RxPharmacist

Long-acting Injectables in Schizophrenia: A Considerable Alternative to Oral Therapy 

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Antipsychotic agents are a key approach in the treatment and management of schizophrenia. Despite their crucial role, medication non-adherence remains a significant concern. Long-acting injectable (LAI) antipsychotics are specifically designed formulations of antipsychotics that release medication consistently over a period of days to weeks, ensuring patients receive stable therapeutic concentrations. LAI’s offer more stable drug levels that minimize peak-related side effects, reduction in the risk of relapse, and improved adherence due to less dosing frequency than oral antipsychotics.  

Who Should Receive an LAI?  

Patients with recent-onset schizophrenia or those who are expected to need long-term antipsychotic therapy may benefit from incorporating LAI into their treatment. In cases where there are concerns about adherence to oral medications, LAIs should be highly considered. LAIs can support autonomy in treatment decisions, which may empower vulnerable populations such as individuals living with schizophrenia. However, the decision to use an LAI should be guided by a patient-centered approach. 

How Do LAI Antipsychotics Treat Schizophrenia?  

The Dopamine Hypothesis of schizophrenia proposes that dysregulation of activity in dopamine receptors located in distinct brain pathways contributes to symptoms. Specifically, excess dopamine in the mesolimbic pathway contributes to positive symptoms such as hallucinations and delusions. On the other hand, decreased dopamine in the mesocortical pathway is associated with negative (flat affect) and cognitive symptoms. The primary therapeutic goal in managing schizophrenia is to restore the balance of dopamine across these pathways.  

The primary mechanism of action for antipsychotic medications is dopamine antagonism, specifically at D2 receptors. Although D2 receptors are inhibitory, blocking them reduces overstimulation and restores normal activity of dopamine.  

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Reformulating traditional dopamine antagonists in a way that allows them to be deposited under the skin or in muscle is what causes the sustained release of the medication. This medication depot allows for an extended dosing interval. Depending on the formulation, the site of injection varies from subcutaneous, deltoid, or gluteal.  

The following antipsychotic medications are available in LAI formulations: 

Please note that not all LAI formulations are FDA approved for the treatment of schizophrenia. 

How do I Know Which LAI is Right for My Patient?  

LAIs offer differing pharmacokinetic properties from each other. Pharmacists play an important role in assessing and selecting the most appropriate LAI for individual patients.  

First generation antipsychotics (FGAs) also known as typical antipsychotics, carry a high binding affinity for D2 receptors. The high binding affinity keeps them bound for longer. This extended period of activity on the receptor is associated with a higher risk of extrapyramidal symptoms (EPS). In contrast, second generation antipsychotics, or atypical antipsychotics, tend to not bind as tightly. As a result, they tend to dissociate more rapidly, making them less likely to cause EPS. However, second generation antipsychotics are associated with a risk of metabolic disturbances (e.g., weight gain, diabetes, high cholesterol). 

Establishing prior tolerance to an oral antipsychotic is a first step in determining what LAI is the most appropriate for your patient. While some LAIs require a period of oral overlap, others do not. Collecting a thorough patient history can offer valuable insight into past medication tolerability, which can guide your selection. For example, you will want to steer away from choosing an FGA LAI if the patient has a history of EPS from prior oral medication. However, if a patient has had a good response with prior oral antipsychotic treatment, it should be used as their LAI. 

Insurance coverage is another key consideration. All LAI formulations of aripiprazole, risperidone, and paliperidone are FDA approved for the treatment of schizophrenia, in addition to fluphenazine and haloperidol. Insurance plans may restrict coverage to FDA approved treatments; FDA-approved options should be prioritized to avoid the prior authorization process or denial. If a patient does not have current prescription coverage, it is vital to discuss out of pocket expenses prior to initiating LAI therapy. Certain LAIs, such as aripiprazole and paliperidone have patient assistance programs.  

Other considerations include post-injection monitoring requirements. For example, patients are at a very high risk for developing Post-Injection Delirium/Sedation Syndrome (PDSS) after each injection of olanzapine pamoate. Because of this, patients are required to be observed at a registered facility for at least 3 hours post injection. 

Reference image: Unsplash

How Do I Start an LAI? 

Certain LAIs require oral overlap before injection. To determine if the LAI you have selected requires an oral bridge, or other important prescribing information, refer to the package insert or the manufacturer’s website.  

Reasons for LAI Underutilization and Addressing These Challenges 

Psychiatric practitioners may carry the false assumption that their patients will reject LAI as a treatment option. Negative attitudes and perceptions are a common barrier to LAIs, with one study identifying perceived negative patient attitudes as the most reported barrier among practitioners. However, the same study found that the presence of a psychiatric pharmacist helped to reduce barriers. This highlights the valuable role of pharmacists in psychiatric care. Pharmacists can provide education about LAIs to help dismiss misconceptions and guide more informed treatment decisions. 

Another barrier is the complex dosing schedules for formulations that require oral overlap. The skills pharmacists carry allow them to be well-equipped in navigating these challenges, including an assessment of the patient’s history. They can help to determine if past treatment failures were caused by medication intolerance or non-adherence. In cases where a patient is hesitant to start or restart oral medications, the pharmacist can guide appropriate LAI selection based on the patient’s side effect profile and treatment history. Additionally, pharmacists can use their clinical expertise to ensure oral overlap requirements have been met.

There is a unique opportunity for hospital pharmacists to evaluate and initiate appropriate long-term treatment plans. Pharmacists can collaborate with the patient’s healthcare team to select a LAI regimen and coordinate the necessary overlap as needed. Because the patient is being monitored and their medications are provided, the concern for adherence is greatly reduced. This strategy can expedite the LAI initiation process, allowing patients to receive their first dose before or shortly after discharge.  

Reference image: Unsplash

The Final Say in the Role of LAIs in Schizophrenia 

LAIs offer a unique alternative to oral antipsychotics. Given the challenges of nonadherence to antipsychotics, LAIs provide an advantage for patients to receive a sustained release of medication without the need for daily dosing. The decision to initiate LAI therapy should be patient-centered, with the selection of a specific agent tailored to the patient’s individualized needs and history. 

Cierra L., APPE student

References:  

  1. Schwartz S, Carilli C, Mian T, Ruekert L, Kumar A. Attitudes and perceptions about the use of long-acting injectable antipsychotics among behavioral health practitioners. Ment Health Clin. 2022;12(4):232-240. Published 2022 Aug 23. doi:10.9740/mhc.2022.08.232  
  1. Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment options. P & T: a peer-reviewed journal for formulary management, 39(9), 638–645. 
  1. Krishna A, Goicochea S, Shah R, Stamper B, Harrell G, Turner A. Long-acting injectable antipsychotics in primary care: A review. J Am Board Fam Med. 2024;37(4):773–784. https://www.jabfm.org/content/37/4/773. Accessed June 5, 2025.  
  1. PsychDB. Long-Acting Injectable (LAI) Antipsychotics. PsychDB. https://www.psychdb.com/meds/antipsychotics/0-long-acting-injectables. Accessed June 9, 2025.  
  1. Acosta, F. J., Hernández, J. L., Pereira, J., Herrera, J., & Rodríguez, C. J. (2012). Medication adherence in schizophrenia. World journal of psychiatry, 2(5), 74–82. https://doi.org/10.5498/wjp.v2.i5.74 
  1. Texas Health and Human Services. Long-Acting Injectable Antipsychotics: Quick Reference Guide. Published February 2022. Accessed June 10, 2025. https://www.hhs.texas.gov/sites/default/files/documents/lai-antipsychotic-quick-reference.pdf 

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