Skip to main content Accessibility help

Comorbidity of substance misuse with anxiety-related and depressive disorders: a genetically informative population study of 3 million individuals in Sweden

  • Suvi Virtanen (a1) (a2), Ralf Kuja-Halkola (a2), David Mataix-Cols (a3) (a4), Nitya Jayaram-Lindström (a3) (a4), Brian M. D'Onofrio (a2) (a5), Henrik Larsson (a2) (a6), Christian Rück (a3) (a4), Jaana Suvisaari (a7), Paul Lichtenstein (a2) and Antti Latvala (a1) (a2)...



Causes of the comorbidity of substance misuse with anxiety-related and depressive disorders (anxiety/depression) remain poorly known. We estimated associations of substance misuse and anxiety/depression in the general population and tested them while accounting for genetic and shared environmental factors.


We studied individuals born in Sweden 1968–1997 (n = 2 996 398) with follow-up in nationwide register data for 1997–2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Substance misuse was defined as ICD-10 alcohol or drug use disorder or an alcohol/drug-related criminal conviction. Three dimensions of ICD-10 anxiety and depressive disorders and a substance misuse dimension were identified through exploratory factor analysis.


Substance misuse was associated with a 4.5-fold (95% CI 4.50–4.58) elevated risk of lifetime generalized anxiety/depression, 4.7-fold (95% CI 4.63–4.82) elevated risk of panic disorder and agora/social phobia, and 2.9-fold elevated risk of phobias/OCD (95% CI 2.82–3.02) as compared to those without substance misuse. The associations were attenuated in within-family analyses but we found elevated risks in monozygotic twin pairs discordant for substance misuse as well as significant non-shared environmental correlations. The association between anxiety/depression and substance misuse was mainly driven by generalized anxiety/depression, whereas other anxiety/depression dimensions had minor or no independent associations with substance misuse.


Substance misuse and anxiety/depression are associated at the population level, and these associations are partially explained by familial liabilities. Our findings indicate a common genetic etiology but are also compatible with a potential partially causal relationship between substance misuse and anxiety/depression.


Corresponding author

Author for correspondence: Suvi Virtanen, E-mail:


Hide All
Bejerot, S and Humble, M (1999) Low prevalence of smoking among patients with obsessive-compulsive disorder. Comprehensive Psychiatry 40, 268272.
Blanco, C, Xu, Y, Brady, K, Pérez-Fuentes, G, Okuda, M and Wang, S (2013) Comorbidity of posttraumatic stress disorder with alcohol dependence among US adults: results from National Epidemiological Survey on Alcohol and Related Conditions. Drug and Alcohol Dependence 132, 630638.
Burns, L and Teesson, M (2002) Alcohol use disorders comorbid with anxiety, depression and drug use disorders: findings from the Australian National Survey of Mental Health and Well Being. Drug and Alcohol Dependence 68, 299307.
Conway, KP, Compton, W, Stinson, FS and Grant, BF (2006) Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Journal of Clinical Psychiatry 67, 247257.
De Bellis, MD (2002) Developmental traumatology: a contributory mechanism for alcohol and substance use disorders. Psychoneuroendocrinology 27, 155170.
de Graaf, R, Bijl, RV, Smit, F, Vollebergh, WA and Spijker, J (2002) Risk factors for 12-month comorbidity of mood, anxiety, and substance use disorders: findings from the Netherlands Mental Health Survey and Incidence Study. American Journal of Psychiatry 159, 620629.
D'Onofrio, BM, Lahey, BB, Turkheimer, E and Lichtenstein, P (2013) Critical need for family-based, quasi-experimental designs in integrating genetic and social science research. American Journal of Public Health 103, 4655.
Ekbom, A (2011) The Swedish multi-generation register. Methods in Molecular Biology 675, 215220.
Farrell, M, Howes, S, Bebbington, P, Brugha, T, Jenkins, R, Lewis, G and Meltzer, H (2001) Nicotine, alcohol and drug dependence and psychiatric comorbidity: results of a national household survey. British Journal of Psychiatry 179, 432437.
Flensborg-Madsen, T, Mortensen, EL, Knop, J, Becker, U, Sher, L and Grønbæk, M (2009) Comorbidity and temporal ordering of alcohol use disorders and other psychiatric disorders: results from a Danish register-based study. Comprehensive Psychiatry 50, 307314.
Fröjd, S, Ranta, K, Kaltiala-Heino, R and Marttunen, M (2011) Associations of social phobia and general anxiety with alcohol and drug use in a community sample of adolescents. Alcohol and Alcoholism 46, 192199.
Galea, S and Tracy, M (2007) Participation rates in epidemiologic studies. Annals of Epidemiology 17, 643653.
Gunasekara, F, Richardson, K, Carter, K and Blakely, T (2014) Fixed effects analysis of repeated measures data. International Journal of Epidemiology 43, 264269.
Kasteenpohja, T, Marttunen, M, Aalto-Setälä, T, Perälä, J, Saarni, SI and Suvisaari, J (2016) Treatment adequacy of anxiety disorders among young adults in Finland. BMC Psychiatry 16, 6376.
Kendler, KS, Walters, EE, Neale, MC, Kessler, RC, Heath, AC and Eaves, LJ (1995) The structure of the genetic and environmental risk factors for six major psychiatric disorders in women: phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. Archives of General Psychiatry 52, 374383.
Kendler, KS, Prescott, CA, Myers, J and Neale, MC (2003) The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Archives of General Psychiatry 60, 929937.
Kessler, RC, McGonagle, KA, Zhao, S, Nelson, CB, Hughes, M, Eshleman, S and Kendler, KS (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Archives of General Psychiatry 51, 819.
Kessler, RC, Berglund, P, Demler, O, Jin, R, Merikangas, KR and Walters, EE (2005 a) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 593602.
Kessler, RC, Chiu, WT, Demler, O and Walters, EE (2005 b) Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 617627.
Kranzler, HR and Rosenthal, RN (2003) Dual diagnosis: alcoholism and co-morbid psychiatric disorders. American Journal on Addictions 12, 2640.
Lahey, BB and D'Onofrio, BM (2010) All in the family: comparing siblings to test causal hypotheses regarding environmental influences on behavior. Current Directions in Psychological Science 19, 319323.
Lai, HMX, Cleary, M, Sitharthan, T and Hunt, GE (2015) Prevalence of comorbid substance use, anxiety and mood disorders in epidemiological surveys, 1990–2014: a systematic review and meta-analysis. Drug and Alcohol Dependence 154, 113.
Langas, AM, Malt, UF and Opjordsmoen, S (2012) In-depth study of personality disorders in first-admission patients with substance use disorders. BMC Psychiatry 12, 180190.
Laramee, P, Leonard, S and Buchanan-Hughes, A (2015) Risk of all-cause mortality in alcohol-dependent individuals: a systematic literature review and meta-analysis. EBioMedicine 2, 13941404.
Ludvigsson, JF, Otterblad-Olausson, P, Pettersson, BU and Ekbom, A (2009) The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. European Journal of Epidemiology 24, 659667.
Ludvigsson, JF, Andersson, E, Ekbom, A, Feychting, M, Kim, JL, Reuterwall, C, Heurgren, M and Otterblad Olausson, P (2011) External review and validation of the Swedish National Inpatient Register. BMC Public Health 11, 450466.
Markkula, N, Suvisaari, J, Saarni, SI, Pirkola, S, Peña, S, Saarni, S, Ahola, K, Mattila, AK, Viertiö, S, Strehle, J, Koskinen, S and Härkänen, T (2015) Prevalence and correlates of major depressive disorder and dysthymia in an eleven-year follow-up – results from the Finnish Health 2011 Survey. Journal of Affective Disorders 1, 7380.
McGue, M, Osler, M and Christensen, K (2010) Causal inference and observational research: the utility of twins. Perspectives in Psychological Science 5, 546556.
Meier, SM, Mattheisen, M, Mors, O, Mortensen, PB, Laursen, TM and Penninx, BW (2016) Increased mortality among people with anxiety disorders: total population study. British Journal of Psychiatry 209, 216221.
Merikangas, KR, Mehta, RL, Molnar, BE, Walters, EE, Swendsen, JD, Aguilar-Gaziola, S, Kolody, B, Vega, WA, Wittchen, HU and Kessler, RC (1998 a) Comorbidity of substance use disorders with mood and anxiety disorders: results of the International Consortium in Psychiatric Epidemiology. Addictive Behaviors 23, 893907.
Merikangas, KR, Stevens, DE, Fenton, B, Stolar, M, O'Malley, S, Woods, SW and Risch, N (1998 b) Co-morbidity and familial aggregation of alcoholism and anxiety disorders. Psychological Medicine 28, 773788.
Neale, MCCL and Cardon, LR (1992) Methodology for Genetic Studies of Twins and Families. Dordrecht, The Netherlands: Kluwer Academic Publishers.
Pickens, RW, Svikis, DS, McGue, M and LaBuda, MC (1995) Common genetic mechanisms in alcohol, drug, and mental disorder comorbidity. Drug and Alcohol Dependence 39, 129138.
Pirkola, SP, Isometsä, E, Suvisaari, J, Aro, H, Joukamaa, M, Poikolainen, K, Koskinen, S, Aromaa, A and Lönnqvist, JK (2005) DSM-IV mood-, anxiety- and alcohol use disorders and their comorbidity in the Finnish general population. Social Psychiatry and Psychiatric Epidemiology 40, 110.
Plana-Ripoll, O, Pedersen, CB, Holtz, Y, Benros, ME, Dalsgaard, S, de Jonge, P, Fan, CC, Degenhardt, L, Ganna, A, Greve, AN, Gunn, J, Iburg, KM, Kessing, LV, Lee, BK, Lim, CCW, Mors, O, Nordentoft, M, Prior, A, Roest, AM, Saha, S, Schork, A, Scott, JG, Scott, KM, Stedman, T, Sørensen, HJ, Werge, T, Whiteford, HA, Laursen, TM, Agerbo, E, Kessler, RC, Mortensen, PB and McGrath, JJ (2019) Exploring comorbidity within mental disorders among a Danish National Population. JAMA Psychiatry. Published online January 16, 2019. doi: 10.1001/jamapsychiatry.2018.3658.
Regier, DA, Farmer, ME, Rae, DS, Locke, BZ, Keith, SJ, Judd, LL and Goodwin, FK (1990) Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA 264, 25112518.
Revelle, W (2018) Psych: Procedures for Personality and Psychological Research. Northwestern University, Evanston, Illinois, USA. Available at; Version = 1.8.4.
Rijsdijk, FV and Sham, PC (2002) Analytic approaches to twin data using structural equation models. Briefings in Bioinformatics 3, 119133.
Saraceno, B (2002) The WHO world health report 2001 on mental health. Epidemiologia e Psichiatria Sociale 11, 8387.
Saraceno, L, Munafó, M, Heron, J, Craddock, N and Van Den Bree, MB (2009) Genetic and non-genetic influences on the development of co-occurring alcohol problem use and internalizing symptomatology in adolescence: a review. Addiction 104, 11001121.
Sartor, CE, McCutcheon, VV, Pommer, NE, Nelson, EC, Grant, JD, Duncan, A, Waldron, M, Bucholz, KK, Madden, PA and Heath, AC (2011) Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychological Medicine 41, 14971505.
Savage, JE, Kaprio, J, Korhonen, T, Pulkkinen, L, Rose, RJ, Verhulst, B and Dick, DM (2016) The effects of social anxiety on alcohol and cigarette use across adolescence: results from a longitudinal twin study in Finland. Psychology of Addictive Behaviors 30, 462474.
Schuckit, MA (2006) Comorbidity between substance use disorders and psychiatric conditions. Addiction 101, 7688.
Sundquist, J, Ohlsson, H, Sundquist, K and Kendler, KS (2017) Common adult psychiatric disorders in Swedish primary care where most mental health patients are treated. BMC Psychiatry 17, 234244.
Swendsen, JD, Merikangas, KR, Canino, GJ, Kessler, RC, Rubio-Stipec, M and Angst, J (1998) The comorbidity of alcoholism with anxiety and depressive disorders in four geographic communities. Comprehensive Psychiatry 39, 176184.
Takayanagi, Y, Spira, AP, Roth, KB, Gallo, JJ, Eaton, WW and Mojtabai, R (2014) Accuracy of reports of lifetime mental and physical disorders: results from the Baltimore Epidemiological Catchment Area study. JAMA Psychiatry 71, 273280.
Tambs, K, Harris, JR and Magnus, P (1997) Genetic and environmental contributions to the correlation between alcohol consumption and symptoms of anxiety and depression. Results from a bivariate analysis of Norwegian twin data. Behavior Genetics 27, 241250.
Teesson, M, Hall, W, Lynskey, M and Degenhardt, L (2000) Alcohol- and drug-use disorders in Australia: implications of the National Survey of Mental Health and Wellbeing. The Australian and New Zealand Journal of Psychiatry 34, 206213.
Toftdahl, NG, Nordentoft, M and Hjorthøj, C (2016) Prevalence of substance use disorders in psychiatric patients: a nationwide Danish population-based study. Social Psychiatry and Psychiatric Epidemiology 51, 129140.
Turner, S, Mota, N, Bolton, J and Sareen, J (2018) Self-medication with alcohol or drugs for mood and anxiety disorders: a narrative review of the epidemiological literature. Depression and Anxiety 35, 851860.
Westman, J, Wahlbeck, K, Laursen, TM, Gissler, M, Nordentoft, M, Hällgren, J and Ösby, U (2015) Mortality and life expectancy of people with alcohol use disorder in Denmark, Finland and Sweden. Acta Psychiatrica Scandinavica 131, 297306.
Whiteford, HA, Degenhardt, L, Rehm, J, Baxter, AJ, Ferrari, AJ, Erskine, HE, Charlson, FJ, Norman, RE, Flaxman, AD, Johns, N, Burstein, R, Murray, CJ and Vos, T (2013) Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010. Lancet 382, 15751586.
Wittchen, HU, Jacobi, F, Rehm, J, Gustavsson, A, Svensson, M, Jönsson, B, Olesen, J, Allgulander, C, Alonso, J, Faravelli, C, Fratiglioni, L, Jennum, P, Lieb, R, Maercker, A, van Os, J, Preisig, M, Salvador-Carulla, L, Simon, R and Steinhausen, HC (2011) The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology 21, 655679.
World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva, Switzerland: World Health Organization.
Xian, H, Chantarujikapong, SI, Scherrer, JF, Eisen, SA, Lyons, MJ, Goldberg, J and True, WR (2000) Genetic and environmental influences on posttraumatic stress disorder, alcohol and drug dependence in twin pairs. Drug and Alcohol Dependence 61, 95102.


Type Description Title
Supplementary materials

Virtanen et al. supplementary material
Virtanen et al. supplementary material 1

 Word (464 KB)
464 KB

Comorbidity of substance misuse with anxiety-related and depressive disorders: a genetically informative population study of 3 million individuals in Sweden

  • Suvi Virtanen (a1) (a2), Ralf Kuja-Halkola (a2), David Mataix-Cols (a3) (a4), Nitya Jayaram-Lindström (a3) (a4), Brian M. D'Onofrio (a2) (a5), Henrik Larsson (a2) (a6), Christian Rück (a3) (a4), Jaana Suvisaari (a7), Paul Lichtenstein (a2) and Antti Latvala (a1) (a2)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.