Abstract
Background
A diagnosis of prostate cancer (PC) may cause psychosocial distress not only in a man but also in his intimate partner. However, long-term risks of depression, anxiety, or suicide in partners of men with PC are largely unknown.
Methods
A national cohort study was conducted of 121 530 partners of men diagnosed with PC during 1998-2017 and 1 093 304 population-based controls in Sweden. Major depression, anxiety disorder, and suicide death were ascertained through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors.
Results
Partners of men with high-risk PC had increased risks of major depression (adjusted HR = 1.34, 95% confidence interval [CI] = 1.30 to 1.39) and anxiety disorder (adjusted HR = 1.25, 95% CI = 1.20 to 1.30), which remained elevated 10 or more years later. Suicide death was increased in partners of men with distant metastases (adjusted HR = 2.38, 95% CI = 1.08 to 5.22) but not other high-risk PC (adjusted HR =1.14, 95% CI = 0.70 to 1.88). Among partners of men with high-risk PC, risks of major depression and anxiety disorder were highest among those 80 years of age or older (adjusted HR = 1.73; 95% CI = 1.53 to 1.96; adjusted HR = 1.70, 95% CI = 1.47 to 1.96, respectively), whereas suicide death was highest among those younger than 60 years of age (adjusted HR = 7.55, 95% CI = 2.20 to 25.89). In contrast, partners of men with low- or intermediate-risk PC had modestly or no increased risks of these outcomes.
Conclusions
In this large cohort, partners of men with high-risk PC had increased risks of major depression and anxiety disorder, which persisted for 10 or more years. Suicide death was increased 2-fold in partners of men with distant metastases. Partners as well as men with PC need psychosocial support and close follow-up for psychosocial distress.
Prostate cancer (PC) is the most commonly diagnosed cancer among men in most countries, with more than 1.2 million new diagnoses worldwide each year (1,2). The stress of PC diagnosis, treatment, and side effects may cause psychosocial distress not only in patients but also in their spouses or intimate partners (hereafter called “partners”) (3-5). Psychosocial distress in a partner may adversely affect quality of life and health outcomes for both the partner and the cancer patient (6-9). However, long-term psychosocial outcomes in partners of men with PC have seldom been studied and are largely unknown. A better understanding of such outcomes is needed to improve interventions and outcomes in the growing number of couples who are coping with PC diagnosis and treatment.
Small clinical studies have suggested that partners of men with PC experience less psychosocial support (4), more psychosocial distress (5), and higher prevalence of depression and anxiety (3) than men with PC themselves. However, those studies were based on small, selected samples of less than 300 partners and lacked a comparison group that included partners of men without PC. To our knowledge, no large population-based studies have been conducted to determine mental health outcomes in partners of men with PC.
We conducted a population-based cohort study of more than 1.2 million people followed for more than 10 years in Sweden to determine the long-term risks of major depression, anxiety disorder, and suicide among partners of men with PC. We hypothesized that partners of men with aggressive PC have long-term increased risks of major depression, anxiety disorder, and/or suicide.
Methods
Study population
This study included the partners of an existing cohort of men with PC and population-based controls. In a national cohort of 180 189 men diagnosed with PC in Sweden during 1998-2017, compared with 1 801 890 population-based control men without PC, we previously reported that aggressive PC was associated with subsequent increased risks of major depression, alcohol use disorder, drug use disorders, and suicide (10,11). Men with PC were identified from the National Prostate Cancer Register (NPCR) of Sweden, which captures 98% of all incident PC cases since 1998 (12). Control men were matched 10:1 to PC cases by randomly sampling men from the general population as identified in the Swedish Total Population Register who had the same birth year and month and were living in Sweden on the date of PC diagnosis for the respective case (ie, index date) (10,11). Residence in Sweden was determined from national census data.
For the present study, a new cohort was formed that consisted of the partners of all men with PC and the partners of all control men without PC in the original cohort. Partners were ascertained from national civil records in the Total Population Register on the basis of registered marriage or having at least one child in common. Among 180 189 men with PC and 1 801 890 control men in the original cohort, 121 530 (67%) and 1 093 304 (61%), respectively, had a partner according to civil records. These two groups of partners composed a new cohort for the present study. Linkages of these partners to diagnoses in the Swedish National Patient Register and primary care records (as detailed below) were conducted using pseudonymous serial numbers to preserve confidentiality. The Swedish National Patient Register (13) includes both the In-Patient Register, which contains primary and secondary hospital discharge diagnoses starting in 1973 with 100% nationwide coverage since 1987 (14), and the Out-Patient Register, which contains all diagnoses from specialty clinics with approximately 87% nationwide coverage starting in 2001 (15). In addition, primary care diagnoses previously collected by our group (16) were available for 20% of the Swedish population starting in 1998, 45% starting in 2001, and 90% starting in 2008.
To assess whether mental health outcomes in partners vary by PC risk group, cancer characteristics were obtained from the NPCR, including tumor grade according to Gleason score, disease stage according to the tumor, nodes, metastasis classification, and PSA level at diagnosis. PC risk groups were defined based on a modification of criteria from the National Comprehensive Cancer Network Practice Guidelines (12,17). Low-risk PC was defined by clinical local stage T1-T2, Gleason score 2-6, and PSA less than 10 ng/mL, and intermediate-risk PC by T1-T2 with Gleason score 7 and/or PSA 10 to less than 20 ng/mL. High-risk PC was defined by clinical stage T3 or T4, Gleason score 8 or higher, and/or PSA 20 ng/mL or higher at the time of diagnosis, and was further stratified as locally advanced (stage T3 and PSA 20 to <50 ng/mL), very advanced/regionally metastatic (stage T4 and/or N1 and/or PSA 50 to <100 ng/mL in the absence of distant metastases [M0 or Mx]), or distant metastases (stage M1 and/or PSA ≥100 ng/mL) (12,17).
This study was approved by the Regional Ethical Review Board in Lund, Sweden (No. 2012/795 and later amendments). Participant consent was not required, because this study used only pseudonymized registry-based secondary data.
Ascertainment of mental health outcomes
The primary outcomes were earliest 1) diagnosis of major depression, 2) diagnosis of anxiety disorder, or 3) death by suicide, which were ascertained from the index date (PC diagnosis date for the respective case in the original cohort) through December 31, 2018, and were examined in separate models. Major depression and anxiety disorder were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes F32-F33 and F40-F42, respectively, in the Swedish In-Patient and Out-Patient Registers and primary care records. Anxiety disorders included generalized anxiety disorder, panic disorder, phobic disorders, obsessive-compulsive disorder, and other or unspecified anxiety disorders. Psychiatric diagnoses in the In-Patient Register have been reported to have positive predictive values in the 85%-95% range (14). Prior studies have suggested that major depression and anxiety disorder diagnoses identified from these combined sources have high validity based on their prevalence, sex ratio, and sibling and twin correlations (16,18).
Death by suicide was identified from the Swedish Cause of Death Register, which includes deaths and ICD codes for cause of death among all persons registered in Sweden since 1960 (10). Prior research has suggested that many suicide deaths are misclassified as deaths of undetermined intent (19). In the present study, intentional deaths (ICD-10 codes X60-X84) and deaths of undetermined intent (ICD-10 codes Y10-Y34) were analyzed together in the primary analysis and separately in a sensitivity analysis (10).
Covariates
Other characteristics that may be associated with PC partner status and mental health outcomes were identified using Swedish national census and health registry data, which were linked using pseudonymous serial numbers. Covariates included age (continuous and categorical by decade: <60, 60-69, 70-79, ≥80 years), birth country (Sweden/other), education level (≤9, 10-12, >12 years), family income (quartiles), region (large cities, other/Southern, other/Northern, unknown), and prior diagnosis of major depression or anxiety disorder at the index date (each modeled as a separate covariate). All covariates were more than 99% complete. Missing covariate data were modeled as a separate category and had little effect on risk estimates because of their rarity.
Statistical analysis
Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for major depression, anxiety disorder, or death by suicide in partners of men with PC compared with partners of population-based control men while stratifying on matched sets. The observation period for each partner began at the index date (ie, PC diagnosis date for the respective case in the original cohort) and ended at the date of the respective outcome (earliest registration of major depression, anxiety disorder, or suicide death, examined in separate models) or December 31, 2018, whichever came first. In analyses of major depression or anxiety disorder, individuals were censored at death as identified in the Swedish Death Register (n = 183 704 and n = 195 860, respectively) or emigration as determined by absence of a Swedish residential address in census data (n = 17 892 and 17 895, respectively). In analyses of suicide death, individuals were censored at death from other causes (n = 220 354) or at emigration (n = 7490). All analyses were adjusted for covariates (as defined above). The proportional hazards assumption was evaluated by examining log-log survival plots, and no substantial departures were found.
In secondary analyses, we also explored associations with “new-onset” major depression by excluding 85 325 [7%] partners who were previously diagnosed with major depression before the index date, and “new-onset” anxiety disorder by excluding 74 580 [6%] partners who were previously diagnosed with anxiety disorder before the index date. To assess periods of heightened susceptibility during the follow-up period, hazard ratios were estimated within narrower time intervals after the index date (eg, <1, 1 to <2, 2 to <5, 5 to <10, ≥10 years) in separate analyses among partners still at risk for the outcome at the beginning of the respective interval, and heterogeneity in these hazard ratios was assessed using Cochran’s Q test (20). Age-specific differences were assessed by stratifying on age at the index date (<60, 60-69, 70-79, ≥80 years) while adjusting for age as a continuous variable within each stratum, and formally testing for interactions between PC partner status and age using likelihood ratio tests. In addition, we assessed for potential interactions between PC partner status and 1) education level, because stronger associations with depression or anxiety were previously suggested among more highly educated partners of men with PC (3); and 2) mental health outcomes in the study participants’ respective partner (ie, prior registration of major depression, anxiety disorder, or suicide death vs none of these in the men with PC or control men). All statistical tests were 2-sided and used a significance level of .05. All analyses were conducted using Stata version 15.1.
Results
Nearly all (>99.9%) partners of men with PC and all control partners were women. Among 121 530 partners of men with PC, the median age at the index date was 67 years (interquartile range [IQR] = 61–73). 59% were partners of men with low- or intermediate-risk PC, and 41% were partners of men with high-risk PC. In 5.9 million person-years of follow-up, 17 647 (15%) partners of men with PC were diagnosed with major depression (compared with 149 472 [14%] control partners), 14 417 (12%) partners of men with PC were diagnosed with anxiety disorder (compared with 124 635 [11%] control partners), and 82 (0.07%) partners of men with PC died by suicide (compared with 604 [0.06%] control partners). The median ages at diagnosis of major depression or anxiety disorder or at death by suicide, respectively, were 74, 74, and 73 years for partners of men with PC and 74, 74, and 72 years for control partners. Among all study participants who did not die during the study period, the median follow-up time among partners of men with PC was 8 years (IQR = 4–13) and among control partners was 8 years (IQR = 4–12).
Table 1 shows characteristics of partners of men with PC, control partners, and all partners diagnosed with major depression or anxiety disorder or who died by suicide. Partners of men with PC were less likely than controls to have a prior diagnosis of major depression or anxiety disorder at the index date. Compared with the overall cohort, those diagnosed with major depression or anxiety disorder during the follow-up period were older, whereas those who died by suicide were younger. Partners with any of these outcomes were more likely to have low education level or low family income, live in large cities, or have a prior diagnosis of major depression or anxiety disorder at the index date.
Table 1.
Characteristics of study participants, 1998-2018, Sweden
| Partners of men with PC | Controls | Major depression | Anxiety disorder | Suicide death | |
|---|---|---|---|---|---|
| n = 121 530 | n = 1 093 304 | n = 167 119 | n = 139 052 | n = 686 | |
| n (%) | n (%) | n (%) | n (%) | n (%) | |
| Female | 121 529 (>99) | 1 093 304 (100) | 167 119 (100) | 139 052 (100) | 686 (100) |
| Age at index date (years) | |||||
| <60 | 27 128 (22) | 251 925 (23) | 34 781 (21) | 30 508 (22) | 170 (25) |
| 60-69 | 49 109 (41) | 430 574 (40) | 58 479 (35) | 50 769 (36) | 263 (38) |
| 70-79 | 35 616 (29) | 318 972 (29) | 57 760 (35) | 45 563 (33) | 203 (30) |
| ≥80 | 9677 (8) | 91 833 (8) | 16 099 (10) | 12 212 (9) | 50 (7) |
| Sweden-born | 108 975 (90) | 951 972 (87) | 145 546 (87) | 120 083 (86) | 572 (83) |
| Education (years) | |||||
| ≤9 | 41 167 (34) | 395 495 (36) | 67 324 (40) | 56 614 (41) | 272 (40) |
| 10-12 | 48 232 (40) | 432 045 (40) | 65 128 (39) | 54 740 (39) | 261 (38) |
| >12 | 32 065 (26) | 264 317 (24) | 34 563 (21) | 27 580 (20) | 153 (22) |
| Unknown | 66 (<1) | 1447 (<1) | 104 (<1) | 118 (<1) | 0 (0) |
| Family income (quartile) | |||||
| 1st (highest) | 40 692 (34) | 334 778 (31) | 36 438 (22) | 31 808 (23) | 130 (19) |
| 2nd | 33 258 (27) | 297 467 (27) | 45 200 (27) | 38 661 (28) | 172 (25) |
| 3rd | 24 826 (20) | 231 191 (21) | 42 682 (26) | 34 452 (25) | 203 (30) |
| 4th (lowest) | 22 698 (19) | 225 209 (21) | 42 295 (25) | 33 662 (24) | 181 (26) |
| Unknown | 56 (<1) | 4659 (<1) | 504 (<1) | 469 (<1) | 0 (0) |
| Region | |||||
| Large cities | 58 501 (48) | 508 153 (47) | 91 538 (55) | 79 258 (57) | 352 (51) |
| Other/Southern | 43 352 (36) | 394 630 (36) | 52 040 (31) | 40 256 (29) | 245 (36) |
| Other/Northern | 19 667 (16) | 189 998 (17) | 23 504 (14) | 19 507 (14) | 89 (13) |
| Unknown | 10 (<1) | 523 (<1) | 37 (<1) | 31 (<1) | 0 (0) |
| Prior diagnoses | |||||
| Major depression | 8083 (7) | 77 242 (7) | 43 541 (26) | 26 430 (19) | 173 (25) |
| Anxiety disorder | 7124 (6) | 67 456 (6) | 25 561 (15) | 34 451 (25) | 149 (22) |
Major depression in partners of men with PC
Partners of men diagnosed with high-risk PC had about a 1.3-fold increased rate of major depression across the entire follow-up period compared with controls (adjusted HR = 1.34, 95% CI = 1.30 to 1.39) (Table 2). This finding was similar among partners of men with locally advanced PC (adjusted HR = 1.32, 95% CI = 1.27 to 1.38), very advanced/regionally metastatic PC (adjusted HR = 1.35, 95% CI = 1.25 to 1.45), or distant metastases (adjusted HR = 1.39, 95% CI = 1.29 to 1.51). The relative rate of major depression also remained similarly elevated across follow-up time, even 10 years or more after the index date (adjusted HR = 1.29, 95% CI = 1.19 to 1.39) (P for heterogeneity = 0.84; Table 2). In contrast, partners of men with low- or intermediate-risk PC had only a modestly increased relative rate of major depression across the entire follow-up period (adjusted HR = 1.14; 95% CI = 1.11 to 1.18).
Table 2.
Relative rates of major depression, anxiety disorder, or suicide death through 2018 in partners of men diagnosed with PC (1998-2017) compared with controls, stratified by time since index date
| Outcome and time since index datea | No. with outcome |
Adjusted modelb |
Heterogeneityc | ||
|---|---|---|---|---|---|
| PC partners | Controls | HR (95% CI) | P | P | |
| Partners of men with high-risk PC | |||||
| Major depression | |||||
| Entire follow-up period | 8103 | 23 329 | 1.34 (1.30 to 1.39) | <.001 | |
| <1 year | 1250 | 3401 | 1.32 (1.20 to 1.46) | <.001 | .84 |
| 1 to <2 years | 860 | 2341 | 1.34 (1.21 to 1.49) | <.001 | |
| 2 to <5 years | 2070 | 5696 | 1.34 (1.25 to 1.42) | <.001 | |
| 5 to <10 years | 2348 | 7356 | 1.28 (1.20 to 1.35) | <.001 | |
| ≥10 years | 1575 | 4535 | 1.29 (1.19 to 1.39) | <.001 | |
| Anxiety disorder | |||||
| Entire follow-up period | 6296 | 18 488 | 1.25 (1.20 to 1.30) | <.001 | |
| <1 year | 947 | 2339 | 1.48 (1.32 to 1.67) | <.001 | <.001 |
| 1 to <2 years | 496 | 1644 | 1.12 (0.98 to 1.28) | .10 | |
| 2 to <5 years | 1442 | 4088 | 1.26 (1.17 to 1.36) | <.001 | |
| 5 to <10 years | 1787 | 5965 | 1.12 (1.05 to 1.20) | .001 | |
| ≥10 years | 1624 | 4452 | 1.27 (1.18 to 1.37) | <.001 | |
| Suicide death | |||||
| Entire follow-up period | 40 | 157 | 1.39 (0.91 to 2.11) | .12 | |
| <2 years | 5 | 31 | 0.64 (0.18 to 2.23) | .49 | .32 |
| 2 to <5 years | 15 | 48 | 2.27 (1.08 to 4.75) | .03 | |
| 5 to <10 years | 11 | 54 | 1.11 (0.52 to 2.36) | .78 | |
| ≥10 years | 9 | 24 | 1.33 (0.48 to 3.64) | .59 | |
| Partners of men with low- or intermediate-risk PC | |||||
| Major depression | |||||
| Entire follow-up period | 9485 | 29 467 | 1.14 (1.11 to 1.18) | <.001 | |
| <1 year | 1892 | 6655 | 1.15 (1.06 to 1.24) | .001 | .008 |
| 1 to <2 years | 1020 | 3750 | 1.02 (0.93 to 1.11) | .73 | |
| 2 to <5 years | 2376 | 7673 | 1.09 (1.03 to 1.15) | .005 | |
| 5 to <10 years | 2653 | 7671 | 1.14 (1.08 to 1.20) | <.001 | |
| ≥10 years | 1544 | 3718 | 1.25 (1.16 to 1.35) | <.001 | |
| Anxiety disorder | |||||
| Entire follow-up period | 8080 | 25 491 | 1.13 (1.09 to 1.16) | <.001 | |
| <1 year | 1454 | 5179 | 1.15 (1.05 to 1.26) | .002 | .14 |
| 1 to <2 years | 788 | 3026 | 1.06 (0.95 to 1.17) | .30 | |
| 2 to <5 years | 1873 | 6464 | 1.05 (0.98 to 1.12) | .16 | |
| 5 to <10 years | 2341 | 6837 | 1.12 (1.06 to 1.19) | <.001 | |
| ≥10 years | 1624 | 3985 | 1.18 (1.10 to 1.27) | <.001 | |
| Suicide death | |||||
| Entire follow-up period | 42 | 161 | 1.32 (0.88 to 1.99) | .18 | |
| <2 years | 6 | 33 | 0.89 (0.29 to 2.71) | .84 | .03 |
| 2 to <5 years | 9 | 48 | 0.64 (0.26 to 1.59) | .34 | |
| 5 to <10 years | 13 | 56 | 1.33 (0.65 to 2.74) | .43 | |
| ≥10 years | 14 | 24 | 4.21 (1.63 to 10.83) | .003 | |
In separate models, each outcome was examined across the entire follow-up period and within narrower time intervals after PC diagnosis. CI = confidence interval; HR = hazard ratio; PC = prostate cancer.
Adjusted for age, birth country, education, family income, region, and prior history of major depression or anxiety disorder at index date.
Cochran’s Q test for heterogeneity of HRs across time intervals from separate models.
In a secondary analysis, new-onset major depression was assessed by excluding all 85 325 (7%) partners with a prior diagnosis of major depression before the index date. This analysis yielded little or no change in relative rate estimates. Across the entire follow-up period, partners of men with high-risk PC had a 1.3-fold rate of new-onset major depression compared with controls (adjusted HR = 1.34, 95% CI = 1.29 to 1.39).
Anxiety disorder in partners of men with PC
Partners of men diagnosed with high-risk PC had about a 1.2-fold increased rate of anxiety disorder across the entire follow-up period, compared with control partners of men without PC (adjusted HR = 1.25, 95% CI = 1.20 to 1.30) (Table 2). This finding was similar among partners of men with locally advanced PC (adjusted HR = 1.24, 95% CI = 1.18 to 1.30), very advanced/regionally metastatic PC (adjusted HR = 1.26, 95% CI = 1.16 to 1.37), or distant metastases (adjusted HR = 1.25, 1.14 to 1.37). The relative rate of anxiety disorder peaked in the first year after the index date (adjusted HR = 1.48, 95% CI = 1.32 to 1.67), but remained elevated even 10 or more years later (adjusted HR = 1.27, 95% CI = 1.18 to 1.37) (P for heterogeneity <.001; Table 2). In contrast, partners of men with low- or intermediate-risk PC had a modestly increased relative rate of anxiety disorder across the entire follow-up period (adjusted HR = 1.13, 95% CI = 1.09 to 1.16).
In a secondary analysis, new-onset anxiety disorder was assessed by excluding all 74 580 (6%) persons who had a prior diagnosis of anxiety disorder before the index date. This resulted in little change in relative rates. Across the entire follow-up period, the adjusted hazard ratio for new-onset anxiety disorder in partners of men with high-risk PC was 1.23 (95% CI = 1.18 to 1.28).
Figures 1 and 2 show adjusted hazard ratios and 95% confidence intervals for major depression and anxiety disorder by time since the index date, fitted using spline curves.
Figure 1.
Adjusted hazard ratios (HRs) for major depression in partners of men with high-risk prostate cancer (PC) or low- to intermediate-risk PC by time since index date, 1998-2018, Sweden.
Figure 2.
Adjusted hazard ratios (HRs) for anxiety disorder in partners of men with high-risk prostate cancer (PC) or low- to intermediate-risk PC by time since index date, 1998-2018, Sweden.
Suicide death in partners of men with PC
Partners of men diagnosed with high-risk PC had a nonsignificant approximate 1.4-fold rate of suicide death across the entire follow-up period, compared with control partners of men without PC (adjusted HR = 1.39, 95% CI = 0.91 to 2.11) (Table 2). Suicide death was increased 2-fold in partners of men with distant PC metastases (adjusted HR = 2.38, 95% CI = 1.08 to 5.22) or (nonsignificantly) with very advanced/regionally metastatic PC (adjusted HR = 2.18, 95% CI = 0.90 to 5.27) but not partners of men with locally advanced PC (adjusted HR = 0.89, 95% CI = 0.48 to 1.64). Among all partners of men with high-risk PC, the relative rate of suicide death peaked at 2 to 5 years after the index date (adjusted HR = 2.27, 95% CI = 1.08 to 4.75) (P for heterogeneity = .32; Table 2).
In contrast, partners of men with low- or intermediate-risk PC had a nonsignificant 1.3-fold rate of suicide death across the entire follow-up period (adjusted HR = 1.32, 95% CI = 0.88 to 1.99) but a 4-fold rate at 10 or more years after the index date (adjusted HR = 4.21, 95% CI = 1.63 to 10.83; on the basis of 14 suicide deaths among partners of men with PC and 24 suicide deaths among control partners). Among all partners who died by suicide, 48% of partners of men with PC and 44% of controls had a diagnosis of major depression, and 29% and 27%, respectively, had a diagnosis of anxiety disorder, during the follow-up period.
In a sensitivity analysis that explored confirmed suicides (n = 547) and deaths of undetermined intent (n = 139) separately, partners of men with PC had elevated relative rates of both outcomes but they were no longer statistically significant because of fewer events. The adjusted hazard ratio for confirmed suicide in partners of men with high-risk PC was 1.25 (95% CI = 0.76 to 2.04), and the corresponding hazard ratio for deaths of undetermined intent was 2.26 (95% CI = 0.92 to 5.52).
Interactions
Significant interactions with age were found for each of the outcomes (Table 3). Among partners of men with high-risk PC, the relative rate of major depression was elevated regardless of age but was highest in partners aged 80 years or older (adjusted HR = 1.73, 95% CI = 1.53 to 1.96) (Table 3). Anxiety disorder had similar findings (ages 80 years or older: adjusted HR = 1.70, 95% CI = 1.47 to 1.96). In contrast, the relative rate of suicide death was increased only in partners aged 60 years or younger (adjusted HR = 7.55, 95% CI = 2.20 to 25.89) (Table 3).
Table 3.
Relative rates of major depression, anxiety disorder, or suicide death in partners of men diagnosed with PC (1998-2017) compared with controls, stratified by partner's age at index date
| Outcome and age at index date | No. with outcome |
Adjusted modela |
Age interaction | ||
|---|---|---|---|---|---|
| PC partners | Controls | HR (95% CI) | P | P | |
| Partners of men with high-risk PC | |||||
| Major depression | <.001 | ||||
| <60 years | 1089 | 3967 | 1.34 (1.21 to 1.48) | <.001 | |
| 60-69 years | 2472 | 6596 | 1.34 (1.24 to 1.44) | <.001 | |
| 70-79 years | 3342 | 9022 | 1.36 (1.28 to 1.44) | <.001 | |
| ≥80 years | 1196 | 2860 | 1.73 (1.53 to 1.96) | <.001 | |
| Anxiety disorder | <.001 | ||||
| <60 years | 818 | 3431 | 1.13 (1.01 to 1.27) | .03 | |
| 60-69 years | 2015 | 5408 | 1.25 (1.15 to 1.35) | <.001 | |
| 70-79 years | 2553 | 6932 | 1.25 (1.17 to 1.35) | <.001 | |
| ≥80 years | 909 | 2063 | 1.70 (1.47 to 1.96) | <.001 | |
| Suicide death | .17 | ||||
| <60 years | 13 | 28 | 7.55 (2.20 to 25.89) | <.001 | |
| 60-69 years | 12 | 54 | 2.23 (0.80 to 6.21) | .13 | |
| 70-79 years | 11 | 55 | 0.90 (0.38 to 2.11) | .80 | |
| ≥80 years | 4 | 13 | 0.35 (0.04 to 3.11) | .35 | |
| Partners of men with low- or intermediate-risk PC | |||||
| Major depression | <.001 | ||||
| <60 years | 2561 | 12 208 | 1.01 (0.95 to 1.07) | .85 | |
| 60-69 years | 3935 | 10 229 | 1.13 (1.07 to 1.20) | <.001 | |
| 70-79 years | 2563 | 5688 | 1.44 (1.34 to 1.56) | <.001 | |
| ≥80 years | 418 | 836 | 1.44 (1.15 to 1.80) | .002 | |
| Anxiety disorder | <.001 | ||||
| <60 years | 2245 | 10 852 | 1.04 (0.98 to 1.11) | .22 | |
| 60-69 years | 3434 | 9098 | 1.15 (1.09 to 1.22) | <.001 | |
| 70-79 years | 2062 | 4506 | 1.33 (1.22 to 1.45) | <.001 | |
| ≥80 years | 335 | 623 | 1.86 (1.43 to 2.42) | <.001 | |
| Suicide death | .02 | ||||
| <60 years | 9 | 73 | 0.69 (0.25 to 1.95) | .49 | |
| 60-69 years | 19 | 51 | 2.14 (0.98 to 4.70) | .06 | |
| 70-79 years | 11 | 28 | 2.05 (0.69 to 6.09) | .20 | |
| ≥80 years | 3 | 6 | NE | NE | |
Adjusted for age, birth country, education, family income, region, and prior history of major depression or anxiety disorder at index date. CI = confidence interval, HR = hazard ratio, NE = not estimable, PC = prostate cancer.
Partners of men with low- or intermediate-risk PC had increased relative rates for major depression or anxiety disorder (but not suicide death) among all age groups except younger than 60 years of age, but with heterogeneity (P < .05 for age interactions), particularly with higher relative rates among older partners (Table 3).
No significant interactions were found between PC partner status and either education level or mental health outcomes in the study participants’ respective partner in relation to any of the study outcomes (P > .05 for each). In stratified analyses, the adjusted hazard ratio for major depression in partners of men who had high-risk PC and who suffered from major depression, anxiety disorder, and/or suicide was 1.51 (95% CI = 1.24 to 1.84), compared with 1.33 (95% CI = 1.29 to 1.39) in partners of men who had high-risk PC but none of those mental health outcomes, relative to control partners of men without PC (P = .43 for difference in HRs). The corresponding hazard ratios for anxiety disorder were 1.57 (95% CI = 1.21 to 2.04) and 1.24 (95% CI = 1.19 to 1.29), respectively (P = .11 for difference in HRs).
Discussion
In this large population-based cohort, partners of men diagnosed with high-risk PC had a 30% increased rate of major depression and 25% increased rate of anxiety disorder compared with partners of men without PC, after adjusting for sociodemographic factors. Moreover, these relative rates remained elevated for more than 10 years. Partners of men with distant PC metastases had more than a 2-fold rate of suicide death. In contrast, partners of men with low- or intermediate-risk PC had modestly (10%-15%) increased rates of major depression and anxiety disorder and no overall increased rate of suicide death.
To our knowledge, this study is the first to examine long-term (≥5 years) risks of major depression, anxiety disorder, or death by suicide in a large population-based cohort of partners of men with PC. The few prior studies of psychosocial outcomes were based on selected samples of less than 300 partners (3-5). A study of 137 spouses and 184 men with PC in Spain reported higher prevalences of depression and anxiety in spouses (16% and 16%, respectively) than in men with PC (14% and 9%, respectively) (3). A US study of 267 patient/spouse couples found that spouses reported less psychosocial support than men with PC and less confidence in their ability to manage the psychosocial effects of the disease course (4). A UK study of 135 patient/spouse couples also reported that spouses had higher prevalences of psychosocial distress or severe distress (76% and 30%, respectively) than men with PC (47% and 11%, respectively) (5). However, gender differences in self-reporting or care-seeking may potentially influence those findings. Other studies have found that men are less likely to report or seek care for psychiatric symptoms and thus have greater underdiagnosis of mental health outcomes compared with women (21,22). No prior studies have included a comparison group of partners of men without PC.
The present study extends prior evidence by assessing long-term mental health outcomes, periods of heightened risk, and high-risk subgroups in a large cohort of partners of men with PC compared with population-based controls. The outcomes varied significantly by PC risk group and age. Partners of men with aggressive PC were at higher risk than partners of men with low- or intermediate-risk PC, including elevated rates of major depression, anxiety disorder, and suicide that persisted 10 years or more after the PC diagnosis. Partners of men with distant metastases had the highest risk of suicide death, although precision was limited by the small number of such persons. High-risk PC also was more strongly associated with depression and anxiety among older partners (≥80 years) but with suicide death among younger partners (<60 years). Most partners who died by suicide had no diagnosis of depression or anxiety, suggesting underdiagnosis of these conditions and the importance of clinical monitoring for psychosocial distress in partners of men with PC. Suicide death was uncommon (<0.1%) among partners, whereas 15% and 12% were diagnosed with major depression and anxiety disorder, respectively. Nearly all partners were women, reflecting the small percentage of same-sex civil partnerships in Sweden during this study period.
We recently reported that men with high-risk PC had an 80% increased rate of major depression and more than 2-fold rate of suicide death compared with control men without PC and that these associations persisted 10 years or more after PC diagnosis (10). In addition, men with high-risk PC had more than a 40% subsequent increased risk of alcohol use disorder and 90% increased risk of drug use disorders compared with control men (11). The present study further shows that PC may cause substantial psychosocial distress not only in the patients themselves but also in their intimate partners. The American Cancer Society currently recommends screening for psychosocial distress and depression in all men with PC (23), and the U.S. Preventive Services Task Force recommends routine screening for depression in the general adult population while acknowledging that patients with cancer are at higher risk (24). Partners of men with PC should also be recognized as an at-risk group. Our findings suggest that psychosocial support and long-term monitoring for distress should be offered not only to men with PC but also to their intimate partners. Psychosocial interventions that include partners of men with PC are understudied but have shown promise for reducing emotional distress and improving quality of life (25-28).
A strength of the present study is its large national cohort design, which enabled well-powered analyses of mental health outcomes and susceptible periods in partners of men with PC compared with population-based controls while adjusting for multiple potential confounders. The availability of clinical diagnoses from all health care settings, including primary care, allowed more complete ascertainment of major depression and anxiety disorder for the first time in a national cohort. Previously reported incidences of depression, anxiety disorder, and suicide are comparable between Sweden and the US (16,29,30).
This study also had certain limitations. Major depression and anxiety disorder were identified using nationwide ICD codes, but we lacked more detailed clinical data needed to validate them. However, prior studies have suggested that these diagnoses have high validity based on their prevalence, sex ratio, sibling and twin correlations, and associations with well-documented psychosocial risk factors (16,18). Depression and anxiety disorder are often undiagnosed, especially milder cases, and such cases could not be identified in this study. However, the inclusion of diagnoses from primary care settings where most depression and anxiety are diagnosed and treated (16) enabled more complete ascertainment than in prior research. This study also was limited to Sweden and will need replication in other countries when feasible, including assessment for potential racial/ethnic differences.
In this large cohort, partners of men with high-risk PC had increased rates of major depression and anxiety disorder compared with population-based controls. These relative rates remained elevated 10 years and longer after the respective PC diagnosis. Partners of men with distant metastases had more than a 2-fold rate of suicide death. In contrast, partners of men with low- or intermediate-risk PC had modestly increased rates of major depression and anxiety disorder and no overall increased rate of suicide death. Partners of men with PC need psychosocial support and long-term monitoring for psychosocial distress.
Acknowledgements
This project was made possible by the continuous work of the National Prostate Cancer Register of Sweden (NPCR) steering group: Johan Styrke, Johan Stranne, Jon Kindblom, Camilla Thellenberg, Andreas Josefsson, Ingrida Verbiene, Hampus Nugin, Stefan Carlsson, Anna Kristiansen, Mats Andén, Thomas Jiborn, Olof Ståhl, Olof Akre, Per Fransson, Eva Johansson, Magnus Törnblom, Fredrik Jäderling, Marie Hjälm Eriksson, Lotta Renström, Jonas Hugosson, Ola Bratt, Maria Nyberg, Fredrik Sandin, Mia Brus, Nina Hageman, Christofer Lagerros, and the patient representatives Hans Joelsson and Gert Malmberg. The funding agencies had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Contributor Information
Casey Crump, Departments of Family and Community Medicine and of Epidemiology, The University of Texas Health Science Center, Houston, TX, USA.
Pär Stattin, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
James D Brooks, Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
Jan Sundquist, Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Alexis C Edwards, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
Kristina Sundquist, Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Weiva Sieh, Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Data availability
Because of ethical concerns, supporting data cannot be made openly available. Further information about the data registries is available from the Swedish National Board of Health and Welfare: https://www.socialstyrelsen.se/en/statistics-and-data/registers/.
Author contributions
Casey Crump, MD, PhD (Conceptualization; Funding acquisition; Investigation; Methodology; Supervision; Writing—original draft; Writing—review & editing), Par Stattin, MD, PhD (Conceptualization; Investigation; Methodology; Supervision; Writing—review & editing), James D. Brooks, MD (Conceptualization; Investigation; Methodology; Writing—review & editing), Jan Sundquist, MD, PhD (Conceptualization; Formal analysis; Investigation; Methodology; Supervision; Writing—review & editing), Alexis C. Edwards, PhD (Conceptualization; Funding acquisition; Investigation; Methodology; Writing—review & editing), Kristina Sundquist, MD, PhD (Conceptualization; Funding acquisition; Investigation; Methodology; Supervision; Writing—review & editing), Weiva Sieh, MD, PhD (Conceptualization; Funding acquisition; Investigation; Methodology; Supervision; Writing—review & editing).
Funding
This work was supported by the National Cancer Institute [R01 CA269553 to C.C., K.S., and W.S.] and the National Institute on Alcohol Abuse and Alcoholism [R01 AA027522 to A.E. and K.S.] at the National Institutes of Health; and the Swedish Research Council.
Conflicts of interest
The authors declare no conflicts of interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Because of ethical concerns, supporting data cannot be made openly available. Further information about the data registries is available from the Swedish National Board of Health and Welfare: https://www.socialstyrelsen.se/en/statistics-and-data/registers/.