Psychiatry and Clinical Neurosciences 2015; 69:

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1 Psychiatry and Clinical Neurosciences 2015; 69: doi: /pcn Review Article Role of cortisol in patients at risk for psychosis mental state and psychopathological correlates: A systematic review Evangelos Karanikas, MD, PhD 1,2 * and Giorgos Garyfallos, MD, PhD 2 1 Psychiatric Department, 424 Military General Hospital of Thessaloniki, and 2 2nd Psychiatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece During recent decades, much evidence has been accumulated concerning the neuroendocrine basis of schizophrenia. Recently, research has focused on stress hormones, with cortisol being the most widely researched, during the prodromal phase of psychosis. Thus, the present study aims to systematically review the evidence concerning the role of cortisol in patients at risk for psychosis mental state and its associations with psychopathological correlates. We systematically reviewed the published reports referring to both at clinical risk for psychosis and at genetic risk for psychosis mental state. Sixteen studies were identified. A trend towards increased cortisol levels in saliva emerged. Findings concerning cortisol levels in the blood were minimal and less consistent. The longitudinal studies, though with divergent results, hinted towards upregulation of cortisol secretion prior to psychotic conversion. Regarding cortisol s reactivity, evaluated through neuroendocrine, psychosocial and naturalistic stressors, the findings were minimal and divergent. The hypothesized relation of psychotic symptomatology with cortisol in subjects at risk for psychosis was not confirmed by the majority of the studies. On the contrary, the anxiety parameter and stress-intolerance index were both positively associated with cortisol. In conclusion, the published reports related to the evaluation of cortisol levels/ function at prodrome are hitherto minimal. Although the evidence favors cortisol s participation in the pathophysiology of psychosis, the exact cause effect sequence and the intertwining of cortisol with psychopathology are still unclear. Key words: cortisol, hypothalamo pituitary adrenal axis, psychopathology, psychosis, risk. DURING THE LAST decade, much effort has been made towards the identification of biological markers that could delineate the etiopathophysiological mechanisms of psychosis. The prevailing neurodevelopmental model suggests that early life trauma damages the hippocampus, thus resulting in heightened vulnerability to the development of psychosis. 1 In addition, a neural diathesis can set the stage for increased susceptibility to developing psychosis in the context of stress. 2 Indeed, this trait in conjunction with a damaged hippocampus and the consequent disruption of the *Correspodence: Evangelos Karanikas, MD, PhD, Karakasi 45A, Thessaloniki, Greece. epkarani@yahoo.com Received 12 May 2014; revised 15 November 2014; accepted 25 November hypothalamo pituitary adrenal (HPA) axis, which can set in a dysfunctional mode cortisol secretion in response to stress, are thought to play a pivotal role in the pathophysiological mechanisms relating to the conversion to psychosis. The study of the HPA axis is of critical importance in order to comprehend the underlying mechanisms of stress-related disorders. The HPA axis, along with the locus ceruleus (LC) norepinephrinergic (NE)/ autonomic system constitute the primary systems to moderate the physiological response to psychological and physiological stressors in mammals. 3,4 This physiological response, known as adaptive response, incorporates a number of alterations of bodily organs and systems, thus ensuring psychosomatic equilibrium. The activation of the HPA axis and the LC NE/autonomic system results in systemic elevations of glucocorticoids and catecholamines, 268

2 Psychiatry and Clinical Neurosciences 2015; 69: Cortisol and psychosis 269 respectively, which act in concert to maintain basal and stress-related homeostasis. 5 The evidence regarding the neuroendocrine basis of schizophrenia has been growing during the last decade. Published reports have focused on the evaluation of pivotal hormones of the HPA axis, such as corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol, either in blood or saliva samples. The majority of the studies were conducted within the context of basal HPA axis functioning (that is, when no stressor is being applied). Only a handful of them looked into HPA axis reactivity through application of dynamic stressors. The results of the studies involving chronic psychosis were divergent. A major reason to explain the contradictory results is the heterogeneity of the studies in terms of diagnoses, comorbidity, phase of illness and exposure to medication. 6 In order for these findings to be further delineated, researchers recently shifted their attention towards the prodromal phase when subtle psychotic symptomatology starts being demonstrated, well before psychotic diagnosis can be substantiated. The selection of this population can provide insight into the etiopathogenetic mechanisms of psychosis from the very early stage without the confounding effect of medication, phase and chronicity. To date, only one other review has been conducted in subjects at risk for psychosis (ARP) mental state. 7 To our knowledge, there has not been a systematic review aiming for the collective integration of cortisol s abnormalities and psychopathological correlates in ARP subjects. We deliberately chose to concentrate on circulating cortisol, as it is the most commonly evaluated stress hormone, rather than dealing with other components of the HPA axis, which might be a distraction from identifying cortisol s patterns. METHODS We conducted this current systematic review electronically with the aid of Medline (PubMed). We used keywords or phrases, such as relatives/ultra high risk/at risk mental state in combination with stress/hpa axis/cortisol and psychosis and psychopathology for the research. After reviewing the articles, we searched for their references when there was a speculation that an article might be of interest. The inclusion criteria were: (i) peer-reviewed studies, written in English, up to August 2014; (ii) studies measuring cortisol levels either in blood or saliva, even if this evaluation was not the primary aim of the study; (iii) studies involving cortisol measurement either at basal condition or with a single or multiple sampling or even after application of different types of stressors; (iv) studies where cortisol levels were evaluated either in comparison with healthy controls (HC) or as part of longitudinal or crossover studies aiming to evaluate the correlation between cortisol and psychopathology, no matter whether or not the two later cases involved an HC group; (v) studies involving first-degree relatives of psychotic patients, without the prerequisite of recent functional decline, thus composing the at genetic risk for psychosis group (AGRP); and (vi) studies involving subjects at clinical risk for psychosis (ACRP) according to the two main classification systems for prodrome, namely the Structured Interview for Prodromal Syndromes (SIPS), along with the Scale of Prodromal Symptoms (SOPS), 8 the Comprehensive Assessment for At Risk Mental State (CAARMS), 9 and their modified versions. Some studies had overlapping samples, which were clearly stated or confirmed after personal contact with the authors. Consequently we excluded the smaller of the overlapping studies. When two studies had overlapping cohorts but different designs, we included both studies. We identified 16 studies referring to cortisol levels in ARP populations (Table 1) The studies referring to the ARP mental state involved 806 subjects and 498 HC. Five studies did not involve an HC group. 12,13,16,19,21 Another six incorporated an extra group of participants composed of chronic psychotic patients (n = 173). For technical reasons, we adopted the concession that subjects being first-degree relatives of psychotic patients, without the prerequisite of recent functional decline, would constitute the AGRP group. In contrast, subjects with a first-degree relative who was a psychotic patient having shown a reduction in social functioning, evaluated by the Global Assessment of Functioning Scale, 26 by at least 30% in the past 12 months, would qualify for the ACRP group. Thus, 240 AGRP subjects were referred in five studies versus 566 ACRP subjects, who were recruited as per the two main classification systems for prodrome or their modified versions, in the remaining 11 of the total 16 studies of this review. A common modification was adopted in studies with schizotypal personality disorder (SPD) patients, of whom any functional decline in the Global Assessment of

3 270 E. Karanikas and G. Garyfallos Psychiatry and Clinical Neurosciences 2015; 69: Table 1. Studies measuring cortisol levels/response and association with psychopathology on ARP subjects (when referred) Findings Study Subjects Methods (cortisol evaluation) Weinstein et al. 20 SPD vs 20 other (1999) 10 PD vs 12 HC Marcelis et al. (2004) FD relatives vs 50 psychotic patients vs 50 HC Multiple (4) saliva samples. At hours and at hourly intervals thereafter. 2DG i.v. infusion, 2 plasma samples pre- and 4 samples post-infusion at 60 min, 90 min, 120 min and 150 min. Thompson et al. (2007) ACRP subjects Single plasma sample at baseline and subsequent clinical evaluations, for transition to psychosis, for 2 years. Thompson et al. (2007) ACRP subjects CRH/DST test with multiple blood samples and clinical evaluations for transition for 2 years. Spelman et al. 44 FD relatives vs 38 (2007) 14 psychotic patients vs 38 HC Brunelin et al. 15 siblings vs 15 (2008) 15 psychotic patients vs 14 HC Walker et al. (2010) SPD & APSS subjects. Yildirim et al. (2011) FD relatives vs 60 psychotic patients vs 60 HC. Single plasma sample ( hours). 2DG i.v. infusion, 2 plasma samples pre- and 4 samples post-infusion at 20 min, 40 min, 60 min, 120 min and 150 min. Multiple saliva samples at baseline (09.00), 7 10 months and months thereafter, with annual clinical evaluations for conversion for 5 years. Single serum sample ( hours). Collip et al. 60 siblings vs 63 HC. Multiple saliva samples (10 (2011) 18 times)/day for 6 days. Mittal and Walker (2011) ACRP subjects. Multiple saliva samples at 09.00, & hours. Cortisol levels/reaction Higher cortisol levels in SPD vs HC (P < 0.05) and other PD (P < 0.02). Greater linear decline in cortisol release in SPD vs HC (P = 0.02). No difference in cortisol change between relatives and HC (P < 0.772). Lower cortisol increase in patients vs HC (P < 0.013). Transition-ACRP subjects had lower cortisol levels at baseline vs non-transition subjects (P = 0.005). Non-transition ACRP subjects had higher cortisol levels during the latter stages of the test vs transition ACRP. Higher cortisol levels in patients vs both relatives and HC (P < 0.001). No group effect for baseline cortisol (P = 0.28). No group effect for cortisol change during stressor (P = 0.3). Higher cortisol levels in converted subjects, at first follow-up (P < 0.01), a trend after 1 year (P = 0.05) and higher AUCg (P < 0.01) and AUCi (P < 0.01) vs non-converters, after control for medication. Higher cortisol levels in relatives vs HC (P < 0.05). No difference in DHEA-S between relatives and HC. Higher cortisol and DHEA- S in patients vs both relatives and HC (P < 0.05). Higher diurnal cortisol at baseline (P = 0.027) and higher reactivity to stress (P = 0.03) in siblings. No difference in the steepness of secreted cortisol s diurnal decline (P = 0.393). Association cortisol psychopathology (within ARP group) Cortisol associated with hassles (r = 0.53, P = 0.051), anxiety (HARS) (r = 0.55, P = 0.017) and depression (HDRS) (r = 0.56, P = 0.017). No correlation of cortisol with BPRS (P = 0.112), BPRS psychotic (P = 0.382) and SANS (P = 0.916). No significant relations of cortisol scores (as indexed by baseline and follow-up means, AUCg, or AUCi) with BDI. Increased cortisol levels in siblings were associated with increased psychotic experiences (ESM items) (P < 0.001) and negative affect (ESM items). Increased MPA were significantly associated with elevated cortisol (r = 0.28, P < 0.05), and at the trend level (P < 0.1) with deficits in both immediate (r = 0.2) and delayed visual memory (r = 0.21) and disorganized symptoms (r = 0.18).

4 Psychiatry and Clinical Neurosciences 2015; 69: Cortisol and psychosis 271 Table 1. (Continued) Findings Study Subjects Methods (cortisol evaluation) Sugranyes et al. 33 ACRP subjects vs (2012) HC Single saliva sample (11.30 hours). Clinical evaluations for 2 years for conversion to psychosis. Corcoran et al. 31 ACRP subjects Single saliva sample (11.00 (2012) 21 hours). Mizrahi et al. (2012) ACRP subjects vs 10 psychotic patients vs 12 HC Pruessner et al. (2013) ACRP subjects vs 21 HC Walker et al. (2013) ACRP subjects vs 141 HC Multiple saliva samples every 12 min during MIST test. TSST performed and saliva cortisol samples taken 45 min (arrival), 30 min, 15 min before test and immediately, 10 min, 20 min, 40 min, 60 min thereafter. Mean of 3 saliva samples over 2.5 h ( hours). Clinical evaluations for conversion for 2 years. Day et al. 52 ACRP vs 42 HC AUCg of multiple saliva samples (2014) 25 (awakening, noon, hours) & CAR-AUCi. Cortisol levels/reaction Trend for increased basal salivary cortisol secretion in ACRP group (P = 0.07). Higher cortisol in ACRP medication-free subgroup vs both HC (P = 0.03) and medicated ACRP (P = 0.04). Non-significantly lower baseline cortisol levels in converted subjects vs non-converters (P = 0.26). Higher AUC cortisol increase in patients (P = 0.04). ACRP subjects showed intermediate response between patients and HC. Lower cortisol levels (P = 0.038) and blunted increase (P = 0.042) in ACRP. No difference in cortisol response between treated and untreated ACRP (P = 0.21). Higher cortisol levels in ACRP (P < 0.05). Converters showed higher baseline cortisol vs HC (P = 0.01) and those in remission (P = 0.03). No difference in AUCg. Significantly lower CAR-AUCi only in the medication-free ACRP subgroup (P = 0.024). Association cortisol psychopathology (within ARP group) Cortisol secretion was not significantly related to positive, negative, disorganized symptoms (SOPS), anxiety (HARS), or depression (HDRS); however, cortisol was associated (at trend level) with stress intolerance (r = 0.53, P = 0.06). No relation between cortisol and positive (SOPS) (P = 0.8), negative symptoms (SOPS) and depression (BDI & CDI). Significant association with anxiety (r = 0.38, P = 0.04) (BAI), suspiciousness (r = 0.38, P = 0.04) and stress intolerance (r = 0.42, P = 0.02) (SOPS). No relation between cortisol and acute stress (P = 0.98), depression (HDRS) (P = 0.25), positive (BPRS) (P = 0.50) and negative (BPRS) (P = 0.16) psychiatric symptoms, global functioning (GAF) (P = 0.82), or any protective factors (all P > 0.33). Significant correlations of cortisol with positive (r = 0.13, P < 0.01), negative (r = 0.09, P < 0.05), general (r = 0.11, P < 0.05), and disorganized symptoms (r = 0.11, P < 0.05) (SOPS). The same trend with dysphoric mood (r = 0.11, P < 0.05), and stress intolerance (r = 0.12, P < 0.05), (SOPS). No association between daytime cortisol and CAR in both the whole sample and the medication-free ARCP subgroup with positive, negative, disorganized symptoms (PQ), neither with depressive symptoms (BDI) (all P > 0.05). 2DG, 2-deoxy-D-glucose; ACRP, at clinical risk for psychosis; APSS, attenuated positive symptom syndrome; ARP, at risk for psychosis; AUCg, area under curve grouping; AUCi, area under curve increase; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BPRS, Brief Psychiatric Rating Scale; CAR, cortisol awakening response; CDI, Children s Depression Inventory; CRH, corticotrophin-releasing hormone; DHEA-S, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; ESM, experience sampling method; FD, first-degree; GAF, Global Assessment of Functioning; HARS, Hamilton Anxiety Rating Scale; HC, healthy controls; HDRS, Hamilton Depression Rating Scale; MIST, Montreal Imaging Stress Task; MPA, minor physical anomalies; PD, personality disorders; PQ, Prodromal Questionnaire; SANS, Scale for the Assessment of Negative Symptoms; SOPS, Scale of Prodromal Symptoms; SPD, schizotypal personality disorder; TSST, Trier Social Stress Test.

5 272 E. Karanikas and G. Garyfallos Psychiatry and Clinical Neurosciences 2015; 69: Functioning Scale, of more than 30% over the past year, was not taken into account. 10,16,24 With regard to the psychopathological parameters in the ARP mental state and their potential connection with cortisol, symptoms such as the prodromal psychotic ones, anxiety, depression and perceived stress were investigated. Their quantitative evaluation involved a number of psychometric tools, the most common of them being the SOPS and its subscales, 8 the Positive and Negative Syndrome Scale and its subscales, 27 the Brief Psychiatric Rating Scale (BPRS), 28 the Hamilton Anxiety Rating Scale 29 and the Hamilton Depression Rating Scale. 30 RESULTS ARP studies with blood samples Only two studies evaluated cortisol levels in blood in the ARP population. 14,17 Cortisol levels were evaluated with a single blood sample and both studies involved three groups, namely, psychotic patients, first-degree relatives and HC. The primary aim was to investigate glucose tolerance by performing an oral glucose tolerance test 14 and a serum cortisol/ dehydroepiandrosterone sulfate (DHEA-S) ratio in AGRP subjects. 17 The results were discordant: in one study, serum cortisol levels were significantly higher in the AGRP subjects in relation to HC, 17 whereas the other study failed to show any difference. 14 Of note, in both studies the psychotic group exhibited significantly higher blood cortisol levels compared with both relatives and HC. Interestingly, the two studies differed in the way the participant groups matched amongst themselves with regard to age and cortisol sampling method (plasma vs serum) whereas in only one of these cases the matching for educational status 17 and smoking status was clearly stated. 14 ARP studies with saliva In five studies, cortisol was estimated in saliva at baseline (without the application of any stressor). 10,18,20,24,25 In one study, cortisol was estimated in a single sample, 20 whereas the rest of the studies involved multiple saliva sampling throughout day. In one study, cortisol fluctuation was evaluated with the experience sampling method, constituted by random saliva sampling and subsequent completion of self-assessment reports of various aspects of psychopathology. 18 Findings converged towards significant increase of cortisol in ARP subjects, no matter whether they referred to AGRP subjects, 18 to ACRP 24 or to SPD patients. 10 Yet, in two studies, the cortisol figures diverted from the previous norm. In the study by Sugranyes et al., cortisol figures were increased at a trend level in the ACRP group compared with HC. 20 This increase of cortisol reached statistical significance for the medication-free ACRP subgroup, compared with the medicated ACRP and HC counterparts. Whereas in the most recent study, by Day et al., there were no differences in the daytime area under the curve (AUC) cortisol, with respect to ground (AUCg), between both the whole sample of the ACRP subjects and the non-medicated ones compared with the HC. 25 Of note, when it comes to the evaluation of cortisol s slope (fluctuation) in saliva throughout the day, the results were contradictory, as Weinstein et al. suggested significantly greater linear decline in cortisol release in SPD compared with HC, 10 as opposed to the Collip et al. study showing no difference in the steepness of diurnal decline in cortisol secretion between siblings and HC. 18 Only lately, the studies involving the estimation of salivary cortisol have extended to the evaluation of cortisol awakening response (CAR), thought to be a mild naturalistic stressor. The only study having evaluated the CAR in ACRP subjects showed blunted AUC cortisol response with respect to increase (CAR- AUCi) at a trend level compared with the HC group. 25 This blunted response reached statistical significance when further analyses commenced on the medication-free ACRP subgroup. ARP studies with metabolic stress Two studies involved the estimation of cortisol levels in ARP subjects through the application of acute metabolic stressor. 11,15 The stressor concerned administration of glucose analogue 2-deoxy-D-glucose (2DG) i.v., which induces a mild transient state of glucoprivation. Plasma cortisol levels were assessed twice before the 2DG infusion and several times after the infusion. Both studies implicated three groups, namely psychotic patients, AGRP and HC. The results indicated increases of cortisol with respect to baseline, during stress condition, without a significant difference between the relatives and the HC groups. Yet, in the one study, the increase in plasma cortisol during the stress condition was significantly less in

6 Psychiatry and Clinical Neurosciences 2015; 69: Cortisol and psychosis 273 psychotic patients compared with HC, 11 whereas this was not the case in the other. 15 ARP studies with psychosocial stress Two recent studies involved the application of psychosocial tests, 22,23 which have been validated as paradigms to evoke hormonal stress response. 31,32 Mizrahi et al. applied the Montreal Imaging Stress Task to three groups: schizophrenia patients, ACRP subjects and HC. 22 Whereas Pruessner et al. utilized the Trier Social Stress Test (TSST) to ACRP subjects and HC along with successive saliva sampling. 23 The studies rendered contradictory results. Specifically, the TSST study demonstrated lower cortisol levels and blunted increase in the ACRP group. On the contrary, the AUC of salivary cortisol with respect to change during the Montreal Imaging Stress Task showed a significant difference between the groups, with the patients exhibiting the largest cortisol response to stress and the ACRP intermediate between the HC and patients. 22 The aforementioned studies, apart from the varied type of the applied psychosocial stressor, differed also in the sample size, the recruitment criteria (CAARMS vs SIPS/SOPS), the matching for educational status, the comorbid depressive component and the number of medicated ACRP participants, thus resulting in heterogeneity on multiple levels. ARP longitudinal studies Five studies incorporated a longitudinal design based on ARP subjects conversion to full psychosis. 12,13,16,20,24 Subjects were followed up with psychometric evaluations for 2 years, except for one study, where this period rose to 5 years. 16 Moreover, this study was the only one that, in addition to psychometric evaluations longitudinally, involved multiple (three) saliva sampling, consecutively at baseline, 7 10 months and months after baseline. Apart from the differential inclusion criteria for prodrome, the design of these studies differed in the methods with which cortisol was evaluated. Specifically, studies used a single plasma sample at baseline, 12 a single saliva sample at baseline, 20 multiple longitudinal saliva samples, 16 multiple saliva samples throughout the day 24 and the combined neuroendocrine test dexamethasone suppression test (DST)/ CRH, which consisted of oral ingestion of 1.5 mg of dexamethasone at h and i.v. administration of 100 μg CRH the following day and subsequent blood drawings for the following 90 min. 13 With regard to the results, the DST/CRH study demonstrated that non-transition ACRP subjects had higher cortisol levels during the later stages of the test. 13 In contrast, the ACRP subjects who developed full-blown psychosis during the follow-up period had lower levels of cortisol at baseline than those who did not convert. 12 To make matters more perplexing, in another study, the ACRP subjects, who consecutively developed psychosis, exhibited significantly higher saliva cortisol at the first follow-up (7 months after baseline), a trend for higher values at the 1-year follow-up and significantly larger AUCg and AUCi of cortisol secretion compared with the non-converter ACRP. 16 Similarly, in a recent study, with the largest sample size, the ACRP converted subjects had significantly higher baseline cortisol in relation to the HC and remission subgroups. 24 On the contrary, Sugranyes et al. found that subjects who later transitioned to psychosis over 2 years showed non-significantly lower baseline cortisol levels. 20 Of note, the aforementioned studies were heterogenous in terms of the medication status and comorbid psychiatric states imposed on the ACRP participants. ARP studies and psychopathological correlations General psychotic index From a total of 16 studies that investigated cortisol levels and function in ARP subjects, only two studies gauged the general index of psychotism, 12,24 with the general scale of BPRS and SIPS, respectively. The results were contradictory, as the most recent study with the largest cohort (n = 256) suggested significant positive association of cortisol levels with prodromal psychotic symptomatology, 24 contrary to the findings of the counterpart study (n = 23). 12 The aforementioned studies differed in their applied ACRP criteria (SIPS/SOPS vs CAARMS) and the sampling methods (multiple saliva vs single blood samples). Positive symptoms With regard to positive psychotic symptomatology and its hypothesized correlation with cortisol, from the six implicated studies, 12,20,21,23 25 the majority of them suggested no significant correlation. 12,20,21,23 This assumption is furthered by another study, which only indirectly suggested no significant association of

7 274 E. Karanikas and G. Garyfallos Psychiatry and Clinical Neurosciences 2015; 69: cortisol with positive symptoms, on the basis that minor physical anomalies in the ARP subjects were well correlated with cortisol but not with positive symptomatology. 19 Only one study obtained a significant, modest positive correlation between saliva cortisol levels at baseline and positive SOPS scale. 24 Interestingly, this latter study showed altered cortisol levels in the ACRP population, thus opposing the former ones, which either did not implicate an HC group 12,21 or failed to find aberrant cortisol levels. 20 The study by Pruessner et al. was the only exception to this. 23 These studies differed in terms of the applied classification criteria (CAARMS 12,23 vs SIP/SOPS 20,24 vs modified versions), 19,21 the utilized psychometric tools (BPRS positive subscale 12,23 vs SOPS positive subscale 19 21,24 vs Prodromal Questionnaire positive) 25 and the methodology of cortisol evaluation (single 12 vs mean multiple counts 19,24 vs AUC 23 vs CAR 24 ) and (saliva 19 21,23,24 vs plasma). 12 Negative symptoms Similarly to the findings concerning the relation between positive psychotic symptoms and cortisol, the same five studies 12,20,21,23,25 also suggested there was no significant connection between negative symptoms evaluated through the SOPS negative, 20,21 the BPRS negative, 23 the Scale for the Assessment of Negative Symptoms, 12 the Prodromal Questionnaire negative subscales, and cortisol. 25 This assumption is indirectly supported by the findings of the minor physical anomalies study. 19 Again, the study by Walker et al., whose strength relies on the sample size and the multiple saliva cortisol sampling, suggested opposite results, as cortisol was positively correlated with negative symptoms. 24 Anxiety symptoms The correlations between the anxiety parameter and cortisol were estimated in three studies and the results were divergent. 12,20,21 Anxiety was evaluated with the Hamilton Anxiety Rating Scale in two studies 12,20 and the Beck Anxiety Inventory in the third. 21 All three studies involved ACRP subjects. Two of them suggested positive correlation between anxiety and cortisol levels at baseline in a single plasma 12 and salivary sample. 21 In contrast, Sugranyes et al. failed to replicate this finding. 20 The aforementioned studies, apart from the criteria for ACRP identification, differed also in their design as two of them were prospective regarding the transition to psychosis 12,20 and the third was crosssectional. 21 In addition, two of these studies did not involve an HC group. 12,21 Furthermore, comorbidity with other axis I disorders was not taken into consideration, except for the study by Thompson et al. 12 Depressive symptoms Six studies investigated the correlation between cortisol and the depressive parameter in the ACRP state. 12,16,20,21,23,25 No significant correlation was found by the majority of the studies. 16,20,21,23,25 On the contrary, only one study suggested positive association. 12 From the above-mentioned studies, Pruessner et al. investigated the cortisol AUCi during psychosocial stress test, 23 Walker et al. both the AUCg and AUCi of cortisol secretion longitudinally, 16 Day et al. both the salivary daytime cortisol AUCg and the CARi, 25 whereas the rest of the studies referred to single salivary cortisol sample at baseline. Stress tolerance Impaired stress tolerance and its positive association with cortisol levels seems to have been a common denominator in the ARP studies. 20,21,24 Yet, this association was significant in two of the studies, referring to a single cortisol sample 21 and the mean of three saliva samples, 24 whereas a subgroup of ACRP subjects in the third study exhibited positive association at trend level. 20 Stress tolerance was evaluated through the relevant SOPS subscale and only Sugranyes et al. clearly stated that stress sensitivity was significantly impaired in ACRP subjects in relation to HC. 20 DISCUSSION The findings concerning cortisol levels in the ARP mental state support the increase of basal cortisol secretion, opposing the minimal and divergent data with regard to cortisol s reactivity. Moreover, cortisol s association with psychotic and depressive symptomatology does not seem to be replicated, whereas anxiety and stress intolerance tend to associate closely with the pre-psychotic state. The finding that tended to be replicated fairly consistently by the majority of the related studies is the increased salivary cortisol levels at baseline of the ARP subjects. The consistency lessened regarding the

8 Psychiatry and Clinical Neurosciences 2015; 69: Cortisol and psychosis 275 steepness of the cortisol slope throughout day (i.e. cortisol s fluctuation). There was one suggestion that the steeper slope, indicating cortisol s decline in daytime secretion in SPD, might constitute an index of heightened response to novelty, 10 thus furthering the vulnerability stress model in psychosis. 2 On the other hand, cortisol s steeper decline was not replicated in a recent study concerning the AGRP subjects but this same study supported the siblings heightened cortisol response to everyday stress. 18 Contrary to the saliva studies, those involving evaluation of cortisol in blood samples were minimal and the findings less consistent. The results of the previous two studies, with single blood samples, were contradictory, thus suggesting issues related not only to the heterogeneity of the participants regarding age, smoking and education status but the reliability of the blood method itself. 14,17 Indeed, cortisol is known to present with fluctuations throughout the day due to circadian variation. 33 This variation combined with the one caused by the sampling time, along with the time of awakening covariates and the distress of the blood sampling method, renders single cortisol blood sampling the least reliable method for cortisol estimation Moreover, other factors (age, education, smoking) that added to the heterogeneity of the participant groups in blood studies could have played a role in the divergence of the results Furthermore, the longitudinal studies in the ARP population, although considered to constitute the most promising type of methodology in the psychoneuroendocrinological field to investigate causal relations between biomarkers and psychopathology severity, are far from delineating the etiopathophysiological mechanisms in psychosis, as the results were divergent and the same goes for their design. 12,13,16,20,24 Nevertheless, the two strongest studies in terms of the sample size 24 and the thoroughness of the design (the only ones where consecutive cortisol evaluations along time were involved), 16 converge towards upregulation of total cortisol secretion and its daytime fluctuation prior to conversion to psychosis. To sum up, the majority of the evidence supports an upregulation of baseline cortisol secretion even during the prodromal stage of psychosis. This evidence lies in line with the existing etiopathological models of psychosis. According to one model, prolonged overproduction of glucocorticoids during adolescence, possibly exacerbated by an altered set point of HPA axis activity, can have a negative effect on an already damaged hippocampus. 3,39 In turn, this is thought to have a negative impact on the regulation of HPA axis activity and a feed-forward circuit can lead to an overdrive of glucocorticoid production. Prolonged heightened cortisol levels also damage the hippocampus, thereby reducing negative feedback even further. This vicious cycle of events is often referred to as the glucocorticoid cascade. 3,4 Heightened HPA axis activity has also been associated with an enhanced dopamine activity in the subcortical brain regions. 2,3 These hormonal and neuronal modifications are thought to unmask the underlying vulnerability to psychosis. When it comes to the evaluation of HPA axis reactivity in the ARP population, the evidence becomes obscure. This is not surprising as the same obscurity has been shown in the studies related to the firstepisode psychosis patients HPA axis function. 42 Specifically, findings related to the evaluation of both the steepness of the cortisol slope throughout day and the HPA axis reactivity to awakening, plus to the application of either metabolic or psychosocial type of stressors, were less consistent compared with the ones regarding cortisol levels at baseline. Analytically, the studies with metabolic stressors failed to show any difference in cortisol change, 11,15 thus suggesting that HPA axis reactivity has not been set in a dysfunctional mode in subjects with genetic vulnerability to psychosis. Alternatively, it could be hypothesized that the use of a metabolic stressor might not exert enough activation of HPA axis, as to constitute an appropriate method to probe HPA axis function at the prodromal stage of psychosis. This stands in line with the outcome of a number of studies that used the metabolic stress paradigm. 11,43,44 On the contrary, the studies where psychosocial type of stress was applied yielded divergent results. 22,23 In addition, evidence from Collip et al. supported enhanced cortisol reactivity to daily stressors. 18 This divergence could stem from the variance of the applied stressors and their respective varied impact on HPA axis function. The mismatch with regard to educational parameter within study groups could also account for the obscure results, as both the propensity of the ACRP population to demonstrate lower educational attainments 10,45,46 and the effect of the educational status on HPA axis could interfere with the outcome. 10,40,41,47 Moreover, the evidence for substantially heterogenous depressive burden in the

9 276 E. Karanikas and G. Garyfallos Psychiatry and Clinical Neurosciences 2015; 69: aforementioned ARP studies, 22,23 along with depression s documented effect on HPA axis function, could account for the diversity of the results Another factor to explain the contradictory results of the studies investigating reactivity of HPA axis could be the speculated dissociation of reactive cortisol evaluations in relation to basal cortisol levels Thus, the seemingly contradictory findings of cortisol hypersecretion at baseline in many studies with schizophrenia patients 54,55 and the increasing number of reports of hypocortisolism in reactive measures could be explained. 11,56 60 Conversely, a major concern regarding research in the field of stress-induced cortisol evaluation is the dependence of increased values on the baseline ones as per the law of initial value (LIV). 61 According to the LIV, the absolute magnitude of stress-induced cortisol increase is likely to be inversely related to baseline cortisol concentration. Moreover, cortisol s pulsatile form of secretion and the need to define a criterion to distinguish salivary cortisol stress response taking into account the previous (baseline) and the concurrent endogenous ultradian cortisol pulsatility prompted Miller et al. to propose recently the autoregressive latent trajectory mixture model. 61 With regard to the studies referring to either the CAR 25 or the psychosocially induced stress in ARP samples, 22,23 only one showed baseline cortisol levels. 23 Herein, the LIV did not seem to apply, as the mean cortisol level and its response, both at baseline and during TSST, were lower in the ARCP group. Nor did medication status seem to play a role as control for medication did not change the outcome. However, past years stress and education, when taken into consideration as covariates, altered the results. But, again the results of Pruessner et al. seemingly contradict LIV and this might be due to the statistical methodology used for the calculation of both baseline cortisol levels and its change during stress, without taking into account the ultradian pulsatile form of cortisol s secretion. Another marker for HPA axis activity is the CAR. It describes the increase of cortisol levels subsequent to awakening during the first hour and it is thought to be a phenomenon distinct from and superimposed on diurnal HPA activity. 62 Although CAR has been evaluated in a number of conditions, such as burnout, pain, posttraumatic stress disorder and recently in first-episode psychosis studies, 37,66 until now this method of investigating HPA axis has been applied to the ARP population in only one, recently published, study, 25 thus rendering this field of research promising. Interestingly, the blunted CAR response, found in the ACRP group, can be interpreted as evidence for abnormal HPA axis responsiveness to stress, which is consistent with the neural stress diathesis model. 2 The above-mentioned divergence of the results could be attributed to a number of factors playing a role in the alteration of HPA axis function, such as alteration in the number and/or sensitivity of GR and disruption of feedback mechanisms within HPA axis. 1 These factors are known to be subjected to alterations after exposure to history of adverse events, 67 childhood physical abuse, 68 childhood parental divorce, 69 bullying, 70 even distress and severity of psychotic experience itself. 71 Apart from the distress related to both external factors and subjective psychological load, the presumption of HPA axis function abnormalities in ARP subjects being caused by endogenous abnormalities in the system and/or its development during adolescence should be taken into consideration. Furthermore, medication and comorbidity are parameters known for their influence on HPA axis activity Most of the studies conducted in the field of psychosis were naturalistic, so a substantial portion of the subjects were already medicated, thus potentially affecting the outcome. Specifically, as far as the studies in this current review are concerned, in all of those involving ACRP subjects, the medication factor was present, as opposed to the studies referring to the AGRP sample, where in only one study a subgroup of the AGRP participants was medicated. 11 From the above-mentioned studies, only four included the commencement of a control for medication effect, without alteration of the outcome. 16,21 23 Additionally, in one study, without an HC group, all the analyses involved medication status as a covariate. 19 Similarly to the previous studies, Walker et al. failed to identify a significant relation between cortisol levels and psychotropic medication in the ACRP population. 24 On the contrary, in two studies (Sugranyes et al. investigated basal cortisol secretion 20 and Day et al. probed the CAR in ACRP populations), 25 after subgrouping the whole sample according to the medication status, the medication-free ACRP subgroup s cortisol figures reached significant difference, thus furthering the medication parameter playing a role in HPA axis function. Notwithstanding the existing published reports supporting the role of both antipsychotic

10 Psychiatry and Clinical Neurosciences 2015; 69: Cortisol and psychosis 277 and antidepressant medications towards dampening HPA axis activity and leading to decreased baseline and stress reactive cortisol levels, the majority of the reviewed studies on ACRP, having controlled the samples for medication, do not confirm it. The fact that only a handful of them proceeded to this level of analysis, along with the relatively small number of participants and the different outcomes in relation to cortisol levels/function, should keep us cautious from making any generalizations. As far as the comorbidity factor is concerned, again, in 13 of 16 studies it has not been excluded, 10 15,19 25 whereas in just three studies, comorbidity constituted an exclusion factor, and in another three where comorbidity was not included as an exclusion criterion, further screening rendered the ARP sample without current axis I diagnoses. 10,14,22 The hypothesized relation between cortisol and psychotic symptomatology in the ARP subjects was not confirmed by the majority of the studies. 12,20,21,23,25 Furthermore, these studies either did not involve an HC group or failed to confirm any significant difference in cortisol levels between ACRP and HC. Yet, two studies that commenced on ACRP and AGRP, respectively, opposed the aforementioned pattern, as cortisol levels were significantly aberrant at prodromal subjects. 18,24 In addition, in these studies, cortisol was positively connected with psychotic symptomatology. Of note, in the study by Walker et al., the affective components with the exception of dysphoric mood such as depression and anxiety, 24 known for their impact on HPA axis function, had not been evaluated. Collectively, the fact that the two aforementioned studies were strong regarding both the sample size (the largest cohorts) and design (multiple saliva samples) makes us skeptical about the seemingly prevailing pattern of dissociation of psychotic symptomatology with cortisol at prodrome. Unlike the dubious association of cortisol with psychotic symptoms, the two affective parameters of depressive and anxiety mood presented with dissociation regarding their correlation with cortisol. In particular, the findings in ARP subjects, though minimal, hinted towards a connection of cortisol with anxiety 12,21 rather than with both depressive and psychotic symptomatology. 12,16,20,21,23,25 The fact that the majority of the studies suggesting positive correlation between anxiety and cortisol levels, in the context of no significant association of cortisol with both positive and negative psychotic symptomatology, suggests that HPA axis dysregulation at prodrome is rather connected to the distressed subjects experience, either from the psychotic experience or from them being vulnerable to life s stressful situations, than to psychosis per se. To make matters more complex, the above-mentioned studies failed to provide evidence of aberrant cortisol levels in the ACRP subjects. Herein, it should be noted that according to the inclusion criteria in the studies on the ACRP subjects, the increase in the intensity of their positive symptoms up to a psychotic level by definition excludes them from the study, thus rendering eligible for participation only those with moderate intensity of symptoms (score of 3 5 in SOPS). Consequently, the restricted range of scores constrains the likelihood of positive symptoms being correlated with biomarkers such as cortisol. In contrast, a recent study with the largest cohort demonstrated aberrant cortisol levels in ACRP compared with HC and significant positive correlations of cortisol levels with both psychotic symptomatology and dysphoric mood, 24 which suggests a close intertwining of the three parameters cortisol, psychosis and dysphoria and emphasizes the need for studies with larger cohorts. Regarding the depressive feature, the evidence does not favor a significant connection with cortisol at prodrome. Furthermore, in the studies focusing on the correlation of cortisol with depression, 16,20,21,23,25 cortisol did not seem to relate significantly to psychotic symptoms. Yet, its levels and response were mostly aberrant in the ARP group, 20,23 the medication-free ACRP subgroup 25 and the converter group, 16 compared with the HC and the nonconverter ARP group, respectively. Conversely, the only study having suggested positive correlation of cortisol with the depressive component 12 was characterized by several flaws, such as small sample size (n = 23), no HC and substantial rate (66.5%) of comorbid diagnoses. Likewise, comorbidity was not taken into account in the rest of the studies investigating the correlation of depressive feature with cortisol, except for the study by Walker et al., where it constituted an exclusion criterion. 16 Collectively, the evidence suggests there is no clear etiopathophysiological connection among cortisol, psychotic and depressive symptomatology, at least at the time the studies were conducted. We cannot exclude the possibility of these correlations being altered while approaching the active phase of conversion.

11 278 E. Karanikas and G. Garyfallos Psychiatry and Clinical Neurosciences 2015; 69: Contrary to the presumption of higher levels of depression in the ARP population and the wellestablished knowledge of cortisol s participation in the pathophysiological mechanisms in affective disorders, 48 50,80 this current review does not confirm the recently suggested notion that dysregulated HPA axis function in ARP individuals may be associated more with comorbid depression symptoms than factors specifically related to the process of emerging psychosis. 13,23 Importantly, one should be cautious with making generalizations due to the hitherto minimal data, heterogenous design and comorbidity. Of note, the ARP subjects compared with both the HC and the non-converters scored higher figures in the depressive component. Taking into account the substantial proportion of them being on antidepressive medication and its dampening effect on HPA axis function, 72,73 the case of untreated depressive symptoms exhibiting significant associations with cortisol cannot be excluded. Contrary to the obscure fields of cortisol s association with psychotic and affective psychopathological parameters, the feature of impaired stress tolerance in the ARP population and its close intertwining with cortisol, though stemming from minimal data, seems to start being replicated with relative consistency. This finding further supports the suggested stress diathesis model of psychosis. 1 As far as the technical segregation of the studies is concerned, regarding the participants classification to ACRP or AGRP, both groups of studies seemed to share a similar trend towards upregulation of cortisol secretion at baseline. But when it comes to the reactivity of cortisol to stressors, the field is obscured by the minimal and contradictory results. Of note, two out of three studies 11,15,18 involving exposure of the AGRP subjects to stressors showed no difference in cortisol s reactivity. 11,15 Whereas the results coming from the ACRP populations in two studies, 22,23 plus from a medication-free ACRP subgroup of a third study, 25 deviated from the previous pattern, exhibiting significant differences compared with the HC s cortisol reactivity, though towards different directions. This observation sounds reasonable given that the ACRP group represented subjects being at prodrome for psychosis, as opposed to the AGRP group, having been comparatively less likely to convert to psychosis, as they did not need to fulfill the prerequisite of recent functional decline, as per the concession in the current review. An explanation might be that any aberrance of cortisol levels in the AGRP group may not be enough to cause further alterations in cortisol reactive mechanisms, thus not allowing even prodromal psychotic symptoms to emerge, at least up to the time the studies had been conducted. Alternatively, basal cortisol secretion could be independent to reactivity mechanisms. Collectively, the evidence indicates the complex pathways from a genetic load to clinical appearance of psychotic disorder. The interplay of genes responsible for cortisol metabolism and the vulnerability for psychosis remains to be elucidated. 24,81 Finally, regarding the comparative cortisol deviation in the ARP subjects in relation to patients with established psychosis and HC, a subtle common pattern seems to arise where cortisol levels in the ARP group tended to be numerically intermediate between the patients group and the HC, though not always of statistically significant difference. Again, this is less evident when it comes to the evaluation of cortisol reactivity to stressors among psychotic patients, ARP subjects and HC. The fact that the majority of the studies was conducted on AGRP rather than ACRP subjects could account for the results not having reached statistical significance. Study limitations The present review incorporates a basic advantage: its systematic nature. Additionally, it seems to constitute the first attempt to integrate systematically cortisol patterns along with psychopathological parameters in the ARP state. Moreover, it has concentrated on the prodromal phase well before psychosis appears as a substantially diagnosed full-blown entity, thus providing insight into this particular phase, while excluding confounding factors. A significant contribution of this current review is to underline the necessity for consensus in the applied classification criteria for prodrome and the methods used for evaluation of both cortisol levels and its function. Specifically, multiple samplings accompanied by psychometric evaluations over time should be preferred instead of a single sample. In addition to the evaluation of cortisol s fluctuation over time, the adoption of statistical methods, taking into consideration the LIV and the ultradian pulsatile type of cortisol s secretion, becomes imperative. On the other hand, our findings must be interpreted in the light of the shortcomings of systematic reviews, in particular publication bias. Furthermore, this review lacks a