?e?te?a ?p?d?

1
?e?te?a ?p?d?µ???????? ?a? Fa?µa???e?ape?t???
?ed?µ??a t?? ?at???????

• G?????? ??. ??eß???p?????, M.D. Ph.D., DFPsych
• ?p??????? ?a????t?? ????at????? ????

2
? ?e???? ?at?????? ?? ?e???? ??t?a ????a??t?ta?
?a???sµ???
T?s? 1990 2020 (??t?µ?s?)
1 ???µ??e?? ?at?te??? a?ap?e?st???? ?s?a?µ??? ?a?d??p??e?a
2 ?e???e???t???? pa??se?? ?e???? ?ata???pt??? ??ata?a??
3 HIV/AIDS ????a?a at???µata
4 ?e???? ?ata???pt??? ??ata?a?? ???e?a?? e??efa???? ??s??
5 ??a??????? ??s?? ?????a ap?f?a?t??? p?e?µ???p??e?a
Murray, CJ, Lopez AD. The Global Burden of
Disease A Comprehensive Assessment of Mortality
and Disability from Diseases, Injuries, Risk
Factors in 1990 Projected to 2020. Cambridge,
MA 1996. n8.764 Spain, Finland, Norway,
Ireland, UK)Prevalence for women was 10.05 and
for men 6.61
3
?? ???e?µµa ?e?ape?a? t?? ?at???????

• S???pe?e?1
• ?p??easµ??? ??????????????µ??? ?e?t???????t?ta
• ????µ??? s?µat??? ?a? ?????? s??-??s?s?
• ????µ???? ???d???? ???s?µ?t?ta?
• ?e??p?? 340.000.000 p?s???? ap? ?at??????
  d?e????2
• ???a? t?? 75 t?? as?e??? µe ?at?????? de? ?????
  ??ße? ?aµ?a ?e?ape?a WHO3

1. Pincus HA, Pettit AR. J Clin Psychiatry.
   200162(suppl 6)5-9.3095-3105.
2. Greden JF. J Clin Psychiatry. 20016226
3. http//www.who.int/mental_health/management/depres
   sion/definition/en/

4
S???pt??? ?e???s? t?? ?at???????
5
THE WORLD FEDERATION FOR MENTAL HEALTH 2005

• ?e??d?????a
• Harris Interactive t??ef????? ??e??a ??a t?
  WFMH , ?at? t? 2005 st?? Brazil, Canada, Mexico,
  Germany ?a? France
• ?e??µa
• ?e??µa 377 e?????e? p?? e??a? d?a???s?e? µe
  ?at?????? ??? ?a? 5 ?????a ap? t?? ep????????a
  ?a? s??e???a? ?a pa?????? a?t??ata???pt??? a????
• 756 ??at??? ????at??? ?a? ?e????? ?at?????, ??
  ?p???? a?t?µet?p??a? ?ata???pt????? as?e?e?? ?a?
  e??a? 2-30 ?????a s?et???? eµpe???a?

6
?s?e?e?? S?µpt?µata ?at???????
S???????, 64 a??fe?a? ?t? ta ep?d??a s?µpt?µata
µ??a ? se s??d?asµ? t??? ?d???sa? st? ??at??.
Mexicogt CanadagtFrancegtGermanygtBrazil).
S?µpt?µata p?? ?d???sa? st? ??at??
A
B
C
D
E
BASE ALL QUALIFIED RESPONDENTS Q400 Thinking
back about the symptoms of your depression that
prompted you to go to your physician, please
indicate the type(s) of symptoms you experienced.
Please select all that apply.
7
? ?at?????? e??a? ??s?? µe ?????? ?a? s?µat???
s?µpt?µat?????a

• 69 t?? ?ata???pt???? a?af????? s?µat???
  e?????µata ?? ta p??te???ta s?µpt?µata e?????s??
  (n1,146 as?e?e?? p??t?ß??µ?a? pe???a????)1

• 43 t?? ?ata???pt???? as?e??? pa???s??????
  s?µat??? ep?d??a e?????µata ??a?t? 10 t?? µ?
  ?ata???pt???? as?e???2

1. Simon GE, et al. N Engl J Med.
19993411329-1335. 2. Ohayon MM, Schatzberg AF.
Arch Gen Psychiatry. 20036039-47.
8
?a s?µat??? s?µpt?µata s???? pa?aß??p??ta?

• 30 t?? ?ata???pt???? as?e??? e??a? s?µat???
  s?µpt?µata a??µ? ?a? 5 ?????a p??? te?e? ?
  d?????s?1

• ?? ad?????st?? as?e?e?? ?pe??ata?a??????
  ?p??es?e? ??e?a? µe ????? ??st?? ?a? ?aµ???
  ap?te?esµat???t?ta2

1. Lesse S. Am J Psychother. 198337456-475.
2. Kroenke K, et al. Arch Intern Med. 1990
1501685-1689.
9
?a ts?µp?µata ?a? ?? p???? e??a? t?s? s?????
st??? ?ata???pt????? ?s? ?a? t? ?????
Adapted from Silverstein B. Am J Psychiatry.
1999156480-482. Silverstein B. Am J
Psychiatry. 20021591051-1052.
10
?e??ss?te?a S?µat??? S?µpt?µata S?et????ta? µe
µ?a ?e?a??te?? ???a??t?ta ?ata???pt???? ??ata?a???
?e ?ata???pt???? ??ata?a???
?s?e??? ???t?ß??µ?a? ?e???a????
????µ?? S?µat???? S?µpt?µ?t?? (N1000)

• ?a s????? s?µat??? s?µpt?µata pe????µßa?a?
  ??p???µ?a, d?ata?a??? t?? eµµ???? ??se??,
  ?efa?a???a, ????? st?? ???a?a, ????, a?s??µa
  pa?µ??, se???a????? d?ata?a???. s?µpt?µata ap? t?
  ?ast?e?te???? (?a?t?a, ?µet??, e????? ? d?spe??a,
  d?s??????t?ta, d??????a), ?????a?? ?????,
  d?sp???a, ??p?s?, a?p??a, a???a???e?, ????? ?????
  ?a? ?sf?a???a.

Adapted from Kroenke K, et al. Arch Fam Med
19943774-779.
11
????? ?p??e?µµat??? s?µpt?µata e??a? s?µat???
Physical symptoms measured by HAMD17 Item 13
somatic symptoms/general
Adapted from Paykel ES, et al. Psychol Med.
1995251171-1180.
12
?a ?p??e?µµat??? s?µpt?µata ap?te???? p??te???ta
???? ?p?t??p??
Paykel ES, et al. Psychol Med. 1995251171-1180.
13
? ?ata???pt???? fa???t?p??
S??a?s??µat??? s?µpt?µata T???? ??s??µata ?a???? ?a? apa?s??d???a? ??s??µata ??tas?? ?e?????t?ta? ?a? a??s???a? ?p??e?a e?d?af????t?? ?a? e??a??st?s?? ??s????a st? s?????t??s? ??s??µata a?a???t?ta? ?pe?ß????? e???? ??e?e??st?t?ta ? a??s???a ??t??t?????? ?d?e? ?a? ?deasµ?? S?µat??? s?µpt?µata ?saf? ts?µp?µata ?a? p???? ?efa?a???e? ????? st?? p??t? ?/?a? µ?s? ??a???e? ??spe??e? ??p?s? ?a? ap??e?a e?e???t???t?ta? ??ata?a??? ?p??? ?etaß???? st?? ??e?? ?a? t? s?µat??? ß???? ????
14
? ?ata???pt???? fa???t?p??
S??a?s??µat??? s?µpt?µata T???? ??s??µata ?e??? ?a? apa?s??d???a? ??s??µata ??tas?? ?e?????t?ta? ?a? a??s???a? ?p??e?a e?d?af????t?? ?a? e??a??st?s?? ??s????a st? s?????t??s? ??s??µata a?a???t?ta? ?pe?ß????? e???? ??e?e??st?t?ta ? a??s???a ??t??t?????? ?d?e? ?a? ?deasµ?? S?µat??? s?µpt?µata ?saf? ts?µp?µata ?a? p???? ?efa?a???e? ????? st?? p??t? ?/?a? µ?s? ??a???e? ??spe??e? ??p?s? ?a? ap??e?a e?e???t???t?ta? ??ata?a??? ?p??? ?etaß???? st?? ??e?? ?a? t? s?µat??? ß???? ????
15
??at?µ?a t?? s??a?s??µat???? d?ata?a???
?pe?d?ast????t?ta t?? aµ??da??? se ?ata???pt????
???a??e?
t-values
?µ??da??
M Bauer et al., Mol. Psychiatry, 2005
16
? a???s? t?? ?????? a??????e? t??
?pe?d?ast????t?ta t?? aµ??da???
Insula
Medial PFC
t-values
Amygdala
6
Medial Orbitofrontal
4
2
()
(-)
z -16 mm
z 2 mm
17
??at?µ?a t?? ?at????????p?d?ast????t?ta st? µ?s?
p??µet?p?a?? f????
Medial PFC
TA Ketter and WC Drevets, Clin. Neurosci. Res.,
2002
18
?p??e?a t?? f??????? e?????? st?? aµ??da??
t-values
3.5
ACC
2.5
1.5
0.5
Amygdala
Control gt MA
MA gt Control
OFC
Environment ? exaggerated
responses ?depression ?anxiety ?craving
19
G?at?
20
?e???????? e?e??e?a??? p????

• ?sfa?µ??? a?t????? ? a?µat??? ??? t?? e??ef????
  a????eta? ?at? t?? ?s??s?
• ? ??? e??a? sta?e?? a?e???t?ta d?ast????t?ta?
  f?s???? ? ??????? 750 ml/min
• Se ??eµ?a ? e???fa??? pa???e? 15 t??
  ?a?d?a??? pa?????
• Se f?s??? d?ast????t?ta ? ?pe??e?t?????a
  ???eta? a?a?ata??µ? st??? µ?e? ?a? pa???e? t? 4
  t?? ?.p./pa?µ?
• ???? t?? 4? a???µ???? ?a?d?a??? pa?µ?? ?
  a?µ?t?s? pa?aµ??? sta?e??.
• ?? s??????? ?ata?a??s??µe?? ?2 pa?aµ??e? ep?s??
  sta?e??

21
?s??s? ?a? ?ata????s? ?2
22
? ?p??es? t?? pa??d???? µet?p?a?a? ?p??e?t?????a?
???efa????? d?µ?? p?? de?????? µetaß???? st??
?ata????s? ?2 30 ?ept? se µ???st?
d?ast????t?ta (Vissing et al., 1996)
?e ded?µ??? ?t? ?? p??µet?p?a?e? pe?????? e??a?
t? µ??ad??? e?µe???e? e??efa???? tµ?µa fa??eta?
?t? a?t? p?? te???? pa?aß??pteta? e??a? ?
e?te?est??? ?e?t???????t?ta
23
?p??e?a t?? f??????? e?????? st?? aµ??da??
t-values
3.5
ACC
2.5
1.5
0.5
Amygdala
Control gt MA
MA gt Control
OFC
Environment ? exaggerated
responses ?depression ?anxiety ?craving
24
?e???ß??????a t?? s??a?s??µat???? µ??µ??
from McGaugh, Science 487 249-252 (2000).
25
?p?d?as? t?? t?a?µat?? st?? a??pt??? ?at???????
Caspi et al, Science 2003
26
? ?ata???pt???? fa???t?p??
S??a?s??µat??? s?µpt?µata T???? ??s??µata ?a???? ?a? apa?s??d???a? ??s??µata ??tas?? ?e?????t?ta? ?a? a??s???a? ?p??e?a e?d?af????t?? ?a? e??a??st?s?? ??s????a st? s?????t??s? ??s??µata a?a???t?ta? ?pe?ß????? e???? ??e?e??st?t?ta ? a??s???a ??t??t?????? ?d?e? ?a? ?deasµ?? S?µat??? s?µpt?µata ?saf? ts?µp?µata ?a? p???? ?efa?a???e? ????? st?? p??t? ?/?a? µ?s? ??a???e? ??spe??e? ??p?s? ?a? ap??e?a e?e???t???t?ta? ??ata?a??? ?p??? ?etaß???? st?? ??e?? ?a? t? s?µat??? ß???? ????
27
???a??sµ?? s??des?? ?at??????? ?a? ep?d????
s?µpt?µ?t??
28
????? ?a? f?e?µ???
ape?e?????s? ??s?a? P
?pe?e?????s? ??s?a? ?
29
??s?a P
?p????aµ??
?µ??da?? ?a? µeta??µ?a??? pe??????
DA ???t?a
?? ???t?a
?p??es? t?? Neurokinin
30
Structure of Pyramidal Neurons Can Contribute to
Depression
December 2002
Computational Neuroscience IAurel Lazar, Rafael
Yuste
30
31
(No Transcript)
32
(No Transcript)
33
Trachtenberg et al Nature, December 2002
34
? ?ata???pt???? fa???t?p??
S??a?s??µat??? s?µpt?µata T???? ??s??µata ?a???? ?a? apa?s??d???a? ??s??µata ??tas?? ?e?????t?ta? ?a? a??s???a? ?p??e?a e?d?af????t?? ?a? e??a??st?s?? ??s????a st? s?????t??s? ??s??µata a?a???t?ta? ?pe?ß????? e???? ??e?e??st?t?ta ? a??s???a ??t??t?????? ?d?e? ?a? ?deasµ?? S?µat??? s?µpt?µata ?saf? ts?µp?µata ?a? p???? ?efa?a???e? ????? st?? p??t? ?/?a? µ?s? ??a???e? ??spe??e? ??p?s? ?a? ap??e?a e?e???t???t?ta? ??ata?a??? ?p??? ?etaß???? st?? ??e?? ?a? t? s?µat??? ß???? ????
35
?e??s? t?? ????? t?? ?pp???µp?? se ?ata???pt?????
Control Volume 3,295 mm3
?p?t??p?????sa ?at?????? Volume 2,015 mm3
Campbell, S and MacQueen, GJ Psychiatry Neurosci.
, 2004
36
???? ??a µ??t??? d?p??? pa??????a?
?ate?????µe?? p??s???
????t?a

• ?????µata a?taµ??ß??
• ?e??µ???? ?????? a?taµ??ß??
• ?p?ß??d??s? ap?st??f??

• ??te?est??? ?????µata
• ??ata?a??? st?? est?asµ?
• ??te?est??? d?s?e?t?????a

?ß????a
Sonuga-Barke. Neurosci Biobehav Rev. 200327593.
37
???s??s? ????t???
Ta p??e?? 100 a? ta ?ataf??e??
???e ta d??at? s??
38
S??ep???? e??s??s? ??a ta a???d? ?a?
s?µat???, 5-?? ??a ta s??a?s??µat??? ?a? DA ??a
?a ß????t??? s?µpt?µata
39
???e?µµata st? ?e?ape?a t?? ?at???????

• ?????? as?e?e?? pa???s?????? e????st? ? µ?de????
  a?tap????s? st?? a????1
• 1/3 t?? as?e??? ?p? SSRI? ep?t???????? ?fes?.2
• S?µa?t???? pa?????te? ap?t???a? e??a? ?
  ?a??asµ??? d?????s? ?a? ? ad??aµ?a a?t?µet?p?s??
  t?? s?µat???? s?µpt?µ?t??.3

1. Fawcett J, Barkin RL. J Clin Psychiatry.
199758(suppl 6)32-39. 2. Thase ME, et al, Br J
Psych. 2001178 234-241. 3. Paykel ES, et al.
Psychol Med. 1995251171-1180.
40
?? ?e?ape?e? e??s??s?? d????? ?a??te?a
ap?te??sµata st? ?e?ape?a t?? ?at???????
Nelson JC, et al. Arch Gen Psychiatry.
199148303-307.
41
? ??p?? ??ast??? t?? ??t???? ?pa?ap??s????? 5-HT
?a? NE ????se t?? ???a??t?ta ?fes??
?es?p?aµ???
F?????et???
F?????et??? ?es?p?aµ???
?fes? ße?t??s? 75
?e???? ??tap????s? ße?t??s? 25-49
??tap????s? ße?t??s? 50-74
??-a?tap????s? ße?t??s? lt 25
Nelson JC, et al. Biol Psychiatry
200455296-300. The MADRS was used to define
Remission and Response
42
?a ??t??ata???pt??? ??p??? ???a??sµ?? ???s?? st?
Te?ape?a t?? ??s??e??µe??? ?s?e??? µe ?at??????

• ??de??e?? ?p?d??????? ?t? ? ?????µ?p?aµ???, ??a
  TCA p?? d?a t?s? st?? 5-HT ?s? ?a? st?? NE, ??e?
  µ?a pe??ss?te?? ??????? ?a? ap?te?esµat???
  ep?d?as? ap? ?,t? ? SSRI pa???et???

25
20

15

S??????? ?a?µ?????a HAMD17
??s? ?e?t??s?

10



5
0
0
2
4
6
0
2
4
6
?ßd?µ?de?
p lt 0,05 ??a?t? ?a???et????
?a???et??? (SSRI)
?????µ?p?aµ??? (TCA)
Danish University Antidepressant Group. J Affect
Disord 199018289-299.
43
Anderson, DepressAnxiety 1998 111-17
44
??ast??? epa?ap??s????? 5-?T/ NE In Vitro
??ast??e?? t?? s??des?? se a????p????? µetaf??e??
p??s????? µ???aµ???? (?i, nM)
?????
NE
5
-
HT
NE/5-HT (1?s????p?a)
Duloxetine
7.5
0.8
9
?e??afa????
2483
82
30
F?????et???
1022
7
146
?a???et???
132
0.4
330
Se?t?a????
715
0.9
794
S?ta??p????
gt10000
9.5
gt1050
Bymaster FP, et al. Neuropsychopharmacology.
200125871-880.
45
Drug Class Drugs and Mechanisms Indications and Contra-Is Side Effects
Selective Serotonin Reuptake Inhibitors (SSRI) Fluoxetine (Ladose) Sertaline (Zoloft) Paroxetine (Seroxatl) Fluvoxamine (Dumirox) Citalopram (Seropram) Unline TCAs and MAO-Is which inhibit both NE and serotonin, SSRIs are specific inhibitors of serotonin reuptake. These are the most widely prescribed drugs in psychiatry. These drugs also have a flat dose-response curve, so that higher dose doesnt mean greater effect. Major Depressive Disorder OCD Panic Disorder w/ or w/o Agoraphobia Social Phobia Bulimia PMS Dysthymic disorder Premature Ejaculation The SSRIs have virtually replaced TCAs and MAO-Is as the first line of treatment for many of these conditions. The side effects can be understood in terms of the various types of serotonin receptors. 5HT3- GI system, over-stimulation leads to diarrhea 5HT1D- CNS, stimulation causes migraines 5HT2C- CNS, involved in appetite and weight 5HT2A- CNS, involved in sex and sleep Early Side effects Decreased Appetite Nausea Diarrhea Jittery feeling Headache These disappear in 1-2 weeks as tolerance develops. Late Side effects Decreased Libido, Delayed Orgasm due to inhibited NO production. Sleep disturbances- can be treated with trazodone, a sedating antidepressant Weight Gain Bad withdrawal syndrome from paroxetine, sertaline and fluvoxamine. Symptoms include nausea and vomiting, vertigo, anxiety, confusion and others.
46
Sexual Side Effects

• Ejacul. Dysfxn. Impotence Decreased Libido
• Paroxetine 23 8 7
• Sertraline 14 -- 6
• Venlafaxine 12 6 2
• Fluoxetine 7 2-7 4
• Escitalopram 9 3 4
• Citalopram 6 3 4
• Duloxetine 3 4 3
• Buproprion -- 3 3

Rates for pts. on placebo ranged from 1-4
across all categories
Physician Desk Reference, Thompson Eds 2006