Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression
Abstract
BACKGROUND: Tobacco smoking is more common among patients with schizophrenia and depression than among healthy individuals. We tested the hypothesis that high tobacco smoking intensity is causally associated with antipsychotic medication use, schizophrenia, antidepressant medication use and/or depression in the general population, and compared results with those for chronic obstructive pulmonary disease. METHODS: We used self-reported smoking intensity in cigarettes/day and a polymorphism in the CHRNA3 gene cluster (rs1051730) associated with smoking intensity, on 63,296 20-100-year-old individuals from the Danish general population; 23,282 were never-smokers and 40,014 ever-smokers. For schizophrenia, we compared our results with those in the Psychiatric Genomics Consortium. RESULTS: In smokers, heterozygotes (CT) and homozygotes (TT) for rs1051730 genotype had higher smoking intensity compared with non-carriers (CC). Furthermore, in ever-smokers homozygotes had increased risk of antipsychotic medication with an odds ratio (OR) of 1.16 [95% confidence interval (CI) 1.02-1.31] compared with non-carriers, whereas in never-smokers the corresponding OR was 1.07 (0.87-1.31) (P-interaction: 0.60). Correspondingly, ORs were 1.60 (0.74-3.47) and 1.02 (0.11-9.10) for schizophrenia (P-interaction: 0.85), 1.02 (0.93-1.13) and 0.99 (0.85-1.15) for antidepressant medication (P-interaction: 0.87), 0.85 (0.66-1.10) and 1.26 (0.87-1.83) for depression (P-interaction: 0.30) and 1.31 (1.16-1.47) and 0.89 (0.58-1.36) for chronic obstructive pulmonary disease (P-interaction: 0.16). Odds ratios per rs1051730 allele for schizophrenia and antipsychotic medication use in ever-smokers in the general population were 1.22 (95% CI: 0.84-1.79) and 1.06 (1.00-1.12). In the Psychiatric Genomics Consortium, the corresponding OR for schizophrenia was 1.06 (1.04-1.08) in ever- and never-smokers combined. CONCLUSION: Our data suggest that tobacco smoking could influence the development of psychotic conditions causally, whereas an influence on depression seems unlikely.
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MR studies using single SNPs found no evidence for a causal association between smoking and primary depression or anxiety.
“Using this genetic instrument, analyses in the Norwegian HUNT study (N=53,601) 46 and the Copenhagen General Population Study and City Heart Study (N=63,296) 47 found no evidence for a causal association between smoking with primary depression or anxiety.”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [47]
In the Danish population, smoking is associated with non-significant increased risk of diagnosed schizophrenia (OR=1.22, 95% CI 0.84-1.79).
“Although the relationship between smoking and diagnosed schizophrenia in the Danish population fell short of statistical significance (OR=1.22, 95% CI: 0.84-1.79), this could have been due to the small number of cases with schizophrenia in the sample (N=57)”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [47]
In the PGC, smoking has significant causal effects increasing risk of schizophrenia (OR=1.60, 95% CI 0.74-3.47).
“Significant causal effects of smoking in increasing the risk of schizophrenia was found in the PGC (OR=1.60, 95% CI: 0.74-3.47).”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [47]
In the Danish population, smoking has a significant causal relationship with lifetime antipsychotic medication use (OR=1.16, 95% CI 1.02-1.31).
“as further analyses examining smoking and odds of lifetime antipsychotic medication use in this sample (N=2,795 cases) found evidence for a significant causal relationship (OR=1.16, 95% CI: 1.02-1.31).”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [47]
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- Authors
- Wium-Andersen, M. K., Orsted, D. D., & Nordestgaard, B. G.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Nordestgaard, B. G.
- ORCID
- Nordestgaard, B. G.
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-04-01
- Volume
- 44
- Issue
- 2
- Pages
- 566-577
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- OpenAlex
- W1914804431
- Cited by
- 59
- References
- 38
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 6 · 2018: 11 · 2017: 7 · 2016: 6 · 2015: 1
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- smoking, antipsychotic use, schizophrenia, depression, antidepressant use, chronic obstructive pulmonary disease, smoking intensity, gene-environment interaction, causal relationship, general population, mental illness, nicotinic acetylcholine receptors
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antidepressive Agents, Depressive Disorder, Female, Heterozygote, Homozygote, Humans, Male, Middle Aged, Receptors, Nicotinic, Schizophrenia, Smoking, Antipsychotic Agents, Pulmonary Disease, Chronic Obstructive, Young Adult, Mendelian Randomization Analysis
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