Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 11001107

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Progress in Neuro-Psychopharmacology & Biological Psychiatry

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Sex-specic cortisol levels in bipolar disorder and schizophrenia during mental challenge Relationship to clinical characteristics and medication
Nils Eiel Steen a,b,, Steinar Lorentzen c,d, Elizabeth A. Barrett b, Trine V. Lagerberg a, Sigrun Hope c,e, Sara Larsson c,a, Akiah O. Berg a,c, Ingrid Agartz c,f, Ingrid Melle a,c, Jens P. Berg c,g,h, Ole A. Andreassen a,c
a

Psychosis Research Unit, Division of Mental Health and Addiction, Oslo University Hospital, Ullevl Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway Acute Psychiatric Emergency Unit, Division of Mental Health and Addiction, Oslo University Hospital, Aker Hospital, P.O. Box 4959 Nydalen, 0424 Oslo, Norway Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway d Department of Research and Development, Division of Mental Health and Addiction, Oslo University Hospital, Aker Hospital, P.O. Box 4959 Nydalen, 0424 Oslo, Norway e Department of Psychiatry, Ostfold Hospital, 1603 Fredrikstad, Norway f Department of Psychiatric Research, Diakonhjemmet Hospital, P.O. Box 85, Vinderen, 0319 Oslo, Norway g Department of Medical Biochemistry, Oslo University Hospital, Ullevl Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway h Hormone Laboratory, Oslo University Hospital, Aker Hospital, P.O. Box 4959 Nydalen, 0424 Oslo, Norway
b c

a r t i c l e

i n f o

a b s t r a c t
Objective: Our objective was to examine the cortisol release during a mental challenge in severe mental disorders versus healthy controls (HC), analyzing effects of sex, clinical characteristics and medication, and comparing Bipolar Disorder (BD) to Schizophrenia (SCZ). Methods: Patients with BD and SCZ (n = 151) were recruited from a catchment area. HC (n = 98) were randomly selected from the same area. Salivary samples were collected before and after a mental challenge and cortisol levels determined. Results: During the challenge there was an interaction between group and sex (P = 0.015) with male patients having a blunted cortisol release compared to male HC (P = 0.037). Cortisol change did not differ signicantly between BD and SCZ. In all patients, the cortisol change correlated with number of psychotic episodes (r = 0.23, P = 0.025), and in females patients, with number of depressive episodes (r = 0.33, P = 0.015). Patients using antidepressants had a greater cortisol release during challenge than those not using antidepressants (P = 0.043). Conclusions: Male patients with severe mental disorders seem to have a uniform abnormal cortisol release during mental challenges which associates with clinical course, and with benecial effects of antidepressants. 2011 Elsevier Inc. All rights reserved.

Article history: Received 14 January 2011 Received in revised form 10 March 2011 Accepted 11 March 2011 Available online 21 March 2011 Keywords: Gender HPA Psychological stress Psychosis Severe mental disorders

1. Introduction Bipolar disorder (BD) and schizophrenia (SCZ) are severe mental disorders with lifetime prevalences of 12% (Merikangas et al., 2007; Perala et al., 2007). The heritability is high, probably involving complex genetic interactions (Barnett and Smoller, 2009; Owen et al., 2009). Because of overlapping symptomatology and shared susceptibility genes, these disorders may be regarded as part of the same psychosis spectrum (Craddock et al., 2009; Lichtenstein et al., 2009). The stress-vulnerability hypothesis is considered important in severe
Abbreviations: BD, bipolar disorder; CBG, corticosteroid binding globulin; CDSS, Calgary Depression Scale; HC, healthy controls; HPA, hypothalamicpituitaryadrenal; IDS-C, Inventory of Depressive Symptoms; SCI-PANSS, Structured Clinical Interview for the Positive and Negative Syndrome Scale; SCZ, schizophrenia (spectrum); TOP, Thematically Organized Psychosis; YMRS, Young Mania Rating Scale. Corresponding author at: Clinic of Mental Health and Addiction, Oslo University Hospital, Aker Hospital, P.O. Box 4959 Nydalen, 0424 Oslo, Norway. Tel.: +47 228 94 000; fax: + 47 229 23 470. E-mail address: n.e.steen@medisin.uio.no (N.E. Steen). 0278-5846/$ see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.03.008

mental disorders (Chabungbam et al., 2007; Hlastala, 2003; Hultman et al., 1997), however, the pathophysiology conveying this vulnerability remains largely unknown. One of the main biological responses to stress involves the cortisol system (de Kloet et al., 2005; Sapolsky et al., 2000). Cortisol secretion from the adrenal cortex is the end product of the closely regulated activity of the hypothalamicpituitaryadrenal (HPA) axis (see Herman et al., 2005 for a review). There is evidence for an increased tone of the HPA axis in BD and SCZ, implicating this dysfunction in the pathophysiology of these disorders (Goldstein et al., 2007; Watson et al., 2004). Most cortisol studies in BD and SCZ are based on pharmacological manipulation (Daban et al., 2005; Walker et al., 2008), and few have assessed the cortisol release during mental challenges. In SCZ, there are studies indicating a blunted cortisol response to mental challenges (Albus et al., 1982; Brenner et al., 2009; Jansen et al., 1998, 2000; van Venrooij et al., 2010), and some examined specically men (Jansen et al., 1998; van Venrooij et al., 2010). In a recent study with men and women, blunted response in men was indicated (Brenner et al., 2009). In BD, Havermans et al.

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(2011) reported a atter diurnal cortisol slope, but no difference in response to negative events compared to healthy controls (HC). Furthermore, in offspring of parents with BD, a normal cortisol response (Ellenbogen et al., 2006) and increased response to mental challenges dependent on structure provided by parents (Ellenbogen and Hodgins, 2009) were indicated. In comparison, there seem to be sex specic effects in patients with depression, with a blunted response in male patients compared to HC (Brooks and Robles, 2009; Chopra et al., 2009; Peeters et al., 2003). Generally, sex is of major importance in these studies, as patterns of cortisol release differ between men and women (Andrews et al., 2007; Wadiwalla et al., 2010). The ndings in severe mental disorders seem conicting, and there are no direct comparisons between BD and SCZ. Large studies are needed to clarify the effects of a mental challenge on cortisol levels with respect to diagnosis, sex, pharmacological treatment and clinical characteristics. Our primary objective was to examine the cortisol levels during a mental challenge in severe mental disorders versus HC. Our secondary objective was to specically examine effects of sex in such a setting. Our hypotheses were that patients would have higher baseline cortisol levels, and that patients with severe mental disorders, mainly the male group, would have a blunted release during the challenge compared to HC. The tertiary objective was to investigate if there were differences in these aspects between BD and SCZ. The hypothesis was that the two patient groups would be equal in both baseline levels and change during testing. The fourth objective was to explore the association of clinical characteristics and medications with the cortisol change. 2. Methods 2.1. Participants Patients were included through referrals to the ongoing Thematically Organized Psychosis (TOP) Study that is carried out by the University Hospitals of Oslo, Norway (for details, see Birkenaes et al., 2007). Inclusion criteria were: being registered in the psychiatric services of any one of the four University Hospitals in Oslo; ages 18 to 65 years; meeting DSM-IV criteria for schizophrenia spectrum disorders or bipolar disorders; and being willing and able to give written, informed consent of participation. Exclusion criteria were: history of moderate or severe head injury, serious somatic illness, neurological disorder or mental retardation. Participation in the present study further required no use of corticosteroid medication in any form, and start of salivary sampling before 12 pm. A representative HC group was randomly selected from statistical records from the same catchment area as the patient groups, and contacted by letter inviting them to participate. Included in the current analyses were 98 HC with measurements of salivary cortisol, who were without a history of medical problems, severe psychiatric disorders including drug abuse/dependency or severe mental disorder reported in close relatives. There were no participants with Addison's disease or Cushing's syndrome among patients or controls. 2.2. Clinical assessments Inclusion and diagnostic interviews were done by trained doctors and psychologists using The Structured Clinical Interview for DSM-IV Axis I Disorders, SCID 1 (First et al., 1995). Inter-rater reliability was good, with an overall kappa score of 0.77 (95% C.I: 0.600.94). Inventory of Depressive Symptoms (IDS-C) (Rush et al., 1996), Calgary Depression Scale (CDSS, for 19 patients with schizophrenia spectrum disorders) (Addington et al., 1990), Young Mania Rating Scale (YMRS) (Young et al., 1978) and Positive and Negative Syndrome Scale (SCIPANSS) (Kay et al., 1987) were used for symptom assessments.

2.3. Mental challenge and cortisol measurements Within 2 weeks after clinical assessments, patients had a routine blood withdrawal followed by a neuropsychological test as part of the standard protocol. The baseline salivary sample was collected at arrival to the test site, before laboratory and neuropsychological testing. The second salivary sample was collected after about 1 h of neuropsychological testing. The patients received a light breakfast and had their medication before the neuropsychological testing as they met fasting in the morning. Some patients also had a short physical examination. The neuropsychological test battery, constituting the mental challenge, consisted of tests on logical memory, visual cognition, digital memory, coding, and working memory. Tests were performed with the presence of an experimenter (psychologist), and two of the tests included speed or time limits. The HC correspondingly had their salivary samplings at arrival for baseline level and after blood sampling and 1 h of neuropsychological testing. The Salivette (Sarstedt AG & Co, Nmbrecht, Germany) was used for sampling of saliva. Saliva were immediately frozen for later analysis of free cortisol with a radioimmunoassay from Siemens Healthcare Diagnostics (Los Angeles, CA, USA) at the Hormone Laboratory at Oslo University Hospital, Aker (inter assay CV% = 11 at 7 nmol/l). Cortisol levels below the reference limit (b 3.5 nmol/L), probably caused by failure of adequate sampling procedure, were treated as missing in the analysis. Relative to the total number of Salivettes, there were 11% and 14% missing values among patients and HC respectively. However, the linear mixed model makes use of available data from participants with incomplete sampling series. 2.4. Ethics The investigation was carried out in accordance with the latest version of the Declaration of Helsinki. After complete description of the study to the persons, written informed consent was obtained. The Regional Ethics Committee and The Data Inspectorate approved the study. The biobank was approved by the Norwegian Directorate of Health. 2.5. Statistical analysis SPSS package version 15.0 (SPSS, Inc., Chicago, Ill., USA) was used for the statistical analyses. Data of salivary cortisol level had a skewed distribution and were logarithmically transformed. Linear mixed model for continuous outcome with random intercept was used to estimate the change in log-transformed salivary cortisol level between groups during testing. For comparisons of severe mental disorders and HC, we constructed two categorical variables: 1) variable groupAll dividing participants into a combined BD and SCZ group (All Patients) and an HC group; 2) variable timec dividing salivary sampling into baseline and second sampling. Models tested had the following factors and covariates: groupAll, timec, sex, age, time of baseline sampling (h), and time between samplings (h). Sex timec was the rst interaction added, to test for expected differences in change of salivary cortisol between male and female participants during the mental challenge (Kudielka et al., 2009). In the second model we additionally included the group timec interaction, in order to test for differences in change of cortisol levels between All Patients and HC during the mental challenge. In the third model we substituted previous interactions with the group timec sex interaction, testing whether differences in change of salivary cortisol levels between All Patients and HC during the mental challenge differ between men and women. Separate analyses for each sex were performed if this interaction was statistically signicant. Rates of smokers varied between All Patients and HC, and the smoking timec interaction was also tested in these 3 main models. For comparison of pre- and post test cortisol

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levels within specic groups, timec, time of baseline sampling (h), and time between samplings (h) were used as independent variables. Differences in cortisol change between BD and SCZ, and association with clinical characteristics (number of psychotic episodes, number of depressive episodes, number of manic episodes, total score of IDS-C, YMRS and SCI-PANSS, positive and negative subscore and items anxiety and hostility of SCI-PANSS) were inspected in the patient subsample with linear mixed model (variables as before except for the variable groupdiagn dividing the subsample in BD and SCZ) and correlation analyses respectively. Signicant ndings from the correlation analyses were further tested by implementing the characteristic into the linear mixed model. Comparisons of salivary cortisol levels between groups at baseline were performed with Analysis of Covariance with adjustments for sex, age and time of sampling (h). The group sex interaction was used for inspection of sex-specic effects. For comparisons of cortisol change between patients on different medications, separate analyses with the linear mixed model were performed between the following groups: antipsychotics (n = 109) versus no antipsychotics (n = 42), mood stabilizers (n = 54) versus no mood stabilizers (n = 97), and antidepressants (n = 58) versus no antidepressants (n = 93) (variable grouptype of medication). For difference in age, total scores of IDS-C, PANSS and YMRS, number of episodes with psychosis and with depression, serum glucose, time between samplings and time of baseline sampling we used KruskalWallis test/MannWhitney U test. Differences in smoking and sex were tested with the chi-square test, and correlations with Spearman's rho. For all statistical analyses the signicance level was set to 0.05 (two-tailed).

Otherwise Specied [n = 8]), in the following termed bipolar disorder (BD) (Table 1). Several factors may affect cortisol levels, and we carefully assessed these in order to perform proper control for confounders, see Table 1. Especially, there were no statistically signicant differences in distribution of men and women between the BD, SCZ and HC groups. Time between samplings was missing in 16% of the participants and imputation was performed with the group mean technique; group differences remained the same after imputation. Sixteen percent of the patients had a lifetime diagnosis of alcohol abuse or dependence. Baseline levels of serum glucose were not signicantly different between BD, SCZ and HC (P = 0.4). In the SCZ group, 65(93%) patients used antipsychotics, 23(33%) used antidepressants and 8(11%) patients used mood stabilizers. In the BD group, 44(54%) patients used antipsychotics, 35(43%) used antidepressants, and 46(57%) patients used mood stabilizers. Nineteen patients (13%) used no psychopharmacological agents. 3.2. Effect of the mental challenge There was a fall in cortisol level from baseline to second sampling in line with the diurnal decline (main effect of timec, P b 0.001). However, effect of the mental challenge was indicated by the cortisol pattern in male HC and by expected sex differences: 1) despite the underlying diurnal decline, cortisol levels in male HC did virtually not change during the mental challenge (P = 0.9); 2) there was a signicant difference in the change of salivary cortisol levels during testing between male and female participants (sex timec interaction, P = 0.006, Fig. 1a), with men having a attened slope compared to women. 3.3. All Patients compared to HC At baseline, there were no signicant differences in cortisol levels between the All Patient and HC groups, and no sex-specic effects. There was no signicant difference in cortisol change between All Patients and HC groups (second model, groupAll timec interaction, P = 0.06). There was a signicant difference between men and women with regard to cortisol change between All Patients and HC (third model, groupAll timec sex interaction, P = 0.015); there was a blunted cortisol release in male patients only, demonstrated by a greater reduction relative to the attened slope in male HC during the

3. Results 3.1. Sample characteristics Included in the current analyses were consecutively referred patients with measurements of salivary cortisol, consisting of a total of 151 patients out of which 70 had a DSM-IV schizophrenia spectrum disorder (Schizophrenia [n = 49], Schizophreniform [n = 7] and Schizoaffective Disorder [n = 14]), in the following termed schizophrenia (SCZ), and 81 had a bipolar disorder (Bipolar I Disorder [n = 46], Bipolar II Disorder [n = 27] and Bipolar Disorder Not
Table 1 Sample characteristics. Sex (N) BD M (33) Smoking regularly (%) Age (year) IDS-C total score PANSS total score YMRS total score Depressions (N)a Psychoses (N)a Time interval (h:min) Time baseline (h (h:min)) Cortisol baseline (nmol/l) Cortisol second (nmol(l)) 53.1c 36.0(24.0) 12.0(20.0) 42.0(13.0) 2.0(9.0) 3.0(6.0) 0.0(1.3) 1:37(0:47)c 9:30(1:12)b 10.7(5.7) 7.6(5.4) F (48) 43.8b 33.0(18.0) 15.0(19.0) 42.0(12.0) 2.0(6.0) 4.0(5.0) 1.0(1.0) 1:40(0:31)c 9:05(0:52) 11.3(7.1) 7.1(5.3)

SCZ M (40) 51.4c 25.5(11.0)d,b 21.0(18.0) 66.0(22.0)e 6.0(8.5) 1.0(2.0)e 1.0(1.0)e 1:27(0:27)c 9:40(0:45)b 9.4(8.4) 8.6(7.5) F (30) 35.7 29.5(15.0) 18.0(22.0) 57.0(23.0)e 6.5(11.3) 1.0(2.3)e 1.0(1.0)e 1:25(0:26)c,d 9:47(0:51)d 9.9(6.1) 6.2(2.5)

HC M (52) 11.1 32.0(15.0) 1:00(0:13) 9:00(1:12) 9.1(6.5) 9.5(5.8) F (46) 17.6 31.5(14.0) 1:00(0:15) 9:30(1:05) 10.2(8.1) 7.5(5.9)

Age, Inventory of Depressive Symptoms (IDS-C) total score, Positive and Negative Syndrome Scale (PANSS) total score, Young Mania Rating Scale (YMRS) total score, (lifetime number of) psychoses, (lifetime number of) depressions, time interval (time between samplings), time (of) baseline (sampling) (a.m.) and salivary cortisol (unadjusted, baseline and second sampling), are presented as median (interquartile range). Twenty-four persons in the schizophrenia spectrum group were assessed with Calgary Depression Scale (CDSS), median (interquartile range): male patients 5.5(7.0), female patients 6.5(8.0). BD = Bipolar disorder; SCZ = Schizophrenia spectrum; HC = Healthy controls; N = number; M = male participants; F = female participants. a Data in 7585% in each group (BD and SCZ). b P b 0.05 versus HC. c P 0.001 versus HC. d P b 0.05 versus BD. e P 0.001 versus BD (lifetime number of psychoses: SCZ N BD).

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a)
% reduction in salivary cortisol

40 30 20 10 0
*

3.5. Clinical course, symptom severity and cortisol change In the total patient group (All Patients), number of psychotic episodes correlated signicantly with cortisol change in both sexes (r = 0.23, P = 0.025), with a trend level in male patients (r = 0.26, P = 0.077), but not in female patients (r = 0.19, P = 0.20). Number of depressive episodes correlated signicantly with cortisol change in female patients (r = 0.33, P = 0.015), but not in male patients (r = 0.17, P = 0.24) nor in both sexes (r = 0.13, P = 0.19). Negative correlations with psychotic and depressive episodes indicate more diminished cortisol release during the challenge with increasing number of episodes. Otherwise there were no signicant correlations between cortisol change and clinical course or symptom severity. We further tested if number of psychotic and depressive episodes affected the comparison of cortisol change between All Patients and HC, selecting patients with maximum one episode of psychosis and depression for analysis respectively; reported sex differences in cortisol change between All Patients and HC remained unchanged (data not shown). 3.6. Medication, alcohol and cortisol change Between groups of medications, there was a signicant greater reduction in cortisol level in patients not using antidepressants compared to those using antidepressants (groupantidepr timec interaction: P = 0.043). In sex-specic analyses, this effect of antidepressants was suggested more pronounced in male than in female patients (groupantidepr timec sex interaction: P = 0.077, male patients: P = 0.035, female patients: P = 0.38). Between the other groups of medications, and between patients with and without a lifetime alcohol-related diagnosis, there were no signicant differences in change of cortisol (data not shown). 3.7. Baseline levels and cortisol change There was a signicant correlation in each diagnostic group and in HC between salivary cortisol level in the baseline sample and change in cortisol level (SCZ: r = 0.72, P b 0.001, BD: r = 0.61, P b 0.001, HC: r = 0.70, P b 0.001). 4. Discussion The main nding of the present study was no signicant difference in cortisol release during mental challenge between patients with severe mental disorders and HC. However, a sex-specic effect was found, with a blunted cortisol release during the challenge in male patients compared to male HC. There were no signicant differences between BD and SCZ. A normalization of the cortisol release with the use of antidepressants was indicated, especially in male patients, and lifetime number of psychotic and depressive episodes correlated with the cortisol change. There were no signicant correlations between symptom severity and cortisol change, and no effects of antipsychotics or mood stabilizers on cortisol release during the challenge. The study is done in a naturalistic setting in relation to a clinical evaluation, and with a large, representative and well dened sample. This suggests that male patients with severe mental disorders have a uniform impaired adaptation to even moderate everyday stressors. 4.1. Mental challenges and cortisol release Mental challenges and cortisol secretion have been studied in laboratory settings and real-life situations (Biondi and Picardi, 1999). Corresponding to the present design, challenges based on cognitive tasks are frequently used (Dickerson and Kemeny, 2004). It is important to interpret our ndings in relation to the diurnal cortisol variation. Despite the diurnal decline in the morning (Krieger et al.,

Men Women

-10 -20

b)
% reduction in salivary cortisol

40
*

30 20 10 0 HC AP BD SCZ

-10

-20
Fig. 1. Change in salivary cortisol during cognitive challenge in the diurnal decline. Percent reduction in salivary cortisol relative to baseline during cognitive challenge in the diurnal decline based on estimated marginal means from a linear mixed model analysis with adjustment for sex, age, time of baseline sampling and time between samplings in (a) all participants, comparing men and women; (b) male participants, comparing the combined bipolar disorder and schizophrenia spectrum group (AP, All Patients) with healthy controls (HC), and the bipolar disorder group (BD) with the schizophrenia spectrum group (SCZ). Error bars: 95% condence intervals. *p b 0.05.

mental challenge (groupAll timec interaction, male participants, P = 0.037, Fig. 1b, female participants P = 0.50). Table 2 shows the mixed model estimates in male participants; interestingly, there was no signicant effect of age. Smoking did not affect the results (smoking timec interaction, n.s.), and was excluded in the nal models.

3.4. Comparison of BD and SCZ The BD and SCZ groups did not differ signicantly in salivary cortisol levels at baseline. During the mental challenge, the BD and SCZ groups did not differ signicantly in cortisol change (groupdiagn timec interaction: P = 0.77), and there was no effect of sex in this comparison (groupdiagn timec sex interaction: P = 0.47, Fig. 1b [male patients]). Including lifetime number of psychotic or depressive episodes as independent continuous variables to the linear mixed models did not affect these results.

Table 2 Estimates of xed effects in male participants comparing All Patients versus healthy controls. Parameter Intercept GroupAll Timec Age Time of baseline sampling (h) Time between samplings (h) GroupAll timec Estimate 24.08 0.91 1.02 1.00 0.92 0.95 1.24 df 116.46 178.24 112.28 115.43 117.48 111.26 111.51 P-value 1.82E-10 0.36 0.78 0.15 0.06 0.56 0.037 95% condence interval 9.7859.27 0.751.11 0.881.19 0.991.00 0.851.00 0.781.14 1.011.52

Estimates of xed effects from the linear mixed model analyses in male participants comparing change in salivary cortisol from baseline to second (reference) sampling (Timec) between All Patients (combined bipolar disorder and schizophrenia spectrum group) and healthy controls (reference group) (GroupAll). Intercept: Constant of the mixed model with random intercept; Estimate: estimates of the xed model effects (percentage change = (estimate 1) 100); df: degrees of freedom; P-value: 2-tailed.

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1971), cortisol levels did virtually not change in male HC. This lack of diurnal decline cannot readily be attributed to random error due to the considerable sample size. Moreover, the present nding of the expected attened slope in male relative to female participants (Kudielka et al., 2009), indicated that the mental challenge affected cortisol secretion. Men generally have increased cortisol release during mental challenges compared to women (Kudielka et al., 2009). Indeed, without a challenge men seem to have the steepest diurnal decline (Vreeburg et al., 2009). Thus, overall the ndings substantiate a relative increase in cortisol levels compared to the diurnal decline. Moreover, analyses of preliminary data obtained with the same protocol in the afternoon, indicate an increase in healthy male persons (data not shown). A meta-analysis suggested that mental challenges should contain uncontrollability or a social-evaluative threat to trigger a rise in cortisol level (Dickerson and Kemeny, 2004). The present challenge included elements of social evaluation and uncontrollability, due to the presence of an experimenter and two of the tests involving speed or time limits. Our ndings are in line with recently suggested sex differences during mental challenge, that is, similar cortisol release in men during low and high levels of social evaluation, and increasing cortisol release in women with increasing level of social evaluation. In fact, men seem to respond strong to even simple forms of social evaluation (Andrews et al., 2007; Wadiwalla et al., 2010). Furthermore, challenges in the morning as in the present study, are frequently used (Dickerson and Kemeny, 2004), and with a reliability comparable to afternoon challenges (Kudielka et al., 2004). The present duration of the challenge corresponds to what is used in other studies, with durations varying from a few minutes to several hours (Biondi and Picardi, 1999). Importantly, age has been implicated in cortisol release (Kudielka et al., 2009), however, there were only small variations across groups, and age was included in the statistics. 4.2. Cortisol release and severe mental disorders The present study is the rst to investigate the effect of a mental challenge on cortisol release across BD and SCZ, with careful testing of clinical characteristics and effects of medication, in a large unselected patient sample. In depression and SCZ there are reports indicating blunted response to mental challenges, some with sex-related effects (Brenner et al., 2009; Brooks and Robles, 2009; Burke et al., 2005; Chopra et al., 2009; Jansen et al., 1998, 2000; van Venrooij et al., 2010). Correspondingly, our ndings indicate a sex-related blunted cortisol release in severe mental disorders, which is similar in BD and SCZ. This supports that there may be similar biological mechanisms underlying BD and SCZ, in line with the psychosis continuum model (Craddock et al., 2009). There were no signicant differences in cortisol change between subtypes of BD or subtypes of SCZ (data not shown). The only previous study of BD and cortisol in relation to mental challenges did not nd an abnormal cortisol response to negative events, but attening of the diurnal slope, and reduced cortisol reactivity to negative events in patients with many previous episodes compared to patients with fewer episodes (Havermans et al., 2011). The present study differs somewhat in type of challenge, medication and patient sample. We also used a sex specic approach based on known differences between men and women in HPA axis function both in mental disorders and healthy persons (e.g. Chopra et al., 2009; Kudielka et al., 2009; Kunzel et al., 2003). It is of note that signicant ndings between groups in the present sample appeared from interactions including sex. In the present study, adjustments for number of psychotic and depressive episodes did not seem to abolish reported sex differences in cortisol change between patients and HC, which is in line with a recent paper on medication-naive patients with a rst episode of

psychosis (van Venrooij et al., 2010). No differences in cortisol change between BD and SCZ is also in line with ndings of comparable HPA axis changes in BD (Daban et al., 2005) and SCZ (Walker et al., 2008). Our nding of blunted release in relation to number of episodes of psychosis and depression is in line with ndings of more previous episodes being associated with reduced cortisol reactivity to negative events (Havermans et al., 2011). None of the studies found an effect of depressive or manic symptom severity on the cortisol change. This indicates that clinical course rather than acute symptoms is associated with cortisol activity during challenge in severe mental disorders. Whether the clinical course affects the HPA axis or the dysregulated HPA axis inuence the course is unknown. However, activation of the HPA axis may predict treatment outcome in depression (Binder et al., 2009; Ising et al., 2007; Schule et al., 2009) with sex specic effects (Binder et al., 2009), and risk of relapse in bipolar disorder (Vieta et al., 1997, 1999). This indicates an effect on the clinical course. We did not nd any group differences in cortisol levels at baseline. This is in accordance with previous studies of BD and SCZ with comparable number of samplings (Watson et al., 2004). However, using frequent samplings, differences in basal cortisol are reported (Cervantes et al., 2001; Ryan et al., 2004). This indicates that the dysregulation of the HPA axis becomes evident during a mental challenge, and supports that abnormal cortisol activation could be an underlying mechanism rendering people with severe mental disorder more vulnerable to stress. The inadequate cortisol regulation might compromise cortisol's homeostatic and adaptive functions in stress (de Kloet et al., 2005). Blunted cortisol release as a vulnerability factor is also suggested by other groups (e.g. Jansen et al., 2000; van Venrooij et al., 2010), however, some would argue the opposite. The naturalistic setting with a representative sample makes the results relevant for cortisol patterns during everyday challenges. Alterations in normal circadian rhythm might have inuenced the present ndings. Whereas diurnal slope is attened in patients with bipolar disorder (Havermans et al., 2011), no difference in the cortisol response to awakening is reported (Deshauer et al., 2006). Hempel et al. (2010) suggest a steeper diurnal decline in male patients with schizophrenia compared to controls, but this does not seem to be supported by a somewhat larger study (Mondelli et al., 2010). However, there are reports of blunted cortisol awakening response in patients with psychosis (Mondelli et al., 2010; Pruessner et al., 2008). Importantly, in order to reach the appointment at the hospital, it is likely that the participants were well beyond their peak cortisol levels before rst sampling. This is supported by similar level of baseline cortisol in the patients and HC. Thus, variation in circadian rhythm does not seem to explain the present results of decreased cortisol release across bipolar disorder and schizophrenia. 4.3. Cortisol release and pharmacological treatment The present ndings of a different cortisol change during challenge in patients using antidepressants is in line with known interactions between the HPA axis and monoaminergic systems (de Kloet et al., 2005; Lanfumey et al., 2008; Swaab et al., 2005), and with antidepressive treatment dampening HPA axis hyperdrive in patients with depression (Schule, 2007). The present ndings indicate a normalizing effect on levels of free cortisol during mental challenges, restoring the defense against threats to the homeostasis. Importantly, the ndings did not confound reported differences in patients and HC, as increased blunting in patients was associated with no use of antidepressants. Inuences from acute stimulating effects on cortisol release during initiation of treatment with antidepressants (Schule, 2007), seem unlikely in this large unselected patient group. No signicant effect of antipsychotics on cortisol release during testing, is in line with a recent report in rst episode psychosis, reporting blunting of the cortisol awakening response that did not seem to be affected by antipsychotic treatment (Mondelli et al., 2010).

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4.4. Cortisol release and sex differences The present sex-related ndings of change in cortisol are in line with previous reports of HPA axis regulation. An increased cortisol release to mental challenges in men compared to women is frequently found in healthy persons (Kudielka et al., 2009). In depression and SCZ, a blunted cortisol release is indicated in male patients during challenges (Brenner et al., 2009; Brooks and Robles, 2009; Chopra et al., 2009; Peeters et al., 2003), and in response to awakening in recent onset psychosis (Pruessner et al., 2008). Furthermore, the personality traits neuroticism and extraversion seem to be associated with cortisol response to mental challenges in a sex specic manner (Oswald et al., 2006). Using pharmacological manipulation of the HPA axis, sex is reported as a strong predictor of cortisol secretion in depressed patients (Kunzel et al., 2003). In the present study, comparing all the patients with the controls irrespective of sex reached trend level signicance, but this was clearly caused by the male participants. Interestingly, some clinical characteristics seem to be sex-specic in BD and SCZ (see Arnold, 2003 and Nasser et al., 2002 for reviews). 4.5. Mechanisms of impaired cortisol release An increased HPA axis tone is shown in BD (Daban et al., 2005) and SCZ (Walker et al., 2008), including clinical effects of antiglucocorticoid treatment in BD (Young et al., 2004), and the association of HPA axis dysregulation with treatment response in SCZ (Garner et al., 2009). The current ndings of a blunted cortisol release among male patients, and negative correlations between baseline cortisol and cortisol change, are in line with the ndings that an increased HPA axis tone dampens the cortisol release during challenges (Burke et al., 2005; Kudielka et al., 2004). In addition to genetic susceptibility (Heim et al., 2009; Kumsta et al., 2007b; van West et al., 2010), potential underlying factors include early life adversities (Goodyer et al., 2001) such as prenatal exposure to alcohol, smoking, maternal nutrient restriction and early trauma. These seem associated with both psychosis spectrum symptoms and increased HPA axis tone (Brown et al., 1995; Faravelli et al., 2010; Morgan et al., 2009; Palomo et al., 2002; Saridjan et al., 2010; Vieau et al., 2007; Weinberg et al., 2008; Zammit et al., 2009). In fact, blunted cortisol response to a social stressor has repeatedly been associated with childhood trauma (Carpenter et al., 2007, 2010). Hippocampal volume reductions have to be considered as a mechanism (Buchanan et al., 2004), however, volume reductions might just as well be a secondary event to HPA axis alterations in affective and psychotic disorders (Corcoran et al., 2001). 4.6. Limitations The present study has some limitations. We measured cortisol levels at baseline and after a mental challenge, which made it difcult to detect brief changes in cortisol levels. There was a variation in time of samplings, but this was adjusted for in the statistical analysis. We measured free, bioactive cortisol, using a relative stress free sampling method. The major portion of cortisol is bound to corticosteroid binding globulin (CBG), which was not measured. Saturation of CBG inuences changes in salivary cortisol; however, this seems to be a minor problem using mild or moderate mental challenges (Hellhammer et al., 2009). Moreover, one study found no association between CBG levels and cortisol change in male participants (Kumsta et al., 2007a). Further limitations were presence of alcohol-related diagnoses and diversity in medication in the patient groups. However, analyses did not reveal any confounding effects of these variables on the reported difference between patients and HC. We did not have enough information to control for menstrual cycle phase, which could mask an effect in female participants. This is, however, less likely due to the large sample size. Personality traits were not assessed, but symptoms close to neuroticism

and extraversion such as negative symptoms, hostility and anxiety, were tested without signicant ndings. Lastly, lack of an absolute increase in cortisol during the mental challenge is an important limitation. The lack of rise was probably due to the underlying diurnal decline. Stronger elements of uncontrollability and social-evaluative threat, or testing in the afternoon would likely have solved this problem. However, this is relevant to everyday life events, and effects of the challenge on the HPA axis were shown by cortisol levels in male HC and by sex specic patterns typical for challenges. 5. Conclusion To the best of our knowledge this is the rst study to investigate the effect of a mental challenge on cortisol release across the psychosis spectrum, with ndings of an abnormal activity in male patients, benecial effects of antidepressants, associations with clinical course, and with no difference in cortisol change between BD and SCZ. The ndings indicate that cortisol dysregulation is especially important in male patients, and that HPA axis dysregulation has an impact on cortisol levels at moderate mental challenges across the psychosis spectrum. This suggests that people with severe mental disorders are vulnerable to moderate challenges in everyday life, and highlights the importance of stress coping strategies. Further studies are needed to more accurately elucidate the underlying mechanisms of the cortisol regulation during mental challenges in BD and SCZ. Acknowledgments The study was supported by grants to the TOP study group from the University of Oslo, Oslo University Hospital, the Research Council of Norway (#167153/V50, #163070/V50), and the South-Eastern Norway Regional Health Authority (#2004-123, and #2008-039). Funding sources had no involvement in study design; in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The authors thank the patients and controls for participating in the study, and the TOP study group members for contributing with data collection. We also want to thank Lien My Diep for statistical advice and Kari Julien for the analyses of the salivary samples, both of Oslo University Hospital. References
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