Continuing Education Activity

Aripiprazole is a medication used to manage and treat schizophrenia, mania associated with bipolar I disorder, irritability associated with an autism spectrum disorder, disjunctive therapy in major depressive disorder, and Tourette syndrome. It is a second-generation antipsychotic medication. This activity reviews the indications, action, and contraindications for aripiprazole as a valuable agent in managing the conditions, as mentioned above. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for the interprofessional team healthcare team members in the care of patients.

Objectives:

• Identify FDA-approved and off-label indications for aripiprazole.

• Explain the mechanism of action of aripiprazole.

• Summarize the most common adverse effects associated with aripiprazole.

• Review the importance of communication and coordination amongst the interprofessional team to ensure appropriate monitoring of potential medication side effects in patients taking aripiprazole.

Indications

Aripiprazole is an atypical antipsychotic that is FDA approved and predominantly used for symptomatic management of psychosis in patients with schizophrenia and monotherapy or adjunctive therapy for acute manic episodes associated with bipolar disorder. The oral tablet and solution are also FDA approved to treat autistic spectrum disorder (ASD). Studies show that short-term use of aripiprazole in patients with ASD resulted in decreased irritability, decreased hyperactivity, and fewer repetitive, purposeless actions (stereotyped behaviors). Aripiprazole can also serve as an adjunctive treatment for major depressive disorder and Tourette syndrome (oral tablet or oral solution only).[1]

There is a long-acting aripiprazole formulation, which is used primarily for maintenance therapy for chronic schizophrenia as well as both acute and maintenance therapy of bipolar I disorder in patients who may lack oral tolerance or medication adherence.[2] 

Off-label uses of aripiprazole include an adjunctive treatment for patients with comorbid psychotic disorders and substance use disorders. It may also have a role in treating psychosis and agitation associated with dementia; however, aripiprazole may increase the risk of cerebrovascular stroke and cognitive decline in this patient population. Aripiprazole may additionally be used to treat delirium and apraxia of eyelid opening with blepharospasm in Parkinson disease.[3][4][5][6]

Aripiprazole is increasingly replacing first-generation antipsychotics due to its improved side effect profile. The regulation of dopamine neurotransmission in aripiprazole has resulted in decreased motor and metabolic side effects as compared to other typical and atypical antipsychotic medications, thus making aripiprazole a valid alternative for patients struggling with persistent side effects or low efficacy of their current drug. Aripiprazole has been shown to decrease psychiatric hospitalization rates, reduce symptoms of tardive dyskinesia, improve cognitive function, and reduce cardiovascular risk factors, lipid plasma concentrations, and prolactin. It has also restored sexual function and decreased alcohol craving in patients with dependence.[7]

Mechanism of Action

Aripiprazole is a quinolinone antipsychotic that is a partial agonist at the D2 and 5HT-1a receptors and an antagonist at the 5HT-2a receptor. It has a high affinity for D2, D3, 5HT-1a, and 5HT2a receptors and moderate affinity for D4, 5HT-2c, 5-HT7, alpha-1 adrenergic, and H1 receptors. Aripiprazole has no affinity for muscarinic receptors at recommended doses. It stabilizes dopamine and serotonin within the nucleus accumbens, ventral tegmental area, and frontal cortex resulting in the management of positive, negative, and cognitive symptoms in schizophrenia. Aripiprazole demonstrates functional selectivity in intracellular signaling pathways by requiring a greater than 90% occupancy rate at D2 receptors to be clinically active, thus not producing as many extrapyramidal symptoms.[8]

Aripiprazole will act as a functional antagonist in areas of high dopamine, such as the mesolimbic pathway, while remaining inactive in areas with normal dopamine, such as the nigrostriatal and tuberoinfundibular pathways. The partial agonism of aripiprazole at D2 receptors may be responsible for the effective management of positive, negative, and cognitive symptoms of schizophrenia. Research has shown that it has more selective effects on the mesolimbic dopaminergic pathway than haloperidol and olanzapine. Due to its partial agonist nature, using aripiprazole with concurrent antipsychotics (another D2 antagonist) may cause an exacerbation of positive symptoms.[9][8][7][10][11]

Administration

Aripiprazole may be administered with or without food and is available in oral tablets, disintegrating tablets (10 mg and 15 mg), oral solution, and intramuscular (IM) injections for acute symptoms and long-acting IM injections. However, the immediate-release injection (9.75 mg/1.3 mL) was discontinued in the United States. Oral dosing ranges from 5 mg to 30 mg/day and is available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets. Both oral and IM routes of administration have similar steady-state serum concentrations and symptom management. The half-life of oral administration is approximately 75 hours. Steady serum concentration doses (based on 15 to 30 mg per day) should occur at approximately 14 days, and therefore it may take up to two weeks to fully assess tolerability. Reaching maximum plasma concentration in patients using depot injections will take place after 5 to 7 days. The long-acting injectable formulation is available in 300 mg or 400 mg prefilled syringes and is administered monthly in patients with the potential for poor medication adherence. The clinician must establish the patient's oral tolerability for aripiprazole before beginning IM medication. It is also important to continue oral aripiprazole for 14 days during the initiation of long-acting IM therapy.[7]

Aripiprazole lauroxil is the prodrug of aripiprazole and is available as a long-acting intramuscular injection (1064 mg, 441 mg, 662 mg, or 882 mg) that can be administered every 4 to 6 weeks and requires a three-week oral medication overlap.

For bipolar I monotherapy, the recommended initial dose of aripiprazole is 15 mg daily, increasing to 30 mg daily as needed. When used as an adjunctive treatment in bipolar I, the recommended target is 15 mg daily. For adjunctive therapy with antidepressants, the initial oral dose is 2 to 5 mg daily, titrating dose up to 5 mg daily in intervals of one week, with a maximum dose of 15 mg/day. The initial dose for treatment of schizophrenia is 10 to 15 mg daily, increasing to a maximum of 30 mg daily. It is important not to titrate the dose more than every two weeks. No dosage readjustment is necessary for renal or hepatic impairment. However, prescribing if aripiprazole with an inducer of CYP3A4 enzyme such as carbamazepine, a higher dose may be required.[12]

Adverse Effects

Although the side effects of aripiprazole are similar to those found in typical and atypical antipsychotics, the degree of extrapyramidal symptoms (EPS) and metabolic syndromes are less due to receptor specificity. EPS such as akathisia, parkinsonian features such as resting tremor and shuffling gait, acute dystonic reactions, oculogyric crises, opisthotonos, and tardive dyskinesia are manageable with benztropine or sodium benzoate. Aripiprazole is associated with lower incidences of weight gain, hypercholesterolemia, glucose dysregulation, cardiovascular abnormalities, and hyperprolactinemia. Hyperprolactinemia may manifest as galactorrhea, gynecomastia in men, sexual dysfunction, amenorrhea, or off-cycle bleeding. Other possible side effects of aripiprazole include somnolence, nausea, vomiting, akathisia, and lightheadedness. Antipsychotics agent use requires caution in older adults because it can cause or exacerbate the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; thus, it is crucial to monitor sodium during initiation and dosage adjustment. Children and adolescents are more susceptible than older patients to experience EPS, weight gain, and other metabolic side effects. The FDA also recently identified an association between aripiprazole use and compulsive or uncontrollable urges to engage in sex, gamble, binge eat, and shopping.[5]

Rare adverse effects may include neuroleptic malignant syndrome, liver function abnormalities and jaundice, seizures, and agranulocytosis. As with other antipsychotics, aripiprazole carries an FDA boxed warning for increased risk of cerebrovascular events and death in elderly patients with psychosis related to the major neurocognitive disorder and suicidal thoughts among children, adolescents, and young adults.[5][13]

Contraindications

Aripiprazole is contraindicated in patients with documented hypersensitivity to it or any component of the dosage form.

Monitoring

Patients require close monitoring for any side effects. It is essential to establish baseline measurements of blood pressure (repeat in three months and annually), weight (remeasure at weeks 4, 8, and 12), height, BMI, waist circumference, electrolytes, liver function, fasting plasma glucose concentration (repeat in three months and annually), lipid panel, abnormal involuntary movement scale (repeat weekly for two weeks after initiation or dose increase), and ocular exam findings. Consider switching antipsychotic medications if weight gain is greater than or equal to five percent of the patient's initial body weight. Monitor the patient's CBC frequently during the first few months in patients with preexisting leukopenia or neutropenia. Closely monitor serum sodium with initiation or dosage adjustment in older adults. As clinically indicated, monitor electrolytes, liver function, changes in menstruation, libido, or other manifestations of hyperprolactinemia.

Aripiprazole metabolism is via hepatic dehydrogenation, hydroxylation, and N-dealkylation via CYP2D6 and CYP3A4. For example, carbamazepine, a CYP3A4 inducer, may cause decreased blood concentrations due to increased aripiprazole clearance. CYP3A4 inhibitors such as ketoconazole, or CYP2D6 inhibitors such as fluoxetine, paroxetine, quinidine, may inhibit aripiprazole elimination and cause increased blood concentrations. The target plasma range is between 150 to 210 nanograms per milliliter.[14]

Toxicity

According to FDA reports, there have been 76 cases of aripiprazole overdose. These include instances of both deliberate and accidental overdose in combination with other substances. There is currently no known antidote for aripiprazole overdose. However, early charcoal administration partially prevents the absorption of the drug if it is ingested orally, e.g., tablet. Management of aripiprazole overdose should focus on supportive therapy. The clinician should obtain an EKG to identify any cardiac arrhythmias, such as QTc prolongation.[15]

Enhancing Healthcare Team Outcomes

Aripiprazole is usually prescribed by a psychiatrist, nurse practitioner, or primary care provider. Due to the array of possible side effects, it is essential to establish baseline measurements, including EKG, blood pressure, CMP, CBC, liver transaminase levels, BUN, and creatinine. Although extrapyramidal symptoms are less common in aripiprazole than in haloperidol, screening for and monitoring any developing EPS using AIMS (Abnormal Involuntary Movement Scale) is crucial. Interprofessional communication is essential in managing a patient on aripiprazole due to potential drug interactions and potentially fatal side effects such as QTc abnormalities, arrhythmias, agranulocytosis, and metabolic changes. Switching from one antipsychotic to another should be done gradually. For example, in the UK, aripiprazole would be started at a minimal clinically efficacious dose and titrated up as needed after two weeks, leaving the previous antipsychotic dose unchanged. Rapid or sudden withdrawal of prior medication may result in a decompensated presentation.[16]

The pharmacist and nurse should encourage the patient to eat a healthy diet and exercise regularly since the drug is known to cause weight gain. Pharmacists must also verify dosing is appropriate and check for drug interactions that may lead to concerns with dosing or adverse effects. Nursing should assist in follow-up monitoring, including assessing therapeutic effectiveness and noting potential signs of adverse effects. For example, regular monitoring of blood sugar and lipids concentrations is necessary as some patients may develop metabolic syndrome. Finally, to relieve the symptoms of schizophrenia, patients must be educated on the importance of adherence, which nursing can also counsel and evaluate. If the patient has a mental health provider involved in their case, then they should also have open communication with the healthcare team, so they can alert the prescriber to any concerns they may have for the patient's regimen. Aripiprazole requires an interprofessional team effort to be effective and minimize potential adverse effects, leading to better patient outcomes. [Level 5]