AFFECTIVE DISORDERSLONG-TERM TREATMENT OF

DEPRESSION

PROF. MUDr. JIŘÍ RABOCH

1.LF UK A VFN

PRAHA

AFFECTIVE DISORDERSin the history

• 4. b.c. Hippokrates - melancholy, mania• 1899 Kraepelin manic depressiv psychosis• 1953 Kleist, Leonhard - unipolar x bipolar

depression

Paradigms of depression and its treatment

duration treatment

start of 20th cent. long-term long-term

1960 - 1970 short-term short-term

1980 - 1990 long-term long-term

1990 long-term short- and long-term

(Hirschfeld, R.M.A.,1998)

THE GLOBAL BURDEN OF DISEASE

Ch.J.L.MURRAY, A.D.LOPEZ, 1997

HARVARD SCHOOL OF PUBLIC HEALTH

WORLD HEALTH ORGANISATION

WORLD BANK

DALY - Disability Adjusted Life Years

DALY = YLL + YLD

YLL - Years of Life Lost

YLD - Years Lived with Disability

% DALY OF NEUROPSYCHIATRIC DISORDERS IN VARIOUS PARTS OF THE WORLD

0

5

10

15

20

25

30

DALY

mark.ec.

form.soc.

lat.Am.

China

Asia

Med.Sea

subsah.Afr.

Disability Adjusted Life Years Murray a Lopez, 1997

10 MAIN CAUSES OF DEATHestablished market economies

0

2000

4000

6000

8000

10000

12000

14000

16000

YLL

IHD

CVD

traf.acc.

lung canc.

selfinf. Inj.

perinat.

resp.inf.

congenit.

colon ca.

stom. Ca.

Years of Life Lost Murray a Lopez, 1997

10 MAIN CAUSES OF DISABILITIES established market economies

0100020003000400050006000700080009000

10000

YLD

depr.

alcohol

osteoart.

dementia

sch

bp

CVD

OCD

traf.acc.

diabetes

Murray a Lopez, 1997Years Lived with Disability

DALY (%)world

1. Respiratory infections 8,2

2. Diarhoea 7,2

3. Perinatal conditions 6,7

4. Major depression 3,7

5. IHD 3,4

6. CVD 2,8

7. Tuberculosis 2,8

8. Measles 2,7

9. Traffic accidents 2,5

10. Congenital anomalies 2,4

Murray a Lopez, 1997

DALY (%) established market economies

1. 9,9

2. Major depression 6,1

3. CVD 5,9

4. Traffic accidents 4,4

5. Alcohol use 4,0

6. Osteoarthritis 2,9

7. Trachea, bronchus, lung cancers 2,9

8. Dementias 2,7

9. Self-inflicted injuries 2,3

10. Congenital anomalies 2,2

Murray a Lopez, 1997

DALY (%) established market economies age 15 -

441. Major depression 12,3

2. Alcohol use 8,9

3. Traffic accidents 8,5

4. Schizophrenia 5,0

5. Self-inflicted injuries 4,2

6. Bipolar disorder 3,7

7. Drug use 2,9

8. OCD 2,7

9. Osteoarthritis 2,7

10. Violence 2,4Murray a Lopez, 1997

DALYformerly socialist countries

0

500

1000

1500

2000

2500

depr.male depr.female dem.male dem.female

1990

2000

2010

2020

Murray a Lopez, 1997

LIFE-TIME PREVALENCE (%)NCS

TOTAL Men Women

Affective disorders

17,1 12,7 21,7

Anxiety disorders 24,9 19,2 30,5

Dependencies 26,6 35,4 17,9

Non-affektive psychoses

0,7 0,6 0,8

Mental disorders 48,0 48,7 47,3

Kessler, 1994

0

10

20

30

40

50

60

70

80

90

100

0 5 15 25 35 45 55 65 75

AGE OF ONSET OF DEPRESSION

CU

MU

LA

TIV

E F

RE

QU

EN

CY

Cumulative frequency of depression according to the decade of birth and the age at the start of the disease

ECA study

1955+

1945-19541935-1944

1925-1934

1915-1924

1905-1914

1905

Wittchen et al., 1994

FIRST OUT-PATIENT PSYCHIATRIC EVALUATION DURING A YEAR

(2 450 106 EVALUATIONS)

DIAGNOSIS 1994 2003 CHANGES (%)

ORGANIC DISORDERS 27 421 45 083 64,4

DEPENDENCIES 31 097 34 484 10,9

SCHIZOPHRENIA 33 805 37 987 12,4

AFFECTIVE DISORDERS 37 915 79 215 108,9

NEUROTIC DISORDERS 103 577 158 168 52,7

CHILDRENS MENTAL DISORDERS

23 460 21 162 -9,8

TOTAL 307 877 419 175 36,2

ÚZIS 2005

13

28

43

52

5962

66 6871

74 7580 81 82 82

87

0

20

40

60

80

100

0,5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

CUMULATIVE FREQUENCY OF RELAPSES OF DEPRESSION

(378 patients with depressive disorder)

years

Cu

mla

tive

fre

qu

ency

(%

)

Rothschild, A. J., 1999)

LONG-TERM COURSE OF DEPRESSION

bez suic.

úvahy suic.

suicidium

2/3 suicidal ideas

7 – 15 % commits suicide

Keller a Sadock, 1991

NUMBER OF COMMITED SUICIDES/100 000

0

10

20

30

40

50

60

70

80

Rus. Hun Franc. ČR GB Gree.

male

female

WHO 2000

0

5

10

15

20

25

30

35

67 70 73 76 79 82 85 88 91 94 97 0

MUŽI

ŽENY

COMITTED SUICIDESCZECH REPUBLIC

/100 000

ÚZIS 2003

CZECH REPUBLIC

2002 - COMMITED SUICIDES 1483 (1 173 men a 310 women)

ÚZIS 2003

FACTORS INFLUENCING THE COURSE OF DEPRESSION

• GENETIC RISK• AGE AT THE START OF DEPRESSION (<25, 60<)• NUMBER OF PREVIOUS EPIZODES AND THEIR LENGTH• REZIDUAL SYMPTOMS• COMORBIDITY• FEMALE GENDER• PSYCHOSOCIAL SITUATION (PARTNER)• BIOLOGICAL FACTORS – SLEEP PATTERN, HHA ACTIVITY

PHASES OF DEPRESSION TREATMENT

(Kupfer, 1991)

time

Depre

ssio

n inte

nsi

ty

acute continuing maintenance

DEPRESSION TREATMENT OPTIONS

• ANTIDEPRESSANTS, OTHER DRUGS • PSYCHOTHERAPY (KBT, IPT)• OTHER BIOLOGICAL METHODS

ECT

rTMS

PHOTOTHERAPY

SLEEP DEPRIVATION

VNS, DBS

PHASES OF DEPRESSION TREATMENT

(Kupfer, 1991)

time

Depre

ssio

n inte

nsi

ty

acute continuing maintenance

FINISHING THE CONTINUING TREATMENT PHASE

• 4 – 9 MONTHS OF EUTHYMIA• NOT FULFILLING THE CRITERIA FOR

MAINTENANCE TREATMENT• THE PATIENT IS ASKING FOR

• DISCONTINUATION SYNDROM – TCA, SSRI WITH SHORT-TERM ELIMINATION HALF-TIME

• SLOWLY DECREASING THE DAILY DOSAGE - 25 % DD PER MONTH

PHASES OF DEPRESSION TREATMENT

(Kupfer, 1991)

time

Depre

ssio

n inte

nsi

ty

acute continuing maintenance

MAINTENANCE THERAPY

Number of previous epizodes Clinical characteristics biological characteristics

- 3 or more previous suicide sleep pattern epizodes farmacoresistency - one previous epizode psychotic depression HHA activity with special clinical somatic features characteristics difficult psychosocial

situationdouble depression

Maixner a Greden, 1998

MAINTENANCE TREATMENT(LONG-TERM)

• WHAT ANTIDEPRESSANT

• WHAT DOSAGE

• HOW LONG

WHAT ANTIDEPRESSANT?

MAINTENANCE TREATMENT(LONG-TERM)

• LITHIUM• CLASSICAL ANTIDEPRESSANTS• IMAO, RIMA• SSRI• OTHER MODERN

ANTIDEPRESSANTS

0

0,2

0,4

0,6

0,8

1

0 10 20 30 40 50 60 70 80 90 100 110

weeks

RESUTLTS OF MAINTENANCE TREATMENT WITH IMIPRAMINE IN 4. AND 5. YEARS IN

COMPARISON WITH PLACEBO

(Kupfer, D.J., et al., 1992)

p<0,006

Imipramin (n=11)

Placebo (n=9)

Cu

mu

lativ

e f

req

ue

ncy

of

pa

tien

ts in

re

mis

sio

ni

SSRIs – inhibition of P450 microsomal enzymes

enzyme citalopram fluoxetine fluvoxamine paroxetine sertraline

CYP1A2 - - +++ - -CYP2D6 + +++ - +++ +CYP3A3/4 ? + ++ - -CYP2C19 ? ++ +++ ? -

? data lacking - no capacity

+ minor capacity ++ less potent

+++ most potent

(Edwards, J.G. a Anderson, I., 1999

POTENTIALLY SERIOUS DRUG INTERACTIONS OF SSRIs

all antikoagulancia zvýšený antikoagulační efekt(warfarin, kumaroly)

all antidepresivaIMAO serotoninergní syndrom(nižší pravděpodobnost u reverzibilních preparátů)Tricyklika zvýšená hladina některých tricyklik

fluoxetine antiarytmikaflecainid zvýšená plasmatická koncentrace

fluoxetine antikonvulziva snižování záchvatového prahufluvoxamine carbamazepin zvýšené plazmatické hladiny

phenytoinall antihistaminika

terfenadin zvýšené riziko arytmiíall lithium CNS toxicitaall sumatriptan CNS toxicitafluoxetinefluvoxamine klozapin zvýšená plazmatická hladina klozapinufluoxetine haloperidol zvýšená plazmatická hladina haloperidoluall ritonavir zvýšení koncentrace SSR1fluvoxamine theophyllin zvýšená plazmatická hladina theophyllinufluoxetine selegilin CNS excitace, hypertenzeall tramadol zvýšené riziko konvulzí

(Edwards, J.G., Anderson, L, 1999)

MAINTENANCE DEPRESSION TREATMENT

• SSRIs > CLASSICAL ANTIDEPRESSANTSSIMILAR EFFECT BETTER TOLERABILITY COMORBID DISORDERS ONCE A DAY DOSAGE

LOW INTOXICATION LETHALITY

• ANDERSON, 1998

HOW LONG?

0,00

0,20

0,40

0,60

0,80

1,00

0 52 104 156 208 260 312 364 416 468 520 572 624 676 728 780

weeks

pat

ien

ts in

rem

issi

on

Recurrences in 105 patients with major depression after 5 years-remission

(Mueller, T.I., et al., 1999)

WHAT DOSAGE?

DOSAGES OF ANTIDEPRESSANTS IN MAINTENANCE TREATMENT OF

DEPRESSION

• IMIPRAMINE – 3-YEARS FOLLOW-UP – 100 mg - 70 % RELAPSES

200 mg - 30 % RELAPSES (FRANK et al., 1993)

• CITALOPRAM 20 i 40 mg EFFECTIVE IN CONTINUING TREATMENT (MONTGOMERY et al., 1993)

• DECREASING THE DOSAGE OF CITALOPRAM FROM 40 TO 20 mg 2-YEARS FOLLOW-UP – 50 % RELAPSES (FRANCINI et al.,1999)

COMPLIANCE

• STRATEGIES FOR IMPROVING

PATIENT – PHYSICIAN RELATIONSHIP

EDUCATIONADEQUATE FARMAKOTHERAPY

Haddad, 2000

PSYCHOFARMACOLOGICAL THERAPY ONLY 13,4 % OF PEOPLE WITH DEPRESSIVE SYMPTOMS (!!!)

0

10

20

30

40

50

%

% 46 13 12 6 2 20

anxiol.antidep

r.hypn. neurol. other ns

Vaněk, Raboch, Vaněk, 2000