Depression is 2–3× more common in people with multiple sclerosis (pwMS) than in the general population, ^{Reference Feinstein, Bar-Or and Benedict1} contributing to reduced quality of life and unemployment. ^{Reference Feinstein, Bar-Or and Benedict1} Contrary to higher rates of depression in females than males in the general population, depression occurs equally in both sexes in pwMS. ^{Reference Feinstein, Bar-Or and Benedict1} This discrepancy emphasizes the need to evaluate sex differences in potential contributors to multiple sclerosis (MS)-related depression, such as nicotine use (e.g., cigarette smoking). ^{Reference Rosso and Chitnis2}

Cigarette smoking has a dose–response relationship with MS risk and is associated with higher lesion load, increased brain atrophy and greater disability progression among people with relapsing-remitting MS (pwRRMS). ^{Reference Rosso and Chitnis2} Reviews suggest that cigarette smoking is associated with increased depressive symptoms in pwRRMS and in the general population. ^{Reference Vong, Simpson-Yap and Phaiju3,Reference Weinberger, Kashan and Shpigel4} While this link with depression is stronger in females than males in the general population, ^{Reference Fan, Gong and Xu5} only one study has examined this question in pwRRMS and found no association. ^{Reference Briggs, Thompson and Conway6} However, this study was limited by a large proportion of participants who were excluded due to missing data or not being seen within 3.5 years of a prior assessment. Excluded participants differed from those who were included regarding smoking status and other clinical characteristics. It thus remains unclear whether sex influences the connection between smoked nicotine and depressive symptoms in pwRRMS. The current study aims to address this research gap.

Participants were a consecutive sample of 281 pwRRMS (ages 18–65) assessed at a tertiary neuropsychiatry clinic from May 2024 to September 2025. As an exploratory study, the sample size was determined by the extent of available data. PwRRMS are typically referred to this clinic for mood, anxiety or cognitive concerns, which may bias the sample to those with elevated neuropsychiatric symptoms. Demographic and disease-related data factors (age, sex, years of education, Expanded Disability Status Scale [EDSS] scores, ^{Reference Kurtzke7} disease subtypes [progressive/relapsing], disease duration and disease-modifying therapy [DMT] use) were obtained from chart review. Current smoked nicotine was assessed from a self-report (absent/present) question (i.e., “do you smoke nicotine?”), and depressive symptoms were measured with the Hospital Anxiety and Depression Scale sub-scale for depression (HADS-D), ^{Reference Zigmond and Snaith8} validated in people with MS. ^{Reference Honarmand and Feinstein9}

Two-factor analyses of variance (for continuous variables) and chi-square analyses (for categorical variables) were used to evaluate whether demographics, disease-related factors or HADS-D scores varied according to sex, smoked nicotine use or the interaction (sex × smoked nicotine use). An analysis of covariance (ANCOVA) was undertaken to evaluate the influences of sex and smoked nicotine use on HADS-D scores, controlling for age, education, EDSS scores, disease duration and DMT use. To clarify the nature of a potential interaction, ANCOVAs were conducted to evaluate whether smoked nicotine use was linked to HADS-D scores in males and females. Significance was designated as p < 0.05.

The mean participant age was 42.0 years (SD = 11.0), 74.7% were female, the mean EDSS was 2.2 (SD = 1.4), 79.0% received disease-modifying therapies, 19.9% smoked nicotine-related substances and the mean HADS-D score was 7.0 (SD = 4.0). Table 1 includes sample data stratified by sex and whether participants smoked nicotine. Males were more likely to smoke nicotine-related substances (29.6%) than females (16.7%, X² = 5.54, φ = 0.14, p = 0.019). Smoked nicotine was linked to lower education (F = 11.33, ƞ² = 0.04, p = 0.001) and reduced DMT use (X² = 7.05, φ = −0.16, p = 0.008). There were no significant differences in age, EDSS or disease duration according to sex or smoked nicotine use.

Table 1.

Participant clinical characteristics stratified by sex and nicotine use

Table 1 Long description

The table presents participant clinical characteristics stratified by sex and nicotine use. It has 10 rows and 8 columns. The columns are labeled as Males No nicotine use, Males Nicotine use, Females No nicotine use, and Females Nicotine use. The rows are labeled as Number, Percentage of total sample, Number of participants, Age, Education, Expanded Disability Status Scale, Disease duration, Hospital Anxiety and Depression Scale sub-scale for depression, and Disease-modifying therapy use (%). Row 1: Number, 50, 21, 175, 35. Row 2: Percentage of total sample, 17.79, 7.47, 62.28, 12.46. Row 3: Number of participants, 281, 281, 281, 281. Row 4: Age, Mean (SD), 42.60 (10.69), 42.81 (12.42), 42.01 (10.88), 40.54 (11.35). Row 5: Education, Mean (SD), 15.72 (2.79), 13.95 (3.06), 16.53 (3.46), 14.80 (2.91). Row 6: Expanded Disability Status Scale, Mean (SD), 2.43 (1.66), 2.33 (1.63), 2.21 (1.41), 1.86 (1.12). Row 7: Disease duration, Mean (SD), 8.83 (7.96), 9.24 (8.36), 8.58 (8.30), 9.43 (8.39). Row 8: Hospital Anxiety and Depression Scale sub-scale for depression, Mean (SD), 7.56 (4.53), 6.62 (3.73), 6.51 (3.76), 8.49 (3.89). Row 9: Disease-modifying therapy use (%), 45 (90.00), 15 (71.43), 140 (80.00), 22 (62.86).

Unadjusted for covariates, there were no significant main effects of sex (F(1, 277) = 0.42, ƞ² < 0.01, p = 0.515) nor smoked nicotine use (F(1, 277) = 0.69, ƞ² < 0.01, p = 0.409) on HADS-D scores. There was a significant interaction between sex and smoked nicotine use on HADS-D scores (F(1, 277) = 5.43, ƞ² = 0.02, p = 0.020), unadjusted for covariates.

When controlling for covariates, the main effects of sex (F(1, 272) = 0.84, ƞ² < 0.01, p = 0.361) and smoked nicotine use (F(1, 272) = 0.94, ƞ² < 0.01, p = 0.334) still did not significantly influence HADS-D scores. The interaction between sex and smoked nicotine use, controlling for covariates, was significantly linked to HADS-D scores (F(1,272) = 6.02, ƞ² = 0.02, p = 0.015). Simple effects analyses showed that smoked nicotine use was associated with elevated HADS-D scores in females (F(1, 203) = 9.91, ƞ² = 0.05, p = 0.002), adjusted mean difference of 2.22 points (95% CI [0.83, 3.61]), but not in males (F(1, 64) = 0.79, ƞ² = 0.01, p = 0.38), adjusted mean difference of −1.01 points (95% CI [−3.27, 1.25]). Figure 1 depicts the relationships between sex, smoked nicotine use and depressive symptoms after controlling for covariates.

Figure 1.

Differences in depressive symptoms (as measured with the Hospital Anxiety and Depression Scale sub-scale [HADS-D]) according to sex and smoked nicotine use, adjusted for covariates. Error bars indicate ± standard error.

This study demonstrates a sex-specific connection between smoked nicotine use and increased depressive symptoms in females with relapsing-remitting MS (RRMS) that remains significant after controlling for potential confounding variables. It is only in female pwRRMS who smoke nicotine-related substances that the mean HADS-D score exceeds the threshold for probable depression. ^{Reference Wu, Olsson, Hillert, Alfredsson and Hedström10} While the cross-sectional design precludes determining whether this is a causal relationship, this novel finding deserves further scrutiny.

Prior research suggests a link between smoking cigarettes and depressive symptoms in pwRRMS in general. ^{Reference Vong, Simpson-Yap and Phaiju3} Yet, most studies have controlled for the influence of sex, rather than testing for differences between males and females. ^{Reference Vong, Simpson-Yap and Phaiju3} Our data, on the other hand, encompassing a large representative sample of pwRRMS, reveal clear associations between female sex, smoked nicotine use and depressive symptoms, consistent with general population data. ^{Reference Fan, Gong and Xu5}

Several explanations have been proposed to account for this finding in the general population. Females may be more likely than males to use smoking as an affect-related coping strategy and may experience more intense emotional responses to quitting smoking than males. ^{Reference Fan, Gong and Xu5} Also, heightened concentrations of estradiol and progesterone may impact the reinforcement of smoked nicotine use and its metabolism. ^{Reference Fan, Gong and Xu5} As previously noted, while there is a 2:1 sex ratio of depression in the general population, there is no sex difference in rates of depression in pwRRMS. ^{Reference Feinstein, Bar-Or and Benedict1} It remains uncertain whether general population mechanisms apply to pwRRMS. In MS, the adverse effects of smoked nicotine use are thought to be due to the pro-inflammatory and neurotoxic effects of smoking. ^{Reference Rosso and Chitnis2} This pro-inflammatory cascade is thought to be generated by lung irritation, suggesting a particular influence of inhalation in contrast to other modes of nicotine delivery, such as oral tobacco. ^{Reference Rosso and Chitnis2} For example, active and passive smoking, but not oral tobacco use, are associated with faster physical disability progression and elevated psychological worsening, suggesting that nicotine replacement therapy may be a safe approach to address smoking in pwMS. ^{Reference Wu, Olsson, Hillert, Alfredsson and Hedström10} It is unknown whether the effects of smoking on MS disease activity differ between males and females and whether potential differences impact depressive symptoms.

Limitations include a cross-sectional design, the inclusion of only pwRRMS and no details on the type or quantity of nicotine use, associated neuroimaging or data about the socioeconomic status or ethnicity of participants. It is relevant to note that this study cannot disentangle the effects of nicotine from its mode of delivery. In addition, the HADS-D only measures depressive symptoms in the past week, and a minimally clinically important difference has not been defined for the HADS-D in pwRRMS. Notwithstanding these caveats, this study reveals a female-specific link between smoked nicotine and depressive symptoms in pwRRMS. Future research should evaluate whether this is a dose–response relationship, whether this link persists longitudinally and whether smoking cessation decreases depressive symptoms in females with RRMS to clarify whether smoked nicotine use is a modifiable contributor to depressive symptoms in females with RRMS. While the underlying mechanism of an interaction between sex and smoked nicotine use is unclear, it highlights the ongoing need to consider the influence of sex-related factors on the development of depression in pwRRMS.