Mood disorder and cognitive impairment in multipLe sclerosis – complex study of evaluation and

treatment

Summary of Phd Thesis

SCIENTIFIC COORDINATOR,

Prof. Univ. Dr. Cristian Dinu Popescu

PhD STUDENT,

Dr. Lăcrămioara Pavăl

IASI

- 2017 –

UNIVERSITY OF MEDICINE AND PHARMACY

GRIGORE T. POPA - IASI

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TABLE OF CONTENTS

Table of contents............................................................................................................i

STATE OF KNOWLEDGE

CHAPTER I- Multiple sclerosis - General data …………………………………..1

I.1. Definition……………………………………………………………………1

I.2. Epidemiology..………………………………………………………………1

I.3. Physiopathology ……………………………………………………............1

I.4. Clinical manifestations ……………………………………………………..2

I.5. EDSS Scale (Kurtzke Expanded Disability Status Scale)…………….…….3

I.6. Diagnosis multiple sclerosis ………………………………………………..3

I.7. Clinical forms of the disease …………..……………………………………4

I.7.1. Relapsing-remitting form …………………………………………………4

I.7.2. Primary-progressive form ………………………………………………...4

I.7.3. Secondary progressive form ……………………………………………...4

I.7.4. Progressive form with relapses …………………………………………...5

I.8. Treatment of multiple sclerosis ……………………………………………..5

I.8.1. Attacks treatment …………………….…………………………………...5

I.8.2. Disease-modifying therapy ………….……………………………………5

CHAPTER II – Complexity of psychiatric disorders in multiple sclerosis ……...7

II.1. Depression………………………………………………………………7

II.2. Anxiety….………………………………………………………………7

II.3. Manic disorder …………………….…………………………………...7

II.4. Cognitive impairment ………..…………………………………………8

II.5. Bipolar disorder……………………………….………………………..9

II.6. Psychotic disorders and schizophrenia ….….…………………………11

II.7. Personality disorders……………………………..……………………11

II.8. Psychiatric effects of immunomodulatory treatment …...…………….13

II.9. Impact of psychiatric disorders on multiple sclerosis …..…………….14

CHAPTER III. Depression in multiple sclerosis …………………………………16

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III.1. Epidemiological data............................................................................16

III.2. Physiopathology...................................................................................16

III.3. Clinical manifestations.........................................................................17

III.4. Suicide in multiple sclerosis …………………………………………18

III.5. DSM V criteria for major depressive episode…..................................18

III.6. Treatment……………………………………………………………. 19

III.6.1. Pharmacological treatment................................................................19

III.6.2. Non-pharmacological treatment........................................................20

CHAPTER IV. Anxiety in multiple sclerosis……………………………………..21

IV.1. General and epidemiological data …………………………………..21

IV.2. Anxiety aetiology …………………………………………………..21

IV.3. Clinical manifestations …………………………….………………..22

IV.4. Types of anxiety disorders in multiple sclerosis….. ………………..22

IV.5. Generalised Anxiety Disorder............................................................22

IV.5.1. Specific symptoms...........................................................................23

IV.5.2. DSM V criteria for Generalised Anxiety Disorder…………..........23

IV.5.3. Physiopathology …………………………………………………...24

IV.5.4. Treatment…………………………………………………………..24

IV.6. Panic disorder……..............................................................................26

IV.6.1. DSM V criteria for panic disorder....................................................26

IV.6.2. Physiopathology …………………………………………………...26

IV.6.3. Treatment…………………………………………………………..27

IV.7. Obsessive Compulsive Disorder..........................................................29

IV.7.1. DSM V criteria for obsessive-compulsive disorder…….................29

IV.7.2. Physiopathology …………………………………………………...30

IV.7.3. Treatment…………………………………………………………..30

CHAPTER V. Cognitive impairment in multiple sclerosis...…………………….34

V.1. General and epidemiological data … …………………………………34

V.2. Aetiology …………………..………………………………………….34

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V.3. DSM V diagnosis criteria for demetia…………………………………35

V.4. Neuropsychological assessment ………….…………………………...36

V.5. Treatment………………………………………………………………37

V.5.1. Disease-modifying therapy …..……………………………………...37

V.5.2. Specific pharmacological treatment of dementia …………….……..38

PERSONAL CONTRIBUTIONS

CHAPTER VI - Motivation and objectives of my personal study ……………....43

VI.1. Introduction…..…………………………………………………..............43

VI. 2. Purpose…………...……………………………………………………….44

VI. 3. Objectives…………….…………………………………………………..44

CHAPTER VII - Material and method……………………………………………45

VII.1. Material…………………………………………………………………..45

VII.2. Work method……………………………………………………………..45

VII.2.1. Psychological tests …...………………………………………………..45

VII.2.1.1. Hamilton Depression Rating Scale …………………………….……45

VII.2.2.2. MADRS scale for depression ..………………………………………47

VII.2.2.3. Hamilton Rating Scale for Anxiety …………….……………………48

VII.2.2.4. MMSE scale for dementia …………………………………………...49

VII.2.2. Psychiatric medication used in the study ……………………………...50

VII.2.2.1. Antidepressants ……………………………………………………...50

VII.2.2.2. Anxiolytics ………………..…………………………………………50

VII.3. Criteria for selection of patients …………………………………….…...50

VII.4. The structure and characteristics of study group ……..…………….…...51

VII.5. Statistical methods ………………………………………………….……52

VII.6. Respecting bioethics and deontological norms of research .…………..…52

CHAPTER VIII – Results...……………………………………………..................53

VIII.1. Epidemiological features …………...………………………………….53

VIII.2. Distribution by age …………………...………………………………..53

VIII.3. Distribution by living environment …...……………………………….54

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VIII.4. Distribution by socio-familial status …………………………………..56

VIII.5. Associated pathologies ………..……………………………………….57

VIII.6. Level of intellectual training …………………………………………..59

VIII.7. Professional integration …..……………………………………………60

VIII.8. Immunomodulatory treatment …….…………………….……………..62

VIII.9. Clinical forms of Multiple Sclerosis ………...…………………………62

VIII.10. EDSS scale (Kurtzke Expanded Disability Status Scale)……………..63

VIII.11. Duration of multiple sclerosis evolution …………………………...…64

VIII.12. Evaluation of depression by HAM-D scale ..........................................64

VIII.13. Evaluation of depression by MADRS scale…………………………..66

VIII.14. Evaluation of anxiety by HAM-A scale................................................68

VIII.15. Evaluation of cognitive disorders by MMSE scale...............................69

VIII.16. Duration of antidepressant treatment ………..………………………..70

VIII.17. The assessment according to antidepressant medication ……………..70

VIII.18. Attacks during antidepressant treatment …………...…………………73

VIII.19. The influence of immunomodulatory therapy on depression .………..74

VIII.20. Correlations between the presence of mental disorder and disability

degree ………………………….…………………………………………………….75

VIII.21. Correlations of immunomodulatory treatment and living

environment…………………………………………………………………………..78

VIII.22. Correlation of degree of disability with professional integration …....79

VIII.23. Patient distribution according to certain psychiatric symptoms

(insomnia, psychotic symptoms, suicidal thoughts, panic attacks, psycho-somatic

symptoms)………………………………….………………………………………...81

VIII.24. Influence of antidepressant therapy on multiple sclerosis evolution

(attacks, EDSS)……………………..………………………………………………..85

VIII.25. Correlation of antidepressant therapy with demographic data ……….88

VIII.26. Correlation of antidepressant therapy with immunomodulatory

treatment …………………………………………………………………………..…94

VIII.27. Correlation of immunomodulatory therapy with disability degree.….95

VIII.28. Subject distribution according to anxiolytic drugs association ……....96

VIII.29. Correlation of anxiolytics association with life environment ………...97

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VIII.30. Correlation of anxiolytics association with age ……………………..98

VIII.31. Correlation of anxiolytics association with immunomodulatory

treatment …………………………………………………………………………....99

VIII.32. Correlation on duration of antidepressant therapy and achieving

remission …………………………………………………………………………...100

VIII.33. Dementia in multiple sclerosis - particular case …………………….102

CHAPTER IX - Discussion……...………………………………………………..106

CHAPTER X - Conclusion …...…………………………………..........................121

CHAPTER XI - Perspective opened by doctoral research …..…...…………….122

REFERENCES ……………………………………………………………………123

Annex. List of published works …………………………………..………………143

PhD thesis is illustrated with 55 tables and 47 figures. Summary selectively restores

iconography and references in the text respecting numbering and the thesis content in

extenso. The bibliographic references presented are identical to those in the thesis.

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Introduction

Multiple sclerosis is a multifaceted neurological disorder, with so many

manifestations throughout the whole body that it came to be known as the disease with a

thousand faces. The dramatic aspect of this disease is the impact it has on the young and

adults of working age, preventing them to carry on their professional activities affecting their

family life, bringing up in this way many questions and fears.

Against this background of vulnerability, amplified by the structural changes in the

brain, emotional imbalances can install themselves in even from the beginnings of multiple

sclerosis, fueled by those of neuro-bio-chemical nature. These imbalances are manifesting in

the form of depression, anxiety, panic attacks, sleep disorders, and, in some cases, delusional

or psychotic disorders in the spectrum of schizophrenia may occur. In almost half of the

patients with multiple sclerosis, cognitive dysfunctions do occur in the early stages of the

disease. All these issues from the psychic scope require attention and adequate medical care.

Multiple sclerosis can become a disabling condition and then, the overlapping of

affective or cognitive disorders emphasize that this cumulation of symptoms and affections

having common cerebral origin, certainly decreases the quality of life and the ability to self-

conduct and self care. Therefore the mental disorders in multiple sclerosis are a public health

problem and it is necessary to represent a continuous concern for professionals involved in

health caring these patients.

The complications of mental affections are serious and may endanger the life of the

sick or their integrity. These are: psychoactive substance abuse, severe stages of dementia,

suicide attempts and the actual suicide act. Direct and indirect costs of care of psychiatric

disorders in multiple sclerosis along with the costs for therapy of the underlying disease

amount to significant sums that challenge the health budgets of countries with high incidence

of this neurological disorder.

This work comes to bring clarification on some controversial aspects from the causal

association of multiple sclerosis with the psychiatric disorders. As shown in the general part

of this work, OMS data shows that depression will become in the coming years the main

cause of morbidity and disability worldwide, its level if incidence surpassing even the

frequency of cardio-vascular diseases. Multiple sclerosis, being the neurological disorder that

affects primarily young adults, is also a potential cause of disability. The overlap of these

pathologies in this age group often force these people out of workforce and brings an

unfavorable outlook on life as a whole.

Depression, anxiety and cognitive disorders in multiple sclerosis were a concern in

recent years, for several branches of medicine in an attempt to establish consistent and

concrete data for specialists directly involved in care to work with for remission of symptoms

and reducing the negative impact on quality of life. Neurology, psychology, psychiatry,

ophthalmology, brain neuroimaging and other branches of traditional medicine developed

tests, techniques and methods for quantifying and studied multiple drug therapies having a

curative tendency or one towards changing the evolution of the disease.

Neuropsychological testing of depression, anxiety and cognitive dysfunction applies

to almost all medical pathology, since any chronic or debilitating disease may be associated

or may cause one or more disorders in the emotional or cognitive scope, in the course of the

affection. So they can be recognized and quantified as diseases ranging from those as well

known as hypertension, diabetes, rheumatoid arthritis and musculoskeletal disorders

involving chronic pain, degenerative diseases and the full oncologic pathology, to the rare or

orphan diseases.

Thus, the more understandable becomes the occurrence of psychiatric pathology in

neurological diseases, having the same system as organic support: the brain and the central

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and peripheral nervous system. The stroke, Parkinson's disease and epilepsy associate

increased prevalence of depression, anxiety and disorders of cognitive functions. Multiple

sclerosis is not an exception, but falls on the same line of epidemiological data with figures

much higher than in the general population of mental disorders.

Neuropsychological testing of these disorders provides a clearer picture and a

measurable one for the affective and cognitive disorders in multiple sclerosis, and drug

treatments come in order for the purpose of symptoms improvement, achieving and

maintaining remission for a time interval as large as possible the ultimate goal being the

curative one.

In anticipation of this doctoral work and aiming to build on specific and up to date

data, I carried out a pilot study in which I highlighted the high frequency of depression,

anxiety and cognitive dysfunctions in multiple sclerosis and the necessity of appropriate

therapies adapted to these pathologies. The study was conducted over a period of 12 months

and included a total of 65 patients and took place at Clinica de Neurologie a Spitalului de

Recuparare, Iași.

The data and conclusions of the study were presented in the form of a scientific paper

entitled “Diversitatea tulburărilor afective şi cognitive în scleroza multiplă” ("Diversity of

the affective and cognitive disorders in multiple sclerosis") as part of the 5th National

Conference of multiple sclerosis with international participation, Iași, 18 to 20 November

2010.

Objectives of paper

- evaluation of casuistic distribution by gender, age, provenance in order to discovery of

certain features related to these parameters for depression, anxiety and dementia in multiple

sclerosis

- establishing the severity of depression, anxiety and cognitive impairment through specific

neuropsychological tests

- the relation between depression, anxiety, and dementia and multiple sclerosis

- assessment specific symptoms of depressive syndrome (suicidal thoughts, panic attacks,

psycho somatization, insomnia)

- the relationship between specific antidepressant, anxiolytic and dementia medication and

evolution of multiple sclerosis

- study and achievement of correlations between antidepressant and anxiolytic treatment and

therapy of multiple sclerosis

- comparing and establishing of correlations between antidepressant and anxiolytic therapy

and clinical and demographic data

- assessing the specific evolution features of psychiatric treatment

Material and methods

The study group consisted of 17 multiple sclerosis patients, hospitalized in the Clinica

de Neurologie a Spitalului Clinic de Recuperare Iaşi and the psychiatric cabinet of the

policlinic adjacent to the hospital, during the period May 2013 - July 2016.

Parameters included in the files of patients in the study group were the ones below:

- Epidemiological characteristics: age, gender, area of origin, living environment

- The level of intellectual preparation and integration into employment

- Associated pathologies: hypertension, other cardiac and vascular disorders,

gastrointestinal pathology, degenerative disorders of osteoarticular, metabolic or algesic

nature, epilepsy

- Immunomodulatory treatment

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- EDSS values

- The clinical forms of multiple sclerosis

- The duration of development of multiple sclerosis

- In my study I have made use of:

- two rating scales for depression: the Hamilton rating scale for depression

(HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS)

- a scale for evaluating anxiety: the Hamilton rating scale for anxiety

(HAM-A)

- and one for evaluating cognitive dysfunctions: Mini-Mental State

Examination (MMSE)

- The pharmaceutical preparations which I have used in the study are:

- antidepressants: tianeptine, duloxetine, escitalopram, trazodone,

mirtazapine, agomelatine

- anxiolytics: lorazepam, alprazolam, bromazepam, nitrazepam, clonazepam

- antidemential: donepezil, memantine

The following were determined: the clinical form of multiple sclerosis, the degree of

disability of the patients, the type of immunomodulatory treatment, the duration of the

development of multiple sclerosis, the number of flare-ups. And evaluated were the severity

of mental disorders by applying neuropsychological tests for depression, anxiety and

cognitive dysfunction. Antidepressant, anxiolytic and antidemential medication was

administered.

Neuropsychological evaluation tests confirm the depression in multiple sclerosis,

associated with disorders in the anxiety spectrum, and cognitive impairment in multiple

sclerosis. Neuropsychological tests used are used in most studies that research affective and

cognitive disorders.

The administered treatment enabled specific tracking of mental disorders in therapy in

relation to multiple sclerosis.

For the realization of this study, the following were used: the Hamilton rating scale

for depression, the MADRS scale for depression, the Hamilton rating scale for anxiety, the

MMSE scale for dementia, antidepressant, anxiolytic and antidemential psychiatric

medication.

Results and discussions

Regarding epidemiological data about multiple sclerosis, the study group complies

with known demographic characteristics.

Thus, the study group include more women than men, with a ratio women:men of 4:1,

being known that the disease is 2-3 times more frequent in women than in men (Băjenaru et

al, 2011).

Fig. 8.2. Structure of lot by age groups

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Also, in terms of age parameter, on the studied cases, the age of onset of the disease,

between 20-40 years, corresponds to 47.1%, i.e. almost half the subjects, consistent with the

data in the specialised literature. Women in the study group are slightly younger than the men

just because multiple sclerosis is more common in women (Băjenaru et al, 2011).

More than 60% of patients with multiple sclerosis and depression show pathological

conditions. In the study group we observe that cardiovascular affections and the algetic

pathology are the most common. Metabolic, osteo-articular, gastrointestinal and epileptic

affections are also associated with multiple sclerosis and depression patients, but in much

smaller percentages.

Cardiovascular affections are correlated statistically significant with age (p = 0.037),

which are present only in patients over 40 years, the aspect being consistent with the data in

the specialised literature on age of onset of cardiovascular diseases and their association with

mental affections such as depression and anxiety. Given that all patients in the study were

diagnosed with depressive syndrome, this association confirms the presence of depression in

chronic diseases.

Fig. 8.7. Correlation between age and associated pathology

In terms of the level of intellectual preparation, most subjects, more than a third, have

completed vocational school. Persons with higher education and high school are less present,

but in relatively equal proportions, and subjects with a low level of education (1-8 grades) are

the fewest.

Most patients in the study group are medically retired or are receiving medical

disability allowance, together representing over 70% of the total. Fewest are the employees

and students.

These data show that multiple sclerosis and depression negatively affect the ability of

patients to cope with the workplace or with the intellectual requirements to complete their

education level.

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Fig. 8.8. Structure of lot by professional integration

The percentage of patients receiving immunomodulatory treatment is slightly

increased compared to that of patients not receiving therapy for modifying the development

of multiple sclerosis, which is more than 50%.

Most patients in the study group present the clinical form of relapsing-remitting

multiple sclerosis, which is consistent with the data in the specialised literature, data

confirming that this clinical form of the disease is the most common.

Fig. 8.11. Structure of lot by the clinical form of multiple sclerosis

More than 70% of the subjects in the study present a disease development with a

duration of between 1 and 10 years, the remaining patients having a disease duration of more

than 10 or even 15 years. These percentages can be explained by the rise in recent years of

the addressability of patients to specialized medical services, the establishing of clearer

criteria and easier to use in diagnostic (McDonald criteria) and evolution of methods of brain

investigation through imaging (MRI), including increased accessibility to these methods of

investigation.

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Fig. 8.13. Structure of lot by the number of years of evolution of multiple sclerosis

As assessed by the Hamilton rating scale for depression (HAM-D), depression

severity was identified as severe in all subjects in the study group. The score obtained by

these persons was higher than 26 points.

Age appears to influence statistically significant the score on the HAM-D scale, so that the

values closer to the limit of moderate depression are found in younger ages and higher scores

are associated with persons over 30 years. A possible explanation for these findings may be

that young people find inner resources and coping methods to diagnosis and neurological

disease, thus reducing the severity of depressive symptoms.

Fig. 8.15. Correlation between age and HAM-D score

Moderate and severe anxiety is encountered in almost 50% of subjects in the study.

The total of people with any form of anxiety is about 70%. These data are consistent with

those in the specialised literature which reported similar data on the prevalence of anxiety in

people with multiple sclerosis (Chwastiak, Ehde, 2007 Korostil, Feinstein, 2007).

12

Fig. 8.18. Structure of lot by HAM-A score

Nearly 60% of patients experience cognitive disorders of light and medium type with

a MMSE score between 19 and 29 points, and 90% have mild cognitive dysfunction. These

data are consistent with those in the literature on the epidemiology of cognitive impairment in

multiple sclerosis, that shows percentages of 45% - 60% for multiple sclerosis patients with

cognitive problems (Guimarães, José Sá, 2012).

A similar percentage of patients maintained the treatment for short periods of 1-2

months but also for periods of time exceeding 2 years. These data show that there are

relatively equal percentages of those who decide to undergo treatment to achieve remission

and of those who renounce antidepressant medication shortly after the symptoms improve.

Fig. 8.20. Structure of lot by duration of antidepressant treatment

When initiating antidepressant therapy, Duloxetine and Tianeptine were the most used

drugs at a rate of more than 70% of patients. Following are Trazodone and then Mirtazapine,

Escitalopram and Agomelatine, the last two having equal percentages.

During the course of the study, the administration of antidepressant treatment was

found to show a distinctive dynamic, meaning changes occuring in therapeutic regimens for

some patients. Duloxetine remains at the forefront of therapeutic choice, but with an increase

in people where it was used. Tianeptine is the second choice for therapy of depression in

multiple sclerosis, being used for the same number of patients as in the beginning of the

study. Escitalopram surpasses trazodone as frequency of use and becomes in order the third

13

drug chosen in therapy. For mirtazapine the percentage of its use remains the same.

Agomelatine does not appear anymore as a treatment option at the end of the study. The

novelty at the end of the study is the requirement of drug combination for achieving

remission in three patients.

These data show differences when compared with data from specialised literature.

Fig. 8.21. Dynamics of antidepressant therapy during the study

► Escitalopram – SSRI- they are the most widely used class of antidepressants for treatment

of depression in multiple sclerosis (Pérez et al, 2015, Bayas et al, 2016); the safety and

efficacy in major depression;

– in my study ranks third in use

► Duloxetine – studied mainly for the antalgic effect in multiple sclerosis (Brown, Slee,

2013, Bayas et al, 2016)

– the first therapeutic choice: multireceptorial profile, for the positive effects

on depression symptoms and those of multiple sclerosis that often overlap with the depressive

symptoms, such as fatigue and algical complaints. Its frequency of use in the study increased

overall precisely because of its effectiveness in achieving remission and safety of

administration.

► Tianeptine – the second therapeutic choice; the share of administration remained constant

until the end of the study;

– It is used successfully in therapy since 1960 (Racagni, 2008). However, the

data from literature regarding the use of tianeptine in depression in multiple sclerosis, is

scarce (Spedding, Gressens, 2008).

► Trazodone, mirtazapine and agomelatine – first study with them as efficient therapeutic

options; the literature offers very little information

► Combinations of antidepressants – improvement/remission

– first study; specialised literature lacks information

In terms of flare-ups during antidepressant treatment, the percentage of patients without

flare-ups was higher than 80%. The antidepressant treatment does not correlate with an

14

increased number of flare-ups, on the contrary, it seems to have a protective role, as only

11.8% of patients manifested flare-ups.

The percentage of patients with depression receiving immunomodulatory therapy based

on interferon represents a majority of 70%. The risk of depression in people receiving

glatiramer acetate is reduced. These data are consistent with the literature which shows higher

risk of psychiatric affections in people receiving tratamnent based on interferon beta

(Feinstein et al, 2002, Chwastiak, Ehde, 2007 Hersh, Fox, 2014).

Fig. 8.23. Structure of lot by administered immunomodulatory

pharmaceutical product

About 40% of studied patients with normal cognitive status have lower scores on the

EDSS, from 1 to 4. The subjects with mild or medium cognitive dysfunction have an

impairment level of absent to very serious.

Fig. 8.21. Correlation between anxiety and the degree of disability

Higher EDSS values are associated with a worsening degree of anxiety, although the

cases studied are not sufficient to achieve statistical validation. The ways to adapt to the

conditions created by the neurological illness progressively decrease together with an

increase in the levels of anxiety and of development of various anxiety spectrum disorders

(Sandford et al, 2000, Chwastiak, Ehde, 2007 Goleman, 2008).

15

Fig. 8.28. Structure of lot by associated psychiatric symptoms

- insomnia - present in about half of patients

< 20% of pacients - symptoms such as hallucinations and delusions

~12% of all subjects manifest suicidal ideation; which figures lower than the data from

literature, 22% (Feinstein, 1997, Kanner, 2005)

- panic attacks - present in approximately 35% of patients; prevalence of panic disorder in

multiple sclerosis: 10% (Korostil, 2007)

50.0%

33.3%

75.0%

60.0%

50.0%

16.7%

25.0% 25.0%

20.0%

75.0%

60.0%

50.0%

50.0%

25.0%

80.0%

20-30 ani

31-40 ani

41-50 ani

51-60 ani

Insomnie

Simptomepsihotice

Ideatiesuicidara

Atacuri depanica

Psihosomatizare

Fig. 8.29. Correlation between age intervals and associated psychiatric symptoms

- a statistically significant correlation between age and panic attacks, which are present only

in patients over 40 years (Chi-squared = 8.461, p = 0.037); the psychotic symptoms, insomnia

and psychosomatisation are not influenced by age.

- the duration of development of multiple sclerosis affects in a statisticaly significant way

insomnia, the panic attacks and the psychosomatisation

- insomnia installs itself in over 75% of patients having more than 5 years of multiple

sclerosis development

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- the risk of panic attacks is higher with increasing number of years of evolution of multiple

sclerosis (Chi-squared = 8.461, p = 0.037)

- psychosomatisation (Chi-squared = 11.266, p = 0.010) - much more present in the first years

after onset (1-5 years), and then after a longer duration of the disease, meaning more than 15

years.

Influence of antidepressant treatment on multiple sclerosis

- lower degree of disability, EDSS < 3, the most commonly used drugs are duloxetine and

tianeptine. In patients with a higher degree of disability most frequently used = duloxetine,

followed by escitalopram. Duloxetine = used regardless of the degree of disability.

- flare-ups – on reduced disability, EDSS < 3, no statistically significant correlation between

flare-ups and EDSS

- flare-ups along antidepressant treatment with tianeptine and respectively, trazodone, no

statistical correlation

- the absence of flare-ups - all drugs used in the study

Antidepressant therapy and demographics

Duloxetine is the most widely used pharmacological product in both social

backgrounds of subjects, but more in the case of urban environment, for half of these patients.

The second in dosing for people from both rural and urban areas is tianeptine, but twice the

percentage for patients in rural areas. Trazodone was more frequently used in rural areas.

Escitalopram and agomelatine were exclusively used in therapy for people residing in urban

environment and mirtazapine was administered only to people in rural areas. Although these

differences are obvious, no statistically significance was obtained.

Fig. 8.33. Correlation between antidepressant treatment and the living environment

Patients receiving therapy based on interferon (Avonex, Rebif, Betaferon), known for

its potential to develop depressive symptoms, received the whole range of drugs used in the

study as antidepressant therapy, but not agomelatine.

Individuals treated with Copaxone for multiple sclerosis received duloxetine and

agomelatine as therapy for depression.

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Fig. 8.39. Correlation between antidepressant therapy and immunomodulatory therapy

Lorazepam and alprazolam = the anxiolytics most used in association as antidepressive

therapy, lorazepam = first place with a percentage of 35.3%. Following in frequency of

administration are: bromazepam, nitrazepam and clonazepam, in similar percentages.

Noticeable, the 23.5% representing associations of two anxiolytics.

35.3%29.4%

17.6%11.8% 11.8%

23.5%

0.0%5.0%

10.0%15.0%20.0%25.0%30.0%35.0%40.0%

Lora

zep

am

Alp

razo

lam

Bro

maz

ep

am

Nit

raze

pam

Clo

na

zep

am

Aso

cier

i de

ca

te 2

anxi

olit

ice

Structura lotului in functie de asocierea de medicamente anxiolitice

Fig. 8.41. Distribution of subjects by association of anxiolytic drugs

- more patients in urban areas needed anxiolytics associated with the antidepressant therapy

than those in rural areas

- all of the youngest patients required the antidepressant therapy to be associated with

anxiolytics

- in the case of patients with therapy for modifying the evolution of the neurological disease,

it was necessary to associate anxiolytics in a higher percentage than in the case for those with

no treatment

Antidepressant therapy and remission

In the studied cases, the following are distinguished:

- 11 pacients – complete remission of depressive symptoms (HAM-D < 7p)

18

- 4 pacients – mild depression (HAM-D = 8 - 17p)

- 2 pacients – moderate depression (HAM-D = 18- 25p)

Fig. 8.46. Structure of lot with regard to obtaining remission

- moderate depression - age between 31 and 40 years.

- half of people with mild depression are either young people between 31-40 years or older,

over 50 years.

- complete remission was obtained for subjects in all age groups, mostly by people between

41 and 50 years, with a percentage of 36.4%.

Fig. 8.45. Correlation of age with remission

- antidepressant therapy for more than 2 years = complete remission

- moderate depression - the shortest duration of treatment for depression, 1-2 months

- mild depression - people with treatment under 24 months

- the duration of antidepressant therapy certainly has an inffluence on obtaining and

maintaining complete remission

19

Fig. 8.47. Correlation of duration of antidepressant therapy with remission

The limitations of the study are caused by the reduced size of the available study group

and therefore between certain parameters a statistically significant correlation could not be

established, although the number and percentage differences were objectified. However, the

data obtained in the study provides valuable information for both the clinician and medical

research.

Conclusions

the most common psychiatric disorders in multiple sclerosis depression, anxiety and

cognitive impairment / dementia

a higher proportion of patients with multiple sclerosis and depression come from

urban areas

depression in multiple sclerosis was found in greater proportion of patients aged over

30 years in rural areas

lack of social and family support is a risk factor for depression and anxiety in multiple

sclerosis

Cardiovascular diseases are present only in persons with multiple sclerosis depression

over 40 years

depression in multiple sclerosis reduces intellectual and professional skills

depression is more frequent in patients with multiple sclerosis at onset

interferon-based immunomodulatory therapy can be a risk factor for development of

depressive symptoms

depression occurs more frequently in people with multiple sclerosis with lower

invalidity score

severity of depression is more emphasized in patients with multiple sclerosis for over

30 years

age over 40 years is a risk factor for the occurrence of panic attacks

evolution of multiple sclerosis for over 5 years increases the frequency of insomnia

20

the most used treatment for depression in multiple sclerosis is represented by

duloxetine (serotonin and noradrenaline re-uptake inhibitor), tianeptine (modulator of

serotonin release) and escitalopram (selective serotonin reuptake inhibitor)

efficient for remission of depressive symptoms are also trazodone, mirtazapine,

tianeptine and agomelatine

duration of antidepressant therapy longer than one year is optimal for complete

remission of depression symptoms

associations of two different classes of antidepressant showed greater efficiency to

achieve remission than maintaining of therapy with a single drug

lorazepam and alprazolam are the most used anxiolytic in treatment of anxiety

associated with depression in multiple sclerosis

antidepressant treatment may be a protective factor against attaks

therapy with memantine has proven effective in improving cognitive status and

slowing deterioration

treatment options for depression, associated anxiety and cognitive disorders in

multiple sclerosis are more varied and a far wider range of antidepressants, anxiolytics and

pharmacological products for dementia can be used in medical practice

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ANNEX. LIST OF PUBLISHED WORKS

Pavăl L., Pavăl D., Popescu C.D., Procognitive effects of immunomodulatory,

anticholinergic and glutamatergic medication in multiple sclerosis, Revista de Chimie, 2016;

67 (9): 1891-1893 (ISSN 0034-7752, Impact Factor – 0.81)

Pavăl L., Popescu C.D., Cognitive Impairment and Dementia in Multiple Sclerosis –

a case report, Indian Journal of Research, 2016; 5 (7): 70-71 (ISSN 2250-1991, Index

Copernicus IC Value: 77,65; Impact Factor – 5,215)

Pavăl L., Achiţei G., Cognitive Impairment and Dementia in Multiple Sclerosis,

Romanian Journal of Psychiatry, 2015; 17 (2): 145 (ISSN: 1454-7848, CNCSIS B+)

Pavăl L., Tescu Grigorovici C., Management of Depression in Multiple Sclerosis,

Romanian Journal of Psychiatry, 2013; 15 (1): 126 (ISSN: 1454-7848, CNCSIS B+)

Communications at scientific events:

Pavăl L., Achiţei G., Cognitive Impairment and Dementia in Multiple Sclerosis.

World Psychiatric Association Congress, with the theme “Primary Care Mental Health:

Innovation and Transdisciplinarity”, Bucharest , 24-27 june, 2015

Pavăl L., Popescu C.D., Depression in multiple sclerosis. The seventh Multiple

Sclerosis National Conference with international participation with theme Current therapies

optimization of multiple sclerosis, Iasi, 14-15 november 2013

Pavăl L., Tescu Grigorovici C., Management of Depression in Multiple Sclerosis. Congress "Innovation and excellence" of World Psychiatric Association, with theme

"Primary health care, mental health and public health integration: the catalytic role of

information and communication technology", Bucharest, 10-13 april, 2013

Pavăl L., Tescu Grigorovici C., Clinical features and therapeutic management in

post-stroke depression, National Conference of Psychiatry with international participation

"Records and values in contemporary psychiatry", Iaşi, 4-7 octombrie, 2012

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