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.