Addressing Barriers to Using Long-Acting Injectable Antipsychotics and Appropriately Monitoring Antipsychotic Adverse Effects

Christoph U. Correll, MD

Recognition and Prevention Program (RAP), The Zucker Hillside Hospital, Glen Oaks; the Department of Psychiatry and Molecular Medicine, Hofstra-North Shore-Long Island Jewish School of Medicine, Hempstead; and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York

The treatment goals of schizophrenia, in both the acute and maintenance phases, include helping patients achieve symptom remission, preventing relapse, and restoring function, a key factor in the ultimate goal of recovery. To achieve these goals, clinicians must select treatments, such as antipsychotics, that are as effective and tolerable as possible with few psychiatric and physical side effects. One barrier to achieving treatment goals is patients’ nonadherence to antipsychotic medication. Nonadherence occurs in about 40% of patients with schizophrenia and increases costs for rehospitalization when patients relapse.1,2

Since nonadherence is a major barrier to effective pharmacotherapy, LAI antipsychotics may provide a clinically useful solution because they remove clinicians’ uncertainty about nonadherence and may give patients the potential to achieve better outcomes.3

Although LAIs are used most often in patients who have experienced multiple relapses and hospitalizations, earlier use has the potential to improve adherence and avoid illness exacerbations as well as increased costs. However, measuring the benefits of LAI versus oral antipsychotics can be challenging due to different trial designs and conflicting results. The following sections examine data on the efficacy of LAIs, the obstacles to their appropriate use, the relevance of physical health monitoring, and possible solutions for increasing the use of LAIs and side effect monitoring.

Efficacy of LAI Antipsychotics According to Study Design

Evidence of the efficacy of LAI versus oral antipsychotics has yielded conflicting results, which can be a barrier to clinicians considering LAIs as a viable treatment option. Interpretation of antipsychotic data must be made within the context of different study designs, which have strengths and weaknesses that affect patient outcomes.

Randomized controlled trials. Double-blind RCTs are considered the gold standard for evidence-based medicine because blinding reduces participant expectations and rater biases, and randomization limits selection bias.4 However, the patients who participate in RCTs are generally more adherent and not as severely ill as many of the patients in usual care who are typically considered candidates for LAI antipsychotic use. Also, the RCT design may improve adherence to oral medication by having more frequent clinical visits than usual care does, measuring adherence, and providing medications directly to patients taking oral antipsychotics, whereas patients in usual care have to refill prescriptions themselves. Therefore, using an RCT design may not reflect usual care and may not be ideal for studying and quantifying LAI-related efficacy and effectiveness.

Meta-analyses3,5 of LAIs versus oral antipsychotics in RCTs of at least 1 year have shown that depot antipsychotics reduce relapse rates in patients with schizophrenia, but the analyses did not reveal any significant improvement in adherence, sometimes due to a lack of data. The most recent meta-analysis6 of RCTs found no significant difference on relapse prevention between LAI and oral antipsychotics, but the authors cautioned the application of these results stating that RCTs are less representative of real-world patients than naturalistic studies are.

Mirror-image studies. In contrast to RCTs, patients in mirror-image studies are more representative of those in clinical practice because they compare the course of illness before and after a given treatment in patients who are candidates for this treatment option. A comprehensive meta-analysis7 of studies using a mirror-image design revealed that patients had significantly lower rehospitalization rates (P=.0001) after being switched to LAIs than when they received oral antipsychotics. However, mirror-image studies have potential weaknesses related to expectation bias, lack of a control group, lack of blinding, and the initiation of treatment after the failure of the first treatment option.

Cohort studies. Cohort studies reduce patient selection bias by being naturalistic and studying all eligible patients, especially when drawing on statewide or national samples. A Finnish retrospective cohort study8 that adjusted for baseline differences in the oral and LAI groups found that, in the 60 days following their first hospitalization, patients in the early phase of schizophrenia receiving depot antipsychotics had one-third the rehospitalization rate of patients receiving the equivalent oral formulation. However, a meta-analysis7 of mixed naturalistic cohort studies showed similar rehospitalization rates between LAI and oral antipsychotic treatment, yet the similar outcome may actually reflect a significant advantage of LAIs, given that patients prescribed LAIs in usual care settings are significantly more prone to relapse than patients prescribed oral antipsychotics. Moreover, disadvantages of cohort studies include that the samples are not randomized, treatments are open, and important confounding patient and illness factors are rarely adequately adjusted in statistical analyses.

AV 1. Meta-Analysis of LAI Versus Oral Antipsychotics by Study Design (00:44)

Adapted with permission from Kirson et al4
Abbreviations are defined before the References

Impact of study design. To assess differences of study design on the magnitude of efficacy of LAI over oral antipsychotics, Kirson et al4 reviewed studies conducted between January 2000 and December 2011. In RCTs, LAI antipsychotics showed no significant superiority over oral antipsychotics, but the prospective and retrospective studies yielded significant advantages for LAIs regarding hospitalization rates, relapse rates, and all-cause discontinuation (AV 1). These results show that study design does influence the comparative effectiveness of antipsychotic formulations.

Future studies should aim to minimize biases while maximizing the generalizability of the population and treatment delivery. Large pragmatic trials that maintain randomization but impose as little changes on the ecology of clinical care and have as few exclusion criteria as possible may be the best tools to assess the real-world effectiveness of LAI antipsychotics.

Obstacles to the Appropriate Use of LAI Antipsychotics

Although LAI antipsychotics have been shown to reduce relapse and rehospitalization, they tend to be underused in clinical practice, especially in first-episode patients who might benefit the most from the consistent treatment offered by an injectable formulation since both response rates and treatment discontinuations and relapse rates are particularly high in this population at a critical stage of illness and opportunity for recovery.

Barriers to implementing LAI treatment include that patients and caregivers are unfamiliar with LAIs and may fear the pain or the large, irreversible dosing associated with shots. They may distrust the medical system, believe the injections cause a loss of control, or associate injections with only the most severely ill patients (ie, stigma). Clinicians may lack the familiarity or training to administer LAI antipsychotics. They may doubt the evidence of efficacy of LAI formulations or dislike the lack of flexible dosing or the possible need for adding oral antipsychotics between dose intervals. They may want to avoid inflicting pain on patients or have limited time with patients to incorporate LAI treatment into the management regimen.

These barriers exist, although data indicate that injection pain is rare (<10%) and that discontinuations due to injection pain are highly uncommon.9 Moreover, adverse effects occurring during LAI treatment are generally manageable, and serious adverse effects are very rare, as patients are required to have demonstrated prior tolerability to the oral formulation.

A dearth of injection clinics or trained nurses can also limit the opportunity to use LAIs, while a fragmented health care system and reimbursement issues may create more obstacles. Clearly, several areas need to change before LAI antipsychotics are more widely accepted as a viable early treatment option for patients with schizophrenia.

Relevance of Physical Health Monitoring to Optimizing Outcomes

Recovery is the main goal in the treatment of patients with mental illness. In the broadest sense, recovery includes symptom remission and improved functional capacity as well as the maintenance or improvement of physical health. Patients with severe mental illnesses are at a greater risk than the general population to develop health problems, such as cardiovascular disease and diabetes.10 The medical health risk in patients with schizophrenia is due to a combination of factors related to disease symptoms, economic status, lifestyle behaviors (eg, substance abuse, smoking, physical inactivity, and poor nutrition), and treatment side effects (eg, sedation, EPS, weight gain, diabetes, hyperlipidemia, hyperprolactinemia, and cardiovascular disease), as well as health care system barriers.11

AV 2. Metabolic Risks Associated With Selected Antipsychotics (01:04)

Based on De Hert et al12
*Limited data

Clinicians can improve their patients’ physical health by regularly monitoring medication-induced adverse effects and motivating patients to make healthy lifestyle changes like dieting, exercising, and quitting smoking.10 Lack of integrated mental and physical health care and time constraints often hinder clinicians from monitoring problem areas associated with antipsychotic treatment, including metabolic issues, cardiovascular side effects, and EPS. However, regularly assessing these areas is crucial to ensure positive outcomes, increased adherence, and reduced adverse physical consequences. Additionally, while antipsychotics in general can cause weight gain and metabolic problems, clinicians should become familiar with each antipsychotic side effect profile and know which ones are associated with greater risks (AV 2).12

Possible Solutions for Increasing the Use of LAI Antipsychotics and Adverse Effect Monitoring

To overcome obstacles to using LAI antipsychotics, patients, caregivers, and clinicians need to understand the link between nonadherence and relapse, how to interpret data from different types of studies, and how LAIs might improve adherence and reduce the risk of relapse.


Reducing the fear and stigma related to LAIs would help clinicians consider these formulations not just for severely ill patients, but also for patients early in their disease course. The ease of LAI use should be stressed, such as not having to remember to take an oral medication daily (AV 3).

AV 3. Recommending LAI Antipsychotic Treatment to a Patient With Schizophrenia (03:05)

Institutional support should be put in place to facilitate both the administration of LAI antipsychotics and routine cardiovascular and metabolic monitoring, monitoring recommended in the APA guidelines13 for patients taking antipsychotics. Institutional guidelines could also be created for clinicians to assess the potential for LAI use in patients taking oral antipsychotics who are not improving, who are nonadherent, or who are hospitalized repeatedly or within short periods of time. Incentives for guideline-consistent behaviors could be provided for clinicians, and reimbursement at the institutional and state levels should be streamlined. Finally, the long-term benefits and cost savings associated with LAI antipsychotic use and routine health monitoring should be emphasized to patients and insurance providers.


To help patients with schizophrenia work toward recovery, clinicians should consider LAI antipsychotics to improve adherence and outcomes. This formulation ensures that patients receive their medication consistently, which can reduce relapses and hospitalizations. When evaluating the efficacy of LAIs, clinicians must understand how different study designs can affect characteristics of the studied population and outcomes of LAI versus oral antipsychotics. Future studies should aim to merge the generalizability and population sizes of cohort studies with the minimal bias of RCTs. Monitoring adverse effects and physical illnesses should be an integral part of care for all patients taking antipsychotics. To reduce the barriers to appropriate use of LAIs and to routine health monitoring, education is needed for clinicians, patients, and caregivers. Institutional guidelines and policies that recognize the long-term benefits of LAI treatment and side effect monitoring can help streamline procedures and provide incentives for quality care.

Clinical Points

  • Understand how study design influences the outcomes of LAI versus oral antipsychotic trials
  • Monitor side effects and physical conditions in patients taking antipsychotics
  • Introduce appropriate LAI antipsychotic treatment to patients who are not improving, who are nonadherent, or who undergo repeated hospitalization


APA = American Psychiatric Association
EPS = extrapyramidal side effect
LAI = long-acting injectable
RCT = randomized controlled trial

Drug Names

aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozaril, FazaClo, and others), haloperidol (Haldol and others), iloperidone (Fanapt), lurasidone (Latuda), olanzapine (Zyprexa and others), paliperidone (Invega), pimozide (Orap), quetiapine (Seroquel and others), risperidone (Risperdal and others), ziprasidone (Geodon and others)

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