***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: Levels of the stress-sensitive hormone cortisol increase dramatically in the first 30 - 40min after waking , an effect known as the  cortisol awakening response ( CAR ) . There is considerable cross-sectional evidence that psychosocial stress is associated with an increased CAR , and the CAR has been found to be altered in the presence of stress-related diseases , including major depressive disorder ( MDD ) . To date , no prospect i ve longitudinal studies have examined whether individual differences in the CAR serve as a premorbid risk factor for MDD . In a sample of 230 late adolescents , clinical diagnoses of MDD were predicted from the CAR as well as other indicators of basal cortisol functioning gathered 1 year earlier , including : waking cortisol levels , bedtime cortisol levels , the size of the CAR , average cortisol , and the slope of the diurnal cortisol rhythm across the waking day . Age and gender , health and health behaviors , baseline neuroticism , exposure to stressful life events and past episodes of mood and anxiety disorders were included as covariates , to help ensure effects are attributable to the CAR rather than related variables . A higher baseline CAR was associated with a significantly increased risk of developing MDD by follow-up , even when excluding individuals with baseline MDD . No other baseline cortisol measures were significant prospect i ve predictors of MDD . In summary , the  CAR  is a significant prospect i ve risk factor for the development of MDD in young adults , providing some support for the possibility that a heightened CAR may play a role in the etiology of major depressive disorder IMPORTANCE This is the first study to date to examine volumetric alterations in the anterior insula ( AI ) as a potential biomarker for the course of childhood major depressive disorder ( MDD ) . OBJECTIVES To examine whether children with a history of preschool-onset ( PO ) MDD show reduced AI volume , whether a specific symptom of PO MDD ( pathological guilt ) is related to AI volume reduction ( given the known relationship between AI and guilt processing ) , and whether AI volumes predict subsequent likelihood of having an episode of MDD . DESIGN , SETTING , AND PARTICIPANTS In a prospect i ve longitudinal study , 306 children ( age range , 3.00 - 5.11 years ) and caregivers completed DSM diagnostic assessment s at 6 annual time points during 10 years as part of the Preschool Depression Study .  Magnetic resonance imaging was completed on a subset of 145 school-age children ( age range , 6.11 - 12.11 years ) . MAIN OUTCOMES AND MEASURES Whole-brain-adjusted AI volume measured using magnetic resonance imaging at school age and children 's diagnosis of MDD any time after their imaging . RESULTS Compared with children without a history of PO MDD , school-age children previously diagnosed as having PO MDD had smaller left and right AI volumes ( Wilks Λ = 0.94 , F2,124 = 3.37 , P = .04 , Cohen d = 0.23 ) . However , the effect of PO MDD on reduced AI volumes was better explained by children 's experience of pathological guilt during preschool ( Λ = 0.91 , F2,120 = 6.17 , P = .003 , d = .30 ) . When covarying for children 's lifetime history of MDD episodes , their experience of pathological guilt during preschool , as well as their sex and age at the time of imaging , schoolchildren 's right-side AI volume was a significant predictor of being diagnosed as having an MDD episode after imaging ( odds ratio , 0.96 ; 95 % CI , 0.01 - 0.75 ; P = .03 ) . CONCLUSIONS AND RELEVANCE These results provide evidence that structural abnormalities in AI volume are related to the neurobiology of depressive disorders starting in early childhood . The present findings are consistent with mounting research in adult MDD suggesting that insula function and structure may be a target biomarker for major depression BACKGROUND There has been increasing evidence that chronic low- grade inflammation is associated with mood disorders . However , the findings have been inconsistent because of heterogeneity across studies and method ological limitations . Our aim is to prospect ively evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6 , tumor necrosis factor (TNF)-α and high sensitivity C-reactive protein ( hsCRP ) with mood disorders . METHODS The sample consisted of 3118 participants ( 53.7 % women ; mean age : 51.0 , s.d . 8.8 years ) , r and omly selected from the general population , who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up ( mean follow-up duration = 5.5 years , s.d . 0.6 ) . Current and remitted mood disorders including bipolar and major depressive disorders ( MDD ) and its subtypes ( atypical , melancholic , combined atypical and melancholic , and unspecified ) were based on semi-structured diagnostic interviews . Inflammatory biomarkers were analyzed in fasting blood sample s. Associations were tested by multiple linear and logistic regression models . RESULTS Current combined MDD [ β = 0.29 , 95 % confidence interval ( CI ) 0.03 - 0.55 ] and current atypical MDD ( β = 0.32 , 95 % CI 0.10 - 0.55 ) at baseline were associated with increased levels of hsCRP at follow-up . There was little evidence for inflammation markers at baseline predicting mood disorders at follow-up . CONCLUSIONS The prospect i ve unidirectional association between current MDD subtype with atypical features and hsCRP levels at follow-up suggests that inflammation may be a consequence of this condition . The role of inflammation , particularly hsCRP that is critically involved in cardiovascular diseases , warrants further study . Future research that examines potential influences of medications on inflammatory processes is indicated We assessed the length and the quality of remission of 13 unipolar endogenous depressed patients , DST non-suppressors before treatment , in a 2-year prospect i ve study . During this period , we recorded stressful life events . Persistent dexamethasone non-suppression , after treatment and complete clinical recovery , correlated highly with early clinical relapse . All six non-normalizers but only one normalizer were rehospitalized within the following 2 years for a major depressive relapse . Persistent  DST non-suppression was unrelated to any impact of drug discontinuation , the occurrence of stressful life events or the length of illness-free intervals in the patient 's prior course of illness . Persistent  DST non-suppression appears to have significant prognostic value Background Major depression and bipolar disorders aggregates in families and are linked with a wide range of neurobiological abnormalities including cortical gray matter ( GM ) alterations . Prospect i ve studies of individuals at familial risk may expose the neural mechanisms underlying risk transmission . Methods We used voxel based morphometry to investigate changes in regional GM brain volume , over a seven-year period , in 37 initially healthy individuals having a mono- or di-zygotic twin diagnosed with major depression or bipolar disorder ( high-risk group ; mean age 41.6 yrs . ) as compared to 36 individuals with no history of affective disorders in the index twin and first-degree relatives ( low-risk group ; mean age 38.5 yrs . ) . Results Groups did not differ in regional GM volume changes over time . However , independent of time , high-risk twins had significantly greater GM volumes in bilateral dorsal anterior cingulate , inferior frontal gyrus and temporoparietal regions as compared to low-risk twins . Further , individuals who developed an affective disorder at follow-up ( n = 12 ) , had relatively the largest GM volumes , both at baseline and follow-up , in the right dorsal anterior cingulate cortex and right inferior frontal cortex compared to high- and low-risk twins who remained well at follow-up . Conclusion This pattern of apparently stable grater regional GM volume may constitute a neural marker of an increased risk for developing an affective disorder in individuals at familial risk Prospect i ve studies have shown during the years preceding and following menopause , also known as “ menopause transition ” , that midlife women are at higher risk for developing first-onset major depressive disorder ( MDD ) . The biological factors associated with risk and resilience in this population are , however , largely unknown . Considering the growing body of evidence suggesting that inflammation , oxidative stress , and brain-derived neurotrophic factor ( BDNF ) are associated with the pathophysiology of MDD , we investigated serum levels of protein carbonyl , lipid peroxidation ( thiobarbituric acid reactive substances — TBARS ) , thiol group content , BDNF , 3-nitrotyrosine , and heat shock protein 70 ( HSP70 ) in a longitudinal cohort of first-onset MDD . One hundred and forty-eight women from the Harvard Study of Moods and Cycles , a prospect i ve study of midlife women monitored throughout the transition to menopause , were studied . Within- and between-groups analyses of these peripheral markers were conducted in 37 women who developed and 111 women that did not develop MDD during the 3-year follow-up period . In women who developed MDD , HSP70 and 3-nitrotyrosine were elevated at baseline , whereas TBARS were elevated 6 months prior to development of MDD , as compared to those who did not develop MDD . Within-group analyses showed that HSP70 , 3-nitrotyrosine , and BDNF decreased over time , whereas protein carbonyl was elevated only at 12 months prior to development of MDD . In women who did not develop MDD , HSP70 and thiol decreased over time . The development of MDD in midlife women may be associated with a systemic cascade of pro-oxidative and pro-inflammatory events including increased HSP70 , 3-nitrotyrosine , protein carbonyl , and lipid peroxidation and decreased BDNF BACKGROUND Although there is cross-sectional evidence that changes in the immune system contribute to the pathophysiology of depression , longitudinal data capable of elucidating cause and effect relationships are lacking . AIMS We aim ed to determine whether sub clinical systemic inflammation , as measured by serum high-sensitivity C-reactive protein ( hsCRP ) concentration , is associated with an increased risk of de novo major depressive disorder . METHOD Major depressive disorder was diagnosed using a clinical interview ( SCID-I/NP ) . This is a retrospective cohort study ; from a population -based sample of 1494 r and omly selected women recruited at baseline during the period 1994 - 7 , 822 were followed for a decade and provided measures of both exposure and outcome . Of these women , 644 ( aged 20 - 84 years ) had no prior history of depression at baseline and were eligible for analysis . RESULTS During 5827 person-years of follow-up , 48 cases of de novo major depressive disorder were identified . The hazard ratio ( HR ) for depression increased by 44 % for each st and ard deviation increase in log-transformed hsCRP ( ln-hsCRP ) ( HR = 1.44 , 95 % CI 1.04 - 1.99 ) , after adjusting for weight , smoking and use of non-steroidal anti-inflammatory drugs . Further adjustment for other lifestyle factors , medications and comorbidity failed to explain the observed increased risk for depression . CONCLUSIONS Serum hsCRP is an independent risk marker for de novo major depressive disorder in women . This supports an aetiological role for inflammatory activity in the pathophysiology of depression The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene ( 5-HTTLPR ) and depression is currently unknown . We therefore investigated whether variation in hippocampus , amygdala , orbitofrontal cortex ( OFC ) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (  MDD  ) between age 13–19 years , in a longitudinal study of 174 adolescents ( 48 % males ) . Increasing copies of S-alleles were found to predict smaller left hippocampal volume , which in turn was associated with increased risk of experiencing a first onset of MDD . Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes , although neither left nor right medial OFC volumes were prospect ively associated with a first episode of MDD during adolescence . The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness . 5-HTTLPR genotype may also impact upon other regions of the brain , such as the OFC , but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence BACKGROUND Tryptophan depletion ( TD ) reduces brain serotonin and may induce acute depressive symptomatology , especially among those with a history of Major Depression . Depressive response to TD among euthymic patients with a history of depression also predicts future depression . Better prediction might result by assessing a putative endophenotype for depressive risk , 
    Output:
    
Only cortisol ( N = 19 , OR = 1.294 , p = 0.024 ) showed a predictive effect on onset/relapse/recurrence of MDD , but not on time until MDD onset/relapse/recurrence .
Thus , there is a lack of evidence for leading biological theories for onset and maintenance of depression .
Only cortisol was identified as potential predictor for MDD , but results are influenced by the disease state .