2026 ECNP Congress

EP02-2090

Sexual dysfunction associated with long-acting injectable antipsychotics: a systematic review

Silvia Tempia Valenta — F. Marcolini, C. Biolchini, L. Carra, O. Ezeifedi, C. Possidente, D. De Ronchi, A.R. Atti · University of Bologna, Department of Biomedical and Neuromotor Sciences DIBINEM, Bologna, Italy

2026 ECNP Congress

Introduction

Long-acting injectable (LAI) antipsychotics can improve adherence and reduce relapse risk in schizophrenia and related disorders [1]. Compared with oral formulations, LAIs provide sustained plasma exposure and limited flexibility in dose adjustment [2]. This may lead to more persistent endocrine effects, particularly with prolactin-raising agents such as risperidone and paliperidone.

Sexual dysfunction, including reduced libido, erectile dysfunction, ejaculatory disorders, amenorrhea, and galactorrhea, is highly prevalent in psychiatric populations and has a major impact on quality of life and treatment adherence [3]. The primary pharmacological mechanism involves dopamine D2 receptor antagonism in the tuberoinfundibular pathway, resulting in hyperprolactinemia, GnRH suppression, and decreased gonadal steroid production [4]. Additional mechanisms include dopaminergic blockade-related anhedonia and alpha-1 adrenergic antagonism [5].

It remains unclear whether the sustained exposure profile of LAIs modifies the magnitude or clinical presentation of sexual dysfunction compared with oral antipsychotics.

Aims

To evaluate the prevalence and clinical features of sexual dysfunction across different LAI formulations in patients with psychiatric disorders.

Methods

This systematic review followed PRISMA 2020 guidelines (PROSPERO: CRD420251047923). PubMed/MEDLINE, Scopus, and the Cochrane Library were searched from inception to May 2025.

Eligible studies reported prolactin levels, hyperprolactinemia, or sexual dysfunction outcomes in patients > 13 years receiving LAI antipsychotics. No restrictions were applied on study design, setting, or ethnicity.

Results

Out of 1639 records, 40 studies were included: 6 randomized controlled trials, 24 observational studies, 8 post hoc or open-label extensions, and 2 pilot studies.

First-generation LAIs showed a variable profile, with sexual dysfunction reported in 42-73% of patients.

Among second-generation LAIs, risperidone LAI and paliperidone palmitate were consistently associated with higher prolactin levels and higher reported rates of sexual dysfunction across studies, with hyperprolactinemia rates ranging from 60% to 91% and sexual dysfunction from 24% to 64%.

Olanzapine LAI showed low rates of hyperprolactinemia (1-1.3%) but still reported sexual dysfunction, suggesting prolactin-independent mechanisms.

In a direct randomized trial, sexual dysfunction at week 28 was significantly lower with aripiprazole LAI (37.9%) compared with paliperidone palmitate (63.1%; p = 0.0012), with a greater effect in women and patients < 35 years (p = 0.0036).

In switch studies, prolactin normalization after transition to aripiprazole lauroxil occurred in 60.5% at 2 months, 85% at 3 months, and 93.7% at 6 months. Sexual dysfunction decreased from 81.3% to 56.3%.

Across formulations, prolactin levels were consistently higher in females (p < 0.05). Findings suggest that endocrine and sexual side effects are more closely related to pharmacodynamic properties than to the route of administration, although direct comparisons across studies are limited by heterogeneity.

Conclusions

LAI antipsychotics are associated with clinically relevant rates of sexual dysfunction, often but not exclusively mediated by hyperprolactinemia. Available evidence suggests a more favorable profile for aripiprazole LAI, while risperidone LAI and paliperidone palmitate appear to be associated with a higher burden of prolactin-related adverse effects.

Heterogeneity across studies limits direct comparisons. These findings support routine assessment of sexual function in patients treated with LAIs, particularly in women and younger individuals, and highlight the need for prospective studies using standardized instruments and hormonal evaluation.

References

  1. Brissos, S., Veguilla, M. R., Taylor, D., & Balanzá-Martinez, V. (2014). The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Therapeutic advances in psychopharmacology, 4(5), 198-219.
  2. Correll, C. U., Kim, E., Sliwa, J. K., Hamm, W., Gopal, S., Mathews, M., … & Saklad, S. R. (2021). Pharmacokinetic characteristics of long-acting injectable antipsychotics for schizophrenia: an overview. CNS drugs, 35(1), 39-59.
  3. Park, Y. W., Kim, Y., & Lee, J. H. (2012). Antipsychotic-induced sexual dysfunction and its management. The world journal of men’s health, 30(3), 153-159.
  4. Bostwick, J. R., Guthrie, S. K., & Ellingrod, V. L. (2009). Antipsychotic‐induced hyperprolactinemia. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 29(1), 64-73.
  5. La Torre, A., Conca, A., Duffy, D., Giupponi, G., Pompili, M., & Grözinger, M. (2013). Sexual dysfunction related to psychotropic drugs: a critical review part II: antipsychotics. Pharmacopsychiatry, 46(06), 201-208.