In February 2013, the FDA approved a long-acting IM aripiprazole formulation for treating adult schizophrenia (Table 1).1 It is the fourth second-generation antipsychotic (SGA) depot formulation approved for treating schizophrenia, and the sixth depot antipsychotic if haloperidol and fluphenazine decanoate are considered.
Table 1
Depot aripiprazole: Fast facts
| Brand name: Abilify Maintena |
| Class: Atypical antipsychotic |
| Indication: Adult schizophrenia |
| Approval date: February 28, 2013 |
| Availability date: March 18, 2013 |
| Manufacturer: Otsuka Pharmaceutical and Lundbeck |
| Dosing form: IM long-acting injection |
| Recommended dosage: 400 mg IM once a month; 200 to 300 mg IM if drug-drug interactions, poor cytochrome P450 2D6 metabolism, or adverse effects |
| Source: Reference 1 |
Clinical implications
Depot medications can improve treatment adherence2; however, long-term antipsychotic use can lead to irreversible adverse effects (dyskinesias), which in some cases were reduced by using newer antipsychotics.3
How it works
Similar to other SGAs, aripiprazole’s mechanism of action is unknown. Aripiprazole was developed based on the dopamine theory, in which dopamine hyperactivity in mesolimbic pathways of the brain leads to hallucinations, delusions, disorganization, and catatonia, and dopamine hypoactivity in mesocortical pathways and the prefrontal cortex causes alogia, anhedonia, autism, avolition, and problems with attention and abstract thinking.
Aripiprazole’s proposed mechanism of action on dopamine receptors is that of partial agonism,1 rather than antagonism, as is the case for other SGAs. In theory, aripiprazole antagonizes postsynaptic D2 receptors and activates presynaptic D2 autoreceptors, with subsequently decreased dopamine production and further stabilization of the dopamine system.4 Its antagonism of 5-HT2A is similar to other SGAs.5
Pharmacokinetics
After depot aripiprazole is injected into the gluteal muscle, the active moiety slowly is released into circulation. The effectiveness of depot aripiprazole is attributable to its active parent drug, aripiprazole monohydrate, and its active metabolite, dehydro-aripiprazole, which is the same as oral aripiprazole. Depot aripiprazole reaches maximum concentration in 5 to 7 days. The elimination half-life of depot aripiprazole is 29.9 days for a 300-mg dose and 46.5 days for a 400-mg dose if administered monthly.1
Aripiprazole does not undergo direct glucuronidation. It is metabolized predominantly through cytochrome P450 (CYP) 2D6 and 3A4 enzymes, which predisposes it to significant drug-drug interactions and may require dose adjustment (Table 2).1
Table 2
Dose adjustments of depot aripiprazole
| Drug-drug interaction | Adjusted dose |
|---|---|
| CYP2D6 poor metabolizers | 300 mg |
| CYP2D6 poor metabolizers taking CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, grapefruit juice) | 200 mg |
| Lithium, valproate, desvenlafaxine, venlafaxine, escitalopram, dextromethorphan, omeprazole, warfarin | No significant interaction No dose adjustment |
| Sex, race, liver impairment, renal impairment, tobacco smokers | No dose adjustment |
| Patients taking 400 mg of depot aripiprazole with: | |
| 300 mg |
| 200 mg |
| Avoid use |
| Patients taking 300 mg of depot aripiprazole with: | |
| 200 mg |
| 160 mg |
| Avoid use |
| CYP: cytochrome P450 Source: Adapted from reference 1 | |
Efficacy
The ability of depot aripiprazole to sustain long-term symptom control in adult patients with schizophrenia was demonstrated in a randomized-withdrawal, double-blind, placebo-controlled trial.1 Adults included had a DSM-IV-TR diagnosis of schizophrenia, had ≥3-year history of the illness, had undergone treatment with ≥1 antipsychotic, and had a history of relapse or symptom exacerbation when not receiving antipsychotics. Psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity scale, the Clinical Global Impression-Improvement (CGI-I) scale, and the Clinical Global Impression-Severity of Suicide (CGI-SS) scale.1
The trial lasted 52 weeks, was divided into 4 phases, and concluded early because of demonstrated efficacy.
Phase I: Conversion phase switched patients from a different antipsychotic to oral aripiprazole. This phase lasted 4 to 6 weeks and included 633 patients. An additional 210 patients already receiving aripiprazole were entered directly into Phase II.
Phase II: Open-label, oral stabilization phase included 710 patients (60% males) age 18 to 60 who had a mean PANSS score 66. Patients received 10 to 20 mg/d of oral aripiprazole until they achieved stabilization, defined as PANSS score
Phase III: IM depot stabilization (uncontrolled single blind) included 576 patients. Patients were started on depot aripiprazole, 400 mg monthly, and continued to take 10 to 20 mg/d of oral aripiprazole for 14 consecutive days. Depot aripiprazole was decreased to 300 mg monthly if a patient developed adverse effects. Patients continued to the double-blind phase when stabilization was achieved, as evidenced by PANSS score
Phase IV: Maintenance (double-blind, randomized, placebo-controlled) included 403 patients. Two-thirds of patients continued to take the same dose of depot aripiprazole they took in Phase III. One-third of patients were switched to placebo. The primary efficacy endpoint was time to impending relapse, defined as the first occurrence of ≥1 criteria: hospitalization due to psychosis; violence toward self, others, or property; CGI-SS score ≥4 on part I or ≥7 on part II; or CGI-I score ≥5 and any individual PANSS score >4 for disorganization, hallucinations, suspiciousness, or abnormal thought content.1