TYPE Original Research PUBLISHED 21 June 2023 DOI 10.3389/fpsyg.2023.1150142 The moderating role of hair OPEN ACCESS cortisol in the association of early and recent stress with EDITED BY Béla Birkás, University of Pécs, Hungary REVIEWED BY Salomon Israel, stress-related phenotypes Hebrew University of Jerusalem, Israel Mary Steinhardt, The University of Texas at Austin, United States Pilar Torrecilla 1 and Neus Barrantes-Vidal 1,2* *CORRESPONDENCE 1 Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Edifici B, Universitat Autònoma Neus Barrantes-Vidal de Barcelona, Barcelona, Spain, 2 CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain neus.barrantes@uab.cat RECEIVED 23 January 2023 ACCEPTED 06 June 2023 PUBLISHED 21 June 2023 Background: Increased hair cortisol concentrations (HCC) have been found CITATION in clinical samples of schizophrenia, first episode psychosis and clinical risk for Torrecilla P and Barrantes-Vidal N (2023) The psychosis, but evidence of such is scarce in schizotypy. High HCC are supposed moderating role of hair cortisol in the to reflect elevated chronic stress. However, HCC were not directly associated association of early and recent stress with stress-related phenotypes. with adversity measures and stress-related phenotypes in previous research. This Front. Psychol. 14:1150142. study tested whether HCC moderated the association between a comprehensive doi: 10.3389/fpsyg.2023.1150142 range of psychosocial stressors with several stress-related phenotypes in a sample COPYRIGHT of nonclinical young adults. It was expected that stressors, either distal (i.e., early- © 2023 Torrecilla and Barrantes-Vidal. This is an open-access article distributed under the life) or recent, would be associated with subclinical features, particularly for those terms of the Creative Commons Attribution with elevated HCC, reflecting the effects of a potential biological sensitization to License (CC BY). The use, distribution or stress. reproduction in other forums is permitted, provided the original author(s) and the Methods: The sample comprised 132 nonclinical young adults belonging to the copyright owner(s) are credited and that the Barcelona Longitudinal Investigation of Schizotypy Study (BLISS). Participants original publication in this journal is cited, in accordance with accepted academic practice. completed a questionnaire of childhood adversity and two complementary No use, distribution or reproduction is measures of recent life events, tapping threatening vs. more general life events. permitted which does not comply with these Both the frequency and subjective impact (positive vs. negative) of general life terms. events were also assessed. Psychotic (i.e., schizotypy, suspiciousness) and non- psychotic (i.e., depression, anxiety) subclinical features as well as appraisals of perceived stress were examined. Hierarchical linear regressions and simple slope analyses were computed. Results: HCC moderated the effects of both early and recent stress on suspiciousness as well as the effects of recent life events on perceived stress, such that those with higher HCC presented increased suspiciousness and perceived stress at higher levels of stress exposure. Positive, but not negative, recent life events were associated with decreased perceived stress and depression, and these associations were moderated by low HCC, indicating a buffering effect for those with a non-impaired HPA axis. Conclusion: In line with the neural diathesis-stress model, results highlight the role of the interplay between the HPA axis and exposure to stressful experiences in exacerbating psychosis features and extend evidence to the nonclinical expression of the psychosis continuum. In addition, findings support the protective effect of positive experiences in decreasing stress appraisals and affective disturbances, which is consistent with emerging research about the relevance of positive factors in reducing the likelihood of psychopathological outcomes. KEYWORDS hair cortisol, psychosocial stress, life events, early adversity, schizotypy, anxiety, depression Frontiers in Psychology 01 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 1. Introduction Although some evidence of an association between early adversity and altered HCC has been found in clinical psychosis (Aas et al., 2019; The classic neural diathesis-stress model focuses on the role of the Schalinski et al., 2019) and clinical at-risk individuals (Söder et al., hypothalamic-pituitary-adrenal (HPA) axis as a mediator of the effects 2019), recent meta-analytic work by Cullen and colleagues (Cullen of stress on triggering and exacerbating psychosis symptoms (Walker et al., 2020) found poor concordance between psychosocial stressors and Diforio, 1997; Walker et al., 2008; Pruessner et al., 2017). The HPA (including both early adversity and recent stressful events) and cortisol axis acts in response to stressful situations or threats by activating a levels (including studies using all types of measurements) in psychosis hormonal cascade that culminates in the release of the glucocorticoid and high-risk individuals. In previous work, we also failed to find a cortisol to facilitate physiological and behavioral responses to threats. direct association between HCC and early adversity as well as This response is suppressed by a negative feedback loop once stressors frequency and subjective appraisals of recent life events in nonclinical are absent. Cortisol is the most frequently used measure to study the young adults with a wide distribution of schizotypy (Torrecilla and HPA axis function and its implication in mental disorders as it can Barrantes-Vidal, 2021). be easily assayed in blood, urine, saliva and hair. Whereas samples of The lack of overall group-level association between HCC, stress- blood serum and saliva have been extensively used to analyze acute related phenotypes, and exposure to early and recent stress in our single point cortisol responses to stress and urine to obtain short term previous study might be influenced by limited statistical power as well levels (i.e., 24 h), hair cortisol concentrations (HCC) have been as the fact that nonclinical samples do not generally present very high proposed as a more accurate measure of chronic stress enabling or persistent levels of stress (Torrecilla and Barrantes-Vidal, 2021). retrospective and long-term examination of cortisol production However, drawing from the stress sensitization framework, we propose (Russell et al., 2012). As hair grows approximately 1 cm per month that this may also be because the association between both early and (Wennig, 2000), a 3 cm-hair sample for instance allows to recent experiences of stress with subclinical psychopathology would retrospectively assess hair cortisol from the last 3 months from the be moderated by HCC. Support for the moderating role of HCC on strand collection providing a valid, reliable, non-invasive, and easily the relationship between stressful experiences and stress-related transported and stored long-term measurement of the stress phenotypes has been found, for instance, in nonclinical samples of glucocorticoid (Stalder et al., 2017). However, very few studies have children (Fuchs et al., 2018), adolescents (Shapero et al., 2019; Xu examined HCC across the psychosis spectrum, reporting elevated et al., 2019) and in clinical depression (Duncko et al., 2019), but little levels in clinical samples of schizophrenia (Streit et al., 2016; Aas et al., work has been conducted across the extended psychosis spectrum 2019), First Episode of Psychosis (FEP) (Andrade et al., 2016) and phenotype despite of considerable research linking psychosis populations at clinical risk for psychosis (Söder et al., 2019). To the vulnerability to HPA axis hyperactivation. Of note, there is a notable best of our knowledge only one study (Torrecilla and Barrantes-Vidal, lack of research examining the psychobiological effects of exposure to 2021) has examined HCC at the nonclinical end of the extended stress transphenomically, even though recent claims from psychosis phenotype, that is, schizotypy, failing to find any significant transdiagnostic approaches recognize the multidimensionality and association between HCC and a wide range of stress-related evolving nature not only of a single diagnostic spectra (e.g., psychosis) phenotypes. Schizotypy is conceptualized as a multidimensional but also across the whole psychopathology spectrum -including construct indexing liability for psychosis-spectrum psychopathology nonclinical manifestations- (van Os, 2015; McGorry et al., 2018), and that is expressed across a broad range of personality, subclinical and ample evidence suggests that HPA axis disruption is present in many clinical psychotic features (Ettinger et al., 2014; Kwapil and Barrantes- psychopathology phenotypes (Naughton et al., 2014; Herane-Vives Vidal, 2015; Grant et al., 2018a). Investigating HCC in nonclinical et al., 2020; Koumantarou Malisiova et al., 2021). individuals with schizotypy traits allows examining the role of HPA The goal of the present study was to examine whether HCC axis in the etiology of psychosis without the confounds associated with moderate the association between a comprehensive range of clinical status and medication, which have commonly been related to psychosocial stressors, including both early and recent stressful inconsistent replication findings when examining baseline cortisol experiences, with the expression of several stress-related phenotypes levels in psychosis populations (Pruessner et al., 2017). in a sample of nonclinical young adults. It was hypothesized that the It is well established that psychotic spectrum disorders are association between early-life and recent stressors with subclinical associated with childhood adversity (Mondelli and Dazzan, 2019; features would be greater for those with elevated HCC. Specifically, Sideli et al., 2020) and heightened stress-sensitivity (Myin-Germeys we expected that the moderating role of the HPA axis biological and van Os, 2007; Van Winkel et al., 2008; Cristóbal-Narváez et al., indicator (i.e., HCC) would be relevant for all the phenotypes that 2016; Rauschenberg et al., 2017). A stress sensitization mechanism have been robustly associated to stress, that is, the paranoid, positive seems to underlie this association; that is, prolonged and/or severe schizotypy, depression and anxiety dimensions, as well as levels of stressful experiences in highly sensitive developmental periods (i.e., perceived stress (e.g., Velikonja et al., 2015; Gibson et al., 2016; childhood) might result in a process of behavioral and biological Bandoli et al., 2017; Anderson et al., 2022), but not with negative sensitization to stress through the disruption of stress regulation schizotypy. Furthermore, we expected that among recent life events systems such as the HPA axis (Read et al., 2001; Yuii et al., 2007; Belda the measure of threatening events would show a greater effect et al., 2015). This mechanism would enhance stress sensitivity by compared to that of general life events given their clear negative or increasing physiological (e.g., cortisol secretion) and behavioral (e.g., even devastating nature. For the measure of recent general life events, greater intensity of stress appraisals) responsivity to subsequent minor we hypothesized that the subjectively rated impact of life events would adversities in adulthood, which has been associated to a broad range yield more interaction effects than the raw number of events endorsed. of phenotypes (McLaughlin et al., 2010; Hammen, 2015; Bandoli et al., Thus, subjective ratings of negative life events were supposed to 2017), including psychosis (Collip et al., 2008; Lataster et al., 2012). increase the presence of subclinical phenotypes in those with higher Frontiers in Psychology 02 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 levels of HCC, whereas those experiencing a greater positive impact experiences from negative to positive plus three blank spaces for other from life events were expected to show a buffering effect by decreasing events (Cronbach’s alpha = 0.78). Forty-seven of them refer to general levels of subclinical features. life events and 10 of them are academic-related. We removed one Several features of this study overcome limitations reported in academic-related item (“Academic probation”) given that there is not previous work that have been suggested as possible sources of an equivalent of it in the Spanish education system. Participants were conflicting results. We investigated the effects of different time frames asked to rate the occurrence (YES/NO) of each life event and the total (early vs. recent), types (common vs. uncommon) and not only sum of events endorsed was used. Additionally, the LES also allows to frequency but also subjective appraisals (positive vs. negative) of rate the subjective impact of each endorsed life event by using a Likert stressors in the same sample. Furthermore, unlike most previous scale ranging from −3 (extremely negative) to +3 (extremely positive). studies, we tested the hypothesis across psychosis and The sum of ratings from −3 to −1 (negative spectrum) of endorsed non-psychosis dimensions. life events was used as the amount of negative impact, whereas the sum of ratings from 1 to 3 (positive spectrum) was used as the amount of positive impact. To ease interpretation of results, negative ratings 2. Methods (−3 to −1) were inversely recoded (3 to 1). 2.1. Participants 2.2.2. Current appraisals of stress The Perceived Stress Scale (PSS; Cohen et al., 1983) is a self- The present sample consisted of 132 nonclinical young adults reported questionnaire of 14 items enquiring about the level of stress (mean age = 27.86, SD = 3.07, range = 26.07, 83% women) belonging to perceived by participants during the last month that provides a total the ongoing Barcelona Longitudinal Investigation of Schizotypy Study score of perceived stress (Cronbach’s alpha = 0.86). (BLISS; Barrantes-Vidal et al., 2013a,b). At Time 1 (T1), a large pool of 547 unselected college students and 2.2.3. Hair cortisol 261 technical school students were initially screened with self-report To determine HCC, 3 cm of hair strands were cut from the base questionnaires. As described in detail elsewhere (Barrantes-Vidal of the scalp. Considering average hair growth of 1 cm per month et al., 2013a,b; Torrecilla and Barrantes-Vidal, 2021), a subgroup (Wennig, 2000), the samples represented the cortisol mean levels oversampled for schizotypy scores continued regular follow-ups (from from the last 3 months. 40 mg of hair were weighed and washed T1 to T5). At T5, 168 (79% of 214 candidate participants) college twice with 4 mL of 2-propanol (SIGMA, Ref: 335639–2.5 L-M) and students and 26 (77% of 31 candidate participants) technical school three extractions were performed overnight with 1.6 mL of students were reassessed. Therefore, a total of 194 participants were methanol (SIGMA, Ref: 34860–2.5 L-M). Methanol was then assessed at T5, when hair samples were collected. From these, 132 evaporated in the Speed Vac. The samples were reconstituted with participants (112 college students and 20 technical school students) 200 μL of 0.1 M phosphate buffer and then processed in the assay successfully provided 3 cm-hair samples and were included in the (25 μL in duplicate). present study. Note that sample size may vary for some measures given HCC were determined after the above extraction using the that three of the participants who provided hair samples did not Salivary cortisol enzyme immunoassay kit, Expanded Range High complete questionnaires at T5 (N = 129). All the psychometric Sensitivity (Salimetrics, Ref: 1-3002-5, UK). In brief, cortisol in measures employed in this study were assessed at T5 along with the standards and samples competes with cortisol conjugated to cortisol sampling, except early adversity, which was assessed at T1 of horseradish peroxidase for the cortisol antibody binding sites on a the BLISS. All participants provided written informed consent microtiter plate. Bound cortisol-enzyme conjugate is measured by the to participate. reaction of the horseradish peroxidase enzyme with the substrate tetramethylbenzidine (blue color), resulting in a yellow color whose optical density is read at 450 nm. Dilution of samples showed good 2.2. Materials and procedure parallelism with the standard curve and recovery of spiking samples was around 100%. In our conditions, the intra-assay coefficient of 2.2.1. Measures of adversity and stressful events variation (CV) was 5.1% and the inter-assay CV 6.7%. Nevertheless, To examine early adversity, the Childhood Trauma Questionnaire all samples were processed within the same assay to avoid inter-assay Short Form (Bernstein et al., 2003) was assessed at T1. CTQ-SF is a variability. Participants reported whether they have ever dyed their self-reported measure including 28 items rating the severity of hair and how many times do they wash their hair weekly. emotional abuse and neglect, physical abuse and neglect and sexual abuse. A total score of childhood trauma comprising all the subscales 2.2.4. Phenotype measures is used in the present study (Cronbach’s alpha = 0.85). Paranoia was assessed using the Suspiciousness scale (Cronbach’s Two complementary recent life events measures were used. As a alpha = 0.70) of the Schizotypal Personality Questionnaire (SPQ: measure of specifically threatening life events, we used The List of Raine, 1991) and schizotypy was assessed with the short forms of the Threatening Events (LTE; Brugha and Cragg, 1990). It consists of 20 Wisconsin Schizotypy Scales (WSS-S; Winterstein et al., 2011), from items (YES/NO) asking about adverse life events that might have which participants were assigned positive and negative schizotypy occurred during the last year (Cronbach’s alpha = 0.59). As a measure factor scores (see Barrantes-Vidal et al., 2013a,b). of more general and frequent life events we employed the Life Events Depressive symptoms were assessed with the Beck Depression Survey (LES; Sarason et al., 1978), which includes 57 life events that Inventory-II (BDI-II; Cronbach’s alpha = 0.88) (Beck et al., 1996) and might have occurred during the last year comprising a full range of Anxiety was assessed with the Anxiety subscale (Cronbach’s Frontiers in Psychology 03 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 alpha = 0.82) of the Symptom Checklist-90-Revised (SCL-90-R; similar pattern was found for the measure of general life events Derogatis, 1994). (Table 4), showing direct effects on positive schizotypy and statistically significant interactions with HCC for both suspiciousness and perceived stress. However, these interactions did not survive FDR 2.3. Statistical analyses correction. Subsequent simple slopes showed that the general life events increased suspiciousness (Figure 3) only at high levels of HCC ANOVA was used to test differences in hair cortisol concentrations (β = 0.24, p < 0.05), whereas none of the slopes of HCC (low, moderate, for academic group, sex, age, and hair dye. Hierarchical linear high) were significant in the association between HCC and regressions were computed to examine direct and interaction effects perceived stress. of HCC with early and recent exposures on subclinical experiences. Regarding the subjective impact of general life events, positive HCC and environmental measures were entered at first step and the appraisals (Table 5) were associated with lower levels of perceived interaction of HCC with the different environmental measures was stress and depression, but to greater levels of positive schizotypy. In entered at the second step. The standardized regression coefficient (β), contrast, negative (Table 6) appraisals were associated with greater change in R2, and effect size f2 were reported for each predictor in the perceived stress and depression. Interaction effects between HCC and regressions. Following Cohen (1992), f2 values above 0.15 are medium a positive impact of life events (Table 5) were only found for perceived and above 0.35 are large effect sizes. The False Discovery Rate (FDR; stress and depression, and were significant after multiple testing Benjamini and Hochberg, 1995) procedure was employed to correct correction. Both associations (Figures 4A,B) were significant for low interaction effects for multiple testing across each environmental (β = −0.49, p < 0.001 for perceived stress; β = −0.43, p < 001 for measure. Finally, simple slope analyses using PROCESS (Hayes, 2013) depression) and moderate (β = −0.30, p < 0.001 for perceived stress; were computed to decompose significant interactions (p-value < 0.05). β = −0.26, p > 0.01 for depression) levels of HCC, indicating that those Statistical analyses were performed using the Statistical Package for with lower levels of HCC reported decreased perceived stress and the Social Sciences (SPSS), Version 22.0 software (Corp Released, depressive symptoms when they had experienced more positive life IBM, 2013). events compared to individuals with high HCC who were not affected Ethical approval was granted by the Ethics Committee of the by the number of positive events. In contrast, no interaction effects Universitat Autònoma de Barcelona. The study was developed in between HCC and negative impact of life events were found (Table 6). accordance with the Declaration of Helsinki for ethical conduct in research. 4. Discussion 3. Results This is the first study to examine the moderating role of hair cortisol as a proxy of HPA dysfunction in the association between One out of 132 participants was excluded because of abnormally early and recent stress with a range of stress-related subclinical increased HCC (244.6 pg./mg) compared to the rest of the sample. phenotypes in young adults. HCC consistently moderated the effects There were not significant differences in mean HCC (p = 0.20) among of both early and recent life stress on suspiciousness and the effects of men (M = 8.20 pg./mg, SD = 8.31) and women (M = 5.81 pg./mg, recent life events on perceived appraisals of stress. The subjectively SD = 3.86), nor between college (M = 6.45, SD = 5.17) and technical rated positive impact of life events was associated with decreases in school (M = 4.98, SD = 3.15) students (p = 0.22). HCC were not affected perceived stress and depression, and these relationships were also by hair dye (p = 0.542) or frequency of washing (p = 0.146). moderated by HCC, such that this buffering effect only occurred for Table 1 shows descriptive statistics and Pearson correlations participants with low and moderate levels of HCC. Although only among study variables. Hierarchical linear regressions results are interaction effects between HCC and threatening as well as positive shown in Tables 2–6. As shown in previous work (Torrecilla and life events survived multiple testing correction, these findings provide Barrantes-Vidal, 2021), no significant main effects for HCC on any of partial support to the hypothesis that individuals with an the stress-related outcomes were detected. Early adversity (Table 2) hyperresponsive HPA axis present stronger associations between showed a main effect on all stress-related phenotypes except for stressors and a variety of subclinical phenotypes robustly associated negative schizotypy, as well as an interaction with HCC in predicting to stress. levels of suspiciousness—a trend-level interaction was found for Consistent with evidence suggesting that the positive dimension positive schizotypy. Simple slopes analysis of the significant interaction of psychosis is more strongly associated with childhood trauma on suspiciousness (Figure 1) revealed that childhood adversity (Velikonja et al., 2015; Gibson et al., 2016), early adversity predicted increased levels of suspiciousness only at high (β = 0.43, p < 0.01) and increased positive, but not negative, psychotic-like features, as well as moderate (β = 0.28, p < 0.01) levels of HCC. However, this interaction depression, anxiety and increased appraisals of current stress, thus effect did not survive FDR correction. supporting the role of early negative environmental influences on the The number of recent threatening life events was directly development of a variety of subclinical psychopathology associated with positive schizotypy (Table 3) and showed an manifestations (McLaughlin, 2016; Conway et al., 2018). HCC interaction effect that survived FDR correction with HCC predicting moderated the effects of childhood adversity and recent stressful life suspiciousness (also for appraisals of perceived stress at a trend level). events (both general and threatening life events) on suspiciousness. In Simple slopes analysis of the significant interaction on suspiciousness all cases, experiencing greater levels of early or recent life stress (Figure 2) revealed that threatening life events predicted higher levels increased levels of suspiciousness specifically in those presenting of suspiciousness only at high levels of HCC (β = 0.24, p < 0.05). A elevated HCC. These findings are consistent with previous evidence Frontiers in Psychology 04 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 TABLE 1 Descriptive statistics and Pearson correlations of the study variables. Descriptive statistics Pearson correlations N M (SD) Range 2 3 4 5 6 7 8 9 10 11 12 1. HCC 131 1.30 (4.94) 1.3–39.7 0.094 0.089 0.102 0.045 0.120 0.089 0.096 0.149 −0.006 −0.046 0.004 2. Early adversity 131 33.91 (8.03) 25–67 0.166 0.203* 0.057 0.229** 195* 0.119 0.348** 0.263** 0.279** 0.284** 3. Threatening life 128 2.27 (1.98) 0–9 0.371** 0.228** 0.207* 0.262** −0.070 0.142 −0.012 0.005 0.072 events 4. General life 129 10.33 (4.91) 2–24 0.685** 0.574** 0.254** −0.064 0.172 0.074 0.064 0.114 events 5. Positive impact 129 12.89 (9.14) 0–50 −0.056 0.326** −0.096 0.063 −0.236** −0.214* −0.067 events 6. Negative impact 129 7.57 (5.9) 0–27 −0.001 −0.060 0.123 0.295** 0.305** 0.217* events 7. Positive 128 −0.66 (0.45) −1.17 to 1.32 0.207* 0.473** 0.181* 0.214* 0.262** schizotypy 8. Negative 128 −0.06 (0.92) −1.03 to 3.26 0.331** 0.243** 0.334** 0.124 schizotypy 9. Suspiciousness 128 1.58 (1.68) 0–8 0.492** 0.511** 0.546** 10. Perceived 128 20.19 (7.63) 5–43 0.736** 0.663** stress 11. Depression 128 5.70 (6.66) 0–35 0.631** 12. Anxiety 128 5.41 (4.75) 0–19 HCC, Hair Cortisol Concentrations. *p < 0.05; **p < 0.01. Sample size may vary for some measures given that three of the participants who provided hair samples (N = 132) did not fully complete the questionnaire assessment at T5 and one participant was excluded for abnormally increased HCC. TABLE 2 Main effects of HCC, early adversity, and their interaction on stress-related outcomes. Step 1 Step 2 Hair cortisol concentrations Early adversity HCC × early adversity (HCC) β ΔR2 f2 β ΔR2 f2 β ΔR2 f2 Positive schizotypy 0.073 0.005 0.005 0.189* 0.035 0.036 0.164+ 0.027 0.029 Negative schizotypy 0.086 0.007 0.008 0.112 0.012 0.013 0.040 0.002 0.001 Suspiciousness 0.120 0.014 0.016 0.337*** 0.113 0.130 0.191* 0.036 0.043 Perceived stress −0.028 0.001 0.001 0.266** 0.070 0.075 0.003 0.000 0.000 Depression −0.070 0.005 0.005 0.285** 0.081 0.088 −0.099 0.010 0.011 Anxiety −0.020 0.000 0.001 0.285** 0.081 0.088 0.020 0.000 0.000 p < 0.10; *p < 0.05; **p < 0.01; ***p < 0.001. + linking childhood trauma as well as recent stress with the HPA axis schizotypy, although only at a trend level. The fact that HCC and function, psychiatric illness in general (Murphy et al., 2022) and childhood trauma only showed interaction effects on psychosis- psychosis in particular (Faravelli et al., 2017; Aas et al., 2019; Herane- spectrum features suggests an increased sensitivity of the HPA axis to Vives et al., 2020). More so, results provide further support for the the effects of early environmental influences for the psychosis neural diathesis-stress model (Walker et al., 2008) and extend findings spectrum, which supports notions of a general psychopathology to nonclinical expressions of psychosis liability. The fact that severity continuum in which psychotic expressions might index a suspiciousness was associated with all forms of stress aligns with greater level of severity (McGorry and van Os, 2013; van Os cognitive theories suggesting that paranoid thoughts develop as a et al., 2020). defensive self-protection mechanism that may arise as a psychological Results showed a similar pattern of results for threatening and response to threatening or stressful experiences (Freeman and Fowler, general recent life events. Both predicted increased levels of positive, 2009). This response was particularly evident in nonclinical but not negative, schizotypy, which is consistent with previous individuals whose HPA axis might be disrupted. Of note, HCC also evidence supporting the link between increased stress-sensitivity and moderated the association between early adversity and positive positive features of psychosis liability (Kocsis-Bogár et al., 2013; Frontiers in Psychology 05 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 TABLE 3 Main effects of HCC, recent threatening life events, and their interaction on stress-related outcomes. Step 1 Step 2 Hair cortisol concentrations Threatening life events HCC × threatening life events (HCC) β ΔR2 f2 β ΔR2 f2 β ΔR2 f2 Positive schizotypy 0.067 0.004 0.004 0.256** 0.065 0.070 0.083 0.007 0.007 Negative schizotypy 0.103 0.011 0.010 −0.079 0.006 0.006 0.137 0.018 0.019 Suspiciousness 0.137 0.019 0.019 0.130 0.017 0.017 0.241** a 0.058 0.063 Perceived stress −0.005 0.000 0.000 −0.011 0.000 0.000 0.152+ 0.023 0.023 Depression −0.047 0.002 0.001 0.009 0.000 0.000 0.125 0.016 0.016 Anxiety −0.002 0.000 0.000 0.072 0.005 0.004 0.118 0.014 0.014 + p < 0.10; **p < 0.01. a Findings survived FDR correction for multiple comparisons. TABLE 4 Main effects of HCC, recent general life events, and their interaction on stress-related outcomes. Step 1 Step 2 Hair cortisol concentrations General life events HCC × general life events (HCC) β ΔR2 f2 β ΔR2 f2 β ΔR2 f2 Positive schizotypy 0.064 0.004 0.004 0.248** 0.061 0.065 0.070 0.005 0.005 Negative schizotypy 0.104 0.011 0.011 −0.075 0.006 0.006 −0.064 0.004 0.004 Suspiciousness 0.132 0.017 0.017 159 + 0.025 0.026 0.209* 0.043 0.047 Perceived stress −0.019 0.000 0.001 0.075 0.006 0.005 0.180* 0.032 0.033 Depression −0.054 0.003 0.003 0.075 0.006 0.006 0.129 0.016 0.016 Anxiety −0.008 0.000 0.000 0.115 0.013 0.013 0.154+ 0.023 0.023 p < 0.10; *p < 0.05; **p < 0.01. + Cristóbal-Narváez et al., 2016; Grattan and Linscott, 2019). HCC showed that experiencing more positive life events significantly moderated the effects of threatening and general life events on decreased appraisals of stress and depressive symptoms, specifically in suspiciousness and current appraisals of perceived stress, although the those with lower levels of HCC, suggesting that positive life events latter only reached a trend level for the effects of threatening life may only exert a protective effect in those who are not biologically events. This slight difference of the effects of threatening events (LTE) sensitized (i.e., showing low HCC). This finding highlights the compared to general life events (LES) on perceived stress might importance of examining the combined effect of both early and recent be related to the greater skewness of the LTE measure in the present experiences of stress as theorized by the stress sensitization hypothesis. sample. As would be expected, most participants may have not Still, though, findings are consistent with emerging literature on the encountered, or not as frequently, the severe and threatening effect of positive environmental influences (Coughlan et al., 2020) as experiences (e.g., “Serious illness, injury or assault to self ” or “Parent, well as positive psychology interventions (Grant et al., 2018b; Grattan child or spouse died”) asked in the LTE (M = 2.27, SD = 1.98). In and Linscott, 2019) in reducing (the likelihood of) psychopathological contrast, the broader and more generally occurring life events outcomes. Interestingly, experiencing positive life events showed a appearing in the LES (e.g., “Major change in sleeping habits,” main effect predicting increased positive schizotypy, which resonates “Outstanding personal achievement”) are more frequently endorsed with the notion of “happy schizotypes” (Mohr and Claridge, 2015). It by young adults (M = 10.33, SD = 4.91) and thus increase the likelihood has been shown that a proportion of nonclinical individuals with high of detecting possible interaction effects. Of note, this finding also levels of positive schizotypy (and low in negative and disorganized indicates that minor adversities or life-changes are also associated to dimensions) also present hypomanic traits (Kemp et al., 2018) and subclinical features in those with a hyperactivated HPA axis, and might reflect “benign schizotypy,” in which psychotic-like experiences suggests the relevance of taking into consideration the developmental are not distressing and might even be rewarding. In fact, as reported phase of study populations when assessing stressful experiences for in a previous study (Grant and Hennig, 2020), “happy schizotypes” further research. experience psychotic-like experiences in association to Contrary to our expectation, life events subjectively rated as momentary happiness. negative did not show any significant interaction effects. In contrast, Lack of significant interactions with the negative impact of life life events whose impact was rated as positive interacted with HCC to events does not necessarily indicate that experiencing negative predict levels of perceived stress and depression. Importantly, results stressful situations do not affect the association between the HPA axis Frontiers in Psychology 06 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 TABLE 5 Main effects of HCC, positive impact of life events, and their interaction on stress-related outcomes. Step 1 Step 2 Hair cortisol concentrations Positive impact of life events HCC × positive impact of life (HCC) events β ΔR2 f2 β ΔR2 f2 β ΔR2 f2 Positive schizotypy 0.075 0.006 0.006 0.323*** 0.104 0.117 0.123 0.013 0.014 Negative schizotypy 0.100 0.010 0.010 −0.100 0.010 0.010 −0.092 0.007 0.007 Suspiciousness 0.146 0.021 0.021 0.056 0.003 0.003 0.075 0.005 0.005 Perceived stress 0.005 0.000 0.000 −0.236** 0.056 0.059 266**a 0.060 0.067 Depression −0.036 0.001 0.001 −0.212* 0.045 0.047 0.229*a 0.045 0.049 Anxiety 0.007 0.000 0.001 −0.067 0.005 0.005 0.133 0.015 0.015 *p < 0.05; **p < 0.01; ***p < 0.001. a Findings survived FDR correction for multiple comparisons. TABLE 6 Main effects of HCC, negative impact of life events, and their interaction on stress-related outcomes. Step 1 Step 2 Hair cortisol concentrations Negative impact of life events HCC × negative impact of life (HCC) events β ΔR2 f2 β ΔR2 f2 β ΔR2 f2 Positive schizotypy 0.091 0.008 0.007 −0.012 0.000 0.000 0.015 0.000 0.000 Negative schizotypy 0.105 0.011 0.010 −0.073 0.005 0.005 −0.071 0.005 0.005 Suspiciousness 0.136 0.018 0.018 0.106 0.011 0.011 0.110 0.011 0.011 Perceived stress −0.042 0.002 0.002 0.300*** 0.088 0.097 0.013 0.000 0.000 Depression −0.084 0.007 0.007 0.315*** 0.098 0.108 −0.001 0.000 0.000 Anxiety −0.022 0.000 0.001 0.220* 0.048 0.050 0.065 0.004 0.003 *p < 0.05; ***p < 0.001. function and psychopathology but that probably the effects are not as to dynamic transactions with the environment and endogenous devastating as we would expect them to be in a clinical or functionally factors (Rutter, 2005), and with recent claims about the need to impaired sample, whereas stronger or persistent negative experiences investigate the etiological factors from a multidimensional might be needed to capture the effects in a nonclinical sample of psychopathology framework to provide further insights on functional young adults (Stalder et al., 2017; Torrecilla and Barrantes- common risk and protective factors across diagnostic spectra Vidal, 2021). (Lynch et al., 2021). Studying a nonclinical sample may have limited Several strengths characterize the present study. A major the ability to detect the expected effects as nonclinical individuals advantage compared to the extant literature is the examination of a have probably not been exposed to very high or extreme levels of comprehensive range of psychosocial stressors. We examined both stress. However, employing a nonclinical sample with significant early (i.e., childhood) and recent (i.e., past 12 months) indicators of variance along schizotypy dimensions offers a promising strategy stress and two complementary measures of recent life events were for studying the possible HPA axis dysfunctions as the many employed to capture the objective frequency of threatening or confounds associated with clinical status and medication are uncommon experiences (LTE) as well as more general and avoided. Although we provided theory-grounded hypotheses for commonly faced situations (LES). In addition, we assessed the the analyses conducted, this was primarily an exploratory study positive vs. negative subjectively rated impact of general life events given that no previous work has examined this particular in order to better understand individual differences in response to moderating effect using the range of outcome measures employed, stress (Smith and Pollak, 2020), which has been suggested to result specifically in the context of psychosis liability (that is, schizotypy). from the individual’s subjective interpretation and appraisal of it Also, our sample size was limited, and this possibly decreased the rather than the event itself (Lazarus and Folkman, 1984; Thomas ability of detecting interaction effects with sufficient statistical et al., 2019). Moreover, we employed a transphenomic approach by power. Future studies with greater sample sizes that also examine assessing traits and subclinical symptoms belonging to the this broad range of relevant stress-related constructs should psychotic, affective and anxiety spectrums. This is consistent with be higher powered to detect interaction effects that remain after the developmental psychopathology notion of multifinality; that is, multiple testing correction. The available sample size prevented us that the same risk factors can yield differential outcomes according from testing a three-way interaction of early and recent stress with Frontiers in Psychology 07 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 cortisol as a moderator to examine how individuals with elevated early-life stress currently facing stressful life events presented with greater subclinical symptoms if biologically sensitized to stress (i.e., with elevated HCC). Future studies with larger sample sizes will also be able to test this and provide further insights on the biological manifestation of the stress sensitization hypothesis and its implications in several psychopathology outcomes. Potential confounders related to HCC such us hair dye, washing frequency, age and sex were examined and did not show any significant FIGURE 1 Significant interaction between HCC and early adversity on associations; however, evidence suggests that other variables such suspiciousness. us body mass index should also be considered (Stalder and Kirschbaum, 2012; Stalder et al., 2017). Finally, current dimensional models of early adversity suggest that different dimensions of adversity might have differential effects on psychopathology (McLaughlin and Sheridan, 2016); however, due to limited statistical power, the present study only examined a general total score of trauma. Further and better powered studies will be able to examine differences across subtypes and co-occurrence of adverse experiences. To conclude, the present findings support the moderating role of retrospective long-term levels of cortisol (i.e., HCC) on the association with both early and recent stressful experiences for a FIGURE 2 wide range of subclinical measures. Also, the buffering effects of Significant interaction between HCC and recent threatening life recent positive experiences contribute to reduce pessimism around events on suspiciousness. subclinical psychological manifestations and supports the importance of further focusing on positive resilience-building early interventions. Data availability statement The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Ethics statement FIGURE 3 Significant interactions between HCC and recent general life events The studies involving human participants were reviewed and on suspiciousness. approved by Ethics Committee of the Universitat Autònoma de Barcelona [Comissió d’Ètica en l’Experimentació Animal i Humana FIGURE 4 Significant interactions between HCC and recent positive life events on (A) perceived stress and (B) depression. Frontiers in Psychology 08 frontiersin.org Torrecilla and Barrantes-Vidal 10.3389/fpsyg.2023.1150142 (CEEAH)]. The patients/participants provided their written informed Acknowledgments consent to participate in this study. The authors want to thank Prof. Thomas Kwapil and Tamara Sheinbaum for their contribution to study design, and to Anna Author contributions Racioppi for her work in data collection. NB-V conceived the study, acquired funding, administered and supervised the project and data acquisition, contributed and revised Conflict of interest the manuscript. PT analyzed the data and wrote the manuscript. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This work was supported by the Spanish Ministry of Science, Publisher’s note Innovation and Universities (Grants numbers PSI2017-87512-C2-1-R; PID2020-11921RB-I00) and the Comissionat per a Universitats All claims expressed in this article are solely those of the authors i Recerca of Generalitat de Catalunya (Grant number 2021SGR01010). and do not necessarily represent those of their affiliated organizations, PT is supported by the Spanish Ministry of Science, Innovation and or those of the publisher, the editors and the reviewers. Any product Universities (Grant number PRE2018-085299). 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