Using a case-control study from Lombardy in Italy, and a nested-case control study from a cohort of US Veteran Affairs hospital inpatients, we found a strongly reduced risk of lung cancer in subjects with a personal history of mood disorders. Participants with a family history of mood disorders also had a similar inverse association with lung cancer risk, even in the absence of personal mood disorders. The inverse association was stronger for subjects who had both personal and family history of mood disorders.
Previous studies on the relationship between lung cancer and mood disorders have been mixed. Most prospective investigations examining this relationship, particularly major depression diagnosis, have not identified an association with lung cancer risk 
, while one study 
, with 240 lung cancer cases, found a positive association. These studies may have been affected by the small sample size (only 3 studies 
included more than 65 cases with prior mood disorder diagnosis). Moreover, most studies did not take into account potential confounders, such as tobacco smoking or COPD 
, allowed for concurrent diagnoses of mood disorders and lung cancer 
or used different ICD codes corresponding to broader and possibly milder forms of mental disorders 
The relationship with both personal and family history of mood disorders and lung cancer suggests that genetic, epigenetic factors or shared environment could be plausible explanations. Indeed, mood disorders have been associated with genetic effects 
, environmental factors 
or a combination of the two 
Treatment for mood disorders may have an effect on lung cancer risk, possibly through the interaction between the use of early generation antidepressants and the inhibition of pro-inflammatory pathways 
or cytochrome p450 enzymes known to activate carcinogens in tobacco 
. However, some studies 
reported that early antidepressant use is associated with increased cancer risk, suggesting that the interplay between smoking and medication, if any, is not straightforward. Also, serotonin appears to stimulate the growth of certain lung cancers 
. Lowered serotonin levels in mood disorders have been reported both in the central nervous system 
and in the periphery 
with possible implications in lung cancer risk.
Mild depression may make individuals less prone to pursue medical assistance 
, with resulting underestimation of mood disorders. However, this should affect all subjects, regardless of future lung cancer diagnosis. Resistance to seek medical care in depressed people may also delay lung cancer diagnosis, but given the inevitable progression and eventual hospitalization, recording of this aggressive disease is a virtual certainty. It can also be argued that subjects with significant mood disorders may seek medical attention on a more frequent basis. Surveillance bias, where lung cancer diagnosis is identified more often in individuals previously followed up due to mood disorder diagnosis would result in a positive association and not inverse, as our study reports, although more surveillance could also result in more frequent smoking cessation counseling that might lessen future cancer rates. Moreover, access to healthcare should not constitute a barrier to identification of a diagnosis of mood disorders in either Italy (which enjoys universal health care) or the US VA System (generally free access for Veterans). While the VA study was based on inpatient data potentially favoring more severe forms of mood disorders, the EAGLE study should have also captured moderate diagnoses treated on an outpatient basis. However, in Italy there is a low propensity for individuals to reveal details of their personal and emotional lives and only a small percentage of those suffering from emotional or mental health problems consult a medical professional 
. Thus, the subjects with self-reported mood disorders in EAGLE may reflect those with more severe diseases similar to those requiring hospitalization as in the VA study.
A potential issue is that some emotional and cognitive signs of mood disorders (e.g. weight loss, sleep perturbation and fatigue) could derive from pre-clinical manifestations of lung cancer itself 
. We addressed this issue by excluding subjects with a discharge record for any disease (in the VA study) or mood disorders (in EAGLE) within a year from the cancer diagnosis.
Another concern is that people with mood disorders would experience increased mortality due to comorbid conditions such as cardiovascular disease or suicide 
, and this would be reflected in an inverse association with cancer. However, further adjustment for stroke and ischemic heart disease did not modify the results, suggesting competing mortality from these sources cannot account for the observation.
Our research had several important strengths: although not fully comparable, both studies represented large populations with standardized access to medical care and different epidemiological designs. The VA cohort study featured extended follow-up among males and data on multiple medical conditions while the EAGLE case-control study considered both personal and family history of mood disorders, as well as psychometric scores for mood disorder symptoms. In addition, while one study design was based on self-reported questionnaire data, the other was based on medical records; both resulted in similar findings with high statistical significance. However, the results may only be generalizable to men, as women were not included in the VA cohort study analysis and were less commonly represented in the EAGLE case-control study.
Although we present the largest effort to date to evaluate the association between a previous history of mood disorders and risk of incident lung cancer, our work has several limitations. Misclassification or under-reporting of personal or family history of mood disorders, particularly in EAGLE, where severe depression requiring medication or hospitalization was the inclusion criterion, cannot be completely excluded. However, any such misclassification or under-reporting would probably be nondifferential.
The self-reported mood disorders in EAGLE may be subject to recall bias. However, the self-reported history of mood disorders among controls (91.7% of whom recalled their date of diagnosis or inpatient mood disorders care) was strongly (P<0.0001, Wald test) positively correlated with the CES-D and HADS scores, suggesting that a self-reported history of mood disorders does reflect a past mood disorder diagnosis. Moreover, the prevalence of mood disorders among EAGLE controls in the Lombardy region (9.1% overall, and 7.0% and 15.9% among males and females, respectively) is very similar to the lifetime prevalence of any mood disorders in Italy's non-institutionalized adult population during 1998 (11.2% overall, and 7.2% and 14.9% among males and females, respectively) 
. Finally, the VA study was based on discharge records, with no risk of recall bias.
Smoking could be an important confounder and/or effect modifier of mood disorders-lung cancer risk associations 
. Our results show a suggestive, but not significant, interaction between a personal history of mood disorders and smoking status in EAGLE. In fact, the negative association between mood disorders and lung cancer risk was evident in current and former smokers, but not in never smokers, although this last category included only a small number of cases. Similarly, in the analyses of other cancers in the VA study, we found that mood disorders-related protection was more frequent in smoking-related cancers than in those less strongly associated with tobacco smoking (Table S6
). However, in the VA study, subjects without smoking-related conditions showed a stronger risk reduction, although we cannot exclude that some smokers were included in this group. Moreover, in the VA study, medical conditions used as surrogate variables for smoking habits or alcohol consumption likely underestimate the actual presence of these exposures. Nonetheless, if these factors were decisive confounders then statistical adjustment for these surrogate variables should decrease the resultant effect estimates, but no major changes were observed. In the EAGLE study we were able to use individual smoking data to directly take into account smoking, and the strength of the inverse association was increased upon adjustment for detailed smoking and alcohol data. Finally, we cannot exclude that cigarette smoking could be used as “self-medication” for mood disorders and in this case, the “non-mood disorders” group used as reference for the association might include some milder forms of mood disorders “treated” by smoking. Since smoking is a strong risk factor for lung cancer and residual confounding from smoking can never be ruled out, follow-up in subjects with other smoking related conditions and in larger samples of non-smoking lung cancer patients is warranted.
In conclusion, using data from two different populations and study designs, we found an inverse association between lung cancer risk and personal or family history of mood disorders. This replicated finding could suggest a new insight in the development of these two widespread and debilitating diseases, although the association could have been affected by tobacco smoking. Further large-scale laboratory and human population and behavior research is necessary to clarify the complex interplay among smoking behavior, inherited susceptibility, mood disorders and cancer risk.