Morning cortisol levels in schizophrenia and bipolar disorder: A meta-analysis

Psychoneuroendocrinology (2014) 49, 187—206

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/locate/psyneuen

Morning cortisol levels in schizophrenia and bipolar disorder: A meta-analysis Leah Girshkin a,c,d, Sandra L. Matheson a,c, Alana M. Shepherd a,c , Melissa J. Green a,b,c,d,∗ a

School of Psychiatry, University of New South Wales, Sydney, NSW, Australia Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia c Schizophrenia Research Institute, Darlinghurst, NSW, Australia d Neuroscience Research Australia, Randwick, NSW, Australia b

Received 17 April 2014; received in revised form 12 July 2014; accepted 12 July 2014

KEYWORDS Hypothalamicpituitary-adrenal axis; HPA; Cortisol; Psychosis; Mood disorders; Meta-analysis; Stress; Vulnerability

Summary Increased peripheral levels of morning cortisol have been reported in people with schizophrenia (SZ) and bipolar disorder (BD), but findings are inconsistent and few studies have conducted direct comparisons of these disorders. We undertook a meta-analysis of studies examining single measures of morning cortisol (before 10 a.m.) levels in SZ or BD, compared to controls, and to each other; we also sought to examine likely moderators of any observed effects by clinical and demographic variables. Included studies were obtained via systematic searches conducted using Medline, BIOSIS Previews and Embase databases, as well as hand searching. The decision to include or exclude studies, data extraction and quality assessment was completed in duplicate by LG, SM and AS. The initial search revealed 1459 records. Subsequently, 914 were excluded on reading the abstract because they did not meet one or more of the inclusion criteria; of the remaining 545 studies screened in full, included studies were 44 comparing SZ with controls, 19 comparing BD with controls, and 7 studies directly comparing schizophrenia with bipolar disorder. Meta-analysis of SZ (N = 2613, g = 0.387, p = 0.001) and BD (N = 704, g = 0.269, p = 0.004) revealed moderate quality evidence of increased morning cortisol levels in each group compared to controls, but no difference between the two disorders (N = 392, g = 0.038, p = 0.738). Subgroup analyses revealed greater effect sizes for schizophrenia samples with an established diagnosis (as opposed to ‘first-episode’), those that were free of medication, and those sampled in an inpatient setting (perhaps reflecting an acute illness phase). In BD, greater morning cortisol levels were found in outpatient and non-manic participants (as opposed to those in a manic state), relative to controls. Neither age nor sex affected cortisol levels in any group. However, earlier greater increases in SZ morning cortisol were evident in samples taken before 8 a.m. (relative to those taken after 8 a.m.). Multiple meta-regression showed

∗ Corresponding author at: c/ UNSW Research Unit for Schizophrenia Epidemiology, St. Vincent’s Hospital, Darlinghurst, NSW 2031, Australia. Tel.: +61 02 9382 8382; fax: +61 02 8382 1584. E-mail address: [email protected] (M.J. Green).

http://dx.doi.org/10.1016/j.psyneuen.2014.07.013 0306-4530/© 2014 Published by Elsevier Ltd.

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L. Girshkin et al. that medication status was significantly associated with morning cortisol levels in SZ, when the effects of assay method, sampling time and illness stage were held constant. Heightened levels of morning cortisol in SZ and BD suggest long-term pathology of the hypothalamic-pituitaryadrenal (HPA) axis that may reflect a shared process of illness development in line with current stress-vulnerability models. © 2014 Published by Elsevier Ltd.

1. Introduction Schizophrenia and bipolar disorder are severe neuropsychiatric disorders likely caused by an interaction of multiple biological and environmental factors, with a prominent role for stress-related pathology proposed within current diathesis-stress models of illness development (Rethelyi et al., 2013). Shared environmental risk factors have been estimated to account for 3—6% of vulnerability for schizophrenia and bipolar disorder (Lichtenstein et al., 2009), and include a higher prevalence of pre- or post-natal insults (Demjaha et al., 2012; Murray et al., 2004), early childhood maltreatment (Aas et al., 2011), and/or cannabis use in adolescence (Leweke and Koethe, 2008; Moore et al., 2007). The impact of early life stressors on the development and function of the hypothalamic-pituitary-adrenal (HPA) axis may be key to understanding the development of these disorders (Collip et al., 2013; Joels et al., 2012). The HPA axis is a key component of the stress-response system (Belsky and Pluess, 2009). Cortisol is the primary hormone released by the HPA axis in response to stress, and operates to maintain homeostasis of various physiological systems (Peters et al., 2007). Cortisol levels have been shown to peak in the first 30—40 min after waking (known as the cortisol awakening response; CAR): cortisol first increases sharply, then declines gradually throughout the day, in line with a normal diurnal rhythm associated with the sleep-wake cycle (Edwards et al., 2001). This response has been shown to vary according to factors such as age (Nicolson et al., 1997) and sex (Kurina et al., 2005), and substantial evidence shows an increase in basal cortisol following childhood maltreatment (Braehler et al., 2005). Chronic hypercortisolemia has been shown to significantly affect neurophysiology, with evidence of anatomical changes in prefrontal, amygdala and hippocampal brain regions (Joels, 2008; Roozendaal et al., 2009; Wellman, 2001), altered stress responsiveness (Bollini et al., 2004), and reduced brain-derived neurotropic factor (BDNF) expression (Hansen et al., 2006). Disruptions to the 24-h diurnal rhythm of cortisol secretion are commonly reported in schizophrenia and bipolar disorder: both disorders show heightened afternoon (Gallagher et al., 2007; Ryan et al., 2004; Walsh et al., 2005) and evening levels of cortisol (Jabben et al., 2011; Linkowski et al., 1994). Heightened levels of cortisol and a flattened diurnal curve have been associated with greater clinical severity (Havermans et al., 2011; Belvederi Murri et al., 2012). In addition, both disorders show increased morning cortisol profiles and a blunted CAR (Braehler et al., 2005; Deshauer et al., 2003; Mondelli et al., 2010; Monteleone et al., 2014). The measurement of baseline levels of cortisol immediately at waking, unlike the dynamic CAR, is reflective

of basal cortisol (Clow et al., 2004; Wust et al., 2000) rather than the fluctuation of the cortisol rhythm. There is considerable evidence of increased levels of morning cortisol (here defined as a single measure taken before 10 a.m.) in both schizophrenia and bipolar disorder relative to controls. However, a number of studies have reported conflicting evidence of no increase in cortisol (Breier and Buchanan, 1992; Brunelin et al., 2008; Davila et al., 1989; Dewan et al., 1988; Duval et al., 2003; Fernandez-Egea et al., 2009; GarciaRizo et al., 2012; Garfinkel et al., 1979; Hardoy et al., 2006; Henderson et al., 2006; Jansen et al., 2000; Judd et al., 1981; Kaneda et al., 2002; Lerer et al., 1988; Maes et al., 1996; Maguire et al., 1997; Maj et al., 1984; Meltzer et al., 1984; Perini et al., 1984; Ritsner et al., 2004; Strous et al., 2004; van Nimwegen et al., 2008; Vieta et al., 1997; Whalley et al., 1985; Wolkowitz et al., 1986), or a significant decrease in morning cortisol levels in these disorders (Kirkpatrick et al., 2009; Phassouliotis et al., 2013). Increased cortisol levels observed in schizophrenia and bipolar disorder have been proposed as endophenotypic markers of illness (Cheng et al., 2010), but the potential effects of moderating variables such as illness stage, mood-state, treatment setting and psychotropic medication deserve further exploration in this context. In particular, there remains uncertainty about differing fluctuations in cortisol levels in association with manic or depressive mood states, and whether dysregulated cortisol levels remain during euthymic periods of bipolar disorder (Cervantes et al., 2001; Manenschijn et al., 2012). Some evidence has shown the depressive phase to be associated with heightened cortisol levels (Maj et al., 1984), with an absence of cortisol dysfunction during mania (Swann et al., 1992) and euthymic periods of remission (Schmider et al., 1995). However, other evidence indicates no clear relationship between cortisol level and illness phase (Deshauer et al., 2006). Additionally, the influence of illness duration on cortisol level remains unclear, with several studies showing a positive relationship between illness duration and cortisol levels (Havermans et al., 2011; Yilmaz et al., 2007) that has not always been replicated (Hempel et al., 2010). Unfortunately, studies of the relationship between illness stage and cortisol levels are often confounded by the use of psychotropic medications (Lee et al., 2011; Venkatasubramanian et al., 2010; Zhang et al., 2005). We set out to conduct a meta-analysis of the available evidence for aberrant morning cortisol levels, measured peripherally (in blood or saliva), in both bipolar disorder and schizophrenia, compared to controls, and directly compared to each other. It was hypothesized that individuals with schizophrenia or bipolar disorder would show greater levels of morning cortisol in comparison to controls, with no difference expected between the two disorders.

Meta-analysis of cortisol levels in schizophrenia and bipolar disorder We examined the effects of potential moderators such as sampling time, participant age, sex, medication status, illness stage, treatment setting, and mood state (in bipolar disorder), upon effect size estimates revealed in primary analyses.

2. Method

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disorder. The schizophrenia search terms were: exp Schizophrenia/, schizophreni$.tw., schizo$.tw. The bipolar disorder search terms were: exp Bipolar Disorder/, bi?polar.tw., bi?polar?disorder$.tw. Each of these searches additionally included the following search terms: hypothalamic-pituitary-adrenal axis.tw., HPA axis.tw., exp cortisol/, glucocorticoids.tw. Hand searching was also conducted.

2.1. Inclusion/exclusion criteria Included studies reported single measure levels of morning cortisol (≤10 a.m.) in blood serum, plasma or saliva, in adult participants with a primary diagnosis of a schizophrenia spectrum disorder (including schizophrenia, schizoaffective disorder, schizophreniform disorder or other non-affective psychoses, and collectively referred to as ‘schizophrenia’; SZ); bipolar disorder (type I or II) or mania (Meltzer et al., 1984; Perini et al., 1984; collectively referred to as ‘bipolar disorder’; BD) compared to controls, and/or presenting a comparison between disorders. Studies reporting measures of diurnal change in cortisol levels (e.g., area under the curve to demonstrate the CAR) were initially included for full review, but there were too few identified for meaningful meta-analysis (BD compared to controls: k = 4; SZ compared to controls: k = 4; SZ compared to BD: k = 2). The authors of 10 studies published since 2000 were contacted to request mean waking levels of cortisol for their samples for inclusion (Cervantes et al., 2001; Cousins et al., 2010; Deshauer et al., 2003; Gunduz-Bruce et al., 2007; Hempel et al., 2010; Lee and Meltzer, 2001; Belvederi Murri et al., 2012; Pruessner et al., 2013; Su et al., 2009; Watson et al., 2012). Usable samples were obtained from five authors: there were three new studies for inclusion in the meta-analysis of SZ compared to controls (Gunduz-Bruce et al., 2007; Pruessner et al., 2013; Watson et al., 2012), two studies for inclusion in the meta-analysis of BD compared to controls (Cervantes et al., 2001; Pruessner et al., 2013), and two studies providing data directly comparing SZ to BD (Belvederi Murri et al., 2012; Pruessner et al., 2013). Excluded studies were those reporting cortisol measures after 10 a.m. or those that did not report sample collection time, studies written in a language other than English, or published only in abstract form. Ineligible populations were those with comorbid Cushing’s disease, or samples predominately comprised of depressed patients with psychotic features, or drug induced psychosis. Other excluded studies were those using incompatible sampling methods such as hair samples (Sharpley et al., 2010), non-peripheral CNS tissue such as cerebral spinal fluid or post-mortem brain tissue (Raubenheimer et al., 2006), or challenge studies (e.g., dexamethasone suppression test) where baseline cortisol values were not reported. Agreement of the inclusion and exclusion of studies was done in duplicate by two of the authors (LG and SM); all disagreements were settled by discussion among all co-authors.

2.2. Search strategy Studies were identified up to June 2014 by searching the databases MEDLINE, Embase and BIOSIS Previews separately for studies of schizophrenia and bipolar

2.3. Data extraction Data extraction was conducted in duplicate by two of the authors (LG and SM), with all disagreements settled by discussion. Variables extracted were: (1) group mean and standard deviation of morning cortisol level as the primary outcome measure; (2) demographic, clinical and treatment characteristics: for example, number of participants in each group, age, sex, medication status (antidepressants, mood stabilizers or antipsychotics), treatment setting and stage of illness; (3) characteristics of cortisol measurement, for example, method of assay, time of sampling, and tissue type used. In cases where collection times were reported as a range, the midpoint was recorded and where sampling times were only available as a cut-off (for example 8 a.m.) this value was recorded. Several studies provided data amenable to planned subgroup analyses (for example, differences between studies in terms of patient ‘treatment setting’ enabled analysis of effect sizes separately for ‘outpatient’ or ‘inpatient’ status); for these analyses, a 70% threshold (referring to the percent of cases in the study with a given subgroup) was used to determine a study’s membership in any given subgroup category.

2.4. Study quality Study quality was assessed using the ‘Strengthening The Reporting of Observational Studies in Epidemiology’ (STROBE) statement (von Elm et al., 2007), with an individual study’s STROBE score reflecting the percentage of checked items of the total thirty-three items (items irrelevant to a study did not affect scores). Non-blinded quality assessments of included studies were conducted in duplicate by two authors (LG and AS). Screening for possible publication bias was undertaken using the classic fail-safe N to identify any potential file-drawer effects, and Egger’s tests of funnel plot asymmetry (Egger et al., 1997). The effects of year of publication were assessed via cumulative analysis (Leimu and Koricheva, 2004). Data quality was assessed in duplicate adapted to the ‘Grades of Recommendation Assessment, Development and Evaluation’ (GRADE) approach (Guyatt et al., 2011). All included data were obtained from observational studies and so were assumed to be of low quality, however ratings were upgraded when sample sizes were large, or when observed effects were consistent (low heterogeneity between studies), precise (tight confidence intervals of effect sizes, ≤0.5 g in either direction), or where comparisons, samples or measures were direct.

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2.5. Data analysis The Comprehensive Meta-Analysis program (CMA v.3) (http://www.meta-analysis.com) was used to conduct the meta-analyses. Heterogeneity across studies was expected; therefore the random effects model was fitted for all analyses (DerSimonian and Laird, 1986). Hedge’s g effect size was used in all analyses as a conservative measure of standardized mean difference (SMD), optimal for analysis of studies with small samples (Borenstein et al., 2005). An effect size of g < 0.4 was considered to be a small effect, g > 0.8 was considered to be a large effect, and the range between to be a medium sized effect (Higgins et al., 2008). A significance threshold was set at p < 0.05 (two-tailed). Heterogeneity was quantified by the I2 statistic, estimating the percentage of between study variability that could not be accounted for by chance. The Q statistic provided an index of the variance within (Qw ) and between (QB ) groups of studies. Meta-regression was conducted using a maximum likelihood (ML) model and z distribution for univariate analyses, and a restricted maximum likelihood (REML) model with a Knapp Hartung distribution for the multivariate regression (Thompson and Sharp, 1999). The proportion of variance explained by each model was quantified by an R2 analog, and multivariate analyses examined collinearity of moderators through the variance inflation factor (VIF); a VIF greater than 3 was indicative of possible collinearity. Three primary meta-analyses were conducted to examine differences in morning cortisol levels between (1) schizophrenia and controls, (2) bipolar disorder and controls, and (3) schizophrenia and bipolar disorder. Additional analyses were conducted to examine effects of potential

Figure 1

moderators including age, sex (percentage of sample that were male), time of sampling, illness stage (first-episode or established illness), treatment setting (inpatient or outpatient), medication status (medicated, naïve, or free of medication with a washout of at least 7 days), and mood state (mania or non-mania [both depression and euthymic states were classified as non-mania]; conducted for bipolar disorder comparisons only). The STROBE score (quality assessment) and year of publication were used to investigate possible relationships between study quality and temporal changes in reporting and effect size.

3. Results 3.1. Search results The initial database search resulted in 1459 unique records (see Fig. 1). Initial screening eliminated 914 studies that did not meet inclusion criteria of reporting morning cortisol levels separately for schizophrenia or bipolar disorder compared to controls, or schizophrenia compared to bipolar disorder. The remaining 545 records were screened in full and a further 484 were excluded because they did not meet one or more of the inclusion criteria; reasons for exclusion included: sampling cortisol in cerebral spinal fluid (CSF) or hair; collection of cortisol after 10 a.m.; not reporting collection time; and/or samples that were taken following an intervention (including a lumbar procedure). Data from the remaining 64 studies were extracted for analysis. Where studies were suspected to have duplicate or overlapping samples (Ritsner et al., 2004, 2007; Venkatasubramanian

Flow diagram showing the flow of information through the different phases of this meta-analysis.

Meta-analysis of cortisol levels in schizophrenia and bipolar disorder et al., 2007, 2010), authors were contacted to clarify, resulting in the exclusion Venkatasubramanian et al. (2007) for all but one analysis (schizophrenia medication naïve subgroup analysis) owing to overlap with the later study by the same author (Venkatasubramanian et al., 2010). During contact with authors of CAR studies it was also identified that one sample (Cousins et al., 2010) overlapped with another (Watson et al., 2012); the larger sample was included (Watson et al., 2012).

3.2. Study characteristics Sixty-four unique studies were identified, with three studies (Lu et al., 1988; Pruessner et al., 2013; Whalley et al., 1985) providing data for both SZ and BD participants compared to each other, and to healthy controls (i.e., these studies were thus able to be included in all three meta-analyses of SZ versus controls, BD versus controls, and SZ versus BD). Thus, meta-analyses thus comprised: 44 studies that compared SZ to controls (see Table 1); 19 that compared BD to controls (see Table 2); and 7 that directly compared SZ to BD (see Table 3).

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3.4. Bipolar disorder compared to controls Meta-analysis of 19 studies (N = 704) showed a significant small increase in morning cortisol levels in BD compared to controls (g = 0.269, s.e. = 0.094, 95% CI 0.084—0.453, p = 0.004), with moderate heterogeneity (Q = 24.99, df = 18, p = 0.125, I2 = 27.97%). One study (Thakore et al., 1996) had a substantially larger effect than other studies (distance >15 s.e. from the overall mean effect) and was subsequently removed from the analysis (and all subsequent moderator analyses); with this study removed, a small but significant effect remained (k = 18, N = 686, g = 0.210, s.e. = 0.079, 95% CI 0.056—0.364, p = 0.008; see Fig. 2), with a substantial reduction in heterogeneity (Q = 12.39, df = 17, p = 0.776, I2 = 0%). These findings provided moderate-to-high quality evidence of increased cortisol levels in BD compared to controls, owing to the consistency and precision of the results, as well as directness of the comparisons and the measures used, although the effect size was small (Atkins et al., 2004). Assessment of publication bias revealed a fail-safe N of 20 studies, and Egger’s test of funnel plot asymmetry was not significant (p = 0.241), suggesting these results are not prone to a file drawer publication bias.

3.5. Schizophrenia compared to controls 3.3. Study quality The mean STROBE score for studies included in the BD meta-analysis was 72.31% (range: 43.75—93.10%), and for the SZ meta-analysis was 75.31% (range: 53.13—93.75%). Regression of the effect sizes by study quality indicated no relationship in either the analyses of SZ (slope = 0.013, Q = 2.51, p = 0.113) or BD (slope = 0.002, Q = 0.068, p = 0.794), relative to controls. A cumulative analysis of year of publication revealed no trend in effect size according to year for the studies of BD (range: 1979—2013), or SZ (range: 1984—2014). The majority of studies measured cortisol from blood plasma (SZ: k = 23; BD: k = 9) and serum (SZ: k = 14; BD: k = 5), relative to those sampling saliva (SZ: k = 4; BD: k = 3). There was no evidence of variation in effect size according to tissue type in either SZ (QB = 2.13, p = 0.345) or BD (QB = 3.40, p = 0.334). The radioimmunoassay (RIA) method of cortisol level detection was most common amongst the included studies (SZ: k = 27; BD: k = 16). Enzymelinked immunosorbent assay (ELISA; SZ: k = 5; BD: k = 1) and other methods such as high performance liquid chromatography (HPLC; SZ: k = 6; BD: k = 0) were less frequently reported. There was no evidence of an effect of publication year on assay method in either SZ or BD. However in studies of SZ compared to controls, the HPLC method (k = 6, n = 391, g = 0.634, s.e. = 0.257, 95% CI 0.131—1.137, p = 0.014, Qw = 26.13, p < 0.001, I2 = 80.87%) and RIA method (k = 27, n = 1539, g = 0.261, s.e. = 0.105, 95% CI 0.054—0.467, p = 0.013, Qw = 91.86, p < 0.001, I2 = 71.70%) yielded higher effect sizes (QB = 5.56, p = 0.006) than ELISA (k = 5, n = 236, g = −0.054, s.e. = 0.163, 95% CI −0.374 to 0.266, p = 0.742, Qw = 5.48, p < 0.241, I2 = 27.02%). There were insufficient data for such comparison in BD. One study, conducting a comparison of SZ and BD utilized a method unique to all other studies (Mattingly, 1962).

Meta-analysis of the 44 studies (N = 2613) showed a small-to-medium increase in morning cortisol levels in SZ compared to controls (g = 0.387, s.e. = 0.119, 95% CI 0.154—0.619, p = 0.001; see Fig. 3) with substantial heterogeneity observed among studies (Q = 327.4, df = 43, p < 0.001, I2 = 86.9%). Two studies (Abel et al., 1996; Yildirim et al., 2011) showed a substantially greater increase in cortisol levels compared to controls than other studies (both distance > 15 s.e. from the overall mean effect). With these studies removed, there remained a small but significant increase in morning cortisol in SZ compared to controls (k = 42, N = 2467, g = 0.253, s.e. = 0.089, 95% CI 0.08—0.427, p = 0.004; see Fig. 3), with reduced but substantial heterogeneity remaining (Q = 168.04, df = 41, p < 0.001, I2 = 75.6%). This evidence was rated as moderate in quality owing to the medium effect size, large sample, precision and directness, but was limited by the substantial heterogeneity (Atkins et al., 2004). A fail-safe N of 306 studies, and a nonsignificant Egger’s test (p = 0.753), suggested no publication bias.

3.6. Bipolar disorder compared to schizophrenia Analysis of the seven studies reporting morning cortisol levels of BD participants compared to SZ participants (N = 392) found no significant differences evident between the disorders (g = 0.038, s.e. = 0.114, 95% CI −0.185 to 0.261, p = 0.738; see Fig. 4), and a homogenous effect across studies (Q = 5.64, df = 6, p = 0.464, I2 = 0%). This evidence was rated as low-to-moderate quality owing to the results being consistent, precise and direct, in the context of the small sample and small effect size (Atkins et al., 2004). For these data, Egger’s test approached significance (p = 0.068) and the fail-safe N was zero (owing to no significant effect having been found) (Rosenthal, 1979).

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Table 1

Characteristics of studies that compared schizophrenia and controls that were included in analysis.

Study name

Group

Sample

N Abel 1996#,§ Altamura 1989§ √ Beyazyüz 2014 Breier 1992 Brunelin 2008 Davila 1989 Duval 2003 Fernandez-Egea 2009 Garcia-Rizo 2012 Gunduz-Bruce 2007‡ Henderson 2006 Herz 1985 Hoshino 1984 Jansen 2000 Jorgensen 2013§ Kaneda 2002 Kirkpatrick 2009§

Lerer 1988

13 13 54 20 60 24 9 7 15 14 11 14 20 23 41 41 33 32 16 29 15 9 15 15 19 26 18 21 40 40 53 23 46 59 107 31 10

(SD)

Units

488.5 333.1 19.31 14.1 9.9 10.34 15.1 12.9 391 541.8 19.6 19.6 357.5 321.5 18.3 22.9 17.6 19.1 0.59 0.6 12.8 10.6 21.5 14.8 8.9 10.1 12 17.6 p = 0.03*

(45.8) (33.9) (4.9) (7.3) (3.5) (3.65) (4.8) (3.9) (105.3) (303.1) (4.6) (4.9) (136.8) (93.5) (5.2) (7.3) (6.2) (6.2) (0.25 (0.32) (4.0) (4.1) (6.4) (3.4) (2.2) (2.6) (27.2) (29.3)

nmol/L

16.4 15.0 18.3 21.2 11.9 9.6 t = 1.73*

(4.8) (5.7) (5.4) (5.9) (4.6) (3.3)

␮g/dL ␮g/dL ␮g/dL nmol/mL ng/mL nmol/L mg/dL ␮g/dL ␮g/dL ␮g/dL ␮g/dL ␮g/dL nmol/L nmol/L ␮g/dL mg/dL ␮g/dL ␮g/dL

Illness stage

Medication status

Treatment setting

Gender (% males)

Assay method

Sampling time (a.m.)

Source

29.5 31.7 31.94 — 27.04 26.67 30.6 28.2 28.6 29.1 30 33 32.5 34.2 29.2 28.2 28.6 26.8 25.8 29.8 44.6 35 32 34.53 35 27 27.7 27 33 31.4 51.9 50.7 29 28.9 33.7 20 43.3

FEP

Naïve

Inpatient

RIA

9:30

Plasma

Established

Medicated

Inpatient

HPLC

8:00

Plasma

Mixed

Mixed

Inpatient

RIA

8:00

Serum

Established

Free

Outpatient

RIA

9:00

Plasma

Established

Medicated

Outpatient

HPLC

9:00

Plasma

Established

Medicated

—

RIA

8:30

Plasma

Established

Free

Inpatient

ELISA

9:00

Serum

FEP

Naïve

Inpatient

RIA

8:30

Plasma

FEP

Free

Inpatient

ELISA

8:30

Serum

FEP

Medicated

—

RIA

8:00

Saliva␴

Established

Medicated

Outpatient

ELISA

7:00

Serum

Established

Mixed

Inpatient

RIA

8:00

Serum

Established

Medicated

—

RIA

10:00

Plasma

Established

Medicated

Outpatient

RIA

8:00

Saliva

Established

Medicated

Mixed

—

9:00

Plasma

Established

Medicated

—

HPLC

6:30

Plasma

FEP

Naïve

Inpatient

—

8:30

—

Established

Free

Mixed

RIA

9:00

Plasma

Established

Free

Inpatient

76.9 — 64.8 — 100 100 100 100 66.7 57.1 100 — 55 47.8 68.3 68.3 60.6 63.6 75 100 80 77.8 46.7 46.7 47.4 53.8 61.1 61.9 50 50 62.3 56.5 72 71.2 76.1 56.4 80

RIA

8.63

Plasma

L. Girshkin et al.

Lee 2011§

SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ

Mean

Age (years)

Maes 1996 Maguire 1997 Manzanares 2014 Marcelis 2004 Meltzer 2001§ Mokrani 2000 Monteleone 1999§ Muck-Seler 1999§ Muck-Seler 2004§ Newcomer 2002 Phassouliotis 2013§ Popovic 2007§ Pruessner 2013‡,,∂ Ritsner 2004 Ritsner 2007§ Ryan 2003§ Strous 2004

Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls

10 36 20 13 21 7 22 65 25 50 50 51 15 47 22 16 16 86 69 20 25 39 22 21 20 18 20 45 30 40 15 43 20 26 26 37 25

19.4 16.2 11.1 8.5 411.0 321.0 21.1 23.5 12.5 12.8 12.1 8.1 344.4 344.0 353.0 264.0 t = 4.06*

(7.3) (6.0) (4.6) (2.5) (150.8) (150.1) (9.9) (10.6) (5.0) (5.4) (4.8) (2.8) (112.2) (154.8) (108.0) (104.0)

533.0 389.0 12.8 17.3 457.0 572.0 518.8 441.9 9.8 11.3 422 381.0 449.4 260.7 499.4 303.2 341.0 391.0

(181.0) (110.0) (5.8) (11.8) (160.0) (185.0) (117.9) (108.7) (7.5) (5.3) (186.0) (205.5) (307.2) (102.7) (161.4) (10.5) (167.0) (200.0)

␮g/dL ␮g/dL nmol/L nmol/L ng/␮L ␮g/dL nmol/L nmol/L nmol/L nmol/L mg/dL nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L

41 28.4 24.7 27.8 25.9 — — 24.4 27 31.2 35 36.6 25.5 32.6 33.9 28.1 28.2 30.4 34 33.1 39.5 39.4 39.61 20.6 22.4 28.8 30.4 21.9 22.9 38 35.1 34.1 37.2 33.6 34.4 27.3 28.1

Established

Free

Inpatient

Established

Medicated

Inpatient

Established

Medicated

—

Established

Medicated

Outpatient

Established

Medicated

Outpatient

Established

Free

—

Established

Free

Inpatient

Established

Free

Inpatient

Established

Free

—

Established

Free

—

Established

Medicated

Mixed

FEP

Naïve

Mixed

Established

Medicated

—

FEP

Medicated

Outpatient

Established

Medicated

Inpatient

Established

Medicated

Inpatient

FEP

Naïve

Inpatient

FEP

Medicated

Inpatient

80 50 100 76.9 66.7 — — 60 44 52 50 82.4 66.7 66 45 50 50 100 — 0 0 70.8 38.7 57 60 50 40 69 48.5 95 86.7 93 90 57.7 57.7 45.9 55.6

RIA

8:00

Plasma

RIA

9:00

Plasma

RIA

9:30

Plasma

ELISA

9:00

Saliva␪

RIA

9.83

Plasma

RIA

8:45

Plasma

RIA

9:00

Serum

RIA

8:45

Plasma

RIA

8:00

Plasma

RIA

8:00

Plasma

RIA

8:30

Plasma

—

9:00

Serum

RIA

8:00

Serum

TRFIA

9:05ϑ

Saliva

RIA

8:30

Plasma

RIA

8:30

Serum

HPLC

8:00

Plasma

RIA

9:00

Serum

Meta-analysis of cortisol levels in schizophrenia and bipolar disorder

Lu 1988

193

194

Table 1 (Continued) Study name

van Nimwegen 2008 √ Venkatasubramanian 2010 ,§ Whalley 1985 √ Wolkowitz 1986 Yildirim 2011#,§ Yilmaz 2007§ √ Zhang 2005 ,§

Group

SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls SZ Controls

Sample

Age (years)

Illness stage

Medication status

Treatment setting

Gender (% males)

Assay method

Sampling time (a.m.)

Source

FEP

Naïve

Mixed

8:00

Plasma

Established

Mixed

—

HPLC

8:30

Serum

Established

Free

Inpatient

RIA

7:30

Plasma

Established

Mixed

Inpatient

RIA

9.33

Serum

Established

Outpatient

ELISA

8:30

Serum

␮g/dL

33.6

Established

HPLC

10:00

Serum

ng/mL

43.8 40.4

Established

Medicated 50 Medicated 50 Mixed

100 100 70.3 60.6 100 100 50 — 51.7 37.3 100 37.3 76.9 73.3

ELISA

nmol/L

23.8 23 33.8 32.2 25.6 29.9 0 — 36.3

RIA

8:00

Serum

N

Mean

(SD)

Units

7 7 33 33 13 13 8 8 60 60 66 28 78 30

207.0 251.0 13.1 9.5 524.0 436.0 12.0 16.9 428.2 295.0 12.5 10.3 90.6 72.2

(52.0) (91.0) (5.1) (4.0) (121.0) (174.0) (4.5) (3.7) (39.6) (31.0) (3.2) (3.1) (37.0) (24.7)

nmol/L ␮g/dL nmol/L ␮g/dL

— Inpatient

SZ, schizophrenia; ELISA, enzyme-linked immunosorbent assay; HPLC, high-performance liquid chromatography; RIA, radioimmunoassay; TRFIA, time resolved fluorescence immunoassay; √ §, study reported a significant group difference; #, excluded from analysis; , data pooled from subgroups; , also eligible for inclusion in analysis for comparison of bipolar disorder/SZ and/or bipolar disorder/controls; , citric acid stimulated drool collected in a plastic vial; ␴, polyester swabs without preparation; ␪, Salivettes; ‡, authors contacted for more information; ∂, sampling conducted at waking; ϑ, analyses were run using sampling time of cases; *, for these studies that did not report sample mean values for each group, the sample size, and test-statistic (or p-value) representing the difference between the two groups, was entered into CMA for analysis.

L. Girshkin et al.

Characteristics of studies that compared bipolar disorder and controls that were included in analysis.

Study name

Group

Amsterdam 1983§ Bei 2013

√ √

Cervantes 2001‡, Dewan 1988 Dinan 1994§

√ El Khoury 2003 ,§ Garfinkel 1979 Hardoy 2006 Judd 1981 Lu 1988 Macritchie 2013 Maj 1984

√

Meltzer 1984 Perini 1984 Pruessner 2013‡,,∂ Thakore 1996#,§ Vieta 1997

BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD Controls BD

Sample

N

Mean (SD)

Units

22 22 14 17 18 5 23 14 7 7 44 11 11 10 17 16 9 7 16 20 25 23 15 15 21 24 8 11 11 30 9 9 39

14.4 (4.0) 14.4 (3.8) 14.96 (2.57) 15.28 (1.65) 18.6 (4.68) 17.9 (4.19) 14.1 (5.7) 11.9 (4.1) 680.0 (268.5) 315.6 (305.3) 549.1 (129.2) 513.4 (112.7) 14.9 (5.9) 19.0 (11.9) 127.7 (40.4) 108.4 (37.2) 14.3 (5.9) 16.0 (6.5) 17.1 (5.9) 16.2 (6.0) 12.3 (8.9) 10.9 (5.4) 161.3 (55.5) 138.3 (35.4) 10.8 (4.6) 9.6 (3.4) 18.0 (5.6) 14.6 (6.3) 10.7 (8.2) 11.3 (5.3) 460.8 (152.1) 182.6 (50.2) 14.4 (5.2)

␮g/dL ␮g/dL ␮g/dL ␮g/dL nmol/L nmol/L mg/dL ng/mL ␮g% ␮g/dL nmol/L ng/mL ␮g/dL ␮g/dL nmol/L nmol/L ng/mL

Age (years)

Illness stage

Affective state

Medication status

Treatment setting

Gender (% males)

Assay method

Sampling time (a.m.)

Source

32 32.1 40.5 42 42.91 35.2 32.9 31.1 39.7 36.8 41.4 41 38.4 31.9 37.2 37.1 43 27 32.9 24.7 43.8 43.9 46.5 45.6 30 29.5 43 — 21.9 22.9 34.1 32.1 37.3

—

Mixed

Free

Outpatient

RIA

8:00

Serum

—

Mixed

Medicated

Mixed

ELISA

8:45

Plasma

Established

Not manic

Medicated

Outpatient

RIA

8:00

Serum

—

Not manic

—

—

RIA

8:00

Plasma

—

Manic

Free

Inpatient

RIA

8:30

—

—

Not manic

Mixed

Outpatient

RIA

7:30

Plasma

—

Manic

Free

Inpatient

RIA

9:00

Plasma

Established

Not manic

Medicated

Outpatient

RIA

9:15

Plasma

—

Manic

Medicated

Inpatient

—

9:00

Serum

—

Not manic

Free

Inpatient

RIA

8:00

Plasma

—

Not manic

—

—

RIA

8:00

Saliva

—

Mixed

Medicated

—

RIA

8:00

Plasma

—

Manic

Free

Inpatient

RIA

10:00

Serum

—

Manic

Medicated

Inpatient

RIA

8:00

Serum

FEP

—

Medicated

Outpatient

TRFIA

9:05ϑ

Saliva

—

Manic

Free

Inpatient

RIA

8:38

Plasma

Established

Not manic

Medicated

Outpatient

50 50 47.6 23.5 61 80 69.6 57.1 100 100 0 0 54.5 60 0 0 93.7 85.7 56.3 100 60 56.5 33.3 33.3 38.1 56 50 — 54.5 48.5 77.8 — 33.3

RIA

8:00

Plasma

Meta-analysis of cortisol levels in schizophrenia and bipolar disorder

Table 2

195

7:30 RIA —

Manic

Free

—

33.3 53 55 100 100 — Medicated Not manic Established

nmol/L

36.7 48 45 29.9 29.9 nmol/L

12.7 (3.4) 9.1 (5.0) 9.03 (4.5) 480.0 (143.0) 436.0 (174.0) Whalley 1985

Watson 2012‡,∂

Controls BD Controls BD Controls

21 49 34 9 13

Units Mean (SD) N

BD, bipolar disorder; RIA, radioimmunoassay; HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbent assay; TRFIA, time resolved fluorescence immunoassay; √ #, excluded from analysis; , data pooled from subgroups; §, studies reported a significant group difference; , passive drool; ␪, salivettes; , collected in plain tubes; , also eligible for inclusion in analysis for comparison of BD/schizophrenia and/or schizophrenia/controls; ‡, authors contacted for more information; ∂, sampling conducted at waking; ϑ, analyses were run using sampling time of cases.

<8:00ϑ RIA

Source Sampling time (a.m.) Assay method Gender (% males) Treatment setting Medication status Affective state Illness stage Age (years) Sample Group Study name

Table 2 (Continued)

Plasma

L. Girshkin et al. Saliva␪

196

3.7. Potential moderator analyses 3.7.1. Effects of sex and age There was no effect of sex (percentage of male cases) on BD (k = 18, slope = −0.001, Q = 0.162, p = 0.687) or SZ (k = 41, slope = 0.00001, Q = 0.0023, p = 0.988) effect sizes (refer to Table 4); nor was there a significant effect of age on results for BD (k = 18, slope = −0.01, Q = 0.74, p = 0.39) or SZ (k = 40, slope = 0.026, Q = 3.5, p = 0.061; see Table 4). Interestingly, increasing age was associated with increasing effect sizes within the studies where schizophrenia participants were medication-naïve (k = 7, slope = 0.15, Q = 8.33, p = 0.004). 3.7.2. Effects of medication The meta-analysis of the subgroup of medicated BD participants (n = 405) showed no significant increase in morning cortisol levels compared to controls, with no heterogeneity evident (k = 10, g = 0.184, s.e. = 0.104, 95% CI; −0.019 to 0.388; p = 0.076; Qw = 6.42, p = 0.697, I2 = 0%). Medication-free BD cases (n = 207) did not differ significantly from controls in levels of morning cortisol (k = 7, g = 0.268, s.e. = 0.169, 95% CI; −0.063 to 0.599, p = 0.113; Qw = 8.649, p = 0.194, I2 = 30.63%). Between-group comparison of medication subgroups revealed no differences in effect size among medicated or medication-naïve BD patients (QB = 0.176, p = 0.675). In contrast, SZ participants free of antipsychotic medication (minimum 7 day wash out) (n = 937) showed a medium effect of increased morning cortisol levels compared to controls (k = 16, g = 0.468, s.e. = 0.115, 95% CI 0.242 to 0.693, p < 0.001), with moderate heterogeneity (Qw = 36.76, p = 0.001, I2 = 59.19%); however, currently medicated participants (n = 1328) were not significantly different from controls (k = 23, g = 0.170, s.e. = 0.101, 95% CI −0.029 to 0.368, p = 0.095) with similarly high heterogeneity (Qw = 64.26, p < 0.001, I2 = 65.76%). In addition, SZ participants free of medication had a greater increase in cortisol (compared to controls) than those who were medicated at the time of sampling, explaining some of the heterogeneity found in the main analysis (QB = 3.78, p = 0.052). Medication-naïve participants (n = 438) showed no difference in morning cortisol levels relative to controls (k = 7, g = 0.036, s.e. = 0.358, 95% CI -0.667 to 0.738, p = 0.920) but very high heterogeneity (Qw = 74.16, p < 0.001, I2 = 91.91%). These comparisons of medication-naïve participants with medication-free participants (QB = 1.32, p = 0.251), and medication-naïve participants with medicated participants (QB = 0.13, p = 0.720) did not significantly explain any between-study heterogeneity. 3.7.3. Effects of Sampling time A meta-regression of the time of day at which samples were collected revealed no significant effect of sampling time on effect sizes for SZ (k = 42, slope = −0.199, Q = 2.65, p = 0.103) or BD (k = 18, slope = −0.003, Q = 0.0007, p = 0.978). However, investigation of the effects of waking time were also possible in subgroup analyses of studies reporting sampling times either before or after a 8 a.m., as the mean waking time of studies reporting this sample characteristic (Duval et al., 2003; Mokrani et al., 2000; Belvederi Murri et al., 2012; Pruessner et al., 2013). In these subgroup analyses,

Characteristics of studies that compared schizophrenia and bipolar disorder that were included in analysis.

Study name

Group

Sample

N Fava 1984 Lu 1988 Belvederi Murri 2012‡ Pruessner 2013‡,,∂ Schlesser 1980 Swigar 1979

Whalley 1985

Mean (SD)

BD SZ BD SZ BD SZ BD SZ BD SZ BD

4 12 16 36 11 60 11 45 94 48 8

17.7 (8.5) 21.2 (8.5) 17.1 (5.9) 19.4 (7.3) 7.38 (2.9) 9.97 (6.33) 10.7 (8.2) 9.8 (7.5) 15.2 (5.1) 14.1 (4.2) 18.5 (9.8)

SZ BD SZ

25 9 13

18.7 (6.9) 480.0 (143.0) 524.0 (121.0)

Age (years)

Illness stage

Medication status

Treatment setting

Gender (% males)

17.68 39.54 32.9 28.4 28 29.3 21.9 21.9 —

—

Medicated

—

Established

Free

Inpatient

FEP

Medicated

Mixed

FEP

Medicated

Outpatient

—

—

Mixed

—

Medicated

Inpatient

—

Established

Free

Inpatient

100 100

Assay method

Sampling Source time (a.m.)

RIA

8:00

Serum

RIA

8:00

Plasma

ELISA

8:00

Saliva

TRFIA

9:05ϑ

Saliva␪

RIA

8:00

Serum

Mattingly method

8:00

Plasma

RIA

7:30

Plasma

Units ␮g/dL ␮g/dL nmol/L nmol/L ␮g/dL ␮g/dL

—

nmol/L

29.9 25.6

78 84.6 56.3 50 45.5 68.9 54.5 69 —

Meta-analysis of cortisol levels in schizophrenia and bipolar disorder

Table 3

SZ, schizophrenia; BD, bipolar disorder; ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay; TRFIA, time resolved fluorescence immunoassay; ‡, authors contacted for data, sample sizes reported may be different than those in the published studies; , also eligible for inclusion in analysis for comparison of BD/controls and/or SZ/controls; ∂, sampling conducted at waking; ␪, salivettes; , mixture of salivettes and sorbettes; ϑ, analyses were run using sampling time of cases.

197

198

L. Girshkin et al. Study name

Statistics for each study

Hedges's g and 95% CI

Hedges's Standard Lower Upper g error limit limit p-Value Amsterdam 1983 Bei 2013 Cervantes 2001 Dewan 1988 Dinan 1994 El Khoury 2003 Garfinkel 1979 Hardoy 2006 Judd 1981 Lu 1988 Macritchie 2013 Maj 1984 Meltzer 1984 Perini 1984 Pruessner 2013 Vieta 1997 Watson 2012 Whalley 1985

0.000 -0.134 0.147 0.417 1.186 0.279 -0.427 0.484 -0.253 0.151 0.185 0.481 0.296 0.536 0.496 0.360 0.014 0.261 0.210

0.296 0.284 0.488 0.335 0.548 0.333 0.425 0.345 0.479 0.328 0.285 0.361 0.295 0.452 0.350 0.269 0.221 0.419 0.079

-0.580 -0.691 -0.809 -0.240 0.112 -0.374 -1.259 -0.192 -1.191 -0.493 -0.373 -0.226 -0.283 -0.351 -0.190 -0.167 -0.419 -0.560 0.056

0.580 0.422 1.103 1.074 2.261 0.932 0.405 1.160 0.684 0.794 0.743 1.188 0.875 1.422 1.182 0.888 0.448 1.082 0.364

1.000 0.636 0.763 0.214 0.030 0.403 0.315 0.160 0.596 0.647 0.515 0.182 0.316 0.236 0.156 0.181 0.948 0.534 0.008 -2.00

-1.00 Controls

Figure 2

0.00

1.00

2.00

Cases

Forest plot for comparison of bipolar disorder and healthy controls.

heightened cortisol levels in SZ were most exaggerated in the early morning, showing a medium effect (≤8 a.m.; k = 15, n = 866; g = 0.521, s.e. = 0.132, 95% CI 0.262—0.781, p = <0.001; Qw = 43.1, p = < 0.001, I2 = 67.51%). No increase in cortisol was seen in studies of SZ conducted after 8 a.m. (k = 27, n = 1601; g = 0.108, s.e. = 0.107, 95% CI −0.102 to 0.318, p = 0.313; Qw = 101.71, p = <0.001, I2 = 74.44%). This subgroup analysis explained a significant portion of heterogeneity between studies in SZ (QB = 5.904, p = 0.015). 3.7.4. Effects of Illness stage In studies comparing SZ and controls, a moderate increase in morning cortisol level was demonstrated in participants with an established illness (k = 33, n = 1672, g = 0.355, s.e. = 0.08, 95% CI 0.191—0.519, p < 0.001; Qw = 87.57, p < 0.001, I2 = 63.46%), but not in first-episode participants (k = 10, n = 421, g = −0.096, s.e. = 0.21, 95% CI −0.506 to 0.313, p = 0.644; Qw = 53.68, p < 0.001, I2 = 83.23%), accounting for a significant portion of between-study variance (QB = 4.019, p = 0.045). There were insufficient studies reporting stage of illness in BD participants to allow examination of this moderator (established illness = 4, firstepisode = 1). 3.7.5. Effects of treatment setting In BD studies, subgroup analyses of inpatients (k = 6, n = 151, g = 0.207, s.e. = 0.195, 95% CI −0.174 to 0.589, p = 0.287, Qw = 6.99, p = 0.221, I2 = 28.50%) and outpatients (k = 6, n = 256, g = 0.295, s.e. = 0.153, 95% CI 0.031—0.559, p = 0.029, Qw = 1.776, p = 0.879, I2 = 0%), revealed a significant effect for outpatients only; however, the difference in effect sizes between subgroups was not significant (QB = 0.137, p = 0.711). For SZ, inpatient samples (k = 19, n = 1076) showed a small significant increase in morning cortisol relative to controls (g = 0.304, s.e. = 0.152, 95% CI 0.006—0.602, p = 0.046), with substantial heterogeneity remaining (Qw = 95.6, p < 0.001, I2 = 81.17%). Relatively

fewer SZ studies of outpatient participants (k = 7, n = 373), demonstrated no significant difference in cortisol levels relative to controls (g = 0.021, s.e. = 0.154, 95% CI −0.282 to 0.323, p = 0.894, Qw = 11.36, p = 0.078, I2 = 47.16), and pairwise comparison of the subgroups was not significant (QB = 1.71, p = 0.191). 3.7.6. Effects of mood state (bipolar disorder studies only) There were no significant differences in morning cortisol levels between manic BD participants compared to controls (k = 8, n = 198, g = 0.150, s.e. = 0.152, 95% CI −0.148 to 0.448, p = 0.323, Qw = 8.130, p = 0.321, I2 = 13.9%). However, there was a small sized increase in morning cortisol level in nonmanic (depressed or euthymic) BD participants compared to controls (k = 10, n = 450, g = 0.231, s.e. = 0.098, 95% CI 0.039—0.422, p = 0.018), with no heterogeneity (Qw = 5.56, p = 0.783, I2 = 0%). Pairwise comparison of the subgroups indicated that differing mood state could not significantly account for the variance in cortisol level found between studies in the main analysis (QB = 0.197, p = 0.657). 3.7.7. Multivariate meta-regression A multivariate regression was conducted for SZ studies (k = 38) to estimate the effects of significant moderators revealed above (method of assay [RIA, HPLC or ELISA], time of sampling [≤8 a.m. or >8 a.m.] illness stage [first episode or established illness] and medication status [medicated, medication free or medication naïve]. Reference categories for the variables ‘method of assay’, ‘time of sampling’, ‘illness stage’ and ‘medication status’ were: ‘RIA’, ‘>8 a.m.’, ‘established illness’, and ‘medicated’, respectively. The overall model was significant (F6,35 = 3.31, p = 0.0109) and explained 42% of between-study variance (R2 analog = 0.42). Within this model, medication status was an important moderator (F2,35 = 3.06, p = 0.059) of effect size when all other covariates were held constant (slope = 0.443, s.e. = 0.187,

Meta-analysis of cortisol levels in schizophrenia and bipolar disorder Study name

199

Statistics for each study Hedges's g

Standard error

0.910 -0.127 0.469 -0.656 -0.008 0.306 -0.719 -0.239 -0.033 0.524 1.272 -0.491 -0.194 0.490 0.298 -0.506 0.537 0.741 0.461 0.738 0.582 -0.236 -0.057 0.890 0.003 0.818 0.653 0.971 -0.533 -0.653 0.665 0.487 0.211 0.713 1.690 -0.273 -0.556 0.773 0.569 -1.119 0.679 0.535 0.253

Altamura 1989 Beyazyuz 2014 Breier 1992 Brunelin 2008 Davila 1989 Duval 2003 Fernandez-Egea 2009 Garcia-Rizo 2012 Gunduz-Bruce 2007 Henderson 2006 Herz 1985 Hoshino 1984 Jansen 2000 Jorgensen 2013 Kaneda 2002 Kirkpatrick 2009 Lee 2011 Lerer 1988 Lu 1988 Maes 1996 Maguire 1997 Manzanares 2014 Marcelis 2004 Meltzer 2001 Mokrani 2000 Monteleone 1999 Muck-Seler 1999 Muck-Seler 2004 Newcomer 2002 Phassouliotis 2013 Popovic 2007 Pruessner 2013 Ritsner 2004 Ritsner 2007 Ryan 2003 Strous 2004 van Nimwegen 2008 Venkatasubramanian 2010 Whalley 1985 Wolkowitz 1986 Yilmaz 2007 Zhang 2005

Lower limit

0.270 0.240 0.484 0.371 0.390 0.302 0.226 0.246 0.306 0.414 0.391 0.301 0.315 0.225 0.248 0.198 0.205 0.444 0.278 0.356 0.429 0.234 0.199 0.300 0.255 0.359 0.165 0.312 0.268 0.315 0.327 0.237 0.299 0.275 0.319 0.257 0.511 0.252 0.388 0.512 0.229 0.216 0.089

0.382 -0.596 -0.479 -1.383 -0.772 -0.286 -1.162 -0.721 -0.633 -0.288 0.505 -1.081 -0.812 0.049 -0.188 -0.895 0.135 -0.129 -0.084 0.040 -0.258 -0.694 -0.446 0.301 -0.498 0.114 0.329 0.359 -1.058 -1.270 0.024 0.024 -0.375 0.175 1.063 -0.776 -1.558 0.279 -0.192 -2.124 0.230 0.111 0.080

Upper limit

Hedges's g and 95% CI p-Value

1.439 0.343 1.417 0.072 0.756 0.897 -0.276 0.243 0.567 1.335 2.039 0.099 0.425 0.930 0.785 -0.117 0.940 1.611 1.007 1.435 1.422 0.223 0.332 1.479 0.504 1.523 0.976 1.582 -0.009 -0.036 1.307 0.951 0.798 1.252 2.316 0.230 0.446 1.268 1.329 -0.115 1.128 0.959 0.427

0.001 0.596 0.332 0.077 0.983 0.311 0.001 0.331 0.914 0.206 0.001 0.103 0.540 0.029 0.230 0.011 0.009 0.095 0.098 0.038 0.174 0.314 0.773 0.003 0.991 0.023 0.000 0.002 0.046 0.038 0.042 0.039 0.480 0.009 0.000 0.288 0.277 0.002 0.143 0.029 0.003 0.013 0.004 -2.00

-1.00

0.00

1.00

Controls

Figure 3

Cases

Forest plot for comparison of schizophrenia and controls.

Study name

Statistics for each study

Hedges's g and 95% CI

Hedges's Standard Lower Upper g error Variance limit limit Z-Value p-Value Belvederi Murri 2012 Fava 1984 Lu 1988 Pruessner 2013 Schlesser 1980 Swigar 1979 Whalley 1985

0.430 0.392 0.328 -0.108 -0.223 0.025 0.325 0.038

0.326 0.550 0.298 0.332 0.177 0.396 0.420 0.114

0.107 0.303 0.089 0.110 0.031 0.157 0.176 0.013

-0.210 -0.686 -0.255 -0.759 -0.570 -0.751 -0.498 -0.185

1.070 1.318 1.471 0.713 0.911 1.102 0.542 -0.326 0.124 -1.260 0.802 0.064 1.148 0.774 0.261 0.334

0.188 0.476 0.271 0.744 0.208 0.949 0.439 0.738 -1.50 -0.75 0.00 0.75 1.50 BD

Figure 4

Forest plot for comparison of schizophrenia and bipolar disorder.

SZ

2.00

200

Table 4

Results summary for studies that compared schizophrenia to controls and bipolar disorder to controls.

Analysis

Schizophrenia k

Overall

g

Bipolar disorder Slope

s.e.

p

42

0.253

—

0.089

0.004

k

g

*

18

0.210

Slope

s.e.

p

—

0.079

0.008*

Medication subgroups

Naïve Free Medicated

7 16 23

0.036 0.468 0.17

— — —

0.358 0.115 0.101

0.920 <0.001* 0.095

— 7 10

— 0.268 0.184

— — —

— 0.169 0.104

— 0.113 0.076

Treatment setting

Inpatient Outpatient

19 7

0.304 0.021

— —

0.152 0.154

0.046* 0.894

6 6

0.207 0.295

— —

0.195 0.153

0.287 0.029*

Mood phase

Manic Non-manic

— —

— —

— —

— —

— —

8 10

0.150 0.231

— —

0.152 0.098

0.323 0.018*

Time of sampling

≤8 a.m. >8 a.m.

15 27

0.521 0.108

— —

0.132 0.107

<0.001* 0.313

— —

— —

— —

— —

— —

Illness stage

Established First episode

33 10

0.355 −0.096

— —

0.080 0.210

<0.001* 0.644

— —

— —

— —

— —

— —

Univariate regressions

Age Sex Time

40 41 42

— — —

0.026 0.00001 −0.199

0.014 0.004 0.122

0.061 0.988 0.103

18 18 18

0.010 0.003 0.120

0.390 0.687 0.978

Multivariate# regressions

Illness stage Method of assay# Medication status# Sampling time

38

— — — —

−0.420 0.591 0.443 0.298

0.281 0.237 0.187 0.167

0.145 0.018* 0.023* 0.084

— — — —

— — — —

— — — —

— −0.001 −0.003 — — — —

— — — —

k, number of studies; g, Hedge’s g; s.e., standard error; , effect size measured by either Hedge’s g or slope; #, full multivariate model: F(6,35) = 3.31; p = 0.0109; R2 analog = 0.42; medication status: F(2,35) = 3.06; p = 0.059; method of assay: F(2,35) = 3.42; p = 0.044. * p ≤ 0.05.

L. Girshkin et al.

Meta-analysis of cortisol levels in schizophrenia and bipolar disorder 95% CI 0.064—0.822, p = 0.023, R2 analog = 0.07), reflecting a higher mean effect size in studies with medication-free participants relative to those reporting effects for medicated SZ. Further, the method of assay was a significant predictor of effect size (F2,35 = 3.42, p = 0.044) when all other covariates were held constant (slope = 0.591, s.e. = 0.237, 95% CI 0.109—1.073, p = 0.018, R2 analog = 0.02), reflecting a higher mean effect size in studies using HPLC compared to those using the RIA method. There was no evidence of collinearity among moderators in the model (VIF < 3). Goodness of fit indices (I2 = 62.31%. Q = 92.87, p < 0.001) suggest an incomplete model that has limited ability in attributing unexplained variance found in the main SZ analysis. No multivariate analyses were performed on the BD studies owing to limited unexplained variance in the primary analysis.

4. Discussion This meta-analysis of 64 studies examining morning cortisol levels in schizophrenia and/or bipolar disorder demonstrated a small to moderate increase in morning cortisol levels in each disorder, relative to controls, with no difference in morning cortisol levels between these disorders when compared directly. Variation in effect sizes among studies was partially accounted for by medication effects in schizophrenia, and illness characteristics such as treatment setting, illness stage (in schizophrenia) and mood state (in bipolar disorder). In schizophrenia, ‘medication-free’ samples showed the greatest increase in morning cortisol level, relative to controls. With regard to illness characteristics, larger effect sizes were noted in ‘established’ (compared to ‘first-episode’) schizophrenia cases, and inpatients, relative to controls; in bipolar disorder, increased cortisol levels were found in participants in a non-manic state, and in outpatient samples, relative to controls. In schizophrenia, increasing age was associated with larger effect sizes in the medication-naïve subgroup (with a non-significant trend in the same direction for all SZ studies) when compared to controls, and large effect sizes in schizophrenia were evident in studies where samples were collected before 8 a.m. There was no influence of sex on effect size estimates. A summary of all meta-analyses and meta-regressions is presented in Table 4. The significant, moderate increase in morning levels of peripheral cortisol in both schizophrenia and bipolar disorder is consistent with previous studies showing disruptions in diurnal variation among patients with psychosis, including increased cortisol levels in the morning, afternoon and evening (Cervantes et al., 2001; Gil-Ad et al., 1986). Abnormally elevated cortisol levels in healthy individuals have been associated with peripheral markers of inflammation (Waterman et al., 2006), cognitive impairment (Schilling et al., 2013), and various neuropathology (Dedovic et al., 2009; Jeanneteau and Chao, 2013; Veer et al., 2012). These findings are also consistent with evidence of maladaptive glucocorticoid receptor (GR) function in these disorders (Ceulemans et al., 2011; Harris et al., 2012). Possible neurobiological underpinnings of this shared increase in morning cortisol include the overexpression of a GR risk isoform and increased metabolism of cortisol (Sinclair et al., 2012b; Steen et al., 2011) that suggests common HPA-axis pathology among schizophrenia and

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bipolar disorder. However, evidence from post-mortem brain studies has also demonstrated variation among schizophrenia and bipolar disorder with respect to reduced GR mRNA expression in differing subregions of the brain (Sinclair et al., 2012a; Webster et al., 2002). In addition, pharmacological manipulation of GR receptor function has demonstrated that blockade improves neurocognition in bipolar disorder but not in schizophrenia (Gallagher et al., 2005; Watson et al., 2012). Shared increases in morning cortisol among schizophrenia and bipolar disorder thus need not reflect similar pathological processes. Investigation of potential moderators of morning cortisol levels suggests a moderating role of treatment setting in both disorders, medication effects and illness chronicity in schizophrenia, and mood state in bipolar disorder. The inconsistent association between effect size and treatment setting (greater levels of cortisol in bipolar disorder outpatients, compared to controls; greater levels of cortisol in schizophrenia inpatients compared to controls) may reflect the smaller number of BD studies, or suggest differential patterns of HPA dysregulation in relation to illness state (if acute psychotic episode can be assumed from schizophrenia inpatient status). The significant increase in effect sizes with increasing illness chronicity is consistent with a previous report (Yilmaz et al., 2007), and implicates compounding effects of illness-related stress such as cellular inflammation (Zhang et al., 2005) perhaps associated with chronic dysregulation of the HPA axis (Souza-Talarico et al., 2009). Long-term effects on the brain may include dopamine mediated hyper-responsivity to stress, and neuropathology in brain regions responsible for negative feedback of cortisol (Deutch et al., 1990; Holmes and Wellman, 2009; Vyas et al., 2002). The significant effect of medication status on levels of cortisol in schizophrenia reflected larger effect sizes in medication-free (post wash-out period) cases relative to medicated patients, and was consistent across univariate and multivariate regression analyses. This finding is consistent with previous evidence for elevated cortisol levels upon withdrawal from antipsychotic medication (Naber et al., 1985). In contrast, there were no significant effects of medication in bipolar disorder. While bipolar disorder samples were predominately taking antidepressants and/or mood stabilizers, a number of studies included patients taking adjunct antipsychotics. Exclusion of these (latter) studies for investigation of potential medication effects would have had detrimental effects on subgroup size and was not deemed necessary owing to the small within-group heterogeneity. Unlike antipsychotics, mood stabilizers have been shown to increase cortisol levels in a dose dependent manner (Platman and Fieve, 1968). The greater effect size estimates in non-manic bipolar (but not manic) samples, relative to controls, is consistent with previous research in bipolar disorder (Swann et al., 1992). However, this finding may appear to be at odds with studies of healthy individuals in which the administration of exogenous corticosteroids has elicited manic symptoms (Sirois, 2003). Reconciliation of these findings might see mood-state effects on cortisol levels in bipolar disorder interpreted as dysregulation of the HPA axis during both manic and depressed states, such that in manic phases there is perhaps a lack of the expected increase in cortisol levels

202 that might normally function to engender (down)regulation of mechanisms associated with the ascent into mania. In relation to the potential influence of the CAR in affecting the effect-size estimates reported here, it is notable that larger effect sizes in schizophrenia compared to controls were revealed in samples taken ≤8 a.m. compared to those collected >8 a.m. This result was obtained in the context of inconsistent reporting of waking time, which precluded analysis of the potential moderating effects of time-lapsed between waking time and sample time. From the few studies that reported waking time, we estimated the average waking time to be 8 a.m., and the average time-lapse between waking and sampling time to be approximately 1 h (Duval et al., 2003; Mokrani et al., 2000; Belvederi Murri et al., 2012; Pruessner et al., 2013). Lack of difference in cortisol levels between schizophrenia cases and healthy controls during later stages of the morning may be consistent with a flattened (or blunted) cortisol awakening response (CAR) that is commonly reported in schizophrenia (Braehler et al., 2005; Mondelli et al., 2010; Monteleone et al., 2014). Finally, the implication of finding greater increases in cortisol in schizophrenia compared to controls according to assay method suggests systematic variation in validity of these methods, in line with previous research showing radioimmunoassay to consistently produce higher concentrations of cortisol than enzyme immunoassay (Raff et al., 2002). Other limitations of this study include the availability of only seven studies for the comparison of schizophrenia and bipolar disorder, and a greater number of male participants in the included studies (almost 80% of the samples were predominantly male) that may have confounded tests of the moderating effect of sex. Moreover, we cannot be sure that estimated effect sizes revealed here were not influenced by the CAR, since the samples analyzed were obtained at anytime prior to 10 a.m., with only a few studies reporting the waking time/s for their sample. As noted above, our analyses of effect sizes according to sampling time suggest that dysfunction in the CAR may indeed account for the lack of differences between schizophrenia and healthy control samples taken after 8 a.m. Similarly, the significant moderator effects of illness stage in schizophrenia must be considered in light of the inconsistent reporting of this illness feature, and of drug class and polypharmacy use (Cohrs et al., 2006; Deuschle et al., 2003; Popovic et al., 2007; Ritsner et al., 2007; Strous et al., 2004; Venkatasubramanian et al., 2010). Finally, while the finding of no difference in effect size between samples collected in blood versus saliva may be seen as promising, inferences about this finding are limited by the small number of studies reporting cortisol levels from saliva samples (k = 7) relative to blood (k = 51). In summary, the meta-analyses presented here demonstrate increased levels of morning cortisol in schizophrenia and bipolar disorder, with no discernable difference in morning cortisol levels between these disorders. Effect sizes were moderated by medication status, and illness chronicity in schizophrenia, and by mood state in bipolar disorder, and by treatment setting in both disorders. These results provide further evidence of dysregulated HPA function, indexed via cortisol levels, in schizophrenia and bipolar disorder, however moderator effects suggest that the neurobiological underpinnings of this dysfunction may not be shared. Future studies of large cross-disorder samples

L. Girshkin et al. are required to characterize the precise pathophysiology of HPA dysfunction in these disorders.

Role of the funding sources This research was supported by the Australian National Health and Medical Research Council (NHMRC Project Grant 630471), and the Schizophrenia Research Institute using infrastructure funding from the NSW Ministry of Health. Salary for M.J.G. was provided by the Australian Research Council (Future Fellowship 0991511, 2009—13), and the NHMRC (R.D. Wright Biomedical Career Development Fellowship, 1061875, 2014—17) during the preparation of this manuscript.

Conflict of interest The authors declare no conflict of interest.

Acknowledgements We acknowledge the advice of Professor Vaughan Carr and Dr. Kristin Laurens in the early stages of planning this study.

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