Long-Acting Injectable Antipsychotics vs Pills: What the Evidence Shows

Long-acting injectable antipsychotics were associated with a lower risk of hospitalization or relapse than oral antipsychotics in a 2021 meta-analysis of 137 studies and 397,319 patients. The size of the difference depended on the study design: the risk ratio was 0.88 in randomized trials, 0.92 in cohort studies, and 0.44 in pre-post studies.¹

A long-acting injectable (LAI) delivers an antipsychotic by injection on a schedule, in place of a daily pill. The difference from pills was smaller in randomized trials and cohort studies than in pre-post studies, and relapse still occurs on an injection.^{1, 8}

The size of the benefit depends on the study design

Source: Kishimoto et al., 2021.¹

Pre-post studies compare the same patients before and after a change in treatment, with no separate comparison group, and they showed the largest difference. For relapse alone, the association was maintained only in pre-post studies.¹

Across 328 other comparisons covering effectiveness, safety, quality of life, and cognitive function, LAIs were more beneficial in 60 (18.3%), no different in 252 (76.8%), and less beneficial in 16 (4.9%). Heterogeneity was significant in all three designs, and publication bias was apparent in the cohort and pre-post studies.¹

Swedish registry data show a lower risk of rehospitalization

A Swedish national cohort followed 29,823 patients with schizophrenia, and 43.7% were rehospitalized during follow-up. The primary analyses used each patient as his or her own control. LAIs were associated with a lower risk of rehospitalization than the equivalent oral formulations, with a hazard ratio of 0.78 (95% CI, 0.72 to 0.84) in the total cohort and 0.68 (0.53 to 0.86) in the incident cohort.²

The study is observational and comes from one country. In the same cohort, clozapine was among the treatments with the lowest rehospitalization risk compared with no antipsychotic use (hazard ratio 0.53).² I've written separately about when to start clozapine.

In early-phase schizophrenia, two randomized trials point different ways

The PRELAPSE trial randomized clinics. Nineteen clinics were assigned to encourage treatment with aripiprazole once monthly, and 20 provided treatment as usual, called clinician's choice, with no restrictions on treatment, including LAIs. The 489 participants were 18 to 35 years old with fewer than 5 years of lifetime antipsychotic use, and 46.0% had 1 year or less.³

Over 2 years, 22% of participants at the aripiprazole once monthly sites and 36% at the clinician's choice sites had at least one hospitalization. The hazard ratio for time to first hospitalization was 0.56 (95% CI, 0.34 to 0.92), and the number needed to treat to prevent one additional hospitalization was 7.³

The EULAST trial, an open-label randomized trial in Europe and Israel, compared LAI paliperidone or aripiprazole with the oral formulations of the same drugs in 511 participants whose first psychotic episode was 6 months to 7 years earlier. Its primary outcome was discontinuation for any cause over 19 months: 64% of the LAI group and 71% of the oral group met that criterion, and the difference wasn't significant (hazard ratio 1.16; 95% CI, 0.94 to 1.43; p=0.18). The authors found no substantial advantage for LAI treatment on time to discontinuation.⁴

The two trials measured different primary outcomes, so the results don't directly contradict each other. A smaller trial randomized 86 patients after a recent first episode to long-acting injectable or oral risperidone. The rate of psychotic exacerbation or relapse was 5% in the injectable group and 33% in the oral group.⁵

Lower mortality with injections is an association

A 2025 meta-analysis of 17 articles and 12,042 patients found that LAIs were associated with lower all-cause mortality than oral antipsychotics (odds ratio 0.79; 95% CI, 0.66 to 0.95). The association held for non-suicide mortality (odds ratio 0.77; 0.63 to 0.94). For suicide mortality the difference wasn't significant (odds ratio 0.86; 0.59 to 1.26). No individual LAI differed significantly from pooled oral antipsychotics, and the authors wrote that better adherence to medication and health services may explain the difference. The abstract doesn't report the mix of study designs.⁶

In the Swedish cohort, 2,515 patients (8.4%) died during a mean follow-up of 5.7 years, and LAIs were associated with 33% lower mortality than the equivalent oral formulations.⁷ That cohort is observational, and these associations don't establish that the injection is the cause.

Relapse still occurs on an injection

An individual participant data meta-analysis reanalyzed the LAI groups of relapse-prevention clinical trials in schizophrenia-spectrum disorders: 19 treatment cohorts and 5,130 people. The pooled incidence of relapse was 22.97 per 100 participant-years. The authors concluded that antipsychotics might not prevent later exacerbations for a proportion of people stabilized on continuous treatment.⁸

Pros and cons the studies can and can't address

• Hospitalization or relapse: lower risk with LAIs in randomized trials and cohort studies, and lower rehospitalization in the Swedish registry, with a smaller difference than in pre-post studies.^{1, 2}
• Early-phase illness: one positive cluster-randomized trial on hospitalization and one null trial on discontinuation.^{3, 4}
• Mortality: an association with lower all-cause mortality, with no significant difference for suicide.⁶
• Patient preference, injection-site problems, and cost: none of the abstracts reviewed here reports them.

A change from pills to an injection, or back, is made with the prescriber.

Limitations of the evidence

This evidence has limitations. First, the estimate varies with study design, and the largest difference comes from pre-post studies with no comparison group. Second, the mortality findings are associations with no randomized trial of mortality as a primary outcome among the sources reviewed here, and the two early-phase trials measured different primary outcomes. Nevertheless, randomized trials, cohort studies, and a national registry agree in direction on hospitalization or relapse, which supports raising an LAI with the prescriber as an option alongside pills, including early in the illness.

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.

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