Relatives' attachment anxiety mediates the association between perceived loss and expressed emotion in early psychosis

A common reaction experienced by family members of patients with psychosis is grief for the loss of their healthy relative. Importantly, high levels of perceived loss have been related to the manifestation of high expressed emotion (EE), which includes the negative attitudes expressed by relatives toward an ill family member. However, the mechanisms underlying the relationship between relatives' perceived loss and EE attitudes in the early stages of psychosis are still not fully understood. In this regard, attachment theory has been suggested as a useful framework for understanding this link. The current study aimed to examine: (1) whether relatives' perceived loss was associated with relatives' EE dimensions (i.e., criticism and emotional over-involvement (EOI)), and (2) whether such associations were mediated by relatives' attachment dimensions (i.e., anxiety and avoidance). Seventy-eight relatives of patients with early psychosis completed the Mental Illness Version of the Texas Inventory of Grief for the assessment of loss reactions. Attachment dimensions and EE attitudes were assessed by the Psychosis Attachment Measure and the Family Questionnaire, respectively. Findings indicated that relatives' perceived loss was associated with EE dimensions. Relatives' attachment anxiety, but not avoidance, mediated the relationship of perceived loss with both criticism and EOI. Findings highlight the importance of examining the role of relatives' attachment characteristics for understanding how perceptions of loss might impact the manifestation of EE attitudes in the early stages of psychosis. Family interventions aimed at assisting relatives to improve their management of negative emotional reactions to loss are fundamental to prevent impairing loss reactions and the entrenchment of high-EE attitudes

Impact of Adverse Childhood Experiences on Psychotic-Like Symptoms and Stress Reactivity in Daily Life in Nonclinical Young Adults

Background: There is increasing interest in elucidating the association of different childhood adversities with psychosis-spectrum symptoms as well as the mechanistic processes involved. This study used experience sampling methodology to examine (i) associations of a range of childhood adversities with psychosis symptom domains in daily life; (ii) whether associations of abuse and neglect with symptoms are consistent across self-report and interview methods of trauma assessment; and (iii) the role of different adversities in moderating affective, psychotic-like, and paranoid reactivity to situational and social stressors. Method: A total of 206 nonclinical young adults were administered self-report and interview measures to assess childhood abuse, neglect, bullying, losses, and general traumatic events. Participants received personal digital assistants that signaled them randomly eight times daily for one week to complete questionnaires about current experiences, including symptoms, affect, and stress. Results: Self-reported and interview-based abuse and neglect were associated with psychotic-like and paranoid symptoms, whereas only self-reported neglect was associated with negative-like symptoms. Bullying was associated with psychotic-like symptoms. Losses and general traumatic events were not directly associated with any of the symptom domains. All the childhood adversities were associated with stress reactivity in daily life. Interpersonal adversities (abuse, neglect, bullying, and losses) moderated psychotic-like and/or paranoid reactivity to situational and social stressors, whereas general traumatic events moderated psychotic-like reactivity to situational stress. Also, different interpersonal adversities exacerbated psychotic-like and/or paranoid symptoms in response to distinct social stressors. Discussion: The present study provides a unique examination of how childhood adversities impact the expression of spectrum symptoms in the real world and lends support to the notion that stress reactivity is a mechanism implicated in the experience of reality distortion in individuals exposed to childhood trauma. Investigating the interplay between childhood experience and current context is relevant for uncovering potential pathways to the extended psychosis phenotype

Interaction of both positive and negative daily-life experiences with FKBP5 haplotype on psychosis risk

Altres ajuts: Fundació La Marató de TV3 (091110)There is limited research on the interaction of both positive and negative daily-life environments with stress-related genetic variants on psychotic experiences (PEs) and negative affect (NA) across the extended psychosis phenotype. This study examined whether the FK506 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. 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). 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. 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

Impact of gene-environment interaction on the real-world expression of psychosis risk : linking genetic variation, childhood adversity and daily-life experiences across the extended psychosis phenotype/

Departament responsable de la tesi: Departament de Psicologia Clínica i de la SalutPremi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2016-2017La investigación en el ámbito de la interacción gen-ambiente, basada en la sinergia de factores genéticos y ambientales, ha tenido una gran relevancia en el campo de la psicosis. El principal objetivo de la tesis fue investigar la interacción entre factores ambientales y de variabilidad genética individual en el fenotipo psicótico usando la técnica Experience Sampling Methodology (ESM). El cuerpo de la tesis incluye cinco capítulos relacionados con temas como: la sinergia entre factores ambientales distales (trauma en la infancia) y factores proximales (estrés momentáneo) en experiencias psicóticas en la vida diaria, la moderación de variantes genéticas en la asociación entre ambos factores, y el análisis de las interacciones gen-ambiente incorporando posibles factores protectores. Específicamente, el Capítulo 1 trata de investigar el impacto de la interacción entre experiencias adversas en la infancia y estrés momentáneo (situacional y social) en las experiencias de tipo psicótico de la vida diaria en una muestra no clínica. Los resultados del estudio indicaron que las adversidades como abuso, negligencia o bullying, caracterizadas por una marcada intencionalidad, fueron asociadas con experiencias de tipo psicótico en la vida diaria. Sin embargo, estas asociaciones no se daban en los casos de adversidades como muertes o eventos traumáticos. Además, a diferencia de los eventos traumáticos, las adversidades de naturaleza interpersonal (como abuso, negligencia, bullying o pérdidas de personas cercanas) aumentaron la reactividad psicótica en respuesta a ambos tipos de estrés. El Capítulo 2 investigó el papel que juegan importantes variantes genéticas, las cuáles están implicadas en sistemas biológicos de regulación del estrés, en interacción con factores ambientales proximales y distales incrementando el riesgo de experiencias psicóticas a lo largo del fenotipo extendido de psicosis, es decir, en participantes de la muestra no clínica y clínica. Los resultados indicaron que los haplotipos de riesgo (FKBP5, RGS4) y el alelo de riesgo del receptor de la oxitocina (OXTR rs2254298) interaccionaron con factores ambientales distales y proximales, respectivamente, incrementando las experiencias de tipo psicótico en la muestra clínica. Los Capítulos 3 y 4 aportan nuevas contribuciones al campo de la investigación gen-ambiente dado que investigan la interacción de variantes genéticas con la acción combinada de ambos factores ambientales. Los resultados indicaron que la interacción del Bullying con el haplotipo de riesgo FKBP5 incrementan las experiencias de tipo psicótico, así como también aumentan la reactividad psicótica y afectiva en respuesta a estrés de tipo social. Similarmente, la exposición a otras adversidades de naturaleza interpersonal en interacción con las variantes COMT (rs4680) and OXTR (53576), también conllevan a un incremento de la reactividad psicótica y afectiva en respuesta a estrés de tipo social. Finalmente, el Capítulo 5 examina si los factores genéticos y ambientales de protección pueden interactuar entre ellos disminuyendo las experiencias de tipo psicótico. Los resultados del estudio revelaron que la interacción entre el haplotipo de protección FKBP5 y las experiencias positivas en la vida diaria tenían un impacto en la disminución de los síntomas en los participantes de la muestra clínica. En resumen, la presente tesis evidencia que la interacción entre ambos factores ambientes y la variabilidad genética individual es importante para identificar posibles factores de riesgo implicados en la expresión de experiencias de tipo psicótico en la vida diaria, y para el descubrimiento de mecanismos subyacentes a lo largo del fenotipo psicótico. Además, el presente trabajo muestra que examinar las diferencias individuales teniendo también en cuenta factores de protección, permite refinar y expandir nuestro conocimiento sobre los procesos de vulnerabilidad y resiliencia implicados en el fenotipo extendido de psicosis. Por último, los hallazgos de la presente tesis pueden tener aplicaciones clínicas sobretodo en el uso de intervenciones ecológicas momentáneas.The gene-environment interaction (GxE) research is based on the synergistic co-participation between nature and nurture factors, and has been considered a remarkable approach for understanding the development of psychosis. The present thesis sought to investigate the interplay between environmental factors and individual genetic variation on the psychotic phenomena using Experience Sampling Methodology (ESM). The body of the thesis includes five chapters investigating issues related to the synergy of distal (childhood trauma) and proximal (momentary stress) environmental factors on psychotic experiences in daily life; the moderating role of genetic variants in the association between distal and proximal environmental factors, and the examination of GxE interactions taking into consideration not only risk factors, but also plausible protective factors. Specifically, Chapter 1 sought to elucidate the mechanisms involved in the contribution of a range of childhood adversities in interaction with situational and social stressors on the real-world expression of psychotic risk in nonclinical young adults. The results of this study indicated that intentional forms of childhood adversity (abuse, neglect and bullying), but not losses or general traumatic events, were associated with psychotic experiences in the realm of daily life. In addition, unlike general traumatic events, adversities of an interpersonal nature (abuse, neglect, bullying and losses) increased psychotic reactivity to both situational and social stressors. Chapter 2 investigated the role of genetic variants, which are involved in relevant biological systems for stress regulation, in interaction with distal and proximal environmental factors on psychotic features across the extended psychosis phenotype, that is, in both nonclinical and early-psychosis individuals. The results showed that the risk haplotypes (FKBP5, RGS4) and the risk allele OXTR (rs2254298) interact with distal and proximal environmental factors, respectively, increasing psychotic experiences in early-psychosis individuals. Chapters 3 and 4 provide novel contributions to GxE research by investigating further the interplay of relevant genetic variation with the combined action of both environmental factors. Results indicated that bullying interacts with the FKBP5 risk haplotype in shaping the real-world expression of psychosis risk and increasing psychotic and affective responses to social stress. Similarly, the exposure to other distal interpersonal adversities (self-reported abuse and neglect) with COMT (rs4680) and OXTR (53576) exacerbated psychotic and affective reactivity to social stressors. Finally, Chapter 5 sought to extend our current understanding of GxE interactions examining the plausible interplay between protective genetic and environmental factors in the amelioration of psychotic experiences in daily life. Results revealed that the interaction of the protective FKBP5 haplotype and positive experiences results in the amelioration of daily-life psychotic experiences in in help-seeking individuals, but not in nonclinical participants. Overall, the present thesis provides evidence that the interaction of both distal and proximal environmental stressors with genetic variants is relevant for identifying plausible risk factors implicated in the real-world expression of psychotic features and, for uncovering mechanistic pathways to the extended psychosis phenotype. Furthermore, the present work show that the examination of individual differences taking into consideration not only adversity but also protective factors on the daily-life expression of psychosis risk, may refine and expand our understanding about the vulnerability and resilience processes involved in the extended psychosis phenotype. The findings may ultimately have implications for identifying relevant key targets that could be useful for ecological momentary interventions

Interaction of Both Positive and Negative Daily-Life Experiences with FKBP5 Haplotype on Psychosis Risk.

Background: There is limited research on the interaction of both positive and negative daily-life environments with stress-related genetic variants on psychotic experiences (PEs) and negative affect (NA) across the extended psychosis phenotype. This study examined whether the FK506 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

The genome-wide associated candidate gene ZNF804A and psychosis-proneness : evidence of sex-modulated association

BACKGROUND: The Zinc finger protein 804A (ZNF804A) is a promising candidate gene for schizophrenia and the broader psychosis phenotype that emerged from genome-wide association studies. It is related to neurodevelopment and associated to severe symptoms of schizophrenia and alterations in brain structure, as well as positive schizotypal personality traits in non-clinical samples. Moreover, a female-specific association has been observed between ZNF804A and schizophrenia. AIM: The present study examined the association of two ZNF804A polymorphisms (rs1344706 and rs7597593) with the positive dimension of schizotypy and psychotic-like experiences in a sample of 808 non-clinical subjects. Additionally, we wanted to explore whether the sexual differences reported in schizophrenia are also present in psychosis-proneness. RESULTS: Our results showed an association between rs7597593 and both schizotypy and psychotic-like experiences. These associations were driven by females, such those carrying the C allele had higher scores in the positive dimension of both variables compared to TT allele homozygotes. CONCLUSION: The findings of the present study support the inclusion of ZNF804 variability in studies of the vulnerability for the development of psychopathology in non-clinical samples and consideration of sex as a moderator of this associatio

Childhood trauma, BDNF Val66Met and subclinical psychotic experiences. Attempt at replication in two independent samples

Childhood trauma exposure is a robust environmental risk factor for psychosis. However, not all exposed individuals develop psychotic symptoms later in life. The Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been suggested to moderate the psychosis-inducing effects of childhood trauma in clinical and nonclinical samples. Our study aimed to explore the interaction effect between childhood trauma and the BDNF Val66Met polymorphism on subclinical psychotic experiences (PEs). This was explored in two nonclinical independent samples: an undergraduate and technical-training school student sample (n = 808, sample 1) and a female twin sample (n = 621, sample 2). Results showed that childhood trauma was strongly associated with positive and negative PEs in nonclinical individuals. A BDNF Val66Met x childhood trauma effect on positive PEs was observed in both samples. These results were discordant in terms of risk allele: while in sample 1 Val allele carriers, especially males, were more vulnerable to the effects of childhood trauma regarding PEs, in sample 2 Met carriers presented higher PEs scores when exposed to childhood trauma, compared with Val carriers. Moreover, in sample 2, a significant interaction was also found in relation to negative PEs. Our study partially replicates previous findings and suggests that some individuals are more prone to develop PEs following childhood trauma because of a complex combination of multiple factors. Further studies including genetic, environmental and epigenetic factors may provide insights in this field

The genome-wide associated candidate gene ZNF804A and psychosis-proneness: Evidence of sex-modulated association

Background: The Zinc finger protein 804A (ZNF804A) is a promising candidate gene for schizophrenia and the broader psychosis phenotype that emerged from genome-wide association studies. It is related to neurodevelopment and associated to severe symptoms of schizophrenia and alterations in brain structure, as well as positive schizotypal personality traits in non-clinical samples. Moreover, a female-specific association has been observed between ZNF804A and schizophrenia. Aim: The present study examined the association of two ZNF804A polymorphisms (rs1344706 and rs7597593) with the positive dimension of schizotypy and psychotic-like experiences in a sample of 808 non-clinical subjects. Additionally, we wanted to explore whether the sexual differences reported in schizophrenia are also present in psychosis-proneness. Results: Our results showed an association between rs7597593 and both schizotypy and psychotic-like experiences. These associations were driven by females, such those carrying the C allele had higher scores in the positive dimension of both variables compared to TT allele homozygotes. Conclusion: The findings of the present study support the inclusion of ZNF804 variability in studies of the vulnerability for the development of psychopathology in non-clinical samples and consideration of sex as a moderator of this association

The Interaction between Childhood Bullying and the FKBP5 Gene on Psychotic-Like Experiences and Stress Reactivity in Real Life

Aim: The present study employed Experience Sampling Methodology to examine whether the interaction between childhood bullying and FKBP5 variability (i) is associated with the expression of psychotic-like experiences, paranoia, and negative affect, and (ii) moderates psychotic-like, paranoid, and affective reactivity to different forms of momentary stress (situational and social) in daily life. Methods: A total of 206 nonclinical young adults were interviewed for bullying with the Childhood Experience of Care and Abuse and were prompted randomly eight times daily for one week to complete assessments of their current experiences, affect, and stress appraisals. Participants were genotyped for three FKBP5 single nucleotide polymorphisms (SNPs) (rs3800373, rs9296158, and rs1360780) that have been linked to hypothalamus-pituitary-adrenal axis reactivity. Multilevel analyses were conducted to examine the effect of the interaction between childhood bullying and the FKBP5 haplotype derived from these three SNPs. Results: The interaction between bullying and the FKBP5 haplotype was associated with positive, but not negative, psychotic-like experiences, paranoia, and negative affect. The bullying x FKBP5 interaction also moderated the association of a social stress appraisal (specifically, being alone because people do not want to be with you) with psychotic-like experiences and negative affect in daily life. Simple slopes analyses indicated that, in all cases, the associations were significantly increased by exposure to bullying in participants with the risk haplotype, but not for those with the non-risk haplotype. Discussion: The present study provides the first evidence of the interplay between childhood bullying and FKBP5 variability in the real-world expression of psychosis proneness and social stress reactivity. The findings underscore the importance of investigating how gene-environment interactions are involved in mechanistic pathways to the extended psychosis phenotype and lend further support to the increasing relevance given to socially defeating appraisals in the experience of reality distortion