Anxiety Disorders an introduction to clinical management and research - part 7 doc

Comorbidity Both in veterans Green et al., 1989; Hovens et al., 1994 and in civilian survivors ofdisaster Green et al., 1992, PTSD is often found in conjunction with other DSMdiagnoses,

1988; Hamner, 1994; Doerfler et al., 1994) or other medical illness (e.g with a stay inhospital acting as a memory of the concentration camp sick barrack), retirement orother reasons for drop-out from work (ending workaholism as a defence mechanism),general anaesthesia (an accidental, unwanted narco-analysis procedure), trains (asso-ciation with the concentration camp transports), etc Before the manifestation of theirPTSD such patients may have had precursors of an aspecific type like surme´nage or

‘‘exhaustion’’ syndromes (adjustment disorders in DSM-IV terminology), functional

syndromes (which are probably best described as undifferentiated somatoform orders) or unspecified psychiatric syndromes They also may have been given entirely

dis-different psychiatric diagnoses because the trauma criterion had not been recognised

or because theflashbacks had been taken for delusions or hallucinations (Mueser andButler, 1987; Spivak et al., 1992), a problem that is also known in dissociative identitydisorder

A retrospective attempt to follow the longitudinal course of chronic PTSD showedthat hyperarousal symptoms developedfirst, followed by avoidance symptoms, andfinally by symptoms of the intrusive cluster Symptoms plateaued within a few yearsafter the Vietnam War, which was the stressor under study Recording of alcohol andsubstance abuse revealed a course grossly parallel to PTSD symptoms (Bremner etal., 1996) Prospectively, it has been confirmed that it takes some time for theconsequences of traumatic exposure to become apparent During a two-year follow-

up of veterans after Operation Desert Storm (the Gulf War), hyperarousal symptomswere more severe than symptoms of re-experiencing or avoidance Only two yearsafter exposure to combat, its level was significantly associated with the score on theMississippi trauma scale (Southwick et al., 1995)

Comorbidity

Both in veterans (Green et al., 1989; Hovens et al., 1994) and in civilian survivors ofdisaster (Green et al., 1992), PTSD is often found in conjunction with other DSMdiagnoses, such as major depression (Shalev et al., 1998b), dysthymia, panic, phobia,alcohol abuse, generalised anxiety disorder, obsessive compulsive disorder (OCD)and somatisation, either at a current or a lifetime base In clinical samples, PTSDrarely develops as a single syndrome It is questionable whether panic, phobia anddysthymia are essentially independent diagnoses with respect to PTSD or, in fact,dimensional morbidity unitsfitting into broader syndromes I refer to my remarks ondimensional diagnosis in which I feel supported by Van Praag’s scepticism abouttraditional comorbidity conceptions (Van Praag, 1990) However, PTSD did occur as

an isolated diagnosis in the above-mentioned studies, a phenomenon which existence

I can confirm from personal clinical experience

Thus, the question comes back to what the essential functional elements inpsychotraumatic syndromes are To my opinion, these are, first, persistently in-creased vigilance and, second, the mnemonic elements of what caused this increasedvigilance These are intricately connected to the neurobiological processes of startle,

defence, long-term potentiation, imprinting, kindling and memory intrusion (Post etal., 1995; Sanes and Lichtman, 1999).

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NEUROANATOMY AND BRAIN AREA FUNCTION

Importantfindings on the psychobiology of post-traumatic stress disorder (PTSD)reported in the literature during the past 10 years cover a wide range of subjects Thelimbic system and especially the amygdala have a critical role in the process ofcomparing sensory imput to stored memory and organising psychological processesand motor and physiological output (LeDoux, 1998) It has become clear thattraumatic experience changes the limbic system and other parts of the brain not onlyfunctionally, but also anatomically at a submicroscopic, microscopic and even grossanatomical level It seems that severe and overwhelming input into the system maycause loss of connections and even cell death (McEwen et al., 1992) Several studieshave reported decreased hippocampal volume on the right side (Bremner et al., 1995)and functional studies have shown increased activity in the amygdala of the righthemisphere and decreased activation of Broca’s area, suggesting a decreased capacity

to put experiences into communicable language (Van der Kolk et al., 1995) Thisseems to support the more or less obligatory observation of alexithymia in PTSDpatients, their inability to express emotions effectively (Sifneos, 1973; Krystal, 1988).Decreased hippocampal volume is also associated with functional deficits in verbal(declarative) memory (Yehuda et al., 1995a) Left hippocampal volume reduction hasbeen found after childhood abuse without the reported correlation with short-termverbal memory deficits (Bremner et al., 1997a; Stein et al., 1997) The explanation

offered for this discrepancy is that neuronal plasticity in the very young has the effectthat short-term memory functions normally mediated by the hippocampus arepartially taken over by other brain structures A decrease in hippocampal volume hasnot been found in all studies of this kind but other gross anatomical differences werethen found in a study of traumatised children, e.g smaller intracranial and cerebralvolumes negatively correlating with abuse duration More specifically, a gender bydiagnosis effect revealed greater corpus callosum area (middle and posterior regions)

Anxiety Disorders: An Introduction to Clinical Management and Research Edited by E J L Griez, C Faravelli, D Nutt

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reduction in males (De Bellis et al., 1999b) which also suggests a link with the problem

of lateralisation in PTSD for which evidence has been found at a neurophysiologicallevel (Brende, 1992; Schiffer et al., 1995; Spivak et al., 1998)

The results of functional anatomical studies using positron or single photonemission are not very conclusive either They point to involvement of the ventralanterior cingulate gyrus and the right amygdala (increased regional bloodflow duringexposure to combat-related stimuli) and suppression of Broca’s area function (alsoreported by others (Van der Kolk et al., 1995) in one study (Shin et al., 1997),activation of the left amygdala and nucleus accumbens during trauma-related stimu-lation in another (Liberzon et al., 1999a), while a third found a decrease in bloodflow

in the medial prefrontal cortex (area 25), which is relevant for inhibiting amygdalafunction and extinction of fear conditioning (see LeDoux, 1998), and a less thannormal activation of the anterior cingulate (area 24) contrasting with the findingmentioned before (Bremner et al., 1999)

NEUROPHYSIOLOGY

Kindling

A basic neurophysiological concept for the understanding of the phenomena ofintrusive memory, traumatic nightmares, acoustic startle, etc is long-term potenta-tion (Teyler and DiScenna, 1987; Lynch et al., 1988) or the kindling model ofepilepsia (Racine, 1978; Adamec, 1990; Wolf et al., 1990; Post et al., 1995) In fact,traumatic dissociative or intrusive memory phenomena have many features incommon with complex behavioural attacks or temporal epilepsy Although speculat-ive, it is conceivable that under certain conditions very strong sensory input maydevelop into limbic seizures In panic disorder with agoraphobia some support hasbeen found to link this condition to complex partial epilepsy under the hypothesis thatthere may be a common neurophysiological substrate (Toni et al., 1996)

Event-related Potentials

Scalp-recorded event-related potentials (ERPs) are the reflections of patterned neuralactivity associated with information processing in the brain Subjects are told todetect infrequent, target (task-relevant) stimuli and ignore other, non-target stimuli.The P3 or P300 component is recorded as a positive deflection typically occurringbetween 300 and 900 msec and reflects the selective perceptual process used inidentifying stimulus relevance The P300 is affected by the personal meaningfulness

of the stimulus to the subject In a study comparing veterans with and without PTSD,combat-related pictures as non-target stimuli enhanced P300 deflections in PTSDsubjects while P300 latencies and reaction times to target stimuli were prolonged Itpoints to an altered state of early and late cognitive selective attention and confirms

the vulnerability to traumatic reminiscences (Attias et al., 1996a) It even provedpossible to discriminate PTSD patients and controls, classifying 90% of the patientsand 85% of the controls correctly (Attias et al., 1996b) In addition, in survivors ofroad traffic accident with mild head injury, accident-related words produced a P300that was very significantly higher in PTSD patients and that correlated well with state

of anxiety (Granovsky et al., 1998) Non-target traumatic pictorial stimuli initiallyproduced earlier and approximatelyfive times greater P300 amplitudes but showedamplitude reduction and latency prolongation on repetition This effect was notobserved for target stimuli It points to the activation of an inhibitory mechanismrelated to the cognitive processing of traumatic stimuli (Bleich et al., 1996)

In an attempt to resolve the conflicting results, with respect to whether theabnormal physiologic responses in PTSD reflect a general abnormality or arerestrictively linked to trauma-related stimuli, a differential analysis was made insurvivors of a ship fire with and without PTSD and other manifest or subclinicalpsychiatric diagnoses for word and non-word (complex) stimuli with respect tointrusion, arousal and avoidance The complex (non-word) stimuli were thought to becausing attenuated amplitudes at an early stage after stimulus onset (100–150 msec.),

a higher positive amplitude in the 200–300 msec time period and to be related tointrusion Arousal and avoidance were related to emotionally meaningful words andcorrelated independently to P300 amplitude, suggesting that avoidance and arousalhave another neurobiological basis than intrusion (Blomhoff et al., 1998) Thefindings of this study in ERP abnormalities preceding the P300 seem to correspondwithfindings in sexually assaulted women with PTSD in whom the ERP phase at50–300 msec., described as mismatch negativity, in response to auditory non-word(tone) stimuli was found to be increased It was concluded that there should beabnormalities in preconscious auditory sensory memory in PTSD (Morgan andGrillon, 1999) in addition to the abnormalities in conscious processing reported inearlier studies It thus seems as if this is a general abnormality not linked totrauma-related stimuli

STARTLE

Acoustic startle is an oligo-synaptic response mediated through the cochlear rootneurons to the nucleus reticularis pontis caudalis in the brain stem, where pre-pulseinhibition by higher structures via the pedunculopontine tegmental nucleus canoccur, to spinal and facial motor neurons resulting in eye-blink and body movements

It occurs at about 300 msec., well within conscious reaction time Pre-pulse inhibitionand habituation of the startle response are stable neurobiological properties of thenormal population (Ornitz and Guthrie, 1989; Cadenhead et al., 1999), even inperiods of war stress (Shalev et al., 1996) Deficiency of pre-pulse inhibition has beenreported for numerous psychiatric disorders (Ornitz et al., 1999) Both clinically and

in the laboratory, acoustic startle is a striking phenomenon in post-traumatic dromes (Butler et al., 1990; Paige et al., 1990; Shalev et al., 1992; Shalev and

syn-Rogel-Fuchs, 1992; Orr et al., 1995; Morgan et al., 1996; Orr et al., 1997) Also inchildren with PTSD, acoustic startle shows little tendency to habituation and showsdecreased pre-pulse inhibition (Ornitz and Pynoos, 1989) Conflicting results in thedemonstration of increased startle in PTSD patients may be a consequence of

different baseline conditions at experimentation Increased startle is perhaps not achronic condition in PTSD but the consequence of a greater conditioned emotionalresponse triggered by anticipation of the test situation Hence, emotionally chargedtest procedures can be especially informative in distinguishing PTSD patients fromother diagnostic groups (Morgan et al., 1995; Grillon et al., 1998a) However, sometest circumstances may result in specific aversively conditioned reactions that areindependent from PTSD, such as darkness increasing startle responses in all combatveterans independently (Grillon et al., 1998b) An interesting result was obtainedwhen the increased startle response was replicated in right-handed women withsexual assault trauma one to 27 years previously In addition to the expected result,asymmetry was found with greater responses for the left orbicularis oculi EMGconfirming a laterality effect that has been found with different methods as well(Brende, 1992; Schiffer et al., 1995; Spivak et al., 1998) The adrenergic
2-receptor isthought to play a role in the generation of the startle response, especially its
2C-subtype as has been found in transgenic mice (Sallinen et al., 1998) The increase ofPTSD symptomatology by yohimbine, an
2-receptor antagonist (Southwick et al.,1993a; Southwick et al., 1999), and the decrease of startle responses in a child byclonidine, an
2-receptor agonist (Ornitz and Pynoos, 1989), are concordant with thisfinding

OLFACTORY STIMULI

Another interesting limbic phenomenon is the EEG response to odours significantlyassociated with traumatic experience (McCaffrey et al., 1993) As is the case inacoustic startle, the alarm centre of the central nervous system cannot be shut off fromolfactory input Mammals do have eyelids but no ear lids or nose lids Also clinically,odours prove to be very strong triggers for conditioned emotional responses

CIRCULATORY, SYMPATHETIC AND MOTOR

RESPONSES

Base-line Blood Pressure and Heart Rate

The development of physical disease after and caused by emotional experience ortraumatic life events has always been intriguing, to the public even more so than toclinical medicine It is a domain of complex interactions and the much neededprospective follow-up studies have rarely been possible to carry out Raised blood

pressure or hypertension is outstandingly such a domain It has been shown, now,that veterans with PTSD and no premorbid or familial burden with hypertensionwho were compared with veterans without PTSD, had significantly higher heart rateand diastolic blood pressure to a degree that is substantial in epidemiological terms(Muraoka et al., 1998) Orthostatic challenging yielded a more or less comparableresult Diastolic blood pressure failed to decrease over time after standing up inmedication-free combat veterans with PTSD studied at their homes (Orr et al.,1998a) Analysis of heart rate variability by means of power spectrum analysis againshowed higher heart rates and lower heart rate variability at rest This was inter-preted as an indication of lower cardiac parasympathetic tone and elevated sympath-etic activity (Cohen et al., 1997).

Psychophysiological Testing (HR, GSR, EMG)

In laboratory settings cardiovascular and other psychophysiological responses,

main-ly galvanic skin response (GSR) and electromyography (EMG), to stimuli of variouskind have been studied extensively Many studies have demonstrated strong specificresponses of blood pressure and especially heart rate to startling aspecific noises and

to individually significant sensory input in subjects with PTSD, combat veterans fromvarious war theatres (Pallmeyer et al., 1986; Pitman et al., 1989; Blanchard, 1990;Blanchard et al., 1991a), and in other populations of trauma survivors (Shalev et al.,1993; Shalev et al., 1997) In addition, in Rorschach testing, the projection oftraumatic content elicited significant increases in skin conductance (sympatheticactivation) and heart rate (Goldfinger et al., 1998)

Vasopressin and oxytocin are two hormones of the central nervous system peptides) that are of special importance in memory processing Behavioural andcardiovascular conditioning in animals has shown that vasopressin increases theretention of, both appetitive and aversive memory while oxytocin in low doses has theopposite effect (Bohus et al., 1978; Wan et al., 1992) Similar results have beendemonstrated in humans with PTSD with respect to psychophysiological parameters

(neuro-in relation to personal traumatic imagery, most specifically exerted by vasopressin onEMG (Pitman et al., 1993)

Yohimbine, an
2-adrenergic receptor antagonist that activates noradrenergicneurons, e.g in the locus coeruleus, hippocampus and amygdala, increased systolicblood pressure significantly more in PTSD subjects than in healthy controls, especial-

ly when they had a flashback and/or a panic reaction after administration of thisdrug The same occurred with heart rate which showed no significant response in thecontrols (Southwick et al., 1993a)

Psychophysiological responses to specific stimuli have been shown to discriminatePTSD from non-PTSD subjects but not to an extent to make it feasible for clinicaldiagnosis, let alone for medico-legal purposes (Blanchard et al., 1986; Pitman et al.,1987; Keane et al., 1998; Orr et al., 1998b) Response specificity has always been anintriguing issue in psychophysiology and psychotraumatology has not failed us in this

respect Comparison of stimuli related to the diagnosis of PTSD (combat sounds) withthe threat of painful electric shocks during a memory task and the presentation ofstandardised emotionally negative visual stimulation produced the expected result ofhyperresponsivity of PTSD subjects to trauma-specific stimuli (Casada et al., 1998).The analysis of heart rate variability as an assessment of differential autonomicactivation did not confirm the hypothesis of specific responsiveness unconditionally.PTSD patients demonstrated a degree of autonomic dysregulation at rest that wascomparable to that seen in the control subjects’ reactions to stress and they seemedunable to marshal a further and more differentiated stress response (Cohen et al.,1998).

OPIOIDS

Addiction to the trauma is a clinical phenomenon in many PTSD patients that waspoorly understood until the role of the opioid peptides was discovered Pain-inducedanalgesia was known as an experimental model in pharmacology for a considerabletime and has been extended, later, to stress-induced analgesia (Van der Kolk andSaporta, 1991; Glover, 1992) It can be blocked with the classical morphine antagon-ist naloxone There are indications thatflashbacks and other dissociative phenomena

in PTSD patients and emotional numbing are opioid-mediated phenomena that can

be blocked by naloxone (Van der Kolk et al., 1989; Pitman et al., 1990) ment of many PTSD symptoms has been reported after the administration ofnalmefene (Glover, 1993), a relative pure opioid -receptor antagonist more potentthan naloxone (Reisine and Pasternak, 1996) It is possible although speculative atthis moment that clinical phenomena like dissociation, auto-mutilation and condi-tioned or self-induced analgesia like the fakir syndrome are mental states in which theopioids play an important role A puzzlingfinding is that plasma levels of -endorphin,both in the morning and the evening, were found in one study to be lower than incontrols (Hoffman et al., 1989) In this same study morning cortisol levels in PTSDsubjects were higher than in controls which is at variance with most laterfindings (seebelow) The above reported opioid responses to traumatic flashbacks were notaccompanied in that study by detectable changes of opioids in the general circulation(B.A van der Kolk, personal communication) The effects may well be confined to theCNS compartment exclusively Again, the connection to the hypothalamic-pituitary-adrenal axis is to be considered in the light of its inhibition by opioids at thehypothalamic level (Hockings et al., 1994)

Improve-NIGHTMARES

Traumatic nightmares belong to the core symptoms of PTSD The differentialdiagnosis of parasomnias (Driver and Shapiro, 1993) in PTSD includes three relevantcategories:

1 Night terrors (pavor nocturnus and incubus) occur during slow wave sleep,

predomi-nantly during thefirst few sleep cycles when slow wave sleep phases are longer;the person does not report to have been dreaming but very suddenly awakens interror

2 Anxious dreams or rapid eye movement (REM) sleep nightmares occur duringthe longer stretches of REM sleep, typically during the last few sleep cycles; thesedreams may contain fantasy material and all aspects of condensation characteris-tic of normal dreaming

3 Post-traumatic nightmares, or better nightlyflashbacks, are not related to anyspecific sleep stage and occur during all stages of sleep, even slumber sleep.Characteristically, they represent a true memory in which the subject is the actor,not an observer (Schreuder, 1996) They are accompanied by autonomic andmotoric arousal like sweating, a pounding heart, hyperventilation (breathless-ness), teeth grinding (bruxism), groaning and other vocalisations, gross bodymovements and evenfighting Awakening is not obligatory and, if it occurs, itdoes not prevent the nightmare from continuing when the person stays in bed tosleep again On a phenomenological basis, it is not possible to distinguishbetween these andflashbacks during daytime; they may be the same from aneurophysiological point of view

An increasing body of evidence points to disturbances in the electrophysiology ofsleep in PTSD, as expressed by REM sleep, slow wave sleep, nightly awakenings, etc.REM sleep is increased in percentage, density, average activity and period duration,not in cycle length, suggesting changes in phasic event generation (Ross et al.,1994),while REM sleep significantly precedes symptomatic awakenings (Mellman et al.,1995) Consistent with this, slow wave sleep is decreased (Fuller et al., 1994)

NEUROENDOCRINOLOGY AND NEUROTRANSMITTERS Feedback Systems

Many studies have addressed the complex interplay between the adrenomedullary system and the hypothalamic-pituitary-adrenocortical (HPA) axis

sympatho-In most studies, PTSD is characterised by increased norepinephrine (NE) release(Kosten et al., 1987; Blanchard et al., 1991b) on the one hand, but decreased totaldaily cortisol production (Mason et al., 1986; Yehuda et al., 1990a; Yehunda et al.,1995b) and circulating cortisol levels on the other (Yehuda et al., 1996a; Boscarino,1996) In one study, lower serum cortisol was paralleled by lowered serum prolactin(Kocijan-Hercigonja et al., 1996) Daily free cortisol excretion was found to benormal at group level but to correlate inversely with intrusive PTSD symptoms in onestudy (Baker et al., 1999), while it was increased similar to patients with majordepression and without any correlation to symptoms in another (Maes et al., 1998).One difference of the last study with the previous one is that it was done in civilians

with a majority of females without control for menstrual cycle phase while most of theprevious studies were done in male combat veterans It was also argued that singletraumatic events might cause an increased HPA-axis response while repetitive andprolonged trauma might do the opposite Some support for this view can be found inother research but this problem has not been solved satisfactorily.

In concordance to the release rates reported above,
2-adrenergic receptors aredown-regulated (Perry et al., 1987; Yehuda et al., 1990b) and glucocorticoid recep-tors are up-regulated (Yehuda et al., 1991; Yehuda et al, 1995c) Norepinephrinerelease and the up-regulation of glucocorticoid receptors correlate with the severity ofPTSD symptomatology (Kellner et al., 1997)

Comorbidity: PTSD and Depression

In PTSD the efficacy of glucocorticoid feedback is increased as demonstrated by asignificantly enhanced dexamethasone suppression in comparison to normals (Ku-dler et al., 1987; Yehuda et al., 1993; Heim et al., 1998) and it is opposite todepression (which is known for its dexamethasone non-suppression) One would evenconclude that PTSD and biological depression as defined in this neuro-endocrineway exclude one another However, many studies describe comorbidity of PTSD andmajor depressive disorder (MDD) (Shalev et al., 1998), not merely dysthymia Itshould be kept in mind that a biological definition of depression is not fully concord-ant with a psychological one Individuals with PTSD and comorbid depression arestill better-than-normal suppressors but less than having PTSD alone (Yehuda et al.,1993) The enhanced negative feedback of cortisol is not reflected by lower levels ofcirculating adrenocorticotropic hormone (ACTH), but the pituitary capacity torelease ACTH is markedly enhanced which excludes pituitary insufficiency andconfirms the increased feedback sensitivity (Yehuda et al., 1996b)

The comorbidity of PTSD and depression seems to influence circulating plasmalevels of NE, but not 3-methoxy-4-hydroxyphenylglycol (MHPG or MOPEG)(Yehuda et al., 1998a), which can be considered as a metabolic parameter of central

NE turnover, reflecting spillover from the CSF compartment into the systemiccirculation (Webster, 1989) Nevertheless, increases in plasma MHPG after adminis-tration of yohimbine (see section Circulatory Responses) have been found in subjectswith PTSD to exceed the increases in healthy controls The effect was stronger inPTSD subjects experiencing panic (14 out of 20) andflashbacks (8 of these) induced

by the drug (Southwick et al., 1993a) The paralleling differences in circulatoryresponse (systolic blood pressure and heart rate) have been mentioned above Yohim-bine is also reported to induce marked exacerbation of anxiety/panic and PTSD-specific symptoms immediately after ingestion in a natural setting (Southwick et al.,1999), which confirms my clinical experience in veterans with PTSD to whom thismedication was prescribed by the urologist for erection problems

The high levels of NE in PTSD are interpreted as reflecting high sympatheticactivity, which corresponds with manyfindings on cardiovascular stimulation and

galvanic skin response (GSR) reactivity A positive correlation between intrusivePTSD symptoms and urinary excretion of the catecholamines dopamine and epi-nephrine points in the same direction (Yehuda et al., 1992) Thus, on one hand,post-traumatic stress disorder with or without accompanying symptoms of depressionseems to be characterised by sympatho-adrenal arousal, which is reflected by in-creased cardiovascular responsiveness and sweat gland activation as signs of thedefence reaction, the paradigm of active survival strategy; on the other hand, it ischaracterised by a decrease in the conservation-withdrawal response and its catabolicsurvival hormone cortisol that induces the organism to consume its intrinsic re-sources, while waiting for better times.

CRH Testing

The response of ACTH to CRH has been found to be blunted in PTSD as

in depression, panic disorder and anorexia nervosa, and to result in slightly butnot significantly lower cortisol responses (Smith et al., 1989) This cannot be under-stood as a feedback effect of functional hypercortisolism as in depression (Gold et al.,1988)

Children: CRH Testing and Urine Sampling

The neuroendocrine pattern in children has not been investigated as intensively as inadults In one study CRH testing was performed in children aged seven to 15 yearsold who were living in a stable and safe environment but who had been sexuallyabused one to 12 years earlier Some of them had concurrent dysthymia and suicidalideation and had attempted suicide but none of them was reported to have PTSD.They showed smaller than normal ACTH responses but nonetheless normal cortisolresponses to this (De Bellis et al., 1994), which resembles the result found in adults

A very different finding is the increased ACTH response to CRH in abusedchildren who experienced ongoing chronic adversity and were rated as depressed.They differed from abused depressive children living in a stable environment,depressive non-abused controls and healthy children who all showed the sameACTH response The increased ACTH response in thefirst group was not followed

by an increased cortisol response, which thereby was the same in all four groups(Kaufman et al., 1997)

A group of children of the same age (8-13) with PTSD was compared with normalcontrols and children with overanxious disorder Childhood PTSD was associatedwith greater comorbid psychopathology including depressive and dissociative symp-toms, lower global assessment of functioning and increased suicidal ideation andsuicide attempts The children in this group excreted significantly greater amounts ofurinary dopamine and norepinephrine per day than in both comparison groups.Their free cortisol excretion was equal to that of the overanxious group but exceeded

the controls Catecholamine and cortisol excretion was correlated to the duration oftraumatisation and to PTSD symptoms (De Bellis et al., 1999a).

It is unclear what the discrepancies between these studies and the results found inadults imply One of the possibilities is that the psychobiological development stage is

a critical factor Also in a broader sense, age may be a factor influencing the HPA-axisresponse to challenge (Seeman and Robbins, 1994) Repetition or perseverance oftraumatisation is likely to influence the neurohumoral response to it as has beenobserved in rape victims (Resnick et al., 1995) Other possibilities accounting for thediscrepancies are that the studies were done on non-patients and patients with

different diagnoses (diagnosing PTSD in young children poses its own difficulties),sample sizes, time of the day and baseline values

Systems Integration

No convincing correlation has been found between HPA-axis activity in the morning,when it is as high in PTSD patients as in controls, and circulating catecholamines orpsychophysiologic parameters like GSR (which reflects sympathetic activity), heartrate or frontalis EMG (Liberzon et al., 1999b) The conclusion was drawn, then, that

no integrated multisystem stress response occurred in PTSD, and this conclusion issupported by otherfindings when the HPA-axis response was studied in connectionwith CNS noradrenergic activity as represented by MHPG spillover (Goenjian et al.,1996; Yehuda et al., 1998b) This may seem but is not necessarily at variance with theabove-describedfindings on the HPA-axis and catecholamine activity It means thatwithin an individual these systems are not being coupled per single event Thisconclusion is in concordance with the insight that the sympatho-adrenal responsesystem and the HPA-axis are not connected to each other through the activation ofCRH, as this neurohormone or neuromodulator acts at different locations in theCNS independently, in different circuits and functions (Schulkin et al., 1998) CRHgene expression in the central nucleus of the amygdala and the bed nucleus of thestria terminalis (BNST) is dissociated from that of the paraventricular nucleus of thehypothalamus which is the classical top of the HPA-axis organisation Direct applica-tion of CRH by infusion into the third ventricle induces multiple physiological stressresponses like increase of plasma epinephrine, norepinephrine, glucose and glucagon,

of mean arterial blood pressure and heart rate, and inhibition of gastric acidproduction, all by autonomic nervous system activation (Lenz et al., 1987) Naloxone

or a vasopressin antagonist could in part, inhibit the gastric inhibition This impliesinvolvement of an opioid neuropeptide as a neuromodulator, e.g a pro-opiomelanocortin (POMC) derived endorphin (De Wied, 1999) The possibility of arelation with dissociation and flashback-related analgesia is intriguing within thiscontext (Pitman et al., 1990) The role of vasopressin is interesting from the viewpoint

of its role in the consolidation of memory (Bohus et al., 1978; Chepkova et al., 1995),including the psychophysiologic concomitants of emotional memory (Bohus et al.,1983; Pitman et al., 1993) and its role in the potentiation of CRH-induced ACTHrelease (Scott et al., 1999)

The Role of CRH

The question of the specificity of CRH activity in the CNS is of special importance inthe case of PTSD as higher levels of this neurohormone have been found in thecerebrospinalfluid of patients compared to controls, which may seem paradoxical atfirst sight given the increased feedback sensitivity of the system (Bremner et al.,1997b; Baker et al., 1999) CRH in the CSF is mainly of extrahypothalamic origin,not related to HPA-axis activity (Garrick et al., 1987) Interestingly, this was accom-panied in patients, but not in controls, by positively correlated CSF levels of somato-statin, which often acts as an inhibitory hormone or neuromodulator both in the CNSand peripherally, but its role in these particular circumstances is unclear It is alsounclear, at this point, what actually causes the increased feedback sensitivity withinthe HPA-axis and whether stimulation of this axis at the level of CRH production bythe paraventricular nucleus (PVN) of the hypothalamus is decreased As mentionedabove, the elevated CRH levels in the cerebrospinal fluid are not likely to begenerated by the PVN but to be due to spillover from the central amygdala, the bednucleus of the stria terminalis and possibly also the locus coeruleus The latter threenuclei have important roles in organising or mediating vigilance, arousal and anxietyreactions and they activate both the central norepinephric system and the sympath-etic nervous system (Lenz et al., 1987) Central norepinephric system activation hasnot systematically been demonstrated (Yehuda et al., 1998b) However, frequentlyrepeated activation of the sympathetic nervous system is a general feature of chronicPTSD Next to PTSD symptoms, panic and flashbacks, yohimbine challengehas indeed produced increases in systolic blood pressure and heart rate, but alsoMHPG as a putative parameter of central norepinehrine activation (Southwick et al.,1993a)

HPA-axis Regulation

One of the options for increased HPA feedback sensitivity is increased glucocorticoidreceptor function in the hippocampus, which is an important centre for control overthe HPA-axis function (Meaney et al., 1989) The hippocampus with its densepopulation of glucocorticoid receptors is now broadly recognised as the top of thesystem by exerting inhibitory control over hypothalamic CRH production (Jacobsonand Sapolsky, 1991) Glucocorticoid receptors may have been up-regulated, con-forming to a theory derived from the model of neonatal handling in rats, in whichattenuation of stress responses in adulthood has been observed (Levine, 1957;Denenberg, 1964) This model has been differentiated by more recent studies thatindividual differences in caring behaviour by the mother animal after separation fromthe litter are responsible for differential effects of such handling The better the caringattention of the mother after replacement of the pup into the litter, the higher theglucocorticoid receptor density in the hippocampus and the more efficacious thefeedback of circulating glucocorticoid hormone (Liu et al., 1997; Sapolsky, 1997).This process is thought to have a protective effect on the hippocampus against later

damage by high glucocorticoid responses under environmental stress, ‘‘allostasis’’ as

it was named by Charles Kahn (see: Sterling and Eyer, 1988) or the ‘‘allostatic load’’(McEwen, 1998) The hippocampal atrophy found in PTSD, as in depressionand Cushing’s disease (Sapolsky, 1996), is not compatible with such protection

if, indeed, the damage is due to high glucocorticoid responses under traumaticcircumstances

Atrophy of the Hippocampus

The smaller volume of the hippocampus, found in several PTSD studies (see sectionNeuroanatomy), is enigmatic in the light of the above-mentioned atrophy found inMDD and Cushing’s disease with their increased levels of cortisol, which is theopposite of what is thought to be happening in PTSD There is not much doubt aboutthe potential harm of glucocorticoids for the hippocampus, especially the pyramidalcells and dendritic outgrowth and sprouting It has been postulated that the impact ofthe initial aversive experience may trigger damaging levels of glucocorticoid releasethus causing the observed atrophy in PTSD (Bremner, 1999) Other causes ofneuronal damage are excitatory amino acid neurotransmitters, especially glutamate,via its N-methyl-D-aspartate (NMDA) receptor and possibly also its kanainate typefeedforward autoreceptor, and serotonin which may also potentate the NMDAreceptor (McEwen and Magarin˜os, 1997) Neuroprotection by GABA-ergic inhibi-tion or by neurotrophins (NT) such as brain-derived neurotrophic factor (BDNF) andNT-3 may decrease under certain stressful circumstances

A postulated consequence of hippocampal atrophy with respect to the strikingdown-tuning of the HPA-axis, is the putative disinhibition of CRH release from thePVN, which then should result in CRH receptor down-regulation in the pituitary andthereby cause a decrease of ACTH stimulation From the viewpoint of classicalendocrinology, however, it seems improbable that this would result in an absolutedecrease of ACTH release from the pituitary, instead of an attenuated increase, andhence produce a decrease of cortisol release from the adrenal and, finally, anenhanced glucocorticoid feedback effect Continuous hormonal overstimulation at apharmacological level does produce receptor down-regulation and a sharp andalmost complete decline of end-organ activity This is applied in the treatment ofprostate cancer by the use of a long-acting LHRH agonist that down-regulatestestosterone production to almost zero, but in physiological circumstances it is notknown to occur and the neuroendocrinology of major depression with its increasedactivity of the HPA-axis does not confirm this either Moreover, experiments inprimates examining the effects of lesions of the hippocampus and other relatedstructures produced chronic glucocorticoid hypersecretion lasting six to 15 months(Sapolsky et al., 1991)

Somatostatin, Vasopressin and the HPA-axis

Thus, there must be other reasons for the opposite characteristics of PTSD and MDDwith respect to the HPA-axis The inhibitory neuropeptide somatostatin has alreadybeen mentioned and in the CSF, its levels were found to be correlated with CRHlevels in PTSD patients but not in controls (Bremner et al., 1997b) Vasopressin isanother candidate for discriminating PTSD and MDD, although this may be part of

a very complex pattern of interaction Vasopressin potentates the release of ACTH(Antoni, 1993; Aguilera, 1998) and it has been shown to co-occur with CRH in themedian eminence in a way modulated by neonatal handling and stress (Bhatnagarand Meaney, 1995) It also has an important role in the consolidation of memory (DeWied, 1999) and could play a role in the conditioned physiologic responses found inPTSD (Pitman et al., 1993) Arginine vasopressin (AVP) is secreted into the medianeminence where it enters the portal blood circulation that brings it to the pituitary.Experiments in rats have shown that this is controlled indepently from CRH byaxonal transport through AVP containing versus AVP deficient CRH neurons, andthat under conditions of chronic or repeated stress plastic changes in hypothalamicCRH neurons evolve, resulting in increased AVP stores and co-localization in CRHnerve terminals (De Goeij et al., 1991) Also under conditions of chronic or intermit-tent stressful stimulation, a shift in hypothalamic signals for ACTH release in favour

of AVP may ensue as it has been found in rats (De Goeij et al., 1992)

Experimental analysis in rats at the level of CRH and AVP responses in the PVNmeasured by primary transcript (heteronuclear) RNA and messenger RNA hasconfirmed that there is a desensitisation of CRH, but not AVP transcription re-sponses to repeated restraint stress It has also been demonstrated that animalsadapted to a chronic homotypic stress show a greater response of CRH and AVPgene transcription in the parvocellular PVN after a novel, heterotypic stress Thehypothalamus clearly has theflexibility to adapt to homotypic stress while at the sametime maintaining its ability to respond to novel stressors (Ma et al., 1999) Theseexperiments show that, as to the responses of the HPA-axis, vasopressin is a mediatorfor the discrimination between chronic and acute, homotypic and heterotypic stres-sors, which, to some extent, can be controlled independently from CRH In humandepression not only an increase in CRH expressing neurones in the PVN was found,

but also an increased co-expression of AVP and of AVP per se (Hoogendy¨k et al.,

2000) If PTSD is indeed the mirror image of depression it seems to be, the enhancedfeedback of cortisol on the hypothalamus should be the result of parallel inhibition byanother central mechanism