Aripiprazole

Contraindications

Contraindications to aripiprazole include known hypersensitivity to aripiprazole, among others.

Adverse effects

In elderly people with dementia-related psychosis who are treated with antipsychotics, there is an increased risk of death. In children, adolescents, and young adults treated with antidepressants there is an increased risk of suicidal thoughts or behavior.

In adults, side effects with greater than 10% incidence include weight gain, mania, headache, akathisia, insomnia, delirium, gastrointestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose.

In 2016, an FDA Drug Safety Communication warned that aripiprazole can rarely cause impulse control issues. The impulse control problems include a strong desire to gamble, binge eat, shop, and engage in sexual activity. These urges can be uncontrollable. The uncontrollable urges were reported to stop when the dose of aripiprazole was lowered or the medication was discontinued.

Uncontrolled movement such as restlessness, tremors, and muscle rigidity may also occur.

Discontinuation

The British National Formulary recommends gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a part of a withdrawal syndrome. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Overdose

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, the primary active metabolite of aripiprazole, in these people were up to four times normal therapeutic levels. As of 2008 no deaths had been recorded.

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.

Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.

Antipsychotics, like aripiprazole, and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects because both drugs affect dopaminergic neurons, but both stimulants and antipsychotics increase synaptic dopamine levels. In antipsychotics, this is caused by the inhibition of dopamine autoreceptors as well as the effects of antipsychotics on non-dopaminergic receptors; in amphetamine this is caused by non-competitive inhibition of dopamine reuptake and agonism of intracellular TAAR1. Therefore, aripiprazole may interact with amphetamine to synergistically increase postsynaptic levels of dopamine. This interaction frequently occurs in the setting of comorbid attention deficit hyperactivity disorder (ADHD, for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics.

Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.

Pharmacology

Pharmacodynamics

Aripiprazole's mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). It shows differential engagement at the dopamine receptor (D₂) and acts as a partial agonist of this receptor. It is also a partial agonist of the serotonin 5-HT_1A receptor. In addition, it is a weak partial agonist of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors.

It appears to show predominantly partial agonistic activity on postsynaptic dopamine D₂ receptors and partial agonist activity on presynaptic dopamine D₂ receptors, D₃, and partially D₄ and is a partial activator of serotonin (5-HT_1A, 5-HT_2A, 5-HT_2B, 5-HT₆, and 5-HT₇). It also shows lower effect on histamine (H₁), as well as the serotonin transporter. Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.

As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D₂ partial agonist (with an intrinsic activity of ~50%) as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown, in vitro, to bind to and/or induce receptor conformations (i.e., facilitate receptor shapes) in such a way as to not only prevent receptor internalization (and, thus, lower receptor density) but even to lower the rate of receptor internalization below that of neurons not in the presence of agonists (including dopamine) or antagonists.

It is often the nature of partial agonists, including aripiprazole, to display a stabilizing effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole's partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D₂ receptor occupancy (approximately 31%, 44%, 75%, 80%, and 95% at daily dosages of 0.5 mg, 2 mg, 10 mg, 30 mg and 40 mg respectively)

Aripiprazole has been characterized as possessing predominantly partial agonist activity on postsynaptic D₂ receptors and partial agonist activity on presynaptic D₂ receptors; however, while this explanation intuitively explains the drug's efficacy as an antipsychotic, as the degree of agonism is a function of more than a drug's inherent properties as well as in vitro demonstration of aripiprazole's partial agonism in cells expressing postsynaptic (D_2L) receptors, it was noted that "It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D₂ receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5–1 pmol/mg).

Instead, the current data are most parsimoniously explained by the "functional selectivity" hypothesis of Lawler et al. (1999)". Aripiprazole is also a partial agonist of the D₃ receptor. In healthy human volunteers, D₂ and D₃ receptor occupancy levels are high, with average levels ranging between approximately 75% at 2 mg/day to approximately 95% 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.

Aripiprazole is also a partial agonist of the postsynaptic serotonin 5-HT_1A receptor (intrinsic activity = 68%). a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found 5-HT_1A receptor occupancy to be only 16% compared to ~90% for D₂. It is a very weak partial agonist of the Postsynaptic 5-HT_2A receptor (intrinsic activity = 12.7%). The drug differs from other atypical antipsychotics in having higher affinity for the D₂ receptor than for the 5-HT_2A receptor. At the 5-HT_2B receptor, aripiprazole has both great binding affinity and acts as a potent inverse agonist, "Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC₅₀ of 11 nM".

Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the postsynaptic 5-HT_2C receptor (intrinsic activity = 82%) this property may underlie the minimal weight gain seen in the course of therapy, however if used while taking antidepressants it will become a functional antagonist and increase weight gain. At the presynaptic 5-HT₇ receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor. Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites such as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors

Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g., at 5-HT₆), sometimes an inverse agonist (e.g., 5-HT_2B), sometimes a partial agonist (e.g., D_2S, D_3S, D_4S, D_2L). Aripiprazole was frequently found to be a partial agonist or full agonist, with an intrinsic activity that could be low (5-HT_2A, 5-HT₇), intermediate (D_2L, 5-HT_1A), or high (5-HT_2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has "functionally selective" actions.

The "functional-selectivity" hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially "sensed" by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D₂-dopamine receptors are clearly cell-type specific (e.g., agonism, antagonism, partial agonism), and are most parsimoniously explained by the "functional selectivity" hypothesis.

Since 5-HT_2C receptors have been implicated in the control of depression, obsessive–compulsive disorder (OCD), and appetite, postsynaptic partial agonism at the 5-HT_2C receptor might be associated with therapeutic potential in obsessive–compulsive disorder, obesity, and depression. 5-HT_2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of postsynaptic 5-HT_2C receptors; it is conceivable that the 5-HT_2C partial agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials.

In terms of potential action as an antiobsessional agent, it is worthwhile noting that a variety of 5-HT_2A/5-HT_2C agonists have shown promise as antiobsessional agents, yet many of these compounds are hallucinogenic. Aripiprazole has a favorable pharmacological profile in being a 5-HT_2C partial agonist. Based on this profile, one can predict that aripiprazole may have antiobsessional and anorectic actions in humans.

Wood and Reavill's (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D₂ receptor without significantly affecting the majority of serotonin receptors. A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D₂ receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT_2A receptor and only 16% occupancy of the 5-HT_1A receptor. It has been suggested that the low occupancy of the 5-HT_1A receptor by aripiprazole may have been an erroneous measurement however.

Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms. Due to its partial agonist activity on D_2L receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduced.

It has also been identified as a potent vesicular monoamine transporter 2 (VMAT2) inhibitor, lessening the degree of tardive dyskinesia, in contrast to other antipsychotic therapy associated with this side effect. (IC₅₀Tooltip half-maximal inhibitory concentration = 36 nM).

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.

Chemistry

Aripiprazole belongs to the chemical class of drugs called 2,3-dichlorophenylpiperazines and is chemically related to cariprazine, nefazodone, etoperidone, and trazodone. It is unusual in having twelve known crystalline polymorphs. Analogues of aripiprazole with higher-efficacy serotonin 5-HT_2A receptor partial agonism and with psychedelic- and antidepressant-like effects have been developed.

Synthesis

Multiple syntheses of aripiprazole have been reported. A procedure using ethanol as the solvent is shown below. Tetrahydroquinoline derivative 2 undergoes an S_N2 reaction with dihalide 1 to give ether 3. This undergoes a further S_N2 reaction with piperazine derivative 4 giving ariprazole.

History

Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical and was called OPC-14597. It was first published in 1995. Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.

It was approved by the US Food and Drug Administration (FDA) for schizophrenia in November 2002, and by the European Medicines Agency in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 1 October 2004; as an adjunct for major depressive disorder on 20 November 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 Therapeutic Goods Administration (TGA) of Australia in May 2003.

Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.

In 2006, the FDA required manufacturers to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS's off-label marketing of aripiprazole for children and older people with dementia.

In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of aripiprazole.

As of 2013, Abilify had annual sales of US$7 billion. In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug. Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.

Otsuka's US patent on aripiprazole expired on 20 October 2014, but due to a pediatric extension, a generic did not become available until 20 April 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. On 15 November 2010, this challenge was rejected by the U.S. District Court in New Jersey.

Otsuka's European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014., The UK Intellectual Property Office decided on 4 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015.

From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.

In April 2015, the FDA announced the first generic versions. In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.

In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.

In November 2017, the FDA approved Abilify Mycite, a digital pill containing a sensor intended to record when its consumer takes their medication.

A long-acting injectable version of aripiprazole was approved by the FDA for the treatment of bipolar disorder 1 and schizophrenia in April 2023.

In 2024, the European Commission approved the 2 month long-acting injectable formulation of aripiprazole for the maintenance treatment of schizophrenia. This came after the 1 month long-acting injectable formulation lost drug exclusivity status in the US and Europe (the market is now open to generics).

Society and culture

Legal status

Classification

Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like haloperidol and second-generation (atypical) antipsychotics like clozapine. It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists. The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.

Brand names

Brand names of aripiprazole include Abilify, Aristada (as aripiprazole lauroxil), Arip MT, Explemed, Abilify Maintena, Abilify Asimtufii, Arivitae, Abilify MyCite, Opipza, and Mezofy, among others.

Involuntary administration

In 2024, Capital Daily and the Investigative Journalism Foundation published an investigation into Kirsten "Kir" Anvik, a 54-year-old single mother in Victoria, British Columbia, who had been involuntarily detained under British Columbia's Mental Health Act since 2016 and forced to receive monthly depot injections of aripiprazole (as Abilify Maintena). Anvik reported debilitating side effects including nerve pain, muscle stiffness, and loss of balance, as well as a compulsive spending episode she attributed to the drug. Under British Columbia's "deemed consent" model — unique among Canadian provinces — involuntarily certified patients are not required to give consent to psychiatric treatment, and physicians are not required to consult a substitute decision-maker. The article noted that at least 1,684 suspected serious adverse reactions to Abilify and Abilify Maintena had been reported to Health Canada since 2014. The constitutional validity of British Columbia's deemed consent provisions was the subject of an ongoing challenge before the British Columbia Supreme Court under the Canadian Charter of Rights and Freedoms.

Research

Attention deficit hyperactivity disorder

Aripiprazole was under development for the treatment of attention-deficit hyperactivity disorder (ADHD), but development for this indication was discontinued. A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD. A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition. Although all six non-controlled open-label studies in the review reported effectiveness, two small randomized controlled trials found that aripiprazole did not significantly decrease ADHD symptoms. A high rate of adverse effects with aripiprazole such as weight gain, sedation, and headache was noted. Most research on aripiprazole for ADHD is in children and adolescents. Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single case report.

Substance dependence

Aripiprazole has been studied for the treatment of amphetamine dependence and other substance use disorders, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed. Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole. As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.