Investigating the Risks of Psychiatric Comorbidities in Melasma Patients Treated With Tranexamic Acid: A Multicenter Cohort Study

Melasma is a hyperpigmentation disorder primarily affecting the face in reproductive-age women, with significant psychological impact [1]. A 2018 study reported stress exacerbated melasma in 54% of patients; depressive disorder (42%) and adjustment disorder (26%) were the most common psychiatric comorbidities [2]. Tranexamic acid (TXA), an anti-fibrinolytic synthetic lysine analog, started being used to treat melasma in 1979 and has been shown to significantly decrease the Melasma Area and Severity Index (MASI) in oral, injectable, and topical routes, as well as in combination with other melasma treatments [1, 3]. Reported side effects are mild and transient (injection pain, erythema, pruritus, urticaria, hyperpigmentation, hypertrichosis, gastritis, and hypomenorrhea), but psychiatric effects remain poorly documented [4, 5]. Given the efficacy of TXA treatment for melasma, the risk of developing psychiatric comorbidities as a result of treatment was hypothesized to be decreased. Utilizing the TriNetX database, the association between TXA use in melasma treatment and the rates of various psychiatric comorbidities was investigated via a multicenter cohort study. The International Classification of Diseases 10th Clinical Modification (ICD-10-CM) billing code L81.1 was searched on the TriNetX database in August 2025 to anonymously identify cases of melasma patients treated with TXA and propensity score-match them to patients not treated with TXA. This resulted in the inclusion of 21,525 patients in each cohort; no exclusions were performed. Demographics, including age, gender, race, and ethnicity, were collected (Table 1). Furthermore, psychiatric comorbidities (depression, anxiety, social anxiety, suicide attempt, sexual dysfunction, nicotine dependence, alcohol abuse, bipolar disorder, schizophrenia, and panic disorder) were collected by searching for their respective ICD-10-CM billing codes and assessed using risk ratios (RRs) and 95% confidence intervals (CIs) via Wald's method (Table 2) for each cohort. Per TriNetX data dissemination guidelines, groups with participant counts < 10 were suppressed. Patients diagnosed with melasma and treated with TXA had statistically significant decreased risks of depression (RR 0.708, CI 0.661–0.759, p-value < 0.0001), anxiety (RR 0.772, CI 0.729–0.818, p < 0.0001), nicotine dependence on cigarettes (RR 0.612, CI 0.541–0.693, p < 0.0001), alcohol abuse (RR 0.757, CI 0.628–0.913, p = 0.0034), and schizophrenia (RR 0.572, CI 0.468–0.699, p < 0.0001). However, the risk ratios of social anxiety (RR 0.773, CI 0.468–1.277, p = 0.3138), suicide attempt (RR 1.001, CI 0.417–2.404, p = 0.9983), sexual dysfunction not due to a substance or a known physiological condition (RR 0.916, CI 0.644–1.303, p = 0.6256), bipolar disorder (RR 0.851, CI 0.661–1.096, p 0.2112), and panic disorder (RR 0.965, CI 0.83–1.122, p = 0.6444) were statistically insignificant. The findings of this study demonstrate that TXA may decrease the risk of psychiatric comorbidities in melasma patients. This, in combination with TXA's alleviation of the physical effects of melasma as demonstrated in the literature, supports the overall satisfaction patients have with TXA treatment for melasma. Therefore, TXA should continue to be recommended to patients with melasma, especially those who are at risk of being affected by psychiatric comorbidities. Limitations of this analysis include the possibility of missing data from the TriNetX database because of using ICD-10-CM billing codes to identify melasma patients and their psychiatric comorbidities, which may not have been complete. Patients may have underreported their psychiatric comorbidities due to the sensitivity of those diseases. Furthermore, the severity of melasma and the method of TXA administration were not documented, which could have influenced risk ratios. This study only provides indirect evidence of mental benefit from TXA, based on diagnostic codes rather than direct patient-reported outcomes. While TXA has been shown to diminish pigmentation, long-term longitudinal studies of melasma patients throughout therapy are required to clarify whether psychological improvement is proportionate to pigmentation reduction and to assess long-term consequences. We gratefully acknowledge TriNetX Database for their contributions, without whom this research would not have been possible, and for making the participant data (and/or samples and/or cohort) examined in this study available. IRB approval status: This study was considered by our IRB to be nonhuman research and thus is exempt from review. Previous publishing or presentation: No prevalence data from this database has been previously published. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.