ORIGINAL RESEARCH published: 11 November 2021 doi: 10.3389/fpsyt.2021.746155 Examining the Relationship Between Hair Cortisol With Stress-Related and Transdiagnostic Subclinical Measures Pilar Torrecilla 1 and Neus Barrantes-Vidal 1,2,3* 1 Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Edifici B, Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Departament de Salut Mental, Sant Pere Claver—Fundació Sanitària, Barcelona, Spain, 3 Centre for Biomedical Research in Mental Health (CIBERSAM), Madrid, Spain Background: Hair cortisol concentrations (HCC) provide a retrospective examination of long-term cortisol production as a measure of the hypothalamic-pituitary-adrenal (HPA) axis functioning, one of the major neural systems implicated in mediating the effects of stress on mental illness. However, evidence about the relationship between HCC Edited by: with stressors and symptoms is scattered. In the present study, we aimed to examine Javier Ortuño Sierra, the association between HCC and a wide range of stress-related and transdiagnostic University of La Rioja, Spain subclinical measures in a sample of non-clinical young adults with a wide distribution Reviewed by: Juan Francisco Rodríguez-Testal, of schizotypy. Sevilla University, Spain Michael John Rieder, Methods: A total sample of 132 non-clinical young adults recruited at college and Western University, Canada technical schools oversampled for schizotypy scores were assessed on distal and *Correspondence: proximal stressful experiences, appraisals of stress, traits and symptoms of the affective, Neus Barrantes-Vidal psychosis and dissociation spectrums, as well as stress-buffering measures, and Neus.barrantes@uab.cat provided 3 cm-hair samples. Specialty section: Results: No significant associations were found between HCC and any of the This article was submitted to Psychopathology, stress-related and subclinical measures. Only suspiciousness and disorganization a section of the journal showed a trend for a positive association with HCC but the magnitude was small. Frontiers in Psychiatry Conclusions: The present findings support previous studies indicating an overall lack Received: 23 July 2021 Accepted: 22 October 2021 of concordance between a broad range of stress-related and (sub)clinical phenotypic Published: 11 November 2021 measures with hair cortisol. This study examined for the first time the relationship of HCC Citation: with the non-clinical expression of the psychosis spectrum, that is, schizotypy, which Torrecilla P and Barrantes-Vidal N (2021) Examining the Relationship complements previous studies on clinical high risk and established psychosis and offers a Between Hair Cortisol With promising strategy for studying possible HPA dysfunctions characterizing the subclinical Stress-Related and Transdiagnostic psychosis continuum without the confounds associated to clinical psychosis. Subclinical Measures. Front. Psychiatry 12:746155. Keywords: hair cortisol, stress, hypothalamic-pituitary-adrenal axis, transdiagnostic, subclinical doi: 10.3389/fpsyt.2021.746155 symptoms, schizotypy Frontiers in Psychiatry | www.frontiersin.org 1 November 2021 | Volume 12 | Article 746155 Torrecilla and Barrantes-Vidal Hair Cortisol in Non-clinical Psychosis INTRODUCTION populations are scant and have yielded mixed findings. HCC in adolescents (26, 27) or adult workers (28) have been positively The Hypothalamic-pituitary-adrenal (HPA) axis is one of the associated with depressive symptoms, but lower HCC (29) or no major neural systems implicated in mediating the effects of stress association (30, 31) have also been reported. Studies examining on mental illness. This axis acts in response to stressors by the relationship between hair cortisol and anxiety in non-clinical releasing glucocorticoid cortisol, thereby affecting brain function participants did not find any significant association (29, 31). and facilitating physiological and behavioral responses to threats. Consistent with the current focus on a broader transdiagnostic The normal functioning of the HPA axis involves not only its approach to etiological research in psychopathology [e.g., (32, activation under high stressful situations, but also the activation 33)], studies on phenotypes that have been traditionally less of a negative feedback-loop that stops cortisol secretion in associated to stress-sensitivity, such as the psychosis spectrum, the absence of stressors (1). However, both the activation and are starting to emerge. There is robust evidence that psychotic- inactivation of the HPA axis can be susceptible of dysregulation, spectrum disorders are associated to childhood adversity (34–37), which has been widely connected with the development of mental heightened stress-sensitivity (38–40), and elevated HPA activity disorders (2). (1, 41), suggesting the HPA axis as a relevant mediator of the Cortisol concentrations have been widely analyzed from blood effects of stress on psychotic symptoms (42, 43). Specifically, serum, saliva or urine. However, these measurements have only elevated HCC has been found in clinical samples of schizophrenia been capable of reflecting acute or short-term responses to (20, 21), First Episode of Psychosis (FEP) individuals (44) and stress, with remarkable intra- and inter-individual variability populations at clinical risk for psychosis (45). However, no and day fluctuations. In contrast, hair cortisol, which enables a studies have examined yet the association of HCC with the non- retrospective examination of long-term cortisol production, has clinical manifestations of the extended psychosis phenotype, that recently been proposed as a more accurate measure of chronic is, schizotypy traits. Schizotypy is a multidimensional construct stress (3). As hair grows ∼1 cm per month (4), a 3 cm-sample that represents the underlying liability for psychosis-spectrum of hair has been considered a reliable and usable segment to psychopathology expressed across a broad range of personality, reflect the cortisol production of the last 3 months from the subclinical and clinical psychotic features (46). strand collection. Moreover, it is a non-invasive technique that Exposure to early life adversity has been associated to avoids any further stress associated to the sampling procedure HPA axis dysregulation, which, in turn, has been found to and can be easily stored and transported. Although hair cortisol be robustly associated to elevated risk for developing mental has been found to be subject to developmental and seasonal illness. Thus, most current etiological models support that variations (5), a considerable degree of intraindividual stability prolonged and/or severe stress exposure in highly sensitive has been assumed and validated so far (6), thus constituting a developmental periods (i.e., childhood) disrupts psychobiological promising method for the retrospective and stable assessment of stress regulation mechanisms resulting in a process of behavioral cortisol functioning. and biological sensitization by which the individual manifests Research has provided emerging evidence on hair cortisol an enhanced stress sensitivity to subsequent minor adversities in concentrations (HCC) alterations in clinical populations, mostly adulthood (47, 48). Early adversity has been associated to HCC in affective and anxiety disorders and, to a lesser extent, in in clinical populations with a psychotic, affective, personality psychosis. However, the direction of these alterations is yet to and/or anxiety disorder (20, 49), in individuals clinically at-risk be elucidated and there is some inconsistency across studies (7). for psychosis (45) and also in non-clinical populations (50–53). Depression has been associated with HPA axis hyperactivity (8) However, the last meta-analysis from Khoury and colleagues (54) and elevated short-term cortisol response (9). Nonetheless, when assessing the strength and direction of the relationship between examining the long-term activity of the HPA axis assessing HCC adverse experiences and HCC (including clinical and non-clinical in depressed patients, results are unclear. A recent meta-analysis samples) found two classes of studies: a first one including a by Psarraki and colleagues (10) shows that most studies found majority of studies (N = 24) showing a positive association no significant differences in HCC between Major Depression between adversity and HCC, and a second minor group of studies Disorder (MDD) patients and controls (11–13), although one (N = 4) showing lower levels of hair cortisol in those exposed to study (14) showed higher HCC and two studies (15, 16) found adverse experiences. All studies in the latter group were assessing lower HCC in MDD patients. Nonetheless, higher levels of HCC childhood maltreatment and showed a moderate effect size; in were found in first episode compared to recurrent depression contrast, the first class of studies included a variety of adversities (17, 18) or when there is comorbidity between MDD and an other than childhood maltreatment (e.g., exposure to natural anxiety disorder (19). Bipolar Disorder patients seem to present disasters or domestic violence) and showed a small effect size. higher HCC compared to controls (20–22) as reported in the This pattern of mixed results might be consistent with theories meta-analysis by Koumantarou Malisiova and colleagues (7), and positing both types of HPA axis alteration following adversity; again, HCC were higher for those with psychiatric comorbidities hyper-activity in the short-term and hypo-activity in the long- (23). In contrast, decreased HCC have been found in patients term (55). It also indicates the need of differentiating among with Generalized Anxiety Disorder (GAD) (24) or other anxiety types of adversities and populations when studying the effects of disorders such as Post Traumatic Stress Disorder (PTSD) (25), adversity on the HPA axis. although other studies have failed to find an association (16, Another critical question is the association between proximal 19). Results regarding stress-related symptoms in non-clinical psychosocial stressors and HPA axis function. A major issue is Frontiers in Psychiatry | www.frontiersin.org 2 November 2021 | Volume 12 | Article 746155 Torrecilla and Barrantes-Vidal Hair Cortisol in Non-clinical Psychosis that the relationship between subjective (i.e., perceived stress, found a positive association between HCC and the amount of subjective impact of life events) and objective (i.e., cortisol, social support in a sample of schizophrenia patients; however, number of life events) measures of stress has not been coherent social support moderated the relationship between stressful across studies and yielded mixed findings. The meta-analysis life events and HCC by attenuating the effects of life events by Stalder and colleagues (25) indicated no association between on cortisol response, thus providing biological support to the subjective perceived stress and HCC across populations exposed buffering hypothesis. to different levels of chronic stress. More recent studies have also In summary, there is a major concern about the lack of failed to find significant associations (30, 56–59), except for Ling “psychoendocrine covariance” between subjective and objective and colleagues (60), who found a negative relationship between measures of stress. As referred in Stalder’s meta-analysis (25), perceived stress and HCC in African non-clinical mothers no consistent associations between HCC and self-reports of (with a quite reduced sample size), and Xu and colleagues perceived stress, social support and depression symptoms (29), who reported, in contrast, a positive association in a emerged in the most recent literature. Moreover, this literature Chinese sample of healthy adolescents differing in stress exposure is very scattered in terms of the types of constructs, measures (incarcerated vs. attending regular high school). On the other and samples used. Importantly, most studies have examined a hand, another widely used measure to assess “objective” stress very narrow range of stress-related and/or phenotypic variables is the quantification of recent life events. This has been mostly presumed to be associated to HCC within the same sample— studied in adolescent samples, and mixed results have been in fact, only meta-analytic studies have offered an integrated found. Shapero and colleagues (26) did not find any association perspective of the association of stress and psychopathology between HCC and number of life events, whereas Xu’s (27) measures with HCC. Therefore, the present study aimed to and Karlén’s (61) studies reported a positive association and investigate the association between HCC with a broad range of Sierau’s (31) a negative one. Finally, Cullen and colleagues (62) psychosocial stressors (childhood adversity, recent life events) reviewed the literature examining the concordance between and stress-related measures (perceived stress). Importantly, the naturally-occurring psychosocial stressors, both distal (trauma) stress-related measures used covered both the “objective” report and proximal (perceived stress and life events), with cortisol of threatening and stressful life events as well as the “subjective” across clinical and at-risk psychosis populations. Although all appraisal of stress impact. In addition, and consistent with types of cortisol measurements were included in the meta- current evidence on the relevance of heightened stress-sensitivity analysis, a poor correlation [r = 0.05 (95% CI: −0.00 to 0.10), as a relevant transdiagnostic mechanism, the association of p = 0.059] was found between stressors and cortisol measures traits and symptoms of the affective (neuroticism, depression, (including HCC). anxiety), psychosis (suspiciousness, schizotypy) and dissociation Research so far has only studied the relationship between spectrums with HCC was examined. Finally, stress-buffering HCC and the occurrence of stressful life events, but any of factors (social support) were also examined in a non-clinical those studies has reached to study the whole spectrum of life sample of young adults oversampled for high levels of schizotypy events, comprising both adverse as well as positive ones (e.g., (i.e., the behavioral liability to psychosis). Examining non- getting married). Additionally, there is no research on the clinical participants with a wide distribution of behavioral risk association between the HCC and the degree of subjective impact for psychosis ensures including a representation of individuals (positive or negative) of these life events on the individual. with a phenotype that has been consistently associated with Given large individual differences in stress-related genetic make- high stress exposures (36, 37) and heightened stress-sensitivity up (e.g., BDNF, FKBP5, COMT, 5-HTTLPR), temperamental (1, 38, 39, 68), which should enrich the variability in the traits (e.g., neuroticism, harm avoidance), gene-environment constructs of interest (stress exposures, HCC and stress-related interactions, and idiographic contextual factors, it is expected phenotypic features). Consistent with evidence supporting the that the same amount of life events can impact very differently dimensional conceptualization of psychopathology and the on individual’s appraisals [e.g., (63)], and, therefore, on levels of transdiagnostic relevance of the HPA-axis dysregulation, we HPA axis dysregulation. expected a general pattern of associations between HCC with the The association between neuroticism, a temperamental trait stress-related measures and the different subclinical spectra in a defined by heightened stress reactivity (64), and HCC has non-clinical sample. only been examined in a twin study, showing no significant correlation (30). Similarly, little is known about the association METHODS of HCC with protective factors related to coping with stress. The buffering hypothesis poses that the presence of social support Participants might help buffering the potential deleterious effects of stressful The sample of this study consisted of 132 non-clinical young situations (65). However, the biological impact of the effects of adults (mean age = 27.86, SD = 3.07, range = 26.07) belonging to social support on stress and, thus, on the HPA axis, has been the ongoing Barcelona Longitudinal Investigation of Schizotypy scarcely investigated. Stalder and colleagues (25) did not find Study (BLISS) (68–70). any significant association between HCC and social support in At T1, a large pool of 547 unselected college students and their meta-analysis, whereas Iob and colleagues (66) reported 261 technical school students were initially screened with self- that low social support was associated to high levels of hair report questionnaires (68, 69). A subsample oversampled with cortisol. In contrast, a recent study from Yang and colleagues (67) elevated scores on both positive and negative schizotypy factors Frontiers in Psychiatry | www.frontiersin.org 3 November 2021 | Volume 12 | Article 746155 Torrecilla and Barrantes-Vidal Hair Cortisol in Non-clinical Psychosis (to ensure enough variance in the measures of interest) from the Affective Symptoms and Personality Wisconsin Schizotypy Scales (WSS-S) (71, 72), the Schizotypal The Beck Depression Inventory-II (BDI-II) (79) was used to Personality Questionnaire (SPQ) (73) and the Community assess depressive symptoms. It has 21 items including a range of Assessment of Psychotic Experiences (CAPE) (74) was selected affective, behavioral, cognitive and somatic symptoms (Cronbach to conduct in-depth examinations comprising a wide range of alpha = 0.88). Anxiety was measured with the Anxiety scale of interview, questionnaire, and experience sampling methodology the Symptom Checklist-90-Revised (SCL-90-R) (80). This scale measurements. At T2, 214 college and 39 technical school consists of 10 items that can be answered with a Likert-scale from students were reassessed (1.7 and 0.4 years later, respectively). At 0 to 4 (Cronbach alpha = 0.82). T3, due to funding constraints, we invited to participate a reduced Neuroticism was measured using the 8-item neuroticism subsample that retained the original distribution of scores; 103 subscale of the Big Five Inventory (BFI) (81), a 44-item inventory college and 31 technical school participants were reassessed (1.4 that measures five predominant dimensions of personality and 1.7 years later, respectively). Of these, 89 college participants (extraversion, convenience, consciousness, neuroticism and were re-assessed at T4 (1.3 years later). Finally, at T5 we were openness) through 5-point Likert scales ranged from “strongly able to successfully reassess 168 (79%) of the college students disagree” to “strongly agree” (Cronbach alpha = 0.83). assessed at T2 7.8 years later (and 3.2 years after T4). In addition, we reassessed 26 (77%) of the technical school participants Psychosis and Dissociation Spectrum Personality at T3 2.4 years later. Therefore, a total of 194 participants Traits and Experiences were assessed at T5, the study phase when hair samples In terms of paranoid personality, the Suspiciousness Scale of were collected. the Schizotypal Personality Questionnaire (SPQ) (73) was used At T5, 132 out of the 194 participants (112 were college (Cronbach alpha = 0.70). Schizotypy personality traits were students and 20 technical school students) were included in assessed with the short forms of the Wisconsin Schizotypy the present cross-sectional study. Participants completed self- Scales (WSS-S) (71, 72), from which participants were assigned report questionnaires (except for childhood adversity, which was positive and negative schizotypy factor scores (68, 69) and the available from T1) and provided 3 cm-hair samples. Sample size Multidimensional Schizotypy Scales Brief (MSS-B) (82), a 39- varies for some measures given that three of the participants item measure which provides positive, negative and disorganized who provided hair samples did not complete the questionnaire scores of schizotypy. The MSS-B was introduced in the protocol assessment (N = 129). All participants provided written informed assessment once the sampling had already started, so only 59 consent to participate. (40 college and 19 technical school students) participants have data for the MSS-B. Of note, the MSS-B has demonstrated Materials and Procedure to overcome limitations associated with existing measures of Stress-Related Measures schizotypy such as unclear conceptual framework, outdated The Perceived Stress Scale (PSS) (75) enquires about the level of items, ethnical/sex differences, or exclusion of disorganized stress perceived by participants during the last month. It is a self- schizotypy and to show good internal reliability and construct reported questionnaire of 14 items that provides a total score of validity (83, 84). Data of the MSS-B for the disorganized perceived stress (Cronbach alpha = 0.86). dimension (Cronbach alpha = 0.75) and the factorially-derived Two complementary measures of life events were used. The dimensional scores based on the WSS for the positive and List of Threatening Events (LTE) (76) consists of 20 items negative dimensions were used. (YES/NO) asking about adverse life events that might have Dissociation was assessed using the Dissociative Experiences occurred during the last year. In contrast, the Life Events Survey Scale (DES–II) (85), a 28-item instrument where participants are (LES) (77) includes 57 life events comprising a full range of prompted to answer from a range of 0% (never) to 100% (all experiences from negative to positive plus three blank spaces for the time) the frequency of each of the dissociative experiences other events. Forty-seven of them refer to general life events and presented (Cronbach alpha = 0.82). 10 of them are academic-related. We removed one academic- related item (“Academic probation”) given that there is not an Stress-Buffering Factors equivalent of it in the Spanish education system. Participants rate The Multidimensional Scale of Perceived Social Support (MSPSS) both the occurrence (YES/NO) of the event and the impact it (86) is a 12-item scale designed to measure perceived social caused on them, capturing both a negative as well as a positive support from three sources: Family, Friends, and a Significant valence by using a Likert scale ranging from −3 (very negative) to Other. The total sum of perceived social support has been used +3 (very positive). In the present study, only the subjective mean in this study (Cronbach alpha = 0.92). impact of life events was included (Cronbach alpha = 0.78). The Childhood Trauma Questionnaire Brief (CTQ-B) (78) Hair Cortisol data was available for participants from the baseline data (T1) Hair strands were cut as close as possible from the posterior collection of the BLISS study. It is a self-reported measure vertex area of the head. Specifically, cortisol concentrations were covering 28 items rating the severity of emotional abuse and determined from the 3 cm hair segment most proximal to the neglect, physical abuse and neglect and sexual abuse. A total score scalp. As hair grows in average 1 cm per month (4), the samples of childhood trauma comprising all the subscales is used in the represented the cortisol mean levels from the last 3 months. All present study (Cronbach alpha = 0.85). samples were stored in aluminum foil at room temperature until Frontiers in Psychiatry | www.frontiersin.org 4 November 2021 | Volume 12 | Article 746155 Torrecilla and Barrantes-Vidal Hair Cortisol in Non-clinical Psychosis the extraction procedure. Then, the samples were washed twice TABLE 1 | Descriptive data of the sample and hair cortisol concentrations (HCC). for 1 min with 10 ml of isopropanol and completely air dried HCC differences at room temperature. After that, samples were further cut into fragments of ∼2−3 mm and mixed with 1.6 methanol overnight Statistic test p-value with continuous rotation. All hair samples weighted within the HCC (M, SD) 6.22 pg/mg, 4.93 – – recommended range required for immunoassay analyses [i.e. 5–50 mg; (61, 87)]. Methanol was recovered in a new clean glass Demographics tube. The extraction was repeated, and the recovered methanol Age (M, SD) 27.84, 3.08 – – a was pooled and dried up under a nitrogen stream. Extracted Sex (N) t = 2.09 0.038* cortisol was re-suspended in 200 µl of PBS and assayed for Male 22 cortisol. HCC were then determined by a radioimmunoassay Female 109 procedure. Also, participants were prompted to answer whether Hair-related variables they have ever dyed their hair and how many times do they wash Hair dye (N) t = 0.612 0.542 their hair in a week. Yes 22 No 109 Statistical Analyses Washing frequency (M, SD) 3.05, 1.76 b r = 0.128 0.146 Statistical analyses were performed using the Statistical a T-Test, b Pearson Correlations. *p < 0.05. M = Mean, SD = Standard Deviation. Package for the Social Sciences (SPSS), Version 22.0 software (88). ANOVA was used to test differences in hair cortisol concentrations for academic group, sex, TABLE 2 | Correlational analyses between stress-related and subclinical age and hair dye, and Pearson correlations were used measures with HCC. to test associations between hair cortisol and hair wash frequency as well as the different environmental, clinical and M, SD r p-value psychosocial measures. Psychosocial stress Distal RESULTS Childhood Trauma 33.91, 8.03 0.094 0.287 Proximal One out of 132 participants was excluded because of abnormally Perceived stress scale 20.19, 7.63 −0.006 0.949 increased HCC (244.6 pg/mg) compared to the rest of the sample. Life events As shown in Table 1, mean cortisol levels of the final sample of List of threatening events (LTE) 2.28, 1.97 0.04 0.656 131 participants were 6.22 pg/mg (s.d. 4.93), ranging from 1.30 to Subjective impact of life events (LES) 0.51, 1.04 −0.026 0.772 39.70 pg/mg. Males (N = 22) showed mean cortisol levels of 8.20 Affective, psychosis and dissociation spectrum traits and symptoms pg/mg (s.d. 8.31) and females (N = 109) 5.81 pg/mg (s.d. 3.86), Neuroticism 2.69, 0.61 −0.097 0.276 with no significant differences (p = 0.20). No differences between Depression 5.70, 6.66 −0.046 0.607 college students and technical school students were found on HCC (p = 0.22). Therefore, the two samples were combined to Anxiety 5.41, 4.75 0.004 0.964 perform the correlational analyses of HCC with the measures Suspiciousness 1.57, 1.67 0.149 0.094+ of interest. HCC were not affected by hair dye (p = 0.542) or Positive schizotypy 0.93, 1.5 0.13 0.326 frequency of washing (p = 0.146). Negative schizotypy 2.13, 2.04 −0.027 0.839 Correlational analyses (Table 2) showed no significant Disorganized schizotypy 0.78, 1.45 0.22 0.094+ associations between HCC and any of the psychosocial or Dissociation 7.89, 7.19 0.043 0.63 phenotypic measures. Only suspiciousness and disorganization Stress-buffering measures showed a trend for an association with HCC with a positive Social support 71.97, 13 −0.01 0.909 correlation of r = 0.149 (p < 0.10) and r = 0.220 (p < +p < 0.10. M = Mean, SD = Standard Deviation. Data was available for N = 131 0.10), respectively. participants for the Childhood Trauma Questionnaire (CTQ) assessed at T1, whereas three participants that provided hair samples at T5 did not complete the questionnaire assessment at T5 (N = 129). DISCUSSION To the best of our knowledge, this is the first study examining a wide range of stress-related variables including both risk Results showed no significant associations between HCC and protective factors, subjective and objective measurements, and the different psychosocial stress measures. Contrary to the and employing a transdiagnostic perspective of stress-related hypothesis, but consistent with previous studies, depression, phenotypes in a sample of non-clinical young adults. Moreover, anxiety and neuroticism were not associated with HCC. In this is the first study examining the relationship of HCC with contrast, suspiciousness and disorganization, both strongly the non-clinical expression of the psychosis spectrum, that is, related to affective symptoms, showed a trend toward a schizotypy and paranoid personality traits along with other significant association with HCC, although the magnitude was stress-related phenotypes. small in both cases. Suspiciousness consistently shows a large Frontiers in Psychiatry | www.frontiersin.org 5 November 2021 | Volume 12 | Article 746155 Torrecilla and Barrantes-Vidal Hair Cortisol in Non-clinical Psychosis association with depression, low self-esteem, and neuroticism to whether this is actually a limitation, as hair cortisol is (89–91). Similarly, the disorganized dimension of schizotypy considered to be a “long-term,” “stable” or even a “chronic” shows the strongest association with negative affect, depression biological indicator of stress. Compared to previous “short- and anxiety compared to positive and negative schizotypy term” techniques such as saliva, blood serum or urine, HCC (92, 93). Interestingly, the disorganization dimension measured represent a long-term measurement of cortisol levels as 3-cm by the MSS scale does not include items that explicitly hair samples provide mean cortisol levels from the last 3 months. assess affect, but disrupted affect (e.g., excessive negative affect Importantly, intraindividual stability has been demonstrated in and inappropriate affect) is possibly equally relevant to this most studies assessing the correlation between repeated hair dimension as disruptions of thought, speech and behavior (93). cortisol assessments (usually two to three time points) across It is likely that the fact that participants were oversampled for periods of one (96), two (97), three (98, 99), four (97), six (5, 6) schizotypy to ensure sufficient variability in these traits allowed and twelve (97) months in adult populations. Nonetheless, all to capture this trend for an association—something that might those studies employed non-clinical populations, usually healthy be missed given the skewed nature of these traits in non- adults or unselected college students, and only two of them clinical samples. Finally, from a transdiagnostic psychopathology (98, 99) focused on individuals explicitly exposed to certain perspective, it is attractive to speculate that weak trends only levels of stress (e.g., postpartum period or high-risk community). emerged for the most severe traits of mental the disorder Findings in depression on higher HCC in the first but not in the spectrum. Both suspiciousness and disorganization traits entail recurrent episodes (17, 18) and the inconsistent association of an intense and enduring disruption of a broad range of cognitive, HCC and childhood trauma (54, 55), raise concerns about the affective and behavioral aspects, usually associated to mental validity of hair cortisol as a measure of chronic stress levels. suffering and impairment. Nonetheless, the weak associations of Of note, a major concern has been the degree of association these constructs with hair cortisol calls for further examination between subjective and objective psychosocial stressors with of the association of HCC with a broad transdiagnostic range of biological markers of stress such as HCC. It has been suggested psychopathology dimensions across non-clinical schizotypy and that exposure to early adversities in life predisposes individuals clinical high-risk populations. to overreact to subsequent stressful experiences in adulthood Overall, the present findings add to previous studies showing due to a biological and behavioral stress sensitization process a lack of psychoendocrine covariance between the long- that, in turn, contributes to the risk of mental illness in general, term hair cortisol measurement with psychosocial stressors, and psychosis in particular (39, 40, 100, 101). Moreover, the symptomatology and other stress-related phenotypes in non- neural diathesis stress model poses that the HPA axis plays clinical samples. It has been suggested that this unexpected a major role as a mediator of the effects of stress on the finding might be related to the fact that samples from studies development of, for instance, depression (102) and psychosis assessing stress and cortisol usually comprise individuals that (1, 103). As hair cortisol has been considered a reliable biomarker have been exposed to either very high (clinical) or very low to capture the HPA function, it is expected to find disrupted (“super normal” controls) levels of stress (25). However, the HCC in those individuals that have experienced higher levels present study aimed to avoid this limitation by employing a of psychosocial stress. Nonetheless, only scarce research has non-clinical sample encompassing a wide range of variance found an association between early adversity, life events or along schizotypy dimensions in order to ensure the presence perceived stress and hair cortisol, and the direction of the of sufficient variability in the constructs of interest (i.e., stress- associations has been contradictory among studies. Cullen and related measures, traits and subclinical symptoms). Another colleagues (62) reviewed studies examining the concordance hypothesis that has been raised to account for this poor between psychosocial stressors and cortisol measures in healthy concordance is that a significant hair cortisol elevation might controls, individuals at clinical high-risk for psychosis and with require an intense and persistent exposure to stress (25). Cross- clinical psychosis, and only weak correlations were found. The sectional studies might not be the most adequate to observe present study complements the studies reviewed (62) by focusing persistent or repeated exposure to stress. In that sense, further on non-clinical individuals with psychometric high risk, although research based on longitudinal assessments is needed to examine more research on the psychoendocrine covariance across the whether a notable HPA axis dysfunction is observable after psychosis continuum is needed. Furthermore, the present study persistent exposure to stressful situations. Also, inconclusive included a critical measure not included in previous studies findings between HCC and stress-related measures have been on HCC: the subjective appraisal of the impact of stressful life attributed to some methodological aspects. For instance, the events. It has been suggested that the effect of a life event on an use of different analytic methods to obtain HCC. Whilst most individual may result more from the appraisal of the perceived studies have been using traditional immunoassay methods impact than the life event itself (104, 105), and most likely, the and exhibiting great sensitivity, liquid chromatography-mass biological impact of such event on the stress system depends on spectrometry (LCMS) based-assays are also employed, which whether individuals do perceive that event as stressful However, might be yielding heterogeneous results in meta-analytic work no association was found with either the “objective” number of including both techniques (7, 94). Another methodological life events or the “subjective” appraisal. A possible explanation limitation has been attributed to the discrepancy between for this lack of associations might be the large individual timeframes captured by hair cortisol and self-reported stress- variation in stress-sensitivity. Stress-sensitivity has been defined related measures (7, 95). However, there is no consensus as as a developmental phenomenon in which individuals tend to Frontiers in Psychiatry | www.frontiersin.org 6 November 2021 | Volume 12 | Article 746155 Torrecilla and Barrantes-Vidal Hair Cortisol in Non-clinical Psychosis be highly reactive to both low and extremal levels of stress ETHICS STATEMENT that emerges from relations between genetic, temperamental and contextual factors (48, 106). Thus, further gene—environment The studies involving human participants were reviewed and person—environment interaction studies are needed to and approved by Ethics Committee of the Universitat better understand the complexity of stress-sensitivity and to Autònoma de Barcelona (Comissió d’Ètica en l’Experimentació integrate individual differences in this trait in designs mostly Animal i Humana (CEEAH); https://www.uab.cat/web/ based on group-level associations. investigacio-humana/presentacio-1345713929159.html). The In conclusion, this study supports previous studies indicating patients/participants provided their written informed consent to an overall lack of concordance between a broad range of participate in this study. stress-related and (sub)clinical symptom measures with hair cortisol. This study examined HCC in individuals oversampled AUTHOR CONTRIBUTIONS for schizotypy traits (i.e., psychometric high risk) for the first time, which complements studies on clinical high risk for NB-V conceived the study, acquired funding, administered and psychosis and offers a promising strategy for studying possible supervised the project and data acquisition, contributed and HPA dysfunctions characterizing the subclinical psychosis revised the manuscript. PT analyzed the data and wrote the continuum without the confounds associated to clinical status manuscript. All authors contributed to the article and approved and medication. Further studies examining hair cortisol and the submitted version. its relationship with stress-related symptoms, phenotypes and psychosocial stressors in non–clinical samples exposed to FUNDING different levels of stress are needed. Also, longitudinal studies might help to study stress persistence as a possible essential This work was supported by the Spanish Ministry of Science, feature for HPA axis disruption. As posed by the RDoC Innovation and Universities (Grant number PSI2017-87512- framework (32), an integrated and translational approach from C2-1-R) and the Comissionat per a Universitats i Recerca of an endocrine, genetic and psychological level, as well as the study Generalitat de Catalunya (Grant No. 2017SGR1612). PT was of their interaction with environmental influences, is needed to supported by the Spanish Ministry of Science, Innovation and completely understand the mechanisms underlying HPA axis Universities (Grant No. PRE2018-085299). dysfunction and its relationship with mental health. ACKNOWLEDGMENTS DATA AVAILABILITY STATEMENT Authors want to thank Prof. Thomas Kwapil, Tamara Sheinbaum The raw data supporting the conclusions of this article will be and Anna Racioppi for their contribution to study design, and to made available by the authors, without undue reservation. Anna Racioppi for her work in data collection. REFERENCES 8. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. (2008) 1. Walker E, Mittal V, Tessner K. Stress and the hypothalamic pituitary adrenal 31:464–8. doi: 10.1016/j.tins.2008.06.006 axis in the developmental course of schizophrenia. Annu Rev Clin Psychol. 9. 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Intra-individual endorsed by the publisher. stability and developmental change in hair cortisol among postpartum mothers and infants: implications for understanding chronic stress. Dev Copyright © 2021 Torrecilla and Barrantes-Vidal. This is an open-access article Psychobiol. (2016) 58:509–18. doi: 10.1002/dev.21394 distributed under the terms of the Creative Commons Attribution License (CC BY). 99. Liu CH, Fink G, Brentani H, Brentani A. An assessment of hair The use, distribution or reproduction in other forums is permitted, provided the cortisol among postpartum Brazilian mothers and infants from original author(s) and the copyright owner(s) are credited and that the original a high-risk community in São Paulo: intra-individual stability publication in this journal is cited, in accordance with accepted academic practice. and association in mother-infant dyads. Dev Psychobiol. (2017) No use, distribution or reproduction is permitted which does not comply with these 59:916–26. doi: 10.1002/dev.21557 terms. Frontiers in Psychiatry | www.frontiersin.org 10 November 2021 | Volume 12 | Article 746155