Association of Anxiety, Depression and Obesity With Asthma
Association of Anxiety, Depression and Obesity With Asthma
In this large prospective study from the general population, adults reporting symptoms of anxiety or depression at baseline had an increased risk of incident asthma at follow-up. We also found that adults with anxiety or depression symptoms and obesity had a particularly increased risk of developing asthma.
Our finding that anxiety or depression symptoms are moderately associated with incident asthma is supported by previous prospective studies. Chida et al. reviewed 34 studies of psychosocial factors on atopic disorders (91% were on asthma), and found a robust relationship between psychological factors and atopic disorders. Further to this, several studies have investigated the association between anxiety or depression and adult asthma, with relative risk estimates ranging from 1.24 to 2.80. Four of these were prospective studies, which found that anxiety or depression were associated with incident asthma. Our findings extend previous research by examining this hypothesis in a very large prospective cohort, with a comprehensive range of covariates to adjust for. Furthermore, our study investigated the joint association of anxiety or depression symptoms and obesity with incident asthma. We found that participants with anxiety or depression symptoms and also obesity had a greater risk of asthma than the sum of their individual risks, as indicated by the RERI.
The association between anxiety or depression symptoms and incident asthma may have biological plausibility. Two main pathways have been suggested, including changes in health behaviours and inflammatory processes. Lifestyle-related behaviours such as smoking, and less physical exercise due to distress, may be mediators leading to the development of asthma. On the other hand, these health behaviour variables may also be confounding factors that cause both psychological distress and asthma. In any case, the attempt of adjustment for these factors (smoking and physical activity) in addition to the other covariates in our models did not substantially alter the association between anxiety or depression symptoms and incident asthma.
Our multivariable analysis suggests that inflammatory processes may be a potential pathway. Several studies have suggested that depression is linked to a state of low-grade chronic inflammation, and anxiety has been associated with increased production of pro-inflammatory cytokines. Furthermore, progression of psychological distress such as anxiety and depression may lead to irregular levels of circulating cortisol, and a glucocorticoid-insensitive state. Glucocorticoid receptor resistance has been observed in healthy adults exposed to long-term stressful experiences, parents of children with cancer and spouses of brain-cancer patients. Consequently, the down-regulation of glucocorticoid receptors may interfere with regulation of inflammation which may increase the risk of inflammatory disorders. Miller et al. found that children with asthma and perceived low support from their parents (a proxy for stress) were more resistant to hydrocortisone's anti-inflammatory effects on pro-inflammatory cytokines, which shed some light on how stress affects asthma. Therefore, a state of inflammation and glucocorticoid insensitivity due to chronic psychological distress might be the underlying pathophysiology for the association we observed.
Obesity is also a chronic inflammatory condition, which will signal cortisol release through normal inflammatory signalling and the hypothalamic–pituitary–adrenal axis. High levels of cortisol due to obesity may additionally contribute to cortisol insensitivity. The further complication of obesity in anxious or depressed participants may worsen a common inflammatory pathway and, at least in part, explain the joint association that we observed. A reciprocal link between obesity and psychological distresses such as anxiety and depression has been reported in observational studies, but further research is needed to investigate the underlying mechanism of this interaction. Our observation that participants with both anxiety or depression and obesity have an excess risk of asthma, suggests that a considerable number of asthma cases may be due to the presence of anxiety or depression and obesity in the same causal mechanism. Identifying people with anxiety or depression symptoms and obesity may make asthma prevention more effective. However, the study findings and their mechanistic implications merit further investigation.
Our study has several major strengths. The prospective study design indicates direction of the association. The size and duration of our study was an advantage to increase study power and the possibility of detecting associations. With the large study size we were able to assess the joint association of anxiety or depression symptoms and obesity with incident asthma, and also to address potential differences between sexes. The comprehensive data set allowed us to control for a range of potential confounding factors. Height and weight were objectively measured and recorded by nurses in standardized clinical examinations. This would have avoided subjective over-reporting of height and under-reporting of weight. We also used another proxy measure for obesity (abdominal obesity) and found results similar to our original analysis. To strengthen our definition of anxiety or depression symptoms, we used an alternative definition adding those who used antidepressant medication into the symptom group, which minimized misclassification of exposure. The findings from these analyses supported our results.
With regard to potential limitations, we acknowledge that even though we controlled for many confounding factors there may still be residual confounding in our study. Another major challenge in epidemiological studies of asthma is the definition, since there is no gold standard for the diagnosis of asthma. Although we verified asthma cases by medication use, we cannot rule out possible misclassification bias since objective airway reversibility or hyper-responsiveness tests, were not performed. Also, misclassification of hyperventilation or shortness of breath as asthma in anxious participants cannot completely be ruled out as an explanation of our finding. However, self–reported asthma has been assessed as a reasonably robust method for population studies. To strengthen our diagnosis of asthma, we used a stricter definition of asthma verified by the use of asthma medication. Further to this, we excluded participants who reported chronic bronchitis, emphysema or COPD in the follow-up questionnaires to reduce possible misclassification of asthma and COPD. The results from all these additional analyses showed similar associations to our main findings.
In the current study, the HADS was used as a screening tool to capture symptoms of anxiety or depression. The ability of the HADS to separate clinical diagnoses of anxiety and depression disorders is uncertain, and the HADS-identified cases may not have a close correspondence to clinical anxiety or depression. For example, we observed the lowest prevalence of anxiety or depression in the youngest group, who have been reported to have the highest prevalence of clinical mental disorders by others. We also observed a high prevalence of depression in men, which is greater than the prevalence from diagnoses based on interviews. The limitations of the HADS to identify clinical anxiety or depression may limit the generalizability of our results.
In summary, this large prospective cohort study suggests that anxiety or depression symptoms may contribute to the development of asthma and that obesity may interact with anxiety or depression symptoms to further increase the risk of asthma in adults. Further research is needed to confirm the presence of synergy between these two common risk factors and to explore the underlying mechanisms.
Discussion
In this large prospective study from the general population, adults reporting symptoms of anxiety or depression at baseline had an increased risk of incident asthma at follow-up. We also found that adults with anxiety or depression symptoms and obesity had a particularly increased risk of developing asthma.
Our finding that anxiety or depression symptoms are moderately associated with incident asthma is supported by previous prospective studies. Chida et al. reviewed 34 studies of psychosocial factors on atopic disorders (91% were on asthma), and found a robust relationship between psychological factors and atopic disorders. Further to this, several studies have investigated the association between anxiety or depression and adult asthma, with relative risk estimates ranging from 1.24 to 2.80. Four of these were prospective studies, which found that anxiety or depression were associated with incident asthma. Our findings extend previous research by examining this hypothesis in a very large prospective cohort, with a comprehensive range of covariates to adjust for. Furthermore, our study investigated the joint association of anxiety or depression symptoms and obesity with incident asthma. We found that participants with anxiety or depression symptoms and also obesity had a greater risk of asthma than the sum of their individual risks, as indicated by the RERI.
The association between anxiety or depression symptoms and incident asthma may have biological plausibility. Two main pathways have been suggested, including changes in health behaviours and inflammatory processes. Lifestyle-related behaviours such as smoking, and less physical exercise due to distress, may be mediators leading to the development of asthma. On the other hand, these health behaviour variables may also be confounding factors that cause both psychological distress and asthma. In any case, the attempt of adjustment for these factors (smoking and physical activity) in addition to the other covariates in our models did not substantially alter the association between anxiety or depression symptoms and incident asthma.
Our multivariable analysis suggests that inflammatory processes may be a potential pathway. Several studies have suggested that depression is linked to a state of low-grade chronic inflammation, and anxiety has been associated with increased production of pro-inflammatory cytokines. Furthermore, progression of psychological distress such as anxiety and depression may lead to irregular levels of circulating cortisol, and a glucocorticoid-insensitive state. Glucocorticoid receptor resistance has been observed in healthy adults exposed to long-term stressful experiences, parents of children with cancer and spouses of brain-cancer patients. Consequently, the down-regulation of glucocorticoid receptors may interfere with regulation of inflammation which may increase the risk of inflammatory disorders. Miller et al. found that children with asthma and perceived low support from their parents (a proxy for stress) were more resistant to hydrocortisone's anti-inflammatory effects on pro-inflammatory cytokines, which shed some light on how stress affects asthma. Therefore, a state of inflammation and glucocorticoid insensitivity due to chronic psychological distress might be the underlying pathophysiology for the association we observed.
Obesity is also a chronic inflammatory condition, which will signal cortisol release through normal inflammatory signalling and the hypothalamic–pituitary–adrenal axis. High levels of cortisol due to obesity may additionally contribute to cortisol insensitivity. The further complication of obesity in anxious or depressed participants may worsen a common inflammatory pathway and, at least in part, explain the joint association that we observed. A reciprocal link between obesity and psychological distresses such as anxiety and depression has been reported in observational studies, but further research is needed to investigate the underlying mechanism of this interaction. Our observation that participants with both anxiety or depression and obesity have an excess risk of asthma, suggests that a considerable number of asthma cases may be due to the presence of anxiety or depression and obesity in the same causal mechanism. Identifying people with anxiety or depression symptoms and obesity may make asthma prevention more effective. However, the study findings and their mechanistic implications merit further investigation.
Our study has several major strengths. The prospective study design indicates direction of the association. The size and duration of our study was an advantage to increase study power and the possibility of detecting associations. With the large study size we were able to assess the joint association of anxiety or depression symptoms and obesity with incident asthma, and also to address potential differences between sexes. The comprehensive data set allowed us to control for a range of potential confounding factors. Height and weight were objectively measured and recorded by nurses in standardized clinical examinations. This would have avoided subjective over-reporting of height and under-reporting of weight. We also used another proxy measure for obesity (abdominal obesity) and found results similar to our original analysis. To strengthen our definition of anxiety or depression symptoms, we used an alternative definition adding those who used antidepressant medication into the symptom group, which minimized misclassification of exposure. The findings from these analyses supported our results.
With regard to potential limitations, we acknowledge that even though we controlled for many confounding factors there may still be residual confounding in our study. Another major challenge in epidemiological studies of asthma is the definition, since there is no gold standard for the diagnosis of asthma. Although we verified asthma cases by medication use, we cannot rule out possible misclassification bias since objective airway reversibility or hyper-responsiveness tests, were not performed. Also, misclassification of hyperventilation or shortness of breath as asthma in anxious participants cannot completely be ruled out as an explanation of our finding. However, self–reported asthma has been assessed as a reasonably robust method for population studies. To strengthen our diagnosis of asthma, we used a stricter definition of asthma verified by the use of asthma medication. Further to this, we excluded participants who reported chronic bronchitis, emphysema or COPD in the follow-up questionnaires to reduce possible misclassification of asthma and COPD. The results from all these additional analyses showed similar associations to our main findings.
In the current study, the HADS was used as a screening tool to capture symptoms of anxiety or depression. The ability of the HADS to separate clinical diagnoses of anxiety and depression disorders is uncertain, and the HADS-identified cases may not have a close correspondence to clinical anxiety or depression. For example, we observed the lowest prevalence of anxiety or depression in the youngest group, who have been reported to have the highest prevalence of clinical mental disorders by others. We also observed a high prevalence of depression in men, which is greater than the prevalence from diagnoses based on interviews. The limitations of the HADS to identify clinical anxiety or depression may limit the generalizability of our results.
In summary, this large prospective cohort study suggests that anxiety or depression symptoms may contribute to the development of asthma and that obesity may interact with anxiety or depression symptoms to further increase the risk of asthma in adults. Further research is needed to confirm the presence of synergy between these two common risk factors and to explore the underlying mechanisms.
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