Impact of Long-Acting Injectable Antipsychotics on Schizophrenia

October 2014, Vol 2, No 5 - Inside Pharmacy
Nicole East, PharmD
Mei T. Liu, PharmD, BCPP
Megan Maroney, PharmD, BCPP

"Pharmacists can counsel patients about the use of LAIs and their benefits to reduce the stigma of injections, improve attitudes toward medication, and increase adherence.”

Schizophrenia affects approximately 1% of the adult population in the United States and accounts for a total of $63 billion a year in direct treatment, societal, and family costs.1

Schizophrenia is a debilitating psychotic disease that is associated with a disruption in a patient’s perception, cognition, and emotion.1 Antipsychotic medications are a key component for positive outcomes in people with many serious psychiatric diagnoses, including schizophrenia, bipolar disorder, and major depressive disorder. Unfortunately, research shows that even with treatment, the majority of patients with schizophrenia relapse within 5 years, with poor adherence to oral antipsychotics being one of the most common causes in more than half of these patients.2

Long-acting injectable (LAI) antipsychotic medications have been promoted as a way to improve medication adherence in this patient population, potentially leading to lower relapse rates, decreased hospitalizations, and a lower economic burden on the healthcare system. There are currently 6 LAI antipsychotics that are commercially available.

This article will focus on the impact of LAIs on medication adherence, the advantages and disadvantages of LAIs, and the potential role that community pharmacists and other retail clinicians can play in mental health treatment.

Impact of Medication Adherence
Literature suggests that the 2 most common causes of relapse in patients with schizophrenia are medication discontinuation and nonadherence. In the Clinical Antipsychotic Trial for Intervention Effectiveness (CATIE) study, results showed that medication discontinuation rates in these patients were as high as 74%.2,3

Moreover, patients who discontinue and restart medications of their own accord are more likely to discontinue again. Patients who are adherent at 6 months are more likely to remain adherent, whereas nonadherence in the first year of treatment with an antipsychotic medication is a predictor of poor outcomes.2

Not only is medication nonadherence associated with high relapse rates, but it also poses an economic burden in the treatment of schizophrenia. Patients who are nonadherent have increased rates of hospital admissions, rehospitalizations, and persistent psychotic symptoms. As a result of nonadherence, treatment resistance, increased risk of suicide, and longer psychiatric hospital stays can occur.2 Strategies currently used to reduce nonadherence include support programs, assertive community treatment, psychoeducation, and LAIs.4,5

Risk factors that can lead to nonadherence are classified into 3 different categories: patient, medication, and family factors (Table).4-6

Available LAIs
The 6 available LAI antipsychotics (2 first-generation and 4 second-generation), products, and information are outlined in a Supplementary Online Table. Mechanism of action and side effects will be discussed within each class, although local injection site pain and redness are possible adverse events with all LAIs.7-12


First-generation.7,8 The first-generation antipsychotics (FGAs) are primarily dopamine-2 (D2) antagonists. These medications are associated with an increased risk of extrapyramidal symptoms (EPS) and hyperprolactinemia. Both haloperidol and fluphenazine require a Z-track administration, which consists of pulling the subcutaneous layers of the skin out of alignment with the muscles to break the junction of each layer. This allows the medication to be trapped in the muscle postinjection. It is also recommended not to massage the area after injection. It is important to note that both formulations are in a sesame seed oil base, and this information should be considered when checking a patient’s allergy history.

Second-generation.9-12 The second-generation antipsychotics (SGAs) are different from the first because of their serotonin type 2A (5HT2A) antagonism effect and D2-antagonism. Although some SGAs still lead to EPS and hyperprolactinemia, the main concern with these medications is the risk of metabolic side effects. EPS is more common with risperidone and paliperidone; increased weight gain and appetite are more common with olanzapine.9-11 It is important to be aware that olanzapine has a black box warning of postinjection delirium/sedation syndrome (PDSS); therefore, a patient must be directly observed by a healthcare professional for 3 hours postinjection for fatigue and dizziness.

This is why the prescriber, patient, facility, and pharmacy must be trained and enrolled in a national registry if dispensing olanzapine via the Risk Evaluation and Mitigation Strategy protocol.11 Most second-generation LAIs must be reconstituted and are dispensed in a kit that gives all the products necessary for the injection process.9-12 Risperidone and aripiprazole LAIs also require overlap treatment with oral medication for the first 2 to 3 weeks after starting the injection.9,12

Advantages of LAIs
A study by Peuskens and colleagues13 demonstrated that LAIs are associated with a decrease in hospitalizations and relapse, as well as improved cost-effectiveness and adherence in patients with schizophrenia compared with oral antipsychotics. This also leads to a decrease in overall healthcare costs.2,13 Not only can LAIs decrease relapse rates through earlier detection of nonadherence, but they can also allow for more predictable and stable serum drug concentrations. This reduces the risk of accidental or deliberate overdose.14 Studies also have shown that patients started and maintained on an LAI prefer it to oral medications, and are twice as likely to remain on an LAI.2

Based on the results of a study by Bartzokis and colleagues,15 it has also been suggested that in patients initiating treatment early, LAIs may be neuroprotective due to an increase in intracortical myelination volume.15

Barriers to LAIs
Injections in the psychiatric population have long been associated with a way of restraint and may pose a stigma for a patient when offered LAIs. This may be why physicians have decreased their use within the past 5 years by about 50%, despite the recognition of better adherence with LAIs.2 Patients also may have concerns with the fear of pain, loss of autonomy, and inconvenience of more frequent clinic visits for the injection.2,4 Psychiatrists may also be deterred by insurance coverage and the possibility of the patient not having access to the medication. Psychiatrist and patient attitudes toward injections are considered barriers to the use of LAIs.2

Community Pharmacists and Retail Clinicians
There are many roles that can be identified for community pharmacists and other retail clinicians, especially related to the barriers to using LAIs. Pharmacists can counsel patients about the use of LAIs and their benefits to reduce the stigma of injections, improve attitudes toward medication, and increase adherence. Also, many insurance providers recognize that LAIs can prevent hospitalizations, and, therefore, cover the cost of medications for these patients.

Community pharmacists and other retail clinicians can bridge the communication gap between the patient and psychiatrist as to whether the patient prefers an LAI, as well as between the psychiatrist and the insurance provider to advocate for the coverage of LAIs in their patients. Also, by following these patients, pharmacists may be able to recognize inadequate adherence by late refills with oral antipsychotics and can follow up with the physician.

It is suggested that outpatient LAI use may be underutilized because of the limited availability of experienced personnel to administer intramuscular formulations at psychiatric office practices and community mental health centers.2 Pharmacists have the ability to administer immunizations in all 50 states, Washington, DC, and Puerto Rico; and 21 states allow pharmacists to administer nonvaccine injections.

Currently, pharmacists in Texas, Washington, Maryland, and Washington, DC, are able to administer LAIs. The programs in Washington and Texas are specifically in community pharmacies.16 Community pharmacists can play a major role if they assist in LAI administration and can become a vital part of reducing the relapse rates within this population.


  1. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1-56.
  2. Kaplan G, Casoy J, Zummo J. Impact of long-acting injectable antipsychotics on medication adherence and clinical, functional, and economic outcomes of schizophrenia. Patient Prefer Adherence. 2013;7:1171-1180.
  3. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.
  4. Ciudad A, San L, Bernardo M, et al. Relapse and therapeutic interventions in a 1-year observational cohort study of nonadherent outpatients with schizophrenia. Prog Neuropsychopharmacol Biol Psych. 2012;36:245-250.
  5. Leucht S, Heres S. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J Clin Psychiatry. 2006;67:S3-S8.
  6. Patel MX, de Zoysa N, Bernadt M, David AS. A cross-sectional study of patients’ perspectives on adherence to antipsychotic medication: depot versus oral. J Clin Psychiatry. 2008;69:1548-1556.
  7. Fluphenazine Decanoate [package insert]. Schaumburg, IL: APP Pharmaceuticals, LLC; 2010.
  8. Haloperidol Decanoate [package insert]. Schaumburg, IL: APP Pharmaceuticals, LLC; 2011.
  9. Risperdal Consta [package insert]. Titusville, NJ: Janssen Pharmaceuticals Ltd; 2014.
  10. Invega Sustenna [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.
  11. Zyprexa Relprevv [package insert]. Indianapolis, IN: Eli Lilly and Company; 2011.
  12. Abilify Maintena (aripiprazole) [package insert]. Rockville, MD: Otsuka America Pharmaceutical Inc; 2013.
  13. Peuskens J, Olivares JM, Pecenak J, et al. Treatment retention with risperidone long-acting injection: 24-month results from the Electronic Schizophrenia Treatment Adherence Registry (e-STAR) in six countries. Curr Med Res Opin. 2010;26:501-509.
  14. Patel MX, Taylor M, David AS. Antipsychotic long-acting injections: mind the gap. Br J Psychiatry. 2009;52:S1-S4.
  15. Bartzokis G, Lu PH, Raven EP, et al. Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia. Schizophr Res. 2012;140:122-128.
  16. Oji V, McKoy-Beach Y, Pagan T, et al. Injectable administration privileges among pharmacists in the United States. Am J Health-Syst Pharm. 2012;69:2002-2005.
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