Hormonal contraception and SSRIs influence on oxytocin and cortisol reactivity to stress in patients with borderline personality disorder

Background: Borderline personality disorder (BPD) involves emotional instability and stress sensitivity linked to oxytocinergic and HPA-axis dysregulation. This study examined oxytocin and cortisol responses to acute psychosocial stress and the modulatory effects of SSRIs and hormonal contraception. Methods: 93 female participants (45 with BPD with/without SSRIs and 48 healthy controls) underwent the Trier Social Stress Test. Linear and generalized linear mixed-effects models were applied to assess time, group, and hormonal contraception effects, and their interactions. Results: During the stress task, both BPD groups reported significantly higher subjective anxiety and anger than controls. All participants showed increased salivary oxytocin (OXT) during stress anticipation, but post-task trajectories diverged: BPD participants without SSRIs exhibited a sharp OXT decline, whereas those on SSRIs mirrored the stable trajectory of controls. Hormonal contraception reversed the OXT decline in untreated BPD participants, resulting in a progressive increase during recovery. Cortisol (CORT) analyses revealed hyporeactivity in BPD participants without SSRIs, a pattern unaffected by hormonal contraception. A significant three-way interaction indicated that higher OXT levels were associated with higher CORT concentrations during late recovery specifically in the BPD SSRI group, a relationship that was marginal in untreated patients and absent in controls. Conclusions: Our findings confirm that neuroendocrine dysregulation in BPD is context-dependent and sensitive to pharmacological modulation. The ability of SSRIs and hormonal contraception to influence stress-response patterns, despite limited efficacy on core symptoms, highlights the importance of controlling for medication and hormonal status in future BPD biomarker research.