A randomized-controlled trial of treatment for self-stigma among persons diagnosed with schizophrenia-spectrum disorders.

PURPOSE: A substantial body of research indicates that self-stigma is associated with poorer outcomes related to recovery among people with severe mental illnesses. Narrative Enhancement and Cognitive Therapy (NECT) is a structured, group-based approach which targets the effects of self-stigma. A randomized-controlled trial was conducted to examine the efficacy of NECT. METHODS: One hundred and seventy persons, recruited from both outpatient and comprehensive treatment settings, meeting criteria for schizophrenia-spectrum disorders and moderate-to-elevated self-stigma, were randomly assigned to NECT or supportive group therapy and assessed at four time points over the course of nearly a year. Participants completed measures of self-stigma, hope, self-esteem, functioning, psychiatric symptoms, coping with symptoms, and narrative insight. RESULTS: Analyses indicated that NECT participants in outpatient sites improved significantly more over time in self-stigma compared to supportive group therapy participants in outpatient sites, while NECT participants in comprehensive (including day treatment and psychiatric rehabilitation program) sites improved significantly more in hopelessness and narrative insight than other participants. NECT participants as a group showed decreases in the social withdrawal component of self-stigma, decreased in their use of avoidant coping strategies, and were more engaged in treatment than supportive group therapy participants. There was no evidence for effects of NECT on social functioning or psychiatric symptoms. CONCLUSIONS: Findings suggest that NECT primarily impacts self-stigma and related outcomes, and that the degree of its effects is partially dependent on the treatment context in which it is offered.

Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD.

Graft-versus-host disease (GVHD) is a systemic inflammatory response due to the recognition of major histocompatibility complex disparity between donor and recipient after hematopoietic stem cell transplantation (HSCT). T-cell activation is critical to the induction of GVHD, and data from our group and others have shown that regulatory T cells (Tregs) prevent GVHD when given at the time of HSCT. Using multiphoton laser scanning microscopy, we examined the single cell dynamics of donor T cells and dendritic cells (DCs) with or without Tregs postallogeneic transplantation. We found that donor conventional T cells (Tcons) spent very little time screening host DCs. Tcons formed stable contacts with DCs very early after transplantation and only increased velocity in the lymph node at 20 hours after transplant. We also observed that Tregs reduced the interaction time between Tcons and DCs, which was dependent on the generation of interleukin 10 by Tregs. Imaging using inducible Tregs showed similar disruption of Tcon-DC contact. Additionally, we found that donor Tregs induce host DC death and down-regulate surface proteins required for donor T-cell activation. These data indicate that Tregs use multiple mechanisms that affect host DC numbers and function to mitigate acute GVHD.

Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease.

Acute graft-versus-host disease (aGvHD) is a major limitation to the use of allogeneic stem cell transplantation for the treatment of patients with relapsed malignant disease. Previous work using animals lacking secondary lymphoid tissue (SLT) suggested that activation of donor T cells in SLT is critically important for the pathogenesis of aGvHD. However, these studies did not determine if impaired migration into, and more importantly, out of SLT, would ameliorate aGvHD. Here, we show that T cells from mice lacking Coronin 1A (Coro 1A(-/-)), an actin-associated protein shown to be important for thymocyte egress, do not mediate acute GvHD. The attenuation of aGvHD was associated with decreased expression of the critical trafficking proteins C-C chemokines receptor type 7 (CCR7) and sphingosine 1 phosphate receptor on donor T cells. This was mediated in part by impaired activation of the canonical NF-κB pathway in the absence of Coro 1A. As a result of these alterations, donor T cells from Coro 1A(-/-) mice were not able to initially traffic to SLT or exit SLT after BM transplantation. However, this alteration did not abrogate the graft-versus-leukemia response. Our data suggest that blocking T-cell migration into and out of SLT is a valid approach to prevent aGvHD.

CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease.

The infusion of donor regulatory T cells (Tregs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early Treg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where Tregs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 Treg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor Treg function in the transplant setting. Donor Tregs lacking CCR8 (CCR8(-/-)), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue Tregs from apoptosis. Instead, CCR8 potentiated Treg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c(+) antigen-presenting cells (APCs) were important for promoting donor Treg maintenance after transplant. In contrast, host CD11c(+) APCs appeared to be dispensable for early activation and expansion of donor Tregs. Collectively, our data indicate that a sustained donor Treg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c(+) APCs.

Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.

Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)γt. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking RORC and as a consequence the isoform RORγt. Recipients given donor CD4(+) and CD8(+) T cells lacking RORC had significantly attenuated acute GVHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC(-/-) CD4(+) T cells alone diminished the severity and lethality of acute GVHD. This was not found when CD4(+) T cells from RORC(-/-) mice were given to completely mismatched BALB/c mice, and it was correlated with absolute differences in the generation of TNF in the colon after transplant. Thus, CD4(+) T cell expression of RORC is important in the pathogenesis of acute GVHD.

Overlap of obsessive compulsive and psychosis risk symptoms in a specialized clinic.

AIM: Psychotic disorders and obsessive-compulsive disorder (OCD) commonly co-occur. Likewise, subthreshold psychosis symptoms (clinical high risk for psychosis; CHR) and obsessive compulsive symptoms (OCS) often overlap and may be difficult to differentiate. This study aimed to replicate research investigating the prevalence of OCD in a CHR clinic sample, validate and investigate factor structure of a self-report OCS measure in a CHR sample, explore how OCS may relate to CHR and co-occurring symptoms, and investigate whether real-world CHR treatment improves OCS and CHR symptoms. METHOD: This study analysed archival clinical data from baseline and 6-month follow-up assessments collected by a specialist outpatient CHR clinic. Data included assessments of CHR symptoms, OCS, and clinician-rated diagnosis. Exploratory factor analysis examined the OCS measure. RESULTS: Within this CHR clinic sample, 13.5% experienced co-morbid OCD. The self-report OCS measure had two factors: (1) checking and counting behaviours and (2) intrusive thoughts and images of harm/guilt. The checking and counting factor correlated with depression and social anxiety. The intrusive thoughts and images of harm/guilt factor significantly correlated with unusual thought content and social anxiety. Between baseline to 6-month follow-up, clients exhibited CHR symptom improvement regardless of OCD diagnosis. However, OCS did not change. CONCLUSIONS: These findings support validity of a self-report OCS measure in a CHR clinic sample and that types of OCS experiences may exhibit different clinical patterns. Additionally, it appears that individuals with comorbid OCD responded similarly to CHR treatment compared to those without OCD.

Cannabis and Psychosis.

Psychosis and cannabis use may overlap in multiple ways in young people. Research suggests that cannabis use increases risk for having psychotic symptoms, both attenuated (subthreshold) and acute. Cannabis use may also exacerbate psychosis symptoms among young people with underlying psychosis risk and psychotic disorders. Although there are suggestions for treating co-occurring psychosis and cannabis use in young people (e.g., incorporating cannabis use assessment and treatment strategies into specialized early psychosis care), there are many gaps in clinical trial research to support evidence-based treatment of these overlapping concerns.

Cannabis and Psychosis.

Psychosis and cannabis use may overlap in multiple ways in young people. Research suggests that cannabis use increases risk for having psychotic symptoms, both attenuated (subthreshold) and acute. Cannabis use may also exacerbate psychosis symptoms among young people with underlying psychosis risk and psychotic disorders. Although there are suggestions for treating co-occurring psychosis and cannabis use in young people (e.g., incorporating cannabis use assessment and treatment strategies into specialized early psychosis care), there are many gaps in clinical trial research to support evidence-based treatment of these overlapping concerns.

Borderline personality features among individuals at clinical high risk for psychosis (CHR-P): A brief report.

AIM: This exploratory study reports on borderline symptomatology within a sample of individuals at clinical high risk for psychosis (CHR-P) through a validated, self-report instrument, the short version of the Borderline Symptom List (BSL-23). METHODS: The sample consisted of 44 help-seeking CHR-P youth (ages 14-29 years) who completed an initial evaluation at a specialized clinic for psychosis-risk. RESULTS: The mean BSL-23 score was 1.5 (SD = 1.0, range 0.1-4.0). Higher scores were strongly associated with greater reported depressive symptoms (r = 0.84, p < 0.001). Additionally, borderline symptoms associated with attenuated positive symptoms (r = 0.32, p = 0.034) and social anxiety (r = 0.34, p = 0.027). Borderline symptomatology was not associated with role or social functioning. CONCLUSIONS: This study is one of the first examinations of borderline symptomatology within a CHR-P sample through a validated self-report measure. Future research replicating these results is required to determine their robustness.

The association between mental health stigma and face emotion recognition in individuals at risk for psychosis.

Self-stigma has been associated with reduced accuracy of face emotion recognition in individuals at clinical high risk for psychosis (CHR). Stigma may also relate to slowing of performance during cognitive tasks for which a negative stereotype is relevant. This study aimed to investigate the association of mental illness stigma with face emotion recognition among CHR individuals. Participants were 143 CHR individuals identified using the Structured Interview for Psychosis-Risk Syndromes (SIPS). Face emotion recognition was assessed using the Penn Emotion Recognition Task (ER-40). Stigma was assessed using discrimination, stereotype awareness, and stereotype agreement subscales of the Mental Health Attitudes Interview for CHR. We tested associations of ER-40 accuracy and response times with these stigma variables, including the role of clinical and demographic factors. Racial/ethnic minoritized participants had higher attenuated positive symptoms than non-minoritized participants. Longer ER-40 response times were correlated with greater stereotype agreement (r=.17, p=.045) and discrimination (r=.22, p=.012). A regression model predicting ER-40 response times revealed an interaction of stereotype agreement with minoritized status (p=.008), with slower response times for minoritized participants as stereotype agreement increased. Greater disorganized symptoms and male gender also predicted longer response times. ER-40 accuracy was not associated with stigma. Overall, minoritized CHR individuals with greater internalized stigma took longer to identify face emotions. Future research is needed to assess whether slower response times are specific to social cues, and if internalized stigma interferes with performance in real-world social situations. Reducing stigma may be an important target for interventions that aim to improve social skills.

Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells.

CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7(-/-)) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7(-/-) T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7(-/-) T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7(-/-) T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7(-/-) T cells were capable of generating robust graft-versus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7(-/-) regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.

Treatment outcomes for young people at clinical high risk for psychosis: Data from a specialized clinic.

AIM: Treatment for youth exhibiting signs of clinical high risk for psychosis (CHR-P) has been emphasized in recent years, but there is need for a greater understanding of the course of symptoms and functioning across treatment. The aim of this study is to describe 10 years of naturalistic treatment outcomes in a real-world, specialized CHR-P outpatient clinic, the Center for Early Detection, Assessment, and Response to Risk (CEDAR) Clinic. METHODS: The CEDAR Clinic routinely collects client outcomes data for the purposes of program development, monitoring treatment effectiveness, and characterizing the clinic population. Clients are assessed at baseline, every 6 months (for up to 2 years depending on duration of treatment), and at the end of treatment. A series of mixed-effects models were performed to analyse change over time in outcomes (symptoms and functioning) between baseline and follow-up time points. RESULTS: Over time, clients' (N = 123) positive (F = 11.8, p < .001) and negative (F = 4.91, p = .002) symptoms declined relative to their baseline. Social functioning improved over time (F = 2.50, p = .049), as did depression (F = 8.60, p < .001) and hopelessness (F = 4.21, p = .004). Clients' total CEDAR treatment hours ranged across type of treatment service, but the amount of treatment clients received was not associated with any clinical outcomes. CONCLUSIONS: Over the course of treatment at this real-world, specialized CHR-P program, clients exhibited significant improvement in clinical outcomes and did not significantly decline in any measured outcomes. We discuss this study in the context of current understanding and guidelines for specialized coordinated specialty care treatment for CHR-P.

Individualized vocational and educational support and training for youth at clinical high risk for psychosis.

AIM: Early intervention for psychosis has been of high interest in the past two decades. Research demonstrates that clinical high risk for psychosis (CHR-p) populations experience impairments in role functioning. Although several vocational and cognitive interventions exist for people living with psychosis, there are no known evidence-based treatments for role functioning difficulties during the CHR-p stage. There is clear evidence for a need for interventions that directly target role functioning. METHODS: This paper describes the theoretical development and implementation of a novel intervention targeting role functioning impairments: Individualized Vocational and Educational Support and Training (InVEST). The CEDAR Clinic, a specialized CHR-p coordinated specialty care (CSC) team, has worked to develop InVEST to target core aspects of role functioning, namely executive functioning, stress sensitivity, and task initiation. The intervention is cost-efficient, as bachelor level clinicians provide the service under supervision of licensed clinicians. This summary describes InVEST, provides a disguised case example, and presents initial exploratory data (N = 135) focused on the intervention's feasibility in this CSC program. RESULTS: Although these preliminary data are limited, available information suggests that InVEST may provide a core treatment modality within CHR-p treatment programs. CONCLUSIONS: More research formally investigating InVEST with a larger sample would provide further evidence of the intervention's efficacy.

Changes in community providers' screening behaviours, referral practices, and clinical confidence following participation in an early psychosis educational campaign.

AIM: Successful delivery of care to individuals with early psychosis depends on the ability of community providers to identify and refer appropriate candidates for services. Although specialty centres commonly rely upon education and outreach campaigns to building bridges with community providers, few studies have examined the effectiveness of these campaigns or the mechanisms by which they may achieve their intended effects. METHODS: We surveyed community clinicians (N = 39) about their screening behaviours, referral practices, and confidence in managing early psychosis just before and 3-6 months after attending an educational event designed to promote recognition and quality treatment of early psychosis. RESULTS: Three to six months following attendance, providers reported screening a greater proportion of clients for early psychosis, referring a greater number of clients to specialty services, and feeling more confident in their ability to respond to clients with early psychosis. Increases in confidence following attendance were associated with corresponding increases in screening behaviour. CONCLUSIONS: The results suggest that outreach campaigns designed to enhance community providers' knowledge about early psychosis assessment and resources may be effective in promoting screening, referrals, and confidence in managing psychosis. Gains in provider confidence may contribute to increases in screening. Given the lack of control group and relatively short follow-up period, more research is needed to determine the effects of early psychosis educational events and the mechanisms by which they may promote successful treatment delivery for young people in need.

In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations.

The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-gamma (IFN-gamma) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-gamma, multiple reports have demonstrated that the lack of IFN-gamma paradoxically exacerbated GVHD lethality. This has led to speculation that another subset of T cells may significantly contribute to GVHD mortality. Several groups have demonstrated a new lineage of CD4+ T helper cell development distinct from TH1 or TH2 differentiation. This lineage is characterized by production of interleukin (IL)-17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells. Here, we demonstrate that a highly purified population of TH17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions. Upon transfer, these cells migrate to and expand in GVHD target organs and secondary lymphoid tissues. Finally, we demonstrate differential roles for tumor necrosis factor-alpha (TNF-alpha) and IL-17A in the clinical manifestations of GVHD induced by TH17 cells. Our studies demonstrate that cells other than TH1/Tc1 can mediate acute GVHD.

Comorbid early psychosis and borderline personality disorder: Conceptualizing clinical overlap, etiology, and treatment.

Despite substantial efforts aimed at the detection and intervention for early symptoms of mental illness, there is relatively limited research on the clinical overlap between borderline personality disorder (BPD) and early psychosis, for example, clinical high risk (CHR) for psychosis, in young people. We present a narrative review of the clinical overlap between BPD and psychosis spectrum symptoms. Both conditions have unstable temporal course, and both are marked by functional impairment, increased suicide risk, and higher rates of psychiatric inpatient services. We then review evidence-based treatments for psychosis and BPD, emphasizing treatments for early presentations of these symptoms and initial research considering treatments for the overlap. Psychotherapies with the strongest empirical support include cognitive behavioral models, with BPD showing limited response to adjunctive pharmacotherapy. We end by discussing specific recommendations for future research, including longitudinal studies to determine the predictors of the course of illness and the development of treatments to target comorbid BPD and CHR symptoms.

Emotional and stigma-related experiences relative to being told one is at risk for psychosis.

OBJECTIVE: Despite the appeal of early intervention in psychosis, there is concern that identifying youth as having high psychosis risk (PR) may trigger stigma. This study employed a pre-post design to measure change in PR participants' emotions about PR upon being told of their PR status and according to whether this was the first time receiving this information. METHODS: Participants (n = 54) identified as at PR via structured interview rated their emotions about PR before and after being told they were at PR. Qualitative analyses explored the valence of participant reflections on being given this information. RESULTS: Participants reported significantly less negative emotion after being told of their PR status (p < .001), regardless of whether they were hearing this for the first time (p = .72). There was no change in positive emotions or the predominant belief that they should keep their PR status private. Most participants commented positively about the process of feedback but negatively about its impact on their self-perceptions and/or expectations of others' perceptions of them. CONCLUSION: This is the first study to collect pre-post data related to being told one is at PR and to examine quantitative and qualitative responses across and within individuals. For a majority of participants, clinical feedback stimulated negative stereotypes even as it relieved some distress. To actively address internalized stigma, clinicians providing feedback to PR youth must attend to the positive and negative impacts on how youth think about themselves as well as how they feel.

Disentangling compliance with command hallucinations: Heterogeneity of voice intents and their clinical correlates.

BACKGROUND: Earlier studies suggested that perceptions of voice intents (benevolence, malevolence) are associated with different psychological and behavioral responses including compliance with command hallucinations (CH). However, to our knowledge, no studies have examined the clinical differences between subgroups of clients with different perceptions of the intents of their CH. In order to better understand the risk for compliance with CH, our objectives were 1) to compare sociodemographic and clinical profiles of subgroups of clients (based on perceptions of CH intents); and 2) to investigate their specific associated risk factors for compliance with CH. METHOD: We analyzed the MacArthur Violence Risk Assessment Study, focusing on 181 participants with psychosis reporting CH. Group comparisons and within-group ordinal logistic regression analyses were performed using sociodemographic and clinical measures such as the BPRS, BIS-11 and NAS-PI. RESULTS: Of the 181 participants, 102 (56.4%) reported having only malevolent voices, 14 (7.7%) rated them as benevolent only, 58 (32.03%) as benevolent and malevolent, and only 7 (3.86%) as neutral only. Results showed that individuals with malevolent voices had more emotional disturbance while those with benevolent CH had more severe positive psychotic symptoms and were more certain that they would comply in the future. Moreover, childhood physical abuse, belief about having to obey as well as psychotic symptoms significantly predict compliance with malevolent CH in a multivariate model. CONCLUSIONS: Our results suggest that researchers and clinicians should consider perceptions of voice intents when both assessing risk of compliance with CH and developing relevant intervention targets.

Development of a Boston Treatment Program for Youth at Clinical High Risk for Psychosis: Center for Early Detection, Assessment, and Response to Risk (CEDAR).

Over the past two decades, increasing attention has been given to the importance of early intervention for psychosis. This article describes the development of the Center for Early Detection, Assessment and Response to Risk (CEDAR), which focuses on early identification and treatment of youth at clinical high risk for psychosis. There are relatively few models in the United States for such programs, and we present our developmental story, focusing mainly on the CEDAR Clinic, as a case study of how such a program can develop. We describe the rationale, infrastructure, and services provided at the CEDAR Clinic, and present some descriptive data from the CEDAR Clinic through 2016. A case example is provided to illustrate treatment at CEDAR. We hope that the cultural history of our program's development is informative for clinicians and policy makers as one model of how to build an early intervention service. We believe that this article is timely in view of the growing momentum in the United States for developing programs for intervening as early as possible for youth at clinical high risk for psychosis.

Participation in peer support services and outcomes related to recovery.

OBJECTIVE: This article presents findings from a naturalistic study that explored the impact of peer support participation on recovery-related outcomes over a 6-month period. In particular, this study hoped to fill gaps in the literature regarding the process through which personal change occurs in peer support organizations. METHOD: Fifty people newly involved in services provided by Baltic Street AEH (Advocacy, Employment, Housing), a consumer-operated organization, participated in the study. Participants were interviewed at entry and 3- and 6-month follow-up. Attendance records were reviewed to determine the number of days attended, and the sample was divided into 2 categories: minimal or nonattenders (n = 25) and moderate or high attenders (n = 21). The relationship between attendance and outcomes related to recovery over time was examined using a mixed effect regression analysis, allowing data to be included for participants with at least 1 follow-up interview (n = 38). RESULTS: Relative to minimal or nonattenders, moderate or high attenders showed statistically significant improvements over time in internalized stigma, self-esteem-self-efficacy, and community activism-autonomy. No statistically significant differences were observed between groups in hopelessness, social functioning, symptom severity, coping with symptoms, or substance use. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This study demonstrates the potential impact of engagement in peer support services on some subjective aspects of mental health recovery. Namely, change mechanisms could be hypothesized to include identity transformation (from patient to peer). Future directions should continue to investigate potential mechanisms of change with larger samples in randomized studies. (PsycINFO Database Record