Rationale Selective serotonin reuptake inhibitors remain the first-line pharmacotherapy for depression and anxiety disorders, yet remission rates are low and variability in treatment outcomes is poorly understood. Reinforcement sensitivity, a trait-based dimension reflecting individual differences in responsiveness to reward and punishment, has been linked to affective vulnerability, but its association with SSRI outcomes has not been systematically examined in humans. Methods We conducted an online study recruiting over 3000 participants, of whom 1979 met strict inclusion criteria and were included in the analyses. Participants were taking citalopram, fluoxetine, or sertraline and provided standardized self-report data on anxiety and depressive-like symptoms. In addition, they completed experimental tasks assessing motivation and reinforcement sensitivity. Based on sensitivity to positive and negative reinforcement, participants were classified into four phenotypes (P-N-, P+N+, P-N+, P+N-). Symptom outcomes were analyzed in relation to treatment type, dose, and phenotype. Results Across antidepressant groups, participants exhibited elevated anxiety and depressive-like symptoms relative to controls, consistent with residual symptomatology. Patterns of symptom differences varied across reinforcement sensitivity phenotypes: Lower insomnia levels were observed primarily in P-N- individuals receiving citalopram or fluoxetine, whereas comparable insomnia levels to controls were observed in P+N+ participants receiving sertraline. Genitourinary symptom levels were lower in P-N- and P-N+ phenotypes among citalopram users, and in P+N- individuals receiving fluoxetine or sertraline. Dose-dependent patterns were also observed. Conclusions We report exploratory associations between reinforcement sensitivity, residual symptom profiles, and antidepressant treatment characteristics, including SSRI type and dosage. These findings highlight reinforcement sensitivity as a potential descriptive framework for understanding heterogeneity in residual symptoms among SSRI users and underscore the value of large-scale online research.

From uniform pharmacotherapy to precision psychiatry: reinforcement sensitivity associations with SSRI outcomes

期刊论文
发表日期：

2026年4月18日

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Michal Piksa,
Agata Cieslik-Starkiewicz,
Rafal Rygula

摘要

Rationale

Selective serotonin reuptake inhibitors remain the first-line pharmacotherapy for depression and anxiety disorders, yet remission rates are low and variability in treatment outcomes is poorly understood. Reinforcement sensitivity, a trait-based dimension reflecting individual differences in responsiveness to reward and punishment, has been linked to affective vulnerability, but its association with SSRI outcomes has not been systematically examined in humans.

Methods

We conducted an online study recruiting over 3000 participants, of whom 1979 met strict inclusion criteria and were included in the analyses. Participants were taking citalopram, fluoxetine, or sertraline and provided standardized self-report data on anxiety and depressive-like symptoms. In addition, they completed experimental tasks assessing motivation and reinforcement sensitivity. Based on sensitivity to positive and negative reinforcement, participants were classified into four phenotypes (P^-N^-, P⁺N⁺, P^-N⁺, P⁺N^-). Symptom outcomes were analyzed in relation to treatment type, dose, and phenotype.

Results

Across antidepressant groups, participants exhibited elevated anxiety and depressive-like symptoms relative to controls, consistent with residual symptomatology. Patterns of symptom differences varied across reinforcement sensitivity phenotypes: Lower insomnia levels were observed primarily in P^-N^- individuals receiving citalopram or fluoxetine, whereas comparable insomnia levels to controls were observed in P⁺N⁺ participants receiving sertraline. Genitourinary symptom levels were lower in P^-N^- and P^-N⁺ phenotypes among citalopram users, and in P⁺N^- individuals receiving fluoxetine or sertraline. Dose-dependent patterns were also observed.

Conclusions

We report exploratory associations between reinforcement sensitivity, residual symptom profiles, and antidepressant treatment characteristics, including SSRI type and dosage. These findings highlight reinforcement sensitivity as a potential descriptive framework for understanding heterogeneity in residual symptoms among SSRI users and underscore the value of large-scale online research.