Psychopharmacology and Clinical Application of Aripiprazole Long Acting Injections – Review of Abilify Maintena & Aristada

EVIDENCE FOR USE OF LONG ACTING INJECTABLES (LAIs)

1. When comparing the efficacy and safety of LAIs and second-generation oral antipsychotics, there was a significantly lower relapse rate, a longer time to relapse, and fewer hospital days favouring LAIs. However, there were no significant differences in hospitalization rate or non-adherence rates between the LAI and oral antipsychotic medication groups. [Park et al., 2018]
2. In a meta-analysis of prospective and retrospective studies, LAIs significantly reduced the rate of hospital re-admission and treatment discontinuation compared to oral antipsychotics. Interestingly, a subgroup analysis revealed that LAIs were significantly better at reducing hospital readmission rates when the publication year was ≥2010 and when the study had an academic sponsor. [Kishimoto et al., 2018]
3. A retrospective study of adherence to oral or LAIs in schizophrenia patients six months after hospital discharge showed that nonadherence was lower in the LAI cohort, and fewer patients were re-hospitalized (significant only for second-generation LAIs). [Marcus et al., 2015]
4. In another retrospective study of hospital re-admission rates, LAIs were significantly associated with a 16 % reduced risk of re-admission after 60 days compared to oral antipsychotic medications. [MacEwan et al., 2016]

PHARMACOLOGICAL PROFILE OF ARIPIPRAZOLE

The US FDA approved aripiprazole LAI in February 2013 for the treatment of schizophrenia. Aripiprazole LAI is more effective than placebo and non-inferior to oral aripiprazole in reducing relapse rates and lengthening the time delay between relapse events. [Shirley and Perry, 2014]

• Aripiprazole is a partial agonist characterized by its stabilizing effect on dopamine neurotransmission and is thus described as a dopamine-system stabilizer (DSS). [Kikuchi et al., 2021]
• A partial dopamine agonist can be considered to be a dopamine modulator adjusting dopamine levels depending on whether they are too high or low (the dimmer switch effect or Goldilocks effect)

• Aripiprazole has a high affinity for dopamine D₂ receptors with 90 to 94% receptor occupancy observed with a 30 mg/d dose. [Mamo et al., 2007]
• Aripiprazole also has a high affinity for serotonin 5-HT2A receptors and a moderate affinity for alpha-1 adrenergic and histamine H1 receptors.

The interaction between antipsychotic drugs and dopamine D₂ receptors is a critical feature that defines how antipsychotic drugs achieve their antipsychotic activity. [Kapur & Mamo, 2003] 

However, the mechanism by how a drug normalizes excessive dopaminergic activity in subcortical regions determines the distinction between first-generation, second-generation, and atypical antipsychotics such as aripiprazole.

• Treatment with aripiprazole reduces pathological activation of dopamine D₂ receptors whilst also preserving the physiological functionality of dopamine pathways.
• Partial agonism is an effective modality because aripiprazole substitutes endogenous dopamine, yet it only elicits partial receptor activity.
• In cases of over-stimulation, aripiprazole, therefore, reduces the functional response whilst still preserving a physiological response in dopamine-rich pathways. [Potkin et al., 2003]
• This effectively means that in most patients, aripiprazole does not induce extrapyramidal symptoms or elevate circulating levels of prolactin. [Shapiro et al., 2003]
• Aripiprazole, however, can be associated with akathisia due to its partial agonist activity.

Reduces positive symptoms:

• Aripiprazole has a lower intrinsic effect than dopamine, and therefore, partial agonism of D2 receptors in the mesolimbic pathway is postulated to reduce hyperfunctioning dopaminergic transmission.

Reduces negative symptoms:

• Aripiprazole’s partial agonism of D2 receptors in the mesocortical pathway increases dopaminergic activity back to normal levels.

Read more on a detailed review of the mechanism of action and clinical application of aripiprazole. 

PHARMACOKINETICS OF ARIPIPRAZOLE LAIs

The best correlate to gauge a drug’s antipsychotic action is its plasma level rather than dose – this is mainly due to patient-related variations in drug metabolism and medication adherence rates. For example, if a patient is to transition to LAI aripiprazole, then determining plasma levels of current oral aripiprazole will assist the clinician in determining whether a lack of response is due to insufficient dopamine D₂ antagonism or due to compliance issues.

The expected plasma levels of oral aripiprazole and its active metabolite dehydroaripiprazole in patients characterized as extensive metabolizers are as follows [Sparshatt et al, 2010]:  [Meyer et al, 2016]

• 10 mg/d – Mean plasma trough level of 126 (78) ng/mL aripiprazole and 35 (4) ng/mL dehydroaripiprazole
• 20 mg/d – Mean plasma trough level of 230 (193) ng/mL aripiprazole and 46 (37) ng/mL dehydroaripiprazole
• 30 mg/d – Mean plasma trough level of 400 (236) ng/mL aripiprazole and 83 (18) ng/mL dehydroaripiprazole

Improvement was best in patients with a serum level between 150 and 300 ng/ml.

If low plasma levels are detected, this could be due to the enhanced metabolism and elimination of aripiprazole.

Ultrarapid metabolites account for 5.5% of the Caucasian population (CYP 2D6 rapid metabolizers) and 29% of African ancestry, although genetic testing can identify CYP polymorphisms. [Ingelman-Sundberg, 2005] 

However, if subsequent plasma level concentrations differ by <30%, this is likely to represent nonadherence to therapy. [Velligan et al., 2007]

See later dose adjustments in patients who are CYP 2D6 inducers and inhibitors.

DOSING INFORMATION FOR ARIPIPRAZOLE LONG ACTING INJECTIONS (ABILIFY MAINTENA & ARISTADA)

As discussed, the decision to transition a patient to an LAI antipsychotic is generally based on whether the patient has poor oral adherence or insufficient dopamine receptor response. A potential third reason is that a monthly injection is simply more convenient than daily pill taking. There are two types of aripiprazole LAIs, and both cannot be loaded, meaning that oral coverage is necessary [Meyer, 2017]:

• Aripiprazole monohydrate crystals (Abilify Maintena) – A dose of 300 to 400 mg (every 4 weeks) will reach T_max in 4-7 days, and therefore there is a requirement for a 14-day oral aripiprazole overlap.
• Aripiprazole lauroxil suspension (Aristada) – A dose of 441 to 1064 mg (every 4 to 8 weeks) will reach T_max in 24.4 to 35.2 days, and therefore there is a requirement for a 21-day oral aripiprazole overlap.

It is then standard practice that once aripiprazole LAI has been established that plasma levels are monitored during the first year of treatment. This is because using the plasma level data from oral aripiprazole treatment will ensure that any further dosing adjustments are in line with plasma levels that were previously reported to be effective and well-tolerated.

Optimal strategies for dosing of Aripiprazole Monohydrate (Abilify Maintena)

• Begin with a 400 mg injection of aripiprazole monohydrate and adjust downward if the patient has side effects.
• After the first injection, plasma levels are expected to drop to 100 ng/mL before the second injection after 4 weeks. [Mallikaarjun et al., 2013]
• Subsequent 400 mg injection of aripiprazole monohydrate should eventually provide a steady-state exposure similar to 20 mg/d oral aripiprazole.
• However, if the patient is adherent and the mean trough plasma level is <230 ng/mL, this may suggest that 300 mg/month is an appropriate and sufficient dose to administer.

Optimal strategies for dosing of Aripiprazole Lauroxil (Aristada)

• Aripiprazole lauroxil has a longer half-life and T_max and can be initiated at a dose of 441 mg, 662 mg, or 882 mg/4 weeks, or it can be initiated at 882 mg/6 weeks or 1,064 mg/8 weeks.
• The 441 mg/month injection of aripiprazole lauroxil is modelled to achieve a mean plasma level similar to 10 mg/d oral aripiprazole.
• The 882 mg/month injection of aripiprazole lauroxil is modelled to achieve a similar mean plasma level as 20 mg/d oral aripiprazole.

Dosing Option 1:  Administer one injection of 675 mg of ARISTADA INITIO® and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection.

Dosing Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection

DOSE ADJUSTMENTS AND MISSED DOSE GUIDELINES

Aripiprazole Monohydrate (Abilify Maintena) Missed Doses: 

Aripiprazole Lauroxil (ARISTADA) Missed Doses : 

Aripiprazole Monohydrate (Abilify Maintena) Dose Adjustments with CYP Inhibitors and Inducers : 

Aripiprazole Lauroxil (ARISTADA) Dose Adjustments with CYP Inhibitors and Inducers : 

SAFETY PROFILE OF ARIPIPRAZOLE LAIs

Commonly adverse events that occur in response to antipsychotic treatments, in general, include motor side effects, hyperprolactinemia, weight gain, dyslipidaemia, type 2 diabetes, and cardiometabolic risks. [Young et al., 2015] 

However, aripiprazole has minimal propensity to induce extrapyramidal symptoms, cardiac effects, hyperprolactinaemia, weight gain, or other metabolic disturbances compared to other second-generation antipsychotics.

This is primarily due to its unique mechanism of action. Aripiprazole is associated with a lower incidence of extrapyramidal symptoms and akathisia than haloperidol [Kasper et al., 2003], [Kane et al., 2007] and a reduced risk of clinically significant weight-gain or metabolic syndrome compared to olanzapine. [Fleischhacker et al, 2009], [Kane et al, 2009]

Aripiprazole also has an overall more favourable cardiovascular tolerability profile compared to olanzapine. [Kane et al., 2009]

Read more on weight gain with antipsychotics. 

Prof David Castle’s video on weight gain in schizophrenia. 

SIDE EFFECTS OF ARIPIPRAZOLE LAIs

Side effects

In general, aripiprazole is well tolerated in patients diagnosed with relapsing or chronic schizophrenia. [Croxtall, 2012] 

Some of the commonly occurring adverse events to treatment include [Abilify Maintena prescribing information, 2016], [Aristada prescribing information, 2017] 

• Mild side effects – Headache, weight gain, drowsiness, agitation, insomnia, fatigue, anxiety, nausea, dizziness, and injection-site pain
• Moderate side effects – Hyperglycaemia, constipation, blurred vision, and sinus tachycardia
• Severe side effects – Bradycardia, seizures, rhabdomyolysis, myocardial infarction, and atrial fibrillation

 Special precautions

Elderly patients with dementia-related psychosis have increased mortality with antipsychotic drug medications, including aripiprazole.

• Furthermore, elderly patients with dementia are at risk of developing a cerebrovascular reaction to second-generation antipsychotics such as aripiprazole.
• Aripiprazole has been detected in human breast milk, and therefore breastfeeding is discouraged while the female patient is being administered aripiprazole.
• Extrapyramidal symptoms have also been observed in infants exposed to antipsychotic drugs during the third trimester of pregnancy.
• There is limited safety data in paediatrics and geriatric patients aged >65 years of age.

Drug Interactions

The coadministration of aripiprazole with CYP2D6 inhibitors (e.g. quinidine, paroxetine, and fluoxetine) or CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, or protease inhibitors) will increase aripiprazole plasma levels—dose adjustments are therefore necessary. For details, visit the PI for Abilify maintena and ARISTADA.

Read a summary on pharmacogenomics and CYP enzymes with tables of substrates, inducers and inhibitors for main CYP enzymes. 

• The coadministration of aripiprazole with CYP3A4 inducers (e.g. carbamazepine, rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John’s Wort) will reduce aripiprazole plasma levels—dose adjustments are therefore necessary.
• Dose adjustments may also be necessary for patients characterized as CYP2D6 poor metabolizers.
• Given the primary CNS effects of aripiprazole, caution should be used during coadministration with other depressants.

CLINICAL APPLICATIONS OF ARIPIPRAZOLE LAIs

First episode psychosis:

• Aripiprazole once-monthly injection was associated with a progressive improvement in positive and negative symptoms, general psychopathology, and a decrease in global severity compared to baseline.  [Giordano et al., 2020]

Schizophrenia and Bipolar Disorder (Relapse Prevention):

• Aripiprazole LAI may be efficacious in reducing relapse of schizophrenia and bipolar disorder in the long term in stabilized patients and in improving symptoms of schizophrenia during its acute phase, with both monohydrate and lauroxil formulations showing efficacy. [Rapinesi et al., 2019]
• A real-life longitudinal study of once-monthly Abilify maintena showed it effectively improved symptoms and functioning in schizophrenia patients treated in regular clinical settings. Akathisia was infrequent (9%), while one-quarter of patients gained clinically significant weight. [Mustafa et al., 2019]

SUMMARY

Aripiprazole is an approved acute and long-term strategy for the management of schizophrenia and is effective at reducing psychotic symptoms, improving a patient’s quality of life, as well as enhancing the recovery prospects of the patient by enhancing compliance and reducing rehospitalisation rates.

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