***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The rationale for treating psychotic major depression with glucocorticoid receptor ( GR ) antagonists is review ed . Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day , double-blind , placebo-controlled crossover study . All the patients completed the protocol and adverse effects were not observed or reported . All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone , and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores . Little , if any , improvement was seen with placebo . These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study , perhaps using higher doses or more treatment days , seems warranted OBJECTIVE To assess the relationships between  shy-inhibited temperament in childhood and anxiety problems in early adolescence using a prospect i ve , longitudinal data set from a large community sample . METHOD Relationships between shyness ratings on age-appropriate  temperament scales  and anxiety problems were analyzed , looking both forward and backward in time from infancy to adolescence . RESULTS Forty-two percent of children rated as shy on 6 or more occasions over 8 surveys in childhood had anxiety problems in adolescence , compared with 11 % who were never shy . Persistence of shyness and its presence in middle childhood increased risk for anxiety . A highly reactive temperament added to shyness did not increase the risk for anxiety . Few children with an anxiety diagnosis in early adolescence had a history of shyness . CONCLUSIONS Prediction from childhood shyness to adolescent anxiety disorder is modest but clinical ly meaningful in a community sample . However , most shy children did not develop an anxiety disorder and most adolescents with anxiety disorders had not been especially shy BACKGROUND Recent evidence has suggested that the short allele of the serotonin transporter ( 5-HTT ) gene-linked polymorphic region ( 5-HTTLPR of the human serotonin gene [ SLC6A4 ] ) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity . We report an investigation design ed to replicate this finding . METHODS Data were available from a non- clinical sample of 4,175 adult men and women , ages 41 - 80 years , selected from participants in the European Prospect i ve Investigation into Cancer and Nutrition in Norfolk ( EPIC-Norfolk , United Kingdom ) study . Evidence of past-year prevalent episodic major depressive disorder ( MDD ) , defined by restricted DSM-IV diagnostic criteria , was assessed through question naire . Adverse experiences in childhood and in adulthood ( during the five years preceding assessment ) were also assessed through self-report . The 5-HTTLPR variant was genotyped according to published protocol s. RESULTS One-year prevalent MDD criteria were met by 298 study participants . The experience of social adversity ( both in childhood and adulthood ) was strongly associated with increased rates of past-year prevalent MDD . No gene by environment ( GxE ) interactions between the 5-HTTLPR genotype , social adversity , and MDD were observed . CONCLUSIONS This study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype , social adversity , and depression One of the major neurobiological alterations in depressive disorders consists in a disturbed regulation of the hypothalamic-pituitary-adrenocortical ( HPA ) system . This is reflected by a pathological increase in the adrenocorticotropin ( ACTH ) and cortisol release after pretreatment with 1.5 mg dexamethasone ( DEX ) the previous night and a challenge with 100 μg corticotropin-releasing hormone ( CRH ) the next day . The changes evoked by this combined DEX-CRH test recede partially with an improvement of the psychopathological symptoms of depressed patients . It is still unclear , however , whether this long-lasting disturbance of the HPA system is due to acquired changes in the acute illness or whether it plays a causal role and could be considered as a trait or vulnerability marker for depression . In a previous study we have examined the HPA function of healthy prob and s with a high genetic load for affective disorders . We found that this group of high-risk prob and s ( HRPs ) showed abnormal DEX-CRH test results with a cortisol release that was between that of a control group and a group of patients with depression . In a follow-up study we now reexamined 14 of the 47 HRPs about 4 years after the index investigation and found surprisingly constant  DEX-CRH test results , so that one of the requirements for a vulnerability marker is fulfilled BACKGROUND Major depressive disorder ( MDD ) is often complicated by anxiety symptoms , and anxiety disorders occur in approximately 30 % of mood cases . This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal ( HPA ) axis response to stress in patients with MDD . METHODS Untreated subjects with pure MDD ( n = 15 ) , MDD with comorbid anxiety disorders ( n = 18 ) , and pure anxiety disorders ( n = 15 ) were recruited by advertising . Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis ( n = 48 ) . All subjects underwent a social stressor , the Trier Social Stress Test ( TSST ) , and blood was collected for adrenocorticotropic hormone ( ACTH ) and cortisol assay . RESULTS When all depressed patients ( n = 33 ) were compared with their matched control subjects ( n = 33 ) , they showed a significantly greater ACTH response to the stressor ; however , this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders . A similar but nonsignificant effect was observed in the cortisol response .  Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST . All patient groups showed similar levels of TSST-induced anxiety . CONCLUSIONS Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression Rationale Patients with major depression show hypothalamic – pituitary – adrenal ( HPA ) axis hyperactivity , but the mechanisms underlying this abnormality are still unclear . Objectives We have compared two synthetic glucorticoids , dexamethasone and prednisolone , in their ability to suppress the hypothalamic – pituitary – adrenal ( HPA ) axis in depressed patients .  Dexamethasone probes glucocorticoid receptor ( GR ) function , while prednisolone probes both GR and mineralocorticoid receptor ( MR ) function . Material s and methods We used a single-blind , repeated-measure design . We administered placebo , prednisolone ( 5 mg ) or dexamethasone ( 0.5 mg ) , at 22:00 , to 18 severe , treatment-resistant depressed in patients ( 15 of them with a history of childhood trauma ) and 14 healthy volunteers . On the following days , we collected salivary cortisol from 9:00 to 22:00 . Results Depressed patients had higher salivary cortisol levels compared with controls , at baseline and after both prednisolone and dexamethasone ( p<0.001 ) . Consistent with previous studies , depressed in patients showed impaired suppression by dexamethasone :  based on the analysis of the areas under the curve ( AUCs ) , suppression by  dexamethasone ( 0.5 mg ) was −85 % in controls vs −46 % in depressed patients ( p=0.018 ) . However , the same depressed patients showed normal suppression  by prednisolone ( 5 mg ) : suppression was −41 % in controls and −36 % in depressed patients ( p=0.6 ) . Conclusions We suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients Early Life Stress ( ELS ) has been associated with a range of adverse outcomes in adults , including abnormalities in electrical brain activity [ 1 ] , personality dimensions [ 40 ] , increased vulnerability to substance abuse and depression [ 14 ] . The present study seeks to quantify these proposed effects in a large sample of non- clinical subjects . Data for the study was obtained from The Brain Re source International Data base ( six laboratories : two in USA , two in Europe , two in Australia ) . This study analyzed  scalp electrophysiological data ( EEG eyes open , closed and target auditory oddball data ) and personality ( NEO-FFI ) , history of addictive substance use and ELS ) data that was acquired from 740 healthy volunteers . The ELS measures were collected via a self-report measure and covered a broad range of events from childhood sexual and physical abuse , to first-h and experience of traumatizing accidents and sustained domestic conflict [ 41 ] . Analysis of covariance , controlling for age and gender , compared EEG data from subjects exposed to ELS with those who were unexposed . ELS was associated with significantly decreased power across the EEG spectrum . The between group differences were strongest in the eyes closed paradigm , where subjects who experienced ELS showed significantly reduced beta ( F1,405=12.37 , p=.000 ) , theta ( F1,405=20.48 , p=.000 ) , alpha ( F1,405=9.65 , p=.002 ) and delta power ( F1,450=36.22 , p=.000 ) . ELS exposed subjects also showed a significantly higher alpha peak frequency ( F1,405=6.39 , p=.012 ) in the eyes closed paradigm . Analysis of covariance on ERP components revealed that subjects who experienced ELS had significantly decreased N2 amplitude ( F1,405=7.73 , p=.006 ) . Analyses of variance conducted on measures of personality revealed that subjects who experienced ELS had significantly higher levels of neuroticism ( F1,264=13.39 , p=.000 ) and openness ( F1,264=17.11 , p=.000 ) , but lower levels of conscientiousness , than controls ( F1,264=4.08 , p=.044 ) . The number of ELS events experienced was shown to be a significant predictor of scores on the DASS question naire [ 27 ] , which rates subjects on symptoms of depression ( F3,688=16.44 , p=.000 , R2=.07 ) , anxiety ( F3,688=14.32 , p=.000 , R2=.06 ) and stress ( F3,688=20.02 , p=.000 , R2=.08 ) . Each additional early life stressor was associated with an increase in these scores independent of age , gender and the type of stressor . Furthermore , the number of ELS experiences among smokers was also found to be a positive predictor of the nicotine dependency score ( Faegstrom Test For Nicotine Dependence , [ 19 ] ) ( F3,104=10.99 , p=.000 , R2=.24 ) , independent of age , gender and type of stressor . In conclusion , we highlight the impact of a history of ELS showed significant effects on brain function ( EEG and ERP activity ) , personality dimensions and nicotine dependence Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene ( SLC6A4 ) in the etiology of anxiety-related traits and depressive disorders . Recently , a significant gene – environment interaction was found between life stressors , the short allele of the SLC6A4 polymorphism and depression . The aim of the present study was to investigate if such a gene – environment interaction could be replicated within a different population with a different risk structure . A total of 1005 subjects from a general population sample ( Study of Health in Pomerania ) were genotyped .  Mental and physical distress were assessed on 38 items of the modified complaint scale ( BL-38 ) . The interaction between the SLC6A4 genotype , social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA . There was no independent association of genotype with mental and physical distress . However , significant interactions between genotype , unemployment and chronic diseases ( F=6.6 ; df=3 , 671 ; P<0.001 ) were found in females but not in males . The genotype explained 2 % of the total variance of the BL-38 score and 9.1 % of the explained variance . The results partly confirm previous findings of a significant gene – environment interaction of the short allele , indicating a higher mental vulnerability to social stressors and chronic diseases . The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies The dexamethasone suppression test ( DST ) , frequently abnormal in mood disorder patients , is considered to measure glucocorticoid receptor-mediated negative feedback . We examined the hypothesis that the , apparently more sensitive , dexamethasone/corticotrophin-releasing-hormone ( dex/CRH ) test unveils subtle hypothalamic-pituitary-adrenal axis disturbance not detected by the DST in 82 patients with mood disorders and 28 controls . There was a close correlation between the cortisol responses on the two tests ( r(s)=0.73 , p<0.0005 ) . However , ROC analysis revealed that the dex/CRH test had better diagnostic performance than the 
    Output:
    
RESULTS Depression is linked to hypercortisolemia in many patients , but not all patients present these hypothalamic-pituitary-adrenal axis dysfunction .
The dexamethasone suppression test is not the most accurate test to measure the hypothalamic-pituitary-adrenal axis function , and its use in the first studies published probably jeopardized the results .
Hypercortisolemia frequently occurs in patients with severe depression , melancholic , either psychotic or nonpsychotic type ; it is linked to the presence of a polymorphism in the promoter of the serotonin transporter gene , with a history of childhood abuse or neglect , or other significant stressful experiences like the loss of a parent during childhood and temperament leading to alterations in the response to stress .
The alterations of the hypothalamic-pituitary-adrenal axis depend on many factors like severity and type of depression , genotype , history of exposure to stress , temperament , and probably resilience .
All these factors together result in an endophenotype thought to be prone to depression