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Research

Original Investigation

Clinical Diagnosis of Mental Disorders Immediately


Before and After Cancer Diagnosis
A Nationwide Matched Cohort Study in Sweden
Donghao Lu, MD; Therese M. L. Andersson, PhD; Katja Fall, MD, PhD; Christina M. Hultman, MD, PhD;
Kamila Czene, PhD; Unnur Valdimarsdóttir, PhD; Fang Fang, MD, PhD

Supplemental content at
IMPORTANCE Psychiatric comorbidities are common among patients with cancer. However, jamaoncology.com
whether or not there is increased risk of mental disorders during the diagnostic workup
leading to a cancer diagnosis was unknown.

OBJECTIVE To examine the relative risks of depression, anxiety, substance abuse,


somatoform/conversion disorder, and stress reaction/adjustment disorder during the periods
before and after cancer diagnosis compared with individuals without cancer.

DESIGN, SETTING, AND PARTICIPANTS Nationwide matched cohort study from January 1,
2001, to December 31, 2010, in a Swedish population and health registers.

MAIN OUTCOMES AND MEASURES We estimated the time-varying hazard ratios (HRs) of the
first clinical diagnosis of the studied mental disorders from 2 years before cancer diagnosis,
through the time of diagnosis, and until 10 years after diagnosis, adjusting for age, sex,
calendar period, and educational level. To assess milder mental conditions and symptoms, we
further assessed the use of related psychiatric medications for patients with cancer
diagnosed during 2008-2009.

RESULTS The study included 304 118 patients with cancer and 3 041 174 cancer-free
individuals who were randomly selected from the Swedish population and individually
matched to the patients with cancer on year of birth and sex. The median age at diagnosis for
the patients with cancer was 69 years, and 46.9% of the patients were female. The relative
rate for all studied mental disorders started to increase from 10 months before cancer
diagnosis (HR, 1.1; 95% CI, 1.1-1.2), peaked during the first week after diagnosis (HR, 6.7;
95% CI, 6.1-7.4), and decreased rapidly thereafter but remained elevated 10 years after
diagnosis (HR, 1.1; 95% CI, 1.1-1.2). The rate elevation was clear for all main cancers except
nonmelanoma skin cancer and was stronger for cancers of poorer prognosis. Compared with
cancer-free individuals, increased use of psychiatric medications was noted from 1 month
before cancer diagnosis and peaked around 3 months after diagnosis among patients with
Author Affiliations: Department of
cancer.
Medical Epidemiology and
Biostatistics, Karolinska Institutet,
CONCLUSIONS AND RELEVANCE Patients diagnosed as having cancer had increased risks of Stockholm, Sweden (Lu, Andersson,
several common mental disorders from the year before diagnosis. These findings support the Hultman, Czene, Valdimarsdóttir,
Fang); Clinical Epidemiology and
existing guidelines of integrating psychological management into cancer care and further call Biostatistics, School of Medical
for extended vigilance for multiple mental disorders starting from the time of the cancer Sciences, Örebro University, Örebro,
diagnostic workup. Sweden (Fall); Faculty of Medicine,
Center of Public Health Sciences,
School of Health Sciences, University
of Iceland, Reykjavík
(Valdimarsdóttir); Department of
Epidemiology, Harvard T. H. Chan
School of Public Health, Boston,
Massachusetts (Valdimarsdóttir).
Corresponding Author: Donghao Lu,
MD, Department of Medical
Epidemiology and Biostatistics,
Karolinska Institutet, Nobels Väg 12A,
JAMA Oncol. doi:10.1001/jamaoncol.2016.0483 PO Box 281, 17177 Stockholm,
Published online April 28, 2016. Sweden (donghao.lu@ki.se).

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Research Original Investigation Mental Disorders Immediately Before and After Cancer Diagnosis

P
atients with cancer are known to have an increased risk
of psychiatric symptoms and disorders,1 cardiovascu- Key Points
lar diseases,2 and suicide.3 Historically, severe comor-
Question Is there increased risk of mental disorders, including
bidities among patients with cancer have largely been attrib- depression, anxiety, substance abuse, somatoform/conversion
uted to the adverse effects of cancer treatments, the complex disorder, and stress reaction/adjustment disorder, temporally
pathophysiology of the underlying malignancy, or simply the associated with the diagnostic workup leading to a cancer
burden of living with a progressing and potentially fatal diagnosis?
disease.4,5 Not only does living with cancer induce severe psy- Findings In this nationwide matched cohort study, highly
chological stress, but being diagnosed as having a cancer is also increased risk of the aforementioned mental disorders was noted
highly stressful. Recently, greatly increased risks of suicide and from 10 months before cancer diagnosis, peaked during the first
cardiovascular events shortly after cancer diagnosis were re- week after diagnosis, and decreased rapidly thereafter but
ported among patients with cancer in different countries, across remained elevated 10 years after diagnosis.
various cancer types, and among both young and adult Meaning Extended vigilance for multiple mental disorders is
patients.6-12 However, these reports likely only represent the needed in cancer care, starting from the time of the cancer
tip of the iceberg for the enormous psychological turmoil re- diagnostic workup.
lated to a newly received cancer diagnosis.
Psychiatric comorbidities, such as depression, anxiety, sub-
stance abuse, somatoform/conversion disorder, and stress re- more than 80% of hospital-based outpatient visits since 2001.
action/adjustment disorder, are common among patients with The Prescribed Drug Register collects information on drugs re-
cancer1,13 and may reflect the broader spectrum of psychologi- deemed with a prescription from all pharmacies in Sweden
cal distress experienced by these patients. Although depres- since July 2005, including prescription, dispensings, and the
sion has been extensively studied,14 evidence is mainly lim- Anatomic Therapeutic Chemical codes.
ited to breast cancer 15 and rarely addressed during the Within the nationwide study base, we subsequently con-
immediate period after a cancer diagnosis.13 Moreover, other ducted a matched cohort study. We first identified 326 404
mental disorders have received less attention.1,13 On the other adult patients (≥18 years old) with a first diagnosis of malig-
hand, although mental disorders are not established risk fac- nancy from January 1, 2001, to December 31, 2009. Cancer
tors for cancer in general,16 some conditions, including addic- cases detected through autopsy were excluded (n = 4221). In
tion to alcohol and tobacco, might lead to higher risk of alcohol- the present study, we defined the 2 years before the date of
related and smoking-related cancers.17 cancer diagnosis as the prediagnostic period, potentially rep-
Most previous related studies are cross-sectional in nature,1 resenting the time window from the emerging prediagnostic
and a longitudinal description of the mental disorder burden cancer symptoms25,26 through the diagnostic workup.27 The
among patients with cancer is lacking to date. Furthermore, period from the date of cancer diagnosis onward was corre-
most clinical and research efforts have addressed the postdi- spondingly defined as the postdiagnostic period.
agnostic period of cancer, focusing on survivorship, the end- Because we aimed to study the effect of the cancer diag-
of-life stage, and, increasingly, the immediate periods after di- nostic workup on newly emerging mental disorders, individu-
agnosis and primary cancer treatment. 1 8 -2 0 However, als with previous psychiatric comorbidities before entry to the
accumulating evidence suggests that the cancer diagnostic cohort (ie, 2 years before the date of diagnosis) were excluded,
workup may also introduce severe psychological distress.21-24 leaving 304 118 patients with cancer in the analysis. We then ran-
Whether or not the diagnostic workup leading to a cancer di- domly selected 10 individuals per patient with cancer from the
agnosis increases the risk of mental disorders is largely un- study base who were free of cancer at the diagnosis date of the
known. To this end, we aimed to investigate risk changes in index patient with cancer (ie, the reference date) and free of psy-
several common and potentially stress-related mental disor- chiatric comorbidities at entry to the cohort (ie, 2 years before
ders from the cancer diagnostic workup to postdiagnosis. the reference date) (n = 3 041 174). Patients with cancer and can-
cer-free individuals were individually matched on year of birth
and sex. All participants were then followed up from 2 years be-
fore the reference date (earliest possible entry on January 1, 1999)
Methods to a first diagnosis of mental disorder, death, emigration, or De-
Study Design cember 31, 2010, whichever came first. Among all cancer-free
Based on the Swedish Population and Housing Census in 1990, individuals, 192 598 (6.3%) developed a cancer after the refer-
we identified all individuals born and living in Sweden in 1990 ence date, and follow-up of these individuals was also cen-
(N = 7 792 012). Using the unique national identification num- sored at the cancer diagnosis. The study was approved by the
bers, we followed up these individuals from January 1, 1991, Central Ethical Review Board in Stockholm, Sweden, which
to December 31, 2010, through cross-linkages to the Swedish waived the requirement of obtaining informed consent from the
Cancer Register, Patient Register, Prescribed Drug Register, study participants.
Cause of Death Register, and Migration Register. The Cancer
Register has been available since 1958 and approaches 100% Cancer Diagnosis
complete data. The Patient Register has collected nationwide According to the Seventh Swedish Revision of the Interna-
information on hospital discharge records since 1987 and on tional Classification of Diseases Codes, we classified cancers into

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Mental Disorders Immediately Before and After Cancer Diagnosis Original Investigation Research

9 subgroups, including prostate, breast (female only), colo-


Figure 1. Hazard Ratios and 95% CIs of Depression, Anxiety,
rectal, lung, nonmelanoma skin, central nervous system (CNS), Substance Abuse, Somatoform/Conversion Disorder,
lymphatic/hematopoietic, severe (pancreatic, hepatic, and and Stress Reaction/Adjustment Disorder Before and After
esophageal), and other cancers (eTable 1 in the Supplement). Cancer Diagnosis in a Matched Cohort Study in Sweden, 1999 to 2010
We obtained information on tumor stage for prostate, breast,
colorectal, and lung cancers from the Cancer Register for pa-
tients diagnosed since 2004 onward. We defined T3/T4/N1-3 10

as locally advanced stage and M1 as distant metastasis.

Hazard Ratio
Mental Disorders
Any first-ever inpatient or outpatient hospital visit with a men-
0.1
tal disorder as one of the registered diagnoses during the follow-
up was identified from the Patient Register using the Tenth Swed-
ish Revision of the International Classification of Disease Codes
(codes F10-F99). As the outcome of interest, we defined a com- –2 –1 0 1 2 3 4 5 6 7 8 9 10
Time Since Diagnosis, y
posite group of the 5 most commonly diagnosed mental disor-
ders among patients with cancer,13 including Tenth Swedish Re-
Hazard ratios were estimated from flexible parametric survival models,
vision of the International Classification of Disease Codes for stress allowing the effect of cancer diagnosis to vary over time. A spline with
reaction/adjustment disorder (code F43), depression (codes F32- 5 df (4 intermediate knots and 2 knots at each boundary, placed at quintiles of
F33), anxiety (codes F40-F41), substance abuse (codes F11-F16 distribution of events) was used for the baseline rate, while 3 df was used for
the time-varying effect. All models were adjusted for sex, age, and calendar
and F18-F19), and somatoform/conversion disorder (codes F44- period at the reference date (2001-2003, 2004-2006, or 2007-2009) as well
F45), which have also been suggested as potentially related to as educational level (high, middle, or low/unknown).
psychological stress.28-30 Because alcohol consumption and to-
bacco use are known risk factors for multiple cancers,31,32 we ex- ard ratios (HRs) and 95% CIs of the mental disorders derived from
cluded alcohol and tobacco abuse or dependence from the group flexible parametric survival models, which allow the HRs to
of substance abuse disorders. change over time.34 Time since cohort entry was used as the un-
To assess the potential importance of differential surveil- derlying timescale. To capture the dramatically increased rates
lance of mental disorders between patients with cancer and around the date of cancer diagnosis, HRs were modeled sepa-
cancer-free individuals, in a sensitivity analysis, we used any rately for the prediagnostic and postdiagnostic periods. Individu-
first-ever inpatient hospital visit with a mental disorder as the als with a mental disorder diagnosed during the prediagnostic
main discharge diagnosis as the outcome of interest, assum- period were excluded from the analysis of the postdiagnostic pe-
ing that differential reporting is less relevant for severer riod (5316 patients with cancer and 37 170 cancer-free individu-
mental conditions. als). The corresponding cancer-free individuals of the 5316
patients were also excluded (n = 52 481). We adjusted for the
Psychiatric Medications matching variables, in addition to educational level, in all sur-
To assess milder mental conditions and symptoms without at- vival models as recommended.35
tended specialist care (not recorded in the Patient Register), we The analysis was further stratified by age, sex, calendar pe-
further assessed the use of psychiatric medications related to the riod, educational level, and region of residence. We sepa-
studied mental disorders, including Anatomic Therapeutic rately analyzed 8 major cancer types and the 4 most common
Chemical codes for antidepressants (code N06A), anxiolytics types, as well as locally advanced and localized cancers along
(code N05B), and hypnotics/sedatives (code N05C) through the with metastatic and nonmetastatic cancers. We further com-
Prescribed Drug Register. For this analysis, we included 68 104 pared cancers of poor prognosis (ie, lung, CNS, and severe can-
patients with cancer and 681 040 cancer-free individuals with cers) with other cancers. Finally, in addition to combining all
a reference date during 2008-2009. These participants were fol- studied mental disorders as one group, we separately as-
lowed up from 2 years before the reference date (earliest possible sessed rate changes of the individual disorders. Given the over-
entry on January 1, 2006) to death, emigration, December 31, all lack of statistical power during the first 6 months of fol-
2011, or 2 years after the reference date, whichever came first. low-up (mainly due to few individuals with a newly diagnosed
We defined current use of the studied medications as previously mental disorder among patients with cancer), we focused on
described.33 Briefly, we defined current use of antidepressants the period from 18 months before cancer diagnosis onward in
or anxiolytics as the 4 months after each prescription claim, these subgroup analyses.
whereas we defined current use of hypnotics/sedatives as the 10 In addition to the aforementioned relative measure-
days after each prescription claim. ments, we calculated the absolute risks of these mental dis-
orders among both patients with cancer and their matched can-
Statistical Analysis cer-free individuals by plotting cumulative incidence curves
In the primary analysis, we investigated the rate of mental dis- for the individual disorders. Competing risk models were ap-
orders from 2 years before diagnosis (year −2), through the date plied for the postdiagnostic period to control for higher mor-
of diagnosis, to 10 years after diagnosis (year 10). Given a gener- tality rates among patients with cancer compared with their
ally violated proportional hazards assumption, we estimated haz- cancer-free counterparts after diagnosis.

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Research Original Investigation Mental Disorders Immediately Before and After Cancer Diagnosis

Table. Hazard Ratios and 95% CIs of Depression, Anxiety, Substance Abuse, Somatoform/Conversion Disorder, and Stress Reaction/Adjustment
Disorder Before and After Cancer Diagnosis, According to Age, Sex, Calendar Period, Educational Level, and Region of Residence, in a Matched Cohort
Study in Sweden, 1999 to 2010a

Time in Relation to Diagnosis


−1 y −1 y −0.5 y 1 wk 0.5 y 1y 2y 3y 5y 7y 10 y
Overall 0.9 0.9 1.8 6.7 2.9 2.2 1.6 1.4 1.3 1.2 1.1
(0.9-1.0) (0.9-1.0) (1.7-1.9) (6.1-7.4) (2.8-3.0) (2.1-2.2) (1.5-1.7) (1.4-1.5) (1.3-1.4) (1.2-1.3) (1.1-1.2)
Age at Diagnosis, y
15-39 0.9 0.9 1.7 7.4 3.2 2.4 1.7 1.6 1.6 1.5 1.5
(0.7-1.1) (0.7-1.1) (1.4-2.0) (5.0-10.8) (2.8-3.7) (2.1-2.7) (1.5-2.0) (1.4-1.8) (1.4-1.8) (1.3-1.9) (1.2-1.9)
40-49 0.8 0.8 1.9 8.1 3.8 2.9 2.1 1.7 1.3 1.2 1.0
(0.6-1.0) (0.6-1.1) (1.6-2.2) (5.9-11.2) (3.4-4.3) (2.6-3.2) (1.8-2.3) (1.5-1.9) (1.2-1.5) (1.0-1.4) (0.8-1.3)
50-54 1.3 1.1 2.1 9.4 3.7 2.7 1.9 1.6 1.3 1.2 1.0
(1.0-1.7) (0.9-1.5) (1.8-2.5) (6.9-12.7) (3.3-4.2) (2.4-3.0) (1.6-2.1) (1.4-1.8) (1.1-1.5) (0.9-1.4) (0.8-1.3)
55-59 1.0 0.9 1.9 8.9 3.8 2.8 2.0 1.7 1.5 1.4 1.3
(0.8-1.2) (0.7-1.1) (1.6-2.2) (6.7-11.8) (3.4-4.3) (2.6-3.1) (1.8-2.2) (1.5-1.9) (1.3-1.7) (1.2-1.7) (1.1-1.6)
60-64 1.1 1.1 1.9 7.3 3.9 2.9 2.1 1.7 1.5 1.4 1.2
(0.9-1.4) (0.9-1.3) (1.7-2.2) (5.7-9.4) (3.5-4.3) (2.7-3.2) (1.9-2.3) (1.6-1.9) (1.3-1.7) (1.2-1.6) (1.0-1.5)
65-69 1.0 1.1 2.0 7.7 3.4 2.5 1.7 1.5 1.4 1.3 1.2
(0.8-1.2) (0.8-1.3) (1.8-2.3) (5.8-10.2) (3.0-3.7) (2.3-2.7) (1.6-1.9) (1.4-1.7) (1.3-1.5) (1.1-1.5) (1.0-1.5)
70-74 1.0 0.9 1.8 9.0 2.8 2.1 1.5 1.3 1.2 1.1 1.0
(0.8-1.2) (0.7-1.1) (1.6-2.1) (6.6-12.2) (2.6-3.1) (1.9-2.3) (1.4-1.7) (1.2-1.5) (1.1-1.3) (1.0-1.3) (0.8-1.2)
75-79 0.9 0.7 1.8 5.3 2.5 1.9 1.4 1.2 1.2 1.2 1.1
(0.7-1.1) (0.6-0.9) (1.6-2.0) (4.1-7.0) (2.2-2.7) (1.7-2.0) (1.2-1.5) (1.1-1.4) (1.1-1.3) (1.0-1.4) (0.9-1.4)
80-84 1.0 0.9 1.7 5.1 1.7 1.4 1.1 1.1 1.1 1.1 1.1
(0.8-1.2) (0.8-1.1) (1.5-1.9) (3.9-6.7) (1.6-1.9) (1.2-1.5) (1.0-1.2) (1.0-1.2) (1.0-1.2) (0.9-1.3) (0.9-1.4)
85-105 0.8 0.9 1.5 3.3 1.4 1.2 1.1 1.1 1.1 1.2 1.2
(0.7-1.0) (0.7-1.1) (1.4-1.7) (2.4-4.5) (1.2-1.6) (1.0-1.3) (0.9-1.2) (1.0-1.2) (1.0-1.4) (0.9-1.5) (0.9-1.7)
Sex
Male 0.9 0.9 1.7 5.4 2.5 2.0 1.6 1.5 1.4 1.3 1.2
(0.8-1.0) (0.8-1.0) (1.6-1.8) (4.6-6.3) (2.4-2.7) (1.9-2.1) (1.5-1.7) (1.4-1.5) (1.3-1.5) (1.2-1.4) (1.1-1.4)
Female 1.0 1.0 1.9 7.6 3.1 2.3 1.6 1.4 1.3 1.2 1.0
(0.9-1.1) (0.9-1.1) (1.8-2.0) (6.8-8.6) (2.9-3.2) (2.2-2.3) (1.5-1.7) (1.3-1.5) (1.2-1.3) (1.1-1.2) (1.0-1.1)
Calendar Period at Diagnosis
2001-2003 0.9 0.9 1.9 7.2 2.6 2.1 1.6 1.5 1.3 1.2 1.1
(0.8-1.1) (0.7-1.1) (1.7-2.1) (6.1-8.5) (2.5-2.8) (2.0-2.2) (1.6-1.7) (1.4-1.5) (1.2-1.3) (1.1-1.3) (1.0-1.2)
2004-2006 0.9 0.9 1.9 6.5 2.8 2.1 1.5 1.3 1.3 1.3 1.2
(0.8-1.0) (0.8-1.0) (1.8-2.0) (5.5-7.6) (2.6-2.9) (2.0-2.2) (1.4-1.6) (1.3-1.4) (1.2-1.4) (1.1-1.4) (1.0-1.3)
2007-2009 1.0 0.9 1.7 6.2 3.1 2.2 1.7 1.6 1.3 1.2 1.0
(0.9-1.1) (0.9-1.0) (1.6-1.8) (5.3-7.4) (2.9-3.3) (2.1-2.4) (1.6-1.8) (1.4-1.7) (1.1-1.5) (1.0-1.4) (0.8-1.3)
Educational Level
High 1.1 0.9 1.7 7.9 3.5 2.6 1.9 1.6 1.4 1.2 1.1
(0.9-1.3) (0.8-1.1) (1.5-1.9) (6.5-9.7) (3.3-3.8) (2.5-2.8) (1.7-2.0) (1.5-1.7) (1.3-1.5) (1.1-1.4) (1.0-1.3)
Middle 0.9 0.9 1.8 7.1 3.0 2.2 1.6 1.4 1.4 1.3 1.2
(0.8-1.0) (0.8-1.0) (1.7-1.9) (6.2-8.2) (2.8-3.1) (2.1-2.3) (1.5-1.7) (1.4-1.5) (1.3-1.4) (1.2-1.4) (1.1-1.3)
Low 0.9 0.9 1.9 5.7 2.4 1.9 1.4 1.3 1.2 1.2 1.1
(0.8-1.0) (0.8-1.0) (1.8-2.0) (4.9-6.6) (2.3-2.6) (1.8-2.0) (1.4-1.5) (1.2-1.4) (1.2-1.3) (1.1-1.3) (1.0-1.2)
Unknown 0.9 1.2 1.4 5.7 1.4 1.4 1.5 1.6 1.7 1.7 1.7
(0.5-1.6) (0.7-2.1) (0.9-2.2) (2.4-13.2) (1.0-2.0) (1.0-2.0) (1.0-2.2) (1.2-2.2) (1.1-2.5) (1.0-2.9) (0.9-3.5)
Region of Residence
Northern 0.9 0.9 1.7 6.6 2.5 1.9 1.5 1.3 1.2 1.2 1.1
(0.8-1.1) (0.8-1.0) (1.6-1.9) (5.5-7.8) (2.3-2.7) (1.8-2.0) (1.4-1.6) (1.2-1.4) (1.1-1.3) (1.1-1.3) (1.0-1.2)
Central 0.9 0.9 1.8 7.2 3.0 2.2 1.6 1.4 1.4 1.3 1.2
(0.9-1.0) (0.8-1.0) (1.7-1.9) (6.4-8.1) (2.8-3.1) (2.1-2.3) (1.5-1.7) (1.4-1.5) (1.3-1.4) (1.2-1.4) (1.1-1.3)
Southern 0.9 0.9 1.7 4.8 2.9 2.3 1.7 1.5 1.3 1.1 1.0
(0.8-1.1) (0.8-1.1) (1.5-1.9) (3.7-6.2) (2.6-3.2) (2.1-2.5) (1.6-1.9) (1.4-1.6) (1.1-1.4) (1.0-1.3) (0.8-1.2)
a
Hazard ratios at each time point were estimated from flexible parametric 2007-2009) as well as educational level (high, middle, or low/unknown). The
survival models, allowing the effect of cancer diagnosis to vary over time. A highest educational level was retrieved from the Swedish Education Register
spline with 5 df (4 intermediate knots and 2 knots at each boundary, placed at and classified into high (college and above), middle (9 years plus 2-3 years of
quintiles of distribution of events) was used for the baseline rate, while 3 df high school), low (<9 years), or unknown. The region of residence was
was used for the time-varying effect. All models were adjusted for sex, age, identified through the Swedish Population and Housing Census in 1990 and
and calendar period at the reference date (2001-2003, 2004-2006, or classified into northern, central, and southern Sweden.

In the secondary analysis, we calculated the proportions correction for multiple testing, the differences in current use
for current use of any of the studied psychiatric medications on a daily basis between patients with cancer and cancer-free
as well as specific medications from 18 months before cancer individuals were examined using the χ2 test. Analyses were per-
diagnosis to 2 years after cancer diagnosis. After Bonferroni formed using statistical software (SAS, version 9.4; SAS

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Mental Disorders Immediately Before and After Cancer Diagnosis Original Investigation Research

Figure 2. Hazard Ratios and 95% CIs of Depression, Anxiety, Substance Abuse, Somatoform/Conversion Disorder, and Stress Reaction/Adjustment
Disorder Before and After Cancer Diagnosis, by Cancer Types, in a Matched Cohort Study in Sweden, 1999 to 2010

Prostate Breast (female only) Colorectal

10 10 10
Hazard Ratio

Hazard Ratio

Hazard Ratio
0.1 0.1 0.1

–2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10
Time Since Diagnosis, y Time Since Diagnosis, y Time Since Diagnosis, y

Lung Nonmelanoma skin CNS

10 10 10
Hazard Ratio

Hazard Ratio

Hazard Ratio
0.1 0.1 0.1

–2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10
Time Since Diagnosis, y Time Since Diagnosis, y Time Since Diagnosis, y

Lymphatic/hematopoietic Severe Other

10 10 10
Hazard Ratio

Hazard Ratio

Hazard Ratio
0.1 0.1 0.1

–2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10
Time Since Diagnosis, y Time Since Diagnosis, y Time Since Diagnosis, y

Hazard ratios were estimated from flexible parametric survival models, allowing esophageal cancers. All models were adjusted for sex, age, and calendar period
the effect of cancer diagnosis to vary over time. A spline with 5 df (4 at the reference date (2001-2003, 2004-2006, or 2007-2009) as well as
intermediate knots and 2 knots at each boundary, placed at quintiles of educational level (high, middle, or low/unknown). CNS indicates central nervous
distribution of events) was used for the baseline rate, while 3 df was used for system.
the time-varying effect. Severe cancer includes pancreatic, hepatic, and

Institute and Stata, version 13.1; StataCorp LP). P < .05 indi- The rate increase immediately before and after cancer di-
cated statistical significance. agnosis was greater among women compared with men (Table).
Younger and better-educated patients had higher HRs after di-
agnosis but not before diagnosis compared with older and less-
educated patients.
Results Largely similar results were observed for all major cancer
The median age at diagnosis for the patients with cancer was types except nonmelanoma skin cancer (Figure 2). The rate in-
69 years, and 46.9% of the patients were female (eTable 1 in crease was greater for cancers of poor prognosis both before and
the Supplement). In total, we identified 3355 patients and after diagnosis compared with other cancers (P < .001 for both).
10 296 patients with a new diagnosis of the studied mental dis- Patients with locally advanced or metastatic cancers had no fur-
orders during the prediagnostic period and the postdiagnos- ther increased rate compared with patients with localized or non-
tic period, respectively. metastatic cancers either before or after diagnosis (eTable 2 in
The overall relative rate of mental disorders started to in- the Supplement). However, toward the end of follow-up, patients
crease from 10 months before cancer diagnosis (HR, 1.1; 95% with locally advanced cancer and those with metastatic breast
CI, 1.1-1.2) and peaked during the week after diagnosis and lung cancers had greater rate increases than the others.
(Figure 1). Although the magnitude of the rate increase de- Largely similar results were also observed for all indi-
creased rapidly thereafter, the rate remained elevated by year vidual mental disorders studied (Figure 3). The magnitude of
10. Using only the main diagnosis of inpatient care as the defi- the rate elevation was comparable before cancer diagnosis
nition for mental disorders (19.9% of all diagnoses) barely across all disorders, whereas the highest rate increase was
changed the temporal pattern, although the magnitude of the noted for stress reaction/adjustment disorder immediately
rate increase dropped slightly (eFigure 1 in the Supplement). after cancer diagnosis.

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Research Original Investigation Mental Disorders Immediately Before and After Cancer Diagnosis

Figure 3. Hazard Ratios and 95% CIs of Individual Mental Disorders Before and After Cancer Diagnosis in a Matched Cohort Study in Sweden,
1999 to 2010

Stress reaction/adjustment disorder Depression Anxiety

10 10 10
Hazard Ratio

Hazard Ratio

Hazard Ratio
0.1 0.1 0.1

–2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10
Time Since Diagnosis, y Time Since Diagnosis, y Time Since Diagnosis, y

Substance abuse Somatoform/conversion disorder

10 10
Hazard Ratio

Hazard Ratio

0.1 0.1

–2 –1 0 1 2 3 4 5 6 7 8 9 10 –2 –1 0 1 2 3 4 5 6 7 8 9 10
Time Since Diagnosis, y Time Since Diagnosis, y

Hazard ratios were estimated from flexible parametric survival models, the time-varying effect. All models were adjusted for sex, age, and calendar
allowing the effect of cancer diagnosis to vary over time. A spline with period at the reference date (2001-2003, 2004-2006, or 2007-2009) as well
5 df (4 intermediate knots and 2 knots at each boundary, placed at quintiles of as educational level (high, middle, or low/unknown). Alcohol and tobacco abuse
distribution of events) was used for the baseline rate, while 3 df was used for or dependence was excluded from the group of substance abuse disorders.

Among patients with cancer, depression had the highest during the year before and the year after diagnosis. The dra-
cumulative incidence during the study, followed by anxiety and matic risk increases noted immediately after cancer diagno-
stress reaction/adjustment disorder (eFigure 2 in the Supple- sis corroborate with previous findings on highly increased risks
ment). Compared with cancer-free individuals, patients with of cardiovascular diseases and suicide right after cancer
cancer had higher cumulative incidences of most mental dis- diagnosis,6-12 whereas the clearly elevated risks during the year
orders except somatoform/conversion disorder. before diagnosis may suggest the effect of prediagnostic can-
Increased use of psychiatric medications was noted from cer symptoms as well as the severe stress of undergoing clini-
1 month before cancer diagnosis (12.2% vs 11.7%, corrected cal evaluation for a suspected malignancy.
P = .04), peaked around 3 months after diagnosis (18.1% vs To a varying extent, there was a similar pattern of risk el-
11.9%, corrected P < .001), and decreased slowly thereafter but evation for most cancer types, with the smallest (if any) risk
remained elevated 2 years after diagnosis (15.4% vs 12.7%, cor- increase observed for nonmelanoma skin cancer. Patients with
rected P < .001) (Figure 4). Increased use was most pro- prostate cancer also had smaller risk elevation compared with
nounced for lung, CNS, and severe cancers, whereas no in- other cancers both before and after diagnosis, likely as a re-
creased use was noted for nonmelanoma skin cancer. Findings sult of increasing knowledge about the disease and its per-
of specific psychiatric medications were similar (eFigure 3 in ceived benign prognosis in the general population.36 How-
the Supplement). ever, no clear variation was noted between either locally
advanced and localized cancers or between metastatic and non-
metastatic cancers until the end of the first year after diagno-
sis, when patients having the same cancers were compared
Discussion with each other. This pattern lends support to the view that,
To the best of our knowledge, our study represents the first during the diagnostic workup, the experience of psychologi-
and largest study to date estimating the burden and its tem- cal distress does not highly correlate with the severity of a ma-
poral pattern of mental disorders that are potentially related lignancy, which seems to be in line with previous findings that
to psychological stress among adult patients with cancer dur- the prevalence of depression and psychological distress did not
ing the prediagnostic to postdiagnostic periods. In line with differ greatly by tumor stage.1 However, the slightly greater risk
previous studies,1,13 we showed that anxiety and stress reac- increase among patients with locally advanced cancer
tion/adjustment disorder were also common among patients beyond 1 year after diagnosis might indicate a direct effect of
with cancer, in addition to depression. Most important, pa- the disease course, treatment adverse effects, and disease cop-
tients with cancer had dramatically increased risks of depres- ing after the primary cancer treatment.
sion, anxiety, stress reaction/adjustment disorder, and sub- In Sweden, the waiting times during the cancer diagnos-
stance abuse (excluding alcohol and tobacco abuse or tic workup vary greatly across cancer types. In 2011, the
dependence), as well as somatoform/conversion disorder, both median intervals between the first referral to a specialist for

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Mental Disorders Immediately Before and After Cancer Diagnosis Original Investigation Research

Figure 4. Use of Antidepressants, Anxiolytics, and Hypnotics/Sedatives Before and After Cancer Diagnosis, by Cancer Types, in a Matched Cohort
Study in Sweden, 2006 to 2011

Overall Prostate Breast (female only)


40 40 40
Use of Psychiatric

Use of Psychiatric

Use of Psychiatric
Cancer
Medications, %

Medications, %

Medications, %
30 30 30
Cancer free
20 20 20

10 10 10

0 0 0
–1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0
Time Since Diagnosis, y Time Since Diagnosis, y Time Since Diagnosis, y

Colorectal Lung Nonmelanoma skin


40 40 40
Use of Psychiatric

Use of Psychiatric

Use of Psychiatric
Medications, %

Medications, %

Medications, %
30 30 30

20 20 20

10 10 10

0 0 0
–1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0
Time Since Diagnosis, y Time Since Diagnosis, y Time Since Diagnosis, y

CNS Lymphatic/hematopoietic Severe


40 40 40
Use of Psychiatric

Use of Psychiatric

Use of Psychiatric
Medications, %

Medications, %

Medications, %
30 30 30

20 20 20

10 10 10

0 0 0
–1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0
Time Since Diagnosis, y Time Since Diagnosis, y Time Since Diagnosis, y

Solid lines and scatters represent the percentages of medication use among a daily basis between patients with cancer and cancer-free individuals (P < .05
patients with cancer, whereas dashed lines represent use among cancer-free corrected for multiple testing). Severe cancer includes pancreatic, hepatic, and
individuals. Lines were plotted using locally weighted scatterplot smoothing. esophageal cancers. CNS indicates central nervous system.
The spike plots indicate a statistically significant difference in medication use on

cancer evaluation and the final diagnosis were 11 to 12 days the fact that no clear risk increase was noted within the sec-
for colorectal cancer and 76 to 82 days for nonmetastatic ond year before cancer diagnosis suggests that patients with
prostate cancer.27 The process from the first symptom onset cancer did not have a higher risk of mental disorders at
or the first health care contact to the final diagnosis is pre- baseline.
sumably much longer.27 Although data are scant, a growing One limitation of our study is the use of clinical diagno-
body of evidence suggests that the workup for a suspected ses through inpatient and outpatient specialist care as the
cancer, regardless of the eventual diagnosis result, clearly outcome measurement, which likely represented only more
affects health and well-being, particularly in terms of the severe demonstrations of the studied mental disorders. The
psychosocial spheres of function. 22, 2 4,37 Such effect is similar temporal pattern (but larger magnitude) of increased
believed to be transient among individuals receiving an ini- use of psychiatric medications further implies the effect of
tial clear result (ie, no evidence of cancer), whereas it is more cancer diagnosis on both severe and milder mental condi-
persistent among individuals eventually diagnosed as hav- tions. Therefore, taking together both clinical diagnoses and
ing a malignancy.21 medication use likely depicts the entire extent of mental
The start of risk increase for the studied mental disor- burden around the time of cancer diagnosis, highlighting the
ders around 10 months before cancer diagnosis may likely clinical significance of our findings. However, because the
suggest a debut of cancer symptoms at a population level, in studied medications are not exclusively prescribed for men-
line with earlier reported increased sickness absence before tal disorders or symptoms, future studies should specify the
cancer diagnosis.26 Besides the potential effect of psycho- underlying reasons for prescription of such medications.
logical stress experienced during the diagnostic workup, Register diagnoses of depression, anxiety, substance abuse,
prediagnostic cancer symptoms26 and paraneoplastic syn- and stress reaction/adjustment disorder have been shown to
drome (eg, anemia25) may also contribute to the increased be of good quality in general.38-41 The validity of conversion
risk of mental disorders and increased use of psychiatric disorder diagnosis might remain a concern. Because it is rare
medications during the prediagnostic period. By contrast, (5% of all somatoform/conversion disorders), results of

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Research Original Investigation Mental Disorders Immediately Before and After Cancer Diagnosis

somatoform/conversion disorder stayed unchanged after ex- spectively and independently collected information on both
cluding conversion disorder. cancer and mental disorders, our study has minimal selec-
We had no information on the exact time course of can- tion and information biases. The use of flexible parametric
cer diagnosis and were unable to disentangle whether the reg- models further enabled us to investigate the temporal pat-
istered date of diagnosis coincided with the date when the pa- tern of risk increase in mental disorders around the time of can-
tient was informed about the diagnosis. Therefore, further cer diagnosis.
studies with detailed information on the cancer diagnostic
workup are warranted. Although our findings highlight the im-
portance of a timely psychological intervention throughout the
cancer diagnosis, it remains to be explored whether or not such
Conclusions
intervention should be specifically tailored for patients with Patients recently diagnosed as having cancer experience dra-
cancer compared with individuals without such life- matically increased risks of several potentially stress-related
threatening conditions. Finally, the generalizability of the mental disorders both immediately before and after cancer di-
present findings in more recent periods or other populations agnosis. Our findings support the existing guidelines of inte-
needs to be investigated. grating psychological management into cancer care42 and call
A major strength of our study is the large-scale, population- for extended vigilance for multiple mental disorders starting
based cohort design and the complete follow-up. Given the pro- from the time of the cancer diagnostic workup.

ARTICLE INFORMATION settings: a meta-analysis of 94 interview-based cancer across major tumor entities. J Clin Oncol.
Accepted for Publication: February 15, 2016. studies. Lancet Oncol. 2011;12(2):160-174. 2014;32(31):3540-3546.

Published Online: April 28, 2016. 2. Hampton T. Cancer therapy can be hard on the 14. Walker J, Holm Hansen C, Martin P, et al.
doi:10.1001/jamaoncol.2016.0483. heart: researchers aim to explain—and Prevalence of depression in adults with cancer:
avoid—cardiotoxicity. JAMA. 2010;303(11):1019-1020. a systematic review. Ann Oncol. 2013;24(4):895-900.
Author Contributions: Drs Lu and Fang had full
access to all the data in the study and take 3. Anguiano L, Mayer DK, Piven ML, Rosenstein D. 15. Suppli NP, Johansen C, Christensen J,
responsibility for the integrity of the data and the A literature review of suicide in cancer patients. Kessing LV, Kroman N, Dalton SO. Increased risk for
accuracy of the data analysis. Cancer Nurs. 2012;35(4):E14-E26. doi:10.1097/NCC depression after breast cancer: a nationwide
Study concept and design: Lu, Andersson, Fall, .0b013e31822fc76c. population-based cohort study of associated
Valdimarsdóttir, Fang. 4. Ganz PA. Monitoring the physical health of factors in Denmark, 1998-2011. J Clin Oncol. 2014;
Acquisition, analysis, or interpretation of data: Lu, cancer survivors: a survivorship-focused medical 32(34):3831-3839.
Andersson, Fang. history. J Clin Oncol. 2006;24(32):5105-5111. 16. Osborn DP, Levy G, Nazareth I, Petersen I,
Drafting of the manuscript: Lu, Fang. 5. Hewitt M, Rowland JH. Mental health service use Islam A, King MB. Relative risk of cardiovascular and
Critical revision of the manuscript for important among adult cancer survivors: analyses of the cancer mortality in people with severe mental
intellectual content: All authors. National Health Interview Survey. J Clin Oncol. illness from the United Kingdom’s General Practice
Statistical analysis: Lu, Andersson. 2002;20(23):4581-4590. Research Database. Arch Gen Psychiatry. 2007;64
Obtained funding: Hultman, Czene, Fang. (2):242-249.
Administrative, technical, or material support: 6. Fall K, Fang F, Mucci LA, et al. Immediate risk for
cardiovascular events and suicide following a 17. Muirhead L. Cancer risk factors among adults
Hultman, Czene, Fang. with serious mental illness. Am J Prev Med. 2014;46
Study supervision: Fang. prostate cancer diagnosis: prospective cohort
study. PLoS Med. 2009;6(12):e1000197. (3)(suppl 1):S98-S103.
Conflict of Interest Disclosures: None reported. doi:10.1371/journal.pmed.1000197. 18. Mitchell AJ, Ferguson DW, Gill J, Paul J,
Funding/Support: This work was supported by 7. Fang F, Keating NL, Mucci LA, et al. Immediate Symonds P. Depression and anxiety in long-term
grant CAN 2014/417 from the Swedish Cancer risk of suicide and cardiovascular death after a cancer survivors compared with spouses and
Society; by grant 2012-0498 from the Swedish prostate cancer diagnosis: cohort study in the healthy controls: a systematic review and
Research Council for Health, Working Life and United States. J Natl Cancer Inst. 2010;102(5): meta-analysis. Lancet Oncol. 2013;14(8):721-732.
Welfare; by partial new doctoral student financing 307-314. 19. Williams K, Jackson SE, Beeken RJ, Steptoe A,
from the Karolinska Institutet (Dr Lu); and by the Wardle J. The impact of a cancer diagnosis on
Swedish Society for Medical Research and a 8. Fang F, Fall K, Mittleman MA, et al. Suicide and
cardiovascular death after a cancer diagnosis. health and well-being: a prospective,
research associate award from the Karolinska population-based study [published online October
Institutet (Dr Fang). N Engl J Med. 2012;366(14):1310-1318.
1, 2015]. Psychooncology.
Role of the Funder/Sponsor: The funding sources 9. Lu D, Fall K, Sparén P, et al. Suicide and suicide
attempt after a cancer diagnosis among young 20. Bidstrup PE, Christensen J, Mertz BG,
had no role in the design and conduct of the study; Rottmann N, Dalton SO, Johansen C. Trajectories of
collection, management, analysis, and individuals. Ann Oncol. 2013;24(12):3112-3117.
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interpretation of the data; preparation, review, or 10. Urban D, Rao A, Bressel M, Neiger D, Solomon with breast cancer: looking beyond the mean. Acta
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