Women with premenstrual disorders had about twice the risk of developing psychiatric disorders, while women with psychiatric disorders were similarly more likely to later receive a diagnosis of premenstrual disorders, according to a nationwide Swedish cohort study involving more than 3.6 million women. The findings suggest shared biologic pathways between these conditions and support sex-specific and menstrual cycle–informed psychiatric care.
Investigators analyzed Swedish national and regional registry data from 2001 through 2022 to examine bidirectional associations between clinically diagnosed premenstrual disorders and 14 psychiatric disorder subtypes. The study, published in JAMA Network Open, included 104,972 women diagnosed with premenstrual disorders matched to unaffected controls at a 1:10 ratio and, separately, to unaffected full sisters. Sibling comparisons were designed to account for shared familial and early environmental factors.
The cohort had a mean follow-up of 8.2 years. Women with premenstrual disorders had a mean age of 35 years at diagnosis.
Psychiatric History Preceding Premenstrual Disorders
In a nested case-control analysis, 48% of women with premenstrual disorders had a prior psychiatric diagnosis compared with 30% of unaffected controls. After demographic adjustment, women with psychiatric disorders had more than twice the odds of later developing premenstrual disorders. In sibling comparisons, the association was attenuated but remained, suggesting shared familial factors did not fully explain the relationship.
Premenstrual Disorders and Subsequent Psychiatric Risk
In the matched cohort analysis, 37% of women with premenstrual disorders developed a subsequent psychiatric disorder during follow-up compared with 21% of unaffected women. Women with premenstrual disorders had more than twice the risk of a later psychiatric diagnosis. The association also persisted in sibling analyses, although with smaller effect sizes.
Type-Specific Associations
Bidirectional associations were observed for 13 of 14 psychiatric categories in the population analysis and 11 of 14 in sibling comparisons.
Depression and anxiety disorders showed some of the strongest bidirectional associations. Women with depression had more than twice the odds of later premenstrual disorders, while women with premenstrual disorders had nearly three times the risk of subsequent depression. Anxiety disorders showed similarly elevated associations in both directions.
Elevated risks were also observed for attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, and personality disorders. Women with premenstrual disorders had more than three times the likelihood of subsequent ADHD, bipolar disorder, and personality disorder diagnoses. Autism also showed significant bidirectional associations.
No bidirectional association was observed for schizophrenia. The authors suggested several possible explanations for the null finding, including diagnostic overshadowing, menstrual irregularities related to antipsychotic treatment, and underrecognition of cyclical symptoms in patients with schizophrenia.
Proposed Mechanisms
The authors emphasized that the findings should be interpreted as evidence of shared pathophysiological pathways rather than causal relationships.
Potential mechanisms included hypothalamic-pituitary-adrenal axis dysregulation, altered sensitivity to hormonal fluctuations, and altered serotonin, dopamine, and γ-aminobutyric acid signaling. The authors also noted evidence for shared genetic susceptibility between premenstrual disorders and several psychiatric conditions.
Twin and family studies cited in the paper estimate heritability for premenstrual disorders at 35% to 56%. Attenuated associations in sibling analyses suggested partial contributions from shared genetic or familial factors.
Data Sources and Sensitivity Analyses
The study used linked Swedish national registries, including patient, prescription, and primary care databases covering approximately 60% of reproductive-age women. Premenstrual disorder cases were identified through clinical diagnoses and prescriptions specifically indicated for these conditions.
Sensitivity analyses included restricting analyses to women with repeated diagnoses, limiting analyses to counties with primary care data, and adjusting for smoking, body mass index, and healthcare utilization. Associations remained largely unchanged across analyses.
Higher bidirectional risks were observed among women born outside Scandinavia and among women younger than 35 years at diagnosis or matching.
Limitations
The authors noted several limitations.
Registry-based diagnoses could not confirm the criterion-standard diagnostic approach for premenstrual disorders, which requires prospective daily symptom ratings across at least two menstrual cycles. However, analyses limited to women with repeated diagnoses yielded similar findings.
The study also relied on timing of clinical diagnoses rather than symptom onset. Because many psychiatric disorders manifest earlier than the mean age of premenstrual disorder diagnosis in the cohort, some conditions may have been underrepresented in analyses of psychiatric disorders occurring after premenstrual disorder diagnosis.
Investigators also acknowledged possible surveillance bias, in which diagnosis of one condition may increase clinical attention toward another. Symptom overlap between premenstrual disorders and mood or anxiety disorders may also contribute to diagnostic misclassification.
“Our findings highlight the need for raising awareness among health care providers on the higher risk of co-occurrence between these conditions and for providing sex-specific and menstrual cycle–informed care in psychiatry,” the authors concluded.
Disclosures can be found in the study.
Source: JAMA Network Open
