LAIAs Safer, More Effective Than Oral Antipsychotics for Schizophrenia

Batya Swift Yasgur, MA, LSW

August 05, 2022

For patients with schizophrenia, long-acting injectable antipsychotics (LAIAs) are associated with a lower risk than oral antipsychotics (OAs) for disease relapse and hospitalization ― and they carry no increased risk for adverse events, new research shows.

Investigators analyzed data for more than 70,000 patients with schizophrenia and found that, compared with OAs, LAIAs were associated with lower risk for hospitalizations for any cause, hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and incident suicide attempts.

Among patients treated fully with LAIAs, there were fewer hospitalizations for somatic disorders and cardiovascular diseases and less extrapyramidal symptoms (EPS) compared with those treated fully with OAs. In addition, among those for whom treatment with LAIAs was initiated early, the reduction in these outcome events was greater in comparison with patients for whom treatment was initiated later.

The results "reinforced that LAIAs were associated with a lower risk of hospitalizations, disease relapses, and suicide attempts than OAs, and this association remained during subsequent treatment periods," write the investigators, led by Esther Chan, PhD, Center for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, University of Hong Kong, China.

The findings were published online July 28 in JAMA Network Open.

Misclassification Common

"Current clinical guidelines on the use of LAIAs are derived mainly from randomized clinical trials in which strict inclusion criteria limit generalizability," the investigators note. In addition, most of these trials were of "relatively short duration," so long-term observational studies are "important to establish the safety and effectiveness of LAIAs," they write.

Moreover, most studies have been based on Western populations, and the findings may not be generalizable to Asian populations, which have been less studied.

Previous studies were also often subject to "misclassification of exposure," since patients treated with LAIAs alone and those treated concurrently with LAIAs and OAs were categorized together as "LAIA" users and were compared with users of OAs alone, the researchers note.

To investigate the long-term safety and efficacy of LAIAs, they assessed data from the Clinical Data Analysis and Reporting System, an electronic health records database of the Hong Kong Hospital Authority. They identified 70,396 patients with schizophrenia (52.8% women; mean age, 44.2 years).

The investigators used a self-controlled case series design ― "within-individual comparison, based on a case-only approach" ― to analyze the data. This model uses incidence rate ratios (IRRs) derived by "comparing the rate of outcomes between exposed and unexposed or reference periods for the same individual." In this approach, "only people with both the exposure and the outcome are eligible."

To be included, a patient had to have received at least one OA and LAIA and had to have had at least one outcome event during the observation period of January 2004 or the date of first schizophrenia diagnosis (whichever came later) through December 2019 or death (whichever came first).

The observation period was further subdivided into four periods: a nontreatment period, a period in which OAs were used alone, a period in which LAIAs were used alone, and a period in which a combination of OAs and LAIAs were used together.

Primary outcomes included healthcare use and disease relapses, such as hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and incident suicide attempt. Secondary outcomes included hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and EPS.

LAIAs Superior

Of the total study population, 23,719 patients (33.7%) were prescribed both OAs and LAIAs (mean age, 41.7 years). Of these participants, 15.4% died during the observation period.

The mean duration of follow-up was 12.5 years. The mean duration of exposure to OAs alone was 5 years; for LAIA exposure alone, 1.4 years; and for OA plus LAIA exposure, 4.4 years.

During the observation period, almost all individuals (92.8%) had one or more emergency department (ED) visits, and most (88.4%) had one or more hospitalizations for any psychiatric disorder. Over three quarters (77.5%) were hospitalized for schizophrenia, and a small percentage (6.1%) had an incident suicide attempt.

Almost all patients experienced EPS (93.5%); over half (64.9%) were hospitalized for somatic disorders; and 15.6% were hospitalized for cardiovascular diseases.

After adjustment, compared with OAs, use of LAIAs was associated with a significantly lower risk for most outcomes.

Outcome % Reduction in Incident Rate Ratio (95% CI)
Hospitalizations for any cause 37%
0.63 (0.61 – 0.65)
Hospitalizations for psychiatric disorders 48%
0.52 (0.50 – 0.53)
Hospitalizations for schizophrenia 47%
0.53 (0.51 – 0.55)
Incident suicide attempts 44%
0.56 (0.44 – 0.71)
Hospitalizations for somatic disorders 12%
0.88 (0.85 – 0.91)
Hospitalizations for cardiovascular diseases 12%
0.88 (0.81 – 0.96)
EPS 14%
0.86 (0.82 – 0.91)


There were no differences between LAIAs and OAs regarding ED visits.

The reduction in EPS suggests that LAIAs "were not associated with a higher risk of those adverse events than OAs," the investigators write.

When the patients were stratified by initiation time of LAIAs, early initiators had 76% fewer hospitalizations for schizophrenia during LAIA vs OA treatment (incident rate ratio [IRR], 0.24; 95% CI, 0.21 ‒ 0 .27), while late initiators of LAIAs had 55% fewer hospitalizations for schizophrenia (IRR, 0.45; 95% CI, 0.40 ‒ 0.49), "suggesting that early LAIA initiators could have greater reduction in disease relapse," the researchers note.

Participants with comorbid substance use had a significantly lower risk for hospitalizations for any cause, hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, hospitalizations for somatic disorders, incident suicide attempts, and EPS during the time they were treated with LAIAs vs the time they were treated with OAs.

Older adults (>65 years) treated with LAIAs had a lower risk for ED visits, hospitalizations for any cause, hospitalizations for psychiatric disorders, and hospitalizations for schizophrenia. They were not at increased risk for hospitalizations for somatic disorders or cardiovascular diseases.

There was, however, a higher risk for EPS during initial treatment with LAIAs, so "caution should be exercised when initiating LAIAs" in older individuals, the investigators write.

Study limitations that were cited include the fact that pooled estimates were used for all LAIAs, rather than for individual antipsychotics. Additionally, the dose of these antipsychotics "was not accounted for because the disease information was recorded in a different way for LAIAs and OAs."

Proactive Approach

Commenting for Medscape Medical News, Brittany Gouse, MD, assistant professor at Boston University School of Medicine and a psychiatrist in the Wellness and Recovery after Psychosis Program, Boston Medical Center, Massachusetts, said the study "adds to the growing body of evidence supporting the longitudinal benefits" of LAIAs for patients with schizophrenia spectrum disorders.

"In particular, there may be a unique benefit to transitioning to long-acting injectable antipsychotics within the first 2 years of illness," said Gouse, who co-authored an accompanying editorial and was not involved with the research.

She also called the study "important," because it suggests that early initiation of LAIAs "may serve as an important tool to reduce morbidity and bridge the premature mortality gap in schizophrenia."

Gouse emphasized the importance of prioritizing "tertiary prevention" right from the onset of psychotic illness.

"Clinicians must take a proactive approach and include long-acting antipsychotics in shared decision-making conversations with patients within the first few years of illness," she said.

The study was funded by the Excellent Young Scientists Fund of the National Natural Science Foundation of China. Chan received grants from the National Natural Science Foundation of China during the conduct of the study; nonfinancial support from the Wellcome Trust; grants from the Research Grants Council (RGC, HKSAR), the Research Fund Secretariat of the Food and Health Bureau (Health and Medical Research Fund, HKSAR), the National Health and Medical Research Council (Australia), the Narcotics Division of the Security Bureau of HKSAR, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, Takeda, and Novartis; and personal fees from Pfizer, Novartis, and the Hong Kong SAR Hospital Authority outside the submitted work. The editorialists report no relevant financial relationships.

JAMA Netw Open. Published online July 28, 2022. Full article, Editorial

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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