Generalized neurocognitive impairment in individuals at ultra-high risk for psychosis: The possible key role of slowed processing speed.

OBJECTIVE: Widespread neurocognitive impairment is well-established in individuals at ultra-high risk (UHR) for developing psychoses, but it is unknown whether slowed processing speed may underlie impairment in other neurocognitive domains, as found in schizophrenia. The study delineated domain functioning in a UHR sample and examined if neurocognitive slowing might account for deficits across domains. METHODS: The cross-sectional study included 50 UHR individuals with no (n = 38) or minimal antipsychotic exposure (n = 12; mean lifetime dose of haloperidol equivalent = 17.56 mg; SD = 13.04) and 50 matched healthy controls. Primary analyses compared group performance across neurocognitive domains before and after covarying for processing speed. To examine the specificity of processing speed effects, post hoc analyses examined the impact of the other neurocognitive domains and intelligence as covariates. RESULTS: UHR individuals exhibited significant impairment across all neurocognitive domains (all ps ≤ .010), with medium to large effect sizes (Cohen's ds = -0.53 to -1.12). Only processing speed used as covariate eliminated significant between-group differences in all other domains, reducing unadjusted Cohen's d values with 68% on average, whereas the other domains used as covariates averagely reduced unadjusted Cohen's d values with 20% to 48%. When covarying each of the other domains after their shared variance with speed of processing was removed, all significant between-group domain differences remained (all ps ≤ .024). CONCLUSION: Slowed processing speed may underlie generalized neurocognitive impairment in UHR individuals and represent a potential intervention target.

Interview and questionnaire assessment of cognitive impairment in subjects at ultra-high risk for psychosis: Associations with cognitive test performance, psychosocial functioning, and positive symptoms.

Impaired cognitive test performance is well-documented in subjects at ultra-high risk (UHR) for psychosis. However, assessment of cognitive deficits as manifested in real life is a neglected area of UHR research that may add to the understanding of cognitive impairment and its relationship with psychosocial functioning and positive symptomatology. This study applied the interview-based Schizophrenia Cognition Rating Scale (SCoRS) and the questionnaire-based Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) in a cross-sectional sample of 39 UHR subjects and 50 healthy controls. Cognitive test performance, psychosocial functioning, and positive symptoms were also assessed. The UHR subjects demonstrated significant cognitive impairment, with large effect sizes for the SCoRS and BRIEF-A composite outcome variables (rs = -0.67 to -0.80) and a neurocognitive composite score (d = -0.97). Within the UHR group, several significant associations between worse cognitive ratings and worse cognitive test performance (rs = -0.210 to -0.343), poorer psychosocial functioning (rs = -0.058 to -0.728), and worse positive symptoms (rs= 0.415 to 0.478) were found. Worse cognitive test performance showed significant associations with more pronounced positive symptoms (rs = -0.299 to -0.457). Interview and questionnaire assessment may hold promise for supplementing traditional performance-based cognitive assessment in identifying treatment targets in the UHR population.

Associations between facial affect recognition and neurocognition in subjects at ultra-high risk for psychosis: A case-control study.

The nature of facial affect recognition (FAR) deficits in subjects at ultra-high risk (UHR) for psychosis remains unclear. In schizophrenia, associations between FAR impairment and poor neurocognition have been demonstrated meta-analytically, but this potential link is understudied in the UHR population. Our study investigated a cross-sectional sample of UHR subjects (n = 22) and healthy controls (n = 50), with the Degraded Facial Affect Recognition (DFAR) Task and a neurocognitive test battery. Our primary aims were 1. to examine associations between FAR and neurocognition in UHR subjects and 2. to examine if associations differed between cases and controls. The secondary aim was to examine group differences in FAR and neurocognitive performance. In UHR subjects, FAR was significantly associated with working memory, a neurocognitive composite score and intelligence, and at trend level with most other assessed neurocognitive domains, with moderate to large effect sizes. There were no significant associations in controls. Associations between FAR and working memory and the neurocognitive composite score differed significantly between cases and controls. UHR subjects did not differ from controls on DFAR Task performance but showed significant deficits in three of six neurocognitive domains. Results may suggest that FAR is associated with working memory in UHR subjects, possibly reflecting a neurocognitive compensatory mechanism.

Cognitive functioning following discontinuation of antipsychotic medication. A naturalistic sub-group analysis from the OPUS II trial.

BACKGROUND: The effect of antipsychotics medication on cognitive functioning in patients diagnosed with schizophrenia is poorly understood. Some studies of second generation antipsychotics indicated that they improved cognitive functioning while other studies have found that they decrease the level of cognitive functioning. METHOD: We included patients with schizophrenia who were in treatment with antipsychotics 1.5 years (baseline) after initiation of treatment and followed them up 3.5 years later (n = 189). At follow-up 60 (32%) had discontinued their antipsychotic treatment and 129 (68%) were still taking antipsychotics. Using the Brief Assessment of Cognition in Schizophrenia (BACS) we assessed cognition at baseline and follow-up. RESULTS: The patients who discontinued their medication had a higher level of cognitive functioning in all domains at baseline, as well as Global cognitive function [mean z-score -1.50 (s.d. 1.24) v. -2.27 (s.d. 1.30), p = 0.00015]. After controlling for relevant confounders those who discontinued antipsychotic medication improved significantly more than those who remained on antipsychotic medication during the course of the follow-up on the Token Motor task [estimated mean change difference -0.46 (95% CI -0.89 to -0.04)], the Speed of Processing Domain [estimated mean change difference -0.38 (95% CI -0.68 to -0.08)] and global cognition [estimated mean change difference -0.36 (95% CI -0.66 to -0.07)]. CONCLUSION: Due to the naturalistic design, we cannot conclude on the direction of the relationship between antipsychotics and cognition. There is no evidence that discontinuation of medication had a negative effect on cognitive functioning. Rather, we found that that discontinuation of medication was associated with better cognitive functioning.

Multiple measures of HPA axis function in ultra high risk and first-episode schizophrenia patients.

INTRODUCTION: Abnormalities within hypothalamus-pituitary-adrenal (HPA) axis might interact with other neurobiological systems to enhance the risk of psychosis. Most of the neurodevelopmental and HPA axis changes occur in adolescence; this is also the period when prodromal and psychotic symptoms occur for the first time. More knowledge about how various stress components interact can advance understanding of the link between psychosis and the HPA axis. METHOD: We examined 41 ultra high-risk (UHR) patients and 40 antipsychotic-naïve first-episode schizophrenia (FES) patients and compared them with 47 matched controls. The Perceived Stress Scale and the Recent Life Events Questionnaire were used to assess the stress levels. Day-time saliva samples were taken to measure cortisol. The pituitary gland volume was measured manually on the structural MRI using stereology. RESULTS: Only the UHR patients, had a higher cortisol increase just after awakening (p = 0.009) compared to healthy controls. In UHR patients, we found a negative correlation between cortisol increase after awakening and symptom severity (p = 0.008). Pituitary gland volume and diurnal cortisol were not significantly different among the three groups. There was no correlation between pituitary gland volume, perceived stress/recent life events and any of the cortisol measures or symptoms. CONCLUSION: Symptom severity during the very early phase of illness (UHR) seems to be associated with altered cortisol increase. Longitudinal studies in UHR patients would be useful to examine how stress levels affect the course of the illness.

Premorbid adjustment in individuals at ultra-high risk for developing psychosis: a case-control study.

AIM: Deterioration in premorbid adjustment is related to ultra-high risk (UHR) individuals developing psychosis, but it has not been examined how UHR individuals' development differs compared to healthy controls. This study investigates differences in premorbid adjustment between UHR individuals and a healthy control group. METHOD: A total of 48 UHR individuals and 50 healthy controls matched on group level for age, gender and parents' socio-economic status were included in the study. Both groups were assessed with the Premorbid Adjustment Scale (PAS). Based on the PAS scores, composite social and academic scales were computed. RESULTS: Compared to the healthy controls the UHR individuals' social and academic premorbid adjustment declined across age periods. Social premorbid adjustment declined particularly between late adolescence and adulthood. Academic premorbid adjustment declined particularly between childhood and early adolescence. The UHR individuals had more premorbid adjustment difficulties on both the social and academic scale, and on the individual PAS scales. CONCLUSION: From childhood UHR individuals have lower levels of social and academic premorbid adjustment compared to healthy controls, and the difficulties increase with age. As such, social and academic premorbid adjustment could be an important focus for early intervention.

Psychopathology and social functioning of 42 subjects from a Danish ultra high-risk cohort.

AIM: To make a thorough characterization of the co-morbidity, psychopathology and demographics in the first Danish ultra high-risk (UHR) sample. METHOD: Forty-two UHR subjects went through comprehensive interviews assessing their psychopathology, psychiatric disorders, substance use and family history of psychiatric disorders. RESULTS: All UHR subjects met the criteria of at least 1 axis I diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and met on average four diagnoses (both axis I and II), mostly within the areas of depression, anxiety and substance abuse. A total of 48% had schizotypal personality disorder and 19% had borderline personality disorder. Level of functioning was low with a mean score on the Social and Occupational Functioning Assessment Scale corresponding to "major impairment in several areas," and mean scores in the Global Functioning: Social and Role scales between "moderate impairment in social functioning" and "very serious impairment independently." Forty-seven percent were unemployed and 29% on sick leave. Fifty-five percent relied financially on public support. CONCLUSION: As seen in previous UHR populations, Danish UHR subjects had low function socio-economically and met criteria of several psychiatric diagnoses, suggesting that they require pharmacological and non-pharmacological psychiatric treatment as well as vocational and educational guidance and support.

Systemic oxidative DNA and RNA damage are not increased during early phases of psychosis: A case control study.

It has been suggested that patients with schizophrenia develop higher levels of oxidative stress, which may contribute to deteriorating mental illness. In order to examine oxidative stress in the early stages of severe mental illness, we examined the levels of systemic Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) oxidation, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine, perceived stress and recent life events in patients at ultra high-risk (UHR) of developing psychosis, in antipsychotic naïve patients with first-episode schizophrenia (FES), and in healthy controls. We included 41 UHR patients, 35 FES patients, and 29 healthy controls. There was no difference in the level of DNA/RNA oxidative damage between UHR patients and FES patients compared with healthy controls. We found no association between levels of DNA/RNA oxidative damage and perceived stress/life events. Based on the results, we suggest that DNA and RNA oxidative markers are not increased during the early stages of illness, but further longitudinal studies in first-episode psychosis should be carried out to examine whether DNA and RNA oxidative damage are potential markers of severe illness.

EFFECTIVENESS OF DIALECTICAL BEHAVIOR THERAPY VERSUS COLLABORATIVE ASSESSMENT AND MANAGEMENT OF SUICIDALITY TREATMENT FOR REDUCTION OF SELF-HARM IN ADULTS WITH BORDERLINE PERSONALITY TRAITS AND DISORDER-A RANDOMIZED OBSERVER-BLINDED CLINICAL TRIAL.

BACKGROUND: Many psychological treatments have shown effect on reducing self-harm in adults with borderline personality disorder. There is a need of brief psychotherapeutical treatment alternative for suicide prevention in specialized outpatient clinics. METHODS/DESIGN: The DiaS trial was designed as a pragmatic single-center, two-armed, parallel-group observer-blinded, randomized clinical superiority trial. The participants had at least two criteria from the borderline personality disorder diagnosis and a recent suicide attempt (within a month). The participants were offered 16 weeks of dialectical behavior therapy (DBT) versus up to 16 weeks of collaborative assessment and management of suicidality (CAMS) treatment. The primary composite outcome was the number of participants with a new self-harm (nonsuicidal self-injury [NSSI] or suicide attempt) at week 28 from baseline. Other exploratory outcomes were: severity of borderline symptoms, depressive symptoms, hopelessness, suicide ideation, and self-esteem. RESULTS: At 28 weeks, the number of participants with new self-harm in the DBT group was 21 of 57 (36.8%) versus 12 of 51 (23.5%) in the CAMS treatment (OR: 1.90; 95% CI: 0.80-4.40; P = .14). When assessing the effect of DBT versus CAMS treatment on the individual components of the primary outcome, we observed no significant differences in the number of NSSI (OR: 1.60; 95% CI: 0.70-3.90; P = .31) or number of attempted suicides (OR: 2.24; 95% CI: 0.80-7.50; P = .12). CONCLUSION: In adults with borderline personality traits and disorder and a recent suicide attempt, DBT does not seem superior compared with CAMS for reduction of number of self-harm or suicide attempts. However, further randomized clinical trials may be needed.

The FOCUS trial: cognitive remediation plus standard treatment versus standard treatment for patients at ultra-high risk for psychosis: study protocol for a randomised controlled trial.

BACKGROUND: Cognitive deficits are a distinct feature among people at ultra-high risk (UHR) for psychosis and pose a barrier to functional recovery. Insufficient evidence exists on how to ameliorate these cognitive deficits in patients at UHR for psychosis and hence improve daily living and quality of life. The aim of the trial is to investigate whether cognitive remediation can improve cognitive and psychosocial function in patients at UHR for psychosis. METHODS: The FOCUS trial (Function and Overall Cognition in Ultra-high risk States) is a randomised, parallel group, observer-blinded clinical trial enrolling 126 patients meeting the standardised criteria of being at UHR for psychosis. Patients are recruited from psychiatric in- and outpatient facilities in the Copenhagen catchment area. Patients are randomised to one of the two treatment arms: cognitive remediation plus standard treatment versus standard treatment. The cognitive remediation consists of 24 weekly group-based and manualised sessions targeting neurocognition and social cognition. In addition to the group sessions, the patients will be offered 12 individual sessions aiming at maximising the transfer of the effects of the cognitive training to their everyday lives. Follow-up assessments will be conducted at 6 and 12 months after randomisation. The primary outcome is the composite score on the Brief Assessment of Cognition in Schizophrenia at cessation of treatment after 6 months. Secondary outcomes are social and daily functioning, psychosis-like symptoms, negative symptomatology, and depressive symptomatology as measured with the Personal and Social Performance Scale, Brief Psychiatric Rating Scale-Expanded Version, Scale for the Assessment of Negative Symptoms, and the Montgomery-Åsberg Depression Rating Scale. DISCUSSION: This is the first trial to evaluate the effects of neurocognitive and social cognitive remediation in UHR patients. The FOCUS trial results will provide evidence on the effect of targeted and comprehensive cognitive rehabilitation on cognition, daily living, and symptomatology as well as long-term outcome in preventing transition to psychosis in UHR patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT 02098408 . Date of registration 18 March 2014.

Predictors of recovery in first episode psychosis: the OPUS cohort at 10 year follow-up.

BACKGROUND: Recovery, the optimal goal in treatment, is the attainment of both symptomatic and functional remission over a sustained period of time. Identification of factors that promote recovery can help develop interventions that facilitate good outcomes for people with first episode psychosis. AIM: To examine long-term outcomes within a cohort of people with first episode psychosis in relation to symptom remission, functioning and recovery, 10 years after diagnosis. METHOD: The study had a prospective design. Participants from the OPUS trial (1998-2000) (n=496) completed a series of interviews and questionnaires to measure current levels of psychopathology and social/vocational functioning, ten years after diagnosis. Predictors of recovery were identified using socio-demographic and clinical characteristics collected at baseline. RESULTS: A total of 304 participants were interviewed, giving a follow-up rate of 61%. A total of 42 people (14%) met the criteria for symptomatic and psychosocial recovery at 10 years. A multivariable binary logistic regression analysis indicated that baseline predictors accounted for 22% of the variance of full recovery. Lower severity of negative symptoms at baseline (Odds Ratio (OR) 0.53, 95% confidence interval CI 0.36-0.78, p<0.001) and earlier age of diagnosis (OR 0.92, 95% CI 0.86-0.99, p<0.05) predicted better rates of recovery at 10 years. CONCLUSION: Results of this study indicated that negative symptoms could play a central role in the process of recovery from schizophrenia. A challenge for clinicians and researchers is to understand the mechanisms behind negative symptoms and develop interventions that can prevent or ameliorate these symptoms in order to promote recovery.