  psychological disturbance after traumatic injury is common , and it is 
 now well recognised that disorders such as posttraumatic stress disorder ( ptsd ) are not confined to combat veterans or the survivors of major civil accidents [ 13 ] . 
 there is a spectrum of posttraumatic problems ; from short - lived adjustment 
 conditions such as acute stress disorder ( asd ) to full ptsd , and a range of 
 comorbidities such as anxiety and depression can coexist with specific 
 posttraumatic symptoms . rather than focusing upon only the most severe extreme , 
 we prefer to consider the full spectrum of posttraumatic psychological ( ptp ) symptoms 
 to describe the range of problems that may occur after a traumatic event . 

we have previously demonstrated that 2 months after a musculoskeletal injury up 
 to 46% of patients have demonstrable psychopathology , falling to 22% by six 
 months .
this ptp is important to the treating trauma surgeon , as there is a 
 clear relationship between psychopathology and impaired functional recovery .
although it is not clear that primary 
 treatment of the psychological problems will necessarily yield an improvement 
 in recovery from the physical aspects of the injury [ 5 , 6 ] , it is certainly 
 clear that holistic care of the injured patient must include management of 
 their psychological state . the ability to predict which patients are at highest 
 risk of ptp , including ptsd , would allow scarce resources to be targeted at 
 those most in need .  
previous work from our and other units has characterised aspects of 
 the injury , including injury severity and the patient 's experience of the 
 accident , which are associated with increased risk of ptp [ 4 , 79 ] .
the 
 awareness of the centrality of the hypothalamic - pituitary - adrenal axis ( hpaa ) 
 to the development of ptp   has led to a search for biological markers that 
 might predict a tendency to develop ptp that is independent of the injury 
 itself .
a recent paper has suggested that low levels of -amino butyric acid 
 ( gaba ) , an inhibitory modulator of the hpaa , may predict ptsd after road 
 traffic accidents .
the proinflammatory 
 cytokines interleukin-6 and its soluble receptor ( il-6 and sil-6r ) and tumour necrosis 
 factor- ( tnf- ) have been identified as indicators of the 
 inflammatory response to physical stress and hpa disruption [ 1217 ] . there is 
 some contradictory evidence for elevation of these cytokines in patients with 
 established ptsd [ 1820 ] and posttraumatic psychopathology .
the relationship between psychiatric illness and 
 cytokine disturbance has been more widely studied , particularly with regard to 
 schizophrenia [ 22 , 23 ] , but it remains to be seen how this can be integrated in 
 the understanding of changes in ptp .
gaba has an important 
 inhibitory role in the function of the hpaa   , and low levels have been 
 associated with increased risk of development of acute ptsd [ 11 , 25 ] .
we wished to study 
 the relationship between gaba and a range of proinflammatory markers , which 
 also reflect hpaa function , and the development of ptp in our centre .
  as part of a wider study of trauma outcomes , a 
 cohort of patients treated in the orthopaedic trauma unit of aberdeen royal 
 infirmary were approached for recruitment .
patients eligible for entry were aged 1770 , with at least 
 one musculoskeletal injury .
head 
 injuries are known to affect psychological perception of injuries and so those 
 with significant head injuries ( unconscious more than 15 minutes , glasgow coma 
 scale less than 13 ) were excluded .
patients were recruited within 48 hours of their injury , by means of 
 discussion , information sheet , and informed consent record .
they were asked to complete the general health questionnaire ( ghq ) at 
 initial presentation , and gave an early morning sample of blood .
demographic 
 data related to their injuries 
 and backgrounds 
 were collected , including injury severity score ( iss ) , the new injury 
 severity score ( niss ) [ 27 , 28 ] , the revised trauma score ( rts ) , and the 
 triss methodology score .
the ghq is a validated and robust self - administered screening measure 
 to detect psychiatric disorders in community and nonpsychiatric clinical 
 settings [ 31 , 32 ] .
it is a 28-item questionnaire , producing a total score ( a 
 higher score representing more severe psychiatric disturbance ) .
the total score 
 further allows a threshold to be applied that defines  casenessthe situation 
 where it is likely that clinical examination by a mental health specialist 
 would identify a genuine psychiatric condition .
this does not define that the 
 patient has a specific psychiatric diagnosis ( this would require a two - stage 
 approach ) , but it is a useful tool for identifying patients who would be so 
 defined . the threshold for this caseness definition is generally taken as a 
 score of 5 and above ( out of   28 ) . in a posttraumatic
setting , there is 
 often extensive symptom overlap , and the ghq allows us to identify those 
 patients with a psychiatric disturbance without narrowing the focus to one or 
 more specific diagnoses ( e.g. , 
 ptsd ) .  
blood was drawn between 0730 and 0830 for each patient , in order to 
 reduce the potential confounding effect of circadian rhythmns in production of 
 biomarkers under investigation .
sampling used a tourniquet and vacutainer 
 technique , taking 20 ml in two - clotting vacutainers .
the clotted samples were 
 centrifuged at 2900 rpm for 15 minutes , and the serum carefully transferred to 
 nonsterile 5 ml vials ( eppendorfs ) using a microtitre pipette ( gilson ) .
the 
 serum samples were stored at 40c for no more than 24 hours before being 
 transferred to a 70c freezer until required , when they were allowed to thaw 
 at room temperature .
tnf- , il-6 , and sil-6r assays were carried out using 
 solid - phase enzyme - linked imunosorbant assay assay ( elisa ) kits ( quantikine , 
 r&d systems inc , minneapolis , minn , usa , distributed in the uk by 
 r&d systems europe , abingdon , oxon , uk ) .
crp assays 
 were carried out in the routine microbiology laboratories of aberdeen royal 
 infirmary .
they were asked to repeat the ghq at two- and six - month follow - up .
statistical analysis was undertaken on the statistical package for 
 social sciences ( spss v 16.0 , spss inc , chicago , 
  ill , usa ) .
differences between ghq caseness rates at 
 different follow - up times were analysed using the wilcoxon signed - ranks 
 test .
relationships between biochemical markers , categorical demographic data , and 
 ghq caseness were explored with the independent samples t - test , and 
 those between the individual biochemical markers and ghq scores with pearson 
 correlation testing .
logistic regression analysis was used to assess the 
 predictive value of the biochemical markers on ghq caseness .
during the course of the study , 84 patients were successfully 
 recruited to the metabolic markers group .
their mean age was 36 years ( range 1668 years ) , and 
 75% were men .
fifty percent were married 
 or cohabiting , while 45% were single , and 5% separated from partners .
alcohol 
 consumption was greater than 20 units per week in 14 ( 17% ) , while 35% were 
 smokers .
only one patient admitted the use of controlled substances , and eight 
 had previous psychiatric services contact .
the patients had 
 sustained a variety of musculoskeletal injuries , predominantly fractures , and 
 28 ( 35.5% ) had multiple injuries .
the modal iss was nine ( range 425 ) , modal niss 
 was also nine ( range 441 ) .
the mode rts was 7.84 ( range 6.387.84 ) , and the 
 modal triss survival probability was 99.40% ( range 93.3099.80% ) .
follow - up for the group was 68 ( 81% ) at two months and 62 ( 74% ) at six 
 months .
the mean ghq score at initial presentation was 1.31 ( out of 28 ) , 
 rising at two months to 6.10 , falling by six months to 3.39 ( differences between 
 follow up and baseline levels p < .001 , wilcoxon signed - ranks 
 test ) .
the initial caseness level was 
 11% , rising to 39% at two months , and falling back partially to 18% by six 
 months ( differences between follow - up and baseline p < .02 , wilcoxon 
 signed - ranks test ) .
the mean standard deviation and the range for each of the biological 
 markers are shown in table 2 . with the exception of gaba , each has a wide 
 range .
the measured quantity of each of the biological variables was normally 
 distributed ( shapiro - wilks test , p < .01 ) .
there were no correlations between levels of 
 biological markers and demographic data including age ( by age bands ) , sex , and type 
 of injury ( independent samples t - test , p > .05 ) and iss score , 
 niss score , triss , and rts ( pearson 's correlation , p > .05 ) .
there were no correlations between gaba level 
 and the levels of other biomarkers under investigation ( il-6 , sil6r , tnf- , and 
 crp ) ( pearson 's correlation , p > .05 ) .  
the levels of gaba , il-6 , sil6r , tnf- , and crp did not correlate 
 with ghq total score at initial assessment and two- or six - month follow up 
 ( pearson 's correlation , p > .05 ) .
similarly , the mean levels were not significantly different between 
 cases and noncases ( ghq cut - off score five and above ) ( independent samples t - test , p > .05 ) .
logistic regression analysis 
 revealed that none of the biochemical markers had any predictive value for ghq 
 caseness ( p > .10 ) .
the relationship between markers of hpaa function after 
 musculoskeletal injury and the risk of developing posttraumatic psychological 
 problems is complex , and we have not been able to identify a simple predictive 
 test from our data .
posttraumatic psychopathology is an important complication of 
 musculoskeletal trauma of the sort that presents every day to orthopaedic 
 trauma surgeons .
it is associated with a significant delay in functional 
 recovery , and it is clear that genuinely holistic care of the injured patient 
 should include the psychological state .
psychological interventions for ptp , 
 including ptsd , are established , but are often limited in resource , and so 
 should be targeted at those most in need .
we have previously reported on the relationship between psychological 
 and physiological state after trauma , but have focused on incident - specific 
 data in the prediction of at - risk status in our patients . the recent 
 suggestion that gaba may be useful in ptsd prediction in the short term   prompted 
 our examination of gaba and proinflammatory markers of the metabolic response 
 to trauma and their relationship to subsequent development of ptp .
cortisol or acth assays are the most direct 
 measures of hpa function and have been used to predict ptsd symnptomatology , 
 but require complex methodology , particularly in specific timing of testing due 
 to the effects of complex circadian rhythmns .
function of hpa and proinflammatory markers of trauma are enmeshed and 
 complex , but it has been suggested that proinflammatory cytokine levels can 
 provide a physiological correlation with hpa function .
it is not possible 
 to identify a single marker of the inflammatory response to trauma .
each of the 
 three cytokines ( il-6 , sil-6r , and tnf- ) that we have tested as well as crp have been 
 used in various studies of the response to physical trauma , including surgery [ 15 , 3448 ] . a focus upon ptsd as the sole psychiatric consequence of trauma is , 
 in our view , too narrow .
there is extensive symptom overlap in posttraumatic 
 conditions , and while some patients will exhibit frank ptsd , others may not 
 reach the diagnostic threshold while still suffering significant distress and 
 dysfunction in their everyday life . for this reason
, we have preferred to 
 consider posttraumatic psychopathology ( ptp ) as representing the full spectrum 
 of pathological reactions to injury , including associated depression or anxiety . 

this has led us to use ghq as a screening tool for general psychiatric 
 symptomatology , rather than focussing on a single diagnosis ; we believe that 
 this approach more truly reflects , in a practical way , the experience of our 
 patients rather than in a research - driven enquiry .
our data suggest no useful prediction of subsequent ptp by the 
 assessment of hpa axis function , as measured by gaba , crp , and proinflammatory 
 cytokines .
we have previously demonstrated the importance of the patient 's 
 perception of the incident , and would suggest that it more strongly predicts ptp than a snapshot 
 of physiological markers .
 
 introduction . 
 posttraumatic psychopathology ( ptp ) describes the spectrum of conditions that can complicate the recovery from commonly occurring musculoskeletal trauma . 
 there is a clear association with the activation of the hypothalamic - pituitary - adrenal axis ( hpaa ) , and we wished to examine the predictive value of proinflammatory markers of the hpaa and of the gaba , which acts as an inhibitory regulator . 
 methods . 
 levels of proinflammatory markers and gaba were measured in 84 patients who had suffered musculoskeletal injuries requiring hospitalisation . 
 ptp was assessed by the use of the general health questionnaire ( ghq ) at presentation and again at two- and six - month reviews . 
 results . 
 significant psychological disturbance was noted in 39% of patients at two months and falling back to 18% by six months . 
 there was no correlation between any of the markers tested at presentation and ptp at follow - up . 
 discussion . 
 the hpaa response to trauma and the development of ptp are extremely complex . 
 it is unlikely that a simple blood assay will provide significant predictive information , while incident specific information and patient perception are of more practical use . 
1. INTRODUCTION
2. MATERIALS AND METHODS
3. RESULTS
4. DISCUSSION