There is tentative evidence that aripiprazole may be useful in schizophrenia, however definitive conclusions are difficult to draw as there was a very high rate of drop out during trials and there is a lack of data on general functioning, behaviour, mortality, economic outcomes or cognitive functioning. It is similar to other typical and atypical antipsychotics with respect to benefit. Compared to typicals 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 the tolerability of aripiprazole was found to be in the middle range of 15 antipsychotics for efficacy and 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 (and 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 that were treated with aripiprazole.
When used by itself for bipolar disorder, aripiprazole does not appear to improve symptoms of depression. It may be useful in preventing mania. Thus if used it is often in combination with an additional mood stabilizer, usage however increases the risk of extrapyramidal side effects.
Aripiprazole shows a benefit in major depressive disorder when used as an additional treatment. There is however, a greater rate of side effects as an adjunctive therapy (such as weight gain and akathisia). Aripiprazole has been found to be the most likely of the antipsychotics studied to produce a response in people with 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 the SSRIs (especially fluoxetine and paroxetine but also to a lesser extent sertraline, escitalopram, citalopram and fluvoxamine) which inhibit CYP2D6, for which aripiprazole is a substrate.
Short term data (8 weeks) shows reduced irritability, hyperactivity, and repetitive actions. Adverse effects included weight gain, sleepiness, drooling and tremors. Long term outcomes are not clear.
Sudden unexplained death has been reported, however the frequency is unknown.
Common in children
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.
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 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.
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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