EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 2021, VOL. 12, 1857955 https://doi.org/10.1080/20008198.2020.1857955 CLINICAL RESEARCH ARTICLE Childhood maltreatment interacts with hypothalamic-pituitary-adrenal axis negative feedback and major depression: effects on cognitive performance Neus Salvat-Pujol a,b,c, Javier Labad c,d, Mikel Urretavizcaya a,c,e, Aida de Arriba-Arnau a,c, Cinto Segalàs a,c,e, Eva Real a,c, Alex Ferrer a,b, José M. Crespoa,c,e, Susana Jiménez-Murcia a,e,f , Carles Soriano-Mas a,c,g, José M. Menchón a,c,e and Virginia Soria a,c,e a Bellvitge University Hospital, Psychiatry Department. Bellvitge Biomedical Research Institute (IDIBELL), Neurosciences Group - Psychiatry and Mental Health, Barcelona, Spain; bCorporació Sanitària Parc Taulí, Department of Mental Health, I3PT, Sabadell, Spain; c Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain; dInstitut d'Investigació i Innovació Parc Taulí (I3PT), Department of Mental Health, Consorci Sanitari del Maresme, Mataró, Spain; eDepartment of Clinical Sciences, School of Medicine, Universitat de Barcelona, Barcelona, Spain; fCentro de Investigación Biomédica en Red de Fisiopatología Obesidad y Nutrición (CIBEROBN), Carlos III Health Institute, Madrid, Spain; gDepartment of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Bellaterra, Spain ABSTRACT ARTICLE HISTORY Background: Childhood maltreatment (CM) is associated with impaired hypothalamic- Received 15 April 2020 pituitary-adrenal (HPA) axis negative feedback and cognitive dysfunction, resembling Revised 17 November 2020 Accepted 18 November 2020 those abnormalities linked to major depressive disorder (MDD). Objectives: We aimed to assess the potential modulating effects of MDD diagnosis or HPA KEYWORDS axis function in the association between different types of CM and cognitive performance in Childhood abuse; childhood adulthood. neglect; cortisol; HPA axis; Methods: Sixty-eight MDD patients and 87 healthy controls were recruited. CM was dexamethasone suppression assessed with the Childhood Trauma Questionnaire. We obtained three latent variables for test; cognition; memory; neuropsychological performance (verbal memory, visual memory and executive function/ major depression processing speed) after running a confirmatory factor analysis with cognitive tests applied. Dexamethasone suppression test ratio (DSTR) was performed using dexamethasone PALABRAS CLAVE abuso infantil; negligencia 0.25 mg. infantil; cortisol; eje HHA; Results: Different types of CM had different effects on cognition, modulated by MDD prueba de supresión de diagnosis and HPA axis function. Individuals with physical maltreatment and MDD pre­ dexametasona; cognición; sented with enhanced cognition in certain domains. The DSTR differentially modulated the memoria; depresión mayor association between visual memory and physical neglect or sexual abuse. Conclusions: HPA axis-related neurobiological mechanisms leading to cognitive impairment 关键词 might differ depending upon the type of CM. Our results suggest a need for early assess­ 童年期虐待; 儿童忽视; 皮 ment and intervention on cognition and resilience mechanisms in individuals exposed to 质醇; HPA轴; 地塞米松抑 CM to minimize its deleterious and lasting effects. 制试验; 认知; 记忆; 重性 抑郁 El maltrato infantil interactúa con la retroalimentación negativa del HIGHLIGHTS • We studied the effects of eje hipotalámico-hipofisario-adrenal y la depresión mayor: efectos childhood maltreatment sobre el rendimiento cognitivo. (CM), HPA axis feedback (DST), and depression on Antecedentes: El maltrato infantil (MI) se asocia con una alteración en la retroalimentación cognition. negativa del eje hipotalámico-hipofisario-adrenal (HHA) y disfunción cognitiva, que se • Different types of CM had a asemejan a las anomalías vinculadas al trastorno depresivo mayor (TDM). distinct impact on cognitive Objetivos: Nuestro objetivo fue evaluar los posibles efectos moduladores del diagnóstico de performance. TDM y de la función del eje HHA en la asociación entre diferentes tipos de MI y el • MDD diagnosis and DST rendimiento cognitivo en la edad adulta. modulated the association Métodos: Se reclutaron 68 pacientes con TDM y 87 controles sanos. El MI se evaluó con el between CM and cognition. Cuestionario de trauma infantil. Se obtuvieron tres variables latentes para el rendimiento neuropsicológico (memoria verbal, memoria visual y función ejecutiva/velocidad de proce­ samiento) tras realizar un análisis factorial confirmatorio con las pruebas cognitivas aplica­ das. La ratio de supresión de cortisol en el test de supresión con dexametasona (DSTR) se realizó usando dexametasona 0,25 mg. Resultados: Los diferentes tipos de MI tuvieron diferentes efectos sobre la cognición, modulados por el diagnóstico de TDM y la función del eje HHA. Los individuos con maltrato físico y TDM presentaron una cognición mejorada en ciertos dominios. El DSTR moduló diferencialmente la asociación entre memoria visual y negligencia física o abuso sexual. Conclusiones: Los mecanismos neurobiológicos relacionados con el eje HHA que conducen al deterioro cognitivo pueden diferir según el tipo de MI. Nuestros resultados sugieren la necesidad de una evaluación e intervención tempranas sobre la cognición y los mecanismos de resiliencia en individuos expuestos a MI para minimizar sus efectos nocivos y duraderos. CONTACT Virginia Soria vsoria@bellvitgehospital.cat Department of Psychiatry, Bellvitge University Hospital-IDIBELL, Feixa Llarga s/n, 08907, L´Hospitalet de Llobregat, Barcelona, Spain Supplemental data for this article can be accessed here. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 N. SALVAT-PUJOL ET AL. 童年期虐待与下丘脑-垂体-肾上腺轴负反馈和重性抑郁障碍的相互作用: 对认知表现的影响 背景: 童年期虐待 (CM) 与下丘脑-垂体-肾上腺 (HPA) 轴负反馈受损和认知功能损伤有关, 类 似于重性抑郁障碍 (MDD) 相关异常。 目的: 我们的目的是在不同类型CM与成年认知表现之间的关联中评估MDD诊断或HPA轴功 能的潜在调节作用。 方法: 招募了68名MDD患者和87名健康对照者。通过儿童创伤问卷评估了CM。在使用认 知测试进行验证性因素分析后, 我们得到了3个神经心理学表现潜变量 (语言记忆, 视觉记 忆和执行功能/处理速度) 。使用0.25mg地塞米松得到地塞米松抑制试验比率 (DSTR) 。 结果: 不同类型CM对认知的影响不同, 受到MDD诊断和HPA轴功能的调节。遭受身体虐待 和MDD的个体在某些领域认知增强。 DSTR有差异地调节了视觉记忆与身体忽视或性虐待 之间的关联。 结论: 导致认知损伤的HPA轴相关神经生物学机制可能因CM类型而异。我们的结果表明需 要对CM暴露个体的认知和韧性机制进行早期评估和干预, 以将其有害和持久影响最小化。 1. Introduction neurobiological changes that persist into adulthood The hypothalamic-pituitary-adrenal (HPA) axis is and resemble the neuroendocrine features of MDD, a major physiological stress response system that including alteration of glucocorticoid receptor func­ regulates its own activity through a negative feed­ tioning and impaired HPA axis feedback (Heim, back loop exerted by cortisol. Patients with major Mletzko, Purselle, Musselman, & Nemeroff, 2008; depressive disorder (MDD) commonly show Heim, Newport, Mletzko, Miller, & Nemeroff, 2008; a hyperactive HPA axis (Wolkowitz, Burke, Epel, Heim, Shugart, Craighead, & Nemeroff, 2010). & Reus, 2009), including an altered feedback inhi­ Indeed, lasting HPA axis dysfunction related to CM bition by endogenous glucocorticoids (Pariante & has been found to be independent of psychopathol­ Miller, 2001). The feedback inhibition of the HPA ogy (Carvalho Fernando et al., 2012; Hinkelmann axis can be assessed with the administration of et al., 2013; Majer et al., 2010). Therefore, it has dexamethasone, a synthetic glucocorticoid recep­ been hypothesized that neuroendocrine abnormalities tor agonist that results in the suppression of the in MDD may be partly explained by the long-lasting secretion of cortisol by the adrenal gland. In effects of CM on the HPA axis and might represent patients with MDD, there is a lack of suppression the vulnerability for the development of depression in of cortisol secretion after dexamethasone intake, response to stress rather than consequences of which indicates a reduced feedback sensitivity and depression (Heim, Newport et al., 2008). is considered a measure of glucocorticoid resis­ Furthermore, studies have linked CM with an tance (Pariante & Miller, 2001; Wolkowitz et al., increased risk of MDD in adulthood, predicting 2009). early-onset, severe, chronic and treatment-resistant Prolonged exposure to glucocorticoids resulting depression (Nelson, Klumparendt, Doebler, & from lowered negative feedback on the HPA axis in Ehring, 2017). MDD has been associated with cognitive impairment There is evidence that HPA axis hyper- and (Behnken et al., 2013; Hansson, Murison, Lund, & hypoactivation emerge sequentially after CM Hammar, 2013; Zobel et al., 2004). Nevertheless, not (Bernard, Frost, Bennett, & Lindhiem, 2017). all patients with MDD suffer such disturbances in the Indeed, maltreated children show hypercortisolemia HPA axis feedback or in cognition, and childhood resulting from sensitization of the HPA axis after maltreatment (CM) is thought to be involved in this stress, followed by hypocortisolemia in adulthood variability. due to a downregulation of the HPA system in CM can be divided into abuse, which is an expo­ response to initially high cortisol levels (Bernard sure to threatening behaviours, and neglect, et al., 2017). Some authors have further pointed out a deprivation of cognitive and psychosocial stimula­ that the basal cortisol pattern may be related to the tion. CM is associated with deficits in memory and severity and the type of maltreatment (van der Vegt, executive function (Majer, Nater, Lin, Capuron, & van der Ende, Kirschbaum, Verhulst, & Tiemeier, Reeves, 2010; Nikulina & Widom, 2013), independent 2009). Specifically, they found that moderate CM of psychopathology (R-Mercier, Masson, Bussières, & was associated with morning hypercortisolemia and Cellard, 2018). Thus, neurobiological consequences of a steep diurnal cortisol slope, whereas severe CM was CM may be deemed as a potential explanation for associated with hypocortisolemia and a flatter slope poor cognitive functioning in MDD (Gould et al., (van der Vegt et al., 2009). This effect on the HPA 2012; Kaczmarczyk, Wingenfeld, Kuehl, Otte, & axis function was stronger for childhood abuse than Hinkelmann, 2018). Additionally, CM induces neglect (van der Vegt et al., 2009). EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 3 The various types of CM have also been linked to cognitive performance in adulthood. We hypothe­ dysfunction of the HPA axis negative feedback in sized that HPA axis dysfunction might play an adulthood (Miller, Chen, & Zhou, 2007). However, important role, as neuroendocrine abnormalities it is not clear whether this influence ultimately leads have been related to CM as well as with MDD. to an enhancement or a suppression of cortisol secre­ More specifically, we hypothesized that the relation­ tion. On the one hand, some studies have related ship between CM and cognitive performance is emotional abuse (Carpenter et al., 2009), emotional modulated by MDD and HPA axis activity: 1) CM, neglect (Carvalho Fernando et al., 2012), or sexual and particularly neglect, is associated with poorer abuse (Stein, Yehuda, Koverola, & Hanna, 1997) to cognitive performance in people with MDD, and 2) hyper-suppression of the HPA axis in response to failure to suppress cortisol levels after dexamethasone dexamethasone administration. On the other hand, administration in patients with MDD and individuals increased cortisol responses to the Dex/CRH test exposed to CM is associated with poor cognitive have been reported in sexual or physical abuse performance. (Heim, Mletzko et al., 2008). Lu, Gao, Huang, Li, and Xu (2016) found that subjects with MDD and CM showed decreased glucocorticoid feedback inhi­ 2. Materials and methods bition compared with healthy individuals without 2.1. Sample MDD or CM. Not only the type of CM but also its severity might be critical for HPA axis responsivity in Our sample included 68 patients with MDD (67.6% the Dex/CRH test. A recent study reported that females, mean age 59.87 ± 11.05 years) recruited from patients with a mood disorder and mild childhood the Psychiatry Department at Bellvitge University emotional neglect had an enhanced HPA axis Hospital (Barcelona) and 87 healthy controls (HC; response, while patients reporting severe neglect did 66.7% females, mean age 56.14 ± 11.61 years) not differ from controls in their cortisol response recruited from the same geographic area. (Watson et al., 2007). Exclusion criteria were an age less than 18 years; The vast majority of literature reports an associa­ a diagnosis of other psychiatric disorders (except tion of CM with poor performance in memory and nicotine dependence), mental retardation, neurolo­ executive function tasks (Dannehl, Rief, & gical or severe medical conditions; pregnancy or Euteneuer, 2017; Majer et al., 2010; Saleh et al., puerperium; electroconvulsive therapy in the 2017; Su, D’Arcy, Yuan, & Meng, 2019). Some previous year, and corticosteroid treatment in the works report that the nature and magnitude of cog­ previous three months. nitive deficits may vary according to the kind of The sample partially overlaps with that used in trauma experienced (Dannehl et al., 2017; Gould previous studies (Labad et al., 2018; Salvat-Pujol et al., 2012; Grainger et al., 2019). In particular, it et al., 2017), which explored different hypotheses. has been suggested by some authors that neglect The Bellvitge University Hospital Ethical Committee might have more detrimental effects on cognition approved the research protocol, and all procedures than abuse (Geoffroy, Pinto Pereira, Li, & Power, complied with the Helsinki Declaration of 1975 (revised 2016; Gould et al., 2012; Grainger et al., 2019; in 2013). All participants provided written informed Majer et al., 2010; Nikulina & Widom, 2013), inde­ consent after having received a full explanation of the pendently of mental health (Geoffroy et al., 2016). study and acknowledged that they cannot be identified Other authors have pointed out that physical abuse via the paper. and neglect might have a more critical influence on memory and executive functions than emotional 2.2. Clinical assessment maltreatment (Dannehl et al., 2017). More counter­ intuitive associations have been found, mostly in All patients were diagnosed with MDD by their samples of adults over 50 years, linking different treating psychiatrist and met DSM-IV-TR criteria types of abuse to better cognitive performance for MDD (American Psychiatric Association, (Dannehl et al., 2017; Feeney, Kamiya, Robertson, 2000). MDD diagnosis was confirmed by an & Kenny, 2013; Ritchie et al., 2011). Biological experienced psychiatrist using the Mini- mechanisms underlying these different CM effects International Neuropsychiatric Interview (MINI) on cognition are unknown. (Sheehan et al., 1998). Depression severity was Although both CM and MDD may contribute to assessed with the 17-item Hamilton Depression the cognitive dysfunction, the neurobiological Rating Scale (HDRS) (Hamilton, 1960). HC had mechanisms underlying this relationship are not yet no history of psychiatric disorders as assessed fully understood. The present study aimed to assess with a semi-structured interview and a score the potential modulating effects of MDD diagnosis in below 7 on the 28-item Spanish adaptation of the the association between different types of CM and Goldberg General Health Questionnaire (GHQ-28) 4 N. SALVAT-PUJOL ET AL. (Lobo, Perez-Echeverria, & Artal, 1986). The ≥10; sexual abuse ≥8; emotional neglect ≥15; and HDRS was also administered to HC, since it was physical neglect ≥10) (Bernstein & Fink, 1998). used as a predictive variable in the multiple linear Cases classified as negative on all subscales were regression analysis. Although some participants considered as not exposed to CM. suffered CM, none met DSM-IV-TR criteria for PTSD (American Psychiatric Association, 2000). 2.3. Neuropsychological assessment Sociodemographic and clinical variables were assessed using a semi-structured interview. Sleep On the same day of clinical assessment, participants quality was evaluated with the Pittsburgh Sleep underwent a neuropsychological evaluation to assess Quality Index (PSQI) (Buysse, Reynolds, Monk, verbal memory, visual memory, processing speed and Berman, & Kupfer, 1989). Weight and height were executive function. Table 1 includes information on measured in all participants to calculate the body the administered tests. mass index (BMI) using the formula weight (kg)/ height (m2). 2.4. Salivary cortisol measurements Exposure to CM was retrospectively assessed using the Childhood Trauma Questionnaire (CTQ) Participants collected saliva samples at home for cor­ (Bernstein & Fink, 1998), which is a self-report tisol analyses shortly after clinical and neuropsycho­ inventory with 28 items rated on a five-point Likert logical assessments using Salivette® (Sarstedt AG & scale depending on their frequency of occurrence. Co., Nümbrecht, Germany) containers and following The CTQ yields a total score and scores for five the same process as in our previous studies (Labad subscales corresponding to different types of mal­ et al., 2018; Salvat-Pujol et al., 2017). Eating, drink­ treatment (emotional, physical, and sexual abuse, ing, smoking, or brushing teeth were not allowed in and emotional and physical neglect). Subscale scores the 15 minutes prior to the collection of each sample. range from 5 (no history of abuse or neglect) to 25 Participants were instructed to collect six saliva sam­ (history of extreme abuse or neglect). Cut-off scores ples at home over two consecutive regular days, for none, low, moderate, and severe exposure to avoiding stressful situations and intense physical maltreatment are provided for each subscale. activity. Exposure to CM was determined when at least one For the present study, two saliva samples were CTQ subscale was rated on or above the moderate considered. Patients were asked to collect a morning cut-off score (emotional abuse ≥13; physical abuse salivary sample at 10 a.m. (day 1), take 0.25 mg of Table 1. Neuropsychological tests and cognitive domains assessed. Cognitive domain Neuropsychological test Test description Verbal Hopkins Verbal Learning Test Subjects are presented with 12 words and asked to recall as many as possible. This procedure is memory RevisedTM (HVLT-R) repeated three times. The outcome measure is the total number of words recalled (range 0–36). Visual Rey Complex Figure Test (RCFT) Subjects are asked to copy a complex line drawing and reproduce it from memory after a short memory delay (immediate recall) and after a 20–30 minute delay (delayed recall). Each reproduction is scored taking into account the accurate position and shape of 18 design elements (total range 0–36). In our study, we considered scores in immediate and delayed recall, as they are measures of visual learning and memory. Processing Trail Making Test Part A (TMT-A) Subjects need to sequentially connect 25 targets (numbers 1 to 25). The outcome measure is the speed number of seconds needed to perform the task. Brief Assessment of Cognition in As quickly as possible, participants write numbers 1 to 9 as matches to symbols on a response Schizophrenia – Symbol Coding sheet for 90 seconds. The outcome measure is the total number of correct responses. This test is (BACS-SC) used not only in schizophrenia but also in affective disorders (Cholet et al., 2014). Category fluency (animal naming) Participants are given 60 seconds to name as many words as possible within the animal category. The outcome measure is the number of unique words generated. Stroop test (direct sub-scores for Subjects are presented with a list of colour names (red, green, blue) written in black ink, and are words) given 45 seconds to read as many as they can (word sub-score). Executive Neuropsychological Assessment There are seven mazes that become progressively more difficult. Mazes are scored based on function Battery® Mazes – NAB-Mazes completeness and completion time. Higher scores indicate better performance. Stroop test (interference scores) After the list of colour names, a second list is presented, containing ‘Xs’ written with red, green, or blue ink; the subject is now asked to give the ink colour (colour sub-score). A third list contains words that name colours which are different to the ink colour in which the words themselves are written; the subject is again asked to give the ink colour (word-colour sub-score). This task requires subjects to inhibit the automatic response of reading and to name the colour the word is written in. After obtaining these sub-scores, an interference score is calculated, which is the difference between real and expected interference. Positive scores indicate adequate inhibition of automatic responses, while negative scores indicate that the subject has inhibited worse than expected. Corsi Block-Tapping Test (CBTT) Ten cubes arranged on a board are presented to the subject. The examiner taps pre-defined progressively longer sequences. The subject is asked to repeat the tapping sequence, forwards and backwards. The outcome measure is the total number of correct items (range 0–32). For all tests, higher scores reflect better cognitive performance, with the exception of TMT-A, in which higher scores reflect poorer cognitive performance. EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 5 dexamethasone at 11 p.m. on the same day (day 1) 2.5. Statistical analyses and collect another salivary sample at 10 a.m. on Data processing was performed using SPSS 21 (SPSS, the day after (day 2). Another sample was taken IBM, USA). We normalized the data as described in immediately before the neuropsychological assess­ previous works (Labad et al., 2018; Salvat-Pujol et al., ment, which was performed in one morning (mean 2017). [SD] starting time 10:37 [00:51] a.m.) prior to home- collection cortisol sampling. To reduce the number of cognitive variables and Samples were stored in refrigerators and returned statistical models, we conducted a confirmatory personally by each participant. After the Salivettes factor analysis (CFA) with R (version 3.5.2 were received, they were stored at −20°C and later [December 2018]) using the lavaan (version 0.6-4 sent to the BioBanc from the Institut d’Investigació [July 2019]) and semPlot (version 1.1.2 Sanitària Pere Virgili (IISPV) for centrifugation [August 2019]) packages. We considered three (3000 rpm for 5 min) and aliquotation, after which latent variables that included information on cog­ they were frozen at −20°C until analysis by enzyme- nitive tasks in three different domains: verbal linked immunosorbent assay (IBL International, memory, visual memory and executive function/ Hamburg, Germany) to determine saliva cortisol processing speed (Figure 1). This later factor levels. resulted from the combination of two latent vari­ The feedback inhibition of the HPA axis was ables (executive functioning and processing speed). assessed with the dexamethasone suppression test The reason for combining both latent variables was (DST). The cortisol suppression ratio in the DST because of the known relationship between proces­ (DSTR) was defined as the ratio [cortisol at 10 a.m. sing speed and executive functioning (Albinet, on day 1]/[cortisol at 10 a.m. on day 2 (post dexa­ Boucard, Bouquet, & Audiffren, 2012), and because methasone)]. The DSTR provides information about this combination improved the fitting of the CFA the negative feedback system of the HPA axis. Higher model. The variances of all latent variables were set DSTR values indicate greater suppression of cortisol equal to one to standardize the model. Three fit secretion after dexamethasone administration, and indexes were considered: Chi-square (χ2), a lack of suppression is considered a measure of Comparative Fit Index (CFI), and Standardized glucocorticoid resistance. Root Mean Square Residual (SRMR). Ideally, for The DSTR was assessed using a very low dose of a model that fits the data, the χ2 would not be dexamethasone (0.25 mg), much lower than the significant (p > 0.05) (Iacobucci, 2010). CFI values conventional 1 mg used in plasma analyses. The >0.90 indicate a reasonably good fit of the SEM reasons for this decision were as follows: (1) sali­ model (Hu & Bentler, 1999). SRMR represents the vary cortisol presents more profound suppression standardized difference between the observed cor­ than does plasma cortisol or plasma ACTH in relation and the predicted correlation. A SRMR a dose–response pattern after different doses of value <0.08 is generally considered a good fit (Hu dexamethasone are admistered; although the rea­ & Bentler, 1999). However, as these indexes, parti­ sons for the greater salivary cortisol suppression cularly χ2, are affected by sample size, some authors by dexamethasone are not clear, the binding of have suggested adjusting χ2 by the degrees of free­ plasma cortisol by cortisol-binding globulin might dom (df) (Iacobucci, 2010). A model demonstrates limit the amount of free diffusible cortisol, so that a reasonable fit if χ2/df ≤ 3. Our CFA model saliva cortisol levels fall more rapidly than the total showed the following fitting indexes: χ2 = 72.655, plasma cortisol concentration (Castro, Elias, Elias, df = 49, p = 0.016; CFI = 0.981; SRMR = 0.048, & Moreira, 2003); (2) higher dexamethasone doses which indicate a good fit, as χ2/df was 1.48. Three are expected to completely suppress the axis and factor scores (one for each main latent variable) are more likely to result in reproducibly undetect­ were computed with the lavPredict() function. able cortisol levels; previous studies (Reynolds Categorical data among groups (MDD vs. HC) et al., 1998) using 0.25 mg doses have reported were compared with Chi-square tests, and T-tests post dexamethasone cortisol levels that are well for independent samples were applied to compare within the detection limits of cortisol assays, show­ continuous variables. ing approximately 30% suppression and greater We performed exploratory partial correlation within-subject variability; (3) we were interested analyses stratified by diagnosis and adjusted by gen­ in exploring DST as a continuous measure (cortisol der, age, and years of education to explore the rela­ suppression ratio), and the use of more conven­ tionship between CM (CTQ scores on emotional, tional dexamethasone doses would not have physical and sexual abuse, and emotional and phy­ allowed us to detect subtle alterations in cortisol sical neglect), cognitive performance (latent vari­ secretion regulation. ables extracted from the CFA) and DSTR. As these 6 N. SALVAT-PUJOL ET AL. Figure 1. Confirmatory factor analysis of neuropsychological variables. We considered three latent variables that included information of cognitive tasks in three different domains: verbal memory, visual memory and executive function/processing speed. Our CFA model showed the following fitting indexes: χ2 = 72.655, df = 49, p = 0.016; CFI = 0.981; SRMR = 0.048. Abbreviations: BACS-SC: Brief Assessment of Cognition in Schizophrenia – Symbol Coding; CBTT: Corsi Block-Tapping Test; HVLT-R_1, HVLT-R_2, HVLT-R_3: Hopkins Verbal Learning Test RevisedTM, trials 1, 2 and 3; NAB-Mazes: Neuropsychological Assessment Battery® Mazes; RCFT_DR: Rey Complex Figure Test, delayed recall; RCFT_IR: Rey Complex Figure Test, immediate recall; TMT-A: Trail Making Test Part A. analyses were exploratory in nature, we did not educational level (t(153) = 4.480, p < 0.001), higher correct for multiple comparisons (Bender & Lange, BMI (t(152) = −2.631, p = 0.009) and reported poorer 2001). sleep quality (t(139) = −5.005, p < 0.001) than HC. We performed separate multiple linear regression Total CTQ scores were higher in MDD patients than (MLR) analyses for each latent variable obtained in in HC (t(153) = −2.111, p = 0.036). the CFA, including all participants, to explore the association of cognitive performance with different 3.2. HPA axis function and cognition types of CM and to assess the potential modulating effects of MDD diagnosis and HPA axis negative Cortisol and cognitive measures are described in Table feedback in the relationship between different types 3. HPA axis measures did not differ between groups, of CM and cognitive performance. We controlled except for cortisol salivary concentrations the morning for potential confounders, including gender, age, after dexamethasone administration (t(153) = −2.123, years of education, BMI, tobacco consumption, p = 0.035), which were higher in MDD patients. HC sleep quality, HDRS scores and cortisol levels at performed better than MDD patients in all cognitive the time of neuropsychological assessment (Salvat- tasks. Pujol et al., 2017). All independent variables were entered into the equation. Interaction terms 3.3. Partial correlation analyses between CM, DSTR, and MDD diagnosis were tested in a final step. Only significant interaction CM, cognitive and cortisol variables did not correlate terms were kept in the final equation. The statistical with each other (see Supplementary Tables 1 and 2 significance level was set at p < 0.05 (bilateral). online). 3.4. Multiple linear regression analyses 3. Results Table 4 displays the results of the MLR analyses. 3.1. Clinical data The demographic and clinical variables for the two 3.4.1. Verbal memory study groups are described in Table 2. MDD patients MDD diagnosis had a negative effect on verbal mem­ were older (t(153) = −2.024, p = 0.045), had a lower ory (β = −0.679, p < 0.001). However, the DSTR EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 7 Table 2. Demographic data and clinical variables by study groups. HC MDD Statistics n = 87 n = 68 (T-test/χ2) Age (years) 56.14 (11.61) 59.87 (11.05) t(153) = −2.024, p = 0.045 Female gender, n (%) 58 (66.7) 46 (67.6) χ2 = 0.017, p = 1.000 Education (years) 12.11 (3.95) 9.16 (4.23) t(153) = 4.480, p < 0.001 BMI (kg/m2) 26.80 (4.90) 28.87 (4.75) t(152) = −2.631, p = 0.009 PSQI 5.26 (3.37) 8.75 (4.92) t(139) = −5.005, p < 0.001 Substance use Smoking, n (%) 14 (16.1) 15 (22.1) χ2 = 1.006, p = 0.405 Tobacco consumption (cigarettes/day) 2.15 (6.63) 3.51 (8.14) t(153) = −1.150, p = 0.252 Daily alcohol intake, n (%) 29 (33.3) 20 (29.4) χ2 = 0.147, p = 0.729 Daily alcohol intake (g/day) 2.70 (6.36) 2.02 (4.24) t(136) = 0.710, p = 0.479 Clinical variables of depression HDRS 0.70 (1.15) 9.56 (8.70) t(153) = −9.398, p < 0.001 Suicide attempts, n (%) 0 (0.0) 14 (20.6) χ2 = 19.690, p < 0.001 Age at onset (years) NA 42.02 (12.79) NA Melancholic symptoms, n (%) NA 56 (82.4) NA Atypical symptoms, n (%) NA 3 (4.40) NA Psychotic symptoms, n (%) NA 3 (4.40) NA Number of depressive episodes NA 3.91 (2.73) NA Number of hospitalizations NA 0.55 (1.54) NA Childhood Trauma Questionnaire n (%) mean (SD) n (%) mean (SD) CTQ – emotional abuse 7 (8.0) 7.11 (2.97) 10 (14.7) 8.12 (4.30) χ2 = 1.734, p = 0.206; t(153) = −1.715, p = 0.088 CTQ – physical abuse 4 (4.6) 5.86 (1.68) 8 (11.8) 6.40 (3.51) χ2 = 2.745, p = 0.131; t(153) = −1.252, p = 0.213 CTQ – sexual abuse 8 (9.2) 5.56 (1.25) 8 (11.8) 5.93 (2.94) χ2 = 0.272, p = 0.607; t(153) = −1.040, p = 0.300 CTQ – emotional neglect 8 (9.2) 9.13 (4.07) 9 (13.2) 10.29 (4.13) χ2 = 0.638, p = 0.448; t(153) = −1.762, p = 0.080 CTQ – physical neglect 8 (9.2) 6.33 (2.21) 10 (14.7) 7.00 (2.60) χ2 = 1.129, p = 0.320; t(153) = −1.722, p = 0.087 CTQ – total score 34.00 (8.61) 37.74 (13.33) t(153) = −2.111, p = 0.036 Exposed to CM 22 (25.3) 22 (32.4) χ2 = 0.937, p = 0.372 Abbreviations: HC, healthy controls; MDD, major depressive disorder; BMI, body mass index; PSQI, Pittsburgh Sleep Quality Index; HDRS, Hamilton Depression Rating Scale; CTQ, Childhood Trauma Questionnaire. All variables presented in mean (SD) or n (%). NA: non applicable. Table 3. Cortisol measures and neuropsychological variables by study groups. HC MDD n = 87 n = 68 T-test Cortisol measures 10-h cortisol (nmol/L) 11.06 (9.72) 12.27 (8.22) t(146) = −1.011, p = 0.314 10-h post-DXM cortisol (nmol/L) 4.55 (4.68) 6.50 (7.82) t(153) = −2.123, p = 0.035 DSTR† 9.97 (20.06) 5.91 (9.71) t(153) = 1.319, p = 0.189 Cortisol at NPS (nmol/L) 10.53 (5.79) 13.11 (9.75) t(149) = −1.208, p = 0.229 Cognitive domains Latent variable 1 (verbal memory) 0.43 (1.32) −0.54 (1.24) t(153) = 4.664, p = <0.001 Latent variable 2 (visual memory) 2.35 (6.37) −3.00 (6.15) t(153) = 5.265, p = <0.001 Latent variable 3 (executive function/processing speed) 5.19 (11.12) −6.64 (13.02) t(153) = 6.101, p = <0.001 Abbreviations: HC, healthy controls; MDD, major depressive disorder; DXM, dexamethasone; NPS, neuropsychological assessment; DSTR, dexamethasone suppression test ratio. All variables presented in mean (SD). Cortisol raw scores and untransformed DSTR are shown, outliers excluded. P values calculated upon transformed cortisol and DSTR values, outliers excluded. † DSTR = 10-h cortisol/10-h post-DXM cortisol. Latent variable 1 (verbal memory) includes the 3 subscores of the Hopkins Verbal Learning Test – Revised (HVLT-R). Latent variable 2 (visual memory) includes scores of immediate and delayed recall of the Rey Complex Figure Test (RCFT). Latent variable 3 (executive function/processing speed) includes scores on Neuropsychological Assessment Battery® Mazes (NAB-Mazes), STROOP interference task, and Corsi Block-Tapping Test for executive function; and category fluency, Brief Assessment of Cognition in Schizophrenia – Symbol Coding (BACS-SC), Trail Making Test part A, and STROOP word subscore for processing speed. modulated this relationship (β = 0.182, p = 0.031), between physical neglect and depression diagnosis reflecting that a greater suppression after dexametha­ (β = 0.621, p = 0.002) suggests that higher physical sone administration in MDD patients exerted neglect scores were associated with enhanced verbal a positive effect on this cognitive domain. memory in MDD patients. Meanwhile, CTQ scores in physical abuse (β = 0.182, p = 0.017) and sexual abuse (β = 0.134, p = 0.040) were positively associated with verbal 3.4.2. Visual memory memory performance, but without significant inter­ Depression diagnosis (β = −0.669, p = 0.002) was actions with DSTR or depression diagnosis. associated with poorer visual memory performance. Physical neglect negatively affected verbal memory Physical abuse (β = −0.270, p = 0.045) and physical (β = −0.409, p < 0.001). Nevertheless, the interaction neglect (β = −0.286, p = 0.007) negatively affected 8 N. SALVAT-PUJOL ET AL. Table 4. Results of multiple linear regression analyses exploring the association between childhood maltreatment, HPA axis function, MDD diagnosis, and cognitive performance. Latent variable 1 Latent variable 2 Latent variable 3 Verbal memory Visual memory Executive function and processing speed R2 final model = 0.594 R2 final model = 0.502 R2 final model = 0.686 β p β p β p Gender 0.127 0.057 −0.181 0.015 −0.059 0.305 Age −0.464 <0.001 −0.425 <0.001 −0.447 <0.001 Years of education 0.200 0.007 0.189 0.022 0.364 <0.001 BMI 0.020 0.763 0.048 0.535 −0.034 0.561 Tobacco consumption (cig/day) 0.026 0.695 −0.099 0.180 −0.014 0.809 HDRS scores −0.207 0.028 −0.079 0.450 −0.132 0.103 MDD diagnosis −0.679 0.001 −0.669 0.002 −0.136 0.048 PSQI −0.176 0.028 −0.075 0.395 −0.070 0.304 CTQ- emotional abuse −0.108 0.212 0.052 0.584 −0.080 0.283 CTQ- physical abuse 0.182 0.017 −0.270 0.045 0.082 0.213 CTQ- sexual abuse 0.134 0.040 0.252 0.009 0.157 0.006 CTQ- emotional neglect 0.094 0.267 −0.101 0.285 0.069 0.347 CTQ- physical neglect −0.409 <0.001 −0.286 0.007 −0.161 0.023 DSTR† −0.075 0.286 0.316 0.485 −0.023 0.657 Cortisol at NPS# (T7) 0.007 0.912 0.028 0.690 0.011 0.840 MDD diagnosis x CTQ- physical neglect 0.621 0.002 NA NA NA NA MDD diagnosis x CTQ- physical abuse NA NA 0.551 0.025 NA NA MDD diagnosis x DSTR† 0.182 0.031 NA NA NA NA DSTR† x CTQ- physical neglect NA NA 0.538 0.018 NA NA DSTR† x CTQ- sexual abuse NA NA −0.919 0.028 NA NA Latent variable 1 (verbal memory) includes the 3 subscores of the Hopkins Verbal Learning Test – Revised (HVLT-R). Latent variable 2 (visual memory) includes scores of immediate and delayed recall of the Rey Complex Figure Test (RCFT). Latent variable 3 (executive function/processing speed) includes scores on Neuropsychological Assessment Battery® Mazes (NAB-Mazes), STROOP interference task, and Corsi Block-Tapping Test for executive function; and category fluency, Brief Assessment of Cognition in Schizophrenia – Symbol Coding (BACS-SC), Trail Making Test part A, and STROOP word subscore for processing speed. Neuropsychological variables were considered as the dependent variables. β: standardized beta coefficient. Abbreviations: BMI, body mass index; HDRS, Hamilton Depression Rating Scale; MDD, major depressive disorder; PSQI, Pittsburgh Sleep Quality Index; CTQ, Childhood Trauma Questionnaire; DSTR, dexamethasone suppression test ratio; NPS, neuropsychological assessment; NA, not applicable. † DSTR = 10-h cortisol/10-h post-dexamethasone cortisol. # Transformed cortisol values. Non-significant interaction terms were excluded in the final equation. visual memory, but significant interactions were 4. Discussion found with DSTR or MDD diagnosis. More specifi­ Apart from a study reporting cognitively beneficial cally, physical neglect interacted with DSTR effects of cortisol administration in depressed women (β = 0.538, p = 0.018); participants with higher phy­ with CM (Abercrombie et al., 2018), to our knowl­ sical neglect scores and greater suppression after dex­ edge, no other studies have assessed the role of MDD amethasone intake showed better performance in diagnosis or HPA axis negative feedback in the asso­ visual memory. In turn, the significant interaction ciation between different types of CM and cognitive between physical abuse and depression diagnosis for performance in adulthood. visual memory (β = 0.551, p = 0.025) suggested that The present study confirmed disturbed cognitive MDD patients with higher physical abuse scores performance in depression (Rock, Roiser, Riedel, & showed better performance in this cognitive domain. Blackwell, 2014). Although post-dexamethasone cor­ Sexual abuse was positively associated with visual tisol levels were higher in patients with MDD, the memory (β = 0.252, p = 0.009). However, DSTR had ratio of cortisol suppression did not confirm an a modulation effect (β = −0.919, p = 0.028), suggesting impaired feedback sensitivity (Salvat-Pujol et al., poorer visual memory performance in participants with 2017). Our results are in part similar to previous higher sexual abuse scores and greater DSTR. findings reporting few differences in cortisol levels (Strickland, Morriss, Wearden, & Deakin, 1998) or 3.4.3. Executive function/processing speed the DSTR (Carvalho Fernando et al., 2012) between MDD diagnosis (β = −0.136, p = 0.048) had a negative depressed and non-depressed subjects. Total CTQ effect on executive function/processing speed. scores were higher in MDD patients than in HC, in Sexual abuse (β = 0.157, p = 0.006) and physical accordance with previous studies that linked depres­ neglect (β = −0.161, p = 0.023) differentially affected sion with higher levels of CM (Chapman et al., 2004). executive function/processing speed. Despite these findings, we did not find any significant No interactions between CM and DSTR or MDD differences between groups in any of the CTQ sub­ diagnosis were found for these cognitive domains. scale scores. EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 9 Physical maltreatment and sexual abuse had dif­ Factors such as sex, predictability of the stress, ferent neurobiological effects on cognition, although degree, duration, nature, and developmental timing these effects, according to our hypothesis, were of the historical stress exposure can influence the modulated by HPA axis function and MDD shape and inflection point of the J-shaped curve diagnosis. (Luine, 2002; Parker & Maestripieri, 2011). Physical neglect was associated with poorer cogni­ Longitudinal studies of animal development support tive performance, in accordance with previous litera­ the notion that intermittent stressful experiences ture (Dannehl et al., 2017; Geoffroy et al., 2016; Majer early in life (a laboratory manipulation called ‘stress et al., 2010; Nikulina & Widom, 2013). Physical abuse inoculation’) enhance long-lasting adaptive function­ did not show a consistent association with cognitive ing, diminishing neurobiological responses to mod­ performance in different domains. In contrast, sexual erate stress and enhancing cognitive control of abuse was associated with enhanced cognition. behaviour (Lyons, Parker, & Schatzberg, 2010). Although most studies indicate that sexual abuse Prefrontal corticolimbic brain circuits have been decreases cognitive performance (Dannehl et al., implicated in resilience, as they play a role in cogni­ 2017; Gould et al., 2012), others found that it did tive control and regulate the HPA axis stress response not predict poorer executive function (Nikulina & (Diorio, Viau, & Meaney, 1993; Konishi, Nakajima, Widom, 2013) or even concluded that sexual abuse Uchida, Sekihara, & Miyashita, 1998; Miller, 2000; is associated with better global cognition, memory, Sullivan & Gratton, 2002). Most studies report that executive function, and processing speed (Feeney early life stress inoculation promotes the develop­ et al., 2013). In the latter study, performed in adults ment of larger prefrontal cortical volumes later in aged 50 years and older, authors argue that other life without affecting hippocampal volumes (Katz studies rely on younger participants, in whom the et al., 2009; Lyons, Afarian, Schatzberg, Sawyer- abuse experience is fresher and its impact greater Glover, & Moseley, 2002; Lyons, Yang, Sawyer- (Feeney et al., 2013). Previous research indicates Glover, Moseley, & Schatzberg, 2001), which may be that older adults tend to be more stress-resilient due to the growth and development of the prefrontal than younger individuals, probably due to prior cortex extending into early adulthood, while hippo­ experience with stressors, more effective coping stra­ campal growth and development occurs primarily in tegies, greater tolerance for negative affect, and better utero (Giedd et al., 1999; Khazipov et al., 2001). emotion regulation (Feeney et al., 2013; Seery, Nevertheless, some studies suggest that stress during Holman, & Silver, 2010). These findings are consis­ childhood increases hippocampal neurogenesis (Hays tent with stress inoculation and resilience theories. et al., 2012). Even though there is some controversy Early exposure to stress has been mostly related to an on whether stress inoculation affects the hippocampal increased risk for the development of psychopathol­ structure, evidence from animal studies suggests that ogy after experiencing subsequent stressors in adult­ stress resilience may be mediated by increased hippo­ hood (Heim, Newport et al., 2008). This is because campal glucocorticoid receptor expression: early life stress alters corticolimbic brain systems that a functional hippocampus adequately inhibits the regulate stress and anxiety, disrupts the acquisition of HPA axis response to subsequent acute stressors appropriate coping styles, induces alterations in base­ (Kaffman & Meaney, 2007; Parker & Maestripieri, line activity as well as stress reactivity of the HPA 2011). These findings suggest that stress inoculation axis, diminishes the volumes of the hippocampus and may either directly alter the neural substrates the prefrontal cortex (Stein, Koverola, Hanna, involved in adaptive functioning and cognitive func­ Torchia, & McClarty, 1997; Van Harmelen et al., tion, or indirectly influence cognitive performance by 2010), and impairs cognition (Heim, Newport et al., primarily changing emotion regulation (Lyons, 2008; Majer et al., 2010; McEwen, 2007; Nikulina & Parker, Katz, & Schatzberg, 2009; Parker & Widom, 2013; Pryce, Dettling, Spengler, Spaete, & Maestripieri, 2011). Brain changes observed after Feldon, 2004; Pryce et al., 2005), independent of early stress constitute neuroplastic adaptive responses psychopathology (R-Mercier et al., 2018). There is to facilitate survival rather than non-specific damage, evidence that prior exposure to moderate (but not reflecting stress resilience rather than stress pathol­ minimal or substantial) stress levels, which are chal­ ogy, and this stress inoculation phenotype persists lenging enough to evoke acute anxiety and transiently into adulthood (Parker, Buckmaster, Lindley, activate the HPA axis, fosters the development of Schatzberg, & Lyons, 2012; Parker, Buckmaster, resilience to subsequent stressors encountered later Sundlass, Schatzberg, & Lyons, 2006; Teicher & in life (Parker, Buckmaster, Hyde, Schatzberg, & Samson, 2016). Considering all these findings, and Lyons, 2019; Parker & Maestripieri, 2011). Thus, the since cognitive tasks assessed in our study involve relationship between early life stress exposure and the hippocampus and the prefrontal cortex, we con­ subsequent resilience can be depicted as a non- clude that the speculatively resilient individuals who linear J-shaped function (Parker et al., 2019). have suffered sexual abuse in our sample may have 10 N. SALVAT-PUJOL ET AL. a more functionally preserved hippocampus and pre­ impairment might differ depending upon the type frontal cortex, which would enable a greater ability to of childhood trauma: a GR resistance (reduced successfully adapt to stress. Thus, we could be obser­ HPA axis negative feedback) would be pathological ving a cognitive phenotype in which individuals with in people with a history of physical neglect, sexual abuse raised in an enriching environment, whereas the pathological condition would be the which has positive effects in neurodevelopment (van opposite in people with a history of sexual abuse, Praag, Kempermann, & Gage, 2000), may present as increased GR binding (enhanced HPA axis nega­ with preserved cognitive performance. tive feedback) was associated with a poorer cogni­ According to a recent study by Trauelsen et al., tive outcome. This last finding is in accordance (2019), and very surprisingly, performance on cold with classical studies reporting an enhanced dexa­ cognitive (neurocognitive) tasks might not be the methasone cortisol suppression in women victims only ones enhanced in individuals with sexual of sexual abuse (Stein et al., 1997). abuse: although in first-episode psychosis, better Depression diagnosis negatively impacted cognition, metacognition abilities were reported in subjects but physical maltreatment modulated this relationship. with CM, including sexual abuse (Trauelsen et al., Contrary to our expectations, individuals with physical 2019). The authors suggested that insight could play maltreatment and MDD presented with enhanced cog­ a role in this association, and recommended future nition in certain domains depending on whether studies to include hot (social cognition) and cold experienced maltreatment was abuse (visual memory) cognition assessment. Even though our study was or neglect (verbal memory). Again, and according to performed in patients with MDD and did not take Trauelsen findings and their interpretation (Trauelsen into account metacognition, it is interesting the fact et al., 2019), patients who recognized physical maltreat­ that findings on the link between sexual abuse and ment might be endowed with higher insight and, enhanced cognition are somehow shared. Future although speculative, be more resilient. This resiliency, longitudinal studies are needed to further assess and coupled with the fact that maltreatment itself may lead clarify the effects of sexual abuse on cognitive abil­ to adaptive cognitive responses, could partially explain ities, taking into account different types of cognition these results. Our findings might be supported by the and the insight of the subject. observation that the absence of major psychopathology Cortisol suppression after dexamethasone was not does not comprise an adequate indicator of resilience related to cognitive function. Previous literature has (Simeon et al., 2007). Future studies are needed to yielded contradictory findings on this issue. address these issues. Specifically, while some studies suggest that lower Upon examination of the significant interaction cortisol suppression with the Dex/CRH could be between DSTR and MDD diagnosis on cognition, related to poorer executive functioning in recovered we found that a greater suppression after dexa­ MDD patients (Behnken et al., 2013), others report methasone administration in MDD patients was no association between cortisol suppression and associated with enhanced verbal memory. Cortisol executive function (Hansson et al., 2013; Krogh non-suppression in response to dexamethasone, et al., 2012) or visual memory (Krogh et al., 2012) suggesting lower sensitivity of the HPA axis nega­ using the DST with dexamethasone 1 mg. tive feedback, has been reported in 40–60% of Surprisingly, we observed a different effect of depressed patients (Carroll et al., 1981). Classical DSTR in its interaction with physical neglect and studies have reported better cognitive outcomes in sexual abuse on visual memory. DSTR showed an MDD patients with greater dexamethasone sup­ association with better visual memory in physically pression (Wauthy, Ansseau, von Frenckell, neglected individuals, reflecting that a more pre­ Mormont, & Legros, 1991). Although it is some­ served HPA axis function would imply a more func­ what speculative, those patients with a more pre­ tionally preserved hippocampus and that despite the served HPA axis function (e.g. greater cortisol history of neglect, individuals would be able to sus­ suppression to dexamethasone) will most likely tain an adequate cognitive performance. Nonetheless, present with higher integrity of the hippocampus the interaction of DSTR with sexual abuse indicates and, hence, better cognitive performance in hippo­ that in those participants with sexual abuse, greater campus-dependent cognitive tasks. suppression of the HPA axis is associated with poorer cognitive performance. 4.1. Limitations and methodological issues The distinct modulation of sexual abuse and physical neglect by DSTR reinforces the idea that Some limitations and methodological issues need to these experiences have a different impact on the be considered. All patients received antidepressant HPA axis and, most likely, cognition. These find­ treatment according to their clinical needs and there ings suggest that potential HPA axis-related neuro­ were no drug-naïve patients in our sample. We are biological mechanisms leading to cognitive aware that this treatment may have impacted cortisol EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 11 or cognitive measures (Jain et al., 2019; Rosenblat, become a potential target for specific treatment inter­ Kakar, & McIntyre, 2015). However, the fact that we ventions in patients with CM (Menke, 2019). still found differences in cognitive performance in patients treated with antidepressants suggests that our findings in drug-naïve patients could be even Acknowledgments stronger. Additionally, the fact that patients were in The authors are very grateful to all of the study participants, a naturalistic setting could facilitate the extrapolation as well as to the staff of the Department of Psychiatry at of our results to clinical populations. Patients were Bellvitge University Hospital who helped to recruit the sam­ recruited from a tertiary source, that may differ from ple for this study. We would also like to thank Anna Ferrer community-based cases, thereby limiting the general­ and Maria Badia from the Pharmacy Department at Bellvitge ization of these results. University Hospital for providing the 0.25 mg dexametha­ sone capsules, the staff of Biopsychology at the Department Although some have indicated that the CTQ and of Psychology of the Technische Universität Dresden for the PSQI could be influenced by recall bias or analysing salivary cortisol samples, and the technicians a depressive state, they are validated psychometric from the Biobanc IISPV of Reus. instruments with good internal consistency and valid­ ity and suitable for clinical and research settings (Buysse et al., 1989; Majer et al., 2010). Disclosure statement Cortisol measures were assessed only once. No potential conflict of interest was reported by the Although we did not repeat the DST on different author(s). days, this HPA axis dynamic test has shown a relatively good individual stability over time (Golden, Wand, Malhotra, Kamel, & Horton, 2011; Funding Huizenga et al., 1998). This study was supported in part by grants from the Carlos Finally, the cross-sectional design precludes causal III Health Institute through the Ministry of Science, inferences, and longitudinal studies are needed to Innovation and Universities (PI10/01753, PI15/00662, and address this issue. Other variables that could modu­ PI16/00950), the European Regional Development Fund late the relationship between MDD diagnosis, CM (ERDF) ‘A way to build Europe’, CIBERSAM, and the and cognitive function should be considered in future Catalan Agency for the Management of University and Research Grants (AGAUR 2017 SGR 1247). We thank studies, including polymorphisms of genes implicated CERCA Programme/Generalitat de Catalunya for institu­ in the HPA axis or resilience, inflammation para­ tional support. The funders had no role in the study design, meters, structural and functional neuroimaging, and data collection and analysis, decision to publish, or pre­ personality traits. The results on these issues may paration of the manuscript. Eva Real was supported by provide greater knowledge and a more effective clin­ a Juan Rodés contract (JR14/00038) from the Carlos III ical assessment and management of individuals with Health Institute. Dr. Soriano-Mas was supported by a Miguel Servet contract from the Carlos III Health a history of CM. Institute (CP10/00604). Javier Labad received an Intensification of the Research Activity Grant (SLT006/ 17/00012) by the Health Department of the Generalitat de 4.2. Conclusions Catalunya. As overall conclusions, physical maltreatment and sexual abuse had different neurobiological effects on cognition, with modulating effects by HPA axis func­ Data availability statement tion and MDD diagnosis. Meanwhile, emotional mal­ The data that support the findings of this study are avail­ treatment did not have an impact on cognitive able on request from the corresponding author. The data performance and it did not interact with DSTR or are not publicly available due to privacy and ethical depression diagnosis. Thus, CM and its subtypes restrictions. should be taken into account in studies involving cognition, HPA axis function and psychopathology. ORCID Our results suggest a need for early assessment and Neus Salvat-Pujol http://orcid.org/0000-0001-5320-331X intervention on cognition and resilience mechanisms Javier Labad http://orcid.org/0000-0003-2214-1886 in individuals exposed to CM to minimize its deleter­ Mikel Urretavizcaya http://orcid.org/0000-0002-9746- ious and lasting effects. Since CM is thought to 4068 increase the risk of MDD and influence its clinical Aida de Arriba-Arnau http://orcid.org/0000-0002-7877- course, our findings may add to the knowledge of the 7341 Cinto Segalàs http://orcid.org/0000-0002-0959-0356 aetiology, prevention and treatment of depression. 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