Global and Specific Profiles of Executive Functioning in Prodromal and Early Psychosis.
ABSTRACT: Objective: Numerous reports on neurocognitive functioning deficits in individuals at clinical high risk (CHR) and first-episode psychosis (FEP) patients suggest particular deficits in executive functioning (EF). However, to date, most of the studies have administered a single or a few EF tests to participants, and few investigations have examined the different components of EF to identify specific subdomains of relative strength and weakness. Method: Forty CHR subjects, 85 FEP patients, and 85 healthy controls (HCs) were assessed with a neuropsychological battery to elucidate the profiles of EF in the subdomains of shift, attention, fluency, and planning. Results: In the subdomains of shift, attention, and fluency, CHR individuals and FEP patients showed deficits compared to HC. The post hoc analysis revealed that CHR individuals had comparable attention shifting and phonemic fluency compared to FEP. CHR showed intermediate deficits between FEP and HCs in spatial working memory and semantic fluency, and the largest effect size was observed in semantic fluency both for CHR and FEP. Conclusion: Overall, the findings of this study, in addition to providing detailed profiles of EF in prodromal and early psychosis patients, highlight the informative value of the specific subdomains of semantic fluency and spatial working memory.
Project description:Neurocognition is a central characteristic of schizophrenia and other psychotic disorders. Identifying the pattern and severity of neurocognitive functioning during the "near-psychotic," clinical high-risk (CHR) state of psychosis is necessary to develop accurate risk factors for psychosis and more effective and potentially preventive treatments.To identify core neurocognitive dysfunctions associated with the CHR phase, measure the ability of neurocognitive tests to predict transition to psychosis, and determine if neurocognitive deficits are robust or explained by potential confounders.In this case-control study across 8 sites, baseline neurocognitive data were collected from January 2009 to April 2013 in the second phase of the North American Prodrome Longitudinal Study (NAPLS 2). The dates of analysis were August 2015 to August 2016. The setting was a consortium of 8 university-based, outpatient programs studying the psychosis prodrome in North America. Participants were 264 healthy controls (HCs) and 689 CHR individuals, aged 12 to 35 years.Neurocognitive associations with transition to psychosis and effects of medication on neurocognition. Nineteen neuropsychological tests and 4 factors derived from factor analysis were used: executive and visuospatial abilities, verbal abilities, attention and working memory abilities, and declarative memory abilities.This study included 264 HCs (137 male and 127 female) and 689 CHR participants (398 male and 291 female). In the HCs, 145 (54.9%) were white and 119 (45.1%) were not, whereas 397 CHR participants (57.6%) were white and 291 (42.3%) were not. In the HCs, 45 (17%) were of Hispanic origin, whereas 127 CHR participants (18.4%) were of Hispanic origin. The CHR individuals were significantly impaired compared with HCs on attention and working memory abilities and declarative memory abilities. The CHR converters had large deficits in attention and working memory abilities and declarative memory abilities (Cohen d, approximately 0.80) compared with controls and performed significantly worse on these dimensions than nonconverters (Cohen d, 0.28 and 0.48, respectively). These results were not accounted for by general cognitive ability or medications. In Cox proportional hazards regression, time to conversion in those who transitioned to psychosis was significantly predicted by high verbal (premorbid) abilities (??=?0.40; hazard ratio [HR], 1.48; 95% CI, 1.08-2.04; P?=?.02), impaired declarative memory abilities (??=?-0.87; HR, 0.42; 95% CI, 0.31-0.56; P?<?.001), age (??=?-0.10; HR, 0.90; 95% CI, 0.84-0.97; P?=?.003), site, and a combined score of unusual thought content or delusional ideas and suspiciousness or persecutory ideas items (??=?0.44; HR, 1.56; 95% CI, 1.36-1.78; P?<?.001).Neurocognitive impairment, especially in attention and working memory abilities and declarative memory abilities, is a robust characteristic of CHR participants, especially those who later develop psychosis. Interventions targeting the enhancement of neurocognitive functioning are warranted in this population.
Project description:The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences. We investigated 12 genes in 394 individuals (27 individuals with CHR, 70 antipsychotic-naive individuals with FEP, 157 CSZ patients, and 140 healthy controls (HCs)). For a subsample, genotype data were also available, and we extracted SNPs that were previously associated with the expression of selected genes in whole blood or brain tissue. We generated a mediation model in which a putative cause (SNP) is related to a presumed effect (disorder) via an intermediate variable (gene expression). MBP and NDEL1 were upregulated in FEP compared to all other groups; DGCR8 was downregulated in FEP compared to HC and CHR; DGCR2 was downregulated in CSZ compared to FEP and HCs; DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression; and UFD1 was upregulated in CSZ and CHR compared to FEP and HC. Our results indicated changes in gene expression profiles throughout the different clinical stages of SZ, reinforcing the need for staging approaches to better capture SZ heterogeneity.
Project description:<h4>Background</h4>Emotion dysregulation is crucial to both poor social functioning and psychotic symptom formation in patients with schizophrenia. The efficient use of emotion regulation strategies, such as cognitive reappraisal, has been less frequently observed in the early phases of psychotic disorder. It is unknown whether neurophysiological responses related to emotion regulation by cognitive reappraisal are altered in early psychosis.<h4>Methods</h4>Fifty-four patients with first-episode psychosis (FEP), 34 subjects at clinical high risk (CHR) for psychosis, and 30 healthy controls (HCs) participated in event-related potential recordings during a validated emotion regulation paradigm to measure the effect of cognitive reappraisal on emotion regulation. Late positive potentials (LPPs), which reflect emotional arousal, were compared across the groups and the 3 conditions (negative, cognitive reappraisal, and neutral). The relationship among LPP modulation by cognitive reappraisal and social/role functioning and severity of psychotic symptoms was investigated in the early psychosis group.<h4>Results</h4>The FEP and CHR participants showed comparably larger LPP amplitudes in the negative and cognitive reappraisal conditions than in the neutral condition, whereas the HCs presented larger LPPs in the negative condition than in the cognitive reappraisal and neutral conditions. LPP modulation by cognitive reappraisal was negatively correlated with positive symptom severity in the FEP patients and with disorganization severity in the CHR subjects.<h4>Conclusions</h4>Inefficient use of cognitive reappraisal may be related to the impaired emotion regulation and psychotic symptoms from the very beginning of psychotic disorder. This study provides the first neurophysiological evidence regarding current concepts of emotion regulation in early psychosis.
Project description:<h4>Background</h4>Functional recovery of patients with clinical and subclinical psychosis is associated with clinical, neuropsychological and developmental factors. Less is known about how these factors predict functional outcomes in the same models. We investigated functional outcomes and their predictors in patients with first-episode psychosis (FEP) or a confirmed or nonconfirmed clinical high risk of psychosis (CHR-P vs. CHR-N).<h4>Methods</h4>Altogether, 130 patients with FEP, 60 patients with CHR-P and 47 patients with CHR-N were recruited and extensively examined at baseline (T0) and 9 (T1) and 18 (T2) months later. Global Assessment of Functioning (GAF) at T0, T1 and T2 and psychotic, depression, and anxiety symptoms at T1 and T2 were assessed. Functional outcomes were predicted using multivariate repeated ANOVA.<h4>Results</h4>During follow-up, the GAF score improved significantly in patients with FEP and CHR-P but not in patients with CHR-N. A single marital status, low basic education level, poor work situation, disorganization symptoms, perceptual deficits, and poor premorbid adjustment in patients with FEP, disorganization symptoms and poor premorbid adjustment in patients with CHR-P, and a low basic education level, poor work situation and general symptoms in patients with CHR-N predicted poor functional outcomes. Psychotic symptoms at T1 in patients with FEP and psychotic and depression symptoms at T1 and anxiety symptoms at T2 in patients with CHR-P were associated with poor functioning.<h4>Conclusions</h4>In patients with FEP and CHR-P, poor premorbid adjustment and disorganization symptomatology are common predictors of the functional outcome, while a low education level and poor work situation predict worse functional outcomes in patients with FEP and CHR-N. Interventions aimed at improving the ability to work and study are most important in improving the functioning of patients with clinical or subclinical psychosis.
Project description:Contextual information is used to support and organize episodic memory. Prior research has reliably shown memory deficits in psychosis; however, little research has characterized how this population uses contextual information during memory recall. We employed an approach founded in a computational framework of free recall to quantify how individuals with first episode of psychosis (FEP, N?=?97) and controls (CON, N?=?55) use temporal and semantic context to organize memory recall. Free recall was characterized using the Hopkins Verbal Learning Test-Revised (HVLT-R). We compared FEP and CON on three measures of free recall: proportion recalled, temporal clustering, and semantic clustering. Measures of temporal/semantic clustering quantified how individuals use contextual information to organize memory recall. We also assessed to what extent these measures relate to antipsychotic use and differentiated between different types of psychosis. We also explored the relationship between these measures and intelligence. In comparison to CON, FEP had reduced recall and less temporal clustering during free recall (p?<?0.05, Bonferroni-corrected), and showed a trend towards greater semantic clustering (p?=?0.10, Bonferroni-corrected). Within FEP, antipsychotic use and diagnoses did not differentiate between free recall accuracy or contextual organization of memory. IQ was related to free recall accuracy, but not the use of contextual information during recall in either group (p?<?0.05, Bonferroni-corrected). These results show that in addition to deficits in memory recall, FEP differed in how they organize memories compared to CON.
Project description:Although the clinical high risk for psychosis (CHR) paradigm has become well-established over the past two decades, one key component has received surprisingly little investigative attention: the predictive validity of the criteria for conversion or transition to frank psychosis. The current study evaluates the predictive validity of the transition to psychosis as measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR individuals. Participants included 33 SIPS converters and 399 CHR non-converters both from the North American Prodromal Longitudinal Study (NAPLS-2), as well as a sample of 67 separately ascertained first-episode psychosis (FEP) patients from the STEP program. Comparisons were made at baseline and one-year follow-up on demographic, diagnostic stability (SCID), and available measurement domains relating to severity of illness (psychotropic medication, psychosocial treatment, and resource utilization). Principal findings are: 1) a large majority of cases in both SIPS converters (n = 27/33, 81.8%) and FEP (n = 57/67, 85.1%) samples met criteria for continued psychosis at one-year follow-up; 2) follow-up prescription rates for current antipsychotic medication were higher in SIPS converters (n = 17/32, 53.1%) compared to SIPS non-converters (n = 81/397, 20.4%), and similar as compared to FEP cases (n = 39/65, 60%); and 3) at follow-up, SIPS converters had higher rates of resource utilization (psychiatric hospitalizations, day hospital admissions, and ER visits) than SIPS non-converters and were similar to FEP in most categories. The results suggest that the SIPS definition of psychosis onset carries substantial predictive validity. Limitations and future directions are discussed.
Project description:It has been found that antipsychotic-naïve patients with first-episode psychosis (FEP) present with impaired hormonal regulation of appetite in terms of low leptin and high insulin levels (the adipoinsular axis). These findings imply that certain intrinsic mechanisms might play a role in the development of metabolic dysregulation in early psychosis. However, clinical correlates of this phenomenon remain unknown. Moreover, these alterations have not been tested in individuals at familial high risk of psychosis (FHR-P). In this study we aimed to assess the levels of adiponectin, insulin, leptin, glucose, total cholesterol, lipoproteins and triglycerides in FEP patients, unaffected offspring of schizophrenia patients (FHR-P individuals) and healthy controls (HCs) with respect to cognitive performance and psychopathological manifestation. Participants were 35 FEP patients, 33 FHR-P individuals, and 32 HCs. Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). The levels of leptin and high-density lipoproteins (HDL) were significantly lower (leptin: 10.7 ± 15.7 vs. 12.6 ± 10.1, p = 0.046, and HDL: 48.0 ± 16.9 vs. 59.8 ± 17.5 mg/dl, p = 0.007), while the levels of triglycerides and insulin were significantly higher (triglycerides: 137.4 ± 58.8 vs. 77.5 ± 33.2 mg/dl, p < 0.001, and insulin: 15.2 ± 13.1 vs. 9.6 ± 5.0 µIU/ml, p = 0.023) in FEP patients compared to HCs. These differences were significant after controlling for the effects of potential confounding factors. No significant differences in the levels of serum markers between FHR-P individuals and HCs were found. There was a significant negative correlation between the level of leptin and the RBANS language score after covarying for potential confounding factors in FEP patients (B = –0.226, p = 0.006) but not in other subgroups of participants. Our findings confirm impairment of adipoinsular axis in early psychosis. However, results of our study do not support the hypothesis that familial liability to psychosis might be associated with metabolic dysregulation. Leptin levels might be associated with cognitive deficits in FEP patients. Longitudinal studies of individuals at risk of psychosis are needed to provide insights into causal mechanisms underlying our results.
Project description:An improvement in negative symptoms and a reduction in the number of visits to the emergency department have been reported in a problem solving based psychoeducational group intervention (PE) for adolescents with psychosis relative to a nonstructured group (NS). One of the factors that may play a role on the response to PE treatment is executive function (EF), a crucial cognitive domain for problem-solving performance. We aimed to examine the role of EF in response to PE treatment versus an NS group. We examined the associations between changes in cognition and in clinical/functional variables within each treatment group using Spearman-ranked and partial correlation analyses. A total of 22 individuals (mean age: 16.3) were randomized to PE (N = 10) and NS (N = 12). We found an association between improvements in EF performance and a reduction in positive symptoms (rs = -0.756, p = 0.030 for semantic fluency), reduction in negative symptoms (r = 0.758, p = 0.029 for semantic; rs = -0,733, p = 0.025 for verbal fluency), and reduction in the number of visits to the emergency department (r = -0,743, p = 0.035 for semantic fluency) in the PE group. No associations were found in the NS group. Our results suggest that EF may play a role in the specific improvements observed in the PE group. This may have implications in the development of new areas of clinical intervention focusing on the role of cognitive functioning in response to psychosocial treatments in psychosis.
Project description:Increased striatal dopaminergic activity and decreased prefrontal functioning have been reported in individuals at clinical high risk (CHR) for psychosis. Abnormal metabolic rate might affect resting-state cerebral blood flow (rCBF) in the respective regions. Here, we examined if striatal and prefrontal rCBF differ between patients with CHR, first-episode psychosis (FEP), chronic schizophrenia-spectrum disorder (SZ) and controls. Two cohorts with a total of 122 participants were included and analyzed separately: 32 patients with SZ and 31 healthy controls (HC) from the University Hospital of Psychiatry, and 59 patients from the Bern Early Recognition and Intervention Center (29 with CHR, 12 with FEP, and 18 clinical controls [CC]). Ultra-high risk criteria were assessed with the Structured Interview for Psychosis-Risk Syndromes, basic symptom criteria with the Schizophrenia Proneness Instrument. rCBF was measured with pseudo-continuous arterial spin labeling 3T-Magnetic Resonance Imaging. Striatal rCBF was significantly increased and prefrontal rCBF significantly decreased in the SZ group compared to HC group and in the CHR and FEP groups compared to CC group. Striatal rCBF correlated significantly with positive symptom scores in SZ and CHR. An inverse correlation between striatal and frontal rCBF was found in controls (HC, CC), but not in patient groups (SZ, FEP, CHR). This is the first study to demonstrate increased neuronal activity within the striatum, but reduced prefrontal activity in patients with CHR, FEP, and SZ compared to the respective controls. Our results indicate that alterations in striatal and prefrontal rCBF are reflecting metabolic abnormalities preceding the onset of frank psychosis.
Project description:Disrupted thalamo-cortical connectivity is regarded as a core psychopathology in patients diagnosed with schizophrenia. However, whether the thalamo-cortical white matter connectivity is disrupted before the onset of psychosis is still unknown. To determine this gap in knowledge, the strength of thalamo-cortical white matter anatomical connectivity in subjects at clinical-high risk for psychosis (CHR) was compared to that of first-episode psychosis (FEP) and healthy controls. A total of 37 CHR, 21 FEP, and 37 matched healthy controls underwent diffusion-weighted magnetic resonance imaging to examine the number of probabilistic tractography "counts" representing thalamo-cortical white matter connectivity. We also investigated the relationship with psychopathology. For FEP, the connectivity between the thalamus and parietal cortex was significantly increased (F= 5.65,P< .05) compared to that of healthy controls. However, the connectivity between thalamus and orbitofrontal cortex was significantly reduced compared to both healthy controls (F= 11.86,P< .005) and CHR (F= 6.63,P< .05). Interestingly, CHR exhibited a similar pattern as FEP, albeit with slightly reduced magnitude. Compared to healthy controls, there was a significant decrease (F= 4.16,P< .05) in CHR thalamo-orbitofrontal connectivity. Also, the strength of the thalamo-orbitofrontal connectivity was correlated with the Global Assessment of Functioning score in CHR (r= .35,P< .05). This observed pattern of white matter connectivity disruptions in FEP and in CHR suggests that this pattern of disconnectivity not only highlights the involvement of thalamus but also might be useful as an early biomarker for psychosis.