2.3 Masterclass: Long-Acting Injectables (LAIs)

In your community practice, you have a unique and often frustrating window into the challenge of medication non-adherence in patients with serious mental illness. You see the refill records with gaps of weeks or months. You receive the panicked calls from family members. You witness the slow, heartbreaking decline that often precedes a full-blown psychotic or manic episode. In almost every case, a psychiatric hospitalization is the direct and inevitable consequence of this non-adherence. The patient stops their oral antipsychotic, their symptoms return and spiral out of control, and they end up in the emergency department in crisis.

The inpatient psychiatric team’s primary goal is to stabilize this acute crisis. But their second, equally important goal is to prevent it from happening again. This is where Long-Acting Injectable (LAI) antipsychotics become the most powerful intervention in the psychiatrist’s toolkit. By initiating an LAI in the controlled hospital environment, the team can solve the primary problem that led to the admission. An LAI breaks the cycle of daily non-adherence by providing a steady, therapeutic level of medication that is administered by a healthcare professional every few weeks or months. It removes the daily burden of remembering to take a pill, a task that can be incredibly difficult for a patient struggling with the cognitive symptoms of their illness.

Initiating an LAI in the hospital is the ultimate act of proactive discharge planning. It is the construction of a pharmacological “bridge” that ensures the patient remains on a therapeutic dose of their medication as they transition from the highly structured and supportive inpatient unit back to the complexities and challenges of community living. Your role as the pharmacist is to be the chief engineer of this bridge, ensuring it is built with the right materials, on the right schedule, and that the hand-off to the outpatient team is flawless.

As a pharmacist, you understand that the formulation of a drug is just as important as the drug itself. This is nowhere more true than with LAIs. Each LAI uses a unique and sophisticated drug delivery technology to achieve its extended duration of action. Mastering these technologies is the key to understanding the complex initiation protocols, loading dose requirements, and oral overlap periods that you will be responsible for verifying.

The First-Generation “Decanoates”: Oil-Based Depot Formulations

The original LAIs, Haloperidol Decanoate and Fluphenazine Decanoate, use a simple but effective technology. The parent drug is esterified with a long-chain fatty acid (decanoic acid), making it highly lipophilic. This ester is then dissolved in a sesame oil vehicle. When injected deep into a large muscle (like the gluteus), it forms an oily pocket, or “depot.” The drug then slowly leaches out of the oil and into the bloodstream, where esterase enzymes cleave the decanoate chain, releasing the active parent drug over a period of several weeks.

Feature	Haloperidol Decanoate	Fluphenazine Decanoate
Dosing Interval	Every 4 weeks	Every 2 weeks
Oral Overlap	Required. Oral haloperidol must be continued for a period after the first injection and gradually tapered.	Required, similar to haloperidol.
Dose Conversion	The monthly injectable dose is typically calculated as 10-20 times the previous daily oral haloperidol dose. Your verification of this math is critical. A patient on 10mg PO daily might be started on 100-150mg IM monthly.	The bi-weekly injectable dose is typically ~1.2 times the previous daily oral fluphenazine dose.
Key Risks & Your Role	The primary concern is the very high risk of Extrapyramidal Symptoms (EPS) and the long-term risk of Tardive Dyskinesia (TD). Because the drug is in the system for weeks, these side effects can be prolonged and difficult to manage. You must ensure an order for PRN benztropine or diphenhydramine is available.

The Microspheres: Risperdal Consta®

Risperdal Consta was a revolutionary step forward, using a biodegradable polymer technology. The active drug, risperidone, is encapsulated into tiny, injectable microspheres made of a polyglactin material (similar to dissolvable sutures). After IM injection, these microspheres slowly absorb water, swell, and then gradually break down, releasing the drug over a period of two weeks.

The Nanocrystals: Paliperidone Palmitate (Invega Sustenna® & Trinza®)

This technology solved the lag-time problem of the microspheres. Paliperidone (the active metabolite of risperidone) is esterified to a palmitate tail and milled into incredibly small nanocrystals. This creates a stable aqueous suspension. After IM injection, the crystals form a depot, and the drug is slowly released from the surface of these crystals via hydrolysis. The key innovation is the dosing schedule.

The Next Step: Invega Trinza® (3-Month Formulation). Once a patient has been stable on Invega Sustenna for at least 4 months, they may be a candidate for Invega Trinza, a quarterly injection. This provides an even greater level of adherence assurance. Your role is to verify the patient’s stability on Sustenna and to calculate the correct corresponding Trinza dose based on their previous Sustenna dose.

The Atypical LAIs: Aripiprazole Formulations

Aripiprazole offers two different LAI formulations with distinct properties that you must master.

Feature	Abilify Maintena®	Aristada® (Aripiprazole Lauroxil)
Formulation	Lyophilized powder of aripiprazole that must be reconstituted.	A prodrug (aripiprazole lauroxil) in a pre-filled syringe as a nanocrystal suspension.
Dosing Interval	Every 4 weeks.	Every 4, 6, or 8 weeks, offering more flexibility.
Oral Overlap	Required. Must continue oral aripiprazole for 14 days after the first injection.	Required. Must continue oral aripiprazole for 21 days after the first injection… UNLESS the “Initio” regimen is used.
The “Initio” Regimen	N/A	To compete with Invega Sustenna’s no-overlap advantage, the makers of Aristada created an optional one-time loading dose called Initio®. It is a separate drug given concurrently with a single 30mg dose of oral aripiprazole and the first Aristada injection. This complex regimen allows therapeutic levels to be reached immediately, eliminating the need for the 21-day oral overlap. Your role is to verify all three components of this regimen are ordered correctly.