01. Long-Acting Injectables: Superior for Reducing Mortality in Schizophrenia?

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Reducing Mortality in Schizophrenia: LAIs vs. Orals

In this Quick Take, we’ll examine an important aspect of care for people with schizophrenia: reducing their premature mortality. Specifically, we’ll look at whether long-acting injectable antipsychotics (LAIs) make a difference compared to oral antipsychotics.

Antipsychotics: Effective but Adherence Issues

Antipsychotics are highly effective in preventing psychotic relapse in patients with schizophrenia. The number needed to treat (NNT) is 3 for antipsychotics for relapse prevention, comparable to many routine medical treatments. However, nonadherence to oral antipsychotics is a significant clinical problem.

Nonadherence can lead to:

• Unstable illness course
• Numerous relapses
• Partial recovery
• Psychosocial toxicity

Psychosocial Toxicity

Psychosocial toxicity can manifest as:

• Time spent in inpatient units instead of school
• Job loss
• Reputation damage
• Legal problems
• Death due to unstable illness (i.e., suicide, accidents poorly treated medical illness)

Reduced Life Expectancy in Schizophrenia

Patients with schizophrenia have a reduced life expectancy of 15 to 20 years on average. It’s important to note that untreated psychiatric patients have the worst outcomes, despite some morbidity and mortality from psychiatric treatments like antipsychotics. Psychiatric treatment truly prevents death.

LAIs vs. Oral Antipsychotics Rationale

Numerous studies have shown that LAIs reduce relapse compared to oral antipsychotics. The rationale that drives this article’s research questions would be:

1. Antipsychotics, when reliably taken, prevent relapse
2. Relapse prevention reduces mortality
3. LAIs are more reliably taken than oral antipsychotics

Meta-Analysis: LAIs and Mortality

A recent meta-analysis published in Molecular Psychiatry by Claudia Aymerich focused on the important clinical endpoint of mortality. The study included clinical trials from across the globe, ensuring broad applicability.

Key findings: When compared to oral antipsychotics:

1. LAIs reduced all-cause mortality (odds ratio 0.79)
2. LAIs reduced non-suicidal mortality (odds ratio 0.77)
3. LAIs were not statistically better for preventing suicide deaths
4. First-episode patients benefited more than chronic patients in mortality reduction

Study Limitations

The analysis had some limitations:

• Not all antipsychotics are available as LAIs
• Differences between individual antipsychotics couldn’t be examined
• Most studies used atypical or second-generation antipsychotics

Implementing LAIs in Clinical Practice

Despite the benefits, proposing LAIs to patients can be challenging. Two strategies may help shift the culture around LAI acceptability:

1. Introduce LAIs early: ° Present them as an excellent first choice ° Normalize LAIs from the first meeting ° Avoid the perception of punitive use
2. Emphasize mortality benefits: ° Highlight the significant improvement in mortality ° Learn from oncology’s approach: prioritize and emphasize treatments that offer proven mortality benefits, not just symptom management.

LAIs in Specific Patient Groups

LAIs may be particularly beneficial for:

• First-episode patients (high-risk group for relapse)
• Patients with potential for violence if they relapse
• People living chaotic lives (e.g., experiencing homelessness)

Clinical Advantages of LAIs

Using LAIs offers several advantages:

• Eliminates guesswork about adherence
• Frees up appointment time for recovery goals
• Reduces family burden of monitoring adherence
• Forces clinics to provide more accountable care

Bottom Line

For any person with schizophrenia needing maintenance treatment to prevent psychotic relapse, LAIs should be a first-line option, not a treatment of last resort. LAIs can stabilize illness course and prevent death from all causes better than oral antipsychotics, most clearly for non-suicide deaths.

Abstract

All-cause mortality risk in long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis

Claudia Aymerich, M.D., Gonzalo Salazar de Pablo, M.D., Malein Pacho, M.D., Violeta Pérez-Rodríguez, M.D., Amaia Bilbao, M.D., Lucía Andrés, M.D., Borja Pedruzo, M.D., Idoia Castillo-Sintes, M.D., Nerea Aranguren, M.D., Paolo Fusar-Poli, M.D., Iñaki Zorrilla, M.D., Ana González-Pinto, M.D., Miguel Ángel González-Torres, M.D. & Ana Catalán, M.D.

Patients with schizophrenia receiving antipsychotic treatment present lower mortality rates than those who do not. However, the non-adherence rate is high, which can be partially addressed using long-acting injectable (LAI) antipsychotics. The impact of LAI treatments on all-cause mortality compared to oral antipsychotics remains unclear. To fill that gap, a random effects meta-analysis was conducted to analyze the odds ratio (OR) of all-cause, suicidal, and non-suicidal mortality among patients taking LAI antipsychotics compared to oral antipsychotics (PROSPERO:CRD42023391352). Individual and pooled LAI antipsychotics were analyzed against pooled oral antipsychotics. Sensitivity analyses were performed for study design, setting, and industry sponsorship. Meta-regressions were conducted for gender, age, antipsychotic dose, and race. Seventeen articles, total sample 12,042 patients (N = 5795 oral, N = 6247 LAI) were included. Lower risk of all-cause mortality for patients receiving LAI antipsychotics vs receiving oral antipsychotics was found (OR = 0.79; 95%CI = 0.66–0.95). Statistical significance was maintained when only studies comparing the same LAI and oral antipsychotic were included (OR = 0.79; 95%CI = 0.66–0.95; p = <0.01), as well as for non-suicidal mortality (OR = 0.77: 95%CI = 0.63–0.94; p = 0.01), but not for suicidal mortality (OR = 0.86; 95%CI = 0.59–1.26; p = 0.44). Mortality reduction was more pronounced for LAI antipsychotics in first-episode psychosis (FEP) (OR = 0.79; 95%CI = 0.66–0.96) compared to chronic psychosis. No individual LAI reported statistically significant differences against all pooled oral antipsychotics. LAI antipsychotics are associated with a lower risk of all-cause and non-suicidal mortality in individuals with schizophrenia compared to oral antipsychotics. Better adherence to the medication and health services may explain this difference. Whenever possible, the use of LAIs should be considered from the FEP. 

Reference

Aymerich, C. M.D., Gonzalo, P. M.D., Malein, P. M.D., Pérez-Rodríguez, V. M.D., Bilbao, A. M.D., Andrés, L. M.D., Pedruzo, B. M.D., Castillo-Sintes, I. M.D., Aranguren, N. M.D., Fusar-Poli, P. M.D., Zorrilla, I. M.D., González-Pinto, A. M.D., González-Torres, M. M.D. & Catalán, A. M.D. (2024). All-cause mortality risk in long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis. Molecular Psychiatry volume 30, pages263–271 (2025)