Childhood adversity and psychosis: Evidence and mechanisms

1. Childhood adversity and psychosis: Evidence and mechanisms Filippo Varese Senior Clinical Lecturer – University of Manchester Director -GMMH Complex Trauma and Resilience Research Unit filippo.varese@manchester.ac.uk

2. Overview of the relationship between childhood adversities and psychosis • Recent work and evidence syntheses considering the psychological mediators of the relationship between childhood adversity and psychosis • Introducing recent developments on interventions that targets these psychological mediators in clients with distressing psychotic symptoms @c_tru_research

3. Co-Directors and members of C-TRU Sandra Bucci Kim Cartwright Eleanor Longden Katherine Berry Kate Allsopp Richard Brown @c_tru_research

4. Tony Morrison Laura Bonnett Carolina Campodonico Catrin Tudur Smith Jessica Williams Richard Bentall Alison Yung Bill Sellwood Doug Turkington Sonya Rafiq Rob Dudley Laura McCartney @c_tru_research

5. Large body of evidence indicating that exposure to life adversities in childhood increases the risk for psychosis People are at particularly elevated risk for psychosis if they have experienced multiple life adversities Up to a third of cases of psychosis could be attributable to the impact of childhood life adversities @c_tru_research @c_tru_research

6. Dose-response effects: the observation of an increased risk of psychosis at increasing levels of exposure to trauma • E.g. Shevlinet al. 2007; People exposed to 1 type of childhood trauma (e.g. sexual abuse) were 2.5 times more likely to have experienced psychosis • People exposed to 5 types of childhood trauma (e.g. sexual abuse, physical abuse, neglect) were 53 times more likely to have experienced psychosis @c_tru_research

7. How common are adverse childhood experiences in psychosis? • In a sample of 324 participants with lifetime • (self-reported) diagnosis of psychosis… • 92.9% reported at least 1 adverse childhood event • 78.8% reported multiple (at least 2) events • 40.1% reported four or more adversities • In the majority of participants: • Events were of interpersonal nature (91.8%) • Involved a relative, friend or significant other (82.4%) • Had prolonged nature i.e. involved more than one exposure to the same adversity (68.2%)

8. Further notable findings • Independent replications of the childhood adversity and psychosis relationship (e.g. Matheson et al., 2013) • The link between trauma and psychosis equally applies to exposures in adulthood (e.g. Beards et al., 2013) • Trauma exposure is linked to greater symptom severity in people with psychosis, particularly in the case of positive symptoms (Bailey et al., 2018) • Phonomenologicalevidence indicating that content and characteristics of psychotic symptoms are influenced by trauma exposure (e.g. Cox, Longden, Morrison & Varese, under review) @c_tru_research

9. Childhood adversities in the At Risk Mental States

10. Emerging findings from ARMS studies • The majority of ARMS individuals report life adversities in childhood (range from 54%-90%) • ARMS individual report higher levels of trauma exposure than controls, in particular emotional abuse, physical abuse and bullying (Peh et al., 2019) • Trauma exposure is associated with greater symptom severity and poorer functioning in ARMS • Associations with heightened transition to psychosis as yet unclear EU-GEI High Risk study (Kraan et al., 2018 Schizophrenia Bulletin)

11. The IPPACTproject The IPPACT project (Improving Prediction of Psychosis in ARMS using a Clinically useful prognostic Tool) co-led by Alison Young and Filippo Varese OBJECTIVES: • Identify most reliable prognostic factors for transition to psychosis in ARMS • Develop and validate a refined prognostic tool that could be implemented in routine clinical practice in the UK Phase 1: Individual Patient Data meta-analysis of prognostic studies in ARMS Phase 2: Development of a refined prognostic / risk stratification tool Phase 3: External validation in a new cohort of 798 ARMS individuals

12. The IPPACTproject • Phase 1 involves an IPD meta-analysis supported by a Consortium of international collaborators to identify demographic, clinical and neurocognitive characteristics that reliably predict transition to psychosis in ARMS individuals • Currently we have data from 2044 ARMS individuals • Childhood trauma is being evaluated in these analyses Phase 1: Individual Patient Data meta-analysis of prognostic studies in ARMS Phase 2: Development of a refined prognostic / risk stratification tool Phase 3: External validation in a new cohort of 798 ARMS individuals

13. Members of the IPPACT Consortium • Anita Riecher-Rössler (University of Besel, CH) • FraukeSchultze-Lutter (University of Cologne, DE) • Helen Stain (Leeds Beckket University, UK) • J. Lee (Institute of Mental Health, SG) • Scott Woods (Yale University, US) • Diana Perkins (University of North Carolina, US) • Jesus Perez (Cambridge University, UK) • William McFarlane (MMCRI, US) • Kristen Woodberry (MMCRI, US) • Magdalena Kotlicka-Antczak (University of Lodz, PL) • Suk KyooAn (South Korea) • Tsutomu Takahashi (Toyoma University, JPN) • Tim Ziermans (Ultrecht University, NL) • Silvia Rigucci (Sapienza University of Rome, IT) • Nicolas Rüsch (University of Zurich, CH) • Patrick Welsh (Durham University, UK) • Anthony Morrison (University of Manchester, UK) • Patrick McGorry (University of Melbourne, AUS) • Barnaby Nelson (University of Melbourne, AUS) • Mark van der Gaag (Vrije Universiteit Amsterdam, NL) • Paolo Fiori Nastro (Sapienza University of Rome, IT) • Alice Masillo (Sapienza University of Rome, IT) • Jean Addington (University of Calgary, CA) • Jun So Kwan (Seoul National University College, KR), • SwapnaK. Verma(Institute of Mental Health, SG) • SiowAnn Kwon(Institute of Mental Health, SG) • Eric Chen (University of Hong Kong) • Peter Jones (Cambridge University, UK) • Jai Shah (McGill Univeristy, CA) • Doreen Nieman (University of Amsterdam, NL) • Paul Amminger (University of Melbourne, AUS) • Peter Ulhaans (University of Glasgow, UK)

14. Bradford Hill criteria for inferring causality from epidemiological data: Strength of association Consistency Temporal relationship Biological gradient/dose-response Plausible mechanisms Austin Bradford Hill (1897-1991) @c_tru_research

15. Why identifying the mechanisms linking trauma and psychosis is important? • The identification of specific pathways/mechanisms linking trauma and psychosis is not just an intellectual quest – it has clinical potential in terms of: • Early detection of individuals at higher risk of developing distressing psychotic experiences • Development of preventive interventions for those exposed to adverse or traumatic events • Understanding if current treatment options for psychosis are likely to be effective in people with psychotic experiences brought about by trauma • Development of more effective interventions @c_tru_research

16. Childhood adversities and dissociation in people with psychosis (Rafiq, Campodonico& Varese, 2018) • Moderate but well-replicated relationship between dissociative experiences and exposure to childhood adversity (r = .39, 95%CI [.41, .47]) • All types of childhood adversities for which it was possible to extract specific effects were positively associated with dissociation • All had small-to-moderate summary effect sizes @c_tru_research

17. Research questions and hypotheses @c_tru_research

18. Dissociation and psychotic experiences: A meta-analysis (Longden et al. in preparation) • Expanded (and replicated) the findings of Pilton et al. (2015): • Robust associations with dissociation are observed for hallucinations in other sensory modalities (visions) • The effects for other positive psychotic symptoms are equally (moderate-to-)large • The effects are observed both in clinical samples and non-clinical/schizotypystudies • Relationships with negative symptoms are small in in many studies absent @c_tru_research

19. Using mediation analysis to identify relevant mechanisms linking trauma and psychosis • Mediation (Baron & Kenny, 1986): A popular analytic approach used to identify “mechanisms” by which an independent variable (trauma exposure) influences an outcome of interest (psychotic experiences) DISSOCIATION TRAUMA VOICES @c_tru_research

20. Williams, Bucci, Berry & Varese (2018) • Clinical or non-clinical quantitative studies (prospective, cross-sectional, and case-control studies) that: • Assessed the association between childhood trauma (before age 18) and presence/severity of psychotic symptoms or diagnosis of psychosis • Tested the effect of one or more psychological/clinical mediating variables on this relationship using appropriate statistical methods • Used narrative synthesis to summarise and appraise these studies @c_tru_research

21. Williams, Bucci, Berry & Varese (2018) • 37 eligible studies (21 clinical, 16 non-clinical) published between 2003 and 2017 • Most studies from the UK (20 studies) • Most studies were cross-sectional, including 9 large-scale epidemiological studies • Sample sizes ranged between 60 to 17,337 participants @c_tru_research

22. The mediators of the trauma-psychosis link • Great variation in the mediators considered in the primary studies • Grouped into 5 “families” of mediators, some with considerable empirical support (1, 2 and 3), others inconclusive (4 and 5) 1 2 3 4 5 @c_tru_research Note. “k” indicates the number of studies that considered a certain moderator

23. The mediators of the trauma-psychosis link • A “post-traumatic sequelae” route i.e. clinical and psychological factors generally recognised as being brought about by exposure to adverse/traumatic experiences e.g. dissociation, post-traumatic intrusions, hyperarousal 1 2 3 4 5 @c_tru_research Note. “k” indicates the number of studies that considered a certain moderator

24. The mediators of the trauma-psychosis link 1 • An “affective” route : Consistent with proposals for an affective route to psychosis (e.g. Garety et al 2001), most studies considering the role of depression, anxiety and/or unhelpful emotion regulation strategies found evidence of mediation 2 3 4 5 @c_tru_research Note. “k” indicates the number of studies that considered a certain moderator

25. The mediators of the trauma-psychosis link 1 2 • A “cognitive” route: Consistent with cognitive models of psychosis (e.g. Morrison, 2001), trauma exposure increases risk for psychosis via formation of negative/unhelpful beliefs about self and the social world 3 4 5 @c_tru_research Note. “k” indicates the number of studies that considered a certain moderator

26. The mediators of the trauma-psychosis link 1 The mediators/mechanisms can be targeted with interventions that are already recommended (but not sufficiently offered) for psychosis and trauma, e.g. CBTp, TF-CBT and EMDR 2 3 4 5 @c_tru_research Note. “k” indicates the number of studies that considered a certain moderator

27. Recognising and treating trauma in psychosis • Increased recognition of the importance of recognising and treating trauma symptoms (i.e. comorbid PTSD) in people with psychosis • Updated NICE guidelines (NICE 2014): recommendation that clients with first episode psychosis should undergo trauma/PTSD assessment routinely, and receive suitable treatment when meeting diagnostic criteria for PTSD (as per NICE, 2005) • Research evaluating the safety and efficacy of trauma-focused interventions aiming to ameliorate PTSD in clients with psychosis • Four systematic reviews / meta-analyses (Brand et al., 2018; Sin & Spain, 2017; Sin et al. 2017; Swan et al, 2017) – further definitive evaluations are required @c_tru_research

28. Are therapies focusing on trauma and its sequelae a promising new direction in the treatment of psychosis? • Trauma-focused interventions reduce the putative psychological mediators of the trauma-psychosis link (e.g. Chen et al. 2014; Lee & Cuijpers, 2013) • Interventions for comorbid PTSD lead to (modest) reductions in the severity of psychotic symptoms (de Bont et al., 2016; Brand et al., 2018) • Process-oriented interventions considering specific mechanisms involved in the trauma-psychosis link? • Adapt trauma interventions to directly target traumatic events linked to the onset, exacerbation and maintenance of psychotic symptoms? @c_tru_research

29. Cognitive therapy for dissociation and voices (Varese et al., in prep) • Established CBT-approaches to the treatment of distressing voices (Morrison et al., 2003) modified to systematically include therapeutic techniques targeting dissociative experiences (Kennerley, 1996) • 24 therapy sessions organised in 4 phases: • Assessment and engagement phase (approx. sessions 1-4) • Introduction of strategies targeting dissociative responses (approx. sessions 5-14) • Longitudinal Formulation/Cognitive Behavioural change strategies phase (approx. sessions 14-22) • Consolidation phase (final 2 sessions) @c_tru_research

30. Cognitive therapy for dissociation and voices (Varese et al., in prep) Intervention evaluated in 20 trauma exposed voice-hearers (all had childhood trauma) in a single arm study Reliable and in many cases clinically significant improvements in: Dissociation (DES-II) Voice severity and distress (PSYRATS) Trauma-related symptoms (IES-R) Recovery (QPR) Anxiety and depression (DASS-21) Gains maintained at 6-months follow-up assessments @c_tru_research

31. Cognitive therapy for dissociation and voices - case study (McCartney et al., 2019) • Unclear whether the clinical gains are due to targeting dissociation • Examination of brief session measures used to monitor levels of symptoms over the course of treatment suggest that large changes in outcomes occurred following the introductions of strategies to manage dissociation @c_tru_research

32. Cognitive therapy for dissociation and voices - case study (McCartney et al., 2019) Unclear whether the clinical gains are due to targeting dissociation Examination of brief session measures used to monitor levels of symptoms over the course of treatment suggest that large changes in dissociation and voices occurred following the introductions of strategies to manage dissociation @c_tru_research

33. EMDR for psychosis (EMDRp) • Using EMDR to directly target trauma memories linked to psychotic symptoms (onset, content, exacerbation) or the consolidation of maladaptive appraisals of symptoms (e.g. van den Berg et al., 2013) • Treatment protocol for clients with first episode psychosis developed by EMDR therapists based in Lancashire (UK) • Longer intervention compared to Dutch trials; additional emphasis on on preparation phase of EMDR • Approach initially evaluated in case studies and now in a NIHR-funded feasibility trial @c_tru_research

34. The EASE trial Robin Logie • A feasibility trial of EMDR in first episode psychosis. • Inclusion criteria: history of traumatic life events, developed FEP in the previous 3 years, presence of positive psychotic symptoms associated with distress • 60 participants randomised to 16 sessions of EMDRp or TAU • Assessment points: baseline, 6 months and 12months post-randomisation • Outcome measures include psychotic symptom severity, perceived recovery, trauma-related measures(dissociation, post-traumatic symptoms) Debra Malkin Gita Buthani David Keane @c_tru_research

35. Take home messages… • There is strong meta-analytic evidence suggesting a robust association between childhood trauma and psychosis • A growing body of studies has been mapping plausible psychological mechanisms involved in this relationship – many are amenable to psychological interventions • Psychological therapies for trauma may represent a promising new direction in the treatment of psychosis, but work in this area is still in its infancy @c_tru_research

36. Thanks for listening