's pharmacology.
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. When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels.
Society and culture
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), of irritability associated with autism in pediatric patients (aged 6–17), and of depression when used along with antidepressants in adults.
Aripiprazole is also used off-label for schizophrenia in children (aged 10–12), and to treat dementia-related psychosis in geriatric patients, though Bristol-Myers Squibb was penalized for promoting such uses in the United States.
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.
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.
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. On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.
- 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]
Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amine:
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). The book Addiction Medicine mentions studies that suggest 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.
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