Long-acting injectable antipsychotics (LAIs) have been shown to reduce acute episodes of schizophrenia spectrum disorders (SSDs). However, breakthrough relapses are frequent, possibly because of underdosing in clinical practice. In this framework, the advantages of therapeutic drug monitoring (TDM) may be overlooked. This study explored the association of low steady-state LAI levels with a higher risk of relapse in SSDs, despite the use of a licensed posology.

Forty-eight clinically stable outpatients with SSD underwent LAI-TDM using liquid chromatography–mass spectrometry for routine observational purposes. Baseline anamnestic, pharmacological, and psychometric evaluations compared subjects with “under-range” versus “in-range” LAI serum levels; between-group comparisons for different LAI treatments were also performed. A binary logistic regression explored which baseline factors (age, sex, previous hospitalizations, psychopathology, specific LAI treatment, and underrange serum levels) predicted relapse during the next 12 months.

Baseline comparisons did not show significant between-group differences, except for a higher percentage of underrange values in individuals receiving olanzapine pamoate. A total of 10 patients (20.8%) relapsed during the follow-up; only underrange LAI levels predicted the event (odds ratio 0.03, 95% confidence interval 0.01–0.36; P = 0.005).

Even if relapse remains as a multifactorial event, LAI-TDM may identify subjects at risk for this negative outcome, thus optimizing antipsychotic maintenance treatment in the context of precision medicine. The finding of underrange LAI plasma levels in real-world practice should prompt adequate monitoring of clinically stable outpatients to identify the early signs of psychopathological deterioration.