Juta Zinkevičiūtė^1*, Gabrielius Tomas Zdanys¹, Robertas Strumila², Dalia Miltinienė³, Edgaras Dlugauskas ^2,

¹Faculty of Medicine, Vilnius University, M. K. Čiurlionio 21, 03101 Vilnius, Lithuania

²Clinic of Psychiatry, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Geležinio Vilko 29A, LT- 01112, Vilnius, Lithuania

³ Clinic of Rheumatology, Orthopaedics Traumatology and Reconstructive Surgery, Centre of Rheumatology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Santariškių str. 2, LT – 08661, Vilnius, Lithuania

Abstract

Introduction. Previous studies suggest that one of the possible reasons of depression is the autoimmune inflammation that causes increased interleukins and cytokines levels and thus affects the mood and behavior.

Aims. To compare the depression and anxiety symptoms among the patients with chronic systemic diseases (inflammatory bowel diseases and rheumatic diseases) receiving biological therapy and patients receiving different medical treatment.

Methods. Quantitative cross-sectional study design was used. Instruments: Ulcerative colitis activity index, Crohn’s disease activity index, the Hospital anxiety and depression scale (HADS) and the Visual Analogue Scale (VAS). Patients diagnosed with active inflammatory bowel disease or rheumatic disease and not using antidepressants were included into study. Participants were divided into an experimental group (receiving biological therapy treatments) and a control group (receiving treatments as usual). 

Results. 132 patients’ data were analyzed. The disease activity index was not significantly different between the experimental group and the control group (9,42 vs 11,45, p>0,05). The mean scores of the Hospital anxiety and depression scale were significantly different between the both groups (7,96 vs 13,68, p< .001), which indicates less depression symptoms in the experimental group. The mean anxiety and depression subscales scores were also significantly lower in the experimental group (anxiety subscale – 5,46 vs 9,39, p< 0.001; depression subscale – 2,44 vs 3,91, p=0,001).

Conclusions. Participants treated with biological therapy experienced fewer depression symptoms than participants showing similar disease activity but receiving treatment as usual.

Keywords: Tumor necrosis factor – α inhibitor, IL-6 inhibitor, autoimmune depression, inflammatory bowel disease, rheumatic disease.

https://doi.org/10.53453/ms.2021.06.13

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

126

Medical Sciences 2021 Vol. 9 (5), p. 126-142, https://doi.org/10.53453/ms.2021.06.13

Reduction of depressive symptoms among patients with

inflammatory bowel disease and rheumatic diseases treated with

biological therapy: a cross sectional study

Juta Zinkevičiūtė

1*

, Gabrielius Tomas Zdanys

1

, Robertas Strumila

2

, Dalia Miltinienė

3

, Edgaras

Dlugauskas

2,

1

Faculty of Medicine, Vilnius University, M. K. Čiurlionio 21, 03101 Vilnius, Lithuania

2

Clinic of Psychiatry, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Geležinio Vilko

29A, LT- 01112, Vilnius, Lithuania

3

Clinic of Rheumatology, Orthopaedics Traumatology and Reconstructive Surgery, Centre of Rheumatology,

Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Santariškių str. 2, LT – 08661, Vilnius,

Lithuania

Abstract

Introduction. Previous studies suggest that one of the possible reasons of depression is the autoimmune

inflammation that causes increased interleukins and cytokines levels and thus affects the mood and behavior.

Aims. To compare the depression and anxiety symptoms among the patients with chronic systemic diseases

(inflammatory bowel diseases and rheumatic diseases) receiving biological therapy and patients receiving

different medical treatment.

Methods. Quantitative cross-sectional study design was used. Instruments: Ulcerative colitis activity index,

Crohn's disease activity index, the Hospital anxiety and depression scale (HADS) and the Visual Analogue Scale

(VAS). Patients diagnosed with active inflammatory bowel disease or rheumatic disease and not using

antidepressants were included into study. Participants were divided into an experimental group (receiving

biological therapy treatments) and a control group (receiving treatments as usual).

Results. 132 patients' data were analyzed. The disease activity index was not significantly different between

the experimental group and the control group (9,42 vs 11,45, p>0,05). The mean scores of the Hospital anxiety

and depression scale were significantly different between the both groups (7,96 vs 13,68, p< .001), which indicates

less depression symptoms in the experimental group. The mean anxiety and depression subscales scores were also

significantly lower in the experimental group (anxiety subscale - 5,46 vs 9,39, p< 0.001; depression subscale -

2,44 vs 3,91, p=0,001).

Conclusions. Participants treated with biological therapy experienced fewer depression symptoms than

participants showing similar disease activity but receiving treatment as usual.

Keywords: Tumor necrosis factor - α inhibitor, IL-6 inhibitor, autoimmune depression, inflammatory bowel

disease, rheumatic disease.

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

127

3. Introduction

Major depressive disorder (MDD) is a common

mental disorder affecting 3 million people

worldwide. Depression not only causes the burden

of illness, but also has the high suicidal rates of

almost 800 000 sufferers every year. By a

considerable part of the medical society and the

public MDD is perceived as the whole of the

changes in the mood, emotions, cognitive functions

and motivation. One of the most important MDD's

etiopathogenetic theories is claimed to be the

monoamines theory. (1) However, many more less

known explanations for the development of MDD

are described in various medical articles. Not only

psychological factors, but also the everyday life

stress, negative and shocking life events and the

changes in the circadian rhythm function are

claimed to contribute to the development of MDD

(2,3). In spite of the possibility of the different

depression etiopathogenesis among patients, the

recommended treatment for major depression

consists of cognitive behavioral therapy (CBT) or

interpersonal therapy (IPT) and antidepressant

medication. (4) This treatment does not necessarily

work for every patient. Thus, in the past decade the

question of the unknown depression pathogenetic

ways and the other MDD treatment approaches as

well as the individualized treatment possibilities

emerged. The evidence of the associations between

depression and inflammation began to build up and

the theory of the individual anti- inflammatory

treatment arose. (5) This theory has developed when

the link between depression symptoms and the

autoimmune inflammatory systemic diseases with

the stormy reaction of cytokines was noted. (6) Such

cytokines as tumor necrosis factor-α (TNF- α),

interleukin 1 (IL-1) and interleukin 6 (IL-6) are the

warning molecules that control the inflammatory

response during the invasion of the pathogens. They

are important not only in the gastrointestinal tract

but also in the central nervous system (CNS). The

acute inflammation instigates the increase of the

cytokines and thus the brain is protected. However,

during the chronic inflammation, the microglia

produces excessive cytokines which disturb the

circulation of the neurotransmitters in the brain and

the integrity of the neurons. (7) The autoimmune

inflammatory diseases with the increased

concentrations of the bodily cytokines (such as

rheumatic diseases, allergies, multiple sclerosis and

inflammatory bowel diseases) are thought to be

connected to the high occurrence of the

neuropsychiatric symptoms. (6) HIV patients with

the increased concentration of the cytokines in the

body often experience such neuropsychiatric

complications as depression and fatigue. (8)

Furthermore, the increased concentration of the

cytokines and the inflammatory phase proteins was

observed in the patients with treatment resistant

depression. (9)

This study investigates the difference of the

major depression symptoms among the

inflammatory bowel disease (Chron's disease and

ulcerative colitis) and rheumatic diseases patients

(rheumatoid arthritis, ankylosing spondylitis and

psoriatic arthritis) receiving biological therapy

medication and just as active diseased patients with

no biological therapy and is claimed to contribute to

the evidence of the depression and inflammation

association.

The hypothesis of this study is that the patients

treated with biological therapy experience less

depressive and anxiety symptoms because of the

biological therapy positive effects for such putative

depression pathogenetic factors as tumor necrosis

factor alpha.

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

128

4. Methods

4.1 Participants

One part of the study population consisted of

inpatients of the Department of Hepatology and

Gastroenterology of the Center of Vilnius

University Hospital Santaros Clinics diagnosed with

inflammatory bowel disease and the other part of

population was comprised of outpatients with

inflammatory bowel disease (Crohn's disease

or/with ulcerative colitis). Criteria for inclusion of

patients with inflammatory bowel disease:

• Confirmed diagnosis of Chron’s

disease or ulcerative colitis.

• At the time of inclusion, patient

received uninterrupted treatment of

biological therapy (TNF-α inhibitors) or

non-biological treatment (non-steroidal

inflammatory drugs, glucocorticoids

and/or immunomodulators) for at least 12

weeks.

• Patient did not use antidepressants

at the time of inclusion.

• Patient is 18-73 years old.

• Patient is fluent enough in

Lithuanian, therefore understands the

concept of the research.

Afterwards, the research was centered around

the patients in the Center of Rheumatology of

Vilnius University Santaros Clinics. During the

research, inpatients and outpatients with

rheumatological diseases (rheumatoid arthritis,

psoriatic arthritis or ankylosing spondylitis) were

investigated. Criteria of the inclusion of the patients

with rheumatological conditions:

• Confirmed diagnosis of

rheumatoid arthritis or psoriatic arthritis or

ankylosing spondylitis.

• At the time of inclusion, patients

received uninterrupted treatment of

biological therapy (TNF-α inhibitors or IL-

6 inhibitors) or non-biological treatment

(non-steroidal inflammatory drugs,

glucocorticoids and/or

immunomodulators) for at least 12 weeks.

• Patient is 18-65 years old.

• Patient is fluent enough in

Lithuanian, therefore understands the

concept of the research.

The data was collected through an interview and

by filling the questionnaires. The permission of the

research in the Department of Hepatology and

Gastroenterology of the Center of Vilnius

University Hospital Santara Clinics was granted on

2017 October 25

th

by Vilnius University Ethics

committee Clinic’s Nr. 17CR-16278. The

permission of the research in the Center of

Rheumatology of Vilnius University Santaros

Clinics was granted on 2019 November 7

th

by

Vilnius University Santaro Clinic’s Ethics

committee Nr. 1R-3774.

The quantitative section study model was chosen

and data was collected from 2017 September to 2019

March and also from 2019 October to 2021 March.

The research did not take place during SARS-CoV2-

19 lockdown during the pandemics from 2020

March 16

th

till June 14

th

and from 2020 November

4

th

until the end of January. The investigation was

resumed during the internship and data was

collected in February and March of 2021st.

Instruments used to assess the subjects with the

inflammatory bowel disease were ulcerative colitis

activity index, Chron’s disease activity index and

Hospital Anxiety and Depression Scale (HADS).

Instruments used to investigate patients with

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

129

rheumatic conditions were Visual disease’s activity

scale and HADS. Inpatients were interviewed in the

hospital, outpatients were interviewed during the

outpatient visit.

The subjects were divided according to their

treatment. The study group was comprised of the

patients diagnosed with inflammatory bowel disease

or rheumatic disease and receiving biological

therapy treatment (TNF-α inhibitors or IL-6

inhibitors). The control group consisted of patients

diagnosed with inflammatory bowel disease or

rheumatic disease and receiving non-steroidal

inflammatory drugs, glucocorticoids and/or

immunomodulators.

In total, 132 patients were analyzed (59,8% -

women, 40,2% - men). 88 patients had the diagnosis

of the inflammatory bowel diseases (57,9% -

women, 42,1 % - men) and 44 patients were

diagnosed with the rheumatological disease (63,6%

- women, 36,4% - men). The age varied from 18 to

73 years old. Among patients with the inflammatory

bowel disease, 33% comprised Chron’s disease and

67% ulcerative colitis. Among patients with

rheumatological conditions, 56,8% comprised

rheumatoid arthritis, 13,6% psoriatic arthritis and

29,6% ankylosing spondylitis. The mean duration of

the inflammatory bowel disease was 8,5 years (from

1 to 33 years) and the mean duration of the

rheumatological disease was 10,8 years (from 1 to

41 years). The mean duration of the disease in

general population was 9,3 years. 66 of the patients

(50 %) received biological therapy and 66 of the

patients (50%) received non-biological therapy. 44

patients (50%) diagnosed with inflammatory bowel

disease received biological therapy and 44 (50%) of

inflammatory bowel disease patients were treated

with non-biological therapy. 22 patients (50%) of

the rheumatic diseases group received biological

treatment and 22 (50%) of rheumatic disease

patients were treated with the non-biological

medication.

Table 1. The characteristics of the inflammatory bowel disease population

Study group

Control group

Sex

Male

Female

23 (52,27%)

21 (47,73%)

14 (31,82%)

30 (68,18%)

Age

39,00 ± 12,87

32,09 ± 8,99

Ulcerative colitis

22 (50%)

37 (84,09%)

Chron‘s disease

22 (50%)

7 (16,01%)

Mean duration of inflammatory

bowel disease

9,75 ± 5,94

7,30 ± 5,95

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

130

Table 2. The characteristics of the rheumatic disease population

Study group

Control group

Sex

Male

Female

7 (31,82%)

15 (68,18%)

9 (40,91%)

13 (59,09%)

Age

51,55 ± 8,60

49,36 ± 12,37

Rheumatoid arthritis

13 (59,09%)

12 (54,55%)

Ankylosing arthritis

7 (31,82%)

6 (27,27%)

Psoriatic arthritis

2 (9,09%)

4 (18,18%)

Mean duration of rheumatological

disease

14,59 ± 10,96

7,05 ± 9,99

Table 3. The characteristics of general study population

Study group

Control group

Sex

Male

Female

30 (45,45%)

36 (54,55%)

23 (34,85%)

43 (65,15%)

Age

43,18 ± 13,00

37,85 ± 13,05

Inflammatory bowel disease

44 (66,67%)

44 (66,67%)

Rheumatological disease

22 (33,33%)

22 (33,33%)

Mean duration of disease

11,36 ± 8,21

7,21 ± 7,46

4.2 Procedure

Patients were introduced with the concept of the

research concept and have given the written consent.

Outpatients were interviewed and filled the

questionnaires during the outpatient visit. Inpatients

were interviewed by the researchers and filled the

questionnaire during the ward rounds. The patients

with diagnosis of the the inflammatory bowel

disease filled HAD scale and inflammatory bowel

disease activity questionnaires. The patients

diagnosed with the rheumatic disease received HAD

scale and VAS. The participation was voluntary and

the patients did not receive any rewards.

4.3 Evaluations according to HADS, Chron’s

Disease Activity Index and Simple Clinical

Colitis Disease Activity Index

4.4 The Hospital Anxiety and Depression

Scale (HADS)

The Hospital Anxiety and Depression Scale

(HADS) was used to evaluate the widespread of the

depressive and anxiety symptoms among the

subjects of the research. This 14 mental health

concerning questions questionnaire was created by

A.S. Zigmund and R.P. Snaith in 1983. Currently, it

is validated and widely used in the whole world to

evaluate the depressive and anxiety symptoms in

patients. One of the major advantages of the HAD

scale is that it is validated among the different ethnic

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

131

groups. What is more, it is convenient to use during

the interview with the patient. HAD scale was

translated in Lithuanian in 1991, however its’ use

has not been validated yet. However, it is widely

used in the clinical practice of Lithuanian medical

doctors. (10)

Seven HADS questions evaluate the depressive

symptoms and the other seven questions evaluate the

anxiety symptoms. In the each of the questions the

patient must choose one of the four statements that

correctly describes their mental wellness during the

past two weeks (0 – no sign of symptom; 3 – strong

adverse effect of the symptom). The depressive and

anxiety subscales are evaluated independently, and

the results may vary between 0 and 21. The total

score is categorized into the different groups: 0-7 –

no signs of the depressive or anxiety symptoms; 8-

10 – borderline abnormal; > 11 – likely depression

or anxiety.

(11)

4.6 Harvey-Bradshaw questionnaire

This questionnaire is a simplified version of

Chron’s disease activity index (CDAI). It was

designed in 1980 to evaluate the activity and severity

of the disease, so it only measures clinical

parameters. Harvey-Bradshaw questionnaire

consists of five questions related to the general well-

being, pain in the abdominal area, enlarged stomach

volume or sensitivity, the frequency of the liquid

stools per day and the presence of any other

complications. For every statement, patients had to

choose the best answer describing his/her well-being

during the past several months. The final score of

less than 5 indicated remission; 5-7 – mild disease;

8-16 moderate disease and more than 16 - severe

disease. (12)

4.7 Simple Clinical Colitis Disease Activity

Index

This index was created in 1988 to evaluate the

activity of ulcerative colitis. This questionnaire is

composed of six questions concerning the bowel

frequency at day/night, the urgency of defecation,

the blood in stool, the general health and the non-

gastrointestinal manifestations. For every question,

patient had to choose the best answer describing

his/her well-being during the past several months.

The final score varied from 0, meaning no sign of

disease activity, to 21, indicating utmost activity of

the disease. (10)

4.8 The evaluation of the activity of rheumatic

diseases

To evaluate the activity of the various rheumatic

diseases, such instruments as DAS28 (Disease

activity score at 28 joints), BASLAI (Bath

Ankylosing Spondylitis), HAQ-DI (Health

Assessment Questionnaire Disability Index) and the

Visual analog scale (VAS, angl. Visual analog scale)

are used in the clinical practice. The activity of the

rheumatoid arthritis is assessed using DAS28, VAS

and HAQ-DI and the activity of the ankylosing

spondylitis is assessed using BASLAI and VAS.

The evaluation of the activity of psoriatic arthritis is

conducted using VAS. In this study, the rheumatic

disease activity of the rheumatic patients was

assessed using VAS while VAS evaluates not only

the disease activity of psoriatic arthritis, but also the

disease activity of rheumatoid arthritis and

ankylosing spondylitis. VAS is a validated and

subjective measure for the acute or chronic pain.

Currently there is a wide selection of VAS scales

ranging from 10-centimeter line to faces, indicating

certain emotion, latter often being used with

children. During this research pain was recorded by

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

132

handwritten mark on a 10-centimeter line, 0

meaning no pain and 10 – the worst pain. (13)

4.9 Statistics

Statistical analysis was conducted using IBM

SPSS Statistics 23.0. The distribution of variables

was analyzed using Kolmogorov-Smirnov test as the

take was more than 50 patients. A two-sample T test

was used to analyze normally distributed means and

Mann-Whitney U test was performed to evaluate the

non-normally distributed means. The chosen p value

of significance was less than 0,05. For the normally

distributed means, the effect size was evaluated

using Cohen d value. The effect size of the non-

normally distributed means was assessed using the

effect size calculator for non-parametric tests.

The subjects were divided into two groups

according to their treatment and described using

CHI test.

5. Results

5.1 Comparisons

This study compared the symptoms of

depression both in the general study population,

which consisted of inflammatory bowel disease and

rheumatic diseases patients, and in the populations

of different disease groups. In the general study

population, the study group included the patients

with inflammatory bowel disease and rheumatic

diseases receiving biological therapy. The control

group was formed of the patients with inflammatory

bowel disease and rheumatic diseases who did not

receive biological medication. There was no

significant difference in the disease activity between

the study and the control groups (Table 4). In the

clinical practice, different scales are used to assess

the activity of the inflammatory bowel disease and

the rheumatic diseases. For this reason, to unify the

disease activity estimate of the general study

population, the inflammatory bowel disease activity

scale was divided into quartiles (1 - very low activity

disease, 2 - low activity disease, 3 - moderate

activity disease, 4 - high activity disease) and the

range of intestinal inflammatory bowel disease

activity estimate was assigned to each quartile. The

estimate of the rheumatic diseases' activity was

converted to the estimate of the newly developed

general disease activity scale. Comparing the means

of the overall HADS score, the difference between

both groups was statistically significant (Table 4).

Differences between the HADS depression subscale

and the anxiety subscale were also statistically

significant (Table 4).

Table 4. Estimates of the disease activity and HADS score in the study and control groups of the general study

population.

Study group

Control group

p value

Disease activity

9,42 ± 3,93

11,45 ± 6,12

0,05

HAD scale

7,96 ± 5,68

13,68 ± 6,72

< .001(n

2

= 0,17; d

cohen

=

0,90)

HADS depression subscale

2,44 ± 2,50

3,91 ± 2,62

0,001 (n

2

= 0,08; d

cohen

=

0,61)

HADS anxiety subscale

5,46 ± 3,89

9,39 ± 4,59

< .001 (n

2

=0,18, d

cohen

=

0,93)

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

133

Analyzing the population of the inflammatory

bowel disease patients alone, we also compared the

incidence of the depressive symptoms between

patients treated with biologic therapy and those

treated with non-biologic therapy drugs. Disease

activity did not differ between the two groups (Table

5). Comparing the means of the overall HADS score

and the means of the HADS depression subscale and

anxiety subscale, the difference between both

groups was also statistically significant (Table 5).

Table 5. Estimates of the disease activity and HADS in the study and control group in the inflammatory bowel

disease population.

Study group

Control group

p value

Disease activity

8,00 ± 2,70

10,46 ± 6,92

0,18

HAD scale

8,30 ± 6,08

12,91 ± 6,21

0,001 (n

2

= 0,13; d

cohen

=

0,78)

HADS depression subscale

2,61 ± 2,72

3,93 ± 2,52

0,01 (n

2

- 0,07; d

cohen

d

cohen

= 0,57)

HADS anxiety subscale

5,66 ± 3,98

8,98 ± 4,25

< .001 (n

2

= 0,15; d

cohen

=

0,85)

Analyzing the study population of the patients

with rheumatic diseases alone, patients were also

divided into the biological therapy group and the

group of patients treated with non-biological

therapy. There was no difference in the disease

activity between the two groups (Table 6).

Comparing the means of the total HADS score, the

difference between both groups was statistically

significant (Table 6). Comparing the means of the

HADS anxiety subscale, the difference was not

statistically significant, but comparing the means of

the depression subscale, the difference between the

two groups was statistically significant (Table 6).

Table 6. Estimates of the disease activity and HADS in the study and control group in the rheumatic disease

population.

Study group

Control group

p value

Disease activity

61,82 ± 22,33

67,86 ± 16,75

0,33

HAD scale

7,27 ± 4,83

15,23 ± 7,56

0,04 (d

cohen

= 0,13)

HADS depression subscale

2,09 ± 2,00

3,86 ± 2,88

0,03 (n

2

= 0,10 d d

cohen

=

0,66)

HADS anxiety subscale

5,05 ± 3,76

10,23 ± 5,23

0,31

A more detailed analysis of the scales is provided in Tables 7-12.

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

134

Table 7. Estimates of the HADS depression subscale of the study and control groups of the general study

population.

Study group

Control group

p value

1. "I feel cheerful"

0,49 ± 0,56

0,85 ± 0,59

0,001 (n

2

= 0,061; d

cohen

= 0,512)

2. "I still enjoy the things

I used to enjoy"

0,43 ± 0,64

0,68 ± 0,77

0,05

3. "I look forward with

enjoyment to things"

0,28 ± 0,48

0,52 ± 0,71

0,06

4. "I feel as if I am slowed

down"

0,69 ± 0,83

0,97 ± 0,80

0,03 (n

2

= 0,03, d

cohen

=

0,33)

5. "I can laugh and see the

funny side of things"

0,03 ± 0,17

0,21 ± 0,48

0,005 (n

2

= 0,01, d

cohen

=

0,23)

6. "I can enjoy a good

book or radio or TV

program"

0,34 ± 0,54

0,42 ± 0,56

0,32

7. "I have lost interest in

my appearance"

0,35 ± 0,69

0,70 ± 0,86

0,01 (n

2

= 0,03; d

cohen

=

0,339)

Table 8. Estimates of the HADS anxiety subscale in the study and control groups of the general study

population.

Study group

Control group

p value

1. "I feel tense or 'wound

up' "

1,00 ± 0,73

1,49 ± 0,88

0,01 (n

2

= 0,06; d

cohen

=

0,5)

2. "I feel restless as I have

to be on the move"

0,75 ± 0,77

1,00 ± 0,74

0,04 (n

2

= 0,02, d

cohen

=

0,3)

3. "I can sit at ease and

feel relaxed"

0,72 ± 0,70

1,32 ± 0,73

< .001 (n

2

= 0,18; d

cohen

=

0,73)

4. "I get sort of frightened

feeling as if something

awful is about to happen"

0,75 ± 0,79

1,38 ± 0,97

< .001 (n

2

= 0,09, d

cohen

=

0,61)

5. "I get sudden feelings

of panic"

0,65 ± 0,65

1,12 ± 0,85

0,01 (n

2

= 0,06; d

cohen

=

0,52)

6. "I get a sort of

frigthened feeling like

'butterflies' in the

stomach"

0,55 ± 0,81

0,82 ± 0,84

0,03 (n

2

= 0,02; d

cohen

=

0,31)

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

135

7. "Worrying thoughts go

through my mind"

0,75 ± 0,79

1,20 ± 1,01

0,01 (n

2

= 0,04, d

cohen

=

0,39)

Table 9. Estimates of the HADS depression subscale of the study and control group in the inflammatory bowel

disease population.

Study group

Control group

p value

1. "I feel cheerful"

0,48 ± 0,59

0,82 ± 0,54

0,004 (n

2

= 0,07, d

cohen

=

0,56)

2. "I still enjoy the things

I used to enjoy"

0,41 ± 0,62

0,59 ± 0,69

0,19

3. "I look forward with

enjoyment to things"

0,30 ± 0,46

0,50 ± 0,70

0,23

4. "I feel as if I am slowed

down"

0,73 ± 0,90

0,80 ± 0,77

0,44

5. "I can laugh and see the

funny side of things"

0,00 ± 0,00

0,25 ± 0,53

0,002 (n

2

= 0,03; d

cohen

=0,36)

6. "I can enjoy a good

book or radio or TV

program"

0,41 ± 0,58

0,41 ± 0,58

0,87

7. "I have lost interest in

my appearance"

0,32 ± 0,71

0,57 ± 0,82

0,10

Table 10. Estimates of the HADS anxiety subscale of the study and control group in the inflammatory bowel

disease population.

Study group

Control group

p value

1. "I feel tense or 'wound

up' "

0,96 ± 0,79

1,50 ± 0,90

0,01 (n

2

= 0,07, d

cohen

=

0,57)

2. "I feel restless as I have

to be on the move"

0,91 ± 0,80

1,05 ± 0,71

0,29

3. "I can sit at ease and

feel relaxed"

0,70 ± 0,70

1,34 ± 0,75

< .001 (n

2

= 0,14; d

cohen

=

0,82)

4. "I get sort of frightened

feeling as if something

awful is about to happen"

0,70 ± 0,77

1,30 ± 1,00

0,004 (n

2

= 0,08; d

cohen

=

0,60)

5. "I get sudden feelings

of panic"

0,68 ± 0,71

1,05 ± 0,86

0,03 (n

2

= 0,04; d

cohen

=

0,41)

6. "I get a sort of

frigthened feeling like

0,50 ± 0,73

0,68 ± 0,77

0,20

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

136

'butterflies' in the

stomach"

7. "Worrying thoughts go

through my mind"

0,82 ± 0,84

1,11 ± 0,99

0,17

Table 11. Estimates of the HADS depression subscale of the study and control group in the rheumatic disease

population.

Study group

Control group

p value

1. "I feel cheerful"

0,52 ± 0,51

0,91 ± 0,68

0,06

2. "I still enjoy the things

I used to enjoy"

0,48 ± 0,68

0,86 ± 0,88

0,13

3. "I look forward with

enjoyment to things"

0,24 ± 0,54

0,55 ± 0,74

0,12

4. "I feel as if I am slowed

down"

0,62 ± 0,67

1,32 ± 0, 78

0,004 (n

2

= 0,12; d

cohen

=

0,75)

5. "I can laugh and see the

funny side of things"

0,10 ± 0,30

0,14 ± 0,35

0,68

6. "I can enjoy a good

book or radio or TV

program"

0,19 ± 0,40

0,46 ± 0,51

0,068

7. "I have lost interest in

my appearance"

0,43 ± 0,68

0,96 ± 0,90

0,04 (n

2

= 0,05; d

cohen

=0,46)

Table 12. Estimates of the HADS anxiety subscale of the study and control group in the rheumatic disease

population.

Study group

Control group

p value

1. "I feel tense or 'wound

up' "

1,05 ± 0,59

1,46 ± 0,86

0,11

2. "I feel restless as I have

to be on the move"

0,43 ± 0,60

0,91 ± 0,81

0,04 (n

2

= 0,06; d

cohen

=

0,49)

3. "I can sit at ease and

feel relaxed"

0,76 ± 0,70

1,27 ± 0,70

0,02 (n

2

= 0,07; d

cohen

=

0,55)

4. "I get sort of frightened

feeling as if something

awful is about to happen"

0,86 ± 0,85

1,55 ± 0,91

0,02 (n

2

= 0,08; d

cohen

=

0,59)

5. "I get sudden feelings

of panic"

0,57 ± 0,51

1,27 ± 0,83

0,003 (n

2

= 0,12; d

cohen

=

0,74)

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

137

6. "I get a sort of

frigthened feeling like

'butterflies' in the

stomach"

0,67±0,97

1,09 ± 0,92

0,07

7. "Worrying thoughts go

through my mind"

0,62 ± 0,67

1,36 ± 1,05

0,02 (n

2

= 0,09; d

cohen

=

0,61)

Estimates of the HADS anxiety subscale of the study and control group in the rheumatic disease population.

5.2 Literature

The research of the literature was conducted

using the strategy of the Center of Evidence based

medicine in Pubmed.

5.3 Reliability

The results of the Simple clinical colitis activity

index, Harvey-Bradshaw questionnaire and HADS

and the results of the HADS depression subscale and

anxiety subscale were not normally distributed

according to the Kolmogorov-Smirnov test

(p<0,05).

The internal compatibility of the scales was

evaluated using Cronbach α. The total internal

compatibility of the HADS was satisfactory

(Cronbach α = 0,88). The internal compatibility of

the HADS depression and anxiety subscales

individually was also very high (Cronbach α = 0,75

and 0,85

5.4 Summary of the results

This study is one of the researches comparing the

onset of the depressive symptoms among patients

with chronic diseases treated with biologic therapy

and those with the same disease but treated with

other medication. The findings of this study

demonstrate a statistically significant difference in

the incidence of the depressive symptoms between

the study and control group, both in the overall study

population and in the populations of inflammatory

bowel disease and rheumatic disease groups alone.

The total score of the HAD scale and the total scores

of the depression and anxiety subscales were

statistically significantly higher among non-

biologically treated patients in the overall study

population and in the inflammatory bowel disease

population. In the rheumatic patient population, a

statistically significant differences of the overall

HAD scale score and the overall depression subscale

score were observed between the study and control

groups. In the general study population and in the

inflammatory bowel disease population, depressive

symptoms were best described by such statements as

"I feel cheerful" and "I can laugh and see the funny

side of things". In the rheumatic disease population,

the depressive symptoms were best described by the

statements "I feel as if I am slowed down" and "I

have lost interest in my appearance". In both general

study population and inflammatory bowel and

rheumatic disease population, anxiety symptoms

were best described by such statements as "I can sit

at ease and feel relaxed", "I get sort of frightened

feeling as if something awful is about to happen" and

"I get sudden feelings of panic".

6. Discussion

6.1 Neuroinflammation

Despite the advance in the treatment of

depression, the traditional treatment of this disease

is not effective for the third of all the patients. In this

paper, the traditional treatment of the depression is

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

138

considered to consist of the antidepressants and

cognitive behavioral therapy or the interpersonal

therapy. As it is more known how this therapy

affects the symptoms of the depression and not the

particular elements of the etiopathogenesis, not all

the patients benefit from it. Thus, the studies of the

undiscovered etiopathogenetic ways of the

depression is the basis for establishing the new and

more individualized depression treatment methods.

In the last decade one of the new ways of the

development of the depression linked to the

inflammation and the kynurenine pathway arose.

(14) It is claimed that so called neuroinflammation

might cause the treatment resistant major

depression. Such autoimmune systemic

inflammatory diseases as rheumatoid arthritis,

Chron's disease or multiple sclerosis are thought to

be the source of the inflammatory markers important

in the pathogenesis of major depression. (15)

The results of this study correspond to latest

research on the inflammatory origin of the

depression. The depression in thought to be linked

to the chronic low activity inflammation, the

activation of the cellular immunity and the

activation of the responsive anti-inflammatory

reflective system. Such pro-inflammatory factors as

the dysregulation of the intestinal microbiota,

obesity and smoking are thought to induce the

inflammation and the depression as well. (16) The

attempts to treat depression with anti-inflammatory

medication also contributes to the evidence of the

relation between depression and inflammation. It is

scientifically proven that that the anti-inflammatory

medication and antidepressants have a better effect

on depressive symptoms in patients with chronic

inflammatory diseases than anti-depressive

treatment alone. (17) The suppression of the

cytokines and other inflammatory pathways might

become the effective way to treat the resistant

depression or improve the depressive and anxiety

symptoms in the chronic inflammatory disease

patients. Moreover, the highly pronounced

depressive and anxiety symptoms in the chronic

inflammatory disease patients might become the

indication to get biological treatment with TNF-

alpha inhibitors or IL-6 inhibitors.

There is an explanation why the chronic

systemic inflammation could cause depression. The

most important inflammatory factors cytokines are

able to cross the blood-brain barrier and enter the

central nervous system. There is evidence, that TNF-

alpha amounts increase in the body of patients with

major depressive disorder as well. The TNF-alpha

and other pro-inflammatory factors upregulate the

kynurenine (KYN) pathway in the human body and

thus contributes to the development of the

depression. Normally, KYN pathway regulates

tryptophan (TRY) metabolism and the serotonergic

system. TRY is metabolized to KYN by

indoleamine-2,3-dioxygenase (IDO) 1, IDO-like

enzyme, IDO 2, and tryptophan-2,3-dioxygenase

(TDO). Then KYN is metabolized to kynurenic acid

and an N-methyl-D-aspartate receptor antagonist.

TRY also can be metabolized to serotonin or 5-

hydroxytryptamine (5-HT). Nevertheless, the pro-

inflammatory cytokines increase the expression of

IDO and activates the different KYN metabolic

pathway, in which KYN is converted to the

neurotoxic quinolinic acid (QA) which contributes

to the neuroinflammation and the reduced

neuroplasticity. Furthermore, the increased

expression of IDO shifts TRY metabolism from

serotonin synthesis to KYN formation and thus the

serotonergic system decompensates. So, the

dysregulated KYN pathways contributes to the

development of depressive and anxiety behavior in

two ways – by dysregulating the serotonergic

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

139

systems and by neurotoxicity to NMDA receptors.

(18)

7.2 The link between depression symptoms

and inflammatory bowel disease

Chron's disease and ulcerative colitis are

inflammatory gastrointestinal tract disorders that

manifest with abdominal pain, diarrhea and the

blood in the stool. About 30% of inflammatory

bowel disease patients suffer from such mental

disorders as anxiety and depression. This rate was

calculated using patient self-assessment tools,

therefore the concept of the anxiety and depression

among inflammatory bowel disease patients should

not be confused with the diagnosis of the generalized

anxiety disorder or major depression. (19)

It is thought that the brain-gut axis disorder is

responsible for the development of both the psychic

abnormalities and the inflammatory bowel diseases.

According to the studies that analyze the links

between mental state and the inflammatory bowel

disease, the mental disorders are related to the

unfavorable outcomes of the inflammatory bowel

disease and the activity of the inflammation is bound

to de novo development of the psychological

disorders. According to the 2018 study by Gracie et

al., the link between mental disorder and

inflammatory bowel disease might be bidirectional.

In other words, they might affect and activate each

other. (16) It is thought that the stress and the

excessive brain-gut axis activity that occur in the

states of the mental disorders could affect the well-

being of the gastrointestinal tract. The inordinate

activity of the brain-gut axis increases the secretion

of the glucocorticoids and makes the walls of the gut

more permeable. The stress induces the rise in the

secretion of the catecholamines. Thus, the increased

activity of the sympathetic nerves system activates

the foamy cells and the macrophages that secrete the

cytokines. All these mechanisms contribute to the

development of the inflammation in the wall of the

gut. (20) The increased permeability of the gut wall

enhances the possibility of the gastrointestinal tract

microbiota to interact with the central nervous

system. According to the animal study of the

ulcerative colitis, the composition of the microbiota

has the impact on the variations of the behavior of

the laboratory mice. (21) Such effects depend on the

reflexes of the vagal nerve. As it is stimulated (for

example, by the high amount of so called "good

bacteria" in the gastrointestinal tract) the pro-

inflammatory cytokines are blocked and the

inflammation decreases. However, the high amounts

of the TNF- α and cortisol inhibit the vagal nerve

reflex and the inflammation in the gut increases.

7.3 The link between depression symptoms

and rheumatic diseases

Depression and anxiety are highly comorbid

with the rheumatic diseases. The prevalence of the

depression is known to be higher in the population

with psoriatic arthritis than in the general

population. The 2017 study by Wu et al. compared

the risk of depression between patients with

psoriasis or psoriatic arthritis and healthy

individuals. According to the study, the risk of the

depression in the psoriasis and psoriatic arthritis

groups was 14% and 22% respectively higher than

in the group of healthy individuals (22). According

to the systematic review conducted in 2019 by

Jamshidi et al., as many as 47-83% of Iranian

citizens with rheumatoid arthritis experience

depressive symptoms. (23) It has been thought for a

long time that depression and anxiety in rheumatic

diseases patients could be caused by chronic pain,

disability and drug side effects. However, the recent

studies of the links between peripheral inflammation

Journal of Medical Sciences. Jun 30, 2021 - Volume 9 | Issue 5. Electronic - ISSN: 2345-0592

140

and changes in the brain have revealed that

rheumatic diseases as possible risk factors of the

mental disorders. Both in the rheumatic diseases and

depression the increased amounts of pro-

inflammatory mediators, acute phase proteins and

chemokines are identified. Some studies have shown

the higher levels of IL-6, IL-17, TNF-alpha in the

depressed patients without comorbidities. The

concentrations of these mediators are also higher in

such rheumatic diseases as psoriatic arthritis. In

other words, the higher concentrations of the

inflammatory mediators in rheumatic disease may

provoke the onset of the depressive symptoms.

However, there are theories that the development

of the rheumatic disease might be activated by the

immune response to the psychiatric stress and the

activation of the hypothalamic-pituitary-adrenal

axis. Because of the hyperactivity of the

hypothalamic-pituitary-adrenal axis, the higher

concentrations of corticoliberin and cortisol are

excreted in the patients with depression. The action

of corticoliberin is associated with the pathological

processes in the joints in arthritis. (24)

The recent studies show that the associations

between rheumatic diseases and depressive

symptoms have the tendency to be bidirectional. Not

only pro-inflammatory mediators in rheumatic

diseases possibly contribute to the onset of the

depressive symptoms, but the dysfunction of the

hypothalamic-pituitary-adrenal axis might also lead

to the persistence of the chronic systemic

inflammation.

8. Conclusions

The Subjects treated with a TNF-alpha inhibitor

or an IL-6 inhibitor experienced fewer depressive

symptoms than those treated with non-biologic

therapy that has fewer specific effects on cytokines.

A reduction in depressive symptoms was observed

among the biologic-treated subjects in both the

overall study population and in the inflammatory

bowel disease and rheumatic disease populations

alone. This supports the hypothesis that rise in the

levels of inflammatory mediators such as TNF-alpha

and IL-6 contribute to the onset of depressive

symptoms, and inhibitors of these mediators reduce

such symptoms. In the general study population and

in the inflammatory bowel disease study population,

biologic therapy had a positive effect on both

depressive and anxiety symptoms (assessed on the

HAD scale by depression and anxiety subscales,

respectively). In the rheumatic disease study

population, the anxiety symptoms were affected less

than the depressive symptoms.

This study contributes to the literature on the

links between systemic inflammation, chronic

diseases and the depression, and to the evidence that

biologic therapy reduces inflammatory mediators

and may be important in identifying and treating the

etiopathogenic factors of depression. This study also

contributes to a broader understanding of the

psychoemotional state of the patients with systemic

chronic diseases.

9. References

1. MÉNARD C, HODES GE, RUSSO SJ.

Pathogenesis of depression: insights from human

and rodent studies. Neuroscience. 2016 May

3;321:138–62.

2. Seo J-S, Wei J, Qin L, Kim Y, Yan Z,

Greengard P. Cellular and molecular basis for stress-

induced depression. Mol Psychiatry. 2017

Oct;22(10):1440–7.

3. Jagannath A, Taylor L, Wakaf Z,

Vasudevan SR, Foster RG. The genetics of circadian

rhythms, sleep and health. Hum Mol Genet. 2017

Oct 1;26(R2):R128–38.