This cohort study examines the association between posttraumatic stress disorder, with and without comorbid depression, and mortality in women.
Key Points
Question
Are comorbid posttraumatic stress disorder (PTSD) and depressive symptoms associated with mortality risk in women?
Findings
In this cohort study of 51 602 women followed up for 9 years, those with high PTSD symptoms and comorbid-probable depression had 3.8-fold increased risk of death compared with women without trauma exposure or probable depression. Decreased body mass index, nonsmoking status, physical activity, and being married were associated with decreased risk of death.
Meaning
These findings suggest that treatment of PTSD and depression in women with symptoms of both disorders and efforts that improve their health behaviors may reduce the increased risk of mortality among this population.
Abstract
Importance
Consistent evidence has found associations between posttraumatic stress disorder (PTSD) and increased risk of chronic disease and greater prevalence of health risk factors. However, the association between PTSD and all-cause mortality has not been thoroughly investigated in civilians.
Objective
To investigate the association between PTSD symptoms, with or without comorbid depressive symptoms, and risk of death.
Design, Setting, and Participants
This prospective cohort study was conducted using data on female US nurses in the Nurses’ Health Study II followed up from 2008 to 2017. Women who responded to a 2008 questionnaire querying PTSD and depressive symptoms were included. Data were analyzed from September 2018 to November 2020.
Exposures
Symptoms of PTSD, measured using the short screening scale for Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) PTSD, and depression symptoms, measured using the Center for Epidemiologic Studies Depression Scale–10 in 2008.
Main Outcomes and Measures
All-cause mortality was determined via National Death Index, US Postal Service, or report of participant’s family. The hypothesis being tested was formulated after data collection. Trauma exposure and PTSD symptoms were jointly coded as no trauma exposure (reference), trauma and no PTSD symptoms, 1 to 3 PTSD symptoms (subclinical), 4 to 5 PTSD symptoms (moderate), and 6 to 7 PTSD symptoms (high).
Results
Among 51 602 women (50 137 [97.2%] White individuals), the mean (range) age was 53.3 (43-64) years at study baseline in 2008. PTSD and probable depression were comorbid; of 4019 women with high PTSD symptoms, 2093 women (52.1%) had probable depression, while of 10 105 women with no trauma exposure, 1215 women (12.0%) had probable depression. Women with high PTSD symptoms and probable depression were at nearly 4-fold greater risk of death compared with women with no trauma exposure and no depression (hazard ratio [HR], 3.80; 95% CI, 2.65-5.45; P < .001). After adjustment for health factors, women with these conditions had a more than 3-fold increased risk (HR, 3.11; 95% CI, 2.16-4.47, P < .001). Women with subclinical PTSD symptoms without probable depression had increased risk of death compared with women with no trauma exposure and no depression (HR, 1.43; 95% CI, 1.06-1.93; P = .02). Among 7565 women with PTSD symptoms and probable depression, 109 deaths (1.4%) occurred for which we obtained cause of death information, compared with 124 such deaths (0.6% ) among 22 215 women with no depression or PTSD symptoms. Women with PTSD symptoms and probable depression, compared with women with no PTSD or depression, had higher rates of death from cardiovascular disease (17 women [0.22%] vs 11 women [0.05%]; P < .001), diabetes (4 women [0.05%] vs 0 women; P < .001), unintentional injury (7 women [0.09%] vs 7 women [0.03%]; P = .03), suicide (9 women [0.12%] vs 1 woman [<0.01%]; P < .001), and other causes of death (14 women [0.19%] vs 17 women [0.08%]; P = .01).
Conclusions and Relevance
These findings suggest that at midlife, women with high PTSD symptoms and co-occurring probable depression are at increased risk of death compared with women without these disorders. Treatment of PTSD and depression in women with symptoms of both disorders and efforts to improve their health behaviors may reduce their increased risk of mortality.
Introduction
Posttraumatic stress disorder (PTSD) has been associated with increased risk of chronic disease, including hypertension, cardiovascular disease, and type 2 diabetes,1,2,3,4,5 and with greater prevalence of health risk factors, such as obesity and smoking.6,7 Furthermore, PTSD has been associated with biological changes involved in several disease processes,8 including hypothalamic-pituitary-adrenal–axis alterations and related inflammation and immune dysregulation,9,10,11 oxidative stress,12 poor sleep,13 and indicators of accelerated aging.5,14 These diseases, health risk factors, and biological changes are associated with increased mortality.15 However, the association between PTSD and all-cause mortality has been investigated almost exclusively in samples of male military veterans. In these studies,16,17,18,19,20,21,22 PTSD has been associated with increased risk of all-cause mortality as well as mortality from cardiovascular disease, cancer, and external causes, such as unintentional and intentional injury, with few exceptions.23 However, PTSD occurs at higher rates among women. In the United States, lifetime prevalence of PTSD in women is more than 2-fold that of men (9.7% vs 3.6%).24 Risk of PTSD following a trauma exposure is similarly 2-fold higher in women compared with men.25,26 Only 1 large study,27 using Danish medical records, has investigated the association of PTSD with mortality in women or civilians, finding more than 2-fold the risk of death in individuals with PTSD vs those without PTSD.
Depression often co-occurs with PTSD28 and, like PTSD, it is far more prevalent in women than men.29,30 Depression has been independently associated with greater prevalence of health risk factors31,32 and risk of mortality.33,34,35,36 Evidence also suggests that PTSD with depression may constitute a particularly severe subtype of posttraumatic response, with unique biological outcomes important for physical health.37 Thus, PTSD with depression may be associated with even greater risk of mortality compared with PTSD alone. However, to our knowledge, only 3 relatively short-term studies have examined this possibility. One study,38 among Japanese earthquake survivors ages 65 years and older, found increased risk of all-cause mortality over 3.3 years of follow-up among individuals who had depression at baseline, regardless of whether they had high PTSD symptoms, compared with individuals who did not have depression at baseline. Individuals with PTSD and depression were not at significantly increased risk of dying during the follow-up period compared with those with depression only. A 2013 study39 of 391 patients with end-stage kidney disease found increased risk of death among patients with both depression and PTSD and patients with depression alone but not among those with PTSD alone, compared with patients with neither disorder, in 3.5 years of follow-up. A 2010 study40 of in-hospital mortality after a coronary artery bypass grafting surgical treatment found that patients with comorbid depression and PTSD were at increased risk of death compared with patients with neither disorder. Patients also had an increased risk of death if they had depression alone or PTSD alone.
Several studies6,31,32,41 have found that individuals with PTSD or depression, compared with individuals without these disorders, have increased prevalence of health risk factors, such as smoking and obesity, which may contribute to increased mortality. Thus, higher prevalence of health risk factors in individuals with co-occurring PTSD and depression may account for possible increased mortality. It remains largely unknown whether PTSD is associated with increased mortality among civilians and women, whether co-occurring depression is associated with further increased risk, and whether health-risk factors are associated with these increased risks of death. In the present study, we examined the association of PTSD and depression symptoms with risk of death in a large prospective cohort of women, the Nurses’ Health Study II.42 We further examined whether health-related factors, including body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), smoking, and exercise, were associated with differences in mortality among individuals with PTSD or depression.
Methods
This cohort study examined women in the Nurses’ Health Study II. The institutional review board of Brigham and Women’s Hospital approved that study’s protocol. Return of the questionnaire by the respondent via US mail constituted implied informed consent. The Nurses’ Health Study II is an ongoing cohort study of 116 429 women, enrolled in 1989 at ages 25 to 42 years (median age, 34.0 years) and followed biennially. In 2008, 60 804 women who completed the most recent biennial questionnaire and an earlier supplemental questionnaire were mailed a supplemental PTSD questionnaire, with 54 687 women responding. As the Nurses’ Health Study II was initially formed to study the health effects of oral contraceptive use, only women were enrolled.
Measures
Trauma, PTSD, and Depression
For each of 15 potentially traumatic events (eg, serious motor vehicle crash) and an additional other event, women in the study reported in 2008 whether they had ever experienced the event. They were asked which event they considered their worst or most distressing event. Seven PTSD symptoms in relation to this worst event were queried with the Short Screening Scale for Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)43 PTSD.44 Trauma exposure and PTSD symptoms were jointly coded as no trauma exposure (reference), trauma and no PTSD symptoms, 1 to 3 PTSD symptoms (subclinical), 4 to 5 PTSD symptoms (moderate), and 6 to 7 PTSD symptoms (high). In a representative sample of Detroit residents ages 18 to 45 years,44 a cutoff of 4 or more identified PTSD cases with sensitivity of 80%, specificity of 97%, positive predictive value of 71%, and negative predictive value of 98%, and a cutoff of 6 or more identified cases with sensitivity of 38%, specificity of 99%, positive predictive value of 87%, and negative predictive value of 95%. We additionally coded PTSD symptoms as a continuous variable (range, 0-7). Past-week depressive symptoms were assessed in 2008 using the Center for Epidemiologic Studies Depression Scale–10 (CESD-10)45 and dichotomized at 10 or more to indicate probable depression.45 We additionally coded depressive symptoms as a continuous variable (range, 0-30). The CESD-10 has been validated against the highly validated longer form, the Center for Epidemiologic Studies Depression Scale–20, in a sample of older adults in a US health-maintenance organization (Cohen κ, 0.97)45 and against clinical evaluations with good psychometrics.46,47
To examine the co-occurrence of PTSD and depression with mortality, we also characterized PTSD and depression with an interaction term, using indicator variables as follows: no depression or trauma (reference), trauma with no depression and no PTSD symptoms, no depression and 1 to 3 PTSD symptoms, no depression and 4 to 5 PTSD symptoms, no depression and 6 to 7 PTSD symptoms, depression and trauma with no PTSD symptoms, depression and 1 to 3 PTSD symptoms, depression and 4 to 5 PTSD symptoms, and depression and 6 to 7 PTSD symptoms.
Mortality
Mortality through December 2017 and cause of death were ascertained from family members, the National Death Index, cancer registries, and the US Postal Service. Owing to time lags between report of death and ascertainment and coding of death record data, cause of death was available for 384 of 555 women (69.1%) who died during follow-up.
Health-Related Factors and Covariates
Health-related factors included BMI, smoking status, physical activity, and marital status at or before study baseline in 2008. We did not time-update these factors, as illness preceding death could lead to weight loss, smoking cessation, and reduced physical activity. Self-reported height in 1989 and weight in 2007 were used to calculate BMI, coded with continuous and squared terms, as this produced the best-fitting model. Smoking was assessed biennially through 2007 and coded as never; past smoker of 1 to 4, 5 to 14, 15 to 24, 25 to 34, 35 to 44, or 45 or more cigarettes per day; or present smoker of 1 to 4, 5 to 14, 15 to 24, 25 to 34, 35 to 44, or 45 or more cigarettes per day. In 2005, respondents reported their mean time spent per week in 10 different recreational activities (eg, swimming or walking). Past-year physical activity was calculated in metabolic-equivalent hours per week from these responses. Respondents reported current marital status in 2008 as married, divorced, separated, widowed, in domestic partnership, or single. We considered parental socioeconomic status during the respondent’s infancy, reported in 2005, as a potential confounder. Highest occupation (ie, jobs that usually have higher status and pay) of either parent during the respondent’s infancy was reported as farmer, laborer, blue-collar (eg, mechanic or bus driver) or lower white-collar worker (ie, secretarial or clerical work), or managerial or professional. Parental education was reported as high school or above, some college, or college graduate or above, and parental home ownership in respondent’s infancy was coded as yes or no. In 2005, respondents indicated their race/ethnicity by selecting 1 or more of the following: White, Black or African American, American Indian or Alaska Native, Native Hawaiian or Pacific Islander, or other. For analyses, race was coded White or non-White, as 50 137 individuals in the sample (97.2%) selected only White. Age was measured in months.
Statistical Analysis
We examined the distribution of health-related factors and covariates by PTSD and depression status in 2008. We then calculated the association of health-related factors with mortality by fitting a single Cox proportional hazard model with all factors included as independent variables, adjusted for age and race/ethnicity. To investigate the association of PTSD and depression with mortality, we first examined the association of PTSD with depression. We then ascertained the best-fitting model, using the Akaike information criterion48 to compare 4 models: PTSD alone; depression alone; PTSD and depression; and PTSD, depression, and a PTSD-depression interaction term, using indicator variables as previously described. Finally, we fit 2 Cox proportional hazard models using the best-fitting model, adjusted for age, race/ethnicity, and childhood socioeconomic status and further adjusted for health-related factors, including BMI, smoking status, physical activity, and marital status. In additional analyses, we examined the association of mortality with depression and PTSD symptoms coded continuously, with an interaction term calculated by multiplying the 2 continuous variables, among women exposed to a traumatic event.
To reduce concerns that illness caused both PTSD or depressive symptoms and death, we excluded 3026 women who reported serious illness as their worst trauma and excluded the first year of person-time after the 2008 PTSD questionnaire, meaning we excluded 52 women who died during that year. We excluded an additional 7 women who did not respond to questionnaires between 2009 and 2017, leaving 51 602 women in the sample. For all models, hazard ratios (HRs) were estimated using the phreg procedure in SAS statistical software version 9.4 (SAS Institute). A 2-sided P < .05 was considered significant in statistical tests. Data analysis was performed from September 2018 to November 2020.
To improve power, we examined cause of death in 3 aggregated groups: women with no depression or PTSD symptoms, women with any (1-7) PTSD symptoms or with depression but not both, and women with any PTSD symptoms and depression. We tested differences between the reference group of women with no depression or PTSD symptoms and each of the other 2 groups using χ2 tests.
Results
At baseline in 2008, this study included 51 602 women, with mean (range) age 53.3 (43-64) years; 50 137 women (97.2%) were White. The 2093 women with co-occurring high PTSD symptoms and probable depression, compared with 8890 women with no trauma exposure and no depression, were more likely to be divorced or separated (519 women [24.8%] vs 717 women [8.1%]), have obesity (699 women ([33.4%] vs 1985 women [22.3%]), and be current smokers (235 women [11.2%] vs 389 women [4.4%]). Women with high PTSD and probable depression were also more likely, compared with 1926 women with high PTSD symptoms and no depression, to be divorced or separated (295 women [15.3%]), have obesity (508 women [26.4%]), and be current smokers (131 women [6.8%]). Additionally, women with high PTSD symptoms and probable depression, compared with 1700 women with depression and no PTSD symptoms, were more likely to be divorced or separated (250 women [14.7%]), have obesity (521 women [30.6%]), and be current smokers (142 women [8.4%]). The 10 529 women with probable depression, regardless of PTSD symptoms, had higher risk of low physical activity compared with 41 073 women without probable depression (2066 women [19.6%] vs 5729 women [14.0%]) (Table 1). Depression and PTSD were not associated with age at interview or race/ethnicity. In a mutually adjusted model, past and current smoking status vs never-smoked status, higher BMI, less physical activity, and divorced or separated status or single status vs married status were associated with increased mortality. For example, current smoking was associated with more than 2-fold increased risk of death (HR, 2.81; 95% CI, 2.18-3.61), being divorced or separated was associated with 30% increased risk of death (HR, 1.30; 95% CI, 1.02-1.65), and low physical activity (ie, less than 3 metabolic equivalents/wk) was associated with nearly 50% increased risk of death compared with high physical activity (ie, 42 or more metabolic equivalents/wk) (HR, 1.49; 95% CI, 1.09-2.04). Childhood socioeconomic status and participant’s race/ethnicity were not associated with increased mortality.
Table 1. Health-Related Characteristics at the Time of PTSD and Depression Assessment, Among 51 602 Women.
Characteristica | Women, No. (%) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Without depression | With depression | |||||||||
No trauma (n = 8890) | PTSD symptoms, No. | No trauma (n = 1215) | PTSD symptoms, No. | |||||||
0 (n = 13 385) | 1-3 (n = 12 513) | 4-5 (n = 4359) | 6-7 (n = 1926) | 0 (n = 1700) | 1-3 (n = 2949) | 4-5 (n = 2572) | 6-7 (n = 2093) | |||
Age, mean (SD), y | 53.2 (4.7) | 53.4 (4.7) | 53.3 (4.6) | 53.3 (4.6) | 53.3 (4.5) | 53.2 (4.8) | 53.3 (4.7) | 53.2 (4.6) | 53.5 (4.5) | 53.6 (4.4) |
Race/ethnicity | ||||||||||
White | 8649 (97.3) | 12 985 (97.0) | 12 143 (97.0) | 4257 (97.7) | 1876 (97.4) | 1181 (97.2) | 1658 (97.5) | 2861 (97.0) | 2498 (97.1) | 2029 (96.9) |
Black | 77 (0.9) | 166 (1.2) | 150 (1.2) | 32 (0.7) | 8 (0.4) | 9 (0.7) | 17 (1.0) | 28 (0.9) | 28 (1.1) | 21 (1.0) |
Asian | 134 (1.5) | 183 (1.4) | 150 (1.2) | 32 (0.7) | 25 (1.3) | 23 (1.9) | 15 (0.9) | 32 (1.1) | 18 (0.7) | 17 (0.8) |
Childhood socioeconomic status | ||||||||||
Parent education, ≤high school | 4794 (53.9) | 7371 (55.1) | 6544 (52.3) | 2298 (52.7) | 998 (51.8) | 710 (58.4) | 986 (58.0) | 1622 (55.0) | 1357 (52.8) | 1136 (54.3) |
Parent occupation, blue collar | 3979 (44.8) | 6195 (46.3) | 5843 (46.7) | 2012 (46.2) | 901 (46.8) | 579 (47.7) | 833 (49.0) | 1419 (48.1) | 1147 (44.6) | 1001 (47.8) |
Parent owned home | 4743 (53.4) | 7066 (52.8) | 6306 (50.4) | 2203 (50.5) | 974 (50.6) | 595 (49.0) | 824 (48.5) | 1472 (49.9) | 1279 (49.7) | 1022 (48.8) |
BMI | ||||||||||
<25 | 3998 (45.0) | 5930 (44.3) | 5399 (43.1) | 1868 (42.9) | 786 (40.8) | 489 (40.2) | 604 (35.5) | 1032 (35.0) | 904 (35.1) | 732 (35.0) |
25 to <30 | 2543 (28.6) | 3808 (28.4) | 3565 (28.5) | 1224 (28.1) | 549 (28.5) | 350 (28.8) | 495 (29.1) | 839 (28.5) | 721 (28.0) | 570 (27.2) |
≥30 | 1985 (22.3) | 3171 (23.7) | 3096 (24.7) | 1106 (25.4) | 508 (26.4) | 326 (26.8) | 521 (30.6) | 967 (32.8) | 854 (33.2) | 699 (33.4) |
Smokingb | ||||||||||
Never | 6386 (71.8) | 9114 (68.1) | 8312 (66.4) | 2765 (63.4) | 1147 (59.6) | 814 (67.0) | 1060 (62.4) | 1807 (61.3) | 1520 (59.1) | 1152 (55.0) |
Former | 2115 (23.8) | 3563 (26.6) | 3551 (28.4) | 1323 (30.4) | 648 (33.6) | 322 (26.5) | 498 (29.3) | 878 (29.8) | 817 (31.8) | 706 (33.7) |
Current | 389 (4.4) | 708 (5.3) | 650 (5.2) | 271 (6.2) | 131 (6.8) | 79 (6.5) | 142 (8.4) | 264 (9.0) | 235 (9.1) | 235 (11.2) |
Physical activity, lowest category (<3 metabolic equivalent h/wk)c | 1249 (14.0) | 1939 (14.5) | 1711 (13.7) | 553 (12.7) | 277 (14.4) | 234 (19.3) | 357 (21.0) | 553 (18.8) | 511 (19.9) | 411 (19.6) |
Marital statusd | ||||||||||
Married | 7092 (79.8) | 10 746 (80.3) | 9935 (79.4) | 3164 (72.6) | 1361 (70.7) | 823 (67.7) | 1201 (70.6) | 2057 (69.8) | 1663 (64.7) | 1229 (58.7) |
Divorced or separated | 717 (8.1) | 1216 (9.1) | 1258 (10.1) | 643 (14.8) | 295 (15.3) | 202 (16.6) | 250 (14.7) | 500 (17.0) | 527 (20.5) | 519 (24.8) |
Never married | 533 (6.0) | 560 (4.2) | 576 (4.6) | 213 (4.9) | 95 (4.9) | 97 (8.0) | 105 (6.2) | 204 (6.9) | 175 (6.8) | 138 (6.6) |
Widowed | 139 (1.6) | 185 (1.4) | 286 (2.3) | 180 (4.1) | 88 (4.6) | 33 (2.7) | 40 (2.4) | 96 (3.3) | 133 (5.2) | 122 (5.8) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); PTSD, posttraumatic stress disorder.
Parents’ education and occupation were assessed in 2005; BMI, smoking, and physical activity were assessed in 2007; marital status was assessed in 2008.
Data missing for 56 women (0.1%).
Data missing for 2021 women (3.9%).
Data missing for 2206 women (4.3%).
We found that PTSD was associated with depression. While probable depression was reported in 1215 of 10 105 women (12%) with no trauma exposure, depression was reported in 2949 of 15 462 women (19%) with 1 to 3 PTSD symptoms, 2572 of 6931 women (37%) with 4 to 5 PTSD symptoms, and 2093 of 4019 women (52%) with 6 to 7 PTSD symptoms. Among 51 609 women, 555 deaths occurred. Women with comorbid PTSD and depression were substantially more likely to die during follow-up compared with women with no trauma exposure and no depression: among 2093 women with high PTSD symptoms and depression, 57 women (2.7%) died, while among 8890 women with no trauma or depression, 63 women (0.7%) died. The best-fitting model of mortality included PTSD, probable depression, and a PTSD-depression interaction term (P for interaction = .06). In models adjusted for age, race/ethnicity, and childhood socioeconomic indicators, co-occurring PTSD and depression were associated with mortality. Women with high PTSD symptoms and depression were at nearly 4-fold increased risk of death compared with women with no trauma exposure or depression (HR, 3.80; 95% CI, 2.65-5.45; P < .001). Women with depression and moderate PTSD symptoms (HR, 2.03; 95% CI, 1.35-3.03; P < .001) and depression and subclinical PTSD symptoms (HR, 2.85; 95% CI, 1.99-4.07; P < .001) were also at increased risk of death compared with women with no trauma or depression (Table 2). With further adjustment for health factors, women with high PTSD symptoms and depression remained at increased risk of death (HR, 3.11; 95% C, 2.16-4.47; P < .001) (Table 2). Women with subclinical PTSD symptoms without probable depression had increased risk of death compared with women with no trauma or depression (HR, 1.43; 95% CI, 1.06-1.93; P = .02) (Table 2). Depression in women without trauma exposure was associated with more than 2-fold increased risk of death (HR, 2.39; 95% CI, 1.44-3.95; P < .001). However, risk of mortality among women with depression and trauma exposure who did not develop PTSD symptoms was not increased compared with the reference group (HR, 1.28; 95% CI, 0.74-2.21; P = .39) (Table 2).
Table 2. Association of Trauma Exposure and PTSD Symptoms With Mortality, by Depression Status, Adjusted for Health Factorsa.
Trauma and PTSD | Deaths/person-years | Hazard ratio (95% CI) | ||||
---|---|---|---|---|---|---|
Model 1b | Model 2c | Model 3d | Model 4e | Model 5f | ||
Without depression | ||||||
No trauma | 63/76 872 | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] |
Trauma, no PTSD | 112/115 673 | 1.15 (0.84-1.56) | 1.14 (0.84-1.55) | 1.15 (0.84-1.57) | 1.13 (0.83-1.54) | 1.15 (0.84-1.56) |
PTSD symptoms, No. | ||||||
1-3 | 130/108 220 | 1.43 (1.06-1.93)g | 1.38 (1.02-1.87)g | 1.41 (1.05-1.91)g | 1.39 (1.03-1.89)g | 1.44 (1.07-1.95)g |
4-5 | 44/37 615 | 1.39 (0.95-2.05) | 1.30 (0.88-1.91) | 1.37 (0.93-2.01) | 1.33 (0.91-1.96) | 1.41 (0.96-2.07) |
6-7 | 17/16 603 | 1.27 (0.75-2.18) | 1.13 (0.66-1.95) | 1.23 (0.72-2.11) | 1.19 (0.69-2.03) | 1.28 (0.75-2.20) |
With depression | ||||||
No trauma | 20/10 441 | 2.39 (1.44-3.95)h | 2.23 (1.34-3.70)i | 2.36 (1.43-3.92)h | 2.27 (1.37-3.76)i | 2.32 (1.40-3.85)i |
Trauma, no PTSD | 16/14 642 | 1.28 (0.74-2.21) | 1.14 (0.66-1.98) | 1.23 (0.71-2.15) | 1.19 (0.68-2.06) | 1.23 (0.71-2.13) |
PTSD symptoms, No. | ||||||
1-3 | 58/25 336 | 2.85 (1.99-4.07)h | 2.52 (1.76-3.61)h | 2.77 (1.94-3.98)h | 2.62 (1.83-3.75)h | 2.76 (1.93-3.94)h |
4-5 | 38/22 120 | 2.03 (1.35-3.03)h | 1.63 (1.08-2.46)g | 1.87 (1.24-2.80)i | 1.84 (1.22-2.75)i | 1.96 (1.30-2.93)i |
6-7 | 57/17 827 | 3.80 (2.65-5.45)h | 3.11 (2.16-4.47)h | 3.57 (2.49-5.13)h | 3.40 (2.67-4.89)h | 3.65 (2.54-5.24)h |
Abbreviations: BMI, body mass index; PTSD, posttraumatic stress disorder.
All models adjusted for individual’s age in months; individual’s race/ethnicity; and parents’ education, occupation, and home ownership in individual’s infancy. Smoking was coded as never; past 1-4, 5-14, 15-24, 25-34, 35-44, or 45 or more cigarettes/d; current 1-4, 5-14, 15-24, 25-34, 35-44, or 45 or more cigarettes/d; or missing smoking status. Physical activity was coded as less than 3, 3 to less than 9, 9 to less than 18, 18 to less than 27, 27 to less than 42, or 42 or more metabolic equivalents/wk or missing exercise data. Marital status was coded as married, divorced or separated, never married, widowed, or missing marital status. BMI was coded as a continuous variable. BMI and BMI-squared terms were included.
Adjusted for childhood socioeconomic factors, race, and age.
Model 1 further adjusted for BMI, smoking, physical activity, and marital status.
Model 1 further adjusted for BMI only.
Model 1 further adjusted for smoking only.
Model 1 further adjusted for physical activity only.
P < .05.
P < .001.
P < .01.
To further explore which potentially modifiable health factors might account for increased risk of death among women with PTSD and depression, we fit 3 additional models separately adjusted for BMI, smoking, and physical activity. The association of PTSD and depression with mortality remained significant in models adjusted for BMI or smoking. For example, among women with depression and high PTSD symptoms, the HR adjusted for BMI was 3.57 (95% CI, 2.49-5.13; P < .001) and the HR adjusted for smoking was 3.40 (95% CI, 2.67-4.89; P < .001) (Table 2).
In analyses among women who had trauma exposure, with PTSD and depression symptoms coded continuously, the best-fitting model included PTSD, depression, and an interaction term. In women without depression symptoms, increased number of PTSD symptoms was not associated with increased mortality (HR per PTSD symptom, 0.97; 95% CI, 0.91-1.04; P = .42). Depression symptoms and depression-PTSD interaction were associated with increased risk of mortality (HR per depression symptom, 1.03; 95% CI, 1.01-1.06; P = .02; HR for interaction, 1.01; 95% CI, 1.00-1.01; P = .02).
Among 7565 women with PTSD symptoms and probable depression, 109 deaths (1.4%) occurred for which we obtained cause of death information, compared with 124 such deaths (0.6%) among 22 215 women with no depression or PTSD. Women with PTSD symptoms and probable depression, compared with women with no PTSD or depression, had higher rates of death from cardiovascular disease (17 women [0.22%] vs 11 women [0.05%]), diabetes (4 women [0.05%] vs 0 women), unintentional injury (7 women [0.09%] vs 7 women [0.03%]), suicide (9 women [0.12%] vs 1 woman [<0.01%]), and other causes of death (14 women [0.19%] vs 17 women [0.08%]). The rate of such deaths among women with PTSD and depression did not differ significantly compared with women with PTSD symptoms alone or probable depression alone (Table 3). Deaths from cancer were not significantly different in women with PTSD and depression compared with women with no depression or PTSD symptoms
Table 3. Incidence of Causes of Death Over Follow-up by PTSD and Depression, Excluding Deaths Without Cause of Death Information Among 51 406 Women.
Cause of deatha | Women, No. (%) | ||
---|---|---|---|
No PTSD symptoms or probable depression (n = 22 215) | PTSD symptoms alone or probable depression alone (n = 21 626) | PTSD symptoms and probable depression (n = 7565)b | |
Cancer | 72 (0.32) | 89 (0.41) | 36 (0.48) |
Cardiovascular disease | 11 (0.05) | 16 (0.07) | 17 (0.22)c |
Respiratory disease | 7 (0.03) | 2 (0.01) | 6 (0.08) |
Diabetes | 0 (0.00) | 1 (0.00) | 4 (0.05)c |
Unintentional injury | 7 (0.03) | 8 (0.04) | 7 (0.09)d |
Suicide | 1 (0.00) | 4 (0.02) | 9 (0.12)c |
Other causes of death | 17 (0.08) | 21 (0.10) | 14 (0.19)d |
All deaths with cause of death information | 124 (0.56) | 151 (0.69) | 109 (1.44)c |
Abbreviation: PTSD, posttraumatic stress disorder.
Percentages shown are small, because 384 individuals (0.7%) with cause of death information died during follow-up.
P values calculated from χ2 compared with no PTSD symptoms or probable depression group.
P < .001.
P < .05.
Discussion
This cohort study, to our knowledge the first large study of co-occurring PTSD and depression, found that women with co-occurring high PTSD symptoms and probable depression had nearly 4-fold increased mortality risk compared with women with no trauma exposure and no depression. These findings are particularly salient given that women have 2-fold the lifetime prevalence of PTSD and depression compared with men.24,25,26 A portion of the association in this study was accounted for by health risk factors, in particular, smoking and BMI, although the association remained even after accounting for major health risk factors. Women with PTSD symptoms and depression had increased incidence of death across nearly all major causes of death. These findings mirror a 2006 study16 of military veterans showing broadly increased risk of death in individuals with PTSD, including from cardiovascular illness, cancer, unintentional and intentional injuries, as well as a large Danish population study49 indicating that suicide alone does not account for the increased risk of death in individuals with depression.
Among women with depression in our study, those who were exposed to a traumatic event but did not develop PTSD symptoms were not at increased risk of death compared with women with no trauma exposure or depression, while other women with depression, including those with no exposure to trauma, were at increased risk. It may be that not developing PTSD symptoms after experiencing trauma is an indicator associated with psychological resilience50 and this resilience may be protective against the physical health effects of depression.
Symptoms of PTSD and depression overlap, with dysphoria and numbing common to both disorders.51 Questions have long been raised as to whether specific psychiatric diagnoses map to distinct phenomena or whether instead there are domains of dysfunction that span disorders (eg, Research Domain Criteria52), or even a single underlying psychopathology factor.53,54,55 Regardless, when PTSD and depression co-occur, it likely indicates more severe distress.37,51,56 Our findings are consistent with prior studies that found that co-occurring PTSD and depression are associated with worse health outcomes compared with either disorder alone. In military veterans and the general population, PTSD with depression has been associated with greater risk of suicidal behaviors57 and suicidal ideation58 compared with PTSD or depression alone. A 2004 study59 of Bosnian refugees found that those with comorbid PTSD and depression had greater social impairment, global dysfunction, and occupational disability compared with refugees with PTSD alone. In studies of US war veterans,60,61 comorbid PTSD and depression have been associated with reduced quality of life and impaired life satisfaction, compared with either disorder alone. In addition, there is evidence that the biological stress response is distinct among individuals with PTSD and depression compared with individuals with PTSD alone,62,63,64,65 which may contribute to these worse health outcomes.
Limitations
Our study has several limitations. Our sample included predominantly White women ages 43 to 64 years, which may limit generalizability. The sample also included only respondents who survived until the PTSD questionnaire was administered, which may have attenuated associations.66 In addition, our measures captured symptoms of both disorders rather than clinical diagnoses, lifetime PTSD symptoms were queried retrospectively, and only past-week depressive symptoms were queried, which may have resulted in misclassification. We lacked information on illicit substance use and abuse, which have been associated with increased risk of death in veterans with PTSD.19,20 Illicit substance use may have accounted for an additional part of the association of PTSD and depression with mortality beyond the health factors we examined.
Conclusions
The findings of this cohort study suggest that treatment of PTSD and depression in women with symptoms of both disorders and efforts to improve their health behaviors may reduce this population’s increased risk of mortality. Our results suggest that future investigations of the associations among PTSD, depression, and physical health outcomes should consider risk associated with co-occurrence of the disorders rather than modeling risk associated with 1 disorder adjusted for the other. Our findings additionally highlight the need for better access to and dissemination of effective treatments for comorbid PTSD and depression.67,68
References
- 1.Roberts AL, Agnew-Blais JC, Spiegelman D, et al. . Posttraumatic stress disorder and incidence of type 2 diabetes mellitus in a sample of women: a 22-year longitudinal study. JAMA Psychiatry. 2015;72(3):203-210. doi: 10.1001/jamapsychiatry.2014.2632 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Sumner JA, Kubzansky LD, Roberts AL, et al. . Post-traumatic stress disorder symptoms and risk of hypertension over 22 years in a large cohort of younger and middle-aged women. Psychol Med. 2016;46(15):3105-3116. doi: 10.1017/S0033291716001914 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sumner JA, Kubzansky LD, Elkind MS, et al. . Trauma exposure and posttraumatic stress disorder symptoms predict onset of cardiovascular events in women. Circulation. 2015;132(4):251-259. doi: 10.1161/CIRCULATIONAHA.114.014492 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Vaccarino V, Goldberg J, Rooks C, et al. . Post-traumatic stress disorder and incidence of coronary heart disease: a twin study. J Am Coll Cardiol. 2013;62(11):970-978. doi: 10.1016/j.jacc.2013.04.085 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lohr JB, Palmer BW, Eidt CA, et al. . Is post-traumatic stress disorder associated with premature senescence? A review of the literature. Am J Geriatr Psychiatry. 2015;23(7):709-725. doi: 10.1016/j.jagp.2015.04.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kubzansky LD, Bordelois P, Jun HJ, et al. . The weight of traumatic stress: a prospective study of posttraumatic stress disorder symptoms and weight status in women. JAMA Psychiatry. 2014;71(1):44-51. doi: 10.1001/jamapsychiatry.2013.2798 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Rosenbaum S, Stubbs B, Ward PB, Steel Z, Lederman O, Vancampfort D. The prevalence and risk of metabolic syndrome and its components among people with posttraumatic stress disorder: a systematic review and meta-analysis. Metabolism. 2015;64(8):926-933. doi: 10.1016/j.metabol.2015.04.009 [DOI] [PubMed] [Google Scholar]
- 8.Dedert EA, Calhoun PS, Watkins LL, Sherwood A, Beckham JC. Posttraumatic stress disorder, cardiovascular, and metabolic disease: a review of the evidence. Ann Behav Med. 2010;39(1):61-78. doi: 10.1007/s12160-010-9165-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Pace TW, Heim CM. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun. 2011;25(1):6-13. doi: 10.1016/j.bbi.2010.10.003 [DOI] [PubMed] [Google Scholar]
- 10.Griffin GD, Charron D, Al-Daccak R. Post-traumatic stress disorder: revisiting adrenergics, glucocorticoids, immune system effects and homeostasis. Clin Transl Immunology. 2014;3(11):e27. doi: 10.1038/cti.2014.26 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Sumner JA, Chen Q, Roberts AL, et al. . Cross-sectional and longitudinal associations of chronic posttraumatic stress disorder with inflammatory and endothelial function markers in women. Biol Psychiatry. 2017;82(12):875-884. doi: 10.1016/j.biopsych.2017.06.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Speer K, Upton D, Semple S, McKune A. Systemic low-grade inflammation in post-traumatic stress disorder: a systematic review. J Inflamm Res. 2018;11:111-121. doi: 10.2147/JIR.S155903 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kobayashi I, Boarts JM, Delahanty DL. Polysomnographically measured sleep abnormalities in PTSD: a meta-analytic review. Psychophysiology. 2007;44(4):660-669. doi: 10.1111/j.1469-8986.2007.537.x [DOI] [PubMed] [Google Scholar]
- 14.Wolf EJ, Logue MW, Morrison FG, et al. . Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation. Psychol Med. 2019;49(5):791-800. doi: 10.1017/S0033291718001411 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Colpani V, Baena CP, Jaspers L, et al. . Lifestyle factors, cardiovascular disease and all-cause mortality in middle-aged and elderly women: a systematic review and meta-analysis. Eur J Epidemiol. 2018;33(9):831-845. doi: 10.1007/s10654-018-0374-z [DOI] [PubMed] [Google Scholar]
- 16.Boscarino JA. Posttraumatic stress disorder and mortality among U.S. Army veterans 30 years after military service. Ann Epidemiol. 2006;16(4):248-256. doi: 10.1016/j.annepidem.2005.03.009 [DOI] [PubMed] [Google Scholar]
- 17.Bullman TA, Kang HK. Posttraumatic stress disorder and the risk of traumatic deaths among Vietnam veterans. J Nerv Ment Dis. 1994;182(11):604-610. doi: 10.1097/00005053-199411000-00002 [DOI] [PubMed] [Google Scholar]
- 18.Ahmadi N, Hajsadeghi F, Mirshkarlo HB, Budoff M, Yehuda R, Ebrahimi R. Post-traumatic stress disorder, coronary atherosclerosis, and mortality. Am J Cardiol. 2011;108(1):29-33. doi: 10.1016/j.amjcard.2011.02.340 [DOI] [PubMed] [Google Scholar]
- 19.Flood AM, Boyle SH, Calhoun PS, et al. . Prospective study of externalizing and internalizing subtypes of posttraumatic stress disorder and their relationship to mortality among Vietnam veterans. Compr Psychiatry. 2010;51(3):236-242. doi: 10.1016/j.comppsych.2009.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Drescher KD, Rosen CS, Burling TA, Foy DW. Causes of death among male veterans who received residential treatment for PTSD. J Trauma Stress. 2003;16(6):535-543. doi: 10.1023/B:JOTS.0000004076.62793.79 [DOI] [PubMed] [Google Scholar]
- 21.Xue Y, Taub PR, Iqbal N, et al. . Cardiac biomarkers, mortality, and post-traumatic stress disorder in military veterans. Am J Cardiol. 2012;109(8):1215-1218. doi: 10.1016/j.amjcard.2011.11.063 [DOI] [PubMed] [Google Scholar]
- 22.Kimbrell T, Pyne JM, Kunik ME, et al. . The impact of Purple Heart commendation and PTSD on mortality rates in older veterans. Depress Anxiety. 2011;28(12):1086-1090. doi: 10.1002/da.20850 [DOI] [PubMed] [Google Scholar]
- 23.Zohar J, Fostick L; Israeli Consortium on PTSD . Mortality rates between treated post-traumatic stress disorder Israeli male veterans compared to non-diagnosed veterans. Eur Neuropsychopharmacol. 2014;24(1):117-124. doi: 10.1016/j.euroneuro.2013.10.009 [DOI] [PubMed] [Google Scholar]
- 24.Harvard Medical School National Comorbidity Survey (NCS): NCS-R appendix tables: table 1: lifetime prevalence of DSM-IV/WMH-CIDI disorders by sex and cohort. Accessed September 25, 2020. https://www.hcp.med.harvard.edu/ncs/index.php
- 25.Breslau N, Chilcoat HD, Kessler RC, Peterson EL, Lucia VC. Vulnerability to assaultive violence: further specification of the sex difference in post-traumatic stress disorder. Psychol Med. 1999;29(4):813-821. doi: 10.1017/S0033291799008612 [DOI] [PubMed] [Google Scholar]
- 26.Ditlevsen DN, Elklit A. Gender, trauma type, and PTSD prevalence: a re-analysis of 18 nordic convenience samples. Ann Gen Psychiatry. 2012;11(1):26-26. doi: 10.1186/1744-859X-11-26 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Gradus JL, Antonsen S, Svensson E, Lash TL, Resick PA, Hansen JG. Trauma, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study. Am J Epidemiol. 2015;182(5):451-458. doi: 10.1093/aje/kwv066 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Rytwinski NK, Scur MD, Feeny NC, Youngstrom EA. The co-occurrence of major depressive disorder among individuals with posttraumatic stress disorder: a meta-analysis. J Trauma Stress. 2013;26(3):299-309. doi: 10.1002/jts.21814 [DOI] [PubMed] [Google Scholar]
- 29.Kuehner C. Why is depression more common among women than among men? Lancet Psychiatry. 2017;4(2):146-158. doi: 10.1016/S2215-0366(16)30263-2 [DOI] [PubMed] [Google Scholar]
- 30.Bracke P, Delaruelle K, Dereuddre R, Van de Velde S. Depression in women and men, cumulative disadvantage and gender inequality in 29 European countries. Soc Sci Med. 2020;113354. doi: 10.1016/j.socscimed.2020.113354 [DOI] [PubMed] [Google Scholar]
- 31.Fluharty M, Taylor AE, Grabski M, Munafò MR. The association of cigarette smoking with depression and anxiety: a systematic review. Nicotine Tob Res. 2017;19(1):3-13. doi: 10.1093/ntr/ntw140 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Pan A, Sun Q, Czernichow S, et al. . Bidirectional association between depression and obesity in middle-aged and older women. Int J Obes (Lond). 2012;36(4):595-602. doi: 10.1038/ijo.2011.111 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Cuijpers P, Smit F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72(3):227-236. doi: 10.1016/S0165-0327(01)00413-X [DOI] [PubMed] [Google Scholar]
- 34.Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173:11-53. doi: 10.1192/bjp.173.1.11 [DOI] [PubMed] [Google Scholar]
- 35.Penninx BW, Geerlings SW, Deeg DJ, van Eijk JT, van Tilburg W, Beekman AT. Minor and major depression and the risk of death in older persons. Arch Gen Psychiatry. 1999;56(10):889-895. doi: 10.1001/archpsyc.56.10.889 [DOI] [PubMed] [Google Scholar]
- 36.Van den Akker M, Schuurman A, Ensinck K, Buntinx F. Depression as a risk factor for total mortality in the community: a meta-analysis. Arch Public Health. 2003;61(6):313-332. [Google Scholar]
- 37.Flory JD, Yehuda R. Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations. Dialogues Clin Neurosci. 2015;17(2):141-150. doi: 10.31887/DCNS.2015.17.2/jflory [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Li X, Aida J, Hikichi H, Kondo K, Kawachi I. Association of postdisaster depression and posttraumatic stress disorder with mortality among older disaster survivors of the 2011 Great East Japan Earthquake and tsunami. JAMA Netw Open. 2019;2(12):e1917550-e1917550. doi: 10.1001/jamanetworkopen.2019.17550 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Edmondson D, Gamboa C, Cohen A, et al. . Association of posttraumatic stress disorder and depression with all-cause and cardiovascular disease mortality and hospitalization among Hurricane Katrina survivors with end-stage renal disease. Am J Public Health. 2013;103(4):e130-e137. doi: 10.2105/AJPH.2012.301146 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Dao TK, Chu D, Springer J, et al. . Clinical depression, posttraumatic stress disorder, and comorbid depression and posttraumatic stress disorder as risk factors for in-hospital mortality after coronary artery bypass grafting surgery. J Thorac Cardiovasc Surg. 2010;140(3):606-610. doi: 10.1016/j.jtcvs.2009.10.046 [DOI] [PubMed] [Google Scholar]
- 41.van den Berk-Clark C, Secrest S, Walls J, et al. . Association between posttraumatic stress disorder and lack of exercise, poor diet, obesity, and co-occuring smoking: A systematic review and meta-analysis. Health Psychol. 2018;37(5):407-416. doi: 10.1037/hea0000593 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Bao Y, Bertoia ML, Lenart EB, et al. . Origin, methods, and evolution of the three Nurses’ Health Studies. Am J Public Health. 2016;106(9):1573-1581. doi: 10.2105/AJPH.2016.303338 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th ed American Psychiatric Association; 1994. [Google Scholar]
- 44.Breslau N, Peterson EL, Kessler RC, Schultz LR. Short screening scale for DSM-IV posttraumatic stress disorder. Am J Psychiatry. 1999;156(6):908-911. doi: 10.1176/ajp.156.6.908 [DOI] [PubMed] [Google Scholar]
- 45.Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med. 1994;10(2):77-84. doi: 10.1016/S0749-3797(18)30622-6 [DOI] [PubMed] [Google Scholar]
- 46.Cheng S-T, Chan ACM. The Center for Epidemiologic Studies Depression Scale in older Chinese: thresholds for long and short forms. Int J Geriatr Psychiatry. 2005;20(5):465-470. doi: 10.1002/gps.1314 [DOI] [PubMed] [Google Scholar]
- 47.Blank K, Gruman C, Robison JT. Case-finding for depression in elderly people: balancing ease of administration with validity in varied treatment settings. J Gerontol A Biol Sci Med Sci. 2004;59(4):378-384. doi: 10.1093/gerona/59.4.M378 [DOI] [PubMed] [Google Scholar]
- 48.Akaike H. A new look at the statistical model identification. IEEE Transactions on Automatic Control. 1974;19(6):716-723. doi: 10.1109/TAC.1974.1100705 [DOI] [Google Scholar]
- 49.Laursen TM, Musliner KL, Benros ME, Vestergaard M, Munk-Olsen T. Mortality and life expectancy in persons with severe unipolar depression. J Affect Disord. 2016;193:203-207. doi: 10.1016/j.jad.2015.12.067 [DOI] [PubMed] [Google Scholar]
- 50.Bonanno GA. Loss, trauma, and human resilience: have we underestimated the human capacity to thrive after extremely aversive events? Am Psychol. 2004;59(1):20-28. doi: 10.1037/0003-066X.59.1.20 [DOI] [PubMed] [Google Scholar]
- 51.Gros DF, Price M, Magruder KM, Frueh BC. Symptom overlap in posttraumatic stress disorder and major depression. Psychiatry Res. 2012;196(2-3):267-270. doi: 10.1016/j.psychres.2011.10.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Insel T, Cuthbert B, Garvey M, et al. . Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167(7):748-751. doi: 10.1176/appi.ajp.2010.09091379 [DOI] [PubMed] [Google Scholar]
- 53.Caspi A, Houts RM, Ambler A, et al. . Longitudinal assessment of mental health disorders and comorbidities across 4 decades among participants in the Dunedin birth cohort study. JAMA Netw Open. 2020;3(4):e203221-e203221. doi: 10.1001/jamanetworkopen.2020.3221 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Caspi A, Houts RM, Belsky DW, et al. . The p factor: one general psychopathology factor in the structure of psychiatric disorders? Clin Psychol Sci. 2014;2(2):119-137. doi: 10.1177/2167702613497473 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Caspi A, Moffitt TE. All for one and one for all: mental disorders in one dimension. Am J Psychiatry. 2018;175(9):831-844. doi: 10.1176/appi.ajp.2018.17121383 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Campbell DG, Felker BL, Liu C-F, et al. . Prevalence of depression-PTSD comorbidity: implications for clinical practice guidelines and primary care–based interventions. J Gen Intern Med. 2007;22(6):711-718. doi: 10.1007/s11606-006-0101-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Ramsawh HJ, Fullerton CS, Mash HBH, et al. . Risk for suicidal behaviors associated with PTSD, depression, and their comorbidity in the U.S. Army. J Affect Disord. 2014;161:116-122. doi: 10.1016/j.jad.2014.03.016 [DOI] [PubMed] [Google Scholar]
- 58.Cougle JR, Resnick H, Kilpatrick DG. PTSD, depression, and their comorbidity in relation to suicidality: cross-sectional and prospective analyses of a national probability sample of women. Depress Anxiety. 2009;26(12):1151-1157. doi: 10.1002/da.20621 [DOI] [PubMed] [Google Scholar]
- 59.Momartin S, Silove D, Manicavasagar V, Steel Z. Comorbidity of PTSD and depression: associations with trauma exposure, symptom severity and functional impairment in Bosnian refugees resettled in Australia. J Affect Disord. 2004;80(2-3):231-238. doi: 10.1016/S0165-0327(03)00131-9 [DOI] [PubMed] [Google Scholar]
- 60.Pittman JOE, Goldsmith AA, Lemmer JA, Kilmer MT, Baker DG. Post-traumatic stress disorder, depression, and health-related quality of life in OEF/OIF veterans. Qual Life Res. 2012;21(1):99-103. doi: 10.1007/s11136-011-9918-3 [DOI] [PubMed] [Google Scholar]
- 61.Ikin JF, Creamer MC, Sim MR, McKenzie DP. Comorbidity of PTSD and depression in Korean War veterans: prevalence, predictors, and impairment. J Affect Disord. 2010;125(1-3):279-286. doi: 10.1016/j.jad.2009.12.005 [DOI] [PubMed] [Google Scholar]
- 62.Oquendo MA, Echavarria G, Galfalvy HC, et al. . Lower cortisol levels in depressed patients with comorbid post-traumatic stress disorder. Neuropsychopharmacology. 2003;28(3):591-598. doi: 10.1038/sj.npp.1300050 [DOI] [PubMed] [Google Scholar]
- 63.de Kloet C, Vermetten E, Lentjes E, et al. . Differences in the response to the combined DEX-CRH test between PTSD patients with and without co-morbid depressive disorder. Psychoneuroendocrinology. 2008;33(3):313-320. doi: 10.1016/j.psyneuen.2007.11.016 [DOI] [PubMed] [Google Scholar]
- 64.Halbreich U, Olympia J, Carson S, et al. . Hypothalamo-pituitary-adrenal activity in endogenously depressed post-traumatic stress disorder patients. Psychoneuroendocrinology. 1989;14(5):365-370. doi: 10.1016/0306-4530(89)90006-1 [DOI] [PubMed] [Google Scholar]
- 65.Young EA, Breslau N. Cortisol and catecholamines in posttraumatic stress disorder: an epidemiologic community study. Arch Gen Psychiatry. 2004;61(4):394-401. doi: 10.1001/archpsyc.61.4.394 [DOI] [PubMed] [Google Scholar]
- 66.Buckley JP, Keil AP, McGrath LJ, Edwards JK. Evolving methods for inference in the presence of healthy worker survivor bias. Epidemiology. 2015;26(2):204-212. doi: 10.1097/EDE.0000000000000217 [DOI] [PubMed] [Google Scholar]
- 67.Angelakis S, Nixon RD. The comorbidity of PTSD and MDD: implications for clinical practice and future research. Behaviour Change. 2015;32(1):1-25. doi: 10.1017/bec.2014.26 [DOI] [Google Scholar]
- 68.Nishith P, Nixon RD, Resick PA. Resolution of trauma-related guilt following treatment of PTSD in female rape victims: a result of cognitive processing therapy targeting comorbid depression? J Affect Disord. 2005;86(2-3):259-265. doi: 10.1016/j.jad.2005.02.013 [DOI] [PMC free article] [PubMed] [Google Scholar]