Triple network model of brain connectivity changes related to adverse mood effects in an oral contraceptive placebo-controlled trial

Combined oral contraceptives (COC) are among the most commonly used contraceptive methods worldwide, and mood side effects are the major reason for discontinuation of treatment. We here investigate the directed connectivity patterns associated with the mood side effects of an androgenic COC in a double-blind randomized, placebo-controlled trial in women with a history of affective COC side effects (n=34). We used spectral dynamic causal modeling on a triple network model consisting of the default mode network (DMN), salience network (SN) and executive central network (ECN). Within this framework, we assessed the treatment-related changes in directed connectivity associated with adverse mood side effects. Overall, during COC use, we found a pattern of enhanced connectivity within the DMN and decreased connectivity within the ECN. The dorsal anterior cingulate cortex mediates an increased recruitment of the DMN by the ECN during treatment. Mood lability was the most prominent COC-induced symptom and also arose as the side effect most consistently related to connectivity changes. Connections that were related to increased mood lability showed increased connectivity during COC treatment, while connections that were related to decreased mood lability showed decreased connectivity during COC treatment. Among these, the connections with the highest effect size could also predict the participants’ treatment group above chance. Significance Statement Mood side effects are the major reason for discontinuation of oral contraceptive (OC) use. However, the neural substrate underlying these adverse mood effects is still unknown. Here, we investigate the connectivity changes during OC use in women with a history of OC-related mood side effects. We show that mood lability experienced during OC use relates to connectivity patterns previously reported across different mood disorders. The dorsal anterior cingulate cortex, crucial for emotional and cognitive regulation, arose as a mediator area between networks. These neural dynamics during OC treatment may affect cognitive processes underlying mood stability. These findings have important implications for women’s mental health and well-being.