Long-Acting Injectable Antipsychotics: Available Options
Multiple LAI antipsychotic formulations are currently available, including both first-generation agents (haloperidol decanoate, fluphenazine decanoate) and second-generation agents (risperidone LAI, paliperidone palmitate, olanzapine pamoate, aripiprazole monohydrate, and aripiprazole lauroxil), with second-generation LAIs being preferred due to better tolerability and fewer neurological side effects. 1, 2, 3
First-Generation LAI Antipsychotics
The original depot formulations include:
- Haloperidol decanoate - administered intramuscularly, typically every 2-4 weeks 2
- Fluphenazine decanoate - administered intramuscularly, typically every 2-4 weeks 2
These first-generation LAIs have declined in use since the advent of second-generation depot agents, primarily due to higher rates of extrapyramidal side effects and tardive dyskinesia 2. First-generation LAIs are not recommended in early-course schizophrenia and are usually inappropriate for bipolar disorder. 4
Second-Generation LAI Antipsychotics
Risperidone LAI (Long-Acting Injectable)
- First atypical antipsychotic available as LAI formulation 2
- Prepared by encapsulating risperidone into biodegradable microspheres 2
- Administered every 2 weeks via intramuscular injection 5
- Requires oral supplementation during initiation (typically 3 weeks of oral antipsychotic coverage while therapeutic levels are achieved) 5
- Approved for schizophrenia and bipolar disorder maintenance 5
- No cases of post-injection delirium/sedation syndrome identified in clinical trials involving approximately 115,000 injections 6
Paliperidone Palmitate
Paliperidone palmitate offers the most flexible dosing schedule among LAI antipsychotics, with formulations available for monthly and 3-monthly administration. 3
- Aqueous suspension of nanocrystal molecules 2
- No oral supplementation required - unique loading dose strategy allows immediate therapeutic levels 7
- Initiation regimen: 150 mg equivalent on day 1, followed by 100 mg equivalent on day 8, both administered into deltoid muscle 7
- Maintenance dosing: 25-150 mg equivalent monthly (recommended 75 mg equivalent), can be administered deltoid or gluteal 7
- 3-monthly formulation available - first LAI to extend beyond monthly dosing 3
- Dosing flexibility: day 8 dose may be given ±2 days, monthly doses ±7 days without clinically significant impact 7
- Only one case of PDSS reported across 10 trials (33,906 injections), and that case occurred in a placebo-treated patient 6
Olanzapine Pamoate
- Microcrystalline salt suspended in aqueous solution 2
- Administered every 2-4 weeks depending on dose 3
- Important caveat: Associated with post-injection delirium/sedation syndrome risk, requiring 3-hour post-injection observation 3
Aripiprazole Formulations
Two distinct aripiprazole LAI formulations exist:
- Aripiprazole monohydrate - monthly administration 3
- Aripiprazole lauroxil - available in monthly, 6-week, and 8-week administration preparations 3
Both demonstrate comparable efficacy and safety to oral formulations, excluding injection site reactions 3
Clinical Positioning and Recommendations
Second-generation LAIs are recommended as first-line maintenance treatment after the first episode of schizophrenia. 4 This represents a significant shift from historical practice patterns that reserved LAIs only for patients with documented non-adherence or frequent relapses 1, 4.
Indications for LAI Antipsychotics
LAI antipsychotics are indicated for:
- Schizophrenia (all phases, including first-episode) 4
- Schizoaffective disorder 4
- Delusional disorder 4
- Bipolar disorder (second-generation LAIs preferred) 4
Key Advantages
- Enhanced medication adherence - primary benefit over oral formulations 3
- Relapse prevention - superior to oral medications in preventing relapse due to guaranteed medication delivery 1
- Reduced hospitalization rates - consequence of improved adherence 1
Common Pitfalls to Avoid
Do not reserve LAI antipsychotics only for patients who have already experienced multiple relapses or demonstrated poor adherence. 1, 4 This outdated approach delays optimal treatment. The expert consensus recommends systematically offering LAI antipsychotics to most patients requiring long-term antipsychotic treatment through shared decision-making 4.
Do not assume first-episode patients will refuse LAI treatment. Studies demonstrate 83-85% of eligible first-episode patients consent to LAI treatment when properly educated 1. Only 15% refused in one study of 60 first-episode patients 1.
Switching Strategies
When switching from oral antipsychotics to LAI:
- Paliperidone palmitate can be initiated the day after discontinuing oral antipsychotic without overlap 7
- For other LAIs (including risperidone LAI), oral supplementation is typically required during the transition period 7
- When switching from another LAI, initiate the new LAI at the time of the next scheduled injection of the previous LAI 7
Special Populations
Renal impairment: Dosage adjustment required for paliperidone palmitate in patients with creatinine clearance 50-80 mL/min 7
Hepatic impairment: No dose adjustment needed for mild-to-moderate hepatic impairment with paliperidone palmitate; no data exist for severe impairment 7
Elderly patients: Use same dosage as younger adults if renal function is normal; adjust for age-related decline in creatinine clearance 7