STUDY PROTOCOL published: 05 February 2020 doi: 10.3389/fpsyt.2019.01023 A Multicenter Phase II RCT to Compare the Effectiveness of EMDR Versus TAU in Patients With a First- Episode Psychosis and Psychological Trauma: A Protocol Design Alicia Valiente-Gómez 1,2,3,4*, Nuria Pujol 2,3,5, Ana Moreno-Alcázar 1,2,3,4, Joaquim Radua 6,7,8, Eila Monteagudo-Gimeno 4,5, Itxaso Gardoki-Souto 1,2,4, Edited by: Bridget Hogg 1,2,4, Maria José Álvarez 9, Gemma Safont 3,4,10, Walter Lupo 1, Błażej Misiak, Victor Pérez 2,3,4,5, Benedikt L. Amann 1,2,3,4 and the FEP-EMDR Research Group Wroclaw Medical University, Poland 1 Centre Forum Research Unit, Institut de Neuropsiquiatria i Addiccions (INAD), Parc de Salut Mar, Barcelona, Spain, 2 IMIM Reviewed by: (Hospital del Mar Medical Research Institute), Barcelona, Spain, 3 CIBERSAM, Madrid, Spain, 4 Department of Psychiatry and Massimo Tusconi, Forensic Medicine, School of Medicine Universitat Autònoma de Barcelona, Barcelona, Spain, 5 Institut de Neuropsiquiatria i University of Cagliari, Addiccions (INAD), Hospital del Mar, Barcelona, Spain, 6 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Italy Barcelona, Spain, 7 Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College Teresa Sanchez-Gutierrez, London, London, United Kingdom, 8 Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Universidad Internacional De Institutet, Stockholm, Sweden, 9 Mental Health Department, Vic Hospital Consortium, Barcelona, Spain, 10 University Hospital La Rioja, Spain Mutua Terrassa, Barcelona, Spain *Correspondence: Alicia Valiente-Gómez Background: Patients with a first episode psychosis (FEP) who are admitted for the first 62648@parcdesalutmar.cat time to a psychiatric hospital frequently have experienced prior psychological trauma. Specialty section: Additionally, 40–80% develop posttraumatic stress symptoms, which are summarized as This article was submitted to a post-psychotic post-traumatic syndrome (PPS). Eye Movement Desensitization and Schizophrenia, reprocessing (EMDR) therapy could be an effective psychotherapy to treat a PPS and prior a section of the journal Frontiers in Psychiatry psychological traumas in this population. Received: 13 November 2019 Objectives: To assess if EMDR therapy leads to: 1) a reduction of relapses after Accepted: 24 December 2019 Published: 05 February 2020 intervention, 2) an improvement of trauma-related, psychotic and affective symptoms, Citation: 3) an improvement of overall functioning, and 4) an improvement in quality of life. Valiente-Gómez A, Pujol N, Methods: This is a multicenter phase II rater-blinded randomized controlled trial in which Moreno-Alcázar A, Radua J, Monteagudo-Gimeno E, 80 FEP patients with a history of psychological trauma will be randomly assigned to EMDR Gardoki-Souto I, Hogg B, Álvarez MJ, (n = 40) or to TAU (n = 40). Traumatic events will be measured by the Global Assessment Safont G, Lupo W, Pérez V. Amann BL and the FEP-EMDR of Posttraumatic Stress Questionnaire, the Cumulative Trauma Screening, the Impact of Research Group (2020) A Multicenter Event Scale-Revised, the Dissociative Experiences Scale, the Childhood Trauma Scale, Phase II RCT to Compare the the Holmes–Rahe Life Stress Inventory, and the Dissociative Experiences Questionnaire. Effectiveness of EMDR Versus TAU in Patients With a First-Episode Clinical symptomatology will be evaluated using the Suicide and Drug Consumption Psychosis and Psychological Trauma: module of the International Neuropsychiatric Interview, Structured Clinical Interview for A Protocol Design. Front. Psychiatry 10:1023. Positive and Negative Syndrome Scale, Young’s Scale for Mania Evaluation, and Beck doi: 10.3389/fpsyt.2019.01023 Depression II Questionnaire. Functionality will be assessed with the Global Assessment of Frontiers in Psychiatry | www.frontiersin.org 1 February 2020 | Volume 10 | Article 1023 Valiente-Gómez et al. EMDR Versus TAU in FEP Functioning and the Quality of Life with the Standardized Instrument developed by the EuroQol Group. The cognitive insight and adherence to the treatment will be assessed with the Beck Cognitive Insight Scale and the Drug Attitude Inventory. All variables will be measured at baseline, post-treatment and at 12-month follow-up. Conclusion: This study will provide evidence of whether EMDR therapy is effective in reducing trauma and clinical symptoms, reducing relapses and in improving functionality and quality of life in patients with FEP and a history of trauma. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03991377 Keywords: first episode psychosis, psychological trauma, post-psychotic posttraumatic stress, comorbidity, EMDR therapy, treatment as usual INTRODUCTION concomitant clinical depression (19). Trauma hinders Outcomes in patients with schizophrenia spectrum disorders and adherence to drug treatment (20), which is already particularly bipolar disorder have remained suboptimal (1, 2). One factor difficult in FEP patients in general (21). Thus, PPS has significant contributing to this is the high prevalence of psychological consequences at both prognostic and treatment levels (15). trauma and adverse life events in psychosis sufferers, nearly All of this evidence suggests there is an urgent need to go beyond four times the rate in the general population (3). Evidence the treatment of psychotic symptoms and integrate trauma-focused suggests traumatic life events are an important environmental psychotherapy into the care plan for FEP patients, especially in the factor implicated in an increased risk for the onset of a range of high-risk period following hospitalization. psychotic spectrum disorders, including first episode of Eye movement desensitization and reprocessing therapy psychosis (FEP) (4, 5) and affective psychosis in bipolar (EMDR) is a psychotherapy based on standardized protocols, disorder (6). Additionally, psychological trauma in patients which integrates the use of bilateral stimulation (such as side-to- with psychosis is associated with poorer service engagement side eye movements) with elements of cognitive-behavioral, (7), worse outcomes in the form of longer stays in hospital and interpersonal and body-centered therapies (22). EMDR has more frequent readmissions (8), more severe positive psychotic been integrated into the World Health Organization guide as a symptoms (9), and increased suicidal ideation (10). first-line psychotherapy for the treatment of PTSD in adults, The physiopathological mechanisms underlying the link children and adolescents (for a review, see (23). Despite the high between trauma and psychosis are not fully understood, but prevalence of comorbid PTSD in psychosis and the strong appear to be due to a complex interplay of trauma, genetic, empirical evidence supporting the efficacy of this therapy, epigenetic and environmental factors (4). Furthermore, the patients affected by psychosis have been commonly excluded prevalence of posttraumatic stress disorder (PTSD) in from clinical trials related to trauma (24). However, this tendency psychosis was estimated at 12.4% in a meta-analysis of 20 has begun to change and early evidence shows that positive and studies (95% CI, 4.0–20.8%) (11). A diagnosis of PTSD in affective symptoms in severe psychiatric disorders, as well as psychosis was associated with poorer social functioning and comorbid trauma-related symptoms, can be ameliorated by more severe psychiatric symptoms (12–14). Of particular note EMDR therapy (25, 26). A randomized controlled multicenter is that the experience of suffering a FEP in and of itself can study has been conducted by (25), with a sample of 155 patients constitute a highly stressful event which triggers symptoms with chronic psychosis and comorbid PTSD. The results of this compatible with PTSD: this clinical condition has been defined study demonstrated the efficacy of EMDR in the treatment of as post-psychotic post-traumatic syndrome (PPS) (15) and is chronic PTSD symptoms in patients with a lifetime diagnosis of estimated to occur in 40–80% of all FEP patients (16). A range of psychosis, with the therapeutic benefits maintained at the 6- issues are potentially traumatic for FEP patients, from the month follow-up and a reduction in adverse events and experience of suffering psychotic symptoms, such as auditory revictimization. Several sub-analyses of the same study have hallucinations involving hearing voices, persecutory delusions or demonstrated the efficacy of EMDR therapy also in patients disorganized behavior, to the experience of being admitted to a with greater dissociative symptoms (27), with psychotic psychiatric unit for the first time. This experience can involve symptoms, depression and social functioning (25), and also a involuntary hospitalizations and/or drug treatment, or other cost-effectiveness study in favor of EMDR therapy when restrictive measures such as mechanical restraints, and is an compared to prolonged exposure (28). important risk factor for traumatization (10), and is associated Therefore, the main objective of the study is to evaluate the with feelings of anger, sadness, distrust or impotence. The risk of efficacy and safety of EMDR therapy in patients with an affective developing PPS following a FEP is increased in patients with or non-affective FEP in the reduction of relapses, as well as the prior childhood trauma (17). The presence of PPS is associated improvement of clinical symptoms, its possible positive impact with an increased severity in psychotic symptoms (18) and on functioning and adherence to pharmacological treatment. Frontiers in Psychiatry | www.frontiersin.org 2 February 2020 | Volume 10 | Article 1023 Valiente-Gómez et al. EMDR Versus TAU in FEP TABLE 1 | SPIRIT Flow diagram: Schedule of enrolment, interventions and METHODS assessments. Design and Study Setting Timepoint** Study Period This multicenter phase II rater-blinded randomized controlled Enrolment Allocation Post- Close-out trial will involve the participation of four different centers in allocation Catalonia: Hospital Parc de Salut Mar, Vic Hospital Consortium, -t1 & t0 0 T1 T2 University Hospital Mutua of Terrassa and Althaia Xarxa Assistencial Universitària of Manresa. The Hospital Parc de Enrolment: Salut Mar is a center of reference for mental health treatment Eligibility screen X and research, among other disciplines, and the collaboration DSM-V criteria for X substances with the rest of the institutions will ensure the recruitment of the TAP X complete sample. BDI-II X X X Participants will be randomized to either treatment as usual YMRS X X X (TAU) or to 20 individual 60-minute EMDR sessions over 5 PANSS X X X EGEP-5 X months, as well as TAU. EMDR therapists participating in this CTQ X trial are highly experienced, have received advanced training in CTS X EMDR protocols, and were recruited through face-to-face IES-R X X X interviews. Assessments will be carried out at three time H-RLSI X points: baseline (T0), post-treatment at 6 months (T1) and at SUD X X X DES X X X 12-month follow-up (T2) (see Table 1). The clinical raters SDQ-20 X X X carrying out evaluations will be blind to the participants’ Informed consent X research condition; however this is not a double-blind study as Allocation X it is not possible to mask from the patient whether they are Interventions: undergoing EMDR therapy or not due to its use of EMDR TAU bilateral stimulation. Assessments: The study has been approved by the Ethic Committees of the GAF X X X IMIM, Parc de Salut Mar (2018/7940/I), Vic Hospital (AC 269), EQ-5D X X X Hospital Mútua of Terrassa, and Althaia Xarxa Assistencial BCIS X X X Universitària of Manresa. All study subjects will sign the DAI X X X informed consent before they can enroll in the study. Further DSM-V, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; TAP, World details of the trial design can be also gathered from Accentuation Test; BDI-II, Beck Depression Inventory; YMRS, Young Mania Rating Scale; PANSS, Positive and Negative Syndrome Scale; EGEP-5, Global Post-Traumatic Stress Supplementary Material (Standard Protocol Items: Assessment; CTQ, Childhood Trauma Questionnaire; CTS, Cumulative Trauma Scale; Recommendations for Interventional Trials [SPIRIT] IES-R, Scale of the impact of events reviewed; H-RLSI, The Holmes-Rahe Life Stress Checklist). The trial has been registered at ClinicalTrials.gov, Inventory; SUD, Subjective Unit of Discomfort; DES, Scale of Dissociative Experiences; SDQ, Somatoform Dissociation Questionnaire; EMDR, Eye movement desensitization and identifier: NCT03991377. reprocessing therapy; TAU, Treatment as usual; GAF, Global Assessment of Functioning Scale; EQ-5D, Standardized Instrument for Evaluating Quality of Life Associated with Study Aim Health developed by the EuroQol group; BCIS, Beck Cognitive Insight Scale; DAI, Drug The main outcome of this project is to analyze whether EMDR Attitude Inventory. therapy, as an adjuvant to TAU, is effective in reducing relapses in patients with an affective or non-affective FEP and a history of 2. Patients in the EMDR group will show fewer psychiatric and comorbid psychological trauma associated with first hospital trauma-related symptoms compared to the control group admission and/or previous stressful life events. A range of after therapy (T1) and at the 12-months follow-up visit (T2). scales, highlighted below, will be used to determine changes in psychiatric symptoms (see Instruments and Measures). 3. Patients in the EMDR group will improve their functional The secondary outcome includes whether EMDR therapy, as capacity in comparison to the control group at evaluations an adjuvant to TAU, is effective in reducing psychiatric after therapy (T1) and at the 12-months follow-up visit (T2). symptoms and post-traumatic stress symptoms, in improving 4. Patients in the EMDR group will show a better adherence to the overall functionality and quality of life associated with health, pharmacological treatment in relation to the control group as well as adherence to pharmacological treatment. A range of after therapy (T1) and at the 12-month follow-up visit (T2). clinical scales will be used the evaluate changes from baseline (see Instruments and Measures). Participants Hypotheses The study sample will consist of 80 outpatients fulfilling criteria for a diagnosis of Schizophrenia or Schizophrenia Spectrum, 1. Patients in the EMDR group will show fewer relapses Major Depressive Disorder with psychotic symptoms, or Bipolar compared to the control group after therapy (T1) and at the I Disorder with psychotic symptoms according to DSM-5 12-month follow-up visit (T2). criteria, who had never experienced psychotic symptoms prior Frontiers in Psychiatry | www.frontiersin.org 3 February 2020 | Volume 10 | Article 1023 Valiente-Gómez et al. EMDR Versus TAU in FEP to the current episode. The diagnosis of all participants will be power of 80% and alpha = 0.005 is n = 36 per intervention group carried out by physicians with extensive experience in the (two groups, total n = 72). According to Chambless and Hollon diagnosis of FEP. (29), a sample of this size should show clinically relevant Inclusion criteria are (1) age between 16 and 65 years at the differences. Assuming a loss percentage of approximately 10– time of first evaluation; (2) have been diagnosed with a first 15% of the patients in the study, it would be necessary to recruit psychotic episode in the last year, with or without approximately 80 patients, 40 for each branch of intervention. pharmacological treatment and/or psychiatric hospitalization; (3) presence of one or more traumatic events causing trauma related symptoms (Impact of Event Scale-Revised, IES-R >0 and Statistical Analysis Subjective Units of Distress, SUD >5); 4) ability to read and write The distribution of socio-demographic, clinical (including in Spanish. psychological trauma), functionality, quality of life and Exclusion criteria are: (1) acute suicidality; (2) presence of treatment adherence characteristics among baseline groups will organic brain diseases; (3) previous trauma-focused therapy in be analyzed using descriptive statistics. Continuous variables the past 2 years. with a normal distribution will be analyzed with the Multivariate Variance Analysis. The change of the clinical Randomization Procedure variables of functionality and quality of life with respect to the After the baseline (T0) assessment (see later), we will randomly baseline assessment at strategic points of the intervention will be allocate participants to the EMDR or TAU group following a analyzed by ANOVA with repeated measurements, including biased coin procedure (29). We want to note that in small clinical time factors, treatment conditions and their interaction. For trials, simple randomization may lead to substantial imbalance in those cases in which the premises of normality are not fulfilled, the relevant confounding factors between groups. The biased the Wilcoxon test will be used. The differences between groups, coin procedure attempts to balance these confounding factors for the categorical and main clinical variables, will be analyzed by but it still randomizes the patients and conceals their allocation means of the Chi-square test. Those variables that are statistically (30). It has been included in the international guidelines for drug significant can be used as covariates for a logistic or linear clinical trials (31) adopted by the European Community, Japan, regression study of the factors associated to the magnitude of United States FDA, Canada and Switzerland (32). the effect and determine which variables are the best predictors of Specifically, a computer in a central location will allocate the functioning. The effect size index (Hedges g or r de Pearson patients as follows: (a) it will randomly allocate the first two index) will be estimated in case of correlation indexes of each of patients to one group or the other with p = 0.5, (b) it will allocate the analyses performed. The statistical software used for the the next patients as follows: (b1) if one group already includes at analyses will be the latest available version of the SPSS (v. 23). least two more patients than the other group, it will randomly For the main statistical analysis, we will conduct an intention- allocate the patient allocated to the smallest group with p = 0.8, to-treat (ITT) analysis. We will impute lost to follow-up with the (b2) otherwise, it will first simulate that the patient is allocated to Last Observation Carried Forward (LOCF) method. EMDR and calculate the sum of the between-group square standardized differences in age, sex and years of education, it will then simulate that the patient is allocated to TAU and STEPWISE PROCEDURES recalculate the sum, and finally it will randomly allocate the patient to the group associated to the smallest sum with p = 0.8. Intervention Following this procedure, the final groups should be balanced in EMDR size and matched in age, sex and years of education. An The patients in the EMDR arm of the study will receive a independent researcher in a central location will control the maximum of 20 individual 60-minute sessions, using the computer program that will carry all steps of the standard EMDR therapy protocol to treat past trauma-related randomization process. symptoms developed by Francine Shapiro (34) and the Recent Traumatic Episode Protocol (R-TEP) protocol developed by Elan Computation of Sample Size Shapiro (35). The study aims to assess the relative efficacy of an EMDR Here is a brief description of the most recent eight-phase intervention protocol for patients with FEP versus TAU mainly standardized protocol: in terms of stabilization and clinical improvement, reduction of anxious, depressive, somatic and/or psychotic symptoms, among 1. Patient history: The therapist collects information regarding others. For this reason, the main variable used is the number of the patient’s biography, including attachment history, clinical relapses after the intervention, with a follow-up of up to medical history, physical health, as well as traumatic events 12 months. Using previous studies as a basis (33), the sample size experienced and their relationship to current symptoms, in has been calculated based on a survival analysis with the order to develop a treatment plan. statistical package “powerSurvEpi” for R, (http://www.r-project. 2. Patient preparation: Following an explanation of EMDR org/) using an alpha = 0.005 instead of 0.05 to allow correction therapy, the therapist checks the patient’s tolerance to for multiple comparisons. The number of patients required to different types of bilateral stimulation, primarily side-to- detect a hazard ratio = 2 in a Cox regression with a statistical side eye movements, but where these are not tolerated, Frontiers in Psychiatry | www.frontiersin.org 4 February 2020 | Volume 10 | Article 1023 Valiente-Gómez et al. EMDR Versus TAU in FEP tapping of the patient’s hands or auditory tones can be used. The Recent Traumatic Episode Protocol (R-TEP) developed Positive resources for emotional regulation are installed. by E. Shapiro and Laub (35) is used in this study for the 3. Patient assessment: A traumatic memory is chosen as a treatment of a recent trauma. This protocol is a new therapeutic target and the therapist assists the patient in comprehensive protocol which extends from the main protocol identifying the image representing the worst part of the of F. Shapiro (34) for recent trauma with additional measures for memory and its associated cognitions, emotions and containment and safety. corporal sensations. The patient then rates their current level of distress using the Subjective Units of Disturbance TAU Scale (SUD), ranging from 0 (neutral or minimum Once patients are discharged from the hospital, they will be disturbance) to 10 (maximum disturbance). treated by the multidisciplinary team of the Intensive Early 4. Memory desensitization: While the patient focuses on the Intervention Programme for Incipient Psychosis (PAE-TPI) as traumatic image and associated negative cognition, emotions part of their usual treatment, which consists of a and physical sensations, 30–40 second sets of bilateral multidisciplinary approach that includes pharmacological stimulation (e.g. through side-to-side eye movements) are treatment and psychological support, as well as visits with applied, during which the patient observes without judgment social workers or nursing staff. An individual care plan is their thoughts, and after each set tells the therapist what they drawn up depending on the patient’s individual needs, which observed. The therapist does not comment, instead applying may include follow-up psychiatric visits to evaluate clinical status further sets until the patient has processed the traumatic and, if necessary, readjust pharmacological treatment, and memory and their subjective distress is at 0 on the SUD scale. psychological visits to assess and detect risk situations and 5. Installing the positive cognition: The patient now focuses on prevent relapses using a non-trauma focused CBT. The TAU the original traumatic memory and a positive cognition psychological treatment will not under any circumstances be which is the opposite of the negative cognition originally focused on PTSD or trauma symptoms. generated by the traumatic memory, and further sets of bilateral stimulation are applied to install the new positive Dropouts and Follow-Up belief. Any patient who is admitted to hospital following a clinical 6. Body scan: While focusing on the original memory and relapse during the 5-month intervention period will be positive belief, the patient is asked to scan their body and considered to be dropout and will be excluded from the trial. notice if there are any physical sensations. If there are any In the case of relapse during follow-up, patients will be removed negative sensations, bilateral stimulation will be continued from the study and relapse-related factors will be collected for until they disappear. If there are positive sensations, short 10– subsequent analysis. 12 second sets of bilateral stimulation will be applied to reinforce them. 7. Closure: At the end of the session, the therapist explains MATERIALS AND EQUIPMENT possible post-session effects, which can include new insights, memories or dreams, and what to do should these occur. Instruments and Measures 8. Reevaluation: In the following session, the therapist checks Trauma-related symptoms will be evaluated using the that the memory has been successfully processed and instruments listed in Table 2: desensitized before selecting either a new traumatic memory, current trigger of distress, or potentially 1. Childhood Trauma Questionnaire (CTQ): The CTQ (36), threatening future event to work on. Spanish validation (37), is a self-administered 28-item scale to measure abuse and neglect suffered in childhood on five TABLE 2 | Measurements to evaluate trauma-related symptoms. subscales: emotional, physical or sexual abuse, and emotional or physical neglect, each subscale scored on a 5-point Likert Clinical Measurement T0 T1 Post- T2 Post- scale. The score for each subscale classifies the severity of the variable interview/self- Baseline treatment 6 treatment 12 report months months abuse and neglect as: “none to minimal,” “low to moderate,” “moderate to severe” and “severe to extreme”. Childhood T. CTQ x 2. Global Assessment of Posttraumatic Stress Questionnaire PTSD EGEP-5 x x x (EGEP-5): The EGEP-5 (38) is a 55-item clinician-applied Traumatic H-RLSI x events scale to determine PTSD diagnosis, based on the current Trauma’s IES-R x x x DSM-V criteria. This scale consists of three sections: events, impact symptoms and functioning. Dissociation DES x x x 3. The Holmes-Rahe Life Stress Inventory (39); Spanish Somatoform D. SDQ-20 x x x validation (40) is used to determine which common Childhood T, Childhood trauma; CTQ, Childhood Trauma Questionnaire; PTSD, post- stressful life events a patient has experienced in the last 12 traumatic stress disorder; EGEP-5, Global Assessment of Posttraumatic Stress Ques- months, with each life event scored according to a tionnaire; H-RLS,: The Holmes-Rahe Life Stress Inventory; IES-R, Impact Event Scale; DES, Scale of Dissociative Experiences; Somatoform D., Somatoform Dissociation; SDQ- standardized measure of their impact (41) and a total score 20, Dissociative Experiences Questionnaire. provided by summing all those applicable to the patient. Frontiers in Psychiatry | www.frontiersin.org 5 February 2020 | Volume 10 | Article 1023 Valiente-Gómez et al. EMDR Versus TAU in FEP Although individual characteristics and coping skills should TABLE 3 | Measurements to evaluate diagnosis, clinical symptoms, and functionality. be taken into account when interpreting scores, scores below 150 reflect low levels of stress, scores between 150 and 299 Clinical Measurement T0 T1 Post-treat- T2 Post-treat- represent a 50% risk of a stress-related illness in the near variable interview/self- baseline ment 6 ment 12 future and scores above 300 represent an 80% risk (39). report months months 4. Impact of Event Scale - Revised (IES-R): The IES-R (42), Diagnosis MINI x Spanish validation (43), is a 22-item self-report measure used suicide to determine the level of subjective distress the subject has Diagnosis S. MINI x experienced over the past week related to a specific stressful life Depression BDI-II x x x Mania YMRS x x x event, with items corresponding directly to 14 of the 17 DSM- Psychotic S. PANSS x x x IV symptoms of PTSD. Each item is scored on a 5-point Likert Functionality GAF x x x scale from 0 to 4, yielding a total score ranging from 0 to 88, with MINI, Mini-International Neuropsychiatric Interview; Diagnosis S, Diagnosis Substance; subscale scores for Intrusion, Avoidance and Hyperarousal. BDI-II, Beck Depression Inventory—II; YMRS, Young Mania Rating Scale; Psychotic S, Higher scores represent greater subjective distress. Psychotic Symptoms; PANSS, Positive and Negative Symptom Scale; GAF, Global 5. Dissociative Experiences Scale (DES): The DES (36), Spanish Assessment of Functioning Scale. validation (44), is a 28-item self-report scale which measures the frequency with which an individual experiences a range of indicates remission; 13–19 indicates minimal symptoms; 20– dissociative experiences, from normal to pathological. An 25 indicates mild mania, 26–37 indicates moderate mania overall mean score ranges from 0 to 100, and there are and 38–60 indicates severe mania. subscales for amnesia, dissociation and depersonalization. 5. Positive and Negative Symptom Scale (PANSS): The PANSS A total score of over 30 indicate high levels of dissociation. (54), Spanish validation (55), is an 30-item clinician- 6. Dissociative Experiences Questionnaire (SDQ-20): The SDQ- administered scale which measures positive, negative and 20 (45), Spanish validation (46), is a 20-item self-report scale general psychopathological symptoms on a scale of 1–7, used to measure somatoform dissociation. Each item refers to based on the severity of the symptom. The semi-structured a physical symptom and is scored from 1 to 5 on a 5-point sci-PANSS interview (56), available in Spanish, will be used to Likert scale, ranging from “1 = this applies to me not at all” to facilitate the PANSS score. “5 = this applies to me extremely”, and the patient is then 6. Global Assessment of Functioning Scale (GAF): The Spanish asked if there is a known physical cause. Total scores can validation version of the GAF, which uses the acronym EEAG range from 20 to 100, with higher scores denoting higher (57), is a brief measure of overall psychological disturbance, levels of somatoform dissociation. providing a global score ranging from 0 to 100. The lower the score, the poorer the functional status. The diagnosis, clinical symptoms and level of functioning are to be assessed using the following instruments (see Table 3): Quality of life associated with health, cognitive insight and adherence to treatment will be assessed using the following 1. Suicide Module of Mini-International Neuropsychiatric instruments (see Table 4): Interview (MINI) (47): This is a short structured diagnostic interview, validated in Spain (48), which assesses the risk 1. Standardized Instrument for Evaluating Quality of Life of suicide. Associated with Health developed by the EuroQol group 2. A diagnosis of substance use disorder will be made according (EQ-5D): EQ-5D is a standardized instrument developed by to DSM-5 criteria; the alcohol abuse and dependence and the EuroQol Group (58), available in a validated Spanish substance abuse and dependence modules of the MINI will version (59), which provides a measure of health-related also be used to determine diagnosis (48). quality of life that can be used in a wide range of health 3. Beck Depression Inventory (BDI-II): The BDI-II (49, 50), conditions and treatments. It is comprised of five Spanish validation (51), is a 21-item clinician-administered dimensions: mobility, self-care, usual activities, pain/ scale designed for use with patients with a prior depression discomfort and anxiety/depression. The total score ranges diagnosis, to quantitatively assess changes in the severity of from 0 to 100, with lower scores indicating a poorer health- depressive symptoms. Scores are summed and the total score related quality of life. indicates: 0–13 minimal depression; 14–19 mild depression; 2. Beck Cognitive Insight Scale (BCIS): The BCIS (60), Spanish 20–28 moderate depression and 29–63 severe depression. validated version (61), is a 15-item self-report scale designed 4. Young Mania Rating Scale (YMRS): The YMRS (52), Spanish to measure the level of awareness of having a mental disorder validation (53), is an 11-item clinician-applied scale which and the need for treatment. The scale comprises two sub- quantifies the severity of manic and hypomanic symptoms. scales: self-reflectiveness (nine items) and self-certainty (six Four items are given more weight to compensate for a lack of items), and a composite score of cognitive insight is given by cooperation in acute patients and are graded on a 0 to 8 scale subtracting self-certainty items from those pertaining to self- (irritability, speech, thought content and disruptive/ reflectiveness. aggressive behavior), while the remaining seven items are 3. Drug Attitude Inventory (DAI-10): The DAI-10 (62), scored from 0 to 4. The scores are interpreted as follows: ≤12 Spanish validated version (63), is a 10-item scale for Frontiers in Psychiatry | www.frontiersin.org 6 February 2020 | Volume 10 | Article 1023 Valiente-Gómez et al. EMDR Versus TAU in FEP TABLE 4 | Quality of life, cognitive insight, and adherence to treatment. exposure therapy in patients with PTSD and chronic Clinical Measurement T0 T1 Post-treat- T2 Post-treat- schizophrenia (66, 67) and other severe mental disorders variable interview/self- baseline ment 6 months ment 12 (23, 26). Up to now, to the best of our knowledge, no study report months has investigated a trauma-focused intervention in FEP patients. The objective of this first trial of this character is Quality EQ-5D x x x life to provide further evidence of a positive effect of EMDR in this Insight BCIS x x x population in a large RCT, in terms of relapse reduction and Drug DAI-10 x x x improvement in clinical variables. The strength of our study is attitude the inclusion of a 1-year follow-up to test if possible EQ-5D, Standardized Instrument for Evaluating Quality of Life Associated with Health improvements are maintained. With the results from a large developed by the EuroQol group; BCIS, Beck Cognitive Insight Scale; DAI-10, Drug RCT, we aim to promote trauma-oriented therapies in Attitude Inventory. patients with a FEP that could be included in specific care units designed to treat this population. Although it has been measuring attitude towards medication, with a total score shown that there is a clear association between PTSD and obtained by summing the 10 items. In items 1, 3, 4, 7, and 10, psychotic disorders, most mental health care programs do not if the answer is correct the score will be 2 and if it is false will offer trauma-oriented therapies for patients with a FEP so far. be 1. In the rest of the items the correct ones score 1 and the false ones 2. The total score can oscillate between 10 and 20. There is no cut-off point but the higher the score, the more LIMITATIONS positive the perceived effect of the medication. One limitation of this study is the inclusion of both affective and non-affective FEP, as well as comorbid substance use disorders, leading to a more heterogeneous sample. These DISCUSSION inclusion criteria were decided on to ensure the study was carried out on a representative real-world population. We There is a relevant and growing interest in establishing a suggest this limitation can be addressed by matching the consensual and protocolled treatment approach in patients samples in both arms. Additionally, the main underlying who have presented a FEP. For this reason, the tendency of clinical variable common to all patients is the presence of public mental health network is to form high-risk psychosis comorbid psychological trauma. Another potential source of and FEP care units (64), employing a multidisciplinary bias is the lack of control regarding pharmacological treatment. treatment approach including psychiatric, psychological, To partly overcome this limitation, a ‘pharmacological nursing and social interventions. While the main objective treatment’ variable will be included and, to the extent it is from a medical perspective is focused on alleviating the possible, patients in the study should not have their drug patients’ psychiatric symptoms, psychosocial approaches therapy altered once they are stabilized. As our unit has mainly aim to support patients and improve their insight extensive experience in treating FEP patients and uses and adherence through psychoeducation and disease standardized treatment protocols, this will also help limit this awareness. The results for specific early interventions in as a potential source of bias. early phase psychosis are more effective than treatment as usual (65), but usually do not include assessment and treatment of the presence of comorbid prior or current psychological trauma. As stated before, patients with ETHICS STATEMENT psychosis have a high prevalence of psychological trauma The study has been approved by the Ethics Committee of the during their lifetime which has an important negative IMIM, Parc de Salut Mar (2018/7940/I), by the Vic Hospital (AC impact on the course and prognosis of the disease (3). 269), Hospital Mutua of Terrassa, and Althaia Xarxa Assistencial Beyond the high prevalence of psychological trauma, the Universitària of Manresa (CEI 19/62). diagnosis of a FEP and psychiatric admission represents per se a further risk factor of developing another vital traumatic event (15), in this case PPS. Taking this into account, it is important to explore new psychological approaches focusing FEP-EMDR RESEARCH GROUP on psychological trauma to reduce its impact in these patients. More recent psychotherapies, such as EMDR, have achieved The group is comprised of: Rebeca Alayón, Montserrat Coll, increasing popularity and interest from clinicians due to their Jairo Santiago García Eslava, Ezequiel Pérez Sánchez, Carla ability to integrate cognitive, emotional and behavioral Llimona, Cristina Macias, Anna Mané, Lorena Marín, Clara components within the same approach. Preliminary Monserrat, Miriam Morales, Ana María Rodríguez, Roberto evidence suggests that EMDR is as effective and safe as Sánchez, Amira Trabsa, Daniel Bergé. Frontiers in Psychiatry | www.frontiersin.org 7 February 2020 | Volume 10 | Article 1023 Valiente-Gómez et al. EMDR Versus TAU in FEP AUTHOR CONTRIBUTIONS acknowledge the generous support by the Centro de Investigación Biomédica en Red de Salud Mental NP and BA had the idea for the project. NP, BA, AM-A and AV-G (CIBERSAM), Madrid, Spain. have contributed to the design of the study. AV-G wrote the first draft of the manuscript, with supervision from NP, AM-A and BA (primary supervisor). JR will carry out the randomization of patients and the statistical analyses. JR, NP, BA, AM-A, WL, ACKNOWLEDGMENT EM-G, IG-S, BH, MA, GS and VP contributed to the revisions and modifications of the manuscript and all have approved the We want to thank to “Secretaria d’Universitats i Recerca del final version. Departament d′Economia i Coneixement (2017 SGR 46 to “Unitat de Recerca del Centre Fòrum”), Generalitat de Catalunya (Government of Catalonia)” for the recognition as an emerging research group. Also, we thanks to EMDR FUNDING therapists: Andreea Apostol, Jessica Arjona, Walter Lupo, Olga de Miguel, Raquel Pérez, Gemma Ros and Jordi Ylla. This work was supported by a grant from the Plan Nacional de I +D+i and co‐funded by the Instituto de Salud Carlos III Subdirección General de Evaluación y Fomento de la Investigación with a Research Project to BA (PI18/00009). SUPPLEMENTARY MATERIAL Also, we want to thank to Instituto de Salud Carlos III for the support to this project by the contract Juan Rodés of AVG (JR19/ The Supplementary Material for this article can be found online 00001). The sources of funding had no influence on the design at: https://www.frontiersin.org/articles/10.3389/fpsyt.2019. and the conducting and reporting of the trial. We further 01023/full#supplementary-material REFERENCES 11. Achim AM, Maziade M, Raymond É., Olivier D, Mérette C, Roy MA. How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a 1. 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Correll CU, Galling B, Pawar A, Krivko A, Bonetto C, Ruggeri M, et al. any commercial or financial relationships that could be construed as a potential Comparison of early intervention services vs treatment as usual for early- conflict of interest. phase psychosis: a systematic review, meta-analysis, and meta-regression. JAMA Psychiatry (2018) 75:555–65. doi: 10.1001/jamapsychiatry. 2018.0623 Copyright © 2020 Valiente-Gómez, Pujol, Moreno-Alcázar, Radua, Monteagudo- 66. Van Den Berg DPG, Bont PAJM, De Vleugel BM, Van Der Roos C, De Jongh A, Gimeno, Gardoki-Souto, Hogg, Álvarez, Safont, Lupo, Pérez, Amann and the FEP- De Minnen A, et al. Trauma-focused treatment in PTSD patients with EMDR Research Group. This is an open-access article distributed under the terms of psychosis: symptom exacerbation, adverse events, and revictimization. (2016) the Creative Commons Attribution License (CC BY). The use, distribution or 42:693–702. doi: 10.1093/schbul/sbv172 reproduction in other forums is permitted, provided the original author(s) and the 67. Van Den Berg DPG, Van Der Gaag M. Treating trauma in psychosis with copyright owner(s) are credited and that the original publication in this journal is EMDR: a pilot study. J Behav Ther Exp Psychiatry (2012) 43:664–71. doi: cited, in accordance with accepted academic practice. No use, distribution or repro- 10.1016/j.jbtep.2011.09.011 duction is permitted which does not comply with these terms. Frontiers in Psychiatry | www.frontiersin.org 10 February 2020 | Volume 10 | Article 1023