Journal of Affective Disorders 273 (2020) 508–516

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Extended overview of the longitudinal pain-depression association: A T

comparison of six cohorts treated for specific chronic pain conditions
⁎
Felix Angsta, , Thomas Benza, Susanne Lehmanna, Stephan Wagnerb, Beat R. Simmenc,
Peter S. Sandòra,d, Michael Gengenbachera,e, Jules Angstf
a
Research Department, Rehabilitation Clinic ("RehaClinic"), Bad Zurzach, Switzerland
b
Department of Angiology, Rehabilitation Clinic ("RehaClinic"), Bad Zurzach, Switzerland
c
Endoclinic, Clinic Hirslanden, Zurich, Switzerland
d
Department of Neurology, Rehabilitation Clinic ("RehaClinic"), Bad Zurzach, Switzerland
e
Department of Musculoskeletal Medicine and Rheumatology, Rehabilitation Clinic ("RehaClinic"), Bad Zurzach, Switzerland
f
Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital Burghölzli, University of Zurich, Switzerland

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

Keywords: Background: The aim was to quantify and to compare the associations between longitudinal changes in pain and
Pain depression in different chronic pain conditions.
Depression Methods: Data were retrieved from 6 observational cohort studies. From baseline to the 6-month follow-up, the
Longitudinal change score changes on the Short Form (36) Health Survey (SF-36) bodily pain (pain) and the SF-36 mental health
Association
(depression) scales (0=worst, 100=best) were quantified, using partial correlations obtained by multiple re-
Correlation
gression. Adjustment was performed by age, living alone/with partner, education level, number of comorbid-
Causality
ities, baseline pain and baseline depression.
Results: Stronger associations were found between changes in levels of pain and depression for neck pain after
whiplash (n = 103, mean baseline pain=21.4, mean baseline depression=52.5, adjusted correlation
r = 0.515), knee osteoarthritis (n = 177, 25.4, 64.2, r = 0.502), low back pain (n = 134, 19.0, 49.4, r = 0.495),
and fibromyalgia (n = 125, 16.8, 43.2, r = 0.467) than for lower limb lipedema (n = 68, 40.2, 62.6, r = 0.452)
and shoulder arthroplasty (n = 153, 35.0, 76.4, r = 0.292). Those correlations were somewhat correlated to
baseline pain (rank r=–0.429) and baseline depression (rank r=–0.314).
Limitations: The construct of the full range of depressive symptoms is not explicitly covered by the SF-36.
Conclusions: Moderate associations between changes in pain and depression levels were demonstrated across 5
of 6 different chronic pain conditions. The worse the pain and depression scores at baseline, the stronger those
associations tended to be. Both findings indicate a certain dose-response relationship – an important char-
acteristic of causal interference. Relieving pain by treatment may lead to the relief of depression and vice versa.

1. Introduction the basis of longitudinal data. Any discovery of a longitudinal re-

The relationship between pain and depression has stimulated re-
search and generated a huge body of scientific literature over the years.
The bulk of those research results is based on cross-sectional assessment
(Angst et al., 2008c; IsHak et al., 2018). For example, the cross-sec-
tional associations between pain and depression remained stable over a
13-year follow-up period and were independent of age, gender, edu-
cation and medication (n = 1528 to 813, 5 follow-ups) (Sanders et al.,
2015). Research data and clinical observation have led to the hypoth-
esis that after a certain latency pain may cause depression and vice
versa (IsHak et al., 2018). This hypothesis needs to be investigated on
lationship between pain and depression could, moreover, yield ther-
apeutic options for improving one condition by treating the other –
without ambitions to solve the chicken-egg problem.
There is already evidence in early life of a causal link between pain
and depression. Recurrent abdominal pain in childhood (3–9 years) was
considered a cause for developing adult depression and anxiety (ICD-10
diagnoses at age 18) (Stein et al., 2017). Stein et al. found that pain and
depression/anxiety were associated by an odds ratio (OR) of 1.41 and
showed a positive dose-response relationship (n = 2474). Moreover, a
history of abdominal pain was associated with negative coping with
pain. Similarly, a US population survey (n = 14,790) quantified the risk

⁎
Corresponding author at: RehaClinic, Quellenstrasse 34, 5330 Bad Zurzach, Switzerland,
E-mail addresses: fangst@vtxmail.ch, f.angst@rehaclinic.ch (F. Angst).

https://doi.org/10.1016/j.jad.2020.05.044
Received 21 November 2019; Received in revised form 21 April 2020; Accepted 10 May 2020
Available online 19 May 2020
0165-0327/ © 2020 Elsevier B.V. All rights reserved.
F. Angst, et al. Journal of Affective Disorders 273 (2020) 508–516

Table 1
Cohort studies, baseline disease-relevant data.
Region Shoulder Lower limb Soft tissue Low back Knee Neck
Diagnosis Osteoarthritis Lipedema Fibromyalgia Chronic pain Osteoarthritis After whiplash

Intervention Arthroplasty Comprehensive Inpatient pain Inpatient pain Comprehensive Inpatient pain
rehabilitation program program rehabilitation program
Patients (n) 153 68 125 134 177 103
Age (years): m (s) 67.3 (10.4) 48.2 (13.5) 45.6 (9.7) 48.3 (12.2) 65.6 (10.3) 38.0 (11.9)
Female (%) 64.5 100.0 89.6 82.1 79.1 79.6
Living alone (%) 26.1 17.6 17.6 23.9 37.9 28.2
Education (%)
Compulsory schooling (8–9 20.3 14.7 32.0 22.4 36.2 2.9
y)
Vocational training 48.6 52.9 48.0 60.4 47.5 19.4
Upper secondary/university 31.2 32.4 20.0 17.2 16.4 77.7
Comorbidities (%)
0 25.4 10.3 9.6 11.9 0.6 16.5
1 23.2 8.8 28.0 23.9 6.8 34.0
2 28.3 19.1 33.6 32.8 18.6 26.2
3 7.2 29.4 16.8 20.7 28.8 14.6
≥4 15.9 32.4 12.0 10.7 45.2 4.9

Legend: n=number of cases, m=arithmetic mean, s=standard deviation, y=years.

of adult depression following chronic pain in childhood by an OR=1.38
(Noel et al., 2016). A 10-year survey (n = 5001) found that pain and
depression/anxiety in adolescence were both associated with adverse
childhood experiences, such as verbal abuse, sexual abuse, parental loss
or parental psychopathology (Sachs-Ericsson et al., 2017). Anxiety and/
or depression were found to both moderate and mediate the relation-
ship between pain and such adverse childhood experiences. In this
context, mediation was defined as the observation that anxiety and
depression were amplified by adverse childhood experiences – in-
dependently of pain – and increased the risk of developing pain in
adolescence. Coping was inversely correlated to the number of adverse
experiences in childhood, leading to the conclusion that developed
coping skills might reduce the extent to which depression/anxiety in-
duce pain.
Most studies have used thresholds to diagnose depression and/or
pain and to determine the frequencies of cases/non-cases and ORs; very
few have used fine-graded scales that measure the levels of severity of
pain and depressivity and allow quantification of their interrelationship
by (partial) correlations (Angst et al., 2008c). The well-known US
Women's Health Initiative (n = 144,956) found that, compared to no/
mild pain, 15.8% of the study participants reported moderate to ex-
treme pain, which was associated with the incidence of depressive
symptoms by a relative risk (RR) of 1.82 in non-veterans and 1.77 in
veterans after 18 years’ follow-up (Patel et al., 2016). In persons with
cognitive impairment (n = 931) over an observation period of 4–6
months, a 1-point increase in pain was associated with a 0.48 (score
points) increase in depression (Erdal et al., 2017). It was concluded that
improving the treatment of pain may lower the levels of depression in
the clinical course.
In line with this hypothesis, pain relief in young adolescents was
found to be positively associated with the relief of depressive symptoms
and vice versa (n = 95, mean age 15.2 years, 1-year observation time)
(Lewandowski Holley et al., 2013). Unfortunately, that study used only
regression coefficients, not correlations, to quantify the associations. In
lumbar spinal stenosis (n = 96, 2-year observation time), pain relief
was significantly associated with the relief of depression when arbitrary
relief thresholds on the visual analogue scale (VAS) for pain and the
Beck Depression Scale were chosen to determine ORs (Sinikallio et al.,
2010).
Findings consistent with the above are available for specific mus-
culoskeletal conditions, as outlined in the discussion. One of the most
valid studies in this context examined a depressed (n = 250) and a
nondepressed (n = 250) cohort in primary care with up to 3 follow-ups
(Kroenke et al., 2011). Change in pain was consistently a strong
predictor of subsequent depression and vice versa in all cohorts and in
all analysis models.
While many population surveys have documented the association
between baseline pain and future depression and vice versa, very few
have examined the associations between changes in the severity of the
two outcomes (Chang et al., 2015; Chou, 2007; Erdal et al., 2017;
Kroenke et al., 2011; Patel et al., 2016). In addition, many studies ex-
amined single pain conditions but did not compare the association of
pain and depression across different chronic pain syndromes using the
same measures. After an extensive review of the literature on the topic,
it became clear that the burden of pain and depression is more salient in
certain conditions, for example in fibromyalgia than in osteoarthritis
(Salaffi et al., 2019).
Our study aimed 1) to quantify the associations of longitudinal
changes in pain and depression with and without adjustment for po-
tential disease-relevant confounders, 2) to compare the results across 6
different chronic pain conditions. As the main outcome our focus was
the correlation of “pain change” with “depression change”. As a sec-
ondary outcome we examined the correlations to baseline pain and
depression. It was hypothesized that the strength of the pain-depression
relationship depends on the level of baseline pain or baseline depres-
sion, i.e. that higher levels of baseline symptoms may increase the
strength of the association.
2. Methods
2.1. Data sources
Data were retrieved from the 6 treated cohort studies characterized
in Table 1. “Treated” means that the data were collected through the
observational measurement of individuals consecutively admitted to
specialized interventions who received standard clinical treatment
(independently of the assessment and the aim of the study), in contrast
to artificially designed intervention studies. Detailed information re-
garding the selection of the patients, refusal rates and possible con-
founding is to be found in the original reports on the individual studies
(Angst et al., 2013, 2010, 2008a, 2006; in review).
Cohort 1 consisted of shoulder osteoarthritis or rheumatoid arthritis
patients (n = 153) who received PROMOS shoulder endoprosthesis at
the Wilhelm Schulthess Clinic for orthopedic surgery, Zurich,
Switzerland (Angst et al., 2008a). The other 5 studies (cohorts 2 to 6)
were conducted at the Rehabilitation clinic ("RehaClinic"), Bad Zur-
zach, Switzerland. These were: (2) patients with lipedema of the lower
extremity (n = 68) who underwent inpatient rehabilitation or

509
F. Angst, et al.
consultation for outpatient management, including complex physical
decongestive therapy (Angst et al., review); patients (3) with fi-
bromyalgia (n = 125) and (4) low back pain (n = 134) who took part
at the “Zurzach Interdisciplinary Pain (Schmerz) Program (ZISP)”, an
inpatient, multidisciplinary rehabilitation program (Angst et al., 2006);
(5) patients with neck pain after whiplash injury (n = 103) who took
part at the “Zurzach Interdisciplinary Cervical Spine (Halswirbelsäule)
Concept (ZIHKo)”, a multidisciplinary inpatient rehabilitation program
(Angst et al., 2010), and (6) patients who underwent inpatient re-
habilitation of knee osteoarthritis (n = 177) in the “Zurzach Osteoar-
thritis Study” (Angst et al., 2013). Except for the shoulder and the
whiplash cohorts (1 and 5), the relevant data sets were updated before
the present analysis in order to include additional entrants and specific
follow-ups of the respective programs; those updates supplement the
originally published data (Angst et al., 2013, 2006, 2020).
In all 6 cohorts, baseline scores were collected on the day of entry
into the clinic and/or (outpatients) at the first visit before start of
treatment. For all cohorts the follow-up assessment was carried out
exactly 6 months later.
2.2. Measures
Sociodemographic and disease-relevant data were recorded using a
standardized questionnaire that has proven its worth in several earlier
studies (Angst et al., 2013, 2010, 2008a, 2006, 2001, 2020). All re-
quisite medical records were obtained to confirm diagnoses and to
evaluate inclusion and exclusion criteria and the number of comorbid
conditions.
The validated German versions of the Short Form 36 Health Survey
(SF-36) were used to quantify pain and depression (Bullinger and
Kirchberger, 1998; Ware et al., 2004, 2000). The SF-36 is the most
widely used questionnaire for the self-assessment of generic health and
quality of life and facilitates good comparability among various health
conditions (Busija et al., 2011).
The SF-36 bodily pain scale consists of 2 items: 1) How much bodily
pain have you had during the past 4 weeks? (none, very mild, mild,
moderate, severe, very severe:6 levels – SF-36 version 1 and 2 iden-
tical), 2) during the past 4 weeks, how much did pain interfere with
your normal work (outside home and home work) (not at all, a little bit,
moderately, quite a bit, extremely: 5 levels – SF-36 version 1 and 2
identical). The internal constancy of the SF-36 bodily pain scale was
Cronbach's Alpha (CA)=0.88 in the normative German general popu-
lation study (n = 2914) (Bullinger and Kirchberger, 1998).
The content and construct validity of the SF-36 bodily pain scale is
clear and has been proven by numerous studies that have applied it to
measure outcome (Busija et al., 2011; Ware et al., 2004, 2000). Of
particular interest is the longitudinal validity, which has been tested in
our fibromyalgia and chronic low back pain setting (n = 273)
(Angst et al., 2008b). The SF-36 bodily pain scale was slightly less re-
sponsive than the Multidimensional Pain Inventory (MPI) pain severity
scale and slightly more responsive than the pain Numeric Rating Scale
(NRS); however neither difference was statistically significant.
The SF-36 mental health consists of 5 items as follows: How much
during the past month 1) have you been a very nervous person, 2) have
you felt so down in the dumps that nothing could cheer you up, 3) have
you felt calm and peaceful, 4) have you felt downhearted and blue, 5)
have you been a happy person? (Possible responses to each item are:
all/most/a good bit/some/a little/none of the time, i.e. 6 levels in SF-36
version 1; and in SF-36 version 2: all/most/some/a little/none of the
time i.e. 5 levels (Bullinger and Kirchberger, 1998; Ware et al., 2000).
The internal constancy of the SF-36 mental health scale was CA=0.80
(Bullinger and Kirchberger, 1998).
The validity of the SF-36 mental health scale for the measurement of
self-rated depressivity (the number and level of depressive symptoms)
or depression is less obvious and is presented below. To simplify no-
menclature, “depressivity” has been replaced by “depression” hereafter.
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Journal of Affective Disorders 273 (2020) 508–516
Various studies have demonstrated that low scores on the SF-36 mental
health dimension represent high levels of nervousness and depression
(Busija et al., 2011). The SF-36 mental health scale has shown high
responsiveness, i.e. longitudinal content and construct validity in
chronic pain (Angst et al., 2008b). It was statistically more responsive
than the Hospital Anxiety and Depression Scale (HADS) depression
scale and of comparable responsiveness to the MPI negative mood scale.
However, the 5 mental health items mentioned do not cover im-
portant symptoms defining depression, namely diminished interest and
pleasure, agitation or retardation, fatigue or loss of energy, feelings of
worthlessness or guilt, lack of self-esteem, feelings of guilt, diminished
ability to think or concentrate, thoughts of death or suicidal ideas as
well as changes in sleep and appetite. Moreover, the SF-36 assesses only
self-rated symptoms.
Nevertheless, the validity of the SF-36 mental health scale for the
measurement of depression has been proven to be high by various
evaluations (Busija et al., 2011). For example, it correlated cross-sec-
tionally by maximum r = 0.57 to the Symptom Checklist 90-Revised
(SCL-90R) affective & behavioural scale and by maximum r = 0.77 to
Beck Depression Inventory II (BDI-II) scale in individuals with trau-
matic brain injury (n = 271) (Findler et al., 2001). In rheumatoid ar-
thritis patients (n = 223), the cross-sectional correlations were
r = 0.80 between the SF-36 bodily pain and the Visual Analogue Scale
(VAS) of pain, and r = 0.80 between the SF-36 mental health and the
HADS (Ruta et al., 1998).
When the SF-36 mental health scale was first constructed, special
focus was laid on the validity criterion (Ware et al., 2004, 2000): Cri-
terion validation was performed using 7 different predefined dichot-
omous criteria (present/absent) and 1 (continuous) measure
(Ware et al., 2004, 2000). The criteria were: 1) dissatisfaction with life:
dissatisfied or very dissatisfied on the Dupuy's quality of life measure,
2) depressive symptom scores on the Centre of Epidemiologic Studies
Depression scale (CES-D) beyond the cut off for clinical depression but
not satisfying DSM-III criteria for major depression, 3) a diagnosis of
depression fulfilling the DSM-III criteria for major depression, dys-
thymia, or both after CES-D score beyond the cut off, 4) suicide ideation
defined by the corresponding item of the Mental Health Inventory
(MHI), 5) outpatient visit(s) for mental health treatment in the past 6
months, 6) visit(s) at formally trained mental health specialist's office,
7) inpatient stay(s) in a hospital for mental health treatment in the past
12 months. The average of the percentages of those (out of a total
n = 2988) who fulfilled criteria 1) to 7) were related to the item re-
sponse categories of the SF-36 mental health items: “all the time” (score
0=most depression) included 58.6% positive cases, “most of the time”
(score 20) 48.1%, “good bit of the time” (score 40) 36.8%, “some of the
time” (score 60) 24.5%, “a little” (score 80) 13.7%, and “none of the
time” (score 100=no depression) 5.8%. This results in a Pearson cor-
relation of r = 0.998 (severe to severe). The 8th criterion, the mental
health scale average score on the 32-item long-form of the MHI, cor-
related with the SF-36 mental health score by r = 0.96.
2.3. Analysis
Both the SF-36 bodily pain and the SF-36 mental health were scaled
from 0=maximum pain/depression to 100=no pain/depression ac-
cording to the original scaling rules (Bullinger and Kirchberger, 1998;
Ware et al., 2004, 2000). While the SF-36 bodily pain scale is scored by
the mean of the two items, which are complexly recoded depending on
various “if” statements, the SF-36 mental health scale is the un-
weighted linear combination of the 5 items, 2 of which have to be in-
versely recoded. As measure of reliability / internal consistency, the
Cronbach's alphas were determined between the baseline and the
follow-up scores for each scale and cohort.
Since for both scales, the baseline, the follow-up scores and the
score changes (baseline to 6-month follow-up) showed approximate
normal Gauss distribution, parametric Pearson correlations were
F. Angst, et al.
computed. The score changes on SF-36 bodily pain and SF-36 mental
health dimensions were determined by bivariate, non-adjusted corre-
lation. Multiple linear regression was used to determine the adjusted
correlations (Backhaus et al., 2016; Hedderich and Sachs, 2016;
Ho, 2013): Change in SF-36 bodily pain (dependent variable) was
modeled by sex, age, living with a partner, education level, number of
comorbidities, baseline SF-36 bodily pain, baseline SF-36 mental
health, score change on the SF-36 mental health scale (independent
variables). The partial correlation of the score change on the SF-36
mental health scale represented the adjusted correlation between pain
and depression. The overall explained variances (%) were depicted to
quantify the fit of the regression models. Finally, in order to test the
initial hypothesis, the levels of the adjusted correlations were related to
the levels of baseline pain and depression by graphic interpretation and
non-parametric rank-correlation analysis.
A minimum sample size of n = 50 has been estimated as necessary
to quantify valid correlation estimates of the basic population with both
normally distributed 95% confidence intervals (Hedderich and
Sachs, 2016). To illustrate the precision of the parameter estimation,
the 95% confidence intervals are in the range of ≤0.23 (lower limit)
and ≤0.17 (upper limit) for n = 50 to 100; for n ≥ 100 the corre-
sponding levels are ≤0.16 and ≤0.13.
3. Results
3.1. Baseline socio-demographic and disease-relevant data
The 6 cohort studies are characterized in Table 1. They are ordered
from left to right according to the adjusted association between pain
change and depression change (Table 2). Both SF-36 scores of all 6
cohorts were approximately normally distributed, as described in detail
in the original reports on the individual studies. The shoulder ar-
throplasty patients (n = 153) were relatively elderly, had the highest
proportion of males, were well-educated, and had few comorbid con-
ditions. The cohort with lower limb lipedema (n = 68), consisted solely
of women; many were well-educated and, although still in middle age,
comorbid conditions were very frequent. The fibromyalgia cohort
(n = 125) was predominantly female, again middle-aged and with a
lower level of educational attainment. Similar characteristics were
found in the low back pain sample (n = 134). The knee osteoarthritis
group (n = 177) was elderly and characterized by multiple co-
morbidities. The members of the cohort with neck pain after whiplash
injury (n = 103) were under forty and very well-educated.
3.2. Pain and depression in the clinical course
As shown in Table 2, the burden of pain at baseline (SF-36 bodily
pain) was relatively heavy in fibromyalgia (mean score 16.8, where
0=maximum pain), low back pain (19.0), knee osteoarthritis (25.4),
and neck pain (21.4) but markedly lower in shoulder osteoarthritis
(35.0) and lower limb lipedema (40.2). Baseline levels of depression
were relatively high in fibromyalgia (mean score 43.2, where
0=maximum depression), low back pain (49.4), and neck pain (52.5)
but lower in the 3 other cohorts (62.2 to 76.4). An analysis of variance
across the 6 cohorts resulted in p<0.001 for both baseline pain and
baseline depression.
At the 6-month follow-up, the greatest improvements in pain were
observed after shoulder arthroplasty (mean change +28.7 score points)
but were smaller in the other 5 cohorts with conservative therapy
(+4.8 to +9.0). On the depression scale, 4 cohorts showed small mean
changes ranging from +4.1 to +7.1 but in two cohorts (shoulder os-
teoarthritis and knee osteoarthritis) mean changes were close to zero.
However, the standard deviations of the score changes were high, both
in pain (17.7 to 26.2) and depression (14.5 to 18.5), reflecting wide
variations in improvement or deterioration between baseline and the
follow-up. This is an important characteristic in determining the
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Journal of Affective Disorders 273 (2020) 508–516
correlations between pain and depression changes. An analysis of var-
iance across the 6 cohorts resulted in p<0.001 for both change on pain
and on depression.
3.3. Correlations between pain and depression
The main outcome correlations, those between changes in pain and
depression, were higher than all the others, including the baseline
scores (Table 2). For interest, we have also listed the bivariate, (un-
adjusted) correlation coefficients for all analyses. The adjusted (partial)
correlations were 0.515 for neck pain, 0.502 for knee osteoarthritis,
0.495 for low back pain, 0.467 for fibromyalgia, 0.452 for lipedema,
and 0.292 for shoulder osteoarthritis. All correlations between changes
in pain and depression were statistically significantly different from
zero (two-sided test, respectively, the 95% confidence intervals ex-
cluded zero). The rank correlation coefficient between the adjusted
change correlations and baseline pain was –0.429 (Fig. 1). There was a
similar but weaker relationship between the adjusted change correla-
tions and baseline depression: rank correlation –0.314 (Fig. 2). The
models, which included the confounding co-factors age, sex, living si-
tuation, education level, the number of comorbidities, and the baseline
scores of pain and depression (see Table 1), explained moderate pro-
portions of variance, ranging from 29.7% for shoulder osteoarthritis to
46.7% for knee osteoarthritis (Table 2).
The 3 secondary correlation analyses showed consistently lower
levels than those of the primary analysis (Table 2). The adjusted cor-
relation between pain change and baseline depression was low for knee
osteoarthritis (adjusted correlation 0.143) and statistically not sig-
nificant but higher for the other 5 cohorts (0.261 to 0.368) and statis-
tically significant. The corresponding levels of adjusted correlations
between depression change and baseline pain were very low to low,
ranging from 0.083 (shoulder osteoarthritis) to 0.271 (lower limb li-
pedema); 4 out of 6 were statistically significant. Baseline pain corre-
lated to baseline depression by adjusted levels from 0.198 (low back
pain) to 0.396 (lipedema), all of which are statistically significant.
The corresponding detailed parameters of the bivariate and multiple
(adjusted) regression models can be found in Table 3.
4. Discussion
This is the first study that has undertaken to correlate changes in
pain with changes in depression using fine-graded scales and to com-
pare the for confounding adjusted results across different chronic pain
conditions. Five of the 6 cohorts analyzed revealed relatively high
correlations between the changes in pain and depression levels (base-
line to 6-month follow-up). These were: neck pain after whiplash (ad-
justed, partial correlation r = 0.515), knee osteoarthritis (r = 0.502),
low back pain (r = 0.495), fibromyalgia (r = 0.467), and lower limb
lipedema (r = 0.452). These are chronic pain conditions, where pain is
still present after conservative therapy. In contrast, much of the pain
experienced in shoulder osteoarthritis was to a large extent/ reduced by
arthroplasty, where the corresponding association was weaker
(r = 0.292).
However, the association between pain change and depression
change was somewhat stronger when pain and depression scores were
higher at baseline, which partly confirmed our initial hypothesis (rank
correlation to baseline pain r=–0.429, to baseline depression
r=–0.314). The outlier was knee osteoarthritis with relatively low le-
vels of depression. Even if those two correlation levels are not high,
they indicate a possible relationship between the pain-depression as-
sociation and the baseline syndrome levels, which can be only partly be
captured by the SF-36 scales that were implemented.
A correlation of r = 0.515, as in neck pain after whiplash, means
that r2=26.5% of the variance of pain change is explained by the
variance of depression change and vice versa, signifying a moderate
level of association (Backhaus et al., 2016). Conversely, 46.9%
F. Angst, et al. Journal of Affective Disorders 273 (2020) 508–516

Table 2
Outcome and correlation data.
Region Shoulder Lower limb Soft tissue Low back Knee Neck
Diagnosis Osteoarthritis Lipedema Fibromyalgia Chronic pain Osteoarthritis After whiplash

Patients (n) 153 68 125 134 177 103

SF-36 Bodily pain (CA) (0.51) (0.74) (0.59) (0.44) (0.53) (0.48)
Baseline m (s) 35.0 (18.5) 40.2 (22.3) 16.8 (13.4) 19.0 (13.8) 25.4 (16.5) 21.4 (14.3)
6-month follow-up: m 63.7 (26.5) 45.1 (23.1) 25.1 (18.8) 27.5 (17.6) 32.6 (19.8) 30.4 (20.9)
(s)
Change Δ 28.7 (26.2) 4.8 (20.6) 8.3 (17.7) 8.4 (19.0) 7.3 (20.6) 9.0 (21.0)
p of Δ (t-test) <0.001 0.059 <0.001 <0.001 <0.001 <0.001
SF-36 Mental health (0.76) (0.65) (0.77) (0.78) (0.77) (0.73)
(CA)
Baseline: m (s) 76.4 (16.0) 62.6 (18.0) 43.2 (18.0) 49.4 (20.4) 64.2 (20.0) 52.5 (19.8)
6-month follow-up: m 75.8 (16.9) 66.7 (18.3) 50.3 (20.6) 53.3 (20.2) 63.5 (20.2) 57.6 (20.9)
(s)
Change Δ −0.6 (14.5) 4.1 (18.5) 7.1 (16.6) 3.9 (17.3) −0.7 (17.1) 5.1 (18.8)
p of Δ (t-test) 0.305 0.072 <0.001 0.010 0.293 0.007
Δ Pain – Δ Depression 29.7 42.7 38.1 44.5 46.7 39.2
(%)
bivariate 0.224 (0.068,0.370) 0.359 (0.132,0.550) 0.398 (0.239,0.536) 0.419 (0.268,0.550) 0.516 (0.399,0.617) 0.466 (0.299,0.605)
adjusted 0.292 (0.140,0.431) 0.452 (0.239,0.623) 0.467 (0.317,0.594) 0.495 (0.355,0.613) 0.502 (0.383,0.605) 0.515 (0.357,0.644)
Δ Pain – B Depression 29.7 42.7 38.1 44.5 46.7 39.2
(%)
bivariate 0.122 (−0.037,0.275) −0.094 0.088 (−0.089,0.260) 0.074 (−0.097,0.241) −0.222 −0.044
(−0.325,0.148) (−0.358,−0.077) (−0.236,0.151)
adjusted 0.321 (0.171,0.456) 0.286 (0.051,0.491) 0.346 (0.181,0.492) 0.368 (0.212,0.506) 0.143 (−0.005,0.285) 0.261 (0.071,0.433)
Δ Depression – B Pain 31.7 45.9 33.6 42.5 41.0 41.9
(%)
bivariate −0.067 −0.183 −0.015 −0.145 −0.149 0.047 (−0.148,0.238)
(−0.223,0.093) (−0.404,0.058) (−0.190,0.161) (−0.307,0.025) (−0.290,−0.002)
adjusted 0.083 (−0.077,0.239) 0.271 (0.035,0.479) 0.264 (0.093,0.420) 0.169 (−0.001,0.329) 0.226 (0.081,0.361) 0.260 (0.070,0.432)
B Pain – B Depression 38.2 46.9 23.9 29.1 37.8 23.7
(%)
bivariate 0.241 0.275 (0.039,0.482) 0.265 (0.094,0.421) 0.104 (−0.067,0.269) 0.387 (0.256,0.506) 0.173 (−0.021,0.355)
adjusted 0.300 (0.148,0.438) 0.396 (0.174,0.580) 0.362 (0.199,0.505) 0.198 (0.029,0.356) 0.301 (0.161,0.429) 0.226 (0.034,0.402)

Legend: n=number of cases, m=arithmetic mean, s=standard deviation, SF-36: Short Form 36, Δ=Change baseline to 6 month follow-up, B=baseline, the construct
of “Pain” was measured by the SF-36 Bodily pain scale, the construct of “Depression” (in fact self-rated depressivity, see in methods) was measured by the SF-36
Mental health scale, p of Δ (t-test)=two-sided type I error of the one-sample t-test of the score change against zero, (%)=explained variance in percent of the
corresponding multiple model (4 models per condition), CA=Cronbach's alpha between the baseline and the follow-up score of the scale, Correlation with (95%
confidence interval): bold are the partial (adjusted) correlation coefficients, exclusion of zero in the 95% confidence interval means statistical significance, i.e., the
correlation coefficient is significantly different from zero with a two-sided type I error of p = 0.050.

Fig. 1. Dependency of the adjusted correlations (pain change with depression change) from baseline pain (n = 6 cohorts).

512
F. Angst, et al.
Fig. 2. Dependency of the adjusted correlations (pain change with depression change) from baseline depression (n = 6 cohorts).
“explained variance” of the model in knee osteoarthritis means that the
total model consisting of depression change and the confounders cor-
related by r=√0.469=0.685 with pain change. These findings indicate
a first dose-response relationship, which is independent of potential
confounders: Greater changes on pain were associated with greater
changes on depression and vice-versa. The confounders were sex, age,
living with a partner, education level, number of comorbidities, base-
line SF-36 bodily pain, baseline SF-36 mental health. The second dose-
response relationship consists in the stronger correlations between pain
change and depression change where baseline pain and baseline de-
pression were worse. A dose-response relationship is one of the clearest
characteristics of the causality of an association (Rothman and
Greenland, 2005). All the other associations, including baseline pain or
baseline depression, were weaker but still present and at levels con-
sistent with the literature.
Our findings of positive associations between changes in levels of
pain and depression are supported by the literature. In the general
population of Taiwan (3–11 years of follow-up) the adjusted relative
risk (RR) of developing depression was RR=6.28 for persons suffering
from fibromyalgia (n = 25,969) and, vice versa, RR=7.46 for people
with depression (n = 17,142) of developing fibromyalgia (Chang et al.,
2015). Depression was found to be a partial mediator of the relationship
between pain intensity and physical functioning in fibromyalgia
(n = 216, 36 months of follow-up), indicating that treating depression
may relieve pain (Steiner et al., 2017).
In early rheumatoid arthritis (n = 520, 2-year observation time),
baseline pain (VAS 0–10) was significantly associated with worsening
on the SF-36 mental health dimension (scaled 0–100) by 0.08 score
points per 1 point VAS pain, whereas no significant association was
found with any of the scores of the Disease Activity Score (DAS) and the
Health Assessment Questionnaire (HAQ) (Euesden et al., 2017). In a
study of psoriatic arthritis (n = 394, 7.5 years observation time), a
condition which tends to be diagnosed later in the course than early
rheumatoid arthritis, pain relief measured by the HAQ was associated
with improvement in mental health measured by the SF-36 mental
component summary (MCS); however, the study showed only regres-
sion coefficients and no partial correlations (Husted et al., 2012).
The same was true for chronic hip, knee and back pain (n = 500, 1
year observation time) in primary care (Kroenke et al., 2011). In this
study, the t (distribution)-values of all types of analysis were very high
(leading to p<0.001 in most cases) indicating strong relationships
513
Journal of Affective Disorders 273 (2020) 508–516
between changes in pain and subsequent levels of depression and vice
versa. Those t levels ranged from 2.90 to 6.46 and were comparable to
ours (3.54 to 7.52, pain change to depression change, adjusted models).
The bivariate correlations between pain/depression change and de-
pression/pain levels at the follow-up ranged between 0.26 and 0.37 in
the report of Kroenke et al. and were, thus, also comparable to our
results. Moreover, this valuable study provides a summary of 8 com-
parable studies.
Again on the basis of assessment by regression coefficients only,
remission of depression and anxiety (DSM-IV diagnoses) was statisti-
cally significantly associated with a decrease in the severity of pain and
the number of locations in n = 2093 subjects over 4 years follow-up
(Gerrits et al., 2015). A systematic review of 13 studies of lumbar spinal
stenosis concluded that preoperative depression was likely to be a
prognostic factor for postoperative symptom severity, including pain, in
lumbar spinal stenosis. There were wide variations, however, in the
levels of the associations (McKillop et al., 2014), a finding in partial
accord with our results.
In contrast, another systematic review of 10 studies found only
moderate evidence that post-injury depression or anxiety were risk
factors for persistent pain after orthopedic trauma (Clay et al., 2012).
Furthermore, since the association between pain and depression dis-
appeared after adjusting for co-twin case-control (n = 1269 twins, 2–4
years observation time), the authors concluded that the relationship
between depression and chronic low back pain is not causal
(Fernandez et al., 2017). However, depression in that study was mea-
sured by one single dichotomous item of the Euro Quality Of Life-5
Dimensions (EQ-5D), to which limited validity has been attributed
(Gignac et al., 2011).
An additional link in establishing causality in the association be-
tween pain and depression would be evidence of etiopathophysiological
pathways (Rothman and Greenland, 2005). Neuroanatomical or neu-
rochemical models describe biochemical pathways. Anatomical and
functional areas, neurotransmitters and receptors (especially those for
Serotonine and Glutamate) that process the perceptions and symptoms
of pain and depression are thought to be shared (Kroenke et al., 2011;
Meerwijk et al., 2013; Sheng et al., 2017; Zis et al., 2017). Functional
MRI, for example, has shown that similar brain regions are active for
pain after injuries and for mood management (Adler-Neal et al., 2019;
Meerwijk et al., 2013). Considering the typical direction of causality,
chronic pain is thought to lead to depression rather than vice versa
F. Angst, et al. Journal of Affective Disorders 273 (2020) 508–516

Legend: n=number of cases, β=standardized regression coefficient of the independent variable, t=Student's t-distribution value of the t-test if β is different from zero, p=two-sided type I error of t (Student's t-test).
(Sheng et al., 2017).

<0.001
<0.001

0.012
0.656

0.638
0.012

0.081
0.092
This hypothesis is supported by the causal characteristics of the

p
relationship of physical and psychological distress, which are provoked
by pain (IsHak et al., 2018). Psychotherapeutic models can also explain

−0.45
the vicious cycle of continuous interaction of cognitions, emotions,
5.29
5.74

2.58

0.47
2.57

1.77
2.22
After whiplash

behavior and somatic reactions (Zis et al., 2017). However, important

t

elements of the underlying mechanisms for the complex association of

−0.044
depression and pain remain unclear and need further elucidation
0.466
0.527

0.242

0.047
0.227

0.173
0.235
Neck

103

(IsHak et al., 2018).

β

The following features are strengths of our study: We compared 6

treated cohorts using the same fine-graded, best validated outcome
<0.001
<0.001

<0.001
<0.001
0.003
0.062

0.047
0.003 scales for pain and depression, identical observation periods, and ad-
p

justment for the same confounders in order to ensure comparability.

The cohorts represent different pain and depression conditions and
−3.01

−2.00
7.96
7.52

1.88

3.01

5.98
4.11
showed large variance in the baseline and change levels on both out-
Osteoarthritis

comes. All cohorts were sufficiently large (n ≥ 50) to provide valid

t

correlation estimates (Backhaus et al., 2016). Adjustment provided

−0.222

−0.149
0.516
0.477

0.126

0.220

0.387
0.284

partial correlations, which are free from confounding by the tested co-
Knee

177

variates. For example, baseline pain and baseline depression, which are
β

very important confounders, were both included into the regression

<0.001
<0.001

<0.001

models. Thus, their “potential” to confound the correlation results was

0.398

0.094
0.058

0.233
0.026

eliminated by adjusting the parameters of the equation through the

p

repetitive recurrent modeling (to minimize the error residuals) of the

linear regression process (Backhaus et al., 2016). In other words,
−1.69
5.30
6.37

0.85
4.42

1.92

1.20
2.26

multiple regression determines the adjusted, partial correlations, as if

t
Chronic pain

all 6 cohorts had the same levels of baseline pain and baseline de-
Low back

pression on the basis of the available empiric data of all 6 cohorts.

−0.145
0.419
0.486

0.074
0.330

0.152

0.104
0.201

A limitation of our study is the relatively short observation period of

134
β

6 months. However, if pain is to be treated indirectly by relieving de-

pression and vice versa, effects achieved over a relatively short period
<0.001
<0.001

<0.001

<0.001
<0.001

will motivate patients to adhere to their treatment and are therefore of

0.331

0.865
0.004

particular relevance for clinical practice. A second limitation is the fact

p

that the construct of the full range of depressive symptoms is not ex-
−0.17

plicitly covered by the SF-36. However, the various criteria and other
4.81
5.67

0.98
3.96

2.94

3.66
4.17

quantitative depression parameters correlated highly with the SF-36

t
Fibromyalgia

mental health scale. This may be due to the high co-prevalence of the
Soft tissue

−0.015

not measured symptoms of depression to those that are measured.

0.398
0.451

0.088
0.330

0.247

0.265
0.383
125
β

5. Conclusions
<0.001
0.003

0.446
0.024

0.136
0.033

0.023
0.001

Moderate associations between the degrees of change in pain on the

one hand and depression on the other were demonstrated over an ob-
p

servation time of 6 months across 5 of 6 different chronic pain condi-

−0.77

−1.51

tions, in which relatively high pain levels persisted after conservative

3.13
3.92

2.31

2.18

2.32
3.34

therapy. The associations between pain change and depression change

t
Lower limb

tended to be stronger if pain and depression were worse at baseline.

Lipedema

−0.094

−0.183

These two observed dose-response relationships are indicative of a

0.359
0.465

0.289

0.274

0.275
0.385

certain degree of causal interference. Our results suggest that relieving

68
β

pain may lead to the relief of depression and vice versa. Our findings
should be further substantiated by specific intervention studies.
<0.001

<0.001
0.007
0.001

0.135

0.427
0.337

0.003
p

Ethics approval and consent to participate and for publication

−0.78

The study was approved by the ethics committee of Aarau, Canton

2.74
3.54

1.50
3.93

0.96

3.03
3.67

Aargau, Switzerland (EK AG 2008/026) and written informed consent

Osteoarthritis

was obtained from all study participants.

Shoulder

−0.067
0.224
0.297

0.122
0.334

0.089

0.241
0.292
153

Consent for publication

β
Regression model results.

Δ Pain – Δ Depression

Δ Pain – B Depression

Δ Depression – B Pain

B Pain – B Depression

Not applicable. Data do not contain any individual persons’ in-

formation.
Patients (n)
Parameter

Availability of data and material

Diagnosis

bivariate

bivariate

bivariate

bivariate
adjusted

adjusted

adjusted

adjusted
Region
Table 3

All data and material are freely available. Please contact the cor-
responding author for data requests.

514
F. Angst, et al.
Funding
There are no sources of funding to declare.
Authors’ contributions
FA planned the study, collected, analyzed and interpreted the data
and wrote the draft study report. TB carried out the analysis of etio-
pathogenetic mechanisms and contributed to the analysis and inter-
pretation of the data. SL helped in study planning, collected the data,
and contributed to the analysis and interpretation of the data. SW was
responsible for the patients of the lipedema study and helped to inter-
pret the data and to finalize the study report. BR was responsible for the
patients of the shoulder arthroplasty study and helped to interpret the
data and to finalize the study report. PS provided the resources for
carrying out the study and helped to interpret the data and to finalize
the study report. MG supervised all the musculoskeletal data inter-
pretations and helped in planning the study, in interpreting the data
and in finalizing the study report. JA oversaw all the psychiatric data
and their interpretation, helped in planning the study, in interpreting
the data and in finalizing the study report.
Declaration of Competing Interest
There are no conflicts of interests or competing interests to declare.
Acknowledgments
This study was supported by the Zurzach Rehabilitation Foundation
SPA, Bad Zurzach, Switzerland. We thank all patients for their volun-
tary participation in the study. We further thank Elizabeth Kyrke for the
linguistic editing of the text.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jad.2020.05.044.
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