European Psychiatry Interaction of both positive and negative www.cambridge.org/epa daily-life experiences with FKBP5 haplotype on psychosis risk Paula Cristóbal-Narváez1,2, Tamara Sheinbaum3, Araceli Rosa2,4,5, Original Article Marta de Castro-Catala4,5, Tecelli Domínguez-Martínez6, Thomas R. Kwapil7 and Cite this article: Cristóbal-Narváez P, Sheinbaum T, Rosa A, de Castro-Catala M, Neus Barrantes-Vidal2,8,9* Domínguez-Martínez T, Kwapil TR, Barrantes- Vidal N (2020). Interaction of both positive and 1 Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain; 2Centre for Biomedical Research negative daily-life experiences with FKBP5 Network on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; 3Department of Psychology, haplotype on psychosis risk. European University of Southern California, Los Angeles, California, USA; 4Secció de Zoologia i Antropologia, Departament de Psychiatry, 63(1), e11, 1–8 https://doi.org/10.1192/j.eurpsy.2019.4 Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain; 5 Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; 6Centro de Investigación en Salud Mental Received: 14 May 2019 Global, Dirección de Investigaciones Epidemiológicas y Psicosociales, Instituto Nacional de Psiquiatría ‘Ramon de la Revised: 02 November 2019 Fuente Muñiz’, México; 7Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, Illinois, Accepted: 03 November 2019 USA; 8Departament de Psicologia Clínica i de la Salut, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain and 9 Sant Pere Claver—Fundació Sanitària, Barcelona, Spain Key words: Gene–environment interaction; ecological validity; experience sampling methodology; Abstract incipient psychosis; vantage sensitivity Background. There is limited research on the interaction of both positive and negative daily-life Author for correspondence: environments with stress-related genetic variants on psychotic experiences (PEs) and negative Neus Barrantes-Vidal, affect (NA) across the extended psychosis phenotype. This study examined whether the FK506 E-mail: neus.barrantes@uab.cat binding protein 51 (FKBP5) variability moderates the association of positive and negative experiences in the moment with PEs and NA in participants with incipient psychosis and their nonclinical counterparts. Methods. A total of 233 nonclinical and 86 incipient psychosis participants were prompted for a 1-week period to assess their day-to-day experiences. Participants were genotyped for four FKBP5 single nucleotide polymorphisms (rs3800373, rs9296158, rs1360780, and rs9470080). Results. Multilevel analyses indicated that, unlike the risk haplotype, the protective FKBP5 haplotype moderated all the associations of positive experiences with diminished PEs and NA in incipient psychosis compared with nonclinical group. Conclusions. Participants with incipient psychosis showed symptomatic improvement when reporting positive appraisals in the interpersonal domain, which suggests that these act as a powerful coping mechanism. The fact that this occurred in daily-life underscores the clinical significance of this finding and pinpoints the importance of identifying protective mechanisms. In addition, results seem to concur with the vantage sensitivity model of gene–environment interaction, which poses that certain genetic variants may enhance the likelihood of benefiting from positive exposures. Introduction Extensive evidence indicates that the psychosis phenotype is expressed across a dynamic continuum that ranges from nonclinical to clinical manifestations [1, 2]. Individuals with © The Author(s) 2020. This is an Open Access nonclinical, subclinical, and early-stage manifestations offer important assets for the study of article, distributed under the terms of the both risk and protective mechanisms, as they are less affected by the wide array of confounding Creative Commons Attribution- effects associated with overt psychopathology and chronicity. Thus, investigating continuities as NonCommercial-NoDerivatives licence (http:// well as discontinuities between clinical and nonclinical expressions may help to elucidate the creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, heterogeneity that characterizes pathways to psychosis and the identification of protective factors distribution, and reproduction in any medium, [3]. In this regard, the study of patterns of gene–environment interactions (G  E) in clinical and provided the original work is unaltered and is nonclinical populations may contribute to our understanding of common and differential properly cited. The written permission of mechanisms operating across the psychosis continuum [4]. Cambridge University Press must be obtained Recent G  E studies indicate that the interaction of genetic variants on the FK506 binding for commercial re-use or in order to create a derivative work. protein 5 (FKBP5) gene with psychosocial stressors is associated with psychotic experiences (PEs) in clinical and nonclinical samples [5-8]. Compelling evidence has suggested that individual variation in the FKBP5 gene is linked to the dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis, which has been identified as a critical neurobiological mechanism underlying the emergence of psychotic symptoms [9]. In particular, the minor risk alleles (C, A, T, T) of at least 4 FKBP5 single nucleotide polymorphisms (SNPs; rs3800373, rs9296158, rs1360780, and 2 Paula Cristóbal-Narváez et al. rs9470080, respectively), as compared with the nonrisk or protec- negative affect (NA), in daily-life across nonclinical and clinical tive alleles (A, G, C, C), have been associated with a decreased levels of expression of the extended psychosis phenotype. Specifi- sensitivity of the glucocorticoid receptor to circulating cortisol, cally, we examined whether the interaction effects of positive and entailing a diminished negative feedback regulation of the HPA negative experiences with the FKBP5 haplotype on PEs and NA axis that results in an abnormal prolongation of the stress response differed between subjects with and without need for care, that is, in [10]. Importantly, the rs1360780 SNPs included in a functional incipient psychosis and nonclinical groups. We predicted that the haplotype confers differential effects in FKBP5 mRNA and protein association of both positive and negative momentary experiences levels mediated by a differential chromatin conformation, resulting with symptoms and NA would be greater in an incipient psychosis in different transcriptional effects between risk and protective group than in a nonclinical group, and that these associations alleles [11]. So far, research has predominantly focused on analyz- would be moderated by FKBP5 variability. ing the effects of the interplay of FKBP5 variation with adverse environmental exposures on psychotic phenomena guided by diathesis-stress model for schizophrenia [12], greatly understudy- Materials and Methods ing the interaction of genetic variation with positive, and thus Participants putative protective, environmental factors. However, individuals may differ in their susceptibility to the environment across a range Data were collected as part of an ongoing longitudinal investigation of exposures (not just negative ones) and, therefore, moderation examining psychosis risk and resilience [20]. The present study effects by genetic variation should also be expected in relation to the included a total of 319 participants reflecting different levels of benefit that individuals may obtain from positive experiences expression of the psychosis phenotype for which ESM and genetic [13]. In light of this, new frameworks under which to consider data were available. The nonclinical group was comprised of G  E interactions have been developed. For example, the differen- 233 students recruited from university and technical schools who tial susceptibility model [14] highlights that individuals traditionally scored across a range on questionnaire assessments of schizotypy considered to carry greater vulnerability may be better conceptu- and psychosis-proneness questionnaires (mean age = 20.0 years, alized as being more plastic, sensitive, or malleable to the environ- SD = 2.9 years; 25.3% males). We invited participants from our ment (“for worse and for better”). That is, it suggests that the same screening samples who had standard scores based upon sample genetic variants involved in increasing the negative effects of norms of at least 1.0 on the positive or negative schizotypy dimen- adverse experiences could also be involved in enhancing the like- sions of the Wisconsin Schizotypy Scales [21], the suspiciousness lihood of benefiting from positive ones. Another relevant model of scale of the Schizotypal Personality Questionnaire [22], or the G  E interactions is vantage sensitivity [15], which poses that positive symptom subscale of the Community Assessment of Psy- certain genetic variants may enhance the likelihood of benefiting chic Experiences [23], and randomly selected participants who had from positive exposures (without also implying an increase in the standard scores below 1.0 on each of these. The goal of this susceptibility to negative exposures)—that is, vantage sensitivity is enrichment procedure was to ensure adequate variability of schi- more than the “bright side” of environmental sensitivity as covered zotypy traits and avoid having a “super healthy” control sample. in differential susceptibility models. Although these approaches The final nonclinical sample contained 198 university and 35 tech- have been scarcely considered within the psychosis field, the per- nical school students. tinence of incorporating the assessment of positive environmental The incipient psychosis group included 86 patients recruited at experiences and examining potential beneficial effects is under- the Sant Pere Claver Health Foundation (mean age = 22.3 years, scored by G  E investigations in other stress-related phenotypes. SD = 4.7 years; 69.8% males). Specifically, the sample for this study For instance, in depression research, it has been shown that the consisted of 55 diagnosed with at-risk mental states for psychosis impact of BDNF Val66Met genotype on stress sensitivity may be (ARMS) and 31 first episode psychosis (FEP) patients (6 of them dependent on the experience of daily-life positive emotions [16]. met criteria for affective psychoses including 4 with bipolar I Another relevant issue that has received increasing attention in disorder and 2 with unipolar depression with psychosis). Patients’ the context of G  E research has been the importance of refining inclusion criteria were age between 14 and 40 years and IQ ≥ 75. environmental measures [17]. In this regard, the enhancement of ARMS-criteria were established by the Comprehensive Assess- precision, reliability, and ecological validity offered by the use of ment of At-Risk Mental States [24] and/or the Schizophrenia ambulatory assessment strategies (such as experience sampling Proneness Instrument-Adult version [25]. FEP-patients met methodology [ESM] or ecological momentary assessment) should DSM-IV-TR criteria for any psychotic disorder or affective disor- be helpful for examining genetic moderation of the effects of both der with psychotic symptoms as established by the Structured positive and negative microlevel experiences (i.e., those occurring in Clinical Interview for DSM-IV [26]. Ethical approval was obtained the moment in real-life contexts; [18]). To the best of our knowledge, from the University Ethics committee and participants provided there are no ambulatory assessment studies investigating the poten- written informed consent. tial moderation of individual genetic variation involved in the reg- ulation of the stress system, such as FKBP5 variants, in the Measures association of positive and negative momentary experiences on the psychosis phenotype. Importantly, there is also a lack of studies with Participants received personal digital assistants that signaled them ecological validity that examine plausible genetic-environmental randomly eight times daily for 1 week to complete brief assessments interplay differences between nonclinical and clinical individuals, of affect, cognition, activities, and PEs on 7-point scales ranging which should allow to identify risk and resilience mechanisms and from 1 (not at all) to 7 (very much). A detailed description of the targets for prophylactic interventions [19]. ESM assessment and validation data can be found in previous Therefore, the present study used ESM to elucidate the extent to studies [20]. The positive and negative experience items used in which the interplay of FKBP5 variability with both positive and the present study focused on two main domains of daily-life: negative exposures impacts the expression of PEs, as well as situational and interpersonal. We focused on two content areas European Psychiatry 3 that have been shown as highly relevant in psychosis and tested out psychosis groups, we assessed the main effects of level 2 predictors on in ESM research: situational stress and appraisals of social rejection level 1 outcome variables (PEs and NA). The level 2 predictors were the [20]. Thus, the negatively valenced items were: “My current situa- FKBP5 haplotype (0 = AGCC/; 1 = AGCC/CATT; 2 = CATT/), tion is stressful” and (when alone) “I am alone because people do the group status (incipient psychosis vs nonclinical groups), and the not want to be with me.” The positively valenced items were: “My interaction term (FKBP5 haplotype  group status). current situation is positive” and “Right now I feel that others care Second, to examine whether the potential moderating role of the about me.” Two ESM indices were created and used as outcome FKBP5 haplotype in the association of momentary appraisals with measures: (i) PEs was computed by averaging the scores for daily-life outcomes differed between nonclinical and incipient psy- 10 items: unusual senses, unusual thoughts, feeling weird, losing chosis groups, cross-level interactions were conducted. Cross-level control, difficulty controlling thoughts, familiar things seeming interactions tested whether level 1 slopes (i.e., the association of strange, feeling suspicious, feeling mistreated, hearing/seeing positive and negative experiences with symptoms and NA) varied things others could not, and passivity (coefficient α = 0.95); as a function of level 2 variables FKBP5 haplotype, group status, and (ii) NA was the mean of four items: feeling anxious, sad, angry, FKBP5 haplotype  group status). Finally, when a level 2 interaction and guilty (coefficient α = 0.89). was significant, the effect of the interaction was examined in each FKBP5 haplotype group using simple slopes analyses. Please note Genetic data that multiple comparisons in multilevel modeling do not present the risk of alpha inflation that is seen in traditional unilevel ana- Genomic DNA was extracted from saliva in the nonclinical sample lyses, so following Gelman et al. [30] multiple testing corrections and blood in the incipient psychosis samples. Four single- were not conducted. nucleotide polymorphisms (SNPs) included in a previously described functional FKBP5 haplotype [27] were genotyped using TaqMan 50 exonuclease assay (Applied Biosystems): rs3800373, Results rs9296158, rs1360780, and rs9470080. Compliance with Hardy– Main effects of level 2 predictors (FKBP5 and group) Weinberg equilibrium was verified for all polymorphisms in both samples (all p > 0.05). Haplotypes were estimated using PHASE, Results indicated that the FKBP5 haplotype was not associated with after confirming that the four SNPs were in high linkage- momentary PEs or NA (Table 1). However, as expected, partici- disequilibrium (D0 > 0.9; r2 > 0.7). Participants were classified into pants in the incipient psychosis group experienced more PEs and three groups for analyses based on previous studies [19,28]: NA than individuals in the nonclinical group (p < 0.001). No (i) carriers of at least one protective haplotype and no risk haplo- interaction effects were found between the FKBP5 haplotype and types (AGCC/, n = 157), (ii) carriers of one risk haplotype and group on PEs or NA in daily-life. Thus, haplotype risk and protec- one protective haplotype (AGCC/CATT, n = 118), and tive groups were unassociated with the overall reports of symptoms (iii) carriers of at least one risk haplotype and no protective hap- and affect in daily life. lotypes (CATT/, n = 44). Haplotypic frequencies are presented in Table S1). Cross-level interactions Cross-level interaction analyses examined whether the FKBP5 hap- Statistical analyses lotype, group status, and their interaction moderated the associa- ESM data have a hierarchical structure in which ESM ratings (level tions of positive and negative experiences with PEs and NA in daily- 1 data) are nested within participants (level 2 data). Linear mixed life (Table 2). All negative appraisals in the moment (situational models were used to control for within-subject clustering of multiple stress and feeling unwanted by others) were associated with observations using the “xtmixed” command in Stata 12 [29]. Graphs increased PEs and NA in the moment, whereas all positive experi- were generated with the R program (www.r-project.org). ences (current situation being positive and feeling cared for by Two types of multilevel analyses were conducted in the present others) were associated with decreased PEs and NA. study. First, in order to examine whether the effect of the FKBP5 Regarding moderation effects, the FKBP5 haplotype did not mod- haplotype on PEs and NA differed between nonclinical and incipient erate the associations of positive or negative appraisals with PEs or Table 1. Main effects of the FKBP5 haplotype, group status, and their interaction on psychotic experiences and negative affect (n = 319). Level 2 predictors FKBP5 haplotype Group: early-psychosis vs nonclinical FKBP5 haplotype  group Level 1 criterion γ01 (df = 316) γ02 (df = 316) γ03 (df = 315) ESM psychosis Psychotic experiences index 0.026 (SE = 0.036) 0.447 (SE = 0.058)*** 0.138 (SE = 0.082) ESM affect Negative affect index 0.031 (SE = 0.051) 0.425 (SE = 0.081)*** 0.122 (SE = 0.114) *p < 0.050. **p < 0.010. ***p < 0.001. The effect of the FKBP5 haplotype  group interaction term was examined over and above the main effects. 4 Paula Cristóbal-Narváez et al. Table 2. Moderation by FKBP5 haplotype, group, and the FKBP5  group interaction of the association between both positive and negative appraisals with psychotic experiences and negative affect (n = 319). Level 1 predictora Level 2 predictors FKBP5 Group: early-psychosis vs FKBP5 haplotype  ESM momentary appraisals haplotype nonclinical groupb γ10 (df = 316) γ11 (df = 316) γ12 (df = 316) γ13 (df = 315) Level 1 criterion Appraisals Coeff. (SE) Coeff. (SE) Coeff. (SE) ESM psychosis Negative appraisals Psychotic experiences index Situation stressful 0.042 (0.007)*** 0.007 (0.007) 0.080 (0.011)*** 0.013 (0.015) Alone b/c not wanted 0.104 (0.032)** 0.016 (0.029) 0.041 (0.040) 0.005 (0.059) Positive appraisals Situation positive 0.059 (0.008)*** 0.005 (0.008) 0.059 (0.013)*** 0.035 (0.018)* Others care about me 0.034 (0.008)*** 0.002 (0.008) 0.045 (0.013)*** 0.040 (0.018)* ESM affect Negative appraisals Negative affect index Situation stressful 0.216 (0.015)*** 0.004 (0.014) 0.065 (0.023)** 0.013 (0.033) Alone b/c not wanted 0.156 (0.050)** 0.086 (0.046) 0.001 (0.060) 0.025 (0.092) Positive appraisals Situation positive 0.277 (0.018)*** 0.021 (0.017) 0.001 (0.026) 0.075 (0.037)* Others care about me 0.133 (0.015)*** 0.009 (0.014) 0.009 (0.023) 0.078 (0.032)* *p < 0.050. **p < 0.010. ***p < 0.001. a The table reports the coefficient of the association of the level 1 predictor and criterion for the analyses of FKBP5 and group variables entered simultaneously. b The effect of FKBP5  group interaction term was examined over and above the main effects. NA. Group status moderated the associations of situational stress with Finally, among risk haplotype carriers (i.e., CATT/), no group PEs and NA (Table 2). Analysis of simple slopes showed that the differences were found in the association of both positive appraisals associations were greater in the incipient psychosis group (PEs: 0.126, with symptoms (situation positive—PEs: 0.017, SE = 0.035, ns; NA: SE = 0.013, p < 0.001; NA: 0.285, SE = 0.023, p < 0.001) compared with 0.135, SE = 0.079, ns; others care about me—PEs: 0.035, SE = 0.027, the nonclinical group (PEs: 0.046, SE = 0.04, p < 0.001; NA: 0.218, SE ns; NA: 0.088, SE = 0.055, ns). = 0.011, p < 0.001). The group status also moderated the associations of the two positive appraisals with PEs, but not NA, in the moment. That is, as positive experiences increased, incipient psychosis Discussion participants experienced greater decreases in symptoms (positive Main findings situation: 0.114, SE = 0.014, p < 0.001; others care about me: 0.078, SE = 0.017, p < 0.001) than their nonclinical counterparts The present work investigated whether the interplay between (positive situation: 0.055, SE = 0.005, p < 0.001; others care about FKBP5 variation and contextual factors is not limited to adverse me: 0.032, SE = 0.004, p < 0.001). experiences, but expands into the full spectrum of positive and The FKBP5 haplotype by group interaction moderated all the negative experiences in real-life contexts. The study raised a novel associations of positive, but not negative, experiences with decreased finding indicating that the interaction of FKBP5 variation with PEs and NA in daily-life (Table 2). As shown in Figure 1, simple slope positive experiences is associated with diminished PEs and NA, analyses indicated that, among protective haplotype carriers in incipient psychosis compared with nonclinical group. Another (i.e., AGCC/), the positive appraisal of the situation was associated relevant finding from the current study was that individuals with with decreased PEs in the incipient psychosis group compared with incipient psychosis, in comparison to their nonclinical counter- the nonclinical group (PEs: 0.087, SE = 0.018, p < 0.001; NA: 0.043, parts, reported greater psychotic reactivity to negative, but also to SE = 0.038, ns). In addition, among protective haplotype carriers, the positive, experiences in daily-life. Notably, the incipient psychosis positive experience of feeling cared for by others was associated group differed from the nonclinical group in terms of symptomatic with decreased PEs, as well as NA, in the incipient psychosis reactivity to positive, but not negative, appraisals in the interper- group compared with the nonclinical group (PEs: 0.096, SE = sonal domain, suggesting that positive interpersonal appraisals may 0.017, p < 0.001; NA: 0.066, SE = 0.033, p < 0.050; see Figure 2). act as a relevant coping mechanism for help-seeking individuals, Furthermore, among the mixed haplotype (i.e., one protective and ameliorating the intensity of symptom expression in the realm of one risk haplotype carriers; AGCC/CATT), the experience of a pos- daily-life. itive situation was associated with diminished PEs in incipient psy- The interpretation of these findings appears relevant at both chosis in comparison to nonclinical group (situation positive—PEs: basic and applied levels. At a basic science level, they seem to concur 0.040, SE = 0.020, p < 0.050; NA: 0.002, SE = 0.040, ns; others care with numerous studies showing that environmental enrichment about me—PEs: 0.004, SE = 0.022, ns; NA: 0.014, SE = 0.036, ns). induces dramatic changes on brain and behavior in animal models European Psychiatry 5 Figure 1. Group differences between nonclinical and early psychosis groups in the interaction of situation positive with FKBP5 haplotype on psychotic experiences and negative affect. [31]. It has been shown that environmental enrichment improves ecologically valid tools [42], providing new opportunities for treat- behavioral impairment in animal models of schizophrenia. Impor- ment. The development of recent positive psychological interven- tantly, environmental enrichment diminishes the long-term nega- tions [43] and the new upsurge of real world interventions in tive effects of stress on altered HPA function [32]. A specific effect mental health [44] may be particularly important in psychosis field. of environmental enrichment on this reversal role of HPA dysre- gulation is seen in animal models of transgenerational and multi- Clinical relevance of individual genetic differences in the generational prenatal stress [33]. In addition, it has been shown that response to positive experiences the exposure to environmental enrichment remarkably reduced the stress-sensitive phenotype induced by ancestral stress and also Although to the best of our knowledge there are no previous studies improved several levels of HPA axis function. investigating whether the FKBP5 haplotype moderates the associ- From a clinical stance, the present findings support increasing ation of positive experiences with symptom expression in daily-life, evidence indicating that environmental factors in general [34], and findings seem to resonate with recent work in the context of daily-life experiences in particular [35], are potent factors in terms responsiveness to psychotherapy in Posttraumatic stress disorder of influencing psychotic reactivity and expression. Research has (PTSD) [45]. The study examined whether improvement in PTSD been predominantly guided by diathesis-stress model, and there is a symptoms after exposure-based therapy differed as a function of growing criticism regarding the disproportionate focus on stressors FKBP5 (rs1360780) variability. They found that, although no and negative life events and the negligence of positive environ- genetic differences on symptoms emerged between baseline and a ments. New conceptual frameworks, such as the diathesis-stress- 4-month follow-up, individuals homozygous for the protective support model [36], suggest that social support can boost skills and rs1360780 C-allele continued to show a reduction in symptoms competences, prevent risk accumulation, and are essential for an in the 10-month follow-up, whereas this was not found for carriers individual’s progress toward recovery. In this sense, the recent of the risk T-allele [45]. According to Pluess [15], these results growing impact of Positive Psychology [37,38] and Positive Psy- suggest that the C-allele may enhance vantage sensitivity in the chiatry [39] has demonstrated that persons with psychosis can context of exposure-based therapy in this population. Given that in experience positive psychological features [40]. Regarding ESM the present study, the protective haplotype was associated with research, one study revealed that individuals with persistent PEs diminished symptoms in the context of positive experiences for showed more social reward sensitivity than individuals without incipient psychosis participants (but not increased symptoms in the persistent PEs [41]. This realization has recently encouraged inter- context of negative ones), our findings would seem to be in line with est in developing momentary clinical interventions with a vantage sensitivity interpretation for incipient psychosis as 6 Paula Cristóbal-Narváez et al. Figure 2. Group differences between nonclinical and early psychosis groups in the interaction of feeling cared for by others with FKBP5 haplotype on psychotic experiences and negative affect. compared with nonclinical group. It must be noted, although, that considered to increase the power and reliability of G  E research we did not employ specific statistical tests [46] to formally inves- [49]. In this sense, the design of the study offers a useful model for tigate such pattern of G  E interactions. researchers wanting to examine complex G  E effects in the real Recent etiological evidence that advocates for positive and world. As regards to limitations, these include gender differences in negative effects of genetic and environment factors on the devel- the composition of nonclinical and clinical samples, which may opmental trajectories of psychosis has not yet been embodied into limit the generalizability of findings; and the fact that causal infer- preventive interventions. In this regard, it is imperative to devise ences of the effects of momentary positive and negative experiences new real-world targeted strategies based on knowledge about the cannot be definitively drawn given that ESM predictor and criterion individual capacity of people at-risk or with psychotic symptoms in variables were measured concurrently. Future G  E longitudinal showing differential reactivity to negative and positive factors. This studies should also examine the association of PE and NA interac- is a critical issue, as many clinicians, even those with knowledge and tions over time in large samples allowing examination of potential sensitivity toward psychological factors in incipient psychosis differences in affective versus nonaffective psychosis diagnoses. services with a preventive framework, continue to treat persons This would shed light on the complex relationship between affect with any degree of psychosis expression in a very different manner and psychosis and potential similarities and differences in pheno- to that employed with persons presenting with risk for or overt non- types with a predominance of each component. psychotic disorders. Most likely, decades of a narrow conceptual- ization of psychosis as the straightforward product of a genetically determined brain disease, the historically engraved “broken brain” Conclusions view of schizophrenia [47] and the youth of a developing agreed upon conceptual framework in which to integrate the dynamic, Overall, the study provides evidence of individual differences in the malleable, and reactive nature of psychosis experiences, partly interaction of genetic variation with proximal environmental fac- account for this situation. tors in nonclinical and incipient psychosis groups. Future studies should employ ambulatory assessments to investigate potential mechanisms involved in the interplay of positive momentary expo- Strengths and limitations sures with protective individual variation in relevant genes for the The present study has a number of strengths, including the estima- homeostasis of the HPA axis, which may result in an adaptive tion of a haplotype that increases the power to detect genetic response to stress in the realm of daily-life. Moreover, empirical associations [48] and the use of valid ecological measures that are evidence from research examining patterns of reactivity to the European Psychiatry 7 environment could encourage real-world targeted strategies based childhood trauma interactions. Nat Neurosci. 2013;16:33–41. http://dx. on the knowledge of individual differences in the reactivity from doi.org/ 10.1038/nn.3275. negative to positive factors in the field of psychosis. This is a critical [12] Walker EF, Diforio D. 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