Purpose To identify specific quantitative and qualitative factors that govern the decision to adhere or decline antidepressant medication in antenatal women with moderate‐to‐severe mood and anxiety disorders. Methods Fifty women (30 adherers, 20 decliners) were recruited between 18 and 34 weeks gestation in a tertiary care clinic for perinatal mothers. They were prospectively monitored 4 weeks apart up to 1‐month postpartum on the: Hamilton Anxiety Scale, Hamilton Depression Scale, Mood Disorders Insight Scale, Antidepressant Compliance Questionnaire, Penn State Worry Questionnaire, and NEO Personality Inventory. Qualitative interviews were conducted at baseline. Hierarchical linear modeling determined illness trajectories of the two groups. Results Significantly different course of illness was observed in adherers versus decliners. Adherers had healthier attitudes toward depression and compliance with medication (P < .005). Decliners had less illness insight (P < .001) and cited fear of fetal exposure, and thought medication was unwarranted. Conclusions Pregnant women experienced significantly divergent illness trajectories depending on if they accepted antidepressant medication therapy for their illness. Risk perception, attitudes, and illness insight impacted decisions surrounding adherence and decline.