# What are the adverse effects of Abilify Maintena in adult patients with schizophrenia over a 12-month treatment period?

## The primary adverse effects of 12-month Abilify Maintena treatment included mild-to-moderate symptoms (insomnia, headache, anxiety), weight gain in up to 25.7% of patients, neurological effects in 7.2-14.3%, and serious adverse events in 14.6% of cases.

# Abstract

This systematic review examined the adverse effects of Abilify Maintena (aripiprazole once-monthly) in adult patients with schizophrenia over a 12-month treatment period. The review included 40 studies of various designs, including randomized controlled trials, observational studies, and systematic reviews, with sample sizes ranging from 15 to over 3,000 participants and study durations from 12 weeks to 6 years.

The most commonly reported adverse events were insomnia, headache, anxiety, akathisia, weight changes, and injection site pain. The frequency of these events varied across studies, with most being reported as mild to moderate in severity. Serious adverse events were relatively rare, with one study reporting serious adverse drug reactions in 14.6% of patients.

Metabolic effects, particularly weight changes and alterations in lipid profiles, were observed but generally less pronounced compared to some other antipsychotics. Clinically significant weight gain (≥7% increase) was reported in 11.2% to 25.7% of patients across different studies. Neurological effects, including akathisia and extrapyramidal symptoms, were reported at rates ranging from 7.2% to 14.3%.

Treatment discontinuation rates varied across studies, ranging from 14.28% to 41%, but were generally lower than those reported for oral antipsychotics. Common reasons for discontinuation included lack of efficacy, patient/caregiver choice, and adverse events. Notably, several studies reported good long-term persistence with Abilify Maintena, with one study finding that 69.6% of patients continued treatment over a four-year follow-up period.

Overall, the evidence suggests that Abilify Maintena has a generally favorable safety and tolerability profile in adult patients with schizophrenia over a 12-month treatment period. However, clinicians should monitor patients for a range of potential side effects, particularly weight changes, metabolic parameters, and neurological effects. The variability in study designs, populations, and reporting methods highlights the need for further long-term, head-to-head comparisons with other antipsychotics to fully elucidate the safety profile of Abilify Maintena.

# Results

## Characteristics of Included Studies

| Study | Full text retrieved | Study Design | Population Size | Duration | Primary Outcomes | Study Quality/Risk of Bias |
| -------- | ------------------- | --------------- | ------------------- | ----------- | ------------------ | ----------------------------- |
| “Efficacy and Tolerability of AOM,” [Missing] | No | Systematic review and meta-analysis of randomized controlled trials | 1,860 | Not specified in abstract | Efficacy and tolerability of aripiprazole once-monthly | Low risk of bias (systematic review methodology) |
| Chue and Chue, 2016 | No | Review of randomized controlled trials and observational studies | Not mentioned | 52 weeks, 38 weeks, and 6 months | Not mentioned | Not assessable (review article) |
| Dawood et al., 2020 | Yes | Non-interventional, retrospective observational study | 57 | Not uniformly specified | Effectiveness and safety of Aripiprazole Lauroxil | Moderate risk of bias (observational design) |
| De Hert et al., 2015 | No | Randomized, double-blind, active-controlled, noninferiority study | 662 | 38 weeks | Relapse rates | Low risk of bias (randomized, double-blind design) |
| Di Lorenzo et al., 2019 | No | Retrospective observational study | 217 | 6 and 12 months | Clinical and functioning improvement, urgent consultations, psychiatric hospitalizations, adverse effects, and dropout | Moderate risk of bias (observational design) |
| Fagiolini et al., 2021 | Yes | Observational, multicenter, retrospective, non-interventional follow-up study | 161 | Mean follow-up period of 48 months | Treatment persistence | Moderate risk of bias (observational design) |
| Fagiolini et al., 2022 | Yes | Multicenter, retrospective, non-interventional observational study | 161 | Mean follow-up period of 48 months | Long-term persistence with aripiprazole once-monthly treatment | Moderate risk of bias (observational design) |
| Fernández-Miranda et al., 2020 | No | Observational, mirror-image study | 150 | 72 months | Effectiveness and tolerability of high doses of second-generation long-acting injectable antipsychotics | Moderate risk of bias (observational design) |
| Fernández-Miranda et al., 2021 | No | Observational mirror-image study with prospective follow-up | 60 | Six-year mirror-image study with 36-month prospective follow-up | Effectiveness and tolerability of aripiprazole once-monthly | Moderate risk of bias (observational design) |
| Fleischhacker et al., 2013 | No | Multi-phase study including randomized, double-blind, placebo-controlled trial | 633 | 52 weeks | Safety and tolerability of aripiprazole once-monthly | Low risk of bias (randomized, double-blind design) |

## Safety and Adverse Effects

### Treatment-Emergent Adverse Events

| Study | Common Adverse Events | Frequency | Severity | Time of Onset |
| -------- | ---------------------- | ----------- | -------- | ---------------- |
| “Efficacy and Tolerability of AOM,” [Missing] | Weight gain | Not specified in abstract | Not specified in abstract | Not specified in abstract |
| Chue and Chue, 2016 | Not mentioned | Not mentioned | Not mentioned | Not mentioned |
| Dawood et al., 2020 | Sexual disinhibition, aggression, deliberate self-harm, impulsive behavior, Parkinsonism, tardive dyskinesia, gambling | Sexual disinhibition (3.5%), aggression (7%), impulsive behavior (<10%), Parkinsonism (10.5%), tardive dyskinesia (1.8%), gambling (1.8%) | Generally not severe | Not specified |
| De Hert et al., 2015 | Insomnia, headache, injection site pain, akathisia, upper respiratory tract infection, weight increase, weight decrease | Varied by obesity status, ranging from 4.7% to 12.6% | Not mentioned | Not specified in abstract |
| Di Lorenzo et al., 2019 | Not mentioned | Not mentioned | Not mentioned | Not mentioned |
| Fagiolini et al., 2021 | Tolerability issues | 6.1% discontinued due to tolerability issues | Not specified | Not specified |
| Fagiolini et al., 2022 | Tolerability issues | 6.1% discontinued due to tolerability issues | Not detailed | Not specified |
| Fernández-Miranda et al., 2020 | Changes in weight and prolactin levels | Not specified in detail | Generally reduced compared to previous treatments | Not specified in abstract |
| Fernández-Miranda et al., 2021 | Not specified in abstract | Not specified in abstract | Three discharges due to adverse effects | Not specified in abstract |
| Fleischhacker et al., 2013 | Insomnia, headache, anxiety, akathisia, increase in weight, injection-site pain, tremor | >5% for each listed adverse effect | Not mentioned | Not specified in abstract |

### Serious Adverse Events

While most studies reported that the majority of adverse events were mild to moderate, some did report on serious adverse events (SAEs). Key findings include:

1. Frequency of Serious Adverse Events:
   - Mustafa et al. (2019) reported serious adverse drug reactions (ADRs) in 14.6% of patients.
   - Peters-Strickland et al. (2015) reported serious treatment-emergent adverse events (TEAEs) in 8.8% of patients.
   - Kane et al. (2013) reported that 19.9% of patients experienced serious TEAEs.
2. Nature of Serious Adverse Events:
   - Peters-Strickland et al. (2015) reported that the most common serious TEAEs were psychotic disorder (1.4%) and schizophrenia (1.9%).
   - Other studies did not provide specific details on the nature of serious adverse events.
3. Discontinuation Due to Adverse Events:
   - Naber et al. (2015) reported that 11.1% of patients discontinued due to adverse events.
   - Fagiolini et al. (2021, 2022) reported that 6.1% discontinued due to tolerability issues.
4. Mortality:
   - No studies reported deaths attributable to aripiprazole once-monthly treatment.
5. Psychiatric Symptoms:
   - Some studies reported exacerbation of psychotic symptoms or new-onset psychiatric symptoms as serious adverse events.

### Metabolic Effects

Metabolic effects, particularly weight changes and alterations in lipid profiles, were reported in several studies:

1. Weight Changes:
   - De Hert et al. (2015) reported weight increase as a common adverse event, but also noted weight decrease in some patients.
   - Majer et al. (2015) reported clinically relevant weight gain (≥7% increase) in 11.2% of patients treated with aripiprazole once-monthly.
   - Mustafa et al. (2019) found significant weight gain (≥7%) in 25.7% of patients.
   - Peters-Strickland et al. (2015) reported weight gain ≥7% in 12.5% of patients and weight loss ≥7% in 7.6% of patients.
2. Lipid Profile Changes:
   - Juncal Ruiz et al. (2017) reported increases in LDL-cholesterol in 16.7% of patients, decreases in HDL-cholesterol in 23.3%, and increases in triglycerides in 66.7%.
3. Glucose Metabolism:
   - While several studies mentioned monitoring glucose levels, specific data on changes in glucose metabolism were not prominently reported in the abstracts.
4. Prolactin Levels:
   - Fernández-Miranda et al. (2020) reported a statistically significant reduction in prolactin levels with aripiprazole once-monthly.
   - Hodgson (2019) noted elevated prolactin levels with paliperidone palmitate, but not with aripiprazole once-monthly.

### Neurological Effects

Neurological effects, particularly extrapyramidal symptoms (EPS) and akathisia, were reported in several studies:

1. Akathisia:
   - Kane et al. (2013) reported akathisia in 7.2% of patients.
   - Mustafa et al. (2019) found akathisia in 9.1% of patients.
   - Fleischhacker et al. (2013) listed akathisia as one of the common adverse events occurring in >5% of patients.
   - Preda and Shapiro (2020) reported akathisia occurring in 10-11% or less of patients.
2. Extrapyramidal Symptoms (EPS):
   - Majer et al. (2015) reported EPS in 14.3% of patients treated with aripiprazole once-monthly.
   - Gentile (2018) mentioned EPS as one of the safety concerns associated with second-generation long-acting injectable antipsychotics.
3. Tremor:
   - Kane et al. (2012) and Wang et al. (2014) listed tremor as one of the common adverse events.
   - Preda and Shapiro (2020) reported tremor occurring in 10-11% or less of patients.
4. Parkinsonism:
   - Dawood et al. (2020) reported Parkinsonism in 10.5% of patients.
5. Tardive Dyskinesia:
   - Dawood et al. (2020) reported tardive dyskinesia in 1.8% of patients.

## Treatment Discontinuation Patterns

| Study | Discontinuation Reason | Frequency | Timing | Patient Characteristics |
| -------- | ----------------------- | ----------- | ---------- | --------------------- |
| Dawood et al., 2020 | Ineffectiveness, side effects, patient request | 25% of patients | By study end | Not specified |
| Di Lorenzo et al., 2019 | Not mentioned | 14.28% | Not specified in abstract | Not mentioned |
| Fagiolini et al., 2021 | Lack of efficacy, patient/caregiver choice, physician’s choice, non-adherence, inconvenience, tolerability issues | 30.4% overall | Mean 32.23 months for non-persistent individuals | Not specified |
| Fagiolini et al., 2022 | Lack of efficacy (30.6%), patient/caregiver choice (18.4%), physician’s choice (16.3%), non-adherence (12.2%), inconvenience (6.1%), tolerability issues (6.1%) | 30.4% overall | Mean 32.23 months for non-persistent individuals | Not specified |
| Fernández-Miranda et al., 2020 | Side effects, lack of effectiveness | Not specified in abstract | Not specified in abstract | Not specified |
| Fernández-Miranda et al., 2021 | Adverse effects | Three discharges | Not specified in abstract | Not specified |
| Greene et al., 2018 | All-cause discontinuation | Not mentioned | Not mentioned | Not mentioned |
| Ishigooka et al., 2015 | All-cause discontinuation | 25.9% for aripiprazole once-monthly, 33.5% for oral aripiprazole | Not specified in abstract | Not mentioned |
| Kane et al., 2013 | Not mentioned | Not mentioned | Not mentioned | Not mentioned |
| Majer et al., 2015 | Adverse events, reasons other than adverse events | Not specified | Not specified | Not mentioned |

#### Key Observations:
- Discontinuation rates for aripiprazole once-monthly are notable but generally lower than those reported for oral antipsychotics.
- The reasons for discontinuation are diverse, with lack of efficacy and adverse events being prominent factors alongside patient/caregiver choice.
- The relatively long mean time to discontinuation in some studies suggests that many patients who do discontinue may do so after an extended period of treatment.
- There is limited information on patient characteristics associated with discontinuation, highlighting an area for future research.
- Adverse event-related discontinuations appear to be relatively low, suggesting that most side effects are manageable.
- Long-term persistence data from some studies indicate that a substantial proportion of patients can maintain treatment over extended periods.

## References
- W. Fleischhacker, R. Sanchez, Brian Johnson, N. Jin, Robert A. Forbes, and 4 more. (2013). Long-term safety and tolerability of aripiprazole once-monthly in maintenance treatment of patients with schizophrenia. International Clinical Psychopharmacology
- T. Peters-Strickland, R. Baker, R. Mcquade, N. Jin, A. Eramo, and 4 more. (2015). Aripiprazole once-monthly 400 mg for long-term maintenance treatment of schizophrenia: a 52-week open-label study. npj Schizophrenia
- S. Mustafa, J. Bougie, M. Miguelez, G. Clerzius, E. Rampakakis, and 2 more. (2019). Real-life assessment of aripiprazole monthly (Abilify Maintena) in schizophrenia: a Canadian naturalistic non-interventional prospective cohort study. BMC Psychiatry
- J. Madera, P. Such, Cathy Zhao, R. Baker. (2019). Symptomatic stability with aripiprazole once-monthly: efficacy analyses from acute and long-term studies. Neuropsychiatric Disease and Treatment
- J. Kane, R. Sanchez, R. Baker, A. Eramo, T. Peters-Strickland, and 6 more. (2015). Patient-Centered Outcomes with Aripiprazole Once-Monthly for Maintenance Treatment in Patients with Schizophrenia: Results From Two Multicenter, Randomized, Double-Blind Studies. Clinical Schizophrenia and Related Psychoses.