Common mental disorders are a leading contributor to the global burden of disease (Prince et al., Reference Prince, Patel, Saxena, Maj, Maselko, Phillips and Rahman2007; Whiteford et al., Reference Whiteford, Degenhardt, Rehm, Baxter, Ferrari, Erskine, Charlson, Norman, Flaxman, Johns, Burstein, Murray and Vos2013), and are associated with excess mortality (Walker et al., Reference Walker, McGee and Druss2015). In particular, major depressive disorder (MDD) has been consistently associated with higher risk of mortality (Cuijpers et al., Reference Cuijpers, Vogelzangs, Twisk, Kleiboer, Li and Penninx2014a), most strongly among men (Cuijpers et al., Reference Cuijpers, Vogelzangs, Twisk, Kleiboer, Li and Penninx2014b; Gilman et al., Reference Gilman, Sucha, Kingsbury, Horton, Murphy and Colman2017; Colman et al., Reference Colman, Kingsbury, Sucha, Horton, Murphy and Gilman2018). There is less consensus on the relationship between anxiety disorders and mortality. Results from some studies have suggested that anxiety disorders, like depression, are associated with excess mortality (van Hout et al., Reference van Hout, Beekman, de Beurs, Comijs, van Marwijk, de Haan, van Tilburg and Deeg2004; Kikkenborg Berg et al., Reference Kikkenborg Berg, Caspar Thygesen, Hastrup Svendsen, Vinggaard Christensen and Zwisler2014). Others have suggested that anxiety may be protective against accidental mortality in early adulthood, but confer increased risk of non-accidental mortality later in life (Lee et al., Reference Lee, Wadsworth and Hotopf2006). Notably, many studies of the relation between anxiety and mortality do not discriminate between specific anxiety disorders, considering generalised anxiety disorder (GAD), panic disorder, obsessive compulsive disorder and others together in a single category (van Hout et al., Reference van Hout, Beekman, de Beurs, Comijs, van Marwijk, de Haan, van Tilburg and Deeg2004; Laan et al., Reference Laan, Termorshuizen, Smeets, Boks, De Wit and Geerlings2011). Others consider ‘trait anxiety’ (Lee et al., Reference Lee, Wadsworth and Hotopf2006), or non-specific symptoms of anxiety (Kikkenborg Berg et al., Reference Kikkenborg Berg, Caspar Thygesen, Hastrup Svendsen, Vinggaard Christensen and Zwisler2014).
Psychiatric comorbidity can be defined as the occurrence of two or more mental disorders in the same individual, either concurrently or over the life span (Brown et al., Reference Brown, Campbell, Lehman, Grisham and Mancill2001). Comorbidity among mental disorders, both concurrently and over the lifetime, is very common (Boyd et al., Reference Boyd, Burke, Gruenberg, Holzer, Rae, George, Karno, Stoltzman, McEvoy and Nestadt1984; Brown et al., Reference Brown, Campbell, Lehman, Grisham and Mancill2001; Kessler et al., Reference Kessler, Wai, Demler and Walters2005; Roca et al., Reference Roca, Gili, Garcia-Garcia, Salva, Vives, Garcia Campayo and Comas2009). In fact, 45–55% of those with a current mood or anxiety disorder meet criteria for at least one other disorder concurrently (Brown et al., Reference Brown, Campbell, Lehman, Grisham and Mancill2001; Kessler et al., Reference Kessler, Wai, Demler and Walters2005), and up to 81% have had at least one additional disorder over their lifetime (Brown et al., Reference Brown, Campbell, Lehman, Grisham and Mancill2001). The experience of multiple psychiatric disorders over the lifetime is associated with worse functional and health outcomes than are unique diagnoses. For example, lifetime comorbidity with an additional mental disorder is associated with poorer outcomes of mood (Brown et al., Reference Brown, Schulberg, Madonia, Shear and Houck1996) and anxiety disorders (Roy-Byrne et al., Reference Roy-Byrne, Stang, Wittchen, Ustun, Walters and Kessler2000), including greater severity of symptoms (Roy-Byrne et al., Reference Roy-Byrne, Stang, Wittchen, Ustun, Walters and Kessler2000), higher likelihood of relapse (Brown et al., Reference Brown, Schulberg, Madonia, Shear and Houck1996; Roy-Byrne et al., Reference Roy-Byrne, Stang, Wittchen, Ustun, Walters and Kessler2000) and higher risk of suicidal behaviour (Henriksson et al., Reference Henriksson, Aro, Marttunen, Heikkinen, Isometsa, Kuoppasalmi and Lonnqvist1993; Nock et al., Reference Nock, Hwang, Sampson and Kessler2010). Alcohol has been causally linked with over 60 unique medical conditions (Rehm et al., Reference Rehm, Room, Graham, Monteiro, Gmel and Sempos2003), and alcohol use disorders have been associated with numerous deleterious health consequences (Room et al., Reference Room, Babor and Rehm2005), including increased risk of death due to both natural and unnatural causes (Harris and Barraclough, Reference Harris and Barraclough1998). When individuals suffer from mood and anxiety disorders in conjunction with alcohol use disorders, there is a substantially higher risk of impairment, disability and suicide (Merikangas et al., Reference Merikangas, Mehta, Molnar, Walters, Swendsen, Aguilar-Gaziola, Bijl, Borges, Caraveo-Anduaga, Dewit, Kolody, Vega, Wittchen and Kessler1998).
Most studies reporting elevated mortality risk among individuals with psychiatric disorders have focused on risk associated with single disorders (Harris and Barraclough, Reference Harris and Barraclough1998); there is much less evidence addressing the concern that the experience of multiple disorders further diminishes life expectancy. Laan et al. reported that among patients receiving psychiatric services, both anxiety disorders and depression were associated with excess mortality, but that the superimposition of the two disorders did not further inflate risk (Laan et al., Reference Laan, Termorshuizen, Smeets, Boks, De Wit and Geerlings2011). Similarly, Naicker et al., using data from a Norwegian population-based study, recently reported that the experience of both depression and anxiety was associated with an increased risk of death – at a level similar to the risk conferred by either disorder alone (Naicker et al., Reference Naicker, Johnson, Skogen, Manuel, Øverland, Sivertsen and Colman2017). Results from the first wave of the Stirling County study suggested that although depression was associated with excess mortality, the superimposition of anxiety (Murphy et al., Reference Murphy, Monson, Olivier, Sobol and Leighton1987) or alcohol abuse (Murphy et al., Reference Murphy, Burke, Monson, Horton, Laird, Lesage, Sobol and Leighton2008) on depression did not confer additional risk. By contrast, Phillips et al. reported that among veterans, the presence of comorbid GAD and MDD was associated with a higher risk of mortality than either disorder in isolation (Phillips et al., Reference Phillips, Batty, Gale, Deary, Osborn, MacIntyre and Carroll2009).
Aims of the study
There is conflicting evidence regarding the extent to which the cumulative experience of multiple psychiatric disorders over the lifetime is itself a risk factor for mortality – beyond the well-established mortality risk associated with individual psychiatric disorders. The purpose of the present study was therefore to evaluate the long-term risk of mortality associated with the comorbidity between pairs of common psychiatric disorder over the lifetime among individuals in the Stirling County Study, a landmark study in psychiatric epidemiology.
METHODS
Data source and procedure
The Stirling County Study was established to describe the epidemiology of psychiatric disorders in a community located in Atlantic Canada. Three random and independent samples of the adult population were selected in 1952 (n = 1003), 1970 (n = 1203) and 1992 (n = 1402). Participation rates were consistently above 79% over the course of the study. Participants gave their informed consent to be interviewed in their homes using a structured interview schedule. The current results are based on respondents from the 1992 sample, randomly selected from the county census, who provided sufficient information on psychiatric disorders (n = 1397). Ethics approval for the present study was obtained from the Institutional Review Boards of the Massachusetts General Hospital and the Ottawa Health Science Network Research Ethics Board.
Mental disorders
Mental disorder was assessed at study entry using the Diagnostic Interview Schedule (DIS), a fully structured interview schedule developed for the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area (ECA) Program to implement the diagnostic guidelines of the Third Diagnostic and Statistical Manual (DSM-III) of the American Psychiatric Association (Robins et al., Reference Robins, Helzer, Croughan and Ratcliff1981). When compared with evaluation by a psychiatrist, the DIS was found to have 93% sensitivity and 83% specificity for the detection of psychiatric disorders (Murphy, Reference Murphy1994). Five common DSM-based diagnoses were available: major depression, dysthymia, panic disorder, GAD and alcohol use disorder.
All DIS diagnoses were made on a lifetime basis. For the present study, alcohol abuse and alcohol dependence were combined into a single indicator of alcohol use disorder.
Mortality
In order to investigate mortality outcomes for the Stirling County Study population, a probabilistic matching of study participants to the Canadian Mortality Database (CMDB) was performed at Statistics Canada using a Generalized Iterative Record Linkage System (Howe and Lindsay, Reference Howe and Lindsay1981; Smith and Newcombe, Reference Smith and Newcombe1982). This process generates probability weights for each potential match between records in the study cohort and the CMDB. Matches with high weights were retained, low weights were discarded and remaining matches were resolved manually. Mortality information was available through 31 December 2011.
Covariates
In addition to DIS diagnoses, we included several covariates, assessed in 1992, known to be associated with both mental illness and mortality: education (<5th, 5th–10th, 11th grade or higher) (Miech and Shanahan, Reference Miech and Shanahan2000; Hummer and Hernandez, Reference Hummer and Hernandez2013), smoking (non-smoker, smokes 1–19 cigarettes per day, smokes 20 or more cigarettes per day) (Lasser et al., Reference Lasser, Boyd, Woolhandler, Himmelstein, McCormick and Bor2000; Ezzati and Lopez, Reference Ezzati and Lopez2003) and obesity (defined by a body mass index above 30) (Adams et al., Reference Adams, Schatzkin, Harris, Kipnis, Mouw, Ballard-Barbash, Hollenbeck and Leitzmann2006; Luppino et al., Reference Luppino, De Wit, Bouvy, Stijnen, Cuijpers, Penninx and Zitman2010).
Statistical analysis
Sex-specific Cox proportional hazard models with age at study entry as the time scale were used to investigate the relationship between DIS diagnoses and mortality in the 1992 sample. Proportionality assumptions of Cox models were checked by including a time-dependent covariate, i.e. an interaction term between the predictor and a function of survival time, in the models and assessing its significance.
The first analysis investigated the association between single disorders and mortality. Individuals in those analyses could have the given disorder with or without comorbid disorders. The reference category for each model consisted of those who did not meet criteria for the index disorder. For example, all individuals with depression were compared with all individuals without depression, regardless of the presence of any comorbid conditions (Table 1). In a sensitivity analysis, participants meeting criteria for a single disorder were compared with those with no disorder (Table 2).
Table 1. HRs (95% CIs) for all-cause mortality associated with DIS-based diagnoses of mental disorders; SCS, 1992−2011
a Adjusted for age and gender.
b Adjusted additionally for education, smoking status and obesity.
Each respondent diagnosed with a particular disorder may be also diagnosed with the other disorders.
Table 2. HRs (95% CIs) for all-cause mortality associated with single DIS-based mental disorders; SCS, 1992−2011
a Adjusted for age and gender.
b Adjusted additionally for education, smoking status and obesity.
In order to assess the degree to which lifetime comorbidity increased mortality risk, a final set of regressions was conducted. Comorbidity was defined as subjects meeting lifetime criteria for two conditions at study baseline in 1992. For each pairwise combination of disorders, participants with both disorders (comorbid group) were compared with those with neither of the two (reference group) (Table 3). Lastly, all models above were further adjusted for education, smoking habits and obesity.
Table 3. HRs (95% CIs) for all-cause mortality associated with co-diagnosis of DIS-based mental disorders; SCS, 1992−2011
a Adjusted for age, gender and the presence of both diagnoses included.
b Adjusted additionally for education, smoking status and obesity.
RESULTS
A total of 1397 respondents were followed-up with respect to mortality for 19 years. In total, 442 deaths (225 among women and 217 among men) were observed during the follow-up.
Prevalence of lifetime DIS disorders in the 1992 sample ranged from 21.6% for alcohol use disorder to 2.5% for panic disorders. Women had at least two times higher prevalence of all the disorders except for alcohol abuse or dependence, which was more than five times more prevalent among men than among women (Table 1).
Despite the higher prevalence of depression and panic disorder among women, mortality risk associated with these two conditions was significantly increased only in men. The elevated risk persisted even after adjusting for education, smoking and obesity: among men, lifetime history of depression (with or without additional comorbidities) was associated with twice the risk of mortality (HR 2.08; 95% CI 1.15–3.75), and lifetime history of panic disorder was associated with nearly three times the risk of mortality (HR 2.87; 95% CI 1.17–7.07). In sensitivity analyses, those with panic disorder alone had 6.5 times the risk of mortality compared with participants with no disorder (HR 6.62, 95% CI 2.07–21.21).
The highest prevalence of comorbidity between two disorders was observed for GAD and depression (5.8%), followed by alcohol abuse or dependence and GAD (5.2%), GAD and dysthymia (4.9%), and depression and dysthymia (3.5%). Men were much more likely than women to meet diagnostic criteria for both alcohol use disorder and GAD (8 v. 2.9%), whereas women more often met criteria for all other combinations of disorders (Table 3).
Again, higher prevalence of comorbidity among women did not translate to higher risk of mortality associated with these diagnoses. After adjusting for potential confounders, men with depression and dysthymia had 2.56 (95% CI 1.12–5.89) times the mortality risk than those with neither diagnosis, and those diagnosed with depression and alcohol use disorder had 2.45 (95% CI 1.18–5.10) times the risk of death than those without the two diagnoses. In the combined sample (males and females), alcohol use disorder seemed to increase risk of mortality among those also meeting criteria for depression, dysthymia and GAD: HRs for depression, dysthymia and GAD with additional alcohol use disorder were 2.20 (95% CI 1.15–4.22), 1.62 (95% CI 0.82–3.21) and 1.31 (95% CI 0.80–2.13), respectively, while HRs for depression, dysthymia and GAD alone were 1.79 (95% CI 0.57–5.64), 1.09 (95% CI 0.35–3.42) and 0.98 (95% CI 0.71–1.37) (Tables 2 and 3).
DISCUSSION
Results from this large community-based cohort study suggest that lifetime comorbidity between common mental disorders is both common and deleterious with respect to mortality.
Prevalence estimates suggested that the experience of more than one common mental disorder over the lifetime is the rule, rather than its exception. With the exception of alcohol use disorders, participants far more often met lifetime criteria for two or more disorders than a single diagnosis. The most common lifetime comorbidities encountered were between mood disorders (major depression; dysthymia) and GAD. Those who had experienced depression, dysthymia and GAD were also highly likely to meet lifetime criteria for alcohol use disorders. These findings are in agreement with an abundance of previous evidence showing a strong relationship between depression and anxiety (Dobson, Reference Dobson1985; Reference Maser and Cloningereds Maser and Cloninger, Reference Maser and Cloninger1990; Lovibond and Lovibond, Reference Lovibond and Lovibond1995), and between mood and anxiety disorders and alcohol use disorders (Lai et al., Reference Lai, Cleary, Sitharthan and Hunt2015).
Mood disorders and mortality
Depression has been consistently associated with excess mortality in community samples (Cuijpers et al., Reference Cuijpers, Vogelzangs, Twisk, Kleiboer, Li and Penninx2014a), and some literature suggests that men may bear a disproportionate burden of this risk (Cuijpers et al., Reference Cuijpers, Vogelzangs, Twisk, Kleiboer, Li and Penninx2014b; Gilman et al., Reference Gilman, Sucha, Kingsbury, Horton, Murphy and Colman2017), though our prior investigation across the six-decade span of the Stirling County Study using a different diagnostic interview for depression suggests that an excess mortality risk among females with depression emerged in the later years of the study (6). Here, mortality risk according to the DIS was doubled among men meeting lifetime criteria for major depressive episode.
The superimposition of major depression on chronic dysthymia is often referred to in the literature as ‘double depression’ (Keller and Shapiro, Reference Keller and Shapiro1982). It has been noted that double depression is present in a majority of cases of dysthymia (Rhebergen et al., Reference Rhebergen, Beekman, de Graaf, Nolen, Spijker, Hoogendijk and Penninx2009). Results from the present study supported this assertion – a majority of individuals meeting criteria for dysthymia also met criteria for major depression.
Double depression has been associated with worse functional outcomes than major depression alone (Rhebergen et al., Reference Rhebergen, Beekman, de Graaf, Nolen, Spijker, Hoogendijk and Penninx2009). In line with these findings, in the present study, co-morbidity between major depression and dysthymia was associated with an increased risk of mortality among men. Small sample sizes precluded direct comparison between those with ‘double depression’ and major depression alone – only one male met criteria for depression in the absence of other disorders. Nonetheless, these results suggest that the combination of both chronic and episodic depressive symptoms may place men at heightened risk of death.
Mechanisms linking depression and mortality are not fully understood, though recent evidence points to increased inflammation among depressed patients (Russ et al., Reference Russ, Stamatakis, Hamer, Starr, Kivimaki and Batty2012), as well as changes in cardiovascular functioning (Larson et al., Reference Larson, Owens, Ford and Eaton2001), as potential explanatory factors. Depression and dysthymia are additionally associated with poor diet quality, physical inactivity, smoking and alcohol use, which may also explain increased mortality risk (Dierker et al., Reference Dierker, Avenevoli, Stolar and Merikangas2002; Holahan et al., Reference Holahan, Moos, Holahan, Cronkite and Randall2003; Whooley et al., Reference Whooley, de Jonge, Vittinghoff, Otte, Moos, Carney, Ali, Dowray, Na, Feldman, Schiller and Browner2008).
Anxiety disorders and mortality
With respect to anxiety, our results indicated that consistent with earlier results of the Stirling County study (Murphy et al., Reference Murphy, Monson, Olivier, Sobol and Leighton1987), GAD on its own, or in combination with other diagnoses, was not a significant predictor of mortality. In fact, the experience of GAD with another lifetime diagnosis seemed to be associated with lower risk of mortality than that for single disorders with no GAD, although small sample sizes precluded our ability to conduct direct statistical comparisons. Though mechanisms are not well understood, it has been suggested that anxiety may confer a protective effect on mortality. Anxiety seems to serve an evolutionary function as a threat-detection mechanism (Bateson et al., Reference Bateson, Brilot and Nettle2011), and some have suggested it may reduce mortality through the increased use of healthcare (Simon, Reference Simon1992).
In contrast, a lifetime diagnosis of panic disorder alone was associated with substantially higher risk of mortality in the full sample – individuals with panic disorder had over six times higher mortality risk than those without. However, as only three individuals met criteria for this diagnosis in isolation, results should be interpreted with caution. Nonetheless, when all individuals with panic (irrespective of other diagnoses) were considered, the risk of death was 2.34 times higher than for participants without panic. Few studies have examined the association between panic disorder and mortality; notwithstanding, this finding is consistent with results from a small US study reporting increased mortality risk among former psychiatric inpatients with panic disorder (Coryell et al., Reference Coryell, Noyes and Clancy1982). Panic disorder has been associated with elevated levels of certain pro-inflammatory cytokines (Hoge et al., Reference Hoge, Brandstetter, Moshier, Pollack, Wong and Simon2009) which may play a role in the development of cardiovascular disease.
Though three times as many women as men met criteria for panic disorder, the association with mortality in the present study was strongest among males. This result is consistent with a study from the Lundby cohort, which reported an increased mortality risk among older males, but not females, with panic disorder (Gräsbeck et al., Reference Gräsbeck, Rorsman, Hagnell and Isberg1996).
Alcohol use disorders
In this study, alcohol use disorders were not, by themselves, associated with excess mortality. However, individuals meeting lifetime criteria for an alcohol use disorder who had also experienced major depression or panic disorder in their lifetime were at significantly elevated risk of mortality. The combination of alcohol use disorders with dysthymia and GAD also seemed to confer increased risk – though these differences were not statistically significant. These results are consistent with previous research suggesting that comorbidity of mood and anxiety disorders with alcohol use disorders is associated with poorer prognosis, including increased risk of impairment, relapse and suicide (Merikangas et al., Reference Merikangas, Mehta, Molnar, Walters, Swendsen, Aguilar-Gaziola, Bijl, Borges, Caraveo-Anduaga, Dewit, Kolody, Vega, Wittchen and Kessler1998; Smith and Randall, Reference Smith and Randall2012).
Alcohol misuse is common among individuals with mood and anxiety disorders (Lai et al., Reference Lai, Cleary, Sitharthan and Hunt2015), and may reflect self-medication – that is, the use of alcohol to relieve unpleasant symptoms of depression and anxiety (Bolton et al., Reference Bolton, Cox, Clara and Sareen2006, Reference Bolton, Robinson and Sareen2009). Self-medication of mood and anxiety disorders has been associated with deleterious outcomes, including greater likelihood of psychiatric comorbidities (Bolton et al., Reference Bolton, Robinson and Sareen2009), and higher rates of suicidal ideation and attempt (Bolton et al., Reference Bolton, Cox, Clara and Sareen2006). However, alcohol dependence has also been found to be a risk factor for the subsequent development of depression (Gilman and Abraham, Reference Gilman and Abraham2001), suggesting that the association between alcohol use disorders and other psychiatric disorders are complex and bi-directional.
Strengths and limitations
Results of this study should be interpreted in light of certain limitations. First, the assessment of mental disorder was conducted at a single time point and included retrospective reports of symptoms over the lifetime. It is likely that some cases remitted during the follow-up period, while others persisted or relapsed. Studies including multiple measurements of mental disorder over time would be better placed to assess the importance of chronicity for outcomes, including mortality. Second, as mentioned, sample sizes for single disorders were very small – for example, only one male met diagnostic criteria for major depression in the absence of other disorders. To draw stronger conclusions about the impact of comorbidities over and above unique diagnoses, larger samples of individuals with each combination of disorders are required.
Notwithstanding, we believe that the use of a community-based random sample is a strength of the current study. Further strengths of the study include its long follow-up (19 years of mortality follow-up) and structured assessments of mental disorders. In addition, few other studies have assessed the mortality burden of comorbid mental illness separately for males and females.
Taken together, results of this study suggest that the cumulative experience of more than one mood, anxiety or alcohol use disorder is extremely common. Comorbid mental disorders were associated with increased risk of mortality, most strikingly among men. Existing literature linking mental disorder with mortality risk has tended to focus on single disorders – these results suggest a shift towards recognising the significant heterogeneity in the presentation of common mental disorders, particularly the importance of considering symptoms of multiple psychiatric conditions over the lifetime.
Author ORCIDs
I. Colman, http://orcid.org/0000-0001-5924-0277
Acknowledgements
The Stirling County Study was initiated by the late Alexander Leighton in 1948 and has been directed by Jane Murphy since 1975. We appreciate the contributions of Richard Trudeau, Yves Decady and Craig Grimes at Statistics Canada for their work in carrying out the linkage to the Canadian Mortality Database, and of the Provincial Registrars who made the information available to us.
Financial support
This work was supported by the Canadian Institutes of Health Research (grant no. 126099); National Institute of Mental Health (RO1-MH39576); the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and thanks to support from the Canada Research Chairs program for Ian Colman.
Conflict of interest
None.
Ethical standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
Availability of data and materials
Data for the Stirling County Study are available through the Harvard MIT data centre. Contact Dr J M Murphy for access approval.
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