Updates on Long-Acting Injectable Antipsychotics for Schizophrenia in Adults

George A. Keepers, MD
Oregon Health & Science University
Portland, Oregon

Key Takeaways

  • Overall, there is no evidence of a difference in efficacy between first- and second-generation long-acting injectable (LAI) antipsychotic agents. Their adverse effect (AE) profiles are similar to those of oral agents. Dosing of LAI antipsychotics should follow guideline recommendations.
  •  The American Psychiatric Association (APA) recommends that healthcare providers discuss the advantages and disadvantages of LAI antipsychotics with patients and their families. Patients receive treatment with an LAI antipsychotic if they (1) prefer such treatment or (2) have risk factors for, or a history of, poor or uncertain adherence to an oral antipsychotic regimen.
  • In an established case of schizophrenia, continuous treatment is recommended with either an oral or an LAI antipsychotic. Tardive dyskinesia, a chronic neurologic AE, can develop in patients taking receiving treatment with an antipsychotic.
  •  Although LAI antipsychotics have a long duration of action, some require supplemental oral medication at the time of their initiation. Recommendations for supplemental oral therapy vary across agents.
  •  Clinicians should seriously consider incorporating LAI antipsychotics into clinical practice and should make every effort to reduce barriers to their use and allow patients to decide whether to be treated with these agents.

George A. Keepers, MD, is the Elda V. Carruthers Professor and Chair of the Department of Psychiatry at Oregon Health & Science University, Portland, Oregon. He is a Distinguished Life Fellow of the APA and first author of the third edition of The APA Practice Guideline for the Treatment of Patients With Schizophrenia.
Schizophrenia is among the 20 leading causes of disability worldwide; it is debilitating for the individual and their family and challenging to treat. Poor tolerability and treatment AEs contribute to nonadherence, which is estimated to affect 40% to 60% of patients with schizophrenia and result in poor disease management and relapse.1
Antipsychotic drugs are recommended to treat acute episodes of schizophrenia and prevent recurrence of psychosis. Long-term goals include relapse prevention, improved adherence to therapy, and improved quality of life (QOL).
Overall, clinical practice guidelines recommend the use of LAI antipsychotics during the first episode of schizophrenia and more broadly across the trajectory of illness, particularly for patients who are nonadherent to treatment. Several second-generation LAI antipsychotics have been approved by the US Food and Drug Administration for the acute or maintenance treatment (or both) of schizophrenia.2
Although LAI antipsychotics have been available for more than 40 years,3 they are generally underutilized. LAI antipsychotics offer healthcare providers an option to help with medication adherence and reduce any potential gaps in treatment. Insights into the differences between first-generation and second-generation LAI antipsychotics, and how they compare with oral antipsychotics, can provide practitioners with guidance for the optimal use of LAI antipsychotics. In this interview, George A. Keepers, MD, provides his perspective on the use of this treatment strategy in the management of schizophrenia.

Are there significant differences between first-generation and second-generation LAI antipsychotics? How do their efficacy and dosing compare with that of oral agents?

First, let me provide some background information about me and context about my insights. I served as Chair of the APA writing group that developed the new practice guideline for the treatment of schizophrenia.4 Many members of that group contributed significantly to the development of the guideline, which is an extensive, evidence-based review of the literature. So, my answers to these questions come from recommendations made in the new practice guideline.
Investigators have looked at whether there are major differences in effectiveness between first-generation and second-generation LAI antipsychotics. Pretty much uniformly, they found no difference in the effectiveness of the 2 generations. For example, McEvoy and colleagues examined the effectiveness of the second-generation LAI paliperidone palmitate and compared it with the older LAI haloperidol decanoate.5 They found no difference in effectiveness between the 2 agents. Findings from other investigators have generally been consistent.
However, there are differences in the AEs of first-generation and second-generation medications. The AE profile of LAI antipsychotics tends to follow the same profile as oral medications. Again, from McEvoy’s study, patients treated with haloperidol had a higher prevalence of akathisia (restlessness) than patients treated with paliperidone, which was expected; patients treated with paliperidone were more sedated than patients treated with haloperidol. Therefore, McEvoy’s findings are consistent with other findings in the literature: The AE profile of LAI antipsychotics parallels that of oral medications.
The dosing of LAI antipsychotics is different from the dosing of oral agents. However, if you examine the tables in the APA guideline, you will see how they relate to each other. Of course, recommendations for using these agents include, for the most part, recommendations on what dosage of the LAI agent to use based on the dosage of the oral agent.
To summarize:
·       In regard to effectiveness, AEs, and dosing, overall, there is no evidence of a difference in efficacy between first-generation and second-generation LAI antipsychotics;
·       The AE profile of the LAI agents tend to follow that of oral agents; and
·       Dosing of LAI and oral agents needs to follow the manufacturers’ recommendations, which are detailed in a comprehensive table in the APA guideline.

Overall guideline consensus on LAI antipsychotics
A systematic review of international guidelines found that 74% recommended the use of LAI antipsychotics in patients who are nonadherent to treatment. Furthermore, 63% of guidelines cited patient preference as a reason to consider LAI agents.

Some studies suggest that, if a patient does not respond to a first agent (usually, an oral antipsychotic for symptom management), an LAI agent can be used. However, other studies suggest that LAI antipsychotics can be used for symptomatic and long-term maintenance therapy. What does the guideline say? 

The guideline statement on this question is a suggestion. What does “suggestion” mean in guideline statements? A recommendation is made where there is robust evidence to support it. A suggestion — as in the case for using LAI agents — in the guideline reflects a lower level of evidence.
This is how the guideline answers your question: APA suggests that patients be treated with an LAI agent if they prefer such treatment or if they have risk factors for, or a history of, inadequate or uncertain adherence.
In the treatment implementation section of the APA guideline, there is discussion of how some investigators recommend using LAI antipsychotics earlier in treatment to promote adherence and reduce relapse. Some studies suggest that, in the setting of treatment failure with oral agents, LAI agents have a place. Of course, the use of LAI agents as maintenance therapy is well established.
Now, the evidence that LAI antipsychotics are more effective than oral agents is limited experimentally.  However, data from registries, which we also reviewed as part of our work during guideline development, show that patients taking an LAI agent have a reduced rate of hospitalization and reduced morbidity in some other areas. In the real world, LAI agents do have an advantage over oral antipsychotics for treating schizophrenia.
The guideline’s suggestion is to discuss the advantages and disadvantages of LAI antipsychotics with patients and adopt a patient-centered approach. Many patients choose to take an LAI agent after a discussion with their provider; they’ll do so because they prefer the convenience of infrequent injections over the inconvenience of keeping up with the regimen of an oral medication. 

First, as the APA guideline suggests, LAI antipsychotics are probably best utilized in patients who prefer them, so there’s no reason not to use them to suit patient preference. Second, LAI agents are useful in patients with a history of nonadherence to oral medication or who have risk factors for nonadherence.

Should LAI antipsychotics be used indefinitely to treat schizophrenia, which can be considered a chronic disease? If they should not, when should treatment stop? If they can be used in an open-ended manner, are there long-term AEs?

Schizophrenia tends to be a chronic disease that requires continuous treatment, either with oral medication or an LAI antipsychotic. To answer your first question, in an established case of schizophrenia, generally speaking, continuous treatment is recommended.
Regarding your second question, antipsychotics, generally, do have AEs, which are detailed in the guideline.4 The clinician who prescribes antipsychotics — whether oral or injectable — has to be aware of multiple potential AEs and alert the patient to what might develop.
The best-known AE associated with antipsychotic treatment is the chronic neurologic condition tardive dyskinesia, a persistent movement disorder or the presence of sensory phenomena. It’s often the case that when an antipsychotic agent — either oral or LAI — is withdrawn, there is an exacerbation of the symptoms of tardive dyskinesia. Often, that exacerbation is temporary, and the symptoms resolve over time. However, there is a phenomenon in which increased tardive dyskinetic movements are seen upon withdrawal of an antipsychotic agent.

A critical advantage of second-generation LAI antipsychotics is, as you noted, their reduced frequency of dosing. Is there a need to provide a bridge with oral therapy between doses of an LAI agent?

An advantage of LAI antipsychotics is that they have a long duration of action. Some LAI antipsychotics require an oral medication at treatment initiation; recommendations for doing this vary among agents. Examples are:
·       With aripiprazole (Abilify Maintena®), the dose of the oral antipsychotic is continued for 2 weeks, then discontinued.
·       With fluphenazine decanoate (Prolixin®), half the dose of the oral antipsychotic is given during the period of the first injection, and the oral dose is discontinued after that.
·       With aripiprazole lauroxil (Aristada Initio®), the dose of the oral antipsychotic is given for 3 weeks after initiating treatment with the LAI agent.
·        Supplementation with an oral medication is not required with olanzapine (Zyprexa Relprevv®).
The point of giving LAI agents is to avoid the need for oral medication. So, dosage adjustments allow you, in most cases, to discontinue oral treatment entirely after these required initial periods of oral supplementation. 

Is there evidence that second-generation LAI antipsychotics improve medication adherence, prevent or reduce relapse, and, overall, improve QOL?

Both first-generation and second-generation LAI agents have been studied in this area. As I mentioned, direct comparisons between oral and LAI agents tend to show no difference in regard to AEs, relapse, and QOL.
However, from studies based only on registries, the treatment of schizophrenia in the real world tends to show a reduction in both the rate of hospitalization and relapse of symptoms with second-generation LAI agents. I can’t say much about improvement in QOL, other than that the reduction in active symptoms, relapse, and hospitalization certainly does improve QOL.

Can you offer practice pearls to clinicians regarding the use of LAI antipsychotics?

First, there is evidence that LAI agents are underutilized in the United States. We have other problems of underutilization, too; for example, the atypical oral antipsychotic clozapine is underutilized in the United States. Undoubtedly, more patients could benefit from treatment with an LAI antipsychotic than are treated currently.
So it’s essential to remove barriers for patients to use these agents. One of the obstacles is the physician’s reluctance to prescribe LAI antipsychotics, sometimes because of their practice location. For example, some physicians might be in a practice setting where they do not have access to an injection site or do not have trained personnel to administer injections. And if they do have access to an injection site, they have to develop a relationship with a site for administering LAI agents. I think that’s an essential responsibility for physicians who treat patients with schizophrenia to take on: developing a relationship with an injection site that allows for treatment of patients who have this disease.
Second, it’s important to discuss the benefits and disadvantages of LAI agents with patients and their families or other caregivers, when appropriate. Many patients and the general public are unaware that these treatments are available and unaware of the relative convenience and potential effectiveness of LAI agents. A patient-centered discussion that focuses on what the patient’s wishes are regarding treatment can help remove barriers.
Third, physicians who intend to give LAI treatments themselves must have an injection site at their practice location. They also need storage equipment for the medications and an identified area for administering injections. They need to monitor the patient after the injection. And they must maintain their skill at administering injections. Most LAI agents are injected intramuscularly, which is relatively easy; there are recommendations for administering agents that need to be given subcutaneously. Keep in mind that not all LAI agents can be administered in the office; some must be delivered in more of an acute-care setting.

To which patients are you targeting the recommendation to increase the number of patients receiving an LAI antipsychotic?

First, as the APA guideline suggests, LAI antipsychotics are probably best utilized in patients who prefer them, so there’s no reason not to use them to suit patient preference. Second, LAI agents are useful in patients with a history of nonadherence to oral medication or who have risk factors for nonadherence. Such factors include patients who don’t have ready access to a pharmacy, who live a great distance from a care center, or who are disorganized and unable to comply with taking oral medication regularly.

The Q&A was edited for clarity and length.


  1. Yeisen RAH, Bjornestad J, Joa I, Johannessen JO, Opjordsmoen S. Experiences of antipsychotic use in patients with early psychosis: a two-year follow-up study. BMC Psychiatry. 2017;17(1):299. doi:10.1186/s12888-017-1425-9
  2. Correll CU, Martin A, Patel C, et al. A systematic literature review of schizophrenia clinical practice guidelines: recommendations on use of long-acting injectable antipsychotic medications. Presented at: Psych Congress 2020 Virtual Experience; September 10-13, 2020. Poster 103.
  3. Llorca PM, Abbar M, Courtet P, Guillaume S, Lancrenon S, Samalin L. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013;13:340. doi:10.1186/1471-244X-13-340

4.     Keepers GA, Fochtmann LJ, Anzia JM, et al.  The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi:10.1176/appi.ajp.2020.177901

  1. McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. 2014;311(19):1978-87. doi:10.1001/jama.2014.4310

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  Reviewed March 2021