Document 6846

REVIEWS
MINERVA ENDOCRINOL 2006;31:27388
alterutions
Roleof endocrine
?fidinflammatory
ln comorbidsomaticdiseases
stressdisorder
of post-traumatic
N. ROHLEDER1.A. KARL2
Since its first description in the Diagnostic and
Statistical Manual for Mental Disorders, posttraumatic stress disorder (PTSD) has been charact€rized as a disorder of altered affective functioning which causes tremendous distress. In
is not
addition, it has b€enrecognizedthatPTsD
only accompanied by "poor health" but also
by a number of specific and non-specific "sornatic" pathologies, such as cardiovascular, autoimpain. It
mune and physical complaints/chronic
has been hypothesized that alterations of the
(HPA) axis, the
hypothalamic-pituitary-adrenal
(SAM) and the
sympathetic-adrenal-medullary
funrnune system may mediate or facilitate these somatic conditions. The aims of ttris review
are to summarize studies that reporrt altered
somatic functioning in PTSD andto reviewhow
endocrine and irnmune function differentially
affect PTSD-related somatic malfirnction. It is
hypothestued that alterations of HPA axis and
of inflamSAM system permit disinhibition
matory mechanisms, which in turn foster the
development of somatic diseases as well as selfreported physical complaints.
- PostKey words: Inflammation-Comorbidities
traumatic stress disorders.
p ost-traumatic stress disorder (PTSD) and
I
its related comorbid somatic diseases are
an important health problem. In the United
States, about 70o/oof women and 5o/oof men
Address reprint requests to: Dr. rer. nat. N. Rohleder,
Department of Psychology, University of British Columbia,
2136 west Mall, Vancouver, B.C. V6T 724, Canada.
E-mail: [email protected]
V o l .3 1 ,N . 4
l Llniuersityof Britisb Columbia, Vancouuer
British Columbia. Canada
2Schoolof Psycbotogy
Soutbampton, UK
of
Soutbampton,
Llniuersit.y
have had PTSD once in their live. While a
large number of original and review articles
have been published since its first description
in the Diagnostic and StatisticalManual for
Mental Disorders(DSM), many questionsare
still open. One important question is how
the psychological disrurbancesin PTSDrelate
to the fact that patients often suffer from
somatic diseases,or even die earlier due to
somatic conditions, such as cardiovascular
disease.
While the association of PTSD with somatic disease has been well documented (see
below), the diseasemechanismsare unclear
so far, especially since a large variety of
somatic symptoms is reported by people with
"medPTSD,and many symptoms are labeled
ically unexplained". Thus, it has been
assumedthat PTSDis associatedwith typical
changes in the endocrine and the immune
system that rnay be, at least in pafi, responsible for the somatic complaints seen in PTSD.
One of these alterations is t|rat a component of the immune systemof PTSD patients
appears to be over-active (while others are
not or even suppressed).It appears that this
over-active part is the unspecific or innate
component of the immune systern. This is a
MINERVA ENDOCRINOLOC ICA
ENDOCRINEAND INFLAXI\{ATORYALTER{TIONSIN PTSf)
ROHI,EDER
rather important subsystem as it builcls the
first defenseline of our bddies againstinvading pathogens from the environment.
Hon'ever. this sub-systemhas a highly damaging potential for host itself. In the healthy
organism, it is therefi)re to be kept under
tight control. One of these controlling systems is tire hypothalamic-pituitary-adrenal
(HPA) axis thrdugh its secretion of the glucocorticoiclhormone cortisol.
Interestingly, in I'TSD the HPA axis is fiequently reported to be under-active,leaving
the possibility of disinhibition of inflarnmatory
responsesmediated by the innate component of the irnmune system.The theory of a
hvoo-activeIIPA aris as a mediatorof disease
bli.tirir-rninition of the inflammatory svstem
is u'eil documentedin animal studiesr,rzrnd
has been proposed for several human psychiatric and sornaticdiseasesj* and specifically fbr cardiovasculardiseasein PTSD.5
In this review. lve will discussthe role of
changes in the endocrine and the innate
immune systen-lin the incidence of somatic
diseasesand phvsical complaints in PTSD.
Therefore. u,'e n ill first describe the symptomatologr.ancl netrr:rlbasis of PTSD.then
on somatic
summarizethe current literatr-rre
cliseasesin I'TSD. follou,ed Lryan analysisof
enclocrineancl inflammatory-alterationsand
a conclusive sllrrllnan'.
r-na CueS111
. 2 a n d e x a g g e r a t e 6 l 5 1 x 1 1 1 9 . 1 t3. .i
Personswith PTSD may also exhibit deficits
in attention and working memory as well as
difficulty encoding information and inhibiting
distractingstimuli.l;,16They may also exhibit enhanced processing of threat stimuli and
cues.ll
an attentionalbias to trauma-relatecl
Vhile on one hand intrusive recollections
(e.g. flashbacks) are very vivid and under
limited strategiccontrol, the episodic (contextual) memories of the trautnatic event are
has
lessverbally accessible.This cl1'5ft1nction
been related to alterationsin a cortico-limbic
network in n'hich amygdala, hippocarnpus
and frontai cortical areas play a major role.
Intrusive recollections,exaggerateclstartle
and enhanced threat processing have Lreen
relatedto enhancedamygdalaactivity,lswhile
lack of strategiccontrol over the trauma memories, attentionalbias and limited inhibition
of distracting stimuli have been reiated tcr
poor frontal fr-rnctioning(prefrontal cortex,te
anterior cingulate cortex2')).Altered episodic
memory functioning has been relatedto profound structural2iand functional alterations22
in the hippocampal formation. Studieson
functional br:rin asyrnmetriesll.23ancl functional neuroimagingstttdiesrlpoint to altered
connectivityin this netvl'ork.Successfuipharmacological or cognitir.'ebehavioral treatment of PTSDl-rasbeen accotnpaniedby beneficial alterationsin the above describednety761[..]5 28
Post-traumatic stress disorder
PTSDhas been obsen'ed as one possible
c()nseqllenceof the exposLtreto a severe
tratrmatic e\rent. PTSD is characterized Lry
s.vmptomsof intrusive recollectionsof the
avoidance of- trauma-relatedemotraur.nzi.
tions and situations,emotional numbing
ancl general hy'perarousal(DSM-IV6).The
prevalcnce of PTSD is a function of trauma
i.e,.interpersonal trautypc anci clr-rratior-r.
rna slrch iis tortllre or serr-ralabutseresults in
irigherplcl.alencerates(-, ,-64"u-s) as compareclto :rcciclents
and naturaidisasters(101 5 ( . ) ( r ! rl 1. ) ) .
PTSI) is relatecl to nLunerolrs cognitivea f i ' e c t i r . ' ep r o c e s s i n g a l t e r a t i o n s , s u c l ' r a s
heiglrtenecl physielr*i.'ll respouses t() traLl-
Thor-rghPTSD is observed subsequent to
severe traumatic experience, its emergence
has to be tl'reresult of a complex interaction
between various pre-, peri- and post-traumatic fhctors.Processesof fear conditioning,
sensitizationancllack of extinction hal'e been
discussed,The highly al,ersitreeurotional
expcriencemav enhancethe consolidationof
tlre trzrumamemory t:ia adrenergic mechais
nisms. Tl-rechronicity of the s.vtnpton-rs
accornpanieclb,v alterations it-tthe HI)A axis
(see belon''), lr'hich rnal' facilitate hip30Rccentl)-,the potenpocarnpalatroph.v.re.
tiai contribution o1'pretraLrmaticrisk factors
(/.e. pretraLlltlatic
l-rasalso been cliscussecl
hippocarnpaiatlophl',3tgenetic polytnor-,
nhism that facilitate alterationsin neuroiransmitter fr:nctionJ-;.
\ I I N I ] R \ - \ E \ I J ( J (- R I N I J L O C I ( . ,
Dicenrlxe -2006
tr\DOCRINEANI) INFI-AMMATORY
ALlERATION*S
lN P'lSD
ROHI-EI)ER
Prevalence of somatic diseases and
physical complaints in post-traumatic
stfess disorder
Chernobyl area had significantly higher IES
scores than comparison sr.rlrjects
together
with higher relative risks (RRs)for self-reporlecl heart disease (1.88 confidence interval
Severalstudies.as well as clinical obser- [CI]:1.09-3.22).
Furthermore,IESscoreswere
vations, harre shourn that the psychiatric corelatecl (r:0.33) with number of self:reporlsymptom complex PTSDappearsto be asso- ed chronic conditions..lT
ciated with somatic diseasesand ohvsical
Ot 1 399 rnale Vietnam veterans investisymptoms.Tlresebecame especiallyappar- gated lry Boscarino,ss
332had lif'etirnePTSD
ent in tJ.S. veterans returning from the as diagnoseclby tl-reDiagnostic Interview
Vietnanr Var33 and also in lsraeli soldiers Schedule(DIS).4eAnalysesof self-reported
However. as surn- disease symptoms revealed, alrlong others,
after the Lebanon\7ar.3a.35
marized beiow and in Table I. somatic corrr- significantly higher odds ratios (ORs) for cirplaints and increased morbidity are not culatorydiseases(1.62).J8
Dobie et al.3einvesrestricteclto military veterans,but also oc--c-ur tigatecl 1 259 f'emzrleVietnarn veterans, 21%u
in PTSD after natr-rraldisasters,physical and of wl-rich \\iere screened positive for PTSD
sexuralabuse,intimate partner violence and using a PTSD Checklist (PTSD Checklist
other trauma. Severaldiseasecategoriesare Civilian Version,PCL-C).50
Vomen with PTSD
observed in people suffering from PTSD. reportecl significantly more strokes.-re
Among them are cardiovascularcliseases, Sawcl-l,rkst 511.10
(2005) investigated1 41,1
inf-lammatorydiseasesancl a large range of Ar-nericanIndian participants. 750/o
of which
sornatic symptoms often describeclas mecl- u,ere di:rgnoseclwith lifetin-rePTSD, r-rsing
iczrllyunerplained.
Tw-elve
the CIDI (\flHO version for PTSD51).
percent of participantswith PTSD reported
carcliovascr.rlar
diseases,as corllpareclto only
C'ardiouascttlar clisease
participants.After correcof nor-r-PTSD
5%
One of the rnajor somatic pathokrgies
tion for Agc, sex, education,cardiovascular
apparentlyassociatedwith PTSDare cardic)risk factors and comorbid deoression. the
vascuiardiseases.In a recent revien'. Gancler
u-as2 ( CI: 1.1OR for cardiovascularcliscrrse
et al. surtmarize several stucliesthat shorv
3.8).i0
highel rates of cardiovascular cliseasesin
In tu''o stuclies, self-reported symptons
PTSI) patients.s
sYx4P]'otis
Sttt,-tigpoit'rED
An increasednumber of self-reoortecl
cardiol'ascr.riar
diseaseol diseasesr'niotourswas
fotrnclin scveralsttrtlies.
Fonler Dtrltlr resistance figl-rtcrs\\'ere studieclb)' Falger et al.:r.
Alrolrt 7/2 of then were diagnoseclr.vithPTSD
using the StructuredClinical Inten'ien. for
DSM-IV(SCID).1-Those ciiagnosedw-ithPTSI)
reportecl rnore CVD risk factors inch-rding
angina pectoli5.3r,
Crvikel et al.J- assessecl
P'fSD syn-rptor-ns
cmploving thc Lnpact of
Event Scale(lES) rs in Israeli imrnigrirntsu,.h<r
previor-rsh,livecl in the area ir-npactecl
by' the
Chernobvinuciearacciclentrrnclcomp:rrison
u'iro inrmigratedfi-orl othcr lrcas.
sr-rlrlccts
no separatL'anal\rsesurere
Llnfortr,rnatelt,,
maclecontrastingPf'SD and non-PTSDpart i c i p a n t s .I l o u e r e r . p a l t i c i p a n t sf r c i r l t h e
\ ' < r l J. 1 . N . r
\vere compared with physician-cliagnosecJ
disease: Shaler,' et al. investigatecl 98 male
combzrt ve'terans, half of wl-rich were diagnosed n ith PTSD using a clinical inten'iewaccording tl-re DSM-III. Veterans rvith PTSD
reportecl significantlr' higl-rer rates of cardiovascplar sylnptolns. However, in a medical
exarnination, inclucling an electrocardiogram
ancl laboratory parameters, fe\\. dif'ferences
iretrl,'een both groups of combat \,'eterans
u,erc' folrncl. Unsurprisingly, r'eterans n'itl-r
PTSD reportecl rnore aclverse health practices. strch as snr<lking ancl ;rlcohol abr-rse.*i
Fort-\'-two months afier a catastr()phic l)Llsir
fir-e in Ar-rstralia.N'lcFarlane el a/. investigatecl
a sarnplc of 70 fire fighters u,'ho hacl clevelopecl PTSD (rs cliegnosccl b.v l)IS ancl IFIS)
and comparecl thcm to 70 firc fighters *'itir()ut symptolns. The PTSD group rcportccl signiflcantlr. hishel' Latcs o1'carcliovasctrlarancl
!II\F]R\,4 E\I)C)(]RINOI-O(;I(]A
ENDOCRINEAND INFLAMMATORYALTERATIONSIN PTSD
ROHLEDER
Teerr I. -
Self-repofied uspbltsician diagnosed cardktuascular cliseasesin PTSDpatients.
Sample
Stncly
Self-reported cardiouascular
Falger et a1.36
Results
disease
Dutch resistance fighters (\7\(/II)
(.n=141)t n=82 (.57o/o)with PTSD
Higher cardiovascular risk factors: angina pectoris, life stressors, vital exhaustion
Cwlkel et a1.31
Immigrants into Israel from Chernobyl
nuclear accident area (n:3Q4) vs immigrants from olher arers (n=JJ4): no
distinct groups but higher IES in
Chernobyl immigrants
Higher RRs in Chernobyl groups for
heart disease (1.88), anhritis/rheumatism
(2.57), or having >3 chronic conditions;
conelation of IES with number of symptoms (r=0.33)
Boscarino3s
Male Vietnam veterans (n:1 399); n=332
(63%) with PTSD
In PTSD higher ORs for circulatory
(1.62), digestive (7.47'), musculoskeletal (1.78), endocrine-metabolic (1.58),
nervous system (2.47), respiratory (1.54)
and infectious diseases (2.14)
Dobre et orl.39
Female Vietnam veterans (n=1 259);
v.tith PTSD
n=266 (.270/o)
More strokes, fibromyalgia, irritable
bowel syndrome, chronic pelvic pain in
PTSD
Sawchuk et al.4o
American Indians (.n=1 471): n:272
(15%) with PTSD
OR 2 for cardiovascular disease, controlling for age, sex, CVD risk factors
and depression
Shelev e,I a/.al
Male Israeli combat veterans (n:98);
n=50 (510lo)with PTSD
More self-reported cardiovascular, neurological, gastrointestinal and pain symptoms in PTSD group
No differences in medical and laboratory examination
Male Australian fire fighters (n:140)
n:70 (50%) wirh PTSD
More self-reported physical symptoms
and doctor visits; More self-repofted cardiovasculaq respiratory, musculoskeletal
a n d n e u r o l o g i c a ls y m p t o m s
No differences in medical examination
McFarlane
et al.a2
Pb ysici an- diagn osed card iouasc u lar
disease
Boscarino43
Analysis of numbers and causes of death
Male Vietnam "theater" veterans (n=7
"era" veterans (n=7
between 1985/1986 and 2000: higher
364); PTSD:
921) vs
theater n:836 (rro/a); era: n:214 (2.9o/o) moftality of PTSD positive veterans; HR
for all-cause mortalify: 2.1; cardiovascular mortality: 1.6; cancer mofiality: 1.5
Schnurr et a1.44
Older male Veterans (W-s7II/Korea);
(n:605); n=6 (70/o)with PTSD
PTSD symptoms predict arterial cardiovascular, gastrointestinal, dermatologic
and musculoskeletal disease
Boscarino et al.4i
M a l e V i e t n a m v c t e r a n s( n : 4 4 6 2 t ; n = 1 4
(1%) with PTSD
More ECG abnormalities indicative of
conduction deficits and MI in PTSD
Shemesh el a/,46
MI survivors (n:61); n=13 (20%) with
PTSD
OR 2.7 for a subsequent cardiovascular
event in PTSD group.
PTSD: post-traurnatic stress disorder; \W'!flI: \World ITar II; RR: relative risk; IES: Impact of Event Scale; ORr odds ratio; CVD: cardiovascular disease; HR: heart rate; ECG: electrocardiogram; MI: myocardial infarction.
276
MINERVA ENDOCRINOLOGICA
Dicembre 2006
ENDOCRINE AND INFLAMMATORY ALTERATIONS IN PTSD
ROHLEDER
other symptoms. Interestingly, here again a dence of self-reported cardiovascularsympmedical examination revealed no higher rates toms and also physician-diagnosedcardioof these diseasesin fire fiqhters wiril pTSD.+z vascular morbidity and mortality.
Oe.lncrvnrv ASSESSED
cARDTovASCULAR
DTsEASE Diseasesassociated witb inflamffiatory conclitions
In 4 studies, cardiovasculardiseasewas
diagnosed by a medical examination or
In a re-analysesof data from the National
review of medical records.In a recent paper, Comorbidity Survey (NCS),Kimerling invesBoscarino analyzed the causes of deltd of tigated medical condirions in a toral of 5 877
Vietnam veterans deceasedbetween 1986 parricipants. Using cIDI, 70.40/o
of women
and the end of 2000.About 770/o
of 7 924 so- and 50/oof men where diagnosed with pTSD.
called "theater" veterans,which had served in
Self-reportedrates of arthritis and hypertenVietnam, had been diagnosed with pTSD sion were largely increased in both genders
compared to 2.90/0of 7 361 "era" veterans, with PTSD, autoimmune diseaseswere sigwhich had served in other areas outside nificantly increasedin female PTSDpatients.::
Vietnam. Resultsshowed that PTSDveterans In a further analyses of a subsample of 2 490
Vietnam veterans'analyzedin earlier studies
had a higher mortaliry: at the rime of followup, 11.8%of PTSDposiriveveteranshad died (see above), rates of autoimmune diseases
in comparisonto 4.9o/o
of PTSDnegativevet- were also significantlyincreasedin the study
erans. Calculated hazard ratios (HRs) were by Boscarino on Vietnam veterans.Those
2.7 (CI 7.7-2.6)for all-causemortalityand 1.6 diagnosed with comorbid PTSD were more
(:CII.1-2.4)for cardiovascularmoftalitv.'13
In likely to have rheumatoid arthritis, psoriasis
or any other autoimmune disease.sa
A higha stlldy of 605 olcler militarv veterans, who
had served during the Word War II or the er RR for arthritis or rheumatism (2.57; CI
1.12-5.88)was also found in the study by
Korea Conflict. Schnurr et al.+* found only
Cwikel
et al.3'7Dobie et al. also reported high1% with fullPTSD, and assessedPTSDsymper
rates
of fibromyalgia and irritable bowel
toms with the Mississippi Scale for Combat
syndrome
in female Vietnam veterans with
RelatedPTSD.52Despite these low numbers
PTSD.39
of PTSD positive veterans, they found
In some studies, the occurrence of diaincreased HRs for PTSD symptoms as predictors of arterial (not hypertensive or betes in patients with PTSD was investigated.
ischemic)cardiovasculardiseases,lower gas- In both of the studies menrioned above, highHigher
trointestinal, dermatologic, and muscu- er rates of diabetes were found.53,54
loskeletal disease.aaIn another study, rates of diabetes (I5o/o)were also reooltecl
Boscarino et al. analyzed resting electrocar- in a group of tgS PTSDpatienrsby Weisberg
diogram (ECG) data of 4 462 male veterans, et al., as compared to trauma (90/o)and no
(6%) controls.5sElevated prevalence
54 of which were diagnosed with PTSDusing trauma
of
diabetes
was furthermore found in anoththe DIS. Controlling for cardiovascular risk
er
sample
of
veteranswith PTSD(n:55;23%)
factors, as well as anxiety and depression,
in
comparison with 38 patients with alcohol
PTSDwas associatedwith ECG abnormalities
dependenc
e (80/o).56
In this study, prevalence
indicativefor conduction deficits(OR 2.81:CI
of
heart
disease
and
osteoarthritiswere also
1.03-7.65)and infarctions(OR 4.44: CI t.2increased.
16.43').45
Shemesh et al. investisated 55
myocardial infarction (MI) survivois 1 year
after the cardiovascularevent. Twenfv Dercent Pby.sical symptoms and somatic complaints
had IES scores higher than the cut-off and
Most studies on physical complaints in
were thus diagnosedwith PTSD.'Ihesewere PTSD appear to be in fact self,reported
fwice as likely to be readmitted due to a car- insteadof physician-diagnoseddiseases,and
diovascular event during follow-up.46In sum- some are therefore summarized as medicalmary, there appears to be an increasedinci- ly "unexplained" symptoms.
V o l .3 1 .N . 4
MINERVA ENDOCRINOLOGICA
IN PTSI)
patients
Jrtllammtrtctrfr;tutoimmune cliseasescotclselJ'-reporteclsymptoms ilt PTSD
T,rnr.rII. -
Sample
KesUlts
Participantsofthe NCS (n=5 877): PTSD
of r'vomen; 50.4ol nlcn
in 10-0,/o
Higher self rcported clisc:rse.Iloth gcn
clers: arthr-itts,cliabetes. ancl hypertension. \Vomen: alltoilnmltne diseases
\{alc Vietnzrmvcter.lns (n=2 :i9O)l n=5+
(2%) u'ith PTSD; n:12'1 (5%) rvith
comorbicl PTSD
Highcr rates of self-rcportccl lut()i1'nmune diseasesin cllrrent and conlorbicl
PTSL)l cr.rrrentPTSD: psoriasis, gl()me
rr.rloncphritis:conlorbitl l)TSL):t'heulll:rt o i c l a r t h r i t i s . 1 ' r s o r - i : r s i sd. i a b e t e s .
Stuclv
I nflant mab t1t o r tu iritn m u ttt: diseases
K r r T l r [ l r n g"
hJ(rsclll lnO
AI,TER{IIONS
ENDOCRINF AND INILAI'{MATORY
ROHLEDER
''
h.vpothyroiclism
\\'eisbrrg e/ a/.tt
Dllrd et al.5('
Self' rn;,onn U s.ymptonl s atrl p h.vsi c a I
complaints
Lttz.et al.1-
I)rimal"- care patients rvith PTSD (n=185)
vs tratlma (n:233) ztncl non-tmrtnla
(n:8,i ) control patients
Nlor-ecliabetcs. arthritis. asthma. ecze
m:r, back pain in PTSI) groLrP
!-cterans n'ith P'fSD (n=i5) r"s pxtients
t-ith alcohol clepenclcnce(n:J8)
rs
N{oreclialttes in PTSD veterans(2JLl'ir)
alcohol clepenclentcolltl-ols ( 81rir)
Vietnalr vcter:tns*'ith ancl s ithotrt PTSD
slrllptollls: tinnittls. rapicl
Selt'-r'eportecl
bleething. tacittg heet-t.sextlal clisintcrest. buttetf-lies in the st<:rlllach. :rt-rcl
n1t Ltseil
\\olfc e,ra/.18
Female Victnam veterans (n:109)t I'TSD
clepencling on cut-<>ff
in 27 .501'tr'l ,1-0rb
P'I'SDscore predrcecl sell-reporteclcar
cLovascular,gastrointestin:ll, gynecokrgical. clcrmrtological, ophtalmologicel
sVmptolns anct Paln
Kirrcrling e/ a/.;e
Fcrn:rle Vietnerll \eter:itls (n:51):
(2J'r'tr) t'tlt PTqL)
tlighel latcs of self'-rcportcclfirlgetfirlncss. flttiglrc. elt-lr :ts'ltkening. restless
sieep. ston-rlchltrttltltttls. tttttsclt l e:tk-
n=ll
NCSS
For:c\et al.6t)
s/agner e1a/.('L
Dolll'e et al.1')
P-l \l):
lr"'t-tr'f, tl LIl.llr(
Culf \{'ar vetcrans (n=31i9): 237 of ri'hich s'erc diagnosecl :rs persistentlv ill ancl
I12 l'ere he:rlthy
PTSI) scolcs s tre higher in pel'sistentlv
ill. n'ho reported gastr-ointestinal.ancl
nltrscle
shin/mr-tcottscourllllints. f :rtigr-le.
or loint pain
Gulf War vcLeret'rs( r-r:2 301: 8(i/0\\'()nlen);
of \\'()tttcn :rncl f .3'l'irof
PTSD in 7.1J0/o
nlen
PTSI) scores werc associated rvith kr*c-t'
sclf rtportccl health
F e n a i e V i e t n e r t . tv e t c r a n s ( n = l 2 5 9 )
n : 2 ( 1 6( l l r , i , ) \ ' i t h P T S D
Loler scorc'son stlbiectilc phlsical
health qtrestiollrtaife(gellcrlrl lrcaltll.
r i t a l i t r ' .b o c l i l v P a i n )
strcss clisorclerr\CS: \lttionri
Ctrllclrbiciin- Srrrvcr
Lrt7.et al. founcl higher self reporled phvs- for PTSD 2rnclfouncl to preclictself-reported
gynecological,
gastrointestinai'
icalcomplaintswhen cornparingsmall groups carcliovllscttlar,
i'
of veterans vn'ithand withor-tt P'fSf) In a dermatological,clphtalmologicaIs,vmptolns
str-rclvon f'ernaleVietnam veterans (n=109). as well as pain.5sKirnerling e/ a/. inr''estigzrtvetPTSDrn'asassessedby the MississippiScelc ed another gr()Llpof 52 female Vietnatn
218
M]NI]R\A F]NI)OCRINOI-OLII(]A
I )i(rernl)re 2006
ROHLEDI.]R
ENDOCRINE ANI) INFLAMMATORY AI,1'I.]RATIONSIN PTSD
erans,12 of which were diagnosedwith PTSD
r-rsingSCID and Clinician-AdministeredPTDS
Scale (CAPS).They found not only higher
rates of self-repofied forgetfulness,fatigue,
early awakening, restlesssleep, stomach
problems, ancl muscle weakness, but also
found that PTSD predicteclhealth perception. Further analyses revealed that more
physical symptoms and lower health perception were primarily associatedwith the
hyperarousal symptom cluster of PTSD.5q
In another study gastrointestinaland other "unexplained" physical symptoms, such
as fatigue, muscle or joint pain, skin/mucous
comDlaints.were associatedwith scroreson
In a cohort of
the MississippiPTSD scale.6o
2301 Gulf War veteransof mixed gender (8%
women), PTSD was assessedusing the
Mississippi Scale.5zPTSD symptoms were
associatedwith low follow-up scoreson selfreported health as assessedby a Health
Symptom Checklist 2 years later.61The 266
ftmale veterans n-ith PTSD from the study
bl' Dobie et al. adclitionallt' hacl lorver scores
assessingsubiectivephyson a questionn2rire
ical syrnptolrs in categoriessttch zlsgeneral
health, boclily pain, and vitality:r (Table II).
Interestingly,many of the symptoms repofied above, such zrsmllscle pain, joint pain,
nallsea, fatigue, skin problems, and even
decreasesin general well-being are typically
found in stateswith heightened inflammatofor example during infections and
ry activity,
labeled "sicknessbehavior".('zIncreaseclconcentrati()nsof circulating inflammatory mediators are capable of lowering pain thresh"medolds63and may thus be able to explain
ically unexplainecl" symptoms.
autoimmune diseases,as well as diabetes
"unexplained" physical comand so-called
plaints, is that all of them are associatedwith
or, at least in part, mediated by circulating
Ingls2sed coninflammatoly mediator5.63-65
mediators, in
inflaurmatory
centrations of
of alterations
the
conseqllence
nray
be
turn,
in the function of the endocrine stressresponse systems, i.e. the HIA axis and the
(SAM) syssyrnpathetic-adrenal-medullary
tem.3,1The following section will therefore be
dedicated to the analyses of literature on
endocrine alterationsin PTSD.
Endocrine changes in post-traumatic
stfess disorder
PTSD is associated with Profound
endocrine changes,most of which appear in
the systems crttcial fbr the stress response,
/.e. the HIA aris ancl the SAM system.
Hypoth ala m usp itu it a4y adrenal axis
The HPA axis is a complex hormone system and severalaspectsof its function can be
altered. We will focus here on basal HPA axis
activity and feedback sensitivity,as these are
the aspectslnost relevant for somatic diseasesand innate immune function. Readers
interested in comprehensive analysesof HPA
axis function are directed to the excellent
review by De Kkter et a1.66
R,qser HvpotHALAMIC-t'ITttITAItYAXISACTIVIT\-
Basal HPA axis activity can be assesseclat
several levels of this hierarchic hormone system. An interesting feature of PTSD is the
Conclttsions
cliscordance between increased activity of
ln summary, PTSD appearsto be associrt- the HPA axis at a central level and lower
ed with many diff'erentsomatic diseasesand activity in the periphery. In detail, cerephysical complaints. Best documented are brospinal fluicl levels of corticotropin releaselevated rates of carcliovasclllardiseases,5 ing l-rormone (CRH) have been found
l)ut rates of diabetes and autoimmllne ()r increased in PTSD patients in 3 independent
although in the latter stucly, the
inf-lammatorydiseasesare also increased. stLldies,6T-6e
was that cerebrospinal fluid
finding
main
physirangle
of
self:reported
a
Furthermore,
(CSF)
are increased and correlated
cortisol
are
detriments
health
ancl
cal complaints
with CSF CRH levels.
reoortecl.
In the periphery, findings are less clear.
A common featurreof cardiovascr,tiarand
V o l .3 1 .N . a
. \ l t N L R \ A F N t ) O C t i l \ ( ) L () C T . \
ENDOCRINEAND INFLAMMATORYALTERATIONS
IN PTSD
ROHLEDER
First resultswere obtained by measuringurinary cortisol excretion over periods of 12 or
24 h. These measurementsorovide an estimate of overall cortisol output over the timespan chosen and are a good marker for basal
HPA axis activity. Lower urinary cofiisol concentrations of PTSD patients have been
reported in the majority of studies, comparing PTSD patients with psychiatric controls,7o,
71traumatized patients without PTSD,uzor
normal 661t161s.73-76
In contrast,urinary cortisol excretion was found increasedin PTSD
patients in 3 studies.l-zq
Several studies have reported on single
time-point measurementsof plasma cortisol.
However, as single measurementsat random
time points arc of rather limited validity given the considerable variability of HPA axis
activity throughout the day, we will only
review studies in which cortisol measurements are obtained over severaltime-points
of the day, with relation to the circadian
rhythm of this hormone system. The first
study reporting on alterations of circadian
cortisol secretion in PTSD patients was published by Yehuda et al. They obtained plasma samples from combat veterans every 30
min over a total period of 24 h. Compared to
healthy controls, veterans with PTSD had significantly lower plasma cortisol levels
throughout the day.aoBremner et al. reported lower plasma cortisol levels in the first
half of the day in abused women with PTSD
as compared to abused and non-abused
women without PTSD.81Through cortisol
measurements in saliva, we were able to
replicate these findings of low cortisol levels
in a sample of civil war refugees from
BosniaTaand in a sample of PTSD patients
traumatizedby severeaccidents,violent crime
or sexLlalassault.sz
Most notably, in both studies we showed for the first time that the normal cortisol awakening response83of the HPA
axis appears to be blunted in PTSD. In a
recent study, Yehuda et al. investigated circadian salivary cortisol levels of Holocaust
sulvivors with and without PTSD (mean age:
69 years) and found that those with PTSD
had flattened cortisol trajectories.s4
Young et al. measured salivary coftisol levels in a larger community sample of 575 par-
ticioants. In contrast to the studies summarized above, 56 indivicluals with PTSD had
increasedevening cortisol levels, while morning levels were unchanged.asLindater et al.
reported higher early morning and total (area
under curue) salivarycofiisol levels in a group
of 12 Dutch police officers with PTSD in relation to traumatized police officers without
PTSD.86The authors' explanation for these
differences is that the trauma in their study
was relatively recent compared to rather long
interuals between trauma and study in most
of the other studies. This interoretation is
consistentwith findings Froma rccent metaanalysisby Miller et al.,where time between
trauma and assessmentwas negatively associated with daily cofiisol output.87This metaanalyses of HPA axis changes following
diverse acute and chronic stressorsincluding trauma furlher revealed that daily corlisol
output was reduced (d=-0.34) and evening
cortisol levels were increased (d=0.47) in
people with PTSD.
FrEogacr
SENSITIVITy
In a comprehensive review of pharmacological and non-pharmacological challenge
tests for the HPA axis, De Kloet et al. also
summarize the results of the low-dose dexamethasone suppression test (DST).66Via
oral ingestion of 0.5 mg of dexamethasonein
the evening and assessmentof cofiisol levels
the following morning, the sensitivity of the
HPA axis towards the negative feedback
effects of glucocorticoids can be tested.While
early studies using the classical 1 mg DST
were not successfulin detecting alterations in
feedback sensitivity in PTSD, studies using
the low-dose DST revealed a tvDical disturbance in PTSD patients, descrihed as supersuppression.The first study to report this
finding was published by Yehuda et al.They
showed that 2L combat veterans with PTSD
had significantly lower plasma cortisol levels
at 08:00h in the morning after ingestion of 0.5
mg dexamethasonecompared to 12 healthy
controls.8sThese findings were subsequently replicated in several other studies from
this group. The findings were also extended
to patients traumatized by childhood sexual
MTNERVAE\ DOCRINOLOCICA
Dicembre2006
ENDOCRINEAND INFLAMMATORYALTERATIONSIN PTSD
eoThe quantitative meta-analysisby
abuse.8e,
Miller et al. also revealed lower postdexamethasone cortisol levels @:-0.25) in PTSD
patients.sT
ROHLEDER
hypoactive HPA axis and hyperactive SAM
system) are theoretically compatible with
such a disinhibition, we will in the following
section review the literature on immune disturbances in PTSD with a focus on signs of
overactive immune processes.
Sympath etic-adrenal -medullary system
Three aspectsof immune function in PTSD
Similar to the HPA axis, the SAM system have been investigatedso far. The vast major'
appears to be over-active at a central level, as ity of studies focused on numbers and perevident for example by the finding of centagesof circulating immune cells and their
increased norepinephrine levels in CSF, subtypes. This is by far the easiest way to
repofted by Geracioti et al. in 11 male com- obtain measures of immune function, but
bat veterans with PTSD.elIn contrast to the also the one with the leastinformation about
HPA axis, this increased central activity is the statusof the immune system.Some studaccompaniedby a higher peripheral activity. ies have employed functional assays,mainly
Enhanced urinary excretion of epinephrine or by applying antigensto the skin and investinorepinephrine has been reported in sever- gating delayed type hypersensitivify responsal studies.For example, in women with PTSD es, while others have assessedthe ability of
after childhood sexual abuse,78in mothers natural killer (NK) cells to fight tumor cells in
with PTSD caused by a child suffering from
uitro.whlle thesefunctional assaysprovided
cancer,75and in Bosnian war refugees with
better information about the ability of the
PTSD (marginally significantra). However,
immune system to fight infection,l+they are
Pitman et aL reported unchanged urinary cat- less useful for predicting the negative outecholamine excretion in a sample of combat comes of immune over-activation.The most
veteranswith PTSD.77
informative measure in this regard are conPlasmalevels of norepinephrine have been centrations of circulating inflammatory medireported to be elevated by Yehuda et al. in ators, such as interleukin-6 QL-6), tumor
PTSDpatientswithout comorbid depression.ez necrosisfactor-cr(TNF-cr),IL-1, and the acute
However, in the study by Geracioti et al. phase protein C-reactiveprotein (CRP),which
despite higher concentrationsin CSF,norep- have proven useful in predicting inflammaineohrine did not differ between PTSD tory disease related morbidity and mortalipatlents and controls in plasma.er
ty.e5
Interestingly, PTSD patients are further
reported to show increased sympathetic and
Immune cell numbers
catecholaminergicresponsesto trauma cues
In summary, PTSD
and other stressors.93
Largely divergent findings have been
patients are characterizedby a noradrenergic reported for immune cell counts and perhyperactivity, which appears to be associat- centages.Some studiesreport higher numbers
ed with the hyperarousalsymptom complex of total leukocytes, lymphocytes and certain
of the disorder.
subtypes for example in combat veterans
with PTSD,e6or in women tratmatized by
childhood 2buse,e7where numbers of total
leukocl'tes, as well as B and T lymphocytes
Imrnune changes in post-traumatic
were correlatedwith PTSDseverity.However,
stfess disorder
several other studies report unchanged or
Based on the factthat many of the somat- lower numbers of the same immune cells.
ic diseasesand physical complaints reported Ironson et al. fotnd that numbers of leukoby PTSD patients could potentially be medi- cytes did not differ between hurricane victims
ated by a disinhibition of inflammatory medi- with and without PTSD,while NK cell numators, and further based on the fact that the bers, but not function, were higher in PTSD
endocrinologic disturbancesin PTSD (i.e. victims.esLower T and B lymphocyes in peo-
V o l .J l , N . 4
MINER\A ENDOCRINOLOGICA
ENDOCRINE AND INFLA}I\,IMORY
ROHLEDI]R
ALI'ER{TIONS
IN PTSL)
of I'TSD patients. One group of researchers
f o u n d l o w e r c o n ( e n t r a t i o n so f C R P i n
refugeesfrom the Iraq suffering from PTSD10e
In contrast to this result, 5 other studiesreport
increased plasma concentrations of inflammatory/mediators. Higher concentrationsof
IL-1, were found by Tucker et al. in 58 PTSD
patients,110
and by Spivak et aL in 19 Israeli
combat veteranswith PTSDrll in contrast to
healthyvolunteers.In the latter sample,PTSD
duration was associatedwith IL-18,levels.
Increasedconcentrationsof IL-5 have been
reoorted in accident victims with PTSD as
and in comcompared to healthy controls,112
Immune cell.function
bat veteranswith PTSD.It-rIn this latter str-rdy,
Six studies have investigatedthe ability of higher IL-6levels were found only in the secNK cells to lyse specified target cells in uitro, ond half of the day, which is interesting as
again with inconsistent results. Four studies cofiisol levels are relatively low at this time of
found that PTSD Datients'NK cells were less day in healthy controls and even more so in
efficient ccrmpa.edto the respective control PTSD patients.Ta
Furthermore, Baker et al.
groups without PTSD or participants with
IL-6 concentrations in
increased
also
found
103
Jqle
less severe PTSD symptoms.es9e,102'
cerebrospinal fluid of their PTSD sample,
studiesreported contrary results, i.e. increased possibly show.inga central disinhibition of
NK cell cytotoxicity in combat veteranswith
inflammation.r1J
PTSD,to+and a sample of rescue workers
Further information about inflammatory
with varying I'TSD severity.to5
processescan be obtained by in uitro stimuThree stlrdies assessedthe efficacy of the
lation of whole blood with mitogens and meacellular immune response by applying antisuring inflammatory cytokines. Such assays
gens to the skin and measuring the local
provide information of the potential responirnmune resDonse. \7hile Boscarino et al.
sivity of the individual's inflammatory system
were not ablb to detect differencesbetween
in the presenceof respectivestimuli, such as
PTSD patients and controls,e6the remaining
pathogens,allergens,or other danger signals.
studies found increases in cell mediated
Two srudiesmeasuredthe T helper 1 cyokine
106
immunity in combat veterans with PTSD
interferon-y (IFN-, after stimulation of whole
and in abusedwomen with PTSD.1o7
blood with lipopolysaccharideand phytohemagglutinin. The results are inconclusive:
Inflammatory,t mecliators
while Kawamura et al. found lower in uitro
As noted above, the peripheral concentra- IFN-y secretion in 12 traumatized men with
tions of inflammatory mediators are of central PTSD, \Woodset al. found the opposite, i.e.
interest for predicting long-term health out- increasedconcentrationsof IFN-A in abused
11:tJlg5e divergent
comes. Inflammatory mediators such as IL-6, women with PTSD.ee.
to results may be explained by gencler differIL-18,TNF-o and CRPare now reco5anized
stimulate atherosclerosis,the main cause of ences.As we have shown earlier,ll' large sexdiseases.6a
to foster insulin differences exist in ex uiuo inflammatory
cardiovascr-rlar
1e responseswith generally higl-rercytokine proresistanceand thus callsetype 2 diabetes,65
lower pain thresholds6:and, thus, increase duction levels in women. In a third study
the likelihood of experiencing any physical assessingthe potential to mount an inflammatory response,we \\,'ereable to show that
symptoms.
In fact, as summarized inTable III, 6 stud- Civii \Warrefugeeswith PTSD(mlred gender)
ies have measured the concentration of dif- producedsignificantlymore lL-6 and TNF-o irz
f-erentinflammatory mediators in the plasma uitro compared to healthy controls.Ta
ple with PTSD were also reported by
Kawamura et al.e9
of immune
In summary,simple assessment
cell numbers in PTSD has not yet revealed a
consistent pattern. More promising may be
the results by Dekaris et al. anclWllson et al.
Both groups of authors report higher nurnbers of immune cells that show a phenotype
indicative of immune activation in PTSDusing
101flsv/svsr, these results
flow cytometry.100,
warrant replication, befbre further conclusions can be drawn.
\4I\FR\A F\I)O'.RI NOLOCTCA
Dicembre 2006
ROHLEDER
IN PTSI)
ENI)OCRINEAND INFLAMMATORYALTE}G-TIONS
Ts,ztu lll.-Inflammatotl)
mediators in PTSDpatients.
Results
Sample
Stucly
Circulating inflammatory
Miller et al.1o8
mediators
Accident or assault victims (n=15) ers No llroup differences in CRP and sIL-6R
comelation of CRP and SIL-6Rwith PTSD
tlauma controls (n:8)
severity
Sonclergaarde/ a/.109
Refugees from lraq (n:tl6); partial PTSD:
n=24; full PTSD: n:32
Lower CRP and serum amyloicl A in
PTSD
Ttcker et al.l\t)
Outpatients with PTSD (mixed trauma;
n=58) erstrauma controls (n=21)
Higher It-1p ancl lower sIL-ZR in PTSD
Spltrk et ctl.111
Israeli combat veterans with PTSD
(n:19) vs healthy controls (n=19)
Highcr lL-1B in PTSD; correlation of ILlB t\irh PTSD duration (r=0.54)
Maes et a\.112
Acciclent victims with PTSD (n:13) z,s Higher IL-(r and sIL-6R in PTSD; r-rodiff'erence in additional inflammatory
healthy controls (n=32)
r n e d i a t o r s( s g p 1 3 0 , I L 1 R A , C C 1 6 , a n d
sCDB)
Btker et al.IlJ
Combat veterans with PTSD (n=11) tr.s Higher IL-6 in samples befbre 14:00 h;
no IL 6 differences in the afternoon;
healthy controls (n:8)
higher IL-6 in CSF
In L'itr() stimuldted
ntetlicttrtrs
Kan'anrura e/ a/.')')
inJlantntator.y
Trauniltizecl workcrs rvith PTSD (n=12)
z'-s
trauma cor-rtrols(n:48)
Lo.ver LPS- .rncl PHA-stimulated ploduction of interi'eron-1 (IFNY) and IL-,1
\(oods e/a/.ir'
intimate partner violence victirns (n:62;
ri'ith PT'SD: n=39) rs non-abused controls (n:39)
Highel LPS- ancl PHA-stimulated IFNY
in abused v!'omen r'vith PTSD
Rol-rleder eI a/.; i
Civil war refugees with PTSI) (n=72) us
hcalthy controls (n:13)
Higher LPS-stimulatedproduction of IL6 and TNF; incrcascd GC sensitivity of
IL-6 and TNF-cr
P r t r e n t su i t h r r p i d l r p l o g r e s . i v c p e r i o dontitis (n=20, all with PTSD) r.sheaithy
controls
Increased incidence of rapidly progressive periodontitis; higher salivaly IL-6
in perioclontitis patients
Patients admitted to the emergency roon
afier a life-threatening e'vent (n:24; n= tl
n-ith PTSI) afier ,i rnonths)
Gene chip/microarray: reducecl expression of genes involvecl in transcriptio
nal activation; distinct expression of
genes involved in inmune activation
Ot h er in llamm.ttotry markers
Ltrer et a1.115
Segm:rn e/ a/.1l6
PHA: phyttthemag
stressclisofder;CRP:C-reactir.eproteini CSF:celebrospinalfluicl;LPS:lipopolysaccharider
P'lSl): post-trllrnatic
'l'NF:
glutininl
tr.rmornecrosislactor;GC; glucocorticoicl.
'I'wo
other studieshave investigatedinflarnmatory parametersin PTSDpatientsutilizing
a nor.'elapproach. Aurer et al. found higher
periodontal inflammation in PTSD patients
corrpared to controls.lls tJsing microarray
technique, Segman et aL investigated gene
erpression of peripheral Lrloodmononuclear
cells that were obtained imrnediatelyas well
\ i , 1 .a i . N . 4
as 'i rrronths after l'reumatization. They were
able to demonstratethat gene profiles could
distinguish those with PTSD from those without PTSD. Interestingly, those with PTSD
(n=13) and higher IES scores showed overexpression of genes that signify immune activation.116
In summary, it appearsthat PTSDpatients
MINERVA ENDOCRINOLOGICA
)Rt
ENDOCRINEAND INFLAMMATORYALTERATIONSIN PTSD
ROHLEDER
response system. Although some of these
data are preliminary and thus have to be
interpreted with caution, we conclude that
in PTSD, all three assumptionsare met. PTSD
Datientsshow more somatic diseasesthat
may be caused or acceleratedby peripheral
inflammation, have a disturbed endocrine
system that may foster inflammation, and
show increased inflammatory activity.
Unfortunately, no study has investigated all
assumptionsin the same sample of subjects.
Therefore, it remains unknown whether the
Conclusions
.
endocrine changes are the consequence of
In the present review, we set out to find PTSD, and whether the endocrine changes
evidence for the hypothesis that the increased are the main cause of inflammatory disinhiincidence of somatic diseasesand physical bition.
Detrimental health behaviors, in turn, could
complaints in PTSD may be mediated by typbe
an additional or alternative mediating facin
the
system,
ical disturbances
endocrine
tor
befween PTSD and inflammatory disininflamwhich in turn foster disinhibition of
hibition.
PTSD patients repofi more drug and
mediators.
matory
In this we regard, we first reviewed stud- alcohol abuse, and are more often smokies reporting that PTSD patients show high- ers.rle Deleterious health behaviors are not
er rates of cardiovascular,autoimmune, and only independent cardiovascular risk factors,
inflammatory diseases,including diabetes. but also foster disinhibition of the inflammaMost of these data stem from self-reportsof tory response, thus being able to increase
PTSD patients, together with many studies the risk of all diseasesreported for PTSD.120,
evidencing a large array of physical com- r21
In eonclusion, the association of somatic
plaints. Interestingly,all of these diseases,
including so-called "medically unexplained" disease,endocrine alterations and inflamsyffrptoms could be explained by assuming a matory disinhibition in PTSD appears promisdisinhibition of the inflammatory response ing in supporting the hypothesisthat inflamwith heightened plasma concentrations of matory disinhibition mediated by endocrine
inflammatorymediatorssuch as IL-6, [-18, or alterations foster the heightened incidence
65Cardiovasculardiseasescan alter- in somatic diseasesin PTSD. However, to
CRP.63
native be explained by the hyperarousal substantiatethis hypothesis, clearly more evisymptom complex mediating damage to the dence is needed, optimally assessingimmune
heart and circulatory system by increasing and endocrine parametersas well as health
heart rate and blood Dressure.llOur review outcomes in longitudinal designs.
of the literature furthermore supported the
assumption that PTSD is characterizedby
typical alterationsin the endocrine systems.
Riassunto
Most, but not all, studies show a hypoactive
HPA axis with lower cortisol levels, which
Disturbo post-traumatico da stress: ruolo delle alterazioni enelocrine e infiammatorie nei rJisturbi somacould be the main factor for disinhibition of
inflammatory response,together with height- tici comorbosi
A partire dalla sua prima descrizione nel Diagnostic
ened activity of the SAM system,which can
and
StatisticalManual for Mental Disorders (DSM), il
stimulate inflammation uia activation of the
disturbo post-traumatico da stress (post-traumatic
1
18
transcription factor NF-r<B.
stressdisorder, PTSD) e stato carattertzzatocome un
In summarizing, studies investigating disturbo del funzionamento affettivo resposabile di
immune functioning in PTSD,we found evi- notevole sofferenza. Inoltre, d stato riconosciuto che
dence for an over-active inflammatory il PTSD non d solamente accompallnato da una compresent with increased circulating levels of
inflammatory mediators. F{owever, these
results have to be interoreted with caution
at this point. as most of the studiesinvestigated a rather low number of subjects.
Furthermore,measurementsof unstimulated
inflammatory mediators in plasma are somewhat troubled by concentrationsclose to the
detection limit of most assaysavailable.
MINERVA ENDOCRINO],OCICA
Dicembre 2006
ROHLEDER
ENDOCRINE AND INFLAMMATORY ALTER{TIONS IN PTSD
promissione generale dello stato di salute, ma anche
da un numcro pii o meno specifico di patologie
somatiche di natura cardiovascolare, autoimtnune,
di disturbi fisici e dolore cronico. E stato. inoltre. ipotizzato che queste condizioni somatiche possano
esseremediate o facilitate da alterazioni dell'asseipotalamo-ipofisario, del sistema simpatico e aclrenomedullare e del sistema immunitario. Gli obiettivi di
questa revisione sono: 1) esarninare gli studi che
riportano alterate funzioni somatiche nel PTSD e 2)
discutere le rnodaliti con cui le funzioni endocrine e
immunologiche incidono in modo differenziale sulle alterazioni somatiche PTSD-correlate. Si ipotizza
che alterazioni dell'asse ipotalamo-ipoflsario e del
sistema simpatico e adreno-medullare t'isultino in r-rna
disinibizione dei meccanismi infiammatori, che, a
loro volta, scatenano lo sviluppo di disturbi somatici e dei sintomi fisici lamentati dal paziente.
Parole chiave: Infiammazione - Comorbiditi Disordini post-traumatici da stress.
References
1. Stcrnberg EM, Hill JM, Chrousos GP, Kamilaris T,
Listwak SJ, Gold Plilr et al. Inflammatory mediatorinduced hypothalamic-pituitary-adrenal axis activati()n
is defective in streptococcal cell wall arthritis surjccptilrle Lewis rats. Proc Natl Acad Sci U S A 1989;86:
2374 8.
2. Sternberg EM, Young WS 3Ld, Bernardini R, Calogero
AE, Clrrousos GP, Gold P'il/ et al. A central nervolls
systeln defect in biosynthesis of corticotropin-relea
sing honnone is associated with susceptibility b strept()coccal cell wall-induced arthritis in Lewis rats. Proc
Natl Acacl Sci U S A 7989:86:4771-5.
3. Heim C, Ehlert U, Hellhammer DH. The potential role
of hypocortisolism in the pathophysiokrgy of stressrelated bodily disorders. Psychoneurocndocrinology
2000;2i:1-35.
.1. Raison CL, Miller AH, When not enough is too much:
the role of insufficientglucocorticoid signaling in the
pathophysiology.of stress related disorders. Am .l
Psvchiatry 2003:760:7i5 4 6i.
5. Gancler ML, von Kanel R. Myocardial inf'arction and
post-traLlffratic stress clisorclcr: frequency, outcome.
:rncl atherosclerotic mechanisms. EurJ Cardiovasc Prev
Rehabil 2006:13 :1.65-7 2
(r. APA. Diasnostic and statisticalmanual of mental disorclers. Washington, DC: Arnerican Psychiatric Association;
1991.
7. Bichescu D, Schauer M, Saleptsi E, Neculau A, Elbert
T, Neuncr F. Long-term consequences of traumatic
experiences: an asscssrnentof former political detainccs
in Romania. Clin Pract Eoidemol Ment Health 2005:1:17.
| { . 5 o l () m () n : D . D . r v i c l . o nj R . T r a r r n a : p r ( v a l ( n ( ( . i r n p J i r rnent. service use, ancl crrst..JClin Psychiatry 791)7;58
S r , r p p9l r i - 1 1 .
9. Kr-rchK. Cox BJ. Evans R.J.Posttrallmatic stress disorder and motor vchicle accidents: a multidisciplinary
r ) \ ( n i c \ ^ . t . a n J l ' s y t h i a t r yl ' ) ( ) 6t l t 2 q - J - l
10, Kohn R, Levav 1, Garcia ID, Machuca ME. Tamashiro R.
Prevalence. risk factors and aging r,'ulnerabiliry fcrr psychopathology following a n:rttrral disaster in a cleve
loping country. Int I Cleriatr Psychiatry 2005;20:
835-11.
\ b l . 3 1 .N . 4
11. Buckley TC, Kaloupek DG. A meta-anal1'ticexamination of basal carcliovascular activity in p()sttraumatic
stress disorder. Psychosom Med 2001;61;585-94.
12. Karl A, Malta LS, Maercker A. Meta analytic review of
event-related potential studies in post-traLrmatic stress
rli'ordcr. Biol Psychol2006;-l: l2J- r-.
13. Shalev AY, Peri T, Orr SP,Bonne O, Pitman RK. Auditory
startle responses in. helpseekingtrauma survivors.
Psychiatry Res 1997;69:1-7.
14. Metzger L.j, Orr SP, Berry NJ, Ahcrn CE, Lasko NB,
Pitman RK. Physiologic reactivity to startling tones in
women with posttrallmatic stress clisorder. J Abnorm
Psychol 1999;108:347-52.
15. VasterlinglJ, Brailey K, ConstansJI, Sutker Pts. Attention
and memory dysfunction in posttraLlmatic stress disorder. Neuropsychology 1998;12:725-33.
16. Vasterling lJ, Duke LM, Brailey K, Constans JI, All.rin
ANJ, Sr-rtkerPB. Attention, learning, and memory perfbr
mances ancl intellectual resollrces in Vietnam veterans:
PTSD and no disorder comparisons. Ncuropsychology
2002:16:5-11.
17. BuckleyTC, Blanchard EB, Neill WT. Information processing and PTSD: a review of the empirical literature.
C l i n P s y c h u l R e v 2 0 0 0 : 2 0 l:0 r I - 6 s .
18. Protopopescu X, Pan H, Tuescher O, Cloitre M,
Goldstein M, Engelien rW et al. Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subiects.
Biol l'sychiatry 2005;57:461-73.
19. Matsuo K, Taneichi K, Matsumoto A. Ohtani T, \'amastte
H. Sakano Y et al. Hypoactivation of tfre prefrontal
cortex dllring verbal fluency test in PTSD: a near infrarecl spectrosc<.rpystlldy. Psychiatry Res 2003;12'i: 1-10.
20. Shin LM, Wl'ralen l' J, Pitman RK, Bush G, Macklin ML,
Lasko NB et al. An fMRI study of anterior cingulate
function in posttraumatic stress disorder. Biol Psychiatry
2001:i0:932-42.
27. Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N,
rJilerner A. A meta-analysis of structural brain abnorrnalities in PTSD. Neurosci Biobehav Rev 2006 [Eputr
aheacl of printl.
22. Shin LM, Shin PS, Heckers S, Krangel TS, Macklin ML,
Orr SP et al. IJippocarnpal function in posttraumatic
stress disorcler. Hippocarrrpus 2004;1'I:292-3Q0.
23. Rabe S, Beauducel A, Zollner T, Maercker A, Karl A.
Regional brain electrical activity in posttraumatic stress
disorder after motor vehicle accident. J Abnorm
Psvchol. In oress 2006.
24. Lanius RA, \izilliamson PC, Densmore M, Boksman K.
Neufelcl RW, Gati JS et al. The nature of traurnatic
mernories: a 4-T FMRI functional connectivity analysis.
Arn J Psychiatry 2001,161:36-44.
25. Fernanclez M, Pissiota A, Frans O, von Knorring L,
Fischer H, Fredrikson M. Brain function in a patient with
torture related post traumatic stress disorder before
and after flLx)xetine treatment: a positron emission
provocation
study. Neurosci Lctt
tomography
2007:297:101-1.
26. Karl A, Maita LS, Alexander J, tslanchard EB. Starile
responses in motor vehicle accident sLul.ivors:a pilot
:223-37.
stucly. Appl Psychop\siol Biofeedlrack 2O04;21)
27. Karl A, Itabe S. Zollner T, Maercker A. Psychophysrological corrclates of PTSD symptom rcchrction induced by psychotherapy. Psychophysiology 2005;50:
28. Vermetten E, Vythilingam M, Southwick SM, Charney
DS. BremnerJD. Long{erm treatmcnt w'ith paroxetine
increases verbal declarative memory and hippocampal
r'olurne in posttraumatic stress clisorcler.Biol Psychiatry
2003:54:693-7O2.
29. McEwen BS. Thc neurobiokrgy and nelrroendocrino-
. \ 4 I N F R V AF N I ) O C R I\ U L O C I C A
285
ROHLEI)ER
EN])OCRINE AND INI.'I,AMMATORY AI,TF]RA'I'IONSIN PTSD
logy of stress. Implications for posttraumatic stress
disorcler from a basic science perspective. Psychiatr
Clin N<rrth Am 2002;25:469-94,ix.
30. Sapolsky RM. Atrophy of the hippocampus in posttraumatic stress disorder: how and when? Hippocampus
2 0 0 1 ; 1 1 : 910.
Gilbertson MW Shcnton NIE, Ciszewski A. Kasai K, Lasko
NB, Orr SP et al. Smaller hippocampal volume pre
dicts pathologic vulnerability to psychological traurna.
N a t N e r r r o s c i2 O O 2 ; 5 : 7 2 172.
Lee HJ, Lee MS. Kang RH, Kim H. Kim SD, Kee BS et al.
Influence of the serotonin tfanspofier pfomoter gene
polyrnorphisrh on susceptibility to posttrallmatic stress
disorcler. f)epress Anxiety 2005;27:735-9.
33. Control Cfl). Health statlrs of Vietnam veterans. II.
Physical flealth. The Centers for Disease Control
Vietnam Experience Str-rcly.JAMA 7988;259:2708 I1+.
3z+.Solomon Z. Mikulincer M. Combat stress reactions,
p()st traumatic stress disorder ancl somatic complaints
a m o n g I s r a e l i s o l c l i e r s .J P s y c h o s o m l i c s 1 9 8 7 : 3 1 :
131-7.
J5. Solon'ronZ, Mikulincer M, Kotler MI.A rwo year tbllorvr-rpc.rfsomatic complaints among Israeli comllat stress
r e a ( t j ( ) n c a s u a l t i e s . .P
l s y c h o s o r nR e s 1 9 l l 7 ; 3 I: 4 6 3 - 9 .
F-alger-PR.Op dcn Velde W, Hovens JE, Schouten EG, De
Crocn.fH. \'an l)uijn H. Cr:rrent posttraumatic stress
c l i s o r c l e ra n d c a r d i o v a s c u l e r c i i s c a s e r i s k i a c t o r s t n
Dutch Resistance veterans from \7<rrlcl War II.
Ps1-c'll,),1r.r
Psvchosom 1992ai7J.61-17.
Cwikel J, Abclelgani A. GoJdsmithJR, Quastel M, Yevelson
II. Ts.'o year fbllorv up study of strcss-rclatcrl clisorclers among imlnigrants to Isr-aclfrom thc Chernobyl
:rrea. llnr.'iron Hcalth i)erspect 1997:105 Suppl 6r
15 , i 5 - 5 0 .
Bosc:rrino JA. Diseases rmong rlren 20 ycars afier erposr-r
fe t() sevefc stress: implications firr clinical research
anrl rneclical c.rrc. Psvchosonr Nlecl 1997:59:605-1.i
Doirie D_J.Kirlahan DR. \laynarcl C. liush KR. Davis TM,
IJlacllct KA. Posttratrmatic stress clisorclcr in female
l e t e f : l n s : e s s ( ) c i : r t i ( ) nr v i t h s e l t r e p o r t e c l h e a l t h p r o
blems :rntl firnctionel inrpairment. Arch Intern NIed
200,i:16.i:.19+-+00.
i 0 . S a r v c h r - r kC N , R o y - I l y r n c P . C l o i c l b e r gJ , M a n s o n S .
Noonan C. BealsJ et al. The rclationship between posttl'aumatic stress disordcr, cltltrcssion and carcliovascuIar discasc in an American Inclian tribe. Psychol Nlecl
2 0 0 5 ; J 5 : 1 7 t 395' + .
: i l . S h e l e v A . I l l c i c h A . { I r s a n o R - 1P
. o s t t r a r r m a t i cs t f e s s
.iisorclcr': sornatic i'omorbiciity ancl cfkrrt tolerance.
P s yc h o s o r n a t i c s19 9 0 ; 31: 1 9 7 - 2 0 3 .
42. Mr:Ferllnc AC, Atcllis()n M, Ilafakrwicz E, P:rpav P.
Ph,vsiceisyllpt()rns in p()sttralll]r:rtic stress disorcler..[
P s y c i t < ; s o mR e s 1 9 9 / + : 3 t t r 7 I 2
56 .
Soscarino .jA. 1)()sttrallmaticstress clisorcier ancl mortelity
:rmong tl.S. Army veterans l0 years after militarv ser."'ice.Ann Epiclen'riol2006;1(r:2+tl-56.
Schnr"rrrI)l). Spiro Ar'. i)aris AH. Phvsician-cliagnoseclnrcdicrl tlisorct:rs in relation to PTSI) symptolns rn olcler
rnele rnilikrry vetLrrans.Heelth [)s_vcht.rl
l(Xl0: I!):9l-7.
lloscarino .fA. Ohang.J. Electrocardiogrem;rbnormalitics
rnen qith strcss reiatecl psychiatri<:rlisorders:
Jr.r.r()ng
in-r1.llic:rtions
firr coronarv heart clise:rseencl clirrical
resealr'h. Ann tJellav l\{ccl 19!9;2I :221-a.+.
Shernesh E, Ychtrda i{, Mikr O. Dinr,rr-I, Rrrclnick A, \'crccl
Z et al. P()sttrarrrlr:ltic
stl'css.nonaclherence..rncl aclverse ()utcolnc ir.t survivors of a rnyocarcli:rl inferction.
Psvchosom X4ed 200'1;66:i21-(r.
'l'he
'Williams.lR.
Stnrctr.rrecl
Ciibbon NI, First N{B.
Spitzel RL,
(.linrcel lntervic'"r fbr DSMllIlt (SCII)). l: Historl'. ratitrrralt. :rncl descriptit>rr. Arch (]en Psychiatry 1992:+\):
6'24,9.
286
Hor<x'itz M, \l(/ilncr N. Alvarez ]W. Impact of Evcnt Scalc:
a measrlre of subjectivc strcss. Psychosom Mecl
1979:1I:201)-78.
Robins L, Helzer.J, Cottler L, Goldring\ u. NIMH Diagnostic
Interview SchecluleVersion III tlevisecl (DIS-lll-R). St.
Louis. MO: Washington University School of Meclicrne;
1989.
rWeathers F, Forcl
J. Psvchomctric Properties of the P'I'SD
Checklist (PCL-C, PCIL-S.PCL-M, PCL-PR). In: Stamm
BH, cclitor. Measurernent of stress, trallma. and adap
tation. Lutherville, Ml): SiclranPress; 1996.
lrittchen HLr. Relialrility and validity studies of the \XrHO:
Cornposite lntern:ltional I)iagnostic Interview (CIDI):
a critical rcview. J Psychiatr Res 1994;28:57-84.
Keanc TM, Cadclell JM, Taylor KL. Mississippi Scale for
Cornbat-Related Posttrar.rmaticStress Disorder: three
stuciiesin reliability and validity..l Consult Clin Psychol
1988;56:85-90.
51. Kirnerling R. An investigation of sex cliflerences in nonpsychiatric morbiclity associate.l with posttralLmatic
strcss clisorcler..f Am Mecl Wcrmens Assoc 2004:59:
/+3-7.
5,i. BoscarinoJA. Posttraumaticrstress clisorder and physical illness: resr.rltsfrom clinical ancl epiclemiologic stu
c l i e s .A n n N Y A c a d S c j 2 0 0 , i r 1 0 3 2 : 1 4 1 - 5 3 ,
55. Veisberg RB. Brtrcc Sts, Machan JT, Kessler RC,
Culpepper L. Kellcr MB. Nonpsychiatric illness among
prirnary care patients rvith trauma histories and posttraumatic stressclisorcler.Psychiatr Sen 2002:53:8,18-5,i.
5 6 . D a v i c i D . W o o c l r v a r c lC . E s < l t t e n a z -i [ . M e l l t n a n T A .
Comparison of comorbici physicai illnesses among
vctcrans rvith PTSI) ancl veterans l'ith alcohol depeni l e n c e . P s y c h i a t rS e n ' 2 0 0 i 1 5 5 : 8 25 .
t 1 . 1 . 1 t 2B T . K e a n c T V t . F i s h e r L . N ' l a r x B . N l o n a c o l V .
Phvsical healtli conrplaints in <ornbat-relateclpost-traur.natic stress clisorcler: A orelin-rinary repolt. .i Traum
S t r e s s1 9 9 2 ; 5I: 3 1 - +L
5tt. \l,krlfeJ, Schnurr PP. fJron'n I' .]. F-urcy.l. Posttr,run'ratic
str-cssdisolclcl lncl n':Lr-zone exp()srlre as cclrrclatcs
lrf pelceivccl hcaitlr in fenralc \,-ietnam \far veterrns. J
22
: 35,i0.
C o n s u l t C l i n I ' s v c h o l 1 9 t ) . i : 6 .1
59. Kinrerling R. (lh.rrnGA, '.)iblfe.l. Relationships among
tl-autnlrexp()slrre, chronic p()sllrtumxtic str-cssclisorcler svlnptoms. and self-reportecl health in q'omen:
r e p l i c a t i o n a n d e x t e n s i o n . - JT r a u n r a S t r e s s 2 0 0 0 : 1 3 :
l l i,18.
/r0. Ford _ll), (irrlpbcll KA. Storzbach D. Rincler LNI. Anger
WK. Rohlman DS. l)osttrar.rnraticstress symptornato
krgv is asstriatrd $'1th unexplainecl illness attributeclto
P e r - s i a nt i r r l f \ V a r -r n i l i t a r y s e r v i c e . P s y c h o s o m M e c l
2001:ti3:rl'129.
tr1. \X/agnerAW, \Xtrlfc.J.Rotnitsky A, Proctor SP,Erickson
D-J.An in!rstigation of the irnpact of posttraumatic
s t r c s s d i s o r c l c r o n p h y s i c a i h e a l t h . . J T r z r u n r aS t r e s s
2000;13:41-i5.
,.'-rl.i)antzcr R. (lytokine-inclr.rcecisickness behavior: r'vhere ckr we stancl?IJlain fJehav Imrnun 2007;75:1-21.
53. Watkins l-R. iVlaier SF. imrnunc rcglrlation of ccntral
ncrvolrs systenr iirnr:tions: fiom sickness responses t()
p a t h o k r g i c a l p a i n . - [ I n t c r n N l e c l2 0 0 5 ; 2 5 r : 1 3 9 - 5 5 .
6'+. Hensson GK, Libby P. ['lrc inrrnrrnc responsc in atlrtrosclcrosisr a dor.rble e'clgctisworci. Nat Rev lmrntrno]
200('r:(r:50819.
ir5. Slohrrhn A. Nystr'<xn l'. intlamnntion and the etiolog,v
oi type 2 rliabetes. l)ialrctcs Nlctelr Res Rer- 2006;22:
.ri-i 0.
56. rie Kloet CS. VcrmLrttenE, (leuzc E, Kavcluars A.
Heijnen C.f. \Vestr:nbcrg FI(1. Asscssmcnt of HIA-exrs
firnction in posttraumatic stress clisorder: pharrnacr:r
Iogical rncl non-pliarmacological challenge tests. a
revies-. -l l)svchi'rtr Rcs 2005 [Fipub ahcacl of printl
\ I T \ F R \ - \ F \ T ) L X R T \ . ) T T ) (i T ( \
Diccmhre 2006
tsNDOCRINEANI) INFLA\'{MA'I'ORY
ALI'ERAI'IONSIN PTSL)
67. tsrenrnerJD. Licinkr.f, I)arnell A, KrystalJH, Owens M.f,
Southlvick SM et al. ElevateclCSF corticotropin-relea
sing factor concentrations in posttrallmatic stress disorclcr. Arn J Psychiatry 7997 t754:621-9.
68. Baker DG, lVest SA, Nicholson \l/E. Bkhator NN.
Kasckow-J\il, Hill KK et al. Serial CSF corticotropinrclc:rsing hormonc lcvcls and aclrenocortical lctivity
in combat vetefans s'ith posttraumatic stress disor'
der. Arn J Psychiatry 1999ri56:5U5-fJ.Erratum in: Am
.J l,sychiatry 1999:1i6:986.
69. Raker lXl, Ekhator NN, Kasckor'.1\17.I)ashevsky B.
Horn PS, Reclnarik L et al. Higher levcls of basal scrial
CSIr cortisol in combat vctcrans with posttranmatic
stress clisorcler. Am J I'sycl'riatry 2005:162:992-1.
70. N{ason.lSil.Giller EL, Kosten TR, Ostroff RLl, Podcl L.
lJrinary fiee-cortisol lcvcls in posttraumatic stress
disorcler patients. J Nen Mcnt l)is i98(i117:i:1.15-9.
71. Ychucla R. Boisonc:ru I), Mason JW. Giller EL.
Cilucocorticoicl receptor number and cofiisol excfetion
in moocl. anriety. and psychotic disorclers. Biol
Psychiatry 791)3:31tt18-25.
7 2 . Y e l ' t r c l aR . K : r h a n a B , R i n d e r - R r y n e s K , S o r - r t h w i c k
SM, MasonJW, Gillci EL. Lo.nvlrrinarl, cortisol cxcretion in Holocaust slrrf ivors v'ith posttraumatic stress
disorder. Am J Psychiatr\' 7995:752:982-6.
7J. Yehuda ll, Southu'ick SM, Nussbaum G, \ilahby V.
Giller FILJ,MasonJW. Lon'urinary cortrsol excrction rn
patients \\'ith posttraumatic strcss disordcr. .f Nerv
M e n t D i s 1 9 9 0 ; 1 7 8 : 3 6 69 .
7.i. Rohlcclct N,joksimovic L, Wcrlf JM, Kirschbaunr C.
tlypocortisolism ancl increirse'dgh,rcocorticoiclscn>itivitl of pro Inflammatory cytokine proclrrction in
Bosnian u'ar re f lrgees n-ith posttratrrnaticslrcss clisorc l e r .B i o l P s v c h i a r n ,2 0 0 a : 5 5 : 7 i 5 - 5 1 .
75. Glover I)A. Polancl RFl.L'rinan cortisol ancl catech<>
lamines in mothers of chiltl cJnLtrr sur\-i\ ors Nith .rnd
n i t h o u t P T S D . P s v c h o n e u r o e n c l o c r i n o l o g l2 0 0 2 ; 2 7 :
8 0 5 - t9 .
76. Thaller \'. Vrkljan M, Hotulac L, Thakore.J. The pote ntial rolc of hypocortisolism in the pathophysiokrgy of
PTSD and psoriasis. Coll Antropol 7999:23677 9.
77. Pitman RK, Orr SP.Twcnty-fbur hotu-lrrinary cortisol
and catecholamine excretion in combat-related posttralrmatic strcss clisorder. Biol Irsychratry 1990;2r-:
2tt5 7.
78. Lemielrx AM. Coe CL. Abuse-relatecl posttraumatic
stress disordcr: cvidence fbl chronic neuroenclocrirrc
activation in nomen. Psychosorn N{ccl 1995t57:
105-1i.
79. Macs M. Lin A. Bonaccorso S, van Hunsel F. Van Gastel
A, Dclmcirc L ct al. Increasecl 2,i hour urinary cortisol
excretion in patients with post-traumatic strcss clisorcler and patients \\,ith nraior clcprc'ssion, bllt not rn
patients $'ith fibl'omyalgia. Acta Psychiatr Scancl
19 9 8 : 9 8 : 1 2 8 - 3 5 .
80. \ehucla R, Teicher MH, Trcstman ItL. Lcvcngoocl RA,
Sicver LJ. Cortisol regulation in posttraumatic stress
c l i s o r c l c ra n d m a j o r c l e p r e s s i o n :a c h r o n o b i o l o g i c a l
analvsis. Riol I)sychiatry 1996;40:79-ulJ.
81. tlrernnc'r-fD. Vythilingarn M. Anclerson Ci. Vermetten
E. \{c(il:rshan T, Heninger (} et al. Assessrlent of the
l'rvpothalarnic-pituitary uclrenal axis r>r.ere 2:i hour
cliurnal pet'iocl ancl in rcsponsc to ncurocnclocrine
cliallenges in r''o1nen rvith and \\,ithout chilclhcxrcl
sexual abuse rncl posttrallmatic stress clisordcr. Biol
Psr,chiatry2003:5,1:710-8.
Rctraction in: 13iolPsychiatry
2 0 0 i : 5 5 : 12 0 2 .
82. V'essa NI. Rohlecler N, Kirschbaum C. Fkrr II. Altcrccl
cortisol arvakcning rcsponsc in posttlaLlmali(' stress
clisorcler.Psvchoneuroencloclinology 2{i06:31:209-15.
u 3 . P n r c s s n e r i C . w o t f O T . H c l l h a r r i r i - r c rL ) H , B t r s k e
\bl. t1. N. +
ROHI,F]DI.]R
Kirschlraum A, r'on Auer K,.Job.it S et al. Free coftisol
levels aftcr :rwakening: a re|able biological mart<cr
fbr the assessment of adrenocrrrtical activitv. l,ife Sci
1997.67:2i39-4c).
84. Ychucla R, Golier.iA, Kaufman S. Circadian rhythm of
s a l i r . a r v c o r t i s o l i n H o l o c a r , r s ts u r v i v o r s w i t h a n c l
withoui PTSI). Am J Psychiatry 2005:i62:99ti-1000.
85. Young EA, Brcslau N. Saliva cortisol in posttrallmatic
strcss disorder: a community epiclemiokrgic' study.
I3iol Psychiatry 2004:56:2059U6. Lindauer R.l,()lff M, van Meijel EI' , Carlier IV Gersons
B]'. Cortisol, learning, memory. in.l attenti()n in rela
tion to smaller hippocampal rroluure in police ofli
cers n'ith posttrallmatic stress clisorcler. 13iol I'sychiatry
2006:51):771-7.
87: Millcr GE. Chen E, Zhor.rE. If it goes up, must it come
dor"n? Chronic stress ancl the hypothalamic pituitery
aclrcnocortical axis in humans. I)sychol Rull. In press
2006
88. \'ehuda R. Sor,rthn'ick SM. Krystal ,JH, Rremner l),
Charney I)S, MasonlV. Enhanceclsuppresskrn ofcortisol follon'ing clexarncthasonc administration in posttralrmatic stress disorder. Am .f Psychiatry 1993;150:
83 6.
U9. Stein MB. Yehuda R. Koverola C, Hanna C. Flnhancecl
dexamethasone suppression of plasma coltisol in adult
lliol
wornen traumatized bv chilclhoocl sexual abr,rser.
Psychiatl 1997\42:680-6.
90. Newport D.l. Heirl C, I}rnsall R. Nliller AH. Nerncroff
responses to stanclard :rncl low'
CB. 1)rtr-ritary-aclrenal
close cle'ramethas()nesuppressi()n tc-stsin aclult survivors of ctrilcl elluse. Bkrl l)s-vchiatry20()1;55:7O-20.
91. Ccracioti TI).fr-.Baker l)G. Ekhator NN. West SA. Hill
KK. Bmce AR et al. CSFnorcpinephrine c()nccntrati()ns
in posttraunratic stress clisorder. Am J Psychiatrv
2 0 0 1 : 15 f 3 : 1
227-30.
92. Yel'ruda R. Siever LJ, Teicher MH, Levengood fuA.,
Ccrber DK, Schn-reidlerJet al. Plasma norepinephri
ne ancl 3 rnethoxy-4J-rydroxyphcnylglycol conccntr2rtions ancl severity of clepression in combat posttraumatic strcss disorder' :rncl major depressive disordcr. Biol Psychiatry 7998:41:56 63.
93. O'Donnell T. Hegadoren KM, Coupland NC.
Noreclrenergic mcchanisms in the pathophysiology
of post-traunatic stress clisorcler-.Neuropsychobiology
200.i;50:273-f13.
9.1. VeclhrrraK, Fox.fD, Vang EC. The measurcment of
str-css-r'elatedimmune dysfunction in psychonetr
roimmunology. Ncurosci Biobcliav Rcv 1999;23:
699-77i.
95. Krabbe KS. Peclcncn M, Brr:unsgaarclH. Inflarnmatory
rnccliatom in the elderly. Erp (lerontol 20O1;39:68799.
96. Boscarino .JA, Cheng J. Higher abnormal leukocytc
ancl lymphocyte collnts 20 ,vears after exposure to
sLrvcrestress: research and clinical irnplications.
Psychosom Mecl I999r(rl:37U ti6.
97. \Woods S.f, $ilinenran NM. Pagc GG, Hall RJ, Alexancler
TS, Campbell JC. Prcclicting immunc status in r''omcn
frc.rmPTSD ancl childhcxrci ancl aclult vurlen<:e.ANS
Aclv Nttrs Sci 2005;2ll:306-19.
98. l'onson C;. Vynings C, Schncidcrman N, Baurn A.
RoclriguezM. Grccnw-ooclD ct al. t'osttrarrmaticstrcss
symptolns, intrusive thougl'rts.loss, ancl in-rmunefunc
tion afte r I Itrrric ane Anclren'. Psychosorn 1\4ecl
1 9 9 7 r 5 9 :2
1 8 - ' l1i .
99. Kalvamr.u'aN. Krm Y, Asukai N. Suppression of cellu
l:Lr imrnunity in r.nen n,ith a past I'ristory of posttraulnatic stressclisolder'.Arn .f Ps.vchiatry2001l 158:.i84-6.
100. I)ekaris l), Sabionccllo A. Mazuran ll, l{alratic S.
S l o b o c l a B e u s a n I . R n c u n i c aN L e t a l . M u l t i p l c c h a n ges of imnrunologic pararneters in prisoners of u,'ar.
NIINER\A ENI)OCRINOI,O(}I(]A
281
ALTERATIO\5I\ PT\I)
tsNDOCRINIA\D INFLA\4l\,IATORY
ROHLEDER
Assessrnents after release from a camp in Manjaca,
Bosnra. JAMA 1993:270:5959.
101. Wilson SN, van der Kolk B, Burbridge J, Fisler R,
Kradin R. Phenorype of blood lymphocytes in PTSD
suggests chronic immune activation. Psychosomatics
7L)99:40:222-5.
102. Mosnaim AD, Wolf ME, Maturana P, Mosnaim G,
Pllente J, Kucuk O et al. In vitro studies of natural
killer cell activity in post traumatic stress disorder
patients. Response to methionine-enkephalin challenge. Immunopharmacokrgy 1993;25:7O7-76.
103. Inoue-Sakurai C, Maruyama S, Morimoto K.
Posttraumatic stress and lifestyles are associated with
natural killer cell activity in victims of the HanshinAwaji earthquake inJapan. Prev Med 2000t37i61-73.
104. Laudenslager ML, Aasal R, Adler L, Berger CL,
Montgomery PT, Sandberg E et al. Elevated cytotoxicity in combat veterans with long-term post-tralrmatic
stress disorder: preliminary obseruations. Brain Behav
Immun 1998;12:74-9.
105. I)elahanty DL, Dougall AL, Craig KJ,.lenkins FJ, Baum
A. Chronic stress and natural killer cell activity after
exposllre to trallmatic death, Psychosom Med
199-:i9:16---6.
106. Vatson IP, Muller HK, Jones IH, Bradley AJ. Cellmediated immunity in combat veterans with posttraumatic stress disorder. MedJ Aust 1993;159:513-6.
107, Altemus M, Cloitre M, Dhabhar FS. Enhanced cellular
immune resDonse in women with I'TSD related to
childhood a6use. AmJ Psychiatry 2003;160:170i 7.
108. Miller R.J,Sutherland AG, Hutchison.jD, Alcxander
DA. C-reactive protein and interleukin 6 receptor in
post-traumatic stress disorder: a pikrt study. Cytokine
2001t73:253-5.
109. Sondergaard HP, Hansson LO, Theorell T. The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without p()sttraumatic
stress disorder. Clin Chim Acta 2004:342:938.
110. Tr-rcker P, Ruwe \WD, Masters B, Parker DE, Hossain A,
Trautman RP et al. Neuroimmune and coftisol changes in selective serotonin reuptake inhibitor and pla
ccbo treatment of chronic posttrallmatic stress clisorder. Biol Psychiatry 20O4:56:7278.
111. Spivak B, Shohat B, Mester R, Avraham S, Gil-Ad I,
Bleich A et al. Elevated levels of serun interleukin 1
beta in combat-related posttraumatic stress disorder.
Biol Psvchiatrv 191)7;12:315-8.
288
112. Maes M, Lin AH, Delmeire L, Van Gastel A, Kenis G,
De.]ongh R et al. Elevated serum interleukin-6 (IL-6)
and IL-6 receptor concentrations in posttraumatic
stress disorder following accidental man-made tratlmatic events. Biol Psychiatry 1999;45:833-9.
113. Baker DG, Ekhator NN, Kasckow J\(, Hill KK,
Zoumakis E, Dashevsky tsA et al. Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraLlmatic stress disorder. Neuroimmunomodulati<;n
2001:9:209-77.
11,1.Voods AB, Page GG, O'Campo P, Pugh LC, Forcl D,
Campbell JC. The mediation effect of posttraum2rtic
stress disorder symptoms on the relationship of intimate partner violence and IFN-gamma levels. Am J
Community Psychol 2005:36:759-7 5.
115. Aurer A, Aurer-KozeljJ, Stavljenic-Rukavina A, Kalenic
S, Ivic-Kardum M, Haban V. Inflammatory mediators
in saliva of patients with rapidly progressive periodontitis clurins war stress induced incidence increase.
Coll Antropol 7999:23:717-24.
116. Segman RH, Shefi N, Goltser-Dubner T, Friedman N,
Kaminski N, Shalev AY. Peripheral blood mononuclear cell gene expression profiles identify emergent
post-traLlmatic stress disorder among traLlma survivors. Mol Psychiatry 2005;i0:500-13, 425. Erratr-rmin:
Mol Psychiatry 2005:10:514.
117. Rohleder N, Schommer NC, Hellhammer DH, Engel R,
Kirschbai-rmC. Sex differences in glucctcorticoid sensitivity of proinflammatory cytokine prodtrctitrn after
72.
psychosocial stress. Psyr'hosom Med 2OO1:63:966
118. Bierhaus A, \ilolf .1,Andrassy M, Rohleder N, Humpcrt
PM, Petrov D et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc
Natl Acad Sci U S A 20031100:1920-5.
119. Vlahov D, Galea S, Resnick H, AhernJ, BoscarinoJA,
Bucuvalas M et al. Increased use of cigarettes, alcohol,
and marijuana among Manhattan, New York, resiclents after the September 11th terrorist attacks. AmJ
Epiclemiol 2002;155:988 96.
I20. I4az.z.anoLA, He J. Mlrntner P, Virpputuri S, Whelton
PK. Relationship between cigarcttc stttoking ancl novel
risk f:rctors for cardiol'ascular cli.t.tst in the United
S t a t e s .A n n I n t e r n M e d 2 0 0 3 ; 1 3 8 : f l (l -) 7 .
121. SfannametheeSG, Lowe GD, Vl-rinctrp PH, Rumley A,
'Walker
M, Lennon L. Physical activity and hemostatic
and inflammatory variables in elderly men. Circulation
2002:105:7785-90.
1\ItNERVAEN DOCRINOIOCT(,A
Dicembre 2006