EMOTIONAL and AFFECTIVE Disturbances in MS

VITTORIO MARTINELLI OSR Milano

Symptoms Commonly Reported by Patients (n=300)

50% Memory problems 42% Visual problems

50% Pain 55% Emotional/mood problems 62% *Bladder/bowel problems 69% Stiffness/spasticity

84% *Fatigue

32% Tremors

75% *Difficulty walking

% Reporting Symptom

MSQLI Working Group (1997)

Disturbi d’ansia

•  Strettamente correlati al vissuto di malattia •  Consapevolezza di avere una malattia

cronica,invalidante,imprevedibile •  Vissuti di frustrazione e di pericolo per la

propria integrità fisica (carrozzina) •  Vissuti negativi di affermazione del ruolo

familiare, lavorativo, sociale

DISTURBI DELLA AFFETTIVITA’

nei pazienti SM n  Distimia/umore depresso n  Forme “mascherate” n  Disturbo di adattamento n  Episodi depressivi maggiori n  Disturbi bipolari

§  Apatia / indifferenza affettiva §  Euforia §  Riso e pianto patologico

Depression in MS: Prevalence •  Depression is frequently

observed in MS patients (Patten et al., Can J Psych 2005)

•  Associated with low quality of life, absence from work, and suicide (Goldman Consensus Group, Mult Scler 2005)

•  Depression is not correlated with level of disability (Feinstein, Mult Scler 2011)

•  What is the reason for the high prevalence of depression in MS?

Patten et al., CJP 2005

Predictors of Depression in Multiple Sclerosis patients

•  Functional Status (EDSS) •  Trait anxiety •  Alexithymia •  Satisfaction with social support system

Depressive Symptoms (or Depressive Syndromes)

in MS patients

•  5 - 20 % at MS onset

•  5 to 10 times more frequent than in HC or in chronic diseases

•  Mild / moderate / severe (not related to MS severity)

Chwastiak et al 2002

Severity of depression and severity of MS

Depressive symptoms: subsyndromal depression

● point prevalence ~ ? % ● Life time prevalence ~ 100% ● Criteria not sufficient for syndromal

diagnosis ● irritability, sadness, tearfulness common ● associated with significant distress ● risk factor for major depression

IDENTIFICATION OF AFFECTIVE DISORDERS IN MS Shortcomings of Current “Real” Practice

•  It has been estimated that as many as 50% of depressions may go underdetected during standard medical evaluation

•  Patients’ behavior is often misinterpreted both by family members and physicians.

•  Screening is unsystematic •  Formal assessment of behavioral/affective

disturbance is infrequent. •  Treatment is sporadic.

Relationship between Depression and QoL

Depressive Disorders are frequently associated with a low QoL perception,

Worse than phisical Disability or Cognitive impairmewnt severity

D’Alisa et al 2006

Lovera et al 2006

Effect of depression on QoL in severely disabled MS patients

(EDSS>7) QUALITY of LIFE and DEPRESSION

Depression (HADS)

Qua

lity

of L

ife (S

F-36

)

0

10

20

30

40

50

60

70

80

90

100

Not DepressedDepressed

Beaumont et al. 2002

QoL in MS patients according to the BDI score

0102030405060708090

PF RP BP GH VT SF RE MH

<1011 17>17

Patti et al. 2003

*

*

* **

**

*

* p < 0.05

Suicide

✦ 7.5x the general population rate (Sadovnik, 1991) 3126 pts - 16 years survey - 145 deaths - 56 MS related - 20 suicides

✦ increased relative to other neurological disorders (Stenager and Stenager, 1992)

✦ At risk: males, < 30 yrs, first 5 years of illness ✦ Linked to major depression and anxiety disorders,

often it goes unrecognised

Suicide

*  Lifetime suicidal intent: 29% *  Lifetime suicide attempt: 6.4% *  General population:

w Lifetime suicidal intent: 13.5% (USA) w Lifetime suicide attempt: 3.8% (Canada)

(Feinstein 2002)

Predictors of Suicidal Intent

* Lifetime diagnosis of major depression * Severity of major depression (↑ HAD scores) * Living alone * Alcohol abuse

70% sensitivity, 95% specificity, overall 87% predictive ability

(Feinstein 2002) 2/3 of depressed patients without therapy

1/3 of suicidal patients without psychological assistance

The effects of stressful life events on the course of MS

•  85% of clinical exacerbations associated with stressful life events in the 6 months before the relapse (Brown and Harris 1978,….)

•  No association (Gasperini et al 1995; Nisipeanu and Korczyn,

1993; Sibley 1997) •  A Metaanalysis by Mohr et (2004) concluded

on a consistent association between stressful life events and subsequent exacerbation in MS

The effects of stressful life events on the course of MS

•  Methodological differences (retrospective vs prospective studies, clinical vs MRI)

•  Definition of “Stressful event” •  Severity of stressful event (non linear relationship

between severity of stress and relapses)

•  Duration of Stressful event (acute vs chronic)

•  Subjective vs Objective definition

The effects of stressful life events on the course of MS

Stress due to the disease itself

“the vicious cycle”

Stressful events relapse level of disability, increase of stressful situations

(reported by the patients) 6 year prospective study on 101 pts (Schwartz et al 1999)

Factors identified as promoting MS relapses

• Vaccinations • Early post-partum period •  Infections x 3 • Stressful events x 2 Buljevac, 2003

HPA axis, which is involved in the mediation of stressful life events, is altered in MS, generally towards hyperreactivity

The Temporal Model

The Temporal Model •  Acute Stress Onset •  Change from acute to chronic Stress Ø  commonly marked by increased level of cortisol Ø  glucocorticoid resistance Ø  down regulation of glucocorticoid receptor number and

function Ø  decrease in control over inflammation •  Resolution of the stressor (reduction in cortisol

production represents a decrease in control over inflammation processes)

Acute Stress: the Mast Cell hypotesis

•  Mast Cell activity is triggered by CRH •  MC activity is also triggered by stress •  Stress may induce MC degranulation •  Increase BBB permeability •  Permissive effect on MS exacerbation

Neurobiology of depression •  Monoamine hypothesis (Adrenaline; Serotonin)

•  Beta Endorfine

•  Hypothalamo-pituitary-adrenal (HPA) axis hyperactivity

•  Inflammation

Krishnan & Nestler, Nature 2008

Interrelazione tra Sistema immunitario/ disturbo depressivo/sistema

serotoninergico ◆ Il trasportatore della Serotonina è coinvolto nella patogenesi della depressione (Stanley et al. 1982)

◆  TNF-α e IFN-γ possono aumentare la attività e la trascrizione del traspostatore della serotonina, che riveste un ruolo rilevante nelle terminazioni serotoninergiche (conseguente riduzione serotonina) (Blakely et al. 1991)

◆ L’ antidepressivo Rolipram, riduce la sintesi di TNF-α e IFN-γ e manifesta effetti preventivi nella EAE (Sommer et al. 1995)

ß-Endorfine

•  Fattore che esercita un effetto inibitorio tonico sulla funzionalita’ del sistema immunitario.

•  La concentrazione delle ß-Endorfine nelle cellule immunitarie è diminuita in patologie nelle quali il sistema immunitario è attivato.

•  L’interleukina 1 iniettata nel ratto a livello intraventricolare aumenta la concentrazione di ß-Endorfine nei linfociti per coinvolgimento del CRH, catecolamine e serotonina (Sacerdote et al)

ß-Endorfine SISTEMA DOPAMINERGICO

SISTEMA SEROTONINERGICO

SISTEMA GABAERGICO

- +

INTERLEUKINA I

+

-

FATTORI CHE INFLUENZANO LA QUANTITÀ DI BETA ENDORFINE

EFFETTO INIBITORIO TONICO SUL SISTEMA IMMUN ITARIO

Possible correlations between Depressive Disorders and

Immune System

•  Serotonin Beta Endorfine pro-inflammatory Citokines

•  Stress and depression can induce TNF-alfa (proinfiammatory citokine)

IMMUNOSOP.

DEPRESSIONE

RIDUZIONE SEROTONINA

RIDUZIONE

ß-ENDORFINE

ATTIVAZIONE SISTEMA IMMUNITARIO

RICADUTA

Longitudinal changes of BDI sum score after a relapse (Kahl et al 2002)

Correlations between cytokine mRNA expression levels and BDI

BDI TNF-α IFN-γ IL10

CTRL 0.21 0.10 0.08

MS T1 0.55* 0.54* 0.01

MS T2 0.64* 0.29 0.02

MS T3 0.14 0.11 0.12

(Kahl et al 2002)

0

5

10

15

20

25

30

35

40

HCMSMD

TNFα in Depressed (MD) and Multiple Sclerosis (MS) patients

Differences among groups: Ancova: p=0.005

pg/m

l MD

HC MS

DEPRESSION Brain

lesion load

Loss of social support

Iatrogenic effect

Loss of social role Adaptative

reaction

Immunological factors

Pathophysiology of Depression in MS pts

Genetic?

Clinical & demographic

variables

MRI AND DEPRESSION IN MS Correlation with brain lesion load and atrophy

•  Absence of relationship: Measures of ventricular size vs. BDI scores (123 MS patients) (Clark et al., 1992)

Ventricular brain ratio, CC area, T2 lesion load (brain, temporal lobes, brainstem) vs. depression scores (25 MS patients) (Moller et al., 1994)

Total brain T2 lesion area and third ventricle width vs. depression scores (35 MS patients) (Benedikt et al., 2002)

Third ventricle, left and right frontal horn diameter vs. HDS, MADRS or BDI scores (74 MS patients) (Berg et al., Arch Neurol 2000)

Depression in MS: Similar pathogenetic biological causes?

– Lesion location

•  Frontal and temporal regions (Bakshi et al., Neuroreport 2000; Pujol et al., Neurology 1997; Berg et al., Mult Scler 2000)

– Regional brain atrophy and functional tissue integrity

•  Frontal and temporal regions (Zorzon et al., JN 2001; Zorzon et al., Eur J Neurol 2002; Feinstein et al., Neurology 2004, Feinstein et al., Mult Scler 2010)

Di Legge 2003

37 CIS patients

HPA axis

Hippocampus Inflammation

Biological substrates of Depression in MS pts

Control MS0

2500

5000

7500

10000

8 a.m. 4 p.m. 9 p.m.-0.50

-0.25

0.00

0.25

0.50

0.75MSControl

*

Gold et al., Biol Psychiatry 2010

Hippocampus and cortisol

Gold et al., Biol Psychiatry 2010

Hippocampal subregions and depression

Cortisol and depression

Gold et al., Biol Psychiatry 2010

Subregional hippocampal volume and cortisol

r=-.46

p=.01

Gold et al., Biol Psychiatry 2010

Gold et al., JNNP 2011

HPA axis in MS patients with MDD

Inflammation and Depression

Gold et al., JNNP 2011

Biological substrates of MS depression

•  Hippocampus •  Hypothalamo-pituitary-adrenal (HPA) axis

hyperactivity •  Inflammation

Gold et al., Biol Psychiatry 2010 Gold et al., JNNP 2011 Gold et al., JNNP 2011

MR vs GR regulation

Sources: Kiecolt-Glaser& Glaser, Nat Rev Immunol 2005; Matthews, Ped Res 2002; Grossman, JCEM 2010, Uni Basel, Seckl et al., Barin Res 1991

MR

GR MR

GR MR

GR MR

GR MR

GR MR

GR

Effetti degli steroidi sul SNC •  Disturbi affettivita’

•  Ipoattivazione Asse ipotalamo-ipofisi-surrene

•  Down regulation dei recettori degli steroidi

•  Effetto variabile degli steroidi

STRESS and DEPRESSION around

MS Diagnosis

STRESS and DEPRESSION around MS Diagnosis

•  Lack of correlation between anxiety symptoms and any particular distribution of MS lesions

•  Stress is reactive to stressful events and not a symptom of the disease (Zorzon et al, 2001)

•  Coping strategies (Problem or Emotion focused CS) may reduce psycological pressure and be useful to manage the demand of stressful situations

Stress-ProblemFocusedCopingStrategies-

MRI activity

The use of PF CS reduces stress perception as well as the risk of appearance of new MRI

lesions (Mohr et al 2002)

Other factors related to stress perception and effects in MS

•  Health Locus of Control (internal or external) •  Optimism (personality aspect) q  Outcome expectancies q  Efficacy expectancies q  Unrealistic thinking

•  Social support and adult attachment styles (secure vs avoidant stile)

•  Age, marital life, gender and education

AVONEX

BETAFERON or EXTAVIA

REBIF 22 mcg

COPAXONE

REBIF 44 mcg TYSABRI

MITOXANTRONE

CYCLOPHOSPHAMIDE  

FIRST TREATMENT

59 59

Today,  people  with  CIS/MS  are  looking  for:  

Reliable and valid information on MS

A better understanding of MS and treatments

A more active role in coping with the disease

Better communication with their healthcare providers

and friends

61

A booklet for patients with a

recent MS diagnosis

Adverse effect of interferons? •  Not mentioned in the Rice et al. Cochrane Review (2001) •  Long history of problems with alpha interferons •  Liberati (1990) – beta interferons safer? •  Pliskin (1996) – emphasized dosing differences •  In SPECTRIMS trial, depressive symptoms were no more

common in patients treated with IFN than in PL (Patten et al. 2002).

•  The frequency of depression declined in RRMS patients followed for 1 year after onset of treatment with IFN (Feinstein et al 2002)

•  The severity of depression was unchanged in patients treated with IFNbeta 1a (Zephir 2003).

•  The suicide risk is unchanged during IFN treatment (Patten 2005)

Pharmacoterapy in MS with MDD Ø  260 patients with MS treated by 35 neurologists.

Ø  67 patients (25.8%) met the criteria for MDD

Ø Among the patients with MDD

–  65.6% received no antidepressant medication

–  4.7% received subthreshold doses from their neurologists

–  26.6% received doses at threshold

–  3.1% received doses exceeding threshold

Ø Depression was undertreated in this sample of patients

with comorbid MS and MDD Mohr 2006

Depressive symptoms

must be recognized,

have an early diagnosis

and an early and personalized treatment (Considering the patient preferences and local circumstances)

Pharmacological Antidepressive Treatments

•  Fatigue SSRI- SNRI •  Urinary Urgency amitryptiline/Desipramine •  Sexual disturbances MIRTAZAPINE/TRAZODONE •  About TCA : Possible Negative effects on memory

and other cognitive functions ! Postural hypotension, dry mouth, costipation, tachycardia.

•  Add low dosage Neuroleptic drug? ( Ser NA DA)

DEPRESSION TREATMENT in MS patients

•  Pharmacotherapy and psychotherapy of depression are more efficient than placebo (Mohr, 1999 ; Lamberg, 2001). –  Comparison between both in large groups has not be done.

•  Pharmacotherapy : few research on small samples on antidepressant pharmacotherapy of depression associated with MS.

•  Psychotherapy : cognitive and behavioral therapy based on stress model (conscious strategies to cope with stressing events better than insight oriented therapy)

Non-pharmacologic therapy

µ Psychotherapies: µ Individual psychotherapy (Minden, 1992)

µ Group therapy: analytical (Barnes et la, 1954); supportive (Spielberg, 1980); insight oriented (Crawford and McIvor, 1985).

µ Cognitive-behavior therapy (Mohr et al, 2001). µ Supportive-expressive therapy (Mohr et al, 2001).

µ Telephone administered cognitive-behavior therapy over 8 weeks helped mood and adherence to interferon beta-1a (Mohr et al, 2000).

Effects of psychological group therapy in MS patients (BDI score)

0

2

4

6

8

10

12

14

T0 T1 T2

TreatedControl

Tesar et al 2003

DEPRESSION TREATMENT IN Multiple Sclerosis

•  Cognitive and behavioural therapies : active

coping strategies problem focussed are more efficient (facing the situation, action planning, looking for social support) than passive coping strategies emotion focussed

•  Perceived social support is correlated with a good emotional adaptation in MS

Psychological interventions may improve the psychological and physical well being of individuals with MS •  by treating mood disorders such as anxiety and depression

•  by improving self-management and adherence, •  by enhancing self efficacy and esteem, •  by reducing stress, improving coping skills and general quality of life.

Aims of Psychological Interventions

• Psychological therapy on an individual basis may help individuals to develop skills to cope with emotions, and to find adjustment to MS diagnosis and symptoms.

•  Group therapy is often used to decrease feelings of alienation, facilitate expression of emotions related to the disease, and provide peer support.

Aims of Psychological Interventions

IDENTIFICATION OF AFFECTIVE DISORDERS IN MS

Assessment Algorithm Formal

Screening (BDI)

BDI > 10 or > 1 on suicide item

Diagnostic interview for affective disorders

(+CMDI?)

No depression detected

Refer to General

Practitioner

Refer to Psychiatry

Anti-Depressive Algorithm

No affective disorder or situational concerns

Situational concerns Suicidal, bipolar, psychotic, etc.

Depressive Spectrum

Grazie dell’attenzione!

Bergamo, 11 Aprile 2013