Psychoneuroendocrinology 115 (2020) 104634

Contents lists available at ScienceDirect

Psychoneuroendocrinology
journal homepage: www.elsevier.com/locate/psyneuen

Rx risk or resistance? Psychotropic medication use in relation to T

physiological and psychosocial functioning of psychiatric hospital workers
Philippe Kerra,b,c,d, Sonia Lupienb,c,d, Robert-Paul Justera,c,d,*
a
Center on Sex⁎Gender, Allostasis, and Resilience, Montréal, Québec, Canada
b
Center for Studies on Human Stress, Montréal, Québec, Canada
c
Department of Psychiatry and Addictology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
d
Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal, Montréal, Quebec, Canada

A R T I C LE I N FO A B S T R A C T

Keywords: To avoid methodological biases, psychoneuroendocrine studies have generally excluded psychotropic medica-
Cortisol tion users. In workplace stress research, this has limited our ability to understand how psychotropic medication
Allostatic load use affects many stress-related measures of interest. In this exploratory study, the effects of psychotropic
Occupational stress medication use on stress physiology, occupational stress, and mental health were measured in a sample of
Psychotropic medication use
healthy adult psychiatric hospital workers (N = 203, 70 % women). Diurnal cortisol was assessed on two non-
Depression
consecutive work-days at five time-points (e.g., awakening, thirty minutes after awakening, 2 P M, 4 P M and
bedtime). Cortisol reactivity was assessed by exposing participants to the Trier Social Stress Test. An allostatic
load index was constructed using 19 neuroendocrine, immune, cardiovascular, and metabolic biomarkers.
Occupational stress (e.g., job strain, effort-reward imbalance) and psychiatric symptoms (e.g., depression,
burnout) were assessed with well-validated self-reports. Results showed that psychotropic medication use had no
significant effects on diurnal cortisol profiles; however, psychotropic users had significantly decreased cortisol
reactivity to the Trier Social Stress Test and higher allostatic load. Psychotropic users also had decreased effort-
reward imbalance, but not job strain. Depressive symptoms did not differ between psychotropic medications
users and non-users; however, burnout symptoms were higher among psychotropic medication users than non-
users. Taken together, our findings do not warrant the systematic exclusion of psychotropic medication users
from psychoneuroendocrine studies if insights into individual differences are sought among workers and other
populations exposed to elevated stress.

1. Introduction physiological and psychosocial functioning is critical to improve health

Economic globalization has changed workplaces worldwide and
contributed to heightened occupational stress in workers, exposing this
population to increased risk of developing stress-related diseases and
subsequent psychotropic medication use (Siegrist, 2016; Milner et al.,
2019). Indeed, antidepressant use has significantly increased world-
wide (OECD, 2013; Steinhausen, 2015). For example, antidepressant
prescription rates have increased by 353 % between the years 1980 and
2000 in Canada (Hemels et al., 2002), where 34 % of workers report
occupational stressors as their primary cause of mental health invalidity
(Howatt, 2017). Depression and burnout are among the most prevalent
causes for leave of absence in Canadian workplaces (Howatt, 2017).
Psychotropic medications are often used for treatment of these condi-
tions (Beck et al., 2005). As such, understanding their effects on
outcomes (Subramaniam et al., 2019).
Two theoretical models of occupational stress have been studied
extensively in relation to health outcomes. First, the Job Demands
Control Support model (Karasek and Theorell, 1990) defines job strain as
a result of chronic exposures to aversive psychosocial work conditions
(e.g., high job demands, low decisional latitude, low social support).
Second, the Effort-Reward Imbalance model (Siegrist, 1996) posits that a
lack of reciprocity between individual- and work-related characteristics
leads to occupational stress. Namely, effortful work that provides lim-
ited rewards will result in chronic stress (Siegrist, 1996). Higher job
strain and greater effort-reward imbalance have been associated with
increased severity of depressive symptoms (Nieuwenhuijsen et al.,
2010; Theorell et al., 2015; Rugulies et al., 2017; Madsen et al., 20177),
burnout symptoms (Marchand et al., 2016; Maslach and Leiter, 2016;

⁎
Corresponding author at: Department of Psychiatry and Addiction, Faculty of Medicine, Université de Montréal, Centre de recherche de l’Institut universitaire en
santé mentale de Montréal, 7331 Hochelaga Street, H1N 3V2, Montréal, Québec, Canada.
E-mail address: robert-paul.juster@umontreal.ca (R.-P. Juster).

https://doi.org/10.1016/j.psyneuen.2020.104634
Received 4 July 2019; Received in revised form 26 February 2020; Accepted 26 February 2020
0306-4530/ © 2020 Elsevier Ltd. All rights reserved.
P. Kerr, et al.
Aronsson et al., 2017) and increased likelihood of using psychotropic
medications (for a review, see Milner et al., 2019).
Chronic stress affects physical and mental health through changes in
physiological functioning (McEwen, 2003; De Kloet et al., 2005; Lupien
et al., 2009; Juster et al., 2011). This implicates the hypothalamic-pi-
tuitary-adrenal-axis (HPA-axis) release of the stress hormone cortisol in
response to psychosocial stress (Mason, 1968; Dickerson and Kemeny,
2004) as well as diurnal variation in cortisol (Kirschbaum and
Hellhammer, 1989; Pruessner et al., 1997). Both abnormal diurnal and
stress reactive HPA-axis responses have been reported in chronically
stressed workers (Pruessner et al., 1999; Steptoe et al., 2004; Chida and
Steptoe, 2009; Chandola et al., 2010; Marchand et al., 2014a, b; De
Vente et al., 2015; Marchand et al., 2016; Eddy et al., 2018). Moreover,
altered HPA-axis function has also been implicated in the aetiology of
depression and burnout (De Kloet et al., 2005; Juster et al., 2011; Zorn
et al., 2017). Therefore, pharmacological interventions that target HPA-
axis function have yielded promising results for the treatment of these
disabling psychiatric conditions (Anacker et al., 2011; Pariante et al.,
2012; Menke, 2019; Fischer et al., 2017; Subramaniam et al., 2019).
Chronic HPA-axis activations can exert cumulative physiological
strain that ultimately disrupt neuroendocrine, immune, cardiovascular
and metabolic processes in a process called allostatic load (McEwen and
Stellar, 1993). AL refers to the ‘wear and tear’ that chronic stress exerts
on the brain and body in synergy with unhealthy behaviors (McEwen,
1998). The allostatic load framework has been applied to the study of
occupational stress and mental health using a count-based index that
incorporates multiple biomarkers (for a review, see Mauss et al., 2014,
2015; Bellingrath et al., 2009; Ali et al., 2016; Juster et al., 2016a;
Carlsson et al., 2017; Juster et al., 2018; Esser et al., 2019; Juster et al.,
2019). As such, elevated allostatic load has been associated with both
depressive and burnout symptoms (Koertge, 2003; Grossi et al., 2003;
Toker et al., 2005; Juster et al., 2011). Collectively, studies of allostatic
load often include HPA-axis indicators to help tease apart depression
and burnout, two conditions that bear much symptom overlap (Juster
et al., 2011).
To ensure methodological rigor, however, psychoneuroendocrine
studies of stress have adopted strict inclusion criterion to avoid con-
founding effects of substances that can generate interference in bioas-
says (Talge et al., 2005; Stalder et al., 2016; Van Hedger et al., 2017; for
a review, see Zänkert et al., 2018). This often includes antidepressant
use, as it may alter subjective experiences of stress, cortisol synthesis/
enzymatic degradation processes, or saliva composition which in turn
influence salivary cortisol concentrations (Granger et al., 2009). In
general, this has led to the exclusion of psychotropic medication users
from this area of investigation, which ultimately eliminates their re-
presentation in much health research. We believe that research must
include psychotropic users to better explain how pharmacological
treatments may contribute to psychosocial functioning through their
effects on stress physiology.
Past studies have shown decreases in systemic diurnal cortisol
output following antidepressant treatment, which were in turn corre-
lated with decreases in depressive symptoms among patients with
major depressive disorder (for a review, see Subramaniam et al., 2019).
Indeed, psychiatric symptoms and psychotropic medication use emerge
from complex interactions between aversive psychosocial work condi-
tions and changes in physiological functioning that result from chronic
occupational stress (Eddy et al., 2016; Bellingrath and Kudielka, 2016;
Eddy et al., 2017, 2018; Milner et al., 2019). However, we know of no
studies that have jointly assessed the effects antidepressant use on HPA-
axis function, allostatic load, mental health and other indicators of
psychosocial functioning in the workplace, such as job strain or effort-
reward imbalance. Also, while medication use is a common covariate in
allostatic load studies (for a review, see Juster et al., 2010), no study
has explored their effect on allostatic load.
Increases in drug prescriptions worldwide suggest that psychotropic
medication use has become common place in specific populations, such
2
Psychoneuroendocrinology 115 (2020) 104634
as children, adolescents and young adults (Wong et al., 2004; Hibel
et al., 2006, 2007; Steinhausen, 2015; Pratt et al., 2017). If psycho-
tropic medication use is also common in the workplace, studies that
exclude psychotropic medication users may limit generalizability of
results to a substantial sub-population. Furthermore, this raises ethical
questions regarding methodological practices that preclude psycho-
tropic medication users from participating in health research. Exclusion
of psychotropic medication users from workplace studies of stress
physiology has left an important gap in our knowledge of psychotropic
users’ HPA-axis, allostatic load, and psychosocial functioning more
broadly.
1.1. Exploratory aims
Past studies have focused on individual- and work-related en-
vironmental factors that lead to depression, burnout, and psychotropic
medication use (Marchand et al., 2014a, b; Theorell et al., 2015; Juster
et al., 2011; Marchand et al., 2010; Marchand et al., 2016; Milner et al.,
2019). What has been overlooked, however, are the processes whereby
psychotropic medication use affects physiological stress responses and
occupational stress in workers who may experience psychiatric symp-
toms but remain at work. Our previous publications using this sample
have focused on sex and gender modulation of the HPA-axis, allostatic
load, and mental health (Juster et al., 2016a, b; Juster et al., 2018).
However, we did not explore the effects of psychotropic medication use.
Given the potential confounding effects of sex and age in this sample,
these variables were set as our a priori control variables in the current
secondary analysis that aimed to explore effects related to psychotropic
medication use.
2. Materials and methods
2.1. Participants
This exploratory analysis used secondary data from a larger study
assessing sex- and gender-based variation in stress physiology in a
sample of psychiatric hospital workers (Juster et al., 2016a, b; Juster
et al., 2018). Participant recruitment was facilitated through use of
large banners, intranet advertisement, face-to-face visits to hospital
units and word of mouth. Prospective participants were instructed to
contact the laboratory for a 15-minute phone interview before sche-
duling appointments. From an initial pool of 295 participants, our final
sample distribution was composed of healthy adult psychiatric workers
(N = 204; 70 % women) aged between 18–72 years old (M=40.39,
SD = 12.14). Participants all worked at the Montreal University Mental
Health Institute, the largest French psychiatric hospital in the Canadian
province of Quebec (Juster et al., 2016a, b; Juster et al., 2018). One
participant was excluded from statistical analyses as they simulta-
neously reported using topical glucocorticoids and showed marginally
higher levels of depressive symptoms (+3.49 SD). As a result, our final
sample was comprised of 203 healthy adult psychiatric hospital
workers.
In the early phases of recruitment for this study, individuals who
reported psychotropic medication use were excluded. However, when
our study began, we observed that approximately 25 % of prospective
participants were psychotropic medication users. We therefore
amended our ethics research protocol in order to include these in-
dividuals that would otherwise not have been represented. As such, we
wish to be transparent in stating that our decision to include partici-
pants on psychotropic medication use was done to facilitate recruitment
of a much larger proportion of psychotropic medication users than what
was originally anticipated. The Canadian Community Health Survey
shows that the prevalence of psychotropic medication use is 7.2 % in
the general population; however, prevalence can reach 19.3 % for in-
dividuals with a lifetime diagnosis of a mental health disorder (Beck
et al., 2005).
P. Kerr, et al.
2.2. Psychotropic medication classification
Research assistants inquired about psychotropic medication use
during screening procedures. When psychotropic medication use was
reported, participants provided any additional information that was
available on prescription labels, such as Anatomical Therapeutic
Chemical (ATC) code, International non-proprietary names (INN) and
daily drug dosage (DDD). Psychotropic medication category was as-
cribed following recommendations of the Anatomical Therapeutic
Chemical and Daily Drug Dosage (ATC/DDD) system of the World
Health Organization (WHO) Collaborating Centre for Drug Statistics
Methodology (https://www.whocc.no/atc_ddd_index/).
Participants reported using anxiolytic (N05B) (n=2), hypnotic/se-
dative (N05C) (n=2), non-opioid analgesic (N02B) (n = 1), gluco-
corticoid (H02A) (n = 1) and antidepressant (N06A) (n = 31) medica-
tion codes. A proportion of psychotropic users were on both
antidepressants and anxiolytics (n = 7). Preliminary analyses did not
warrant the exclusion of users of N05B and N05C medication codes nor
poly-medicated individuals. Therefore, psychotropic medication use
was binary coded, resulting in psychotropic medication users (n=41)
and non-users (n=162).
2.3. Physiological stress assessment
2.3.1. Diurnal cortisol
Participants were given kits and instructions for saliva collection.
Participants were instructed to provide samples at 5 time-points
(awakening, 30 min after awakening, 2 P M, 4 P M and bedtime) to as-
sess diurnal cortisol profiles that were defined as the average of two
non-consecutive workdays (Juster et al., 2016a, b).
2.3.2. Time compliance
Participants recorded sampling times themselves with logbooks and
their adherence to scheduled collection time was monitored using the
Medication Event Monitoring System (MEMS™, AARDEX Ltd., Sion,
Switzerland). The MEMS cap registers times and dates when the closure
is opened with a micro-electronic circuit. Once opened, tubes were
retrieved, filled with saliva until 2 ml was attained, and then stored in a
plastic bag and then refrigerated. A MEMS Reader USB Serial number
10,959 was used to record information when returned to our laboratory
and compiled using Powerview software. MEMS compliance deviation
was calculated as the sum absolute difference in minutes for both
weekdays between the actual sampling time according to MEMS re-
cordings and the scheduled sampling time for pre-determined time-
points +30 min after awakening, 14h00, and 16h00.
Both AM and PM minutes deviation were summed (M =49.58 min,
SE = 5.65) for use as a covariate in our main analysis. Diurnal cortisol
time-points for the two sampling days were averaged to maximize
generalizability. This was justified as reliability among diurnal cortisol
time points were acceptable when controlling for MEMS compliance
deviation with partial correlations ranging from r = .43 to 0.61. Main
analyses of diurnal cortisol also controlled for mean awakening time
(M = 6:59:57, SE = 0:05:12).
2.3.3. Cortisol reactivity
During a first afternoon visit, participants were exposed to the Trier
Social Stress Test (TSST) (Kirschbaum et al., 1993). Participants arrived
at the laboratory between 12 PM and 7 PM to control for cortisol cir-
cadian rhythms. Six saliva samples were collected in 10-minute incre-
ments (−30, −20, −10, 0, 10, 20 and 30 min) throughout the TSST
protocol in order to assess HPA-axis reactivity (Kirschbaum et al.,
1993).
2.3.4. Cortisol assay information
Assays were conducted at the Saliva Laboratory of the Center for
Studies on Human Stress. For both diurnal cortisol and cortisol
3
Psychoneuroendocrinology 115 (2020) 104634
reactivity, sterilized 5 ml 57 × 15.3 mm screw cap tubes (Sarstedt®,
Item No. 62.558.201) were used to collect 2 ml of saliva guided with
thick straws. Tubes had 34.9 × 12.7 mm cryogenic labels and 11 mm
circular cryogenic labels of different colors to designate different time-
points and different hormones so as to help guide participants, as re-
ported elsewhere (Juster et al., 2016b). Frozen samples were brought to
room temperature and centrifuged at 1500×g (3000 RPM) for 15 min.
All assays were run in duplicates and averaged. High-sensitivity enzyme
immunoassays were used for cortisol analysis (Salimetrics®, No. 1-
3102, sensitivity: 0.012−3 μg/dl).
2.3.5. Allostatic load
Repeated measures of cortisol allowed us to assess cortisol reactivity
and diurnal cortisol variation that were summarized using time-de-
pendent formula and then incorporated into our allostatic load index.
For reactive cortisol, our six measurements of cortisol were transformed
using the area under the curve with respect to ground formula (AUCg)
(Pruessner et al., 2003). Likewise, heart rate AUCg, systolic blood
pressure AUCg, and diastolic blood pressure AUCg were used based on
four cardiovascular recordings obtained throughout the TSST session.
For diurnal cortisol, we calculated two values representing the diurnal
cortisol awakening response (difference between +30 min after awa-
kening and awakening cortisol levels) (Stadler et al., 2016) and diurnal
cortisol bedtime based on the average for two non-consecutive work-
days reported in detail elsewhere (Juster et al., 2016a, b; Juster et al.,
2018).
After a 12 -h fasting, a licensed nurse extracted 44 ml of blood from
participants during their second visit. Serum dehydroepiandrosterone-
sulphate, C-reactive protein, albumin, creatinine, glycosylated he-
moglobin, total cholesterol, high-density lipoprotein, and triglycerides
were assayed at the local hospital. Serum insulin and fibrinogen levels
were shipped and assayed at Maisonneuve-Rosemont Hospital
(Montreal, Canada). Interleukin-6 was assayed in isolated plasma at the
Center for Studies on Human Stress.
Our allostatic load index was calculated using 19 biomarkers (see
Table 2) representing neuroendocrine, immune, cardiovascular and
metabolic biological systems. As a rule, we used clinical cut-offs for
biomarkers that had clinical cut-offs and the sample’s distribution for
biomarkers that did not have clinical cut-offs. For those biomarkers
with clinical cut-offs, the 75th percentile was used for biomarkers in
which high levels are dangerous, the 25th percentile was used for
biomarkers in which low levels are dangerous. For those biomarkers
where clinical cut-offs existed, we used both one-tailed or two-tailed
percentiles based on our sample as previously done (Seplaki et al.,
2005). In this manner, both the 12.5th and 87.5th percentiles were used
for biomarkers in which both hypoactive and hyperactive functioning is
considered potentially dangerous. Biomarkers attaining these critical
cut-offs were ascribed a score of “1,” whereas those in a healthy range
were ascribed a score of “0”. In sum, the allostatic load index represents
the number of dysregulated biomarkers for each individual that could
theoretically range from 0-19.
2.4. Psychosocial measures
2.4.1. Job content questionnaire
The 26-item Karasek Job Content Questionnaire (JCQ; Karasek
et al., 1998) was administered to assess psychosocial work conditions
using three scales: psychological demands, decisional latitude, and so-
cial support. All items were scored on a 4-point Likert scale ranging
from ‘1; Strongly Disagree’ to ‘4; Strongly Agree’ in accord to statements
such as ‘My job allows me to make a lot of decisions on my own’. Original
psychometrics of the JCQ revealed high test-retest reliability (r=0.59-
0.74) and adequate to high internal consistency (α = 0.69-0.83) for
subscales, which were similar in our sample (α = 0.71).
P. Kerr, et al.
2.4.2. Effort-reward imbalance at work questionnaire
The 17-item Effort-Reward Imbalance at Work Questionnaire (ERI;
Siegrist et al., 2004) was administered to assess ratios between efforts
and rewards in the workplace using three subscales: efforts, rewards
and overcommitment. All items were scored on a 5-point Likert scale
ranging from ‘1; Disagree’ to ‘5; Agree and I am very distressed’ in accord
to statements such as ‘I have constant time pressure due to a heavy
workload’. Original psychometrics of the ERI revealed acceptable test-
retest reliability (r = 0.60-0.44) in a one-year interval and high internal
consistency (α > 0.70), which were similar in our sample (α = 0.82).
2.4.3. Beck depression inventory - II
The 21-item Beck Depression Inventory II (BDI-II; Beck et al., 1996)
was administered to assess depressive symptoms. All items were scored
using a 4-point Likert scale ranging from 0 to 3 in accord to statements
(e.g., I feel sad) within the last 2 weeks. Original psychometrics re-
vealed high test-retest reliability (r = 0.93) and internal consistency
(α = 0.91), which were identical in our sample (α = 0.91).
2.4.4. Maslach burnout inventory
The 16-item Maslach Burnout Inventory General Survey (MBI-GS;
Schaufeli, 1996) was administered to assess burnout symptoms on three
scales: exhaustion, cynicism and personal accomplishment. All items
were scored on a 7-point Likert scale ranging from 0 to 6 in accord to
statements (e.g., I feel drained by my work). Original psychometrics for
subscales revealed high test-retest reliability (r = 0.72) and high in-
ternal consistency (α = 0.89) through all subscales. Our sample showed
lower but nonetheless acceptable internal consistency (α = 0.72).
2.5. Data management and statistical analyses
Statistical analyses were done using IBM® SPSS® 25 software. The
proportion of missing data for all variables included in our analyses
ranged between 2.4 % and 10.6 %. Specifically, proportion of missing
data was distributed as follows: diurnal cortisol (9.2 %), reactive cor-
tisol (2.4 %), allostatic load (1.4 %), job demands (8.2 %), decisional
latitude (7.7 %), social support (8.2 %), efforts (8.2 %), rewards (8.2
%), overcommitment (8.2 %), depressive symptoms (10.6 %) and
burnout symptoms (8.2 %).
Because of their important modulating effects on our study out-
comes all analyses were adjusted for age and sex (Juster et al., 2013,
2016a; Juster et al., 2016b). Repeated measures analysis of covariance
(RM-ANCOVA) were used to investigate between-group differences in
diurnal cortisol and reactive cortisol profiles. For analyses of diurnal
cortisol, participant awakening time and a sampling time deviation
score were included as covariates to control for circadian rhythms and
to maximize measurement objectivity. Greenhouse-Geisser corrections
were used when assumptions of sphericity were violated. Univariate
analysis of variance (ANOVA) were performed to investigate between-
group differences in allostatic load, occupational stress (JCQ, ERI) and
mental health (BDI-II, MBI) among psychotropic medication users and
non-users. Because physiological stress responses, occupational stress
and mental health vary by age and sex, all analyses adjusted for age and
sex (Juster et al., 2013).
3. Results
3.1. Sociodemographic characteristics
Sociodemographic characteristics did not differ importantly be-
tween psychotropic medication users and non-users (see Table 1).
However, it should be noted that psychotropic medication users were
more likely to be women, to endorse higher feminine gender-roles or to
suffer from and/or have received a prescription for a physical health
condition. Psychotropic medication users were also more likely to have
a family or personal psychiatric history and to have experienced a sick
4
Psychoneuroendocrinology 115 (2020) 104634
leave during their lives.
3.2. Stress physiology and psychotropic medication use
3.2.1. Diurnal cortisol
Diurnal cortisol profiles did not differ between psychotropic medi-
cation users and non-users (F(1,179) = 0.46, p = 0.50, η2p = 0.003) (see
Fig. 1A). However, we found a significant covariation effect of time for
diurnal cortisol x awakening time (F(4, 2,277) = 3.791, p = 0.019,
η2p = 0.021).
3.2.2. Reactive cortisol
Relative to non-users, psychotropic medication users showed sig-
nificantly decreased cortisol reactivity throughout the TSST
(F(1,197) = 7.40, p=0.007, η2p = 0.036). A multivariate analysis of
covariance corrected with Bonferroni adjustment for multiple com-
parisons revealed significant group effects - that is, psychotropic med-
ication users and non-users’ did not significantly differ at TSST baseline
(p=0.112), but they did thereafter (p = 0.01 – 0.029, η2p = 0.013
-0.034) (see Fig. 1B). We found a covariation effect for sex
(F(1,197) = 4.070, p=0.045, η2p = 0.020). That is, men showed sig-
nificantly higher reactivity throughout the TSST in comparison to
women (F(1,199) = 6.092, p = 0.014, η2p = 0.030).
3.2.3. Allostatic load
Psychotropic medication users showed significantly higher allostatic
load when compared to non-users (F(1,199) = 3.91, p = 0.049,
η2p = 0.019) (see Fig. 1C). We found a covariation effect of age
(F(1,199) = 23.83, p < 0.001, η2p = 0.107). As such, age was positively
correlated with allostatic load (r=0.321, p < 0.001).
3.3. Occupational stress and psychotropic medication use
3.3.1. Job control-demands-support
Psychological demands, decisional latitude or social support did not
differ between psychotropic medication users and non-users (p > 0.41)
(see Fig. 2A-B-C). We found covariation effects of age for psychological
demands (F(1,184) = 5.25, p=0.023, η2p = 0.028) and social support
(F(1,184) = 4.65, p=0.032, η2p = 0.025). That is, age was positively
correlated with psychological demands (r = 0.16, p=0.026) and ne-
gatively correlated with social support (r=−0.15, p=−0.046).
3.3.2. Effort-reward imbalance
Our analyses revealed that psychotropic medication users and non-
users did not differ for efforts (p=0.687); however, psychotropic
medication users reported higher rewards (F(1,185) = 8.03, p=0.005,
η2p = 0.042) and lower levels of overcommitment (F(1,185) = 4.79,
p=0.030, η2p = 0.025) (see Fig. 2D-E-F). We found covariation effects
of age for efforts (F(1,185) = 16.18, p < 0.001, η2p = 0.080) and over-
commitment (F(1,185) = 5.73, p=0.018, η2p = 0.030). Here, age was
positively correlated with efforts (r=0.28, p < 0.001) and over-
commitment (r = 0.16, p=0.023) (Fig. 2)
3.4. Mental health and psychotropic medication use
3.4.1. Depressive symptoms
Our analyses revealed that psychotropic medication users and non-
users did not differ in depressive symptom severity (p = 0.163)
(Fig. 3A).
3.4.2. Burnout symptoms
Our analyses revealed that relative to non-users, psychotropic
medication users showed significantly higher burnout symptoms
(F(1,185) = 4.04, p=0.046, η2p = 0.021) (Fig. 3B).
P. Kerr, et al. Psychoneuroendocrinology 115 (2020) 104634

Table 1
Sociodemographic characteristics.
Information All Non-medicated Medicated p
N 203 162 41 –

Sex, Gender, and Sexual Orientation

Sex, woman, % 70.6 66.6 85.4 .013
Bem masculine gender-roles, M (SE)A 4.63 (0.04) 4.70 (0.05) 4.38 (0.10) .004
Bem feminine gender-roles, M (SE)A 5.31 (0.31) 5.26 (0.09) 5.49 (0.07) .003
Kinsey sexual orientation, M (SE)B 0.32 (0.08) 0.34 (0.10) 0.24 (0.16) .613
Demographics
Age, M (SE) 40.4 (0.85) 40.31 (0.99) 41.00 (1.63) .746
Socio-economics
Working hours per week, M (SE) 34.7 (0.58) 34.66 (0.69) 34.81 (0.93) .914
Education, years schooling M (SE) 16.5 (0.23) 16.5 (0.27) 16.4 (0.44) .885
Civil status
Partnered, % 55.2 58.3 54.5 .641
Parenthood, number of children, M (SE) 0.98 (0.08) 0.95 (0.89) 1.10 (0.18) .455
Parents with children living at home, % 64.3 48.7 24.3 .162
Health behaviors
Caffeine beverages per day, M (SE) 1.64 (0.11) 1.62 (0.13) 1.68 (0.18) .829
Tobacco smokers, % 16.3 15.4 19.5 .337
Alcohol consumers, % 68.6 66.7 69.2 .718
Alcohol Use Disorders Identification Test, M (SE) 4.28 (0.28) 4.44 (0.33) 3.63 (0.50) .258
Illicit drug use, % 7.4 8.6 2.4 .152
Drug Abuse Screening Test, M (SE) 0.30 (0.05) 0.32 (0.06) 0.19 (0.10) .308
Physical and mental health
Physical health condition(s)
None, % 56.7 58.0 51.2 .086
1, % 29.5 30.9 24.4 .086
≥ 2, % 13.8 11.1 24.4 .086
Medication(s) for physical conditions
None, % 54.7 58.6 39.0 .006
1, % 31.0 30.9 31.7 .006
≥ 2, % 14.3 10.5 29.3 .006
Psychiatric history
Past history, % 18.2 12.9 39.0 < .001
Family history, % 29.1 35.2 4.9 < .001
Both past and family history, % 16.7 8.6 48.8 < .001
Past psychiatric sick leave, % 34.0 21.0 85.3 < .001
Psychiatric symptoms
Beck Depression Inventory-II, M (SE) 7.28 (0.57) 6.82 (0.60) 9.13 (1.51) .102
Maslach Burnout Inventory, M (SE) 25.49 (0.83) 24.61 (0.92) 28.98 (1.85) .035

A
Bem (1981).
B
Kinsey (1948).

4. Discussion appears like psychotropic medication users are demonstrating some

The objective of our exploratory study was to investigate the effects
of psychotropic medication use on HPA-axis function, allostatic load,
occupational stress and mental health in a sample of psychiatric hos-
pital workers. Contrary to excluding psychotropic medication users, the
main findings of our exploratory study show that psychotropic medi-
cation use is related to distinct physiological and psychosocial profiles
of methodological significance to our field.
Our main finding shows that psychotropic medication users exhibit
decreased cortisol reactivity throughout the TSST in comparison to non-
users. This result is consistent with the literature demonstrating that
glucocorticoid secretion is dampened by serotoninergic down-regula-
tion (Holsboer and Barden, 1996). Psychotropic medication use may
also alter subjective experiences to environmental events and have ef-
fects on physiological stress reactivity (Granger et al., 2009). While
some authors have suggested that blunted cortisol reactivity consists of
an adaptive biological coping mechanism that precludes harmful effects
of chronic HPA-axis activations on health, others have argued that this
may be equally detrimental to health as potentiated cortisol reactivity
(Wekenborg et al., 2019). Indeed, chronic exposure to glucocorticoids
leads to impaired glucocorticoid receptor signaling resulting in dis-
turbed negative feedback inhibition of the HPA-axis (Anacker et al.,
2011), while altered physiological stress reactivity is found in various
psychopathologies (Burke et al., 2005). While our exploratory study’s
cross-sectional design does not allow interpretation of directionality, it
form of resistance in their HPA-axis stress reactivity.
By contrast, diurnal cortisol profiles did not differ between psy-
chotropic medication users and non-users. Existing literature shows
dysregulated glucocorticoid receptor function in 80 % of patients with
major depressive disorders, resulting in impaired negative feedback
inhibition of the HPA-axis (Heuser et al., 1994; Anacker et al., 2011).
However, antidepressant treatment may regulate how cortisol affects
the brain (Pariante et al., 2004), hence contributing in improving glu-
cocorticoid receptor signalling that restores HPA-axis function in pa-
tients with major depressive disorder (Anacker et al., 2011; Pariante
et al., 2012). While purely speculative, psychotropic medication users
may have shown diurnal cortisol profiles that were similar to those of
non-users because of the effects that pharmacological treatment exert
on physiological stress responses. As such, this may have restored their
negative feedback inhibition of the HPA-axis and normalization of
diurnal cortisol rhythmicity (Anacker et al., 2011; McKay and Zakzanis,
2010; Subramaniam et al., 2019).
Glucocorticoid receptor signalling is more prominent in HPA-axis
reactivity versus mineralocorticoid receptor signalling which is further
involved in regulating HPA-axis circadian rhythmicity (Wilkinson and
Brown, 2015). Moreover, upregulation of mineralocorticoid receptors
has also been associated with improved cognitive function in patients
with major depressive disorder (de Kloet et al., 2016; Otte et al., 2015).
Differences in pharmacological effects on glucocorticoid (reactivity
endophenotype) versus mineralocorticoid (diurnal endophenotype)

5
P. Kerr, et al. Psychoneuroendocrinology 115 (2020) 104634

Table 2 disorders (Ising et al., 2019). Nevertheless, both impaired glucocorti-

Empirical and clinical biomarker cut-points for allostatic load index formula- coid and mineralocorticoid receptor signalling have been implicated in
tion. depression and more studies are required to discuss their role in the
Biomarkers (Unit) Cut-Off(s) etiology of various psychopathologies, including depression and
burnout (Anacker et al., 2011; de Kloet et al., 2016; Subramaniam et al.,
Neuroendocrine functioning 2019).
Cortisol, diurnal CAR (μg/dl, M difference) > .072 or < -.020
Psychotropic medication users showed significantly higher allostatic
Cortisol, diurnal bedtime (μg/dl, M) > .233 or < .047
Cortisol, TSST systemic output (AUCg) > 13.83 or < 3.85 load. We speculate that elevated allostatic load in psychotropic medi-
Dehydroepiandrosterone-sulphate (μmol/L) > 3.5 cation users could have been driven by physiological changes that op-
Immune/inflammation erated as a result of pharmacological treatment or perhaps even vice-
Interleukin-6 (pg/mL) > 1.88
versa. In the context of severe mental illness, changes in allostatic load
C-reactive protein (mg/L) > 3.75
Fibrinogen (g/L) > 4.62
brought on by medication has been referred to as pharmacological al-
Lipid metabolism lostatic load by our group (Bizik et al., 2013). That is, psychotropic
Triglycerides (mmol/L) > 1.4 medication’s mechanisms can impact a variety of allostatic processes
Total cholesterol (mmol/L) > 4.4 including cortisol reactivity, immune function, metabolic regulation,
High density lipoprotein cholesterol (mmol/L) < 1.18
and unhealthy behaviors (Bizik et al., 2013). As a result, psychotropic
Glucose metabolism
Insulin (pmol/L) > 120.25 medication use may be effective acutely for clinical symptom treat-
Glycosylated hemoglobin (%) > .057 ment; however, chronic psychotropic medication use could inad-
Renal and liver functioning vertently induce deleterious effects that can negatively contribute to
Creatinine (μmol/L) > 96.0
comorbidities (Bizik et al., 2013) and multi-morbidities (Juster et al.,
Albumin (g/L) < 38.75
Cardiovascular functioning
2016c). Unfortunately, directionality cannot be inferred from our cross-
Heart rate, TSST systemic output (AUCg) < 3147.5 or > sectional design, as elevated allostatic load could also have predisposed
4402.5 chronically stressed workers to psychotropic medication use. Further-
Systolic blood pressure, TSST systemic output (AUCg) < 5466.25 or > more, the temporality of psychotropic medication use could not be
6962.5
assessed nor was duration of use measured in our exploratory study.
Diastolic blood pressure, TSST systemic output < 3397.5 or >
(AUCg) 4461.25
Anthropometric
Waist-hip ratio (ratio) > .95 4.1. Methodological and ethical implications
Body mass index (kg/m2) > 30.34

Our findings underline the need to study the effects of psychotropic

medication use on HPA-axis function (Subramaniam et al., 2019). For
receptors may point to different structural and functional neuroendo-
example, understanding the effects of psychotropic medication use on
crine mechanisms that modulate risk and/or resilience to affective
stress physiology may provide new leads for the development of
disorders, such as depression and burnout. For example, glucocorticoid
pharmacological treatments that target the HPA-axis (Anacker et al.,
receptors are found ubiquitously in the brain, while a higher density of
2011; Ising et al., 2019; Menke, 2019; Subramaniam et al., 2019).
mineralocorticoids are found in limbic regions of the brain (Wilkinson
Importantly, in studies that take interest in populations where psy-
and Brown, 2015). Unfortunately, our cross-sectional study design has
chotropic medication use is common, it would be unethical to exclude
limited information on medication dosages and time of use warrants
participants on this basis. Looking towards the future, we recommend
further empirical investigation of these differential receptor mechan-
that investigators systematically monitor (e.g., active ingredient,
isms.
chronicity, dosage, washout) and integrate psychotropic medication use
Exposure to chronic stress and antidepressant use may exert sy-
as a variable in studies of HPA-axis function (Granger et al., 2009;
nergistic effects that alter physiological stress responses (McEwen,
Subramaniam et al., 2019).
1998; Bizik et al., 2013). That is, both affect the expression of genetic
Psychotropic medication use is of particular relevance in the context
factors that regulate glucocorticoid receptor availability and function in
of occupational stress research (for a review, see Milner et al., 2019).
the brain (Anacker et al., 2011; Ventura-Juncá et al., 2014; Turecki and
Whether psychotropic medication use may alleviate physiological or
Meaney, 2016; Fischer et al., 2017; Ising et al., 2019). Among others, a
psychosocial strain in workers who report psychiatric symptoms, but
recent study showed that increased expression of FK506-binding pro-
remain in the workplace functioning, has been completely overlooked.
tein 51 (FKBP51), an important genetic modulator of glucocorticoid
With regards to job strain, JDCS factors did not differ as a function of
receptor signalling, was associated with impaired HPA-axis function
psychotropic medication use. This suggests that psychotropic medica-
(Ising et al., 2019). Decreased FKBP51 expression was not associated
tion use was effective in alleviating depressive symptoms in this sample.
with restored HPA-axis function but was in turn found to predict anti-
In addition, depressive symptom alleviation may also include allevia-
depressant treatment response in patients with major depressive
tion of negative cognitive biases towards one’s psychosocial work

Fig. 1. Stress physiology and psychotropic medication use.

6
P. Kerr, et al.
Fig. 2. Occupational stress and psychotropic medication use.
environment (JDCS, ERI) following pharmacological treatment. While
purely speculative, this is partially supported by the absence of differ-
ences in depressive symptoms among psychotropic medication user and
non-users. Despite reporting similar levels of occupational efforts,
psychotropic medication users reported higher rewards and less over-
commitment in comparison to non-users, which is also in line with a
symptom alleviation perspective. More precisely, this suggests that
psychotropic medication use may diminish the severity of psychiatric
symptoms that are experienced by workers and therefore lower feelings
of overcommitment. Notwithstanding, the fact that psychotropic med-
ication users experience less overcommitment is a perplexing finding
that we can only interpret as potentially related to remediation or some
other unmeasured phenomena.
4.2. Clinical and psychometric implications
As previously mentioned, we found no significant group differences
in depressive symptoms between psychotropic medication users and
non-users. By contrast, differences in burnout symptoms were sig-
nificant between users and non-users. Whether depression and burnout
represent distinct psychiatric entities is still controversial (Bianchi
et al., 2015). However, our findings are in line with literature demon-
strating that symptom overlap is associated with symptom severity
Fig. 3. Mental health and psychotropic medication use.
7
Psychoneuroendocrinology 115 (2020) 104634
(Ahola et al., 2005). According to the World Health Organization’s In-
ternational Classification of Disease 11, burnout is recognized as an
occupational syndrome, but not a medical condition per se (World
Health Organization, 2018). To date, burnout is not yet recognized as a
condition in North American diagnostic assessment methods.
4.3. Limitations and future directions
Several limitations warrant discussion. As a study of psychiatric
hospital workers recruited from the same hospital, our results could
have been influenced by a selection bias induced by our recruitment
procedures. Note that individuals who did not participate were not lost
due to exclusion criteria per se (Juster et al., 2016a). Moreover, our
results could have been influenced by a lop-sided sex-distribution in our
sample (e.g., 70 % women). However, these proportions are re-
presentative of this specific psychiatric hospital’s occupational context
(68 % women) and are not likely to have influenced our results, as sex
was included as a covariate in all our analyses. It should also be noted
that familywise error rate was not controlled for across the reported
statistical analyses. Given the exploratory nature of our study using
secondary data from a same sample (Juster et al., 2016a, b; Juster et al.,
2018), we chose to limit risks of type II error rather than applying strict
multiple comparison corrections to our analyses (Perneger, 1998;
P. Kerr, et al.
Nakagawa, 2004). As such, results from our exploratory study are
preliminary and we therefore encourage replication.
The proportion of individuals who reported psychotropic medica-
tion use was high compared to other studies measuring prevalence of
psychotropic medication use in Canadian workers (6.2 %) (Marchand
and Blanc, 2010). This is possibly due to the specific occupational
context of psychiatric hospitals, where women represent the majority of
the distribution of workers. Importantly, women are more likely to be
diagnosed with depression and prescribed antidepressants than men
(Marchand and Blanc, 2010). This may influence generalizability to
other occupational contexts. Also, a skewed distribution of psychotropic
medication use in our sample could have made our results vulnerable to
artificially inflated statistical differences. To ensure this was not the
case, only a minimal number of covariates were included in our ana-
lyses. Nevertheless, our findings of covariation effects of age and sex
suggests that pathways linking psychotropic medication use to altered
physiological stress responses, occupational stress and mental health
may differ among working men and women of diverse age strata (Juster
et al., 2013). However, additional studies are required to better explain
their relation to our study outcomes and psychotropic medication use.
Our exploratory study used a cross-sectional design which limits our
capacity to discern causality. Also, even if most psychotropic medica-
tion users reported using selective-serotonin reuptake inhibitors, binary
coding of psychotropic medication use limits our capacity to account
for variability in active ingredients, action mechanisms, and pharma-
cokinetics for each molecule and complicates dosage comparison be-
tween these substances. However, past studies suggest that while these
parameters differ between antidepressant types, they have similar ef-
fects on stress physiology which are in turn associated with decreased
severity of symptoms (for a review, see Subramaniam et al., 2019).
Nevertheless, we encourage future studies to monitor psychotropic
medication use with available systematic assessment methods (Granger
et al., 2009).
Given the exploratory nature of this secondary analysis from a study
that had a broader objective, three key factors could not be measured in
this study. First, participant awakening time and time of diurnal cortisol
sampling could not be assessed with more objective tools (e.g., heart
rate, Actimeters). In spite of this, we did minimize possible self-report
bias by assessing a MEMS deviation score and participant awakening
time as covariates in statistical analyses of diurnal cortisol. Second, no
information was available on how long workers had been on anti-
depressant treatment. This is important because antidepressants exert
pharmacogenetic effects that alter neuroendocrine function over time
(Anacker et al., 2011; Bizik et al., 2013; Ising et al., 2019; Subramaniam
et al., 2019). Lastly, current non-users with a history of psychiatric
leave may have also been treated with psychotropic medication in the
past. In this sense, future studies should also monitor medication
washout periods and history of use in more detail.
4.4. Conclusion
Including psychotropic medication users in stress research is critical
to better understand their effects on biopsychosocial functioning of
populations exposed to elevated stress. Our findings provide grounds
for further investigation of these mechanisms. In addition to this, much
more research needs to be done to tease apart the complex pathophy-
siological interactions that lead to distinct adverse mental health tra-
jectories for depression and burnout, respectively. This should help
shed further light on potential physiological mechanisms that should be
targeted to develop better pharmacological treatments for depression
and burnout.
Ethical statement
This study was approved by the local Research Ethics Board and was
conducted in accordance with the Declaration of Helsinki. All
8
Psychoneuroendocrinology 115 (2020) 104634
participants provided written and informed consent prior to enroll-
ment.
Role of the Funding Source
This study was supported by the Canadian Institutes of Health
Research (CIHR) Institute of Gender and Health (Grant No. 222055)
awarded to S.J. Lupien (Principal Investigator), E. Kouassi and A.
Lesage. S.J. Lupien held a senior investigator chair on Gender and
Mental Health from the CIHR Institute of Gender and Health (Grant No.
GSC 91039). R.P. Juster held a doctoral scholarship from the CIHR
Institute of Aging (Grant No. SIA 95402), support from the Research
Team on Work and Mental Health (ERTSM) and received support from
a CIHR Frederick Banting Postdoctoral Award. PK received salary
support from a CIHR Foundation Operating Grant (Grant No.
FDN143282) awarded to S.J. Lupien (Principal Investigator) and the
Institut universitaire en santé mentale de Montréal Foundation be-
stowed to R. P. Juster. SL now holds the Canada's Research Chair on
Human Stress.
CRediT authorship contribution statement
Philippe Kerr: Data curation, Formal analysis, Visualization,
Writing - original draft. Sonia Lupien: Conceptualization, Funding
acquisition, Supervision, Writing - review & editing. Robert-Paul
Juster: Conceptualization, Formal analysis, Project administration,
Validation, Funding acquisition, Methodology, Supervision, Writing -
review & editing.
Declaration of Competing Interest
The authors report no conflicts of interest.
Acknowledgements
We thank Alain Marchand for his expertise and guidance.
References
Ahola, K., Honkonen, T., Isometsä, E., Kalimo, R., Nykyri, E., Aromaa, A., Lönnqvist, J.,
2005. The relationship between job-related burnout and depressive dis-
orders—results from the Finnish Health 2000 Study. J. Affect. Disord. 88 (1), 55–62.
Ali, O.S., Badawy, N., Rizk, S., Gomaa, H., Saleh, M.S., 2016. Allostatic load assessment
for early detection of stress in the workplace in Egypt. Open Access Maced. J. Med.
Sci. 4 (3), 493.
Anacker, C., Zunszain, P.A., Carvalho, L.A., Pariante, C.M., 2011. The glucocorticoid
receptor: pivot of depression and of antidepressant treatment?
Psychoneuroendocrinology 36 (3), 415–425.
Aronsson, G., Theorell, T., Grape, T., Hammarström, A., Hogstedt, C., Marteinsdottir, I.,
et al., 2017. A systematic review including meta-analysis of work environment and
burnout symptoms. BMC Public Health 17 (1), 264.
Beck, A.T., Steer, R.A., Brown, G.K., 1996. Beck depression inventory-II. San Antonio 78
(2), 490–498.
Beck, C.A., Williams, J.V., Wang, J.L., Kassam, A., El-Guebaly, N., Currie, S.R., et al.,
2005. Psychotropic medication use in Canada. Can. J. Psychiatry 50 (10), 605–613.
Bellingrath, S., Kudielka, B.M., 2016. Psychobiological pathways from work stress to
reduced health: naturalistic and experimental studies on the ERI model. Work Stress
and Health in a Globalized Economy. Springer, Cham, pp. 145–170.
Bellingrath, S., Weigl, T., Kudielka, B.M., 2009. Chronic work stress and exhaustion is
associated with higher allostastic load in female school teachers: original research
report. Stress 12 (1), 37–48.
Bem, S.L., 1981. Bem sex-role inventory. Professional Manual.
Bianchi, R., Schonfeld, I.S., Laurent, E., 2015. Burnout–depression overlap: a review. Clin.
Psychol. Rev. 36, 28–41.
Bizik, G., Picard, M., Nijjar, R., Tourjman, V., McEwen, B.S., Lupien, S.J., Juster, R.P.,
2013. Allostatic load as a tool for monitoring physiological dysregulations and co-
morbidities in patients with severe mental illnesses. Harv. Rev. Psychiatry 21 (6),
296–313.
Burke, H.M., Davis, M.C., Otte, C., Mohr, D.C., 2005. Depression and cortisol responses to
psychological stress: a meta-analysis. Psychoneuroendocrinology 30 (9), 846–856.
Carlsson, R.H., Hansen, A.M., Nielsen, M.L., Blønd, M., Netterstrøm, B., 2017. Changes in
Allostatic Load during workplace reorganization. J. Psychosom. Res. 103, 34–41.
Chandola, T., Heraclides, A., Kumari, M., 2010. Psychophysiological biomarkers of
workplace stressors. Neurosci. Biobehav. Rev. 35 (1), 51–57.
P. Kerr, et al.
Chida, Y., Steptoe, A., 2009. Cortisol awakening response and psychosocial factors: a
systematic review and meta-analysis. Biol. Psychol. 80 (3), 265–278.
De Kloet, E.R., Joëls, M., Holsboer, F., 2005. Stress and the brain: from adaptation to
disease. Nat. Rev. Neurosci. 6 (6), 463.
De Kloet, E.R., Otte, C., Kumsta, R., Kok, L., Hillegers, M.H.J., Hasselmann, H., et al.,
2016. Stress and depression: a crucial role of the mineralocorticoid receptor. J.
Neuroendocrinol. 28 (8).
De Vente, W., van Amsterdam, J.G., Olff, M., Kamphuis, J.H., Emmelkamp, P.M., 2015.
Burnout is associated with reduced parasympathetic activity and reduced HPA axis
responsiveness, predominantly in males. Biomed Res. Int. 2015.
Dickerson, S.S., Kemeny, M.E., 2004. Acute stressors and cortisol responses: a theoretical
integration and synthesis of laboratory research. Psychol. Bull. 130 (3), 355.
Eddy, P., Heckenberg, R., Wertheim, E.H., Kent, S., Wright, B.J., 2016. A systematic re-
view and meta-analysis of the effort-reward imbalance model of workplace stress
with indicators of immune function. J. Psychosom. Res. 91, 1–8.
Eddy, P., Wertheim, E.H., Kingsley, M., Wright, B.J., 2017. Associations between the
effort-reward imbalance model of workplace stress and indices of cardiovascular
health: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 83,
252–266.
Eddy, P., Wertheim, E.H., Hale, M.W., Wright, B.J., 2018. A systematic review and meta-
analysis of the effort-reward imbalance model of workplace stress and hypothalamic-
pituitary-adrenal axis measures of stress. Psychosom. Med. 80 (1), 103–113.
Esser, A., Kraus, T., Tautz, A., Minten, H., Lang, J., 2019. Building an allostatic load index
from data of occupational medical checkup examinations: a feasibility study. Stress
22 (1), 9–16.
Fischer, S., Macare, C., Cleare, A.J., 2017. Hypothalamic-pituitary-adrenal (HPA) axis
functioning as predictor of antidepressant response–Meta-analysis. Neurosci.
Biobehav. Rev. 83, 200–211.
Granger, D.A., Hibel, L.C., Fortunato, C.K., Kapelewski, C.H., 2009. Medication effects on
salivary cortisol: tactics and strategy to minimize impact in behavioral and devel-
opmental science. Psychoneuroendocrinology 34 (10), 1437–1448.
Grossi, G., Perski, A., Evengård, B., Blomkvist, V., Orth-Gomér, K., 2003. Physiological
correlates of burnout among women. J. Psychosom. Res. 55 (4), 309–316.
Hemels, M.E., Koren, G., Einarson, T.R., 2002. Increased use of antidepressants in Canada:
1981–2000. Ann. Pharmacother. 36 (9), 1375–1379.
Heuser, I., Yassouridis, A., Holsboer, F., 1994. The combined dexamethasone/CRH test: a
refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28 (4), 341–356.
Hibel, L.C., Granger, D.A., Kivlighan, K.T., Blair, C., Family Life Project Investigators,
2006. Individual differences in salivary cortisol: associations with common over-the-
counter and prescription medication status in infants and their mothers. Horm.
Behav. 50 (2), 293–300.
Hibel, L.C., Granger, D.A., Cicchetti, D., Rogosch, F., 2007. Salivary biomarker levels and
diurnal variation: associations with medications prescribed to control children’s
problem behavior. Child Dev. 78 (3), 927–937.
Holsboer, F., Barden, N., 1996. Antidepressants and hypothalamic-pituitary-adrenocor-
tical regulation. Endocr. Rev. 17 (2), 187–205.
Howatt, W., 2017. The mental health experience in Canada’s workplaces: what is your
experience. Morneau Shepell.
Ising, M., Maccarrone, G., Brückl, T., Scheuer, S., Hennings, J., Holsboer, F., Turck, C.W.,
Uhr, M., Lucae, S., 2019. FKBP5 gene expression predicts antidepressant treatment in
depression. Int. J. Mol. Sci. 20, 405. https://doi.org/10.3390/ijms20030485.
Juster, R.P., McEwen, B.S., Lupien, S.J., 2010. Allostatic load biomarkers of chronic stress
and impact on health and cognition. Neurosci. Biobehav. Rev. 35 (1), 2–16.
Juster, R.P., Sindi, S., Marin, M.F., Perna, A., Hashemi, A., Pruessner, J.C., Lupien, S.J.,
2011. A clinical allostatic load index is associated with burnout symptoms and hy-
pocortisolemic profiles in healthy workers. Psychoneuroendocrinology 36 (6),
797–805.
Juster, R.P., Moskowitz, D.S., Lavoie, J., D’Antono, B., 2013. Sex-specific interaction ef-
fects of age, occupational status, and workplace stress on psychiatric symptoms and
allostatic load among healthy Montreal workers. Stress 16 (6), 616–629.
Juster, R.P., Pruessner, J.C., Desrochers, A.B., Bourdon, O., Durand, N., Wan, N., et al.,
2016a. Sex and gender roles in relation to mental health and allostatic load.
Psychosom. Med. 78 (7), 788–804.
Juster, R.P., Raymond, C., Desrochers, A.B., Bourdon, O., Durand, N., Wan, N., et al.,
2016b. Sex hormones adjust “sex-specific” reactive and diurnal cortisol profiles.
Psychoneuroendocrinology 63, 282–290.
Juster, R.P., Russell, J.J., Almeida, D., Picard, M., 2016c. Allostatic load and comorbid-
ities: a mitochondrial, epigenetic, and evolutionary perspective. Dev. Psychopathol.
28 (4pt1), 1117–1146.
Juster, R.P., Sasseville, M., Giguère, C.-É., Signature Consortium, Lupien, S.J., 2018.
Elevated allostatic load in individuals presenting at psychiatric emergency services. J.
Psychosom. Res. 115, 101–109. https://doi.org/10.1016/j.jpsychores.2018.10.012.
Juster, R.P., de Torre, M.B., Kerr, P., Kheloui, S., Rossi, M., Bourdon, O., 2019. Sex dif-
ferences and gender diversity in stress responses and allostatic load among workers
and LGBT people. Curr. Psychiatry Rep. 21 (11), 110.
Karasek, R., Theorell, T., 1990. Health Work, Stress, Productivity, and the Reconstruction
of Working Life. Basic Book. Inc., New York.
Karasek, R., Brisson, C., Kawakami, N., Houtman, I., Bongers, P., Amick, B., 1998. The Job
Content Questionnaire (JCQ): an instrument for internationally comparative assess-
ments of psychosocial job characteristics. J. Occup. Health Psychol. 3 (4), 322.
Kinsey, Alfred C., et al., 1948. /1998). Sexual Behavior in the Human Male. W.B.
Saunders; Bloomington: Indiana U. Press, Philadelphia, pp. 636–659 First publication
of Kinsey’s Heterosexual-Homosexual Rating Scale. Discusses Kinsey Scale.
Kirschbaum, C., Hellhammer, D.H., 1989. Salivary cortisol in psychobiological research:
an overview. Neuropsychobiology 22 (3), 150–169.
Kirschbaum, C., Pirke, K.M., Hellhammer, D.H., 1993. The ‘Trier Social Stress Test’–a tool
9
Psychoneuroendocrinology 115 (2020) 104634
for investigating psychobiological stress responses in a laboratory setting.
Neuropsychobiology 28 (1-2), 76–81.
Koertge, J., 2003. Vital Exhaustion and Coronary Artery Disease in Women: Biological
Correlates and Behavioral Intervention. Institutionen för folkhälsovetenskap/
Department of Public Health Sciences.
Lupien, S.J., McEwen, B.S., Gunnar, M.R., Heim, C., 2009. Effects of stress throughout the
lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10 (6), 434.
Madsen, I.E., Nyberg, S.T., Hanson, L.M., Ferrie, J.E., Ahola, K., Alfredsson, L., et al.,
2017. Job strain as a risk factor for clinical depression: systematic review and meta-
analysis with additional individual participant data. Psychol. Med. 47 (8),
1342–1356.
Marchand, A., Blanc, M.E., 2010. Chronicité de la consommation de médicaments psy-
chotropes dans la main-d’œuvre canadienne: quelle est la contribution de la profes-
sion et des conditions de l’organisation du travail? Revue d’épidémiologie et de Santé
Publique 58 (2), 89–99.
Marchand, A., Durand, P., Juster, R.P., Lupien, S.J., 2014a. Workers’ psychological dis-
tress, depression, and burnout symptoms: associations with diurnal cortisol profiles.
Scand. J. Work Environ. Health 305–314.
Marchand, A., Juster, R.P., Durand, P., Lupien, S.J., 2014b. Burnout symptom sub-types
and cortisol profiles: what’s burning most? Psychoneuroendocrinology 40, 27–36.
Marchand, A., Juster, R.P., Durand, P., Lupien, S.J., 2016. Work stress models and diurnal
cortisol variations: the SALVEO study. J. Occup. Health Psychol. 21 (2), 182.
Maslach, C., Leiter, M.P., 2016. Burnout. In Stress: Concepts, Cognition, Emotion, and
Behavior. Academic Press, pp. 351–357.
Mason, J.W., 1968. A review of psychoendocrine research on the pituitary-adrenal cor-
tical system. Psychosom. Med. 30 (5), 576–607.
Mauss, D., Li, J., Schmidt, B., Angerer, P., Jarczok, M.N., 2014. Measuring allostatic load
in the workforce—a systematic review. Ind. Health.
Mauss, D., Jarczok, M.N., Fischer, J.E., 2015. A streamlined approach for assessing the
Allostatic Load Index in industrial employees. Stress 18 (4), 475–483.
McEwen, B.S., 1998. Protective and damaging effects of stress mediators. N. Engl. J. Med.
338 (3), 171–179.
McEwen, B.S., 2003. Mood disorders and allostatic load. Biol. Psychiatry 54 (3), 200–207.
McEwen, B.S., Stellar, E., 1993. Stress and the individual: mechanisms leading to disease.
Arch. Intern. Med. 153 (18), 2093–2101.
McKay, M.S., Zakzanis, K.K., 2010. The impact of treatment on HPA axis activity in
unipolar major depression. J. Psychiatr. Res. 44 (3), 183–192.
Menke, A., 2019. Is the HPA axis as target for depression outdated, or is there a new
hope? Front. Psychiatry 10, 101.
Milner, A., Scovelle, A.J., King, T.L., Madsen, I., 2019. Exposure to work stress and use of
psychotropic medications: a systematic review and meta-analysis. J. Epidemiol.
Community Health 73 (6), 569–576.
Nakagawa, S., 2004. A farewell to Bonferroni: the problems of low statistical power and
publication bias. Behav. Ecol. 15 (6), 1044–1045.
Nieuwenhuijsen, K., Bruinvels, D., Frings-Dresen, M., 2010. Psychosocial work environ-
ment and stress-related disorders, a systematic review. Occup. Med. 60 (4), 277–286.
OECD, 2013. Publishing, & Organization for Economic Cooperation and Development
(OECD) Staff. (2013). Health at a Glance. OECD indicators. OECD publishing.
Otte, C., Wingenfeld, K., Kuehl, L.K., Kaczmarczyk, M., Richter, S., Quante, A., et al.,
2015. Mineralocorticoid receptor stimulation improves cognitive function and de-
creases cortisol secretion in depressed patients and healthy individuals.
Neuropsychopharmacology 40 (2), 386.
Pariante, C.M., Thomas, S.A., Lovestone, S., Makoff, A., Kerwin, R.W., 2004. Do anti-
depressants regulate how cortisol affects the brain? Psychoneuroendocrinology 29
(4), 423–447.
Pariante, C.M., Alhaj, H.A., Arulnathan, V.E., Gallagher, P., Hanson, A., Massey, E.,
McAllister-Williams, R.H., 2012. Central glucocorticoid receptor-mediated effects of
the antidepressant, citalopram, in humans: a study using EEG and cognitive testing.
Psychoneuroendocrinology 37 (5), 618–628.
Perneger, T.V., 1998. What’s wrong with Bonferroni adjustments. BMJ 316 (7139),
1236–1238.
Pratt, L.A., Brody, D.J., Gu, Q., 2017. Antidepressant Use among Persons Aged 12 and
Over: United States, 2011-2014. NCHS Data Brief. Number 283. National Center for
Health Statistics.
Pruessner, J.C., Wolf, O.T., Hellhammer, D.H., Buske-Kirschbaum, A., Von Auer, K., Jobst,
S., et al., 1997. Free cortisol levels after awakening: a reliable biological marker for
the assessment of adrenocortical activity. Life Sci. 61 (26), 2539–2549.
Pruessner, J.C., Hellhammer, D.H., Kirschbaum, C., 1999. Burnout, perceived stress, and
cortisol responses to awakening. Psychosom. Med. 61 (2), 197–204.
Pruessner, J.C., Kirschbaum, C., Meinlschmid, G., Hellhammer, D.H., 2003. Two formulas
for computation of the area under the curve represent measures of total hormone
concentration versus time-dependent change. Psychoneuroendocrinology 28 (7),
916–931.
Rugulies, R., Aust, B., Madsen, I.E., 2017. Effort–reward imbalance at work and risk of
depressive disorders. A systematic review and meta-analysis of prospective cohort
studies. Scand. J. Work Environ. Health 43 (4), 294–306.
Schaufeli, W.B., 1996. Maslach Burnout Inventory-General Survey (MBI-GS). Maslach
burnout inventory manual.
Seplaki, C.L., Goldman, N., Glei, D., Weinstein, M., 2005. A comparative analysis of
measurement approaches for physiological dysregulation in an older population. Exp.
Gerontol. 40 (5), 438–449.
Siegrist, J., 1996. Adverse health effects of high-effort/low-reward conditions. J. Occup.
Health Psychol. 1 (1), 27.
Siegrist, J., 2016. A theoretical model in the context of economic globalization. Work
Stress and Health in a Globalized Economy. Springer, Cham, pp. 3–19.
Siegrist, J., Starke, D., Chandola, T., Godin, I., Marmot, M., Niedhammer, I., Peter, R.,
P. Kerr, et al.
2004. The measurement of effort–reward imbalance at work: european comparisons.
Soc. Sci. Med. 58 (8), 1483–1499.
Stalder, T., Kirschbaum, C., Kudielka, B.M., Adam, E.K., Pruessner, J.C., Wüst, S., et al.,
2016. Assessment of the cortisol awakening response: expert consensus guidelines.
Psychoneuroendocrinology 63, 414–432.
Steinhausen, H.C., 2015. Recent international trends in psychotropic medication pre-
scriptions for children and adolescents. Eur. Child Adolesc. Psychiatry 24 (6),
635–640.
Steptoe, A., Siegrist, J., Kirschbaum, C., Marmot, M., 2004. Effort–reward imbalance,
overcommitment, and measures of cortisol and blood pressure over the working day.
Psychosom. Med. 66 (3), 323–329.
Subramaniam, A., LoPilato, A., Walker, E.F., 2019. Psychotropic medication effects on
cortisol: implications for research and mechanisms of drug action. Schizophr. Res.
213, 6–14.
Talge, N.M., Donzella, B., Kryzer, E.M., Gierens, A., Gunnar, M.R., 2005. It’s not that bad:
error introduced by oral stimulants in salivary cortisol research. Dev. Psychobiol. 47
(4), 369–376.
Theorell, T., Hammarström, A., Aronsson, G., Bendz, L.T., Grape, T., Hogstedt, C., et al.,
2015. A systematic review including meta-analysis of work environment and de-
pressive symptoms. BMC Public Health 15 (1), 738.
Toker, S., Shirom, A., Shapira, I., Berliner, S., Melamed, S., 2005. The association between
burnout, depression, anxiety, and inflammation biomarkers: C-reactive protein and
fibrinogen in men and women. J. Occup. Health Psychol. 10 (4), 344.
Turecki, G., Meaney, M.J., 2016. Effects of the social environment and stress on gluco-
corticoid receptor gene methylation: a systematic review. Biol. Psychiatry 79 (2),
10
Psychoneuroendocrinology 115 (2020) 104634
87–96.
Van Hedger, K., Bershad, A.K., de Wit, H., 2017. Pharmacological challenge studies with
acute psychosocial stress. Psychoneuroendocrinology 85, 123–133.
Ventura-Juncá, R., Symon, A., López, P., Fiedler, J.L., Rojas, G., Heskia, C., et al., 2014.
Relationship of cortisol levels and genetic polymorphisms to antidepressant response
to placebo and fluoxetine in patients with major depressive disorder: a prospective
study. BMC Psychiatry 14 (1), 220.
Wekenborg, M.K., von Dawans, B., Hill, L.K., Thayer, J.F., Penz, M., Kirschbaum, C.,
2019. Examining reactivity patterns in burnout and other indicators of chronic stress.
Psychoneuroendocrinology 106, 195–205.
Wilkinson, M., Brown, R.E., 2015. An Introduction to Neuroendocrinology. Cambridge
University Press.
Wong, I.C.K., Murray, M.L., Camilleri-Novak, D., Stephens, P., 2004. Increased pre-
scribing trends of paediatric psychotropic medications. Arch. Dis. Child. 89 (12),
1131–1132.
World Health Organization, 2018. International Statistical Classification of Diseases and
Related Health Problems (11th Revision). Retrieved from. https://icd.who.int/
browse11/l-m/en.
Zänkert, S., Bellingrath, S., Wüst, S., Kudielka, B.M., 2018. HPA axis responses to psy-
chological challenge linking stress and disease: What do we know on sources of intra-
and interindividual variability? Psychoneuroendocrinology.
Zorn, J.V., Schür, R.R., Boks, M.P., Kahn, R.S., Joëls, M., Vinkers, C.H., 2017. Cortisol
stress reactivity across psychiatric disorders: a systematic review and meta-analysis.
Psychoneuroendocrinology 77, 25–36.