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Original Article |

Cortisol and Catecholamines in Posttraumatic Stress Disorder An Epidemiologic Community Study FREE

Elizabeth A. Young, MD; Naomi Breslau, PhD
[+] Author Affiliations

From the Department of Psychiatry and Mental Health Research Institute,University of Michigan, Ann Arbor (Dr Young), and the Department of Epidemiology,College of Human Medicine, Michigan State University, East Lansing (Dr Breslau).


Arch Gen Psychiatry. 2004;61(4):394-401. doi:10.1001/archpsyc.61.4.394.
Text Size: A A A
Published online

Background  Prior research has connected posttraumatic stress disorder (PTSD) to increased levels of catecholamines. However, studies of cortisol levels have produced mixed results.

Objective  To examine urinary catecholamine and cortisol levels in individuals with PTSD in a community sample.

Design  A representative cohort of young adult community residents, assessed periodically during a 10-year period for exposure to trauma and PTSD, was used to select a subset for urine collection studies conducted in a sleep laboratory across 2 consecutive nights and the intermediate day.

Setting  The sample of young adults was randomly selected from a large health maintenance organization and is representative of the geographic area except for the extremes of the socioeconomic status range.

Participants  A subsample was selected from the 10-year follow-up cohort (n = 913; 91.1% of the initial sample). Eligibility criteria were: (1) persons exposed to trauma during the preceding 5 years, (2) other individuals who met PTSD criteria, and (3) a random preselected subsample. Of 439 eligible individuals, 292 (66.5%) participated, including 69 with lifetime PTSD.

Main Outcome Measures  Measures of cortisol and catecholamine levels in urine.

Results  The lifetime PTSD group demonstrated significantly higher catecholamine levels than the group exposed to trauma without PTSD and the nonexposed group. Individuals exposed to trauma without PTSD demonstrated significantly lower urine catecholamine levels than the nonexposed and the PTSD groups. Mean cortisol levels did not differ across groups. When analyzed by comorbidity with major depressive disorder (MDD), the PTSD-only group did not differ in cortisol levels from the groups with neither PTSD nor MDD. Women with MDD plus PTSD demonstrated significantly higher cortisol levels than women with neither disorder or with either disorder alone.

Conclusions  Trauma per se does not lead to sustained increases in cortisol or catecholamine levels. Posttraumatic stress disorder is associated with higher catecholamine levels. In contrast, persons with PTSD had neither an increase nor a decrease in mean urinary cortisol levels. Women with PTSD and comorbid MDD had higher cortisol levels.

Figures in this Article

Stress has been viewed as a precipitant for a number of psychiatricdiseases. A unique form of stress, psychologic trauma is viewed in the DSM as linked in an essential way with a specific syndrome,that of posttraumatic stress disorder (PTSD).1 Ithas been proposed that PTSD demonstrates a paradoxical cortisol profile incomparison with the expected response to stress, with evidence of low basalcortisol levels in urine and plasma and enhanced negative feedback to dexamethasone.24 The low cortisol levelswere accompanied by increased catecholamine secretion in urine, leading tothe claim that there is a disconnect between basal cortisol and catecholaminein individuals with PTSD.2,3 Whilethere was some (but incomplete5) consistencyamong early studies with regards to the urinary cortisol findings in malecombat veterans,3 recent reports suggest thateven these findings are uncertain.6 The generalizabilityof these findings to the general community, where PTSD occurs predominantlyin women, is questionable.

Studies in women with PTSD, generally recruited by advertising, havefocused on childhood sexual abuse, which may not reflect the effects of traumain adulthood. The results of these studies are inconsistent, with one studysuggesting increased cortisol levels,7 andanother, low cortisol levels,8 while stillanother, no difference from control subjects.9 Studiesof individuals who have experienced natural disasters have focused on symptomsof anxiety or distress but not on DSM-defined PTSD.1014 Anexception is a study by Maes et al,13 whichreported a higher mean urinary free cortisol (UFC) level in subjects withPTSD following natural disasters. However, in that study, subjects were volunteersand a comparison with persons exposed to trauma without PTSD was not included.Studies of individuals who have experienced disasters1014 havereported elevated mean cortisol levels in urine, saliva, or plasma. Boscarino4 studied a representative sample of male veterans,but there have been no reports from representative community samples on basalcortisol levels in individuals exposed to trauma with PTSD.

Three studies have examined 24-hour urinary catecholamine levels inveterans with PTSD, yielding conflicting results. Kosten et al15 andYehuda et al16 reported an increase in urinaryepinephrine and norepinephrine levels in veterans with PTSD, compared withpatients with other psychiatric disorders15 orhealthy control subjects.16 Pittman and Orr5 reported no difference in catecholamine levels betweencombat veterans with PTSD and combat veterans without PTSD. The nature ofthe control group might be critical because exposure to trauma may alter urinaryepinephrine and norepinephrine levels. This possibility is supported by evidenceof increased urinary norepinephrine levels in a civilian population exposedto the Three Mile Island nuclear accident, compared with individuals residing80 miles away17 and increased urinary catecholaminelevels in American hostages shortly after they were freed from Iran.18 Urinary catecholamine levels in persons exposed totrauma with and without PTSD compared with nonexposed persons have not beenexamined.

Because PTSD is highly comorbid with major depressive disorder (MDD),19,20 the effect of MDD, which shows hypothalamic-pituitary-adrenalaxis activation, on the neuroendocrine picture of PTSD is an important question.Results have been inconsistent. In earlier studies, the presence of comorbidMDD did not appear to alter the low cortisol findings in PTSD.3 Incontrast, a recent study reported that MDD and PTSD influenced 24-hour UFClevels in opposite directions, with no interaction, so that the comorbid groupshowed an intermediate cortisol excretion.21

In this report, we examine urinary catecholamine and cortisol levelsin relation to PTSD and exposure to traumatic events. The study was conductedin the context of an ongoing longitudinal community study in the Detroit,Mich, metropolitan area. We present data on 24-hour UFC and catecholaminelevels, collected from a subset of the sample in a sleep research center.The key questions addressed concern the association of exposure to traumaand PTSD with urinary cortisol and catecholamine levels and the role of comorbidMDD in the relationship of PTSD with these hormonal measures.

SAMPLE AND PROCEDURES

The neurobiologic investigation was nested in a large-scale longitudinalcommunity study of young adults. The study was described previously.19,22 In brief, a sample of 1200 individualswas randomly selected from all 21- to 30-year-old members of a large healthmaintenance organization in southeast Michigan. The membership of the healthmaintenance organization was representative of the population of the geographicarea as depicted in the 1990 US census, with the exception of the extremesof the socioeconomic status range. Personal interviews were conducted in 1989with 1007 members (84%) of the sample. Follow-up personal interviews wereconducted in 1992, 1994, and 1999 through 2001. In each wave, more than 90%follow-up completion was achieved. In the 10-year follow-up in 1999 through2001, 913 members (91.1%) of the initial sample completed interviews. Biologicmeasures were collected on a subset of these respondents.

The following persons from among those who completed the 10-year follow-upwere eligible for the sleep and urine collection study: (1) all persons whowere exposed to traumatic events in the 5-year interval between 1994 and thelast assessment, (2) other individuals (not from group 1) who met PTSD criteriain previous assessments, and (3) other individuals (not from groups 1 or 2)from a randomly preselected subsample of the total sample. Persons who movedaway from the Detroit metropolitan area were not eligible. Persons with recentsubstance abuse, use of psychotropic medications, and smokers who reportedthat they could not abstain for the 8-hour sleep period were not eligiblefor this study. However, in this general population study, no subjects wereexcluded based on these criteria. Eligible respondents were invited to spend2 consecutive nights and the intermediate day at the Sleep Center of HenryFord Hospital, Detroit. Bedtimes were determined by matching the respondents'regular bedtimes at home. Respondents stayed in bed for 8 hours each night.Of a total 439 eligible individuals, 292 (66.5%) participated.

Urine collection during the 32-hour stay at the sleep center was madein 4 parts, with each covering an 8-hour period. The first collection coveredthe first night, the second collection covered 8 hours from rising to earlyafternoon, the third collection covered the late afternoon and evening, andthe fourth, the second night. The procedure provided total 24-hour measuresand had the added capacity to provide separate timed measures that capturedthe morning surge (in the 8 AM hour) and the evening low (inthe 8 PM hour) for an examination of effects related to diurnalphase. At the time of collection, urine was split into 2 aliquots, with theurine for catecholamine level testing acidified with 7 mL of 6 N hydrochloricacid as a preservative, and the urine for cortisol level testing was frozenwithout further processing. Data on 13 persons were deleted because of lowcreatinine levels, defined as less than 1 g/24 h, leaving a sample of 275persons for the analysis.

ASCERTAINING PTSD

The National Institute of Mental Health—Diagnostic Interview Schedule(NIMH-DIS)23 for DSM-III-R was used to diagnose psychiatric disorders. The baseline interviewin 1989 inquired about lifetime history of disorders, and each follow-up assessmentinquired about disorders occurring during the interval period since the previousassessment. The diagnosis of PTSD in DSM-III-R requiresexposure to a qualifying traumatic event and the presence of PTSD criterionsymptoms that are linked to the traumatic event. Two earlier studies reportedhigh concordance between NIHM-DIS–diagnosed PTSD and independent clinicalreinterviews.20,24 The latter24 used the clinician-administered PTSD scale25,26 and reported sensitivity of 76% andspecificity of 97%.24

HORMONE ASSAYS

We assayed UFC levels with DPC Coat-a-Count cortisol kits (DPC, LosAngeles, Calif). Urine was extracted using dichloromethane following the instructionsfrom the kit. Interassay variation for cortisol levels was 6%. Urine catecholaminelevels were assayed by high-pressure liquid chromatography using a commerciallaboratory (Warde Medical Laboratories, Ann Arbor, Mich).

STATISTICAL ANALYSIS

All statistical analyses were performed on log-transformed data, whichnormalized distributions of the hormone measures. Comparisons of nonsmokerswho had never smoked (n = 156), current smokers (n = 58), and past smokers(n = 61) showed no significant differences in total 24-hour UFC levels (P = .44). We found no significant effect of oral contraceptives(n = 84) on 24-hour UFC levels (P = .77).

Two series of analyses were conducted for cortisol, epinephrine, norepinephrine,and dopamine levels. The first consisted of comparisons across 3 groups: (1)PTSD (n = 69; 16 men, 53 women, 10 of whom met criteria for current PTSD atthe time of the interview), (2) exposed to trauma without PTSD (n = 105; 38men, 67 women), and (3) no exposure to trauma (n = 101; 40 men, 61 women).This provided 2 control groups with which PTSD could be compared, includinga group of persons who were never exposed to trauma, according to the baselineinterview and the 3 follow-up assessments. The second series examined comorbidityof PTSD with MDD and consisted of comparisons across 4 groups defined by historyof PTSD and MDD: (1) neither disorder (n = 139; 61 men, 78 women), (2) MDDonly (n = 67; 17 men, 50 women), (3) PTSD only (n = 23; 5 men, 18 women),and (4) both disorders (n = 46; 11 men, 35 women). All persons in the MDDgroup had reported at least 1 exposure in their lifetime, either precedingor following MDD onset. In each series of analyses and for each hormone, wefirst examined total 24-hour urine hormone levels and then we examined thenight, morning (AM), and evening (PM) urine hormone levels, using an analyticalapproach that took into account diurnal variation.

Correlation of the first and second night cortisol levels was 0.43.The correlations of dopamine, epinephrine, and norepinephrine levels werehigher, 0.67, 0.62, and 0.65, respectively. Differences between the 2 nightsoverall or across diagnostic groups were not significant, as tested by paired t tests, and consequently, hormone values of the 2 nightswere averaged. Averaging across 2 nights yields a more reliable measure. Analysisof the 4 time periods, with each night treated separately, did not alter theresults. For the total 24-hour measures, we combined the average of the 2nights with the 8-hour AM and the 8-hour PM values.

We tested whether current PTSD or MDD cases (ie, with symptoms continuingin the preceding 12 months) differed from remitted cases but found no significantdifferences in cortisol or catecholamine levels. We therefore used lifetimedisorders in the analyses. The neither-disorder group comprised 38 persons(27.3%) who were exposed to trauma and 101 who were never exposed. Comparisonof these 2 subgroups in the neither-disorder group revealed significant differencesonly in dopamine levels, with persons who were exposed to trauma having alower mean value than those never exposed. In a separate analysis, we used2 no-disorder groups, classified by the presence vs the absence of exposureto trauma. The analysis with 2 no-disorder groups yielded the same resultsas the 4-group analysis.

Analysis of variance (ANOVA) was used to compare total 24-hour urinarymeasures across groups. Significant results were followed up with post hocpaired comparisons using the Tukey test. We tested the effects of sex, race,education, and interactions between group membership and these variables.When a significant covariate or an interaction was detected (using α= .05), models that included these variables were displayed. Sample size wasslightly smaller in the total 24-hour analyses because persons without 3 consecutive8-hour urine collections (n = 19) were excluded.

Multiple regression analysis was used, applying generalized estimatingequations (GEEs),2729 totest and estimate associations between group membership and each of the 4hormones across 3 time periods of the 24-hour diurnal cycle—night, AM,and PM. The GEE approach permits simultaneous modeling of the relationshipbetween group classification and hormone measures at the 3 time periods. TheGEE approach takes into account correlations within persons across the multiplemeasures and uses information on persons with incomplete data. Interactionterms were used to examine whether differences across groups varied by timeand by covariates (eg, sex). No significant interactions between time andgroup membership were detected; post hoc tests of differences by group membershipacross night, AM, and PM were not performed. The estimated log-transformedmeans in the GEE results were averaged across the night, AM, and PM measures.In the analyses of cortisol levels, we found a significant interaction betweendiagnostic groups and sex. The final model for the cortisol analysis is illustratedin the equation

Y = α + β1 (group) + β2 (sex) + β3 (group × sex) + β4 (time)

where log cortisol measures at 3 times (night, AM, and PM) are the outcomes (Y).

No significant differences in the biologic subsample were observed insex, race, age, education, and substance use disorders in comparison withthe entire sample (Table 1). The4 diagnostic groups defined by history of PTSD and MDD did not differ on thesecharacteristics from the total sample.

Table Graphic Jump LocationTable 1. Sample Characteristics: Sex, Race, Age, Lifetime Prevalenceof Alcohol and Drug Use Disorders*
URINARY CORTISOL LEVELS: EFFECTS OF TRAUMA EXPOSURE AND PTSD

The raw mean ± SD of total 24-hour urinary cortisol levels forthe entire sample with complete data (n = 256) was 52.0 ± 32.2 µg/24h (143.5 ± 88.8 nmol/d). The ANOVA of total 24-hour urinary cortisollevels in persons with PTSD, exposure to trauma without PTSD, and no exposureto trauma revealed neither a significant group difference nor a sex ×group interaction. The GEE analysis on night, AM, and PM data (n = 275) revealeda significant diurnal variation (P<.001) and asignificant group × sex interaction (P = .04).However, sex-specific analyses detected no significant effects of group membershipin either men (P = .21) or women (P = .09).

We explored the potential effect of type of trauma (assaultive vs nonassaultive)on cortisol levels and found no support for such an effect. We found no supportfor effects of early trauma (≤16 years of age) vs late trauma or historyof prior exposure to trauma vs no prior exposure on cortisol levels. Recencyof exposure (ie, within the preceding year) showed an effect on cortisol levelsin men only, with those who were recently exposed exceeding significantlythose who experienced a trauma more than 1 year ago, as well as those withno trauma exposure in their lifetime.

We explored whether restricting the analysis to current (active) PTSDwould suggest different conclusions. There were no men with current PTSD;thus, the analysis was restricted to women. Current and past PTSD in womendid not differ significantly (P = .46). Log mean± SDs of no exposure to trauma and current PTSD in women were virtuallyidentical, 2.50 ± 0.06 and 2.49 ± 0.18, respectively (P = .97).

URINARY CORTISOL LEVELS: COMORBIDITY WITH MDD

We evaluated the role of comorbidity of PTSD and MDD in total 24-hourUFC levels. Four groups were compared: MDD alone, PTSD alone, PTSD comorbidwith MDD, and neither disorder. The ANOVA revealed a significant group ×sex interaction (P = .02). However, sex-specificmodels revealed a nonsignificant group effect in men (P = .12) and women (P = .07).

The GEE analysis on night, AM, and PM UFC levels revealed a significantdiurnal variation (P<.001) and group × sexinteraction (P = .003). Group effects were significantin women (P = .03) and men (P =.04) (Table 2). In women, thePTSD/MDD comorbid group had significantly higher cortisol levels, comparedwith each of the other 3 groups (ie, MDD alone, PTSD alone, and no disorder).No other comparisons were significant. In men, the MDD group had a significantlyhigher mean cortisol level than the no-disorder and the comorbid PTSD/MDDgroups. No other comparisons were significant. To illustrate the results,data on cortisol levels at night, AM, and PM from these analyses are displayedin Figure 1 and Figure 2.

Table Graphic Jump LocationTable 2. Generalized Estimating Equations Model of Urinary Free CortisolLevels (8 Hour) Controlling for Diurnal Variation (n = 275)*
Place holder to copy figure label and caption
Figure 1.

Urine cortisol excretion levelsin the night, morning (AM), and evening (PM) in women by psychiatric diagnoses.The comorbid posttraumatic stress disorder (PTSD)/major depressive disorder(MDD) group demonstrated significantly elevated urinary free cortisol excretionlevels compared with the other 3 groups; differences in the evening were particularlynoticeable.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Urine cortisol excretion levelsin the night, morning (AM), and evening (PM) in men by psychiatric diagnoses.The major depressive disorder (MDD) group differed significantly from theMDD/posttraumatic stress disorder (PTSD) group and the no-disorder group.

Graphic Jump Location
URINARY CATECHOLAMINE LEVELS: EFFECTS OF PTSD AND TRAUMA EXPOSURE

The sample raw mean ± SD for 24-hour dopamine levels was 381.5± 334.8 µg/24 h; epinephrine, 11.0 ± 9.1 µg/24 h[60.1 ± 49.7 nmol/d]; and norepinephrine, 50.3 ± 8.2 µg/24h [297.3 ± 48.5 nmol/d]. Table 3 presents comparisons of the PTSD, exposed to trauma without PTSD,and no exposure to trauma groups. There were significant effects of groupmembership on the 3 catecholamine levels. The group with PTSD had higher meanlevels of all 3 urinary catecholamines, compared with the exposed to traumawithout PTSD and no exposure groups. (See Table 3 for significant pairwise comparisons.) Pairwise comparisonsalso revealed significant differences between the exposed to trauma withoutPTSD and no exposure groups in dopamine (P = .02)and epinephrine (P = .02) levels, although in theopposite direction from the expected (ie, lower in the exposed to trauma withoutPTSD group than in the no exposure group). Subjects with past vs current PTSDdid not differ significantly on any catecholamine measure (P>.25). The GEE models yielded similar results and, in addition, revealedsignificant diurnal variations (P<.002).

Table Graphic Jump LocationTable 3. Total 24-Hour Dopamine, Epinephrine, and Norepinephrine Levelsin Groups Exposed to Trauma, Not Exposed to Trauma, and With PosttraumaticStress Disorder (PTSD) (n = 256)*
URINARY CATECHOLAMINE LEVELS: COMORBIDITY WITH MDD

Group means of total 24-hour urine dopamine, epinephrine, and norepinephrinelevels across the 4 diagnostic groups are displayed in Table 4. A significant race difference was detected in the analysisof dopamine levels, with African American individuals' levels exceeding thoseof white individuals; the mean ± SEs of dopamine levels in Table 4 are race-adjusted. For all 3 outcomes,there were significant effects of group membership. Pairwise comparisons showedthat, across the 3 catecholamine measures, the comorbid group of PTSD plusMDD had significantly higher means than the groups with neither disorder andwith MDD only. The group with PTSD only also exceeded the groups with neitherdisorder and with MDD on all 3 measures; however, the excess did not alwaysreach significance (Table 4).A consistent finding across the 3 catecholamine measures was the absence ofa significant difference between 2 PTSD groups (ie, the PTSD/MDD comorbidgroup and the PTSD-only group). The GEE analysis yielded similar results and,in addition, detected a significant diurnal variation (P<.002). The data for catecholamine levels across night, AM, andPM are shown in Figure 3, Figure 4, and Figure 5.

Table Graphic Jump LocationTable 4. Total 24-Hour Dopamine, Epinephrine, and Norepinephrine LevelsAcross Diagnostic Groups (n = 256)*
Place holder to copy figure label and caption
Figure 3.

Urine norepinephrine excretionlevels in night, morning (AM), and evening (PM) (men and women) by psychiatricdiagnoses. The groups with posttraumatic stress disorder (PTSD) only and PTSDcomorbid with major depressive disorder (MDD) had significantly higher levelsthan the other 2 groups.

Graphic Jump Location
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Figure 4.

Urine epinephrine excretion levelsin night, morning (AM), and evening (PM) (men and women) by psychiatric diagnoses.The groups with posttraumatic stress disorder (PTSD) only and PTSD comorbidwith major depressive disorder (MDD) had significantly higher levels thanthe other 2 groups.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Urine dopamine excretion levelsin night, morning (AM), and evening (PM) by psychiatric diagnosis (men andwomen). The groups with posttraumatic stress disorder (PTSD) alone and PTSDcomorbid with major depressive disorder (MDD) had significantly higher levelsthan the MDD group, and the PTSD/MDD group had significantly higher levelsthan the group with neither disorder.

Graphic Jump Location
RELATIONSHIP BETWEEN CORTISOL AND CATECHOLAMINE LEVELS

Both urinary cortisol and catecholamine levels are indices of stresshormonal systems, but the extent to which these 2 systems are correlated isunclear. Using Spearman rank correlations, we examined whether there was evidenceof a disconnect between the 2 systems in PTSD and, if observed, whether sucha disconnect was unique to PTSD. We found that in the total sample, dopamine,epinephrine, and norepinephrine are robustly intercorrelated; Spearman rankcorrelations ranged from 0.47 to 0.69, with a mean of 0.60. However, noneof the catecholamine levels had a significant correlation with cortisol levels(ρ = 0.04-0.08). We further examined correlations between catecholamineand cortisol levels within subgroups (ie, exposed to trauma without PTSD,no trauma exposure, PTSD, MDD, and PTSD plus MDD), but, with one exception,correlations were less than 0.15 and not significant. There was a low butsignificant correlation (0.20) between cortisol and epinephrine levels inthe group not exposed to trauma. We conclude there is no evidence of a disconnectbetween cortisol and catecholamine levels as a feature of PTSD.

The results for the 4 diagnostic groups, defined by history of PTSDand MDD, can be summarized as follows: (1) with respect to catecholamine levels,we found significantly higher mean levels of dopamine, epinephrine, and norepinephrinein persons with lifetime PTSD (with and without comorbid MDD), compared withpersons with MDD alone or neither disorder; (2) with respect to cortisol levels,we found no distinct pattern associated with PTSD in either sex and no differencewas detected between past and current PTSD; (3) a finding incidental to thePTSD-cortisol relationship was a significantly higher mean cortisol levelin women with lifetime MDD comorbid with PTSD, compared with women with neitherdisorder or with either disorder alone and a significantly higher mean cortisollevel in men with lifetime MDD alone, compared with men with neither disorderor with both disorders. Our analysis provides no support for the hypothesisthat PTSD is associated with lower UFC levels.3 Personswith PTSD did not show lower UFC levels than persons with no history of traumaor than persons with history of trauma but not of PTSD; neither did they showlower UFC levels than persons with a history of MDD or persons with neitherdisorder

Higher mean catecholamine levels have been reported in anxiety disorders,among them PTSD.15,3032 Thenoradrengergic and dopaminergic systems are implicated in arousal disturbance,31 which is one of the hallmark symptoms of PTSD. Ourfindings of higher catecholamine levels in men and women with lifetime PTSD(alone or comorbid with MDD) are consistent with these reports. They extendthe previous reports to lifetime PTSD in the general population.

Higher mean cortisol levels have been observed in patients with MDDcompared with healthy control subjects.3335 Ourfinding of a higher mean urinary cortisol level in women with lifetime MDDcomorbid with PTSD and in men with lifetime MDD alone is consistent with thesereports. This finding in lifetime MDD is also consistent with a previous reportthat demonstrated higher mean saliva cortisol levels in women with past MDDcompared with women with no history of MDD.36

Our results, taken together, are consistent with neurobiologic modelsof anxiety and MDD, namely, the involvement of the sympathetic nervous systemin anxiety disorders and the involvement of the hypothalamic-pituitary-adrenalaxis in MDD. Evidence of sympathetic nervous system involvement in PTSD wassimilar in both sexes, whereas evidence of hypothalamic-pituitary-adrenalaxis activation in MDD varied by sex. In men, higher mean cortisol levelswere observed in cases with lifetime MDD alone but not in the small numberof cases with MDD comorbid with PTSD. In women, higher mean cortisol levelswere observed in comorbid cases but not in cases with lifetime MDD alone.Our results suggest that in women, MDD alone might be a less severe disorderthan MDD combined with PTSD. Previous studies have reported that MDD comorbidwith anxiety disorders is more severe than "pure" MDD in terms of depressivesymptoms, course of illness, and treatment response.3742 Theinterpretation of the observed sex differences in urinary cortisol levelsis unclear.

Our findings on UFC levels in women with MDD comorbid with PTSD arein agreement with a study by Heim et al,43 whichreported that depressed women with history of early trauma (11 of the 13 metcriteria for PTSD) demonstrated enhanced cortisol secretion in response toa stressor, whereas women with MDD without early trauma showed normal cortisolresponses, compared with healthy control subjects. A report by Rasmusson etal9 of women with childhood abuse and PTSDalso is consistent with these findings. The women with PTSD had either activeor past MDD and showed enhanced cortisol responses to corticotropin-releasingfactor and to corticotropin infusion, as well as a trend toward higher 24-hourUFC levels. A study by Lemieux and Coe7 ofwomen with childhood sexual abuse found higher 24-hour UFC levels in womenwith PTSD than with no PTSD. While the researchers did not report on comorbidMDD, they indicated that 5 of the 11 women with PTSD were taking antidepressants;the possibility that others may have had a history of depression was not ruledout. Our study and these previous studies converge in suggesting that alterationsin hypothalamic-pituitary-adrenal axis, specifically a higher level of UFC,might be observed in women with MDD comorbid with PTSD. These studies highlightthe importance of diagnosing both MDD and PTSD in research focusing on theneurobiology of either disorder.

An effect of exposure to trauma per se on urinary catecholamine levelswas observed in both sexes. However, instead of a stress-like effect (ie,higher levels of these stress hormones), we observed lower levels in the exposedto trauma without PTSD group than the no exposure group. It is possible thatthe long-term adaptation to trauma exposure is associated with lower catecholaminelevels. An alternative explanation is that exposure to trauma segregated individualsinto a susceptible group (PTSD) and a nonsusceptible group (exposed to traumawithout PTSD), who had before differed on baseline catecholamine levels beforeexposure to trauma. The nonexposed group (which showed higher mean catecholaminelevels than the exposed group) might include a subset of persons who havea susceptibility to the PTSD-inducing effects of trauma but have never beenexposed. A further possibility is that the subset of unexposed persons witha susceptibility to PTSD have a higher level of basal catecholamines. Thepresence of these persons would push upward the average level of catecholaminesof the unexposed group as a whole. Evidence that preexisting anxiety disorders,which would be accompanied by increased secretion of catecholamines,30,31 predict PTSD19,44 supportsthis interpretation.

Four limitations in this study are noted. First, the 66.5% participationrate in the biologic studies, although high, considering respondents' burden,limits the generalizability of the results. However, the exceptionally highfollow-up participation in the epidemiological study across multiple assessmentsallows us to evaluate and confirm the representativeness of the biologic sampleon sociodemographic characteristics and history of substance use disorders.Differences on unmeasured variables cannot be ruled out. Second, althoughwe found no difference between current and past PTSD, the small number ofcases with current PTSD limits our ability to examine this question more definitively.Third, the small number of men with PTSD, either "pure" or comorbid with MDD,limits the reliability of our findings in men. The possibility of a sex differencein UFC levels merits further attention.

The fourth limitation is the use of the NIMH-DIS at baseline and acrossall follow-up assessments rather than a clinical assessment. However, theNIMH-DIS has been found to be highly specific but more conservative than aclinician-administered instrument.24 Thus,cases designated as PTSD are "true" cases, although it is possible that somecases of PTSD undetected by the NIMH-DIS were included in the exposed to traumawithout PTSD group. However, the availability of persons who were never exposed,according to baseline and multiple follow-up reassessments, addresses theconcern that any misclassification of cases of PTSD might have obscured potentialdifferences in cortisol levels associated with PTSD. The analyses comparingPTSD with the 2 control groups (exposed to trauma without PTSD and no exposure)showed no significant differences with regards to cortisol levels betweenPTSD and either of these control groups. In the analyses of comorbidity, theneither-disorder group (no PTSD/no MDD) was separated into (1) exposed totrauma without PTSD and (2) no exposure. No differences in cortisol levelswere observed in a comparison that included only the no exposure group asreference from what was reported when the total group with neither disorderwas used.

Important strengths of the study deserve mention. The most importantstrength is the representative community sample from which the data came.Previous studies on the neurobiology of PTSD in nonveteran populations haveused clinical samples or samples of volunteers, which undoubtedly are biasedin terms of severity of psychopathology, other clinical features, and socialfactors that influence self-selection to treatment and clinical research.In sharp contrast, our neurobiologic study is nested in a longitudinal epidemiologicstudy, with multiple psychiatric assessments during a 10-year period and anexceptionally high follow-up completion rate of the initial cohort. A comparisonof the total sample with the subset on whom data on 32-hour urine samplesare available indicates that we have been successful in achieving a representativesample of the total cohort. The study thus offers an opportunity for an unbiasedevaluation of neurobiologic factors in PTSD. The large sample size is anotherimportant strength. We also introduced a methodologic advance over previousstudies that used total 24-hour urinary hormone secretion levels. It involvedcollecting urine in 8-hour increments linked to the wake-sleep cycle. Thismethod revealed an overall circadian rhythm in cortisol and catecholaminelevels. By taking into account the data from night, AM, and PM, GEE analysisoffered enhanced statistical power for detecting differences across diagnosticgroups, which were obscured in the analysis of total 24-hour UFC levels.

Corresponding author: Elizabeth A. Young, MD, Mental Health ResearchInstitute, University of Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI 48109-0720(e-mail: eayoung@umich.edu).

Submitted for publication February 3, 2003; final revision receivedNovember 10, 2003; accepted November 24, 2003.

This study was supported by grants MH 48802 (Dr Breslau) and MH 01931(Dr Young) from the National Institutes of Health, Bethesda, Md.

We would like to acknowledge the statistical assistance of Lonni Schultz,PhD, and Alissa Kapke, MA.

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Pittman  RGOrr  SP Twenty-four hour urinary cortisol and catecholamine excretion in combat-relatedposttraumatic stress disorder. Biol Psychiatry. 1990;27245- 247
PubMed Link to Article
Mason  JWWang  SYehuda  RLubin  HJohnson  DBremner  JDCharney  DSouthwick  S Marked lability in urinary cortisol levels in subgroups of combat veteranswith posttraumatic stress disorder during an intensive exposure treatmentprogram. Psychosom Med. 2002;64238- 246
PubMed Link to Article
Lemieux  AMCoe  CL Abuse-related posttraumatic stress disorder: evidence for chronic neuroendocrineactivation in women. Psychosom Med. 1995;57105- 115
PubMed Link to Article
Stein  MBYehuda  RKoverola  CHanna  C Enhanced dexamethasone suppression of plasma cortisol in adult womentraumatized by childhood sexual abuse. Biol Psychiatry. 1997;42680- 686
PubMed Link to Article
Rasmusson  AMLipschitz  DSWang  SHu  SVojvoda  DBremner  JDSouthwick  SMCharney  DS Increased pituitary and adrenal reactivity in premenopausal women withposttraumatic stress disorder. Biol Psychiatry. 2001;50965- 977
PubMed Link to Article
Aardal-Eriksson  EEriksson  TELars-Håkan  T Salivary cortisol, posttraumatic stress symptoms and general healthin the acute phase and during 9-month follow-up. Biol Psychiatry. 2001;50986- 993
PubMed Link to Article
Anisman  HGriffiths  JMatheson  KRavindran  AVMerali  Z Posttraumatic stress symptoms and salivary cortisol levels. Am J Psychiatry. 2001;1581509- 1511
PubMed Link to Article
Davidson  LMBaum  A Chronic stress and posttraumatic stress disorders. J Consult Clin Psychol. 1986;54303- 308
PubMed Link to Article
Maes  MLin  ABonaccorso  Svan Hunsel  FVan Gastel  ADelmeire  LBiondi  MBosmans  EKenis  GScharpe  S Increased 24-hour urinary cortisol excretion in patients with post-traumaticstress disorder and patients with major depression, but not in patients withfibromyalgia. Acta Psychiatr Scand. 1998;98328- 335
PubMed Link to Article
Fukuda  SMorimota  KKanae  MMaruyama  S Effect of the Hanshin-Awaji earthquake on posttraumatic stress, lifestylechanges, and cortisol levels of victims. Arch Environ Health. 2000;55121- 125
PubMed Link to Article
Kosten  TRMason  JWGiller  ELOstroff  RBHarkness  L Sustained urinary norepinephrine and epinephrine elevation in post-traumaticstress disorder. Psychoneuroendocrinology. 1987;1213- 20
PubMed Link to Article
Yehuda  RSouthwick  SGiller  ELMa  XMason  JW Urinary catecholamine excretion and severity of PTSD symptoms in Vietnamcombat veterans. J Nerv Ment Dis. 1992;180321- 325
PubMed Link to Article
Davidson  LMFleming  RBaum  A Chronic stress, catecholamines and sleep disturbance at Three MileIsland. J Human Stress. 1987;1375- 83
PubMed Link to Article
Rahe  RHKarson  SHoward  NSRubin  RTPoland  RE Psychological and physiological assessment on American hostages freedfrom captivity in Iran. Psychosom Med. 1990;521- 16
PubMed Link to Article
Breslau  NDavis  GCPeterson  ELSchultz  LR A second look at comorbidity in victims of trauma: the post-traumaticstress disorder-major depression connection. Biol Psychiatry. 2000;48902- 909
PubMed Link to Article
Kessler  RCSonnega  ABromet  EHughes  MNelson  CB Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;521048- 1060
PubMed Link to Article
Yehuda  RHalligan  SLBierer  LM Cortisol levels in adult offspring of Holocaust survivors: relationto PTSD symptom severity in the parent and child. Psychoneuroendocrinology. 2002;27171- 180
PubMed Link to Article
Breslau  NDavis  GCSchultz  L PTSD and the incidence of nicotine, alcohol and drug disorders in victimsof trauma. Arch Gen Psychiatry. 2003;60289- 294
PubMed Link to Article
Robins  LNHelzer  JECottler  LBGolding  E NIMH Diagnostic Interview Schedule, Version III,Revised.  St Louis, Mo Washington University1989;
Breslau  NKessler  RPeterson  EL PTSD assessment with a structured interview: reliability and concordancewith a standardized clinical interview. Int J Methods Psychiatr Res. 1998;7121- 127
Link to Article
Blake  DDWeathers  FWNagy  LMKaloupek  DGGusman  FDCharney  DSKeane  TM The development of a clinician-administered PTSD scale. J Trauma Stress. 1995;875- 90
PubMed Link to Article
Weathers  FWLitz  BT Psychometric properties of the clinician-administered PTSD scale, CAPS-1. PTSD Res Q. 1994;52- 6
Diggle  PJLiang  KYZeger  SL Analysis of Longitudinal Data.  New York, NY Oxford University Press1994;
Liang  KYZeger  SL Longitudinal data analysis using generalized linear models. Biometrika. 1986;7313- 22
Link to Article
Zeger  SLLiang  KY Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42121- 130
PubMed Link to Article
Nesse  RMCameron  OGBuda  AJMcCann  DSCurtis  GCHuber-Smith  MJ Urinary catecholamines and mitral valve prolapse in panic-anxiety patients. Psychiatry Res. 1985;1467- 75
PubMed Link to Article
Charney  DSDeutch  AYKrystal  JHSouthwick  SMDavis  M Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry. 1993;50295- 305
PubMed
Uhde  TESiever  LJPost  RMJimerson  DCBoulenger  JBuchsbaum  MS The relationship of plasma free MHPG and psychophysical pain in normalvolunteers. Psychopharmacol Bull. 1982;18129- 131
PubMed
Rubin  RTPoland  RELesser  IMWinston  RABlodgett  N Neuroendocrine aspects of primary endogenous depression, I: cortisolsecretory dynamics in patients and matched controls. Arch Gen Psychiatry. 1987;44328- 336
PubMed Link to Article
Halbreich  UAsnis  GMSchindledecker  RZurnoff  BNathan  RS Cortisol secretion in endogenous depression, I: basal plasma levels. Arch Gen Psychiatry. 1985;42909- 914
PubMed Link to Article
Young  EACarlson  NEBrown  MB 24 Hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology. 2001;25267- 276
PubMed Link to Article
Young  EAAggen  SHPrescott  CAKendler  KS Similarity in saliva cortisol measures in monozygotic twins and theinfluence of past major depression. Biol Psychiatry. 2000;4870- 74
PubMed Link to Article
Brown  CSchulberg  HCMadonia  MJShear  KMHouck  PR Treatment outcomes for primary care patients with major depressionand lifetime anxiety disorders. Am J Psychiatry. 1996;1531293- 1300
PubMed
Clayton  P The comorbidity factor: establishing the primary diagnosis in patientswith mixed symptoms of anxiety and depression. J Clin Psychiatry. 1990;5135- 39
PubMed
Coryell  WEndicott  JWinokur  G Anxiety symptoms as an epiphenomena of primary major depression: outcomeand familial psychopathology. Am J Psychiatry. 1992;149100- 107
PubMed
Grunhaus  L Major depressive disorder and panic disorder: the syndrome and itscharacteristics. Greden  JFGrunhaus  LedsSevere DepressiveDisorders. Washington, DC American Psychiatric Press1994;159- 194
Joffe  RTBagby  RMLevitt  A Anxious and nonanxious depression. Am J Psychiatry. 1993;1501257- 1258
PubMed
Lydiard  B Coexisting depression and anxiety: special diagnostic and treatmentissues. J Clin Psychiatry. 1991;5248- 54
PubMed
Heim  CNewport  DJHeit  SGraham  YPWilcox  MBonsall  RMiller  AHNemerof  CB Pituitary-adrenal and autonomic responses to stress in women aftersexual and physical abuse in childhood. JAMA. 2000;284592- 597
PubMed Link to Article
North  CSNixon  SJShariat  SMallonee  SMcMillian  JCSpitznagel  ELSmith  EM Psychiatric disorders among survivors of the Oklahoma City bombing. JAMA. 1999;282755- 762
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Urine cortisol excretion levelsin the night, morning (AM), and evening (PM) in women by psychiatric diagnoses.The comorbid posttraumatic stress disorder (PTSD)/major depressive disorder(MDD) group demonstrated significantly elevated urinary free cortisol excretionlevels compared with the other 3 groups; differences in the evening were particularlynoticeable.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Urine cortisol excretion levelsin the night, morning (AM), and evening (PM) in men by psychiatric diagnoses.The major depressive disorder (MDD) group differed significantly from theMDD/posttraumatic stress disorder (PTSD) group and the no-disorder group.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Urine norepinephrine excretionlevels in night, morning (AM), and evening (PM) (men and women) by psychiatricdiagnoses. The groups with posttraumatic stress disorder (PTSD) only and PTSDcomorbid with major depressive disorder (MDD) had significantly higher levelsthan the other 2 groups.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Urine epinephrine excretion levelsin night, morning (AM), and evening (PM) (men and women) by psychiatric diagnoses.The groups with posttraumatic stress disorder (PTSD) only and PTSD comorbidwith major depressive disorder (MDD) had significantly higher levels thanthe other 2 groups.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Urine dopamine excretion levelsin night, morning (AM), and evening (PM) by psychiatric diagnosis (men andwomen). The groups with posttraumatic stress disorder (PTSD) alone and PTSDcomorbid with major depressive disorder (MDD) had significantly higher levelsthan the MDD group, and the PTSD/MDD group had significantly higher levelsthan the group with neither disorder.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Sample Characteristics: Sex, Race, Age, Lifetime Prevalenceof Alcohol and Drug Use Disorders*
Table Graphic Jump LocationTable 2. Generalized Estimating Equations Model of Urinary Free CortisolLevels (8 Hour) Controlling for Diurnal Variation (n = 275)*
Table Graphic Jump LocationTable 3. Total 24-Hour Dopamine, Epinephrine, and Norepinephrine Levelsin Groups Exposed to Trauma, Not Exposed to Trauma, and With PosttraumaticStress Disorder (PTSD) (n = 256)*
Table Graphic Jump LocationTable 4. Total 24-Hour Dopamine, Epinephrine, and Norepinephrine LevelsAcross Diagnostic Groups (n = 256)*

References

Breslau  NChase  GAnthony  J The uniqueness of the DSM definition of post-traumaticstress disorder: implications for research. Psychol Med. 2002;32573- 576
PubMed Link to Article
Mason  JWGiller  ELKosten  TROstroff  RBPodd  L Urinary-free cortisol levels in posttraumatic stress disorder patients. J Nerv Ment Dis. 1986;174145- 159
PubMed Link to Article
Yehuda  R Current status of cortisol findings in post-traumatic stress disorder. Psychiatr Clin North Am. 2002;25341- 368
PubMed Link to Article
Boscarino  JA Posttraumatic stress disorder, exposure to combat and lower plasmacortisol among Vietnam veterans: findings and clinical implications. J Consult Clin Psychol. 1996;64191- 201
PubMed Link to Article
Pittman  RGOrr  SP Twenty-four hour urinary cortisol and catecholamine excretion in combat-relatedposttraumatic stress disorder. Biol Psychiatry. 1990;27245- 247
PubMed Link to Article
Mason  JWWang  SYehuda  RLubin  HJohnson  DBremner  JDCharney  DSouthwick  S Marked lability in urinary cortisol levels in subgroups of combat veteranswith posttraumatic stress disorder during an intensive exposure treatmentprogram. Psychosom Med. 2002;64238- 246
PubMed Link to Article
Lemieux  AMCoe  CL Abuse-related posttraumatic stress disorder: evidence for chronic neuroendocrineactivation in women. Psychosom Med. 1995;57105- 115
PubMed Link to Article
Stein  MBYehuda  RKoverola  CHanna  C Enhanced dexamethasone suppression of plasma cortisol in adult womentraumatized by childhood sexual abuse. Biol Psychiatry. 1997;42680- 686
PubMed Link to Article
Rasmusson  AMLipschitz  DSWang  SHu  SVojvoda  DBremner  JDSouthwick  SMCharney  DS Increased pituitary and adrenal reactivity in premenopausal women withposttraumatic stress disorder. Biol Psychiatry. 2001;50965- 977
PubMed Link to Article
Aardal-Eriksson  EEriksson  TELars-Håkan  T Salivary cortisol, posttraumatic stress symptoms and general healthin the acute phase and during 9-month follow-up. Biol Psychiatry. 2001;50986- 993
PubMed Link to Article
Anisman  HGriffiths  JMatheson  KRavindran  AVMerali  Z Posttraumatic stress symptoms and salivary cortisol levels. Am J Psychiatry. 2001;1581509- 1511
PubMed Link to Article
Davidson  LMBaum  A Chronic stress and posttraumatic stress disorders. J Consult Clin Psychol. 1986;54303- 308
PubMed Link to Article
Maes  MLin  ABonaccorso  Svan Hunsel  FVan Gastel  ADelmeire  LBiondi  MBosmans  EKenis  GScharpe  S Increased 24-hour urinary cortisol excretion in patients with post-traumaticstress disorder and patients with major depression, but not in patients withfibromyalgia. Acta Psychiatr Scand. 1998;98328- 335
PubMed Link to Article
Fukuda  SMorimota  KKanae  MMaruyama  S Effect of the Hanshin-Awaji earthquake on posttraumatic stress, lifestylechanges, and cortisol levels of victims. Arch Environ Health. 2000;55121- 125
PubMed Link to Article
Kosten  TRMason  JWGiller  ELOstroff  RBHarkness  L Sustained urinary norepinephrine and epinephrine elevation in post-traumaticstress disorder. Psychoneuroendocrinology. 1987;1213- 20
PubMed Link to Article
Yehuda  RSouthwick  SGiller  ELMa  XMason  JW Urinary catecholamine excretion and severity of PTSD symptoms in Vietnamcombat veterans. J Nerv Ment Dis. 1992;180321- 325
PubMed Link to Article
Davidson  LMFleming  RBaum  A Chronic stress, catecholamines and sleep disturbance at Three MileIsland. J Human Stress. 1987;1375- 83
PubMed Link to Article
Rahe  RHKarson  SHoward  NSRubin  RTPoland  RE Psychological and physiological assessment on American hostages freedfrom captivity in Iran. Psychosom Med. 1990;521- 16
PubMed Link to Article
Breslau  NDavis  GCPeterson  ELSchultz  LR A second look at comorbidity in victims of trauma: the post-traumaticstress disorder-major depression connection. Biol Psychiatry. 2000;48902- 909
PubMed Link to Article
Kessler  RCSonnega  ABromet  EHughes  MNelson  CB Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;521048- 1060
PubMed Link to Article
Yehuda  RHalligan  SLBierer  LM Cortisol levels in adult offspring of Holocaust survivors: relationto PTSD symptom severity in the parent and child. Psychoneuroendocrinology. 2002;27171- 180
PubMed Link to Article
Breslau  NDavis  GCSchultz  L PTSD and the incidence of nicotine, alcohol and drug disorders in victimsof trauma. Arch Gen Psychiatry. 2003;60289- 294
PubMed Link to Article
Robins  LNHelzer  JECottler  LBGolding  E NIMH Diagnostic Interview Schedule, Version III,Revised.  St Louis, Mo Washington University1989;
Breslau  NKessler  RPeterson  EL PTSD assessment with a structured interview: reliability and concordancewith a standardized clinical interview. Int J Methods Psychiatr Res. 1998;7121- 127
Link to Article
Blake  DDWeathers  FWNagy  LMKaloupek  DGGusman  FDCharney  DSKeane  TM The development of a clinician-administered PTSD scale. J Trauma Stress. 1995;875- 90
PubMed Link to Article
Weathers  FWLitz  BT Psychometric properties of the clinician-administered PTSD scale, CAPS-1. PTSD Res Q. 1994;52- 6
Diggle  PJLiang  KYZeger  SL Analysis of Longitudinal Data.  New York, NY Oxford University Press1994;
Liang  KYZeger  SL Longitudinal data analysis using generalized linear models. Biometrika. 1986;7313- 22
Link to Article
Zeger  SLLiang  KY Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42121- 130
PubMed Link to Article
Nesse  RMCameron  OGBuda  AJMcCann  DSCurtis  GCHuber-Smith  MJ Urinary catecholamines and mitral valve prolapse in panic-anxiety patients. Psychiatry Res. 1985;1467- 75
PubMed Link to Article
Charney  DSDeutch  AYKrystal  JHSouthwick  SMDavis  M Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry. 1993;50295- 305
PubMed
Uhde  TESiever  LJPost  RMJimerson  DCBoulenger  JBuchsbaum  MS The relationship of plasma free MHPG and psychophysical pain in normalvolunteers. Psychopharmacol Bull. 1982;18129- 131
PubMed
Rubin  RTPoland  RELesser  IMWinston  RABlodgett  N Neuroendocrine aspects of primary endogenous depression, I: cortisolsecretory dynamics in patients and matched controls. Arch Gen Psychiatry. 1987;44328- 336
PubMed Link to Article
Halbreich  UAsnis  GMSchindledecker  RZurnoff  BNathan  RS Cortisol secretion in endogenous depression, I: basal plasma levels. Arch Gen Psychiatry. 1985;42909- 914
PubMed Link to Article
Young  EACarlson  NEBrown  MB 24 Hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology. 2001;25267- 276
PubMed Link to Article
Young  EAAggen  SHPrescott  CAKendler  KS Similarity in saliva cortisol measures in monozygotic twins and theinfluence of past major depression. Biol Psychiatry. 2000;4870- 74
PubMed Link to Article
Brown  CSchulberg  HCMadonia  MJShear  KMHouck  PR Treatment outcomes for primary care patients with major depressionand lifetime anxiety disorders. Am J Psychiatry. 1996;1531293- 1300
PubMed
Clayton  P The comorbidity factor: establishing the primary diagnosis in patientswith mixed symptoms of anxiety and depression. J Clin Psychiatry. 1990;5135- 39
PubMed
Coryell  WEndicott  JWinokur  G Anxiety symptoms as an epiphenomena of primary major depression: outcomeand familial psychopathology. Am J Psychiatry. 1992;149100- 107
PubMed
Grunhaus  L Major depressive disorder and panic disorder: the syndrome and itscharacteristics. Greden  JFGrunhaus  LedsSevere DepressiveDisorders. Washington, DC American Psychiatric Press1994;159- 194
Joffe  RTBagby  RMLevitt  A Anxious and nonanxious depression. Am J Psychiatry. 1993;1501257- 1258
PubMed
Lydiard  B Coexisting depression and anxiety: special diagnostic and treatmentissues. J Clin Psychiatry. 1991;5248- 54
PubMed
Heim  CNewport  DJHeit  SGraham  YPWilcox  MBonsall  RMiller  AHNemerof  CB Pituitary-adrenal and autonomic responses to stress in women aftersexual and physical abuse in childhood. JAMA. 2000;284592- 597
PubMed Link to Article
North  CSNixon  SJShariat  SMallonee  SMcMillian  JCSpitznagel  ELSmith  EM Psychiatric disorders among survivors of the Oklahoma City bombing. JAMA. 1999;282755- 762
PubMed Link to Article

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