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The association between tobacco smoking and depression and anxiety in people with multiple sclerosis: A systematic review

  • Vincent Vong
    Affiliations
    Neuroepidemiology Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Level 3, 207 Bouverie St, Carlton, Melbourne, VIC 3053, Australia
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  • Steve Simpson-Yap
    Affiliations
    Neuroepidemiology Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Level 3, 207 Bouverie St, Carlton, Melbourne, VIC 3053, Australia

    Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
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  • Spreeha Phaiju
    Affiliations
    Neuroepidemiology Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Level 3, 207 Bouverie St, Carlton, Melbourne, VIC 3053, Australia
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  • Rebekah A Davenport
    Affiliations
    Melbourne School of Psychological Sciences, The University of Melbourne, Melbourne, Australia
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  • Sandra L Neate
    Affiliations
    Neuroepidemiology Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Level 3, 207 Bouverie St, Carlton, Melbourne, VIC 3053, Australia
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  • Mia I Pisano
    Affiliations
    Faculty of Medicine and Health Sciences, The University of Melbourne, Melbourne, Australia
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  • Jeanette C Reece
    Correspondence
    Corresponding author.
    Affiliations
    Neuroepidemiology Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Level 3, 207 Bouverie St, Carlton, Melbourne, VIC 3053, Australia
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Open AccessPublished:January 04, 2023DOI:https://doi.org/10.1016/j.msard.2023.104501

      Highlights

      • Systematic review of studies examining associations between smoking and depression and anxiety in people living with MS found;
      • Strong evidence of a smoking-depression relationship, with 1.3–2.3-fold higher depression prevalence in current-smokers.
      • Depression levels were significantly higher in people who quit smoking than in non-smokers.
      • Strong evidence of a smoking-anxiety relationship, with 20% higher anxiety prevalence in current-smokers than non-smokers.
      • Anxiety levels were similar between people who had quit smoking and non-smokers.

      Abstract

      Background

      The link between tobacco smoking and Multiple Sclerosis (MS) onset and progression is well-established. While clinical levels of depression and anxiety are highly prevalent in people living with MS (plwMS), and both are recognized as common MS-related symptoms, the relationships between smoking behavior and depression and anxiety are unclear. This systematic review aimed to synthesize evidence on the relationships between current-smoking and former-smoking and depression and anxiety in plwMS.

      Methods

      Systematic review of all studies investigating associations between tobacco smoking and depression and anxiety in plwMS was conducted. Relevant studies published before 26 April 2022 were identified by searching seven databases; MEDLINE® (Ovid and PubMed), Embase, CINAHL®, Cochrane Library and PsycInfo), and citation and reference list checking. Joanna Briggs Institute Critical Appraisal Checklists for respective study designs assessed the risk of bias.

      Results

      Thirteen publications reporting on 12 studies met study inclusion criteria. Nine of 12 studies examining current-smoking and depression in plwMS identified a positive association. Four prospective studies provided evidence supporting a causal smoking-depression relationship, with 1.3–2.3-fold higher depression prevalence found in current-smokers than non-smokers. Three cross-sectional studies found no smoking-depression association. Four of five included studies found current-smoking was associated with anxiety, with three prospective studies indicating anxiety prevalence was around 20% higher in current-smokers. Former-smoking was associated with increased prevalence of depression, but not anxiety.

      Conclusion

      We provide strong evidence for increased depression prevalence in plwMS who are either current-smokers or former-smokers. However, only current-smoking was associated with increased prevalence of anxiety.

      Graphical abstract

      Keywords

      1. Introduction

      People living with MS (plwMS) frequently experience fatigue, pain, decreased mobility, depression, and anxiety (
      • Bishop M.
      • Rumrill P.D.
      Multiple sclerosis: etiology, symptoms, incidence and prevalence, and implications for community living and employment.
      ). In particular, depression and anxiety are highly prevalent in plwMS and contribute a significant burden of disease (
      • Hanna M.
      • Strober L.B.
      Anxiety and depression in multiple sclerosis (MS): antecedents, consequences, and differential impact on well-being and quality of life.
      ). Among the 2.8 million plwMS worldwide (
      • Walton C.
      • King R.
      • Rechtman L.
      • Kaye W.
      • Leray E.
      • Marrie R.A.
      • Robertson N.
      • La Rocca N.
      • Uitdehaag B.
      • van der Mei I.
      • Wallin M.
      • Helme A.
      • Napier C.A.
      • Rijke N.
      • Baneke P.
      Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition.
      ), 25–54% and 36% are predicted to develop a clinical depressive and anxiety disorder in their lifetime, respectively, relative to 16 and 29% in the general population (
      • Patten S.B.
      • Williams J.V.A.
      • Lavorato D.H.
      • Bulloch A.G.M.
      • Wiens K.
      • Wang J.
      Why is major depression prevalence not changing?.
      ). Collectively, depression and anxiety symptoms represent one of the most common comorbidities seen in plwMS, and research in MS suggests this form of psychological comorbidity results in greater consequences compared with single and uncomplicated presentations of other symptoms (
      • Berrigan L.I.
      • Fisk J.D.
      • Patten S.B.
      • Tremlett H.
      • Wolfson C.
      • Warren S.
      • Fiest K.M.
      • McKay K.A.
      • Marrie R.A.
      Epidemiology, C.T.I.T., Impact of Comorbidity on Multiple, S.
      Health-related quality of life in multiple sclerosis: direct and indirect effects of comorbidity.
      ).
      Several studies have reported associations between current-smoking and MS progression (
      • McKay K.A.
      • Jahanfar S.
      • Duggan T.
      • Tkachuk S.
      • Tremlett H.
      Factors associated with onset, relapses or progression in multiple sclerosis: a systematic review.
      ), worsening of clinical symptoms and neurological disability (
      • Hempel S.
      • Graham G.D.
      • Fu N.
      • Estrada E.
      • Chen A.Y.
      • Miake-Lye I.
      • Miles J.N.
      • Shanman R.
      • Shekelle P.G.
      • Beroes J.M.
      • Wallin M.T.
      A systematic review of modifiable risk factors in the progression of multiple sclerosis.
      ;
      • Heydarpour P.
      • Manouchehrinia A.
      • Beiki O.
      • Mousavi S.E.
      • Abdolalizadeh A.
      • Lakeh M.M.
      • Sahraian M.A.
      Smoking and worsening disability in multiple sclerosis: a meta-analysis.
      ;
      • Pittas F.
      • Ponsonby A.L.
      • van der Mei I.A.
      • Taylor B.V.
      • Blizzard L.
      • Groom P.
      • Ukoumunne O.C.
      • Dwyer T.
      Smoking is associated with progressive disease course and increased progression in clinical disability in a prospective cohort of people with multiple sclerosis.
      ), and 1.6–2.5 times higher risks of conversion from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS) (
      • Healy B.C.
      • Ali E.N.
      • Guttmann C.R.
      • Chitnis T.
      • Glanz B.I.
      • Buckle G.
      • Houtchens M.
      • Stazzone L.
      • Moodie J.
      • Berger A.M.
      • Duan Y.
      • Bakshi R.
      • Khoury S.
      • Weiner H.
      • Ascherio A.
      Smoking and disease progression in multiple sclerosis.
      ;
      • Hempel S.
      • Graham G.D.
      • Fu N.
      • Estrada E.
      • Chen A.Y.
      • Miake-Lye I.
      • Miles J.N.
      • Shanman R.
      • Shekelle P.G.
      • Beroes J.M.
      • Wallin M.T.
      A systematic review of modifiable risk factors in the progression of multiple sclerosis.
      ). Further studies suggest a possible relationship between smoking and depression and anxiety in plwMS (
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ;
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ). However, the clinical picture remains unclear, complicated by limited research examining the relationships between smoking and depression and anxiety and mixed findings (
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      ;
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ). Despite the prevalence and adverse impact of depression and anxiety on plwMS, these symptoms are frequently under-recognized and under-treated (
      • McGuigan C.
      • Hutchinson M.
      Unrecognised symptoms of depression in a community-based population with multiple sclerosis.
      ;
      • Mohr D.C.
      • Hart S.L.
      • Fonareva I.
      • Tasch E.S.
      Treatment of depression for patients with multiple sclerosis in neurology clinics.
      ). Therefore, understanding comorbid depression and anxiety in relation to smoking may help clarify these relations and inform existing psychological and pharmacological interventions.
      While previous systematic review findings in the general population highlighted associations between smoking and depression and anxiety (
      • Fluharty M.
      • Taylor A.E.
      • Grabski M.
      • Munafo M.R.
      The association of cigarette smoking with depression and anxiety: a systematic review.
      ), to date no systematic review on smoking and depression and anxiety in plwMS has been performed. Given the adverse effects of depression, anxiety and smoking on health outcomes in plwMS (
      • Boeschoten R.E.
      • Braamse A.M.J.
      • Beekman A.T.F.
      • Cuijpers P.
      • van Oppen P.
      • Dekker J.
      • Uitdehaag B.M.J.
      Prevalence of depression and anxiety in Multiple Sclerosis: a systematic review and meta-analysis.
      ;
      • Hempel S.
      • Graham G.D.
      • Fu N.
      • Estrada E.
      • Chen A.Y.
      • Miake-Lye I.
      • Miles J.N.
      • Shanman R.
      • Shekelle P.G.
      • Beroes J.M.
      • Wallin M.T.
      A systematic review of the effects of modifiable risk factor interventions on the progression of multiple sclerosis.
      ), increased understanding of the association between smoking and these symptoms is highly relevant. In the present study, we conducted a systematic review to clarify relationships between smoking and depression and anxiety. Specifically, we aimed to examine whether current-smokers or former-smokers are at increased risk of depression and/or anxiety compared to non-smokers.

      2. Methods

      2.1 Study design

      A systematic review of relevant quantitative studies following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines was performed (
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • Shamseer L.
      • Tetzlaff J.M.
      • Akl E.A.
      • Brennan S.E.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ). The review was pre-registered in PROSPERO  (ID: CRD42022329427).

      2.2 Search strategy

      Seven databases were searched for literature relevant to psychological conditions in plwMS from database conception to 26 April 2022: MEDLINE via OVID and PubMed, Web of Science, EMBASE, APA PsycInfo, Cochrane Central Register of Controlled Trials and Cumulative Index of Nursing and Allied Health Literature (CINAHL). The search strategy was a connexion of general terms for “multiple sclerosis”, “tobacco smoking”, AND combinations of “depression” OR “anxiety” across all fields (i.e., title, abstract, keywords) to capture relevant articles to the exposure (tobacco smoking) and outcomes (depression or anxiety) in plwMS. Exploded terms and Medical Subject Headings (MeSH) were used to maximize results. Search strategies are presented in Supplementary Table 1. Citation and reference checking of included studies was performed to identify articles not identified by electronic searching.
      Two independent reviewers (V.V. and S.P.) identified full-text articles complying with study inclusion criteria:
      • study participants ≥18 years with a clinical diagnosis of MS
      • included a sample of current-smokers and/or former-smokers
      • included a quantitative self-report psychometric tool for the assessment of depression and/or anxiety symptoms, validated for the MS population
      • Exclusion criteria:
      • Studies not in English
      • Reviews, protocols, case studies, editorials or conference abstracts

      2.3 Data extraction and analysis

      Data [study type, country, smoking status (current-, former- and non-smoking), MS type, participant characteristics, outcome measurement tools and results] was extracted from eligible studies by three independent reviewers (V.V., M.I.P. and S.P.) using a standardized data extraction form (

      Cochrane Effective Practice and Organisation of Care, E., 2017. Screening, data extraction and management: EPOC resources for review authors, 2017. https://epoc.cochrane.org/sites/epoc.cochrane.org/files/public/uploads/Resources-for-authors2017/screening_data_extraction_and_management.pdf (accessed 30 March 2022).

      ). Any disagreements were resolved through consultation with co-authors (S.S-Y and J.C.R).

      2.4 Assessment of bias

      Risk of bias was assessed by independent reviewers (V.V. and S.P.) using respective Joanna Briggs Institute (JBI) critical appraisal checklists (

      Joanna Briggs Institute, 2020. Critical appraisal tools. https://jbi.global/critical-appraisal-tools. (accessed May 17 2022).

      ). Checklists contain 8–12 questions with answer options “yes”, “no”, “unclear”, or “not applicable”. The level of bias was determined by the proportion of “yes” answers; >80% positive responses indicate low risk of bias, 60–80% indicate moderate risk and <60% indicate high risk (
      • Reece J.C.
      • Neal E.F.
      • Nguyen P.
      • McIntosh J.G.
      • Emery J.D.
      Delayed or failure to follow-up abnormal breast cancer screening mammograms in primary care: a systematic review.
      ). All relevant studies were included in the review regardless of risk bias for completeness of study findings, as suggested by
      • Shea B.J.
      • Reeves B.C.
      • Wells G.
      • Thuku M.
      • Hamel C.
      • Moran J.
      • Moher D.
      • Tugwell P.
      • Welch V.
      • Kristjansson E.
      AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
      .

      2.5 Narrative synthesis

      A narrative synthesis of included studies was performed to summarize the main study characteristics and findings (
      • Green B.N.
      • Johnson C.D.
      • Adams A.
      Writing narrative literature reviews for peer-reviewed journals: secrets of the trade.
      ). Data from each study was extracted and individual study findings were evaluated and summarized prior to combining results for the narrative synthesis. A meta-analysis could not be performed due to heterogeneity in study design and assessment tools used to measure depression and anxiety across studies. That is, no two included studies had the same study design and used the same assessment tool to measure depression or anxiety.

      3. Results

      In all, 1666 studies were identified via electronic searching and two studies were identified from citation and reference checking (Fig. 1). The title and abstract of 1361 studies were screened for eligibility, resulting in full-text examination of 22 studies. Of these, nine studies were unsuitable for study inclusion due to: evaluating a different outcome (n = 2) or research question (n = 1); unsuitable (qualitative) outcome measurement tools (n = 5); or were a conference abstract (n = 1). In total, 13 studies reporting on 12 individual studies were eligible for study inclusion, with two studies analysing data from the same study both cross-sectionally (
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ), and prospectively (
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ).
      Fig. 1
      Fig. 1PRISMA Flow Diagram of study selection.
      Participant characteristics of the 13 included studies are presented according to study design and chronologically in Table 1. Eight studies were cross-sectional (
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      ;
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      ;
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ;
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      ;
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ;
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ;
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      ;
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ), three were prospective cohorts (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ), and one was a retrospective cohort (
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      ). The
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      study comprised both retrospective and prospective studies.
      Table 1Summary of study characteristics of included studies.
      Study (year)Study TypeCountrySettingExposureOutcomeMeasurement ToolNo. participantsMean ageFemale  (%)MS Type –  (%)
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      Cross-sectionalTurkeyNeurology clinic, Instanbul, TurkeyHeavy-smoker vs non-smoker

      DepressionBDI

      (no cut-offs provided; compared BDI scores across study groups)
      44 total participants

      (24 non-smokers; 20 heavy-smokers)
      37.3  (10.7)50.0PPMS – 6.8

      RRMS – 77.3

      SPMS – 15.9
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      Cross-sectionalInternationalOnline recruitment from 57 countriesCurrent-smoker vs non-smoker

      Former-smoker vs non- smoker
      DepressionPHQ-2

      (scores > 2 indicate positive depression screen)
      2459 total participants

      (96 current-smokers, 890 former- smokers, 1072 never-smokers)
      N/A82.4PPMS – 7.2

      PRMS – 2.1

      RRMS – 61.3

      SPMS – 11.5

      Benign – 4.3

      Unsure – 13.6
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      Cross-sectionalCanadaMS outpatient clinic at University of CalgaryCurrent-smoking vs non-smokingAnxietyHADS-anxiety

      (cut-off score of ⩾8 on the HADS scale were used to define anxiety)
      244 total participants

      (39 current-smokers;

      238 non-smokers)
      49.5  (11.6)73.0PPMS – 9.4

      RRMS – 66.4

      SPMS – 20.9

      Unknown – 3.3
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      Cross-sectionalAustraliaPopulation-based [Australian Multiple Sclerosis

      Longitudinal Study  (AMSLS)]
      Current-smoker vs non-smokingDepression and anxietyHADS

      (cut-off ≥8 for HADS-depression and HADS- anxiety)
      1500 total participants

      (1344 non-smokers;

      156 current-smokers)
      56.0  (11.2)79.5PPMS – 8.7

      PRMS – 2.0

      RRMS – 61.9

      SPMS – 15.0

      Unsure – 12.5
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      Cross-sectionalCanadaPopulation-based; participants of Canadian

      Survey of Health, Lifestyle and aging with Multiple Sclerosis

      (study inclusion criteria included >55 years with MS symptoms > 20 years)
      Current-smoker vs non-smokingDepressionHADS-depression

      HADS-anxiety

      (a score >11 suggested abnormal symptoms of

      depression and a report of a confirmed diagnosis was provided)

      742 total participants

      (412 with no depression symptoms; 103 with low depression symptoms; 87 with high depression symptoms; 140 with high symptoms (undiagnosed)
      64.6  (6.2)77.6PPMS – 13.3

      PRMS – 2.2

      RRMS – 51.9

      SPMS – 8.8

      Benign – 5.8

      Other – 1.1

      Unknown – 17.0
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      Cross-sectionalSaudi ArabiaSampling of plwMS from population-based cohort in Jeddah, Saudi ArabiaCurrent-smoker vs non-smokingDepressionPHQ-9

      (0–4 no or minimal depression, 5–9 mild depression, 10–14 moderate

      depression, 15–19 moderately severe depression, and ≥20 is severe depression)

      341 total participants

      (85 current-smokers; 243 non-smokers)

      34.8  (9.9)65.4N/A
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.


      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      Cross-sectionalTurkeyOutpatient clinic of the Neurology Department of Gaziantep University Hospital, Gaziantep, TurkeyCurrent-smoker vs non-smokersDepressionBDI80 total participants

      (40 current-smokers;

      40 non-smokers)
      35.3  (8.7)62.3N/A
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      Cross-sectionalTurkeyOutpatient MS Clinic of Dokuz Eylül

      University Hospital, Izmir, Turkey.
      Current-smoker vs non-smokersDepressionBDI279 total participants

      (95 current-smokers;

      184 non-smokers)
      35.7  (10.9)71.3PPMS – 1.1

      RRMS – 95.0

      SPMS – 3.9
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      Prospective and retrospective cohortUK

      Population- based  (participants registered in the United Kingdom MS Register 2011–2020)Retrospective study:

      Current-smoker vs never-smoker

      Prospective study:

      Current-smoker vs never-smoker

      Former-smoker vs never-smoker

      Depression and anxietyHADS-depression

      HADS-anxiety

      (a 2-point change in either of these

      sub-scores was considered a clinically relevant change)
      7983 total participants

      (1315 current-smokers;

      2815 former-smokers;

      3853 never-smoker

      Prospective parallel analysis group = 923 participants

      Time to event analyzes:

      4511 current-smokers
      57.7  (12.3)71.3(progressive as reference vs not progressive)
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      Prospective CohortAustraliaTwo MS clinics in Sydney,

      Australia
      Current-smoker vs non-smokerDepression and anxietyBDI

      (score > 13 indicative of high depression levels)

      STAI

      (no cut-off provided)
      101 total participants

      (18 current-smokers, 183 non-smokers)
      42.6  (10.7)80.1RRMS – 74.4

      SPMS – 25.6
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.


      Prospective CohortCanadaFour MS clinics in British Columbia, Alberta, Manitoba and Nova ScotiaCurrent-smoker vs never-smokerDepression and anxietyHADS-depression

      HADS-anxiety

      (cut-off scores of ⩾8 on the HADS scale were used to define depression and anxiety)
      Total participants: 947 at baseline

      (411 never-smokers;

      341 former-smokers;

      195 current-smokers)

      911 at 1-year follow-up

      (398 never-smokers;

      330 former-smokers;

      180 current-smokers)

      885 at 2-year follow-up

      (382 never-smokers;

      336 former-smokers;

      165 current-smokers)

      48.6  (11.4)75.2CIS – 0.5

      PPMS – 6.3

      RRMS – 72.4

      SPMS – 20.3

      Unknown – 0.4
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      Prospective CohortInternationalOnline recruitment from 57 countriesCurrent-smoker vs never-smoker

      Former-smoker vs never-smoker
      Depression

      PHQ-2 was used to measure changes in depression from baseline to 2.5-year review

      (cut-off scores > 2 indicated a positive depression screen)

      PHQ-9 was used to assess for symptoms of depression at 2.5 years.

      (cut-off scores > 9 indicated positive depression screen)
      1309 total participants

      (701 never-smokers;

      527 former-smokers;

      102 current-smokers)
      45.7  (10.5)82.4PPMS – 7.2

      PRMS – 2.0

      RRMS – 61.6

      SPMS – 11.4

      Benign – 4.1

      Unsure – 13.6

      Missing – 1.9
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      Retrospective CohortUSATertiary MS referral

      center at the Cleveland Clinic, Ohio, US
      Current-smoker, former-smoker and never-smokersDepressionPHQ-9

      (no cut-off provided)
      1271 total participants

      (328 current-smokers; 518 former-smokers; 848 never-smokers)
      43.0

      (10.4)
      74.4RRMS – 100
      Multiple sclerosis (MS); Hospital Anxiety and Depression Scale (HADS); Patient Health Questionnaire (PHQ); BECK depression inventory (BDI); Not available (N/A)
      One study presented data collected from Saudi Arabia (
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      ), one from the United States (
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      ) and one from the United Kingdom (
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ). Two studies included data from Australia (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ), and three analyzed data from Turkey (
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      ;
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      ;
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ) and Canada (
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ;
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      ). Two further studies analyzed data from 57 countries [Health Outcomes and Lifestyle In a Sample of plwMS (HOLISM) study] (
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ,
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ).
      Participant number ranged from 44 (
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ), to 7983 (
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ). Participant characteristics in all studies were comparable to other large MS cohorts (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Campagnolo D.
      • Vollmer T.
      Smoking status over two years in patients with multiple sclerosis.
      ), except one (
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ), where 50% of participants were female compared with 62.3–82.4% in other studies. Mean age ranged from 35 to 65 years. RRMS was the most common MS type (52–95% of cases).

      3.1 Risk of bias

      Ten studies were judged to have low risk of bias (
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      ;
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ;
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ;
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ;
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ,
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ), one had moderate risk (
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ), and two had high risk (
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      ;
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      ) (Table 2, Supplementary Tables 2 and 3).
      Table 2Summary of findings from included studies.
      StudyStudy TypeAssociation between smoking and depressionAssociation between smoking and anxietyRisk of bias
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      Cross-sectionalBDI scores between heavy-smokers and non-smokers (mean ± SE) were not significantly different; 17.05 ± 11.57 for heavy-smokers and 16.04 ± 13.70 for non-smokers; p = 0.516)

      Backward stepwise logistic regression was used to identify factors statistically predictive of cognitive impairment.
      N/AModerate
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      Cross-sectionalCurrent-smokers are 2.3 times more likely to screen positive for depression. Adjusted odds ratio (aOR) for examining smoking and the risk of depression: aOR = 2.29 [95% CI 1.60, 3.27], p < 0.001

      Former-smokers were at higher odds of screening positive for depression than non-smokers: aOR = 1.54 [95%CI 1.6, 3.27]) p < 0.01

      (Adjusted odds ratios of screening positive for depression were adjusted for years since diagnosis, number of comorbidities, level of disability, clinically significant fatigue, age, gender, marital status and level of education.)
      N/ALow
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      Cross-sectionalN/ACurrent-smoking vs non-smoking with associated with anxiety in plwMS: aOR = 2.43 [95% CI, 1.18, 5.00]

      p = 0.015

      (Statistical model adjusted for age and sex)

      After adjusting for further confounders (age, sex, education, smoking, relapse-remitting MS and depression), the association between smoking and anxiety was no longer significant

      (aOR=2.01; 95%CI 0.90–4.50; p = 0.087)
      Low
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      Cross-sectionalNon-smoking status was associated with lower depression severity

      Prevalence ratio of depression in non-smokers = 0.75 (95%CI: 0.59, 0.94) p < 0.05; Symptom severity adjusted -1.12 (95%CI: -1.76, -0.48) p < 0.05

      (All models were adjusted for age, sex, Patient‐Determined Disease Steps score, depression treatment, fatigue level, education level and

      socio‐economic status)
      Non-smoking status was associated with lower anxiety severity

      Prevalence ratio of depression in non-smokers = 0.85 (95%CI: 0.68, 1.00) p ≥ 0.05; Symptom severity adjusted -1.33 (95%CI: -2.10, -0.55) p < 0.05

      (All models were adjusted for age, sex, Patient‐Determined Disease Steps score, anxiety treatment, fatigue level, education level and

      socio‐economic status)
      Low
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      Cross-sectionalThere was no difference in the % of non-smokers vs non-smokers in plwMS that had symptoms of depression compared with those that had no symptoms of depression (χ2 (3) = 4.54, p = 0.21)

      (Hierarchical logistic regression was used to examine smoking-depression associations controlling for age, years diagnosed with MS, MS type at diagnosis and level of disability, as measured using the Barthel Index in the first step in the model).
      N/ALow
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      Cross-sectionalCurrent-smoking was not associated with the rate of depression

      (24.9% of people with depression were smokers compared with 71.3% non-smokers; p = 0.113)
      N/AHigh
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      Cross-sectionalBDI scores were significantly higher in current-smokers than non-smokers: BDI score in smokers was 21.32±2.12 compared with the BDI score in non-smokers (BDI=15.95±1.53);

      p = 0.04

      (Adjusted analyzes were not performed as age, gender, marital status and duration of illness, neurological fatigue index-MS, nicotine addiction, and EDSS scores were not different between groups. However, BDI scores were lower in both groups in those with higher education)
      N/AHigh
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      Cross-sectionalBDI scores were significantly higher in smokers than non-smokers

      (pη2 = 0.015, p = 0.044)

      (One-way analysis of covariance was used to measure the difference between current-smoker and non-smoker groups, adjusted for age, gender, EDSS, and disease duration.)
      N/ALow
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      Prospective and retrospective cohortProspective analysis of smoking impact over 4 years in 923 smokers:

      Current-smokers had worsening HADS-depression scores [0.71 (0.47, 0.96)] over 4 years using linear mixed models.

      Average HADS-depression scores increased steadily with each year from baseline.

      Prospective time to event analyzes of 4511 smokers (streak length ranged from 180 days to 8 years):

      Current-smoking was associated with a quicker time to a worsening in HADS-depression scores

      (Adjusted Hazard Ratio (aHR)=1.25 (95%CI 1, 1.57; p < 0.0001)

      Retrospective analyzes

      At baseline, current-smokers had higher depression [HADS-depression scores = 8 (5–11)] compared with never-smokers [6 (3–9)]

      Former-smokers had no clinically significant improvement in HADS-depression scores since quitting smoking

      (−0.08, 95%CI [−0.11, −0.04], n = 2779)

      For every additional pack year of smoking, there was a significant increase in HADS-depression scores of 0.03.

      Current-smokers had higher mean increases in HADS-depression scores than never-smokers [HADS increase =0.74  (0.28, 1.20) β (95% CI) p = 0.0015]



      (Multivariable analyzes adjusted for age at baseline, time since onset,

      MS type at diagnosis, ethnicity and DMT usage)

      Prospective analysis of smoking impact over 4 years in 923 smokers:

      Current-smokers had stable HADS-anxiety scores over 4 years using linear mixed models.

      Current-smokers had higher HADS-anxiety scores compared to never smokers [1.14 (0.52, 1.76)]

      Prospective time to event analyzes of 4511 smokers (streak length ranged from 180 days to 8 years):

      Current-smoking was associated with a quicker time to a worsening in HADS-anxiety scores

      (Adjusted hazard ratio (aHR)=1.25 (95%CI 1, 1.56; p = 0.0017)

      Retrospective analyzes

      At baseline, current-smokers had higher anxiety [HADS-anxiety scores = 9 (6–12)] compared with never-smokers [7 (4–10]

      Former-smokers had improvement in HADS-anxiety scores since quitting smoking  (−0.19, 95%CI [−0.22, −0.15], n = 2779)

      For every additional pack year of smoking, there was a significant increase in HADS-anxiety scores of 0.03

      Current-smokers had higher mean increases in HADS-anxiety scores than never smokers [HADS increase =0.79 (0.31, 1.26) β (95% CI) p = 0.0012])

      (Multivariable analysis adjusted for age at baseline, time since onset, MS type at diagnosis, ethnicity and DMT usage)

      Low
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      Prospective CohortLongitudinal model predicted high depression levels in smokers, with lower BDI score changes found in non-smokers vs smokers [BDI score -2.31 (SE, 0.47)] in adjusted analyzes, p < 0.0001

      (For final longitudinal model, a backwards elimination approach was used to find the most suitable predictors.

      Confounders: Anxiety, fatigue, exercise, recreational drugs, planful coping gender)
      Longitudinal model predicted high anxiety levels in smokers, with increased BDI score changes of 2.50 (SE, 0.84) found in smokers vs non-smokers in adjusted analyzes, p = 0.003

      (For final longitudinal model, a backwards elimination approach was used to find the most suitable predictors. Confounders: depression, immunotherapy, relaxation, optimism, age, gender, caffeine)

      Low
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.


      Prospective CohortIn prevalence analyzes, current-smoking compared with non-smoking was associated with an increased odds of depression at all time points [baseline, 1-year and 2-years] (aOR = 1.37 [95% CI 1.04, 1.78], p unreported)

      In a prospective follow-up of incident depression cases at the 1- and 2-year follow-up from baseline, current-smoking was NOT associated with an altered risk of depression

      (aOR = 0.94 [95% CI 0.54, 1.64], p unreported)

      (multivariable analyzes were adjusted for: age, sex, EDSS, and alcohol dependence in multivariable analyzes)
      In prevalence analyzes, current-smoking compared with non-smoking was associated with an increased odds of anxiety (Adjusted Odds ratio = 1.29 [95%CI 1.02, 1.63], p unreported)

      In a prospective follow-up of incident anxiety cases at the 1- and 2-year follow-up from baseline, current-smoking was NOT associated with an altered risk of anxiety

      (aOR = 1.20 [95% CI 0.71, 2.04], p unreported)

      (multivariable analyzes were adjusted for: age, sex, EDSS, and alcohol dependence in multivariable analyzes)

      Low
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      Prospective Cohort
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      replicated their previous cross-sectional results at the 2.5-year follow-up, and found higher depression prevalence in current-smokers than never-smokers (adjusted Prevalence Ratio (aPR)=1.96, 95%CI, 1.51–5.55; p < 0.001).

      At the 2.5-year follow-up, current-smoking was a predictor of depression risk vs no depression using PHQ-9 (i.e. was a predictor of depression;

      Minimal depressive symptoms vs no symptoms: Adjusted prevalence ratio (aPR) = 1.34; 95%CI 1.02, 1.75; p = 0.071 for current-smokers compared with never-smokers

      Major depressive symptoms vs no symptoms: Adjusted prevalence ratio (aPR) = 1.99; 95%CI 1.45, 2.74; p < 0.001 for current-smokers compared with never-smokers

      Current-smoking was NOT associated with a change in the risk of depression from baseline to 2.5 years.

      (Multivariable analyzes were adjusted for P-MSSS, age, fatigue, and anti-depressant medication use)
      N/ALow
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      Retrospective CohortCurrent-smokers compared to never-smokers had 2.21 higher depressive PHQ-9 scores (p < 0.001) [β  (95% CI): 1.76, 2.65]

      Former-smokers compared to never-smokers had 0.88 higher depressive PHQ-9 scores [β (95% CI): 0.53, 1.24] (p < 0.001)

      N/ALow
      Multiple sclerosis (MS); Hospital Anxiety and Depression Scale (HADS); Patient Health Questionnaire (PHQ); BECK depression inventory (BDI); Confidence interval (CI); Adjusted prevalence ratio (aPR); Adjusted odds ratio (aOR); Disease modifying therapy (DMT); Not available (N/A).

      3.2 Tools for measuring depression and anxiety

      All included/eligible studies used a quantitative self-reported psychometric tool to assess depression and/or anxiety symptoms, validated for the MS population. These included the 14-item Hospital Anxiety and Depression Scale (HADS) with seven questions each for depression and anxiety (
      • Honarmand K.
      • Feinstein A.
      Validation of the hospital anxiety and depression scale for use with multiple sclerosis patients.
      ), most frequently used survey in five studies (
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ;
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ); the 9-item Patient Health Questionnaire (PHQ-9) tool for depression, used in three studies (
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      ;
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      ;
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ); the 2-item PHQ-2 questionnaire (
      • Patrick S.
      • Connick P.
      Psychometric properties of the PHQ-9 depression scale in people with multiple sclerosis: a systematic review.
      ), used in one study (
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ), the 21-item Beck Depression Inventory (BDI) (
      • Sacco R.
      • Santangelo G.
      • Stamenova S.
      • Bisecco A.
      • Bonavita S.
      • Lavorgna L.
      • Trojano L.
      • D'Ambrosio A.
      • Tedeschi G.
      • Gallo A.
      Psychometric properties and validity of beck depression inventory II in multiple sclerosis.
      ), used in four studies (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      ;
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      ;
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ); and one study (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ), used the 20-item State-Trait Anxiety Inventory (STAI) to measure anxiety state (
      • Santangelo G.
      • Sacco R.
      • Siciliano M.
      • Bisecco A.
      • Muzzo G.
      • Docimo R.
      • De Stefano M.
      • Bonavita S.
      • Lavorgna L.
      • Tedeschi G.
      • Trojano L.
      • Gallo A.
      Anxiety in multiple sclerosis: psychometric properties of the state-trait anxiety inventory.
      ). Of note, no studies eligible for inclusion used other psychometric tools to assess for depression or/anxiety such as subscores of the Neuro-QoL (Quality of life in neurological disorders) (
      • Miller D.M.
      • Bethoux F.
      • Victorson D.
      • Nowinski C.J.
      • Buono S.
      • Lai J.S.
      • Wortman K.
      • Burns J.L.
      • Moy C.
      • Cella D.
      Validating Neuro-QoL short forms and targeted scales with people who have multiple sclerosis.
      ).

      3.3 Smoking and depression

      3.3.1 Cross-sectional studies

      Four of seven cross-sectional studies found current-smoking was positively associated with depression (
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      ;
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      ;
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ;
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      ;
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ) (Table 2). In a large international study, Taylor et al. found depression prevalence was 2.3 times higher in current-smokers than non-smokers (OR=2.29; p < 0.001) (
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ). Similarly, a large Australian study found 15% lower depression prevalence in non-smokers than current-smokers (p < 0.05) (
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ). A further two Turkish studies found BDI scores were significantly higher in current-smokers than non-smokers (
      • Ekmekyapar Firat Y.
      • Akçalı A.
      • Geyik S.
      • Çomruk G.
      • Cengiz E.
      • Erten M.
      Relationship of smoking with fatigue and depression in patients with multiple sclerosis.
      ;
      • Kahraman T.
      • Ozdogar A.T.
      • Abasiyanik Z.
      • Ozakbas S.
      Associations between smoking and walking, fatigue, depression, and health-related quality of life in persons with multiple sclerosis.
      ).
      In three cross-sectional studies where current-smoking was not associated with depression, a small Turkish study found depressive BDI scores were not significantly different between heavy-smokers (n = 20; 17.05 ± 11.57) and non-smokers (n = 24; 16.04±13.70; p = 0.516) (
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ). However, this study had a higher proportion of males to females (1:1) than other studies (around 1:4), with lower depression prevalence reported in males (
      • Albert P.R.
      Why is depression more prevalent in women?.
      ). Ozcan et al. also examined ‘heavy-smokers’ (≥10 pack-years), limiting the comparability of this study to other studies not considering pack-years. Two further studies from Saudi Arabia and Canada found no difference in the proportion of current-smokers vs non-smokers with depression (
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      ;
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      ).

      3.3.2 Cohort studies

      Four prospective studies found evidence for a relationship between current-smoking and depression (
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      ;
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ). In the large UK MS Register (UKMSR) study, HADS-depression scores in current-smokers increased over a 4-year period (HADS = 0.71; 0.47–0.96) and at a quicker rate than never-smokers (p < 0.0001) (
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ). Similarly, an international study found current-smoking vs never-smoking was a predictor of major depression at the 2.5-year follow-up (aPR=1.99; p < 0.001) (
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ), consistent with an earlier Australian study that found current-smoking vs non-smoking predicted higher BDI depression scores at the 2-year follow-up (p < 0.0001) (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ).
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      also found the prevalence of depression was higher in current-smokers vs non-smokers at baseline, but depression scores did not increase from baseline to the 2-year follow-up. Overall, depression risk was found to be 1.3–2.3 higher in current-smokers vs non-smokers.
      In studies examining associations between former-smokers and depression, retrospective analyzes by
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      found HADS-depression scores in former-smokers at baseline did not significantly improve after smoking cessation. Similarly, a retrospective analysis by
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      found both current-smokers and former-smokers had higher PHQ-9 depressive scores than non-smokers. In the
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      prospective study, the odds of depression were 1.5 higher in former-smokers than never-smokers.

      3.4 Smoking and anxiety

      3.4.1 Cross-sectional studies

      Two cross-sectional studies examining current-smoking and anxiety had conflicting findings (Table 2). Gascoyne et al. found smokers had a higher prevalence of anxiety symptom severity than non-smokers after adjusting for disability, anti-anxiety treatment, fatigue, education and socio-economic status (
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ). However,
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      found current-smoking was not associated with anxiety, after adjusting for age, sex, education, relapse-remitting MS and depression (aOR=2.01; p = 0.087).

      3.4.2 Cohort studies

      Three prospective studies found associations between current-smokers and anxiety (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ).
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      found smoking was predictive of higher anxiety levels after 2 years (p = 0.003).
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      found current-smokers had significantly higher HADS-anxiety scores at baseline than never-smokers and scores remained stable over 4 years. Similarly,
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      found anxiety prevalence was higher in current-smokers than never-smokers at baseline (OR=1.29, 95%CI 1.02–1.63), and also remained consistent over 2 years.
      In retrospective analyzes, Rodgers et al. found current-smokers had higher HADS-anxiety scores at baseline than non-smokers, and smoking cessation improved scores [-0.19, 95%CI, (-0.22)- (-0.15)].

      4. Discussion

      To the authors’ knowledge, the present study represents the first systematic review examining the association between tobacco smoking and depression and anxiety in plwMS. This review identified convincing evidence of positive associations for both outcomes. Among included studies, nine identified positive associations between current-smoking and depression with 1.3–2.3-fold higher depression prevalence compared with non-smokers. Four studies reported positive associations between current-smoking and anxiety, with around 1.2-fold higher anxiety prevalence compared with non-smoking. Former-smoking was associated with increased depression risk, but not increased anxiety risk. A meta-analysis could not be performed due to heterogeneity across studies.

      5. Smoking and depression

      All four prospective studies included in the review found positive associations between current-smokers and depression (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ;
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ), confirming the potential importance of current-smoking on mental-health outcomes in plwMS, and the clinical presentation of depression.
      Studies suggest CNS impairment (
      • Jasielski P.
      • Piedel F.
      • Rocka A.
      • Petit V.
      • Rejdak K.
      Smoking as a risk factor of onset and relapse of multiple sclerosis - a review.
      ), and/or inflammatory damage may exacerbate mental health disorders in plwMS (
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ). These pathways may partially explain the role of smoking in increased MS activity via chronic lung inflammation and increased pro-inflammatory cytokines and/or neurotoxic components facilitating neurological damage (
      • Arneth B.
      Multiple sclerosis and smoking.
      ;
      • Feinstein A.
      • Magalhaes S.
      • Richard J.F.
      • Audet B.
      • Moore C.
      The link between multiple sclerosis and depression.
      ). Further, links between smoking and depression could be partly attributable to the immunomodulatory effects of smoking, with immune system alterations theorized to increase depression risks in plwMS (
      • Edwards A.C.
      • Kendler K.S.
      A twin study of depression and nicotine dependence: shared liability or causal relationship?.
      ). In support of these mechanisms, increased inflammation and pro-inflammatory cytokine levels have been found in plwMS with depression (
      • Gold S.M.
      • Irwin M.R.
      Depression and immunity: inflammation and depressive symptoms in multiple sclerosis.
      ;
      • Pokryszko-Dragan A.
      • Frydecka I.
      • Kosmaczewska A.
      • Ciszak L.
      • Bilińska M.
      • Gruszka E.
      • Podemski R.
      • Frydecka D.
      Stimulated peripheral production of interferon-gamma is related to fatigue and depression in multiple sclerosis.
      ).
      Moreover,
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      found depression in current-smokers worsened over a 4-year period, and at a faster rate than never-smokers analysing UKMSR data after accounting for several confounders including DMT use and time since diagnosis. In particular, DMT use may be relevant to the smoking-depression relationship as smoking can negate immune-based therapies such as interferon-beta (
      • Petersen E.R.
      • Oturai A.B.
      • Koch-Henriksen N.
      • Magyari M.
      • Sørensen P.S.
      • Sellebjerg F.
      • Søndergaard H.B.
      Smoking affects the interferon beta treatment response in multiple sclerosis.
      ), which may result in increased inflammation over time (
      • Edwards A.C.
      • Kendler K.S.
      A twin study of depression and nicotine dependence: shared liability or causal relationship?.
      ). Notably, two prospective studies found depression scores in current-smokers did not increase over 2- and 2.5 years, respectively (
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ). However, these studies did not adjust for DMT usage.
      Five cross-sectional studies found current-smoking was associated with depression; however, this study design precludes temporality inferences between smoking and depression. Further, the potential for reverse causality exists, consistent with previous research reporting a bi-directional relationship between smoking and depression in the general population (
      • Leung J.
      • Gartner C.
      • Hall W.
      • Lucke J.
      • Dobson A.
      A longitudinal study of the bi-directional relationship between tobacco smoking and psychological distress in a community sample of young Australian women.
      ), and qualitative findings suggesting smoking is employed as a means of alleviating depressive and MS symptoms in plwMS (
      • Hunter A.
      • Grech L.B.
      • Borland R.
      • das Nair R.
      • White S.L.
      • Marck C.H.
      Barriers and motivators for tobacco smoking cessation in people with multiple sclerosis.
      ).
      Notably, three additional cross-sectional studies found no significant association between current-smoking and depression. However, null findings may be attributable to methodological limitations;
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      had a small study cohort (n = 44), 50% males and examined ‘heavy-smoking';
      • Algahtani H.
      • Almarri A.K.
      • Alharbi J.H.
      • Aljahdali M.R.
      • Haimed R.A.
      • Hariri R.
      Multiple sclerosis in Saudi Arabia: clinical, social, and psychological aspects of the disease.
      presented unadjusted results of current-smokers vs non-smokers with depressive symptoms and
      • Ploughman M.
      • Wallack E.M.
      • Chatterjee T.
      • Kirkland M.C.
      • Curtis M.E.
      • Health L.
      Aging with, M.S.C.
      Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.
      examined data from a select cohort (aged >55 years with MS symptoms >20 years) and used stricter criteria to measure depressive symptoms than other studies (HADS-depression cut-off >11, and a report of a depression diagnosis). In contrast, studies identifying positive smoking-depression associations, including other cross-sectional studies (
      • Gascoyne C.R.
      • Simpson S.
      • Chen J.
      • van der Mei I.
      • Marck C.H.
      Modifiable factors associated with depression and anxiety in multiple sclerosis.
      ;
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ), and the prospective study by
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      used HADS-depression cut-off scores ≥8 inferring potential bias for identifying a significant smoking-depression relationship. Notably, the HADS-depression cut-off >8 also has a sensitivity and specificity of 82% and 68%, respectively, (
      • Marrie R.A.
      • Zhang L.
      • Lix L.M.
      • Graff L.A.
      • Walker J.R.
      • Fisk J.D.
      • Patten S.B.
      • Hitchon C.A.
      • Bolton J.M.
      • Sareen J.
      The validity and reliability of screening measures for depression and anxiety disorders in multiple sclerosis.
      ;
      • Watson T.M.
      • Ford E.
      • Worthington E.
      • Lincoln N.B.
      Validation of mood measures for people with multiple sclerosis.
      ), which may reduce the level of confidence in reporting positive smoking-depression associations.

      6. Smoking and anxiety

      Three of four prospective studies examining current-smoking and anxiety identified positive associations (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ), rather than reduced perceived anxiety due to smoking. Further, two studies reported stable HADS-anxiety scores over 2-year or 4-years (
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ), suggesting smoking may consistently contribute to anxiety and not exacerbate symptoms over time as seen for depression (
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ). Of note, the cross-sectional study not identifying a significant smoking-anxiety association did not control for several predictive factors, including anti-anxiety medication use (
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ).

      7. Limitations of studies identifying positive associations

      While several studies provided evidence of an association between smoking and depression and anxiety, these studies had limitations that may affect the validity of these results. Many studies were susceptible to selection bias and may represent cohorts of plwMS more susceptible to depression and/or anxiety. In particular, the UKMSR population-based cohort was over-represented by older males with progressive MS and lower smoking rates than the total population (
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ). Similarly, longitudinal studies with high attrition (
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ), or from certain MS clinics (
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      ;
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      ;
      • Pham T.
      • Jette N.
      • Bulloch A.G.M.
      • Burton J.M.
      • Wiebe S.
      • Patten S.B.
      The prevalence of anxiety and associated factors in persons with multiple sclerosis.
      ) may not be representative of the MS community. Moreover, as depression is more prevalent in progressive MS than RRMS (
      • Peres D.S.
      • Rodrigues P.
      • Viero F.T.
      • Frare J.M.
      • Kudsi S.Q.
      • Meira G.M.
      • Trevisan G.
      Prevalence of depression and anxiety in the different clinical forms of multiple sclerosis and associations with disability: a systematic review and meta-analysis.
      ), higher proportions of people with progressive MS in studies could over-represent plwMS with depression. Studies were also limited by the psychometric tool employed; the 2-item PHQ-2 tool for assessing depression (
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ,
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ), has less precision than the 9-item PHQ-9, and the STAI instrument has been found to identify a higher prevalence of anxiety than the HADS-anxiety in certain studies (
      • Emons W.H.
      • Habibovic M.
      • Pedersen S.S.
      Prevalence of anxiety in patients with an implantable cardioverter defibrillator: measurement equivalence of the HADS-A and the STAI-S.
      ). However, only one included study used the STAI (
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      ).

      8. Smoking cessation

      Former-smokers had clinically significant improvements in HADS-anxiety scores after quitting smoking, whereas HADS-depression scores did not improve after smoking cessation (
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ). Similarly,
      • Briggs F.B.S.
      • Thompson N.R.
      • Conway D.S.
      Prognostic factors of disability in relapsing remitting multiple sclerosis.
      and
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      found while former-smokers had lower depressive scores than current-smokers, depressive scores were higher than non-smokers. Collectively, these studies suggest biopsychosocial mechanisms underlying the smoking-depression and smoking-anxiety relationships may be different. Subsequently, detrimental effects of smoking on depression could persist for some time following smoking cessation. Further, depression is often referred to as a symptom of MS (
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ;
      • Wallin M.T.
      • Wilken J.A.
      • Turner A.P.
      • Williams R.M.
      • Kane R.
      Depression and multiple sclerosis: review of a lethal combination.
      ), which may help explain the persistence of depression in former-smokers and high depression rates in non-smokers. This finding could also suggest the presence of more severe comorbid, or possibly pre-morbid, depressive disorders among plwMS, which is likely maintained by a complex interplay of factors, warranting more intensive, longer-term intervention (
      • Fekadu A.
      • Rane L.J.
      • Wooderson S.C.
      • Markopoulou K.
      • Poon L.
      • Cleare A.J.
      Prediction of longer-term outcome of treatment-resistant depression in tertiary care.
      ).

      9. Strengths and limitations

      The present study represents the first systematic review to evaluate the relationships between smoking and depression and anxiety. Participant characteristics of all included studies were comparable to other MS studies (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Campagnolo D.
      • Vollmer T.
      Smoking status over two years in patients with multiple sclerosis.
      ), except one (
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ), maximizing potential generalizability of findings to the wider MS community.
      Potential study limitations include differences in smoking behaviors and types of tobacco across countries and smoking habits across genders in included studies (

      World Population Review, 2022. Smoking rates by country 2022, https://worldpopulationreview.com/country-rankings/smoking-rates-by-country (accessed 25 August 2022).

      ). Further, search strategies did not include key words for newer methods of inhalation, such as vaping. All studies except
      • Taylor K.L.
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis.
      ,
      • Taylor K.L.
      • Simpson S.
      • Jelinek G.A.
      • Neate S.L.
      • De Livera A.M.
      • Brown C.R.
      • O'Kearney E.
      • Marck C.H.
      • Weiland T.J.
      Longitudinal associations of modifiable lifestyle factors with positive depression-screen over 2.5-years in an international cohort of people living with multiple sclerosis.
      ), were confined to single countries with high human development index (HDI) levels, therefore findings may not be relevant to countries with lower HDI levels.
      Confounders adjusted for in multivariable analyzes across studies were not consistent, and future studies should consider as many potential confounders as possible. For instance,
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Patten S.B.
      • Fiest K.
      • Berrigan L.
      • Marrie R.A.
      Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: a prospective multisite study.
      was the only study to identify and adjust for alcohol dependence in multivariable analyzes. Likewise, only
      • Brown R.F.
      • Valpiani E.M.
      • Tennant C.C.
      • Dunn S.M.
      • Sharrock M.
      • Hodgkinson S.
      • Pollard J.D.
      Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.
      was the only study to adjust for caffeine and coping mechanisms, and only
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      adjusted for DMTs.
      Further, the associations identified between smoking and depression and anxiety may be partially confounded by the extraneous effects of social, educational and financial variables, as well as healthcare access. For instance, smoking has been found to vary according to socio-economic status (SES) (
      • Corsi D.J.
      • Boyle M.H.
      • Lear S.A.
      • Chow C.K.
      • Teo K.K.
      • Subramanian S.V.
      Trends in smoking in Canada from 1950 to 2011: progression of the tobacco epidemic according to socioeconomic status and geography.
      ), and SES is also associated with elevated depressive and anxiety symptoms (
      • Wang Y.
      • Tian F.
      • Fitzgerald K.C.
      • Bhattarai J.J.
      • Naismith R.T.
      • Hyland M.
      • Calabresi P.A.
      • Mowry E.M.
      Socioeconomic status and race are correlated with affective symptoms in multiple sclerosis.
      ). However, as this systematic review did not include a meta-analytic synthesis, these factors could not be controlled for and future observational and meta-analytic research should aim to additionally control for social variables (i.e., education, SES) to identify any direct effects of smoking on depression and anxiety.
      Included studies were limited by potential recall bias as data across all studies was collected by self-report, with only
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      validating smoking status using healthcare records. Unstandardized self-reported smoking measures were used, with self-reported smoking status previously found to be an unreliable measure of smoking behavior (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Campagnolo D.
      • Vollmer T.
      Smoking status over two years in patients with multiple sclerosis.
      ). Additional smoking factors to consider include nicotine levels, tobacco quality, brand, or inhalation method. Similarly, pack-years [packet number (20 cigarettes) smoked per day multiplied by the number of years] was only considered in two studies (
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • Kocer A.
      • Asil T.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ;
      • Rodgers J.
      • Friede T.
      • Vonberg F.W.
      • Constantinescu C.S.
      • Coles A.
      • Chataway J.
      • Duddy M.
      • Emsley H.
      • Ford H.
      • Fisniku L.
      • Galea I.
      • Harrower T.
      • Hobart J.
      • Huseyin H.
      • Kipps C.M.
      • Marta M.
      • McDonnell G.V.
      • McLean B.
      • Pearson O.R.
      • Rog D.
      • Schmierer K.
      • Sharrack B.
      • Straukiene A.
      • Wilson H.C.
      • Ford D.V.
      • Middleton R.M.
      • Nicholas R.
      The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
      ), but increasing pack-years could affect depression and anxiety severity, similar to increased exacerbation of MS symptoms associated with increasing pack-years (
      • Poorolajal J.
      • Bahrami M.
      • Karami M.
      • Hooshmand E.
      Effect of smoking on multiple sclerosis: a meta-analysis.
      ).
      Consequently, future studies implementing uniform measurements for smoking and outcomes (depression and anxiety) with consistent cut-offs and accounting for as many confounders in multivariable analyzes as possible are advised to allow comparisons across studies and a future meta-analysis to be performed.

      9.1 Clinical implications

      This review contributes to a growing body of literature linking smoking with adverse health outcomes in plwMS (
      • Arneth B.
      Multiple sclerosis and smoking.
      ;
      • Jasielski P.
      • Piedel F.
      • Rocka A.
      • Petit V.
      • Rejdak K.
      Smoking as a risk factor of onset and relapse of multiple sclerosis - a review.
      ). Prospective study findings suggest current-smoking predicts increases in depressive and anxiety symptoms. Former-smoking predicted increases in depressive symptoms, but not anxiety, suggesting former-smoking may have specific potency for depression. These findings suggests that current-smokers should be monitored for depression and anxiety, with monitoring of depression in former-smokers also advised.
      As seen in other populations, bidirectional relationships between smoking and affective symptoms are plausible (
      • Mathew A.R.
      • Hogarth L.
      • Leventhal A.M.
      • Cook J.W.
      • Hitsman B.
      Cigarette smoking and depression comorbidity: systematic review and proposed theoretical model.
      ), whereby depression and anxiety increase the severity of nicotine cravings and withdrawals, and smoking acutely alleviates negative affective states, thereby reinforcing positive meta-beliefs about the value of smoking. The importance of increasing awareness and support for smoking cessation has been emphasised (
      • Weld-Blundell I.
      • Grech L.
      • Borland R.
      • White S.L.
      • das Nair R.
      • Marck C.H.
      Smoking habits, awareness and support needs for cessation among people with multiple sclerosis in Australia: findings from an online survey.
      ), and may have important therapeutic effects on singular or comorbid symptoms of depression or anxiety. Contrariwise, targeting depression and anxiety may help promote smoking cessation, thereby reducing reliance on smoking as a means of regulative negative affective states. Cognitive-behavioral therapies which integrate psychoeducation on the effects of smoking, motivation strategies for reducing smoking ambivalence and restructuring techniques for altering positive meta-beliefs about smoking have been effective in reducing smoking in other populations (
      • Marks D.F.
      • Sykes C.M.
      Randomized controlled trial of cognitive behavioural therapy for smokers living in a deprived area of London: outcome at one-year follow-up.
      ;
      • Patnode C.D.
      • Henderson J.T.
      • Coppola E.L.
      • Melnikow J.
      • Durbin S.
      • Thomas R.G.
      Interventions for tobacco cessation in adults, including pregnant persons: updated evidence report and systematic review for the US preventive services task force.
      ), and may have benefit for plwMS. Future interventional research is required to determine the efficacy of psychological therapies for smoking cessation, with or without embedded smoking cessation programs. Moreover, it is uncertain whether the treatment of depression and/or anxiety should be prioritized over smoking cessation therapies and beyond the scope of the review of examining positive associations between smoking and depression and anxiety.
      Smoking is thought is to have an anxiogenic effect, increasing panic symptoms (
      • Isensee B.
      • Wittchen H.U.
      • Stein M.B.
      • Hofler M.
      • Lieb R.
      Smoking increases the risk of panic: findings from a prospective community study.
      ), and so anxiety symptoms may not be as severe when an individual is no longer smoking regularly. To better understand the relationship between current-smoking / former-smoking and depressive symptoms, future research may consider the differential effects of depressive subtypes (i.e., persistent depression vs. acute, time-limited episodes). Some existing research suggests that individuals with dysthymia may be prone to heavier smoking in other populations (
      • Dierker L.C.
      • Avenevoli S.
      • Stolar M.
      • Merikangas K.R.
      Smoking and depression: an examination of mechanisms of comorbidity.
      ).

      10. Conclusion

      Systematic review of relevant studies found a strong association between current-smoking and former-smoking and depression, and current-smoking and anxiety in plwMS. Findings may add to the evidence for smoking cessation programs in the treatment of depression and anxiety, and the ongoing use of cognitive-behavioral approaches in promoting smoking cessation. Future prospective studies with uniform measurements of smoking and validated tools and consistent cut-offs for depression and anxiety to confirm suggested relationships between current-smoking and former-smoking and depression and anxiety are advised, which in turn would enable a future meta-analysis to be performed.

      Author contributions

      JCR and SSY were involved in study design and conceptualization. VV and SP identified the articles and screened the titles and abstracts; VV and SP screened the full-text articles; VV, SP, JCR and MIP extracted the data; VV, SSY, RD, MIP, SLN and JCR analyzed and interpreted the data; VV, JCR, RD and SSY wrote the manuscript. All authors reviewed and approved the manuscript.

      Data and material availability

      All data is available for this study.

      Funding

      We gratefully acknowledge the financial support of Mr Wal Pisciotta and other anonymous philanthropic donors to the Neuroepidemiology Unit. Funders played no role in the design, review or approval of the study.

      Declaration of Competing Interest

      SN is a co-editor of Overcoming Multiple Sclerosis Handbook: Roadmap to Good Health. SN is a facilitator of Overcoming MS educational workshops for people with MS.

      Acknowledgments

      We thank University of Melbourne library staff for their valuable assistance in the systematic review literature search.

      Appendix. Supplementary materials

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