Article

Neurocognitive Deficits in Adolescents With Schizophrenia: Longitudinal Stability and Predictive Utility for Short-Term Functional Outcome

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  • MediSys Health Network
  • Portland Mindfulness Therapy
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Abstract

Previous cross-sectional studies in adolescents with early-onset schizophrenia (EOS; onset of psychotic symptoms by 18 years of age) have reported patterns of generalized neurocognitive deficits as compared to healthy comparison subjects (HCSs). Here, the authors examined the longitudinal stability of neuropsychological deficits in adolescents with EOS relative to HCS and the associations of these deficits with short-term functional outcome in patients. Fifty-two subjects (26 EOS, 26 HCS) were evaluated using a comprehensive neuropsychological test battery a median of 13 months after baseline examination. The stability of scores and the relationship between baseline test performance and functional outcome in patients was explored. Adolescents with EOS were impaired across neurocognitive domains at baseline and follow-up compared to HCSs; these deficits remained relatively stable over time. Follow-up social/communication, personal living, and community living skills were significantly related to attention/vigilance, working memory and verbal memory at baseline; individual cognitive domains were more strongly related to functional outcome than a global measure of intelligence. Neuropsychological impairment in patients with EOS appears to remain relatively stable over time regardless of changes in clinical state. In addition, this report offers preliminary support for a longitudinal relationship between neurocognitive performance in specific domains and functional outcome.

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... The impairments of real-life functioning in adolescents with EOS include domains of social interaction / communication skills, personal living skills, and community living skills (Cervellione et al., 2007) and the overall level of real-world functioning (Cohen´s d = −1.8) (Puig et al., 2012). ...
... Further, overall adaptive functioning and its subdomains showed small to moderate, cross-sectional associations with intelligence, motor speed, working memory, attention, problem solving, inhibition, and social cognition in children and adolescents with EOS (Hooper et al., 2010). In line with this, attention / vigilance, working memory, and verbal memory, but not intelligence, were found to be associated with personal living skills and community living skills in adolescents with EOS both cross-sectionally and longitudinally (Cervellione et al., 2007). Additionally, the functional impairments, for example in social functioning (Cohen´s d = −1.9), of adults earlier diagnosed with EOS were longitudinally associated with two or more neurocognitive functions, for example auditory working memory, verbal memory, and flexibility in their adolescence (Øie et al., 2011). ...
... The level of adaptive functioning observed in our EOS group is relatively similar to earlier findings in EOS (Cervellione et al., 2007) and its large effect size is in line with an earlier result in EOS (Cohen´s d = 1.80) (Puig et al., 2012). ...
Article
Background: Few studies have explored associations between adaptive functioning and cognition in adolescents with early-onset schizophrenia spectrum disorders (EOS). Methods: Adaptive functioning, cognition, positive, negative, and general symptoms were characterized in adolescents with EOS and healthy controls. A modified scale of negative, respectively, general symptoms was used. Bivariate analyses identified correlates of adaptive functioning to be included in multivariate analysis. Results: Adolescents with EOS showed significant impairments of social- and neurocognitive functions (-0.86 < Cohen´s ds < -0.58) and adaptive functioning (Cohen´s d = -2.23). Visual memory, verbal working memory, processing speed, reaction time, social cognition, and modified negative and general symptoms correlated significantly with adaptive functioning. The multiple regression analysis revealed only verbal working memory as uniquely associated with adaptive functioning (explaining 22.7 % of its variance). Verbal working memory also associated significantly with adaptive functioning in the context of the nonsignificant modified negative and the significant modified general symptoms dimension. Conclusions: Adolescents with first-episode EOS had large impairments in adaptive functioning and moderate to large cognitive deficits. Verbal working memory was an important associate to concurrent adaptive functioning and may be a treatment target for trials to improve cognitive and adaptive functioning in adolescents with EOS.
... Early-onset schizophrenia (EOS), defined as an illness-onset under the age of 18, yields severe neurocognitive deficits across a wide range of domains [1,2]. Neurocognitive and social cognitive deficits of schizophrenia are closely related to severe impairments in personal living, social, and communication skills [1,3]. ...
... Early-onset schizophrenia (EOS), defined as an illness-onset under the age of 18, yields severe neurocognitive deficits across a wide range of domains [1,2]. Neurocognitive and social cognitive deficits of schizophrenia are closely related to severe impairments in personal living, social, and communication skills [1,3]. ...
... Moreover, the severity of psychotic symptoms is somewhat linked to neurocognitive deficits in youth subjects [8,10,20,21]. Some follow-up studies also suggested neurocognitive improvements in the early-onset illness [21,22], while others suggested a relatively stable course (i.e., milder improvements) of EOS over time [1,23,24]. However, few studies focused on neurocognitive and social-cognitive differences between symptomatic EOS (EOS-S) and EOS in remission (EOS-R), using the stringent remission criteria proposed by the previous literature [25]. ...
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Previous studies demonstrated neurocognitive impairments in early-onset schizophrenia (EOS) and other psychotic spectrum disorders (PSD). This study aimed to compare remitted and symptomatic cases in terms of neurocognition and theory of mind (ToM). 50 healthy controls (HC) and 106 patients diagnosed schizophrenia in remission (EOS-R, n=38), symptomatic schizophrenia (EOS-S, n=34), and other PSD (n=34) were included in our study. The Positive and Negative Symptom Scale, Columbia-Suicide Severity Rating Scale, Reactive and Proactive Aggression Questionnaire were used to evaluate psychopathology. A cognitive battery was conducted to measure verbal learning/memory, visual learning/memory, executive functions (EF), inhibition, processing speed (PS), verbal fuency skills. Reading Mind in Eyes Test (RMET) and Faux-Pas tests were implemented to assess ToM. Principal Component Analysis was used to identify cognitive domain scores. Patient groups had poorer performance in cognitive domains than the HC group. The cognitive impairment and psychopathology levels of EOS-R and the PSD groups were comparable for all cognitive domains. The EOS-S group also had poorer scores in Rey verbal learning score (d=0.87), RMET (d=0.72), verbal fuency (d=0.66), PS/EF (d=0.82) and visual learning/ memory (d=0.83) test scores than the PSD group. Only RMET (d=0.72) and executive function/processing speed domain (d=0.63) were signifcantly impaired in the EOS-S group than the EOS-R group Cognitive impairments seen in remitted psychotic disorders were on the same continuum. Impaired EF/PS and ToM skills could be a cognitive marker for symptomatic illness in youth.
... Few studies have investigated putative associations between neurocognition and functional outcome in EOP. Two studies, including patients with EOS, found that neurocognitive deficits in speed of processing, verbal learning, attention, working memory and executive functioning were associated with impaired functional outcome at follow-up [19,29]. As neurocognition is not part of the diagnostic criteria of psychotic disorders, symptom reduction on clinical rating scales (e.g. the Positive and Negative Syndrome Scale (PANSS) [30]) is often used as the only indicator of treatment success in clinical trials of schizophrenia. ...
... The present study examined whether neurocognitive performance, assessed with the MCCB, was associated with global functioning in EOP, and whether symptom domains from the Wallwork/Fortgang five-factor model mediated this relationship. Based on previous research in adolescent schizophrenia [19,29], we hypothesized that speed of processing, verbal learning, attention, working memory and global cognition would be associated with global functioning in EOP. Furthermore, based on a previous systematic review [35] and research in adult schizophrenia [39,40], we hypothesized that the Negative and Disorganized/concrete symptom factors would mediate this relationship, while no significant mediation effects would be found for positive symptoms. ...
... The main finding was that verbal learning was positively associated with global functioning, explaining 20% of the variance in the level of functioning, and that this association was significantly mediated by negative and disorganized symptoms. Our finding showing a significant association between verbal learning and global functioning is in accordance with two previous studies of patients with EOS [19,29]. Our results are also in accordance with two previous studies including adult schizophrenia patients, showing that negative symptoms mediated the relationship between neurocognitive performance and global functioning, while positive symptoms did not [39,40]. ...
Article
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Neurocognitive deficits are associated with impaired global functioning and psychotic symptoms. However, whether symptoms can mediate the relationship between neurocognition and global functioning in adolescent psychosis is unclear. Here, we investigated if symptoms assessed with the Positive And Negative Syndrome Scale (PANSS), mediated the relationship between neurocognitive performance and global functioning in adolescents with non-affective early-onset psychotic disorders (EOP). Sixty-one adolescent EOP patients (age 12–18 years) from 2 Norwegian clinical cohorts were included. Linear regression models were applied to investigate associations between neurocognitive domains from the MATRICS Consensus Cognitive Battery (MCCB) and global functioning. PANSS symptoms were analyzed using the Wallwork/Fortgang five-factor model. Using the INDIRECT macro for SPSS, mediation effects were tested using bootstrapping with 95% bias corrected confidence intervals. Verbal learning was positively associated with global functioning (P < 0.001) and negatively associated with the disorganized symptom factor (P = 0.002), controlling for age, sex and cohort. Testing of indirect effects, controlling for age, sex and cohort, showed that the Negative (point estimate = 1.56, 95% CI 0.22, 3.47) and Disorganized (point estimate = 1.24, 95% CI 0.05, 3.69) symptom factors significantly mediated the relationship between verbal learning and global functioning. We found that verbal learning, negative and disorganized symptoms influenced global functioning in adolescents with EOP, while reality-distorted positive symptoms did not. These results suggest that assessing these domains in EOP is helpful for planning treatment and rehabilitation programs focusing on functional outcome.
... Impairments in working memory (WM) are considered a core cognitive deficit in schizophrenia (1, 2) with significant consequences on the patients' functional outcomes (3,4). Even though extensively investigated, the nature of WM deficits in patients with schizophrenia (PSZ) is not yet fully understood. ...
... (3,138) = 5.45, p < 0.01, η 2 = 0.11, see also response accuracy].Sensitivity (d ′ ) and Response Criterion (c)2 × 4 repeated-measures ANOVA were conducted to test for differences in sensitivity and the response criterion as a function of delay length (1, 2, 4, 6 s) and group (PSZ vs. HC) (see Supplementary Material 1.1 for a description of the fulfillment of the ANOVA's assumptions).Because the daily CPE dose correlated with d ′ (r = 0.42, p < 0.05, see section Correlations with medication status), individual CPE dose was included as a covariate in the ANOVA. The sensitivity of the discrimination between target and non-target position in the DRT (as determined using Signal Detection Theory sensitivity index d ′ ) was significantly lower in PSZ compared to HC [F(1,44) = 26.36, ...
... p < 0.01, η 2 = 0.20; quadratic trend, F (1, 44) = 1.74, p = 0.19; cubic trend, F (1, 44) = 0.25, p = 0.62]. As indicated by a significant interaction between the factors delay length and group [F (3, 132) = 2.83, p < 0.05, η 2 = 0.06], this delay-dependent decrease was only slightly stronger in PSZ [F(3,63) =3.61, p < 0.05, η 2 = 0.15], than HC [F(3, 69) =3.15, p < 0.05, η 2 = 0.12] (seeFigure 4).The response criterion c also increased with longer delay lengths [F (2.61, 120.15) = 13.40, p < 0.001, η 2 = 0.23] and was also explained best by a linear trend [F(1,46) = 32.74, ...
Article
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Even though extensively investigated, the nature of working memory (WM) deficits in patients with schizophrenia (PSZ) is not yet fully understood. In particular, the contribution of different WM sub-processes to the severe WM deficit observed in PSZ is a matter of debate. So far, most research has focused on impaired WM maintenance. By analyzing different types of errors in a spatial delayed response task (DRT), we have recently demonstrated that incorrect yet confident responses (which we labeled as false memory errors) rather than incorrect/not-confident responses reflect failures of WM encoding, which was also impaired in PSZ. In the present study, we provide further evidence for a functional dissociation between confident and not-confident errors by manipulating the demands on WM maintenance, i.e., the length over which information has to be maintained in WM. Furthermore, we investigate whether these functionally distinguishable WM processes are impaired in PSZ. Twenty-four PSZ and 24 demographically matched healthy controls (HC) performed a spatial DRT in which the length of the delay period was varied between 1, 2, 4, and 6 s. In each trial, participants also rated their level of response confidence. Across both groups, longer delays led to increased rates of incorrect/not-confident responses, while incorrect/confident responses were not affected by delay length. This functional dissociation provides additional support for our proposal that false memory errors (i.e., confident errors) reflect problems at the level of WM encoding, while not-confident errors reflect failures of WM maintenance. Schizophrenic patients showed increased numbers of both confident and not-confident errors, suggesting that both sub-processes of WM—encoding and maintenance—are impaired in schizophrenia. Combined with the delay length-dependent functional dissociation, we propose that these impairments in schizophrenic patients are functionally distinguishable.
... [33] Erken başlangıçlı şizofreni hastalarında sözel bellek, yürütücü işlevler, işlem hızı ve çalışma belleği sosyal işlevselliğin belirleyicileridir. [34,35] Ayrıca dikkat, çalışma belleği, sözel belleğin erken başlangıçlı şizofreni hastalarında kişisel yaşam becerilerini yordayan kognitif bileşenler olduğu gösterilmiştir. [34] Kronik ve stabil şizofreni hastalarında ise sosyal işlevsellik yürütücü işlevlerle ilişkili bulunmuştur. ...
... [34,35] Ayrıca dikkat, çalışma belleği, sözel belleğin erken başlangıçlı şizofreni hastalarında kişisel yaşam becerilerini yordayan kognitif bileşenler olduğu gösterilmiştir. [34] Kronik ve stabil şizofreni hastalarında ise sosyal işlevsellik yürütücü işlevlerle ilişkili bulunmuştur. [36] Çalışma belleği, sosyal ilişkilerdeki memnuniyetle de ilişkili bulunmuştur. ...
... [41] Sözel bellek, yatan hastalarda fonksiyonel bağımsızlık, toplumda yaşama yetileri ile ilişkiliyken; adölesan başlangıçlı şizofreni hastalarında, hastalığın başlangıcındaki dikkat, sözel bellek ve çalışma belleği sonraki dönemdeki sosyal iletişim, kişisel ve toplumsal yaşam ile anlamlı biçimde ilişkili bulunmuştur. [34] Bir başka çalışmada ise yürütücü işlevlerin uzun vadede sosyal işlevselliği en çok etkileyen test olduğu gösterilmiştir. [42] Literatürde şizofrenide genel işlevselliği ve prognozu doğrudan etkileyen bilişsel semptomları tanımanın, takip etmenin ve tedavi hedeflerinin içine almanın önemli olduğu vurgulanmaktadır. ...
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Şizofreni, dünya çapında 24 milyondan fazla erişkini etkilemektedir. Şizofreni bireysel, sosyal ve ekonomik yük ile ilişkilendirilmektedir. Bu yükün çoğu şizofreni hastalarının işlevselliklerindeki bozulmayla ilişkilidir. Şizofreni hastaları okul başarısı, iş bulma ve çalışmayı sürdürme, sosyal ilişki kurma, bağımsız yaşama ve günlük ihtiyaçlarını karşılama konusunda zorluk çekmektedirler. Bilişsel defisitler, şizofreninin ana semptomlarındandır ve işlevsellikte bozulmayla güçlü bir şekilde ilişkilidir. Bu derlemede güncel bilgiler doğrultusunda şizofreni hastalarında gözlenen nörobilişsel bozulma ve bunun işlevsellikle ilişkisinin gözden geçirilmesi amaçlanmıştır.
... In a review of cross-sectional studies of neuropsychological functioning in individuals with EOS, Frangou (2010) found impairments of medium to large effect sizes in IQ, attention, memory and executive functions compared with TD controls. One-year and two-year longitudinal studies of neuropsychological impairments in EOS found no change in the magnitude of deficits in patients with EOS (Cervellione, Burdick, Cottone, Rhinewine, & Kumra, 2007;Juuhl-Langseth, Holmen, Thormodsen, Oie, & Rund, 2014;Teigset et al., 2018). In two studies featuring four-year and 13-year follow-up intervals, there was a decline in verbal memory, attention and processing speed in individuals with EOS (Frangou, Hadjulis, & Vourdas, 2008;Oie et al., 2011;Wozniak, Block, White, Jensen, & Schulz, 2008). ...
... Still, small sample size may represent a weakness in this study. A small sample, however, is a common problem in longitudinal studies of EOS, due to the rarity of the illness and the challenges of long-term follow-up of this population (Cervellione et al., 2007). Other strengths of this study are the use of a neuropsychological test battery and the longitudinal design. ...
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Introduction: Cognitive impairments are common in both Autism Spectrum Disorders (ASD) and schizophrenia, but it is unclear whether the pattern of difficulties is similar or different in the two disorders. This cross-sectional and longitudinal study compared the neuropsychological functioning in adolescents with ASD with adolescents with Early Onset Schizophrenia (EOS). Methods: At baseline and at two-year follow-up, participants were assessed with a brief neuropsychological test battery measuring executive functions, visual and verbal learning, delayed recall and recognition and psychomotor speed. Results: We found similar levels of neuropsychological impairment across groups and over time in the adolescents with ASD or EOS. Adolescents in both groups did not improve significantly on verbal learning, verbal delayed recall, visual learning, visual delayed recall or visual delayed recognition, and both groups performed poorer on verbal recognition. Both groups improved on measures of psychomotor processing and executive functions. Conclusion: The findings suggest that it may be difficult to differentiate adolescents with EOS and ASD based on neuropsychological task performance. An implication of the results is that adolescents with either disorder may benefit from a similar approach to the treatment of cognitive impairment in the disorders.
... They predate the onset of psychotic symptoms and may underlie deficits in other cognitive domains (3,4). Most important, they are strongly predictive of impairments in social and vocational outcomes such as employment status, educational achievement, and independent living (5,6). Specifically, in adults with schizophrenia, working memory test performance predicts work or education functioning (6). ...
... Specifically, in adults with schizophrenia, working memory test performance predicts work or education functioning (6). In adolescents with schizophrenia, baseline working memory performance is significantly related to social, communication, personal, and community living skills at a follow-up visit one year later (5). No current treatment is able to ameliorate the distress caused by this core cognitive deficit (7). ...
Article
Objective: Working memory impairments represent a core cognitive deficit in schizophrenia, predictive of patients' daily functioning, and one that is unaffected by current treatments. To address this, working memory is included in the MATRICS Consensus Cognitive Battery (MCCB), a standardized cognitive battery designed to facilitate drug development targeting cognitive symptoms. However, the neurobiology underlying these deficits in MCCB working memory is currently unknown, mirroring the poor understanding in general of working memory deficits in schizophrenia. Methods: Twenty-eight participants with schizophrenia were administered working memory tests from the MCCB and examined with resting-state functional MRI. Intrinsic connectivity networks were estimated with independent component analysis. Each voxel's time series was correlated with each network time series, creating a feature vector for voxel-level connectivity analysis. This feature vector was associated with working memory by using the distance covariance statistic. Results: The neurobiology of MCCB working memory tests largely followed the multicomponent model of working memory but revealed unexpected differences. The dorsolateral prefrontal cortex was not associated with working memory. The central executive system was instead associated with delocalized right and left executive control networks. The phonologic loop within the multicomponent model, a subsystem involved in storing linguistic information, was associated with connectivity to the left temporoparietal junction and inferior frontal gyrus. However, connections to the language network did not predict working memory test performance. Conclusions: These results provide supporting evidence for the multicomponent model of working memory in terms of the biology underlying MCCB findings.
... Despite consistent evidence showing executive function deficits in schizophrenics, there is still ongoing debate about the course of altered cognitive functioning in these patients. Several previous studies suggested a relative stability of cognitive functioning in patients with schizophrenia (Cervellione et al., 2007;Frangou et al., 2008;Oie et al., 2010). For example, executive function impairments seen in adolescent schizophrenics remained unchanged over a 2-year follow-up period (Cervellione et al., 2007), planning accuracy in early onset schizophrenia patients maintained at the same level of performance over a 4-year follow-up period (Frangou et al., 2008), and the performance of early onset schizophrenia patients on abstraction and perseveration (measured using the WCST) did not change over a 13-year follow-up period (Oie et al, 2010). ...
... Several previous studies suggested a relative stability of cognitive functioning in patients with schizophrenia (Cervellione et al., 2007;Frangou et al., 2008;Oie et al., 2010). For example, executive function impairments seen in adolescent schizophrenics remained unchanged over a 2-year follow-up period (Cervellione et al., 2007), planning accuracy in early onset schizophrenia patients maintained at the same level of performance over a 4-year follow-up period (Frangou et al., 2008), and the performance of early onset schizophrenia patients on abstraction and perseveration (measured using the WCST) did not change over a 13-year follow-up period (Oie et al, 2010). On the other hand, other studies suggested a process of cognitive deterioration mainly within the first 5-10 years after the onset of schizophrenia (Albus et al., 1996;Braw et al., 2008;Lieberman et al., 2001;Saykin et al., 1994). ...
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Working memory is a cognitive process dedicated to the transitory maintenance and online manipulation of information. Patients with schizophrenia, a heterogeneous brain disease, show several types of working memory deficits, including in visuospatial working memory, phonological working memory, and executive functioning. These deficits may underlie other schizophrenia symptoms and predict patient outcomes. Furthermore, there is increasing evidence suggesting that working memory deficits may provide a behavioral marker of genetic liability for schizophrenia. While the dominant role of the prefrontal dysfunction in working memory deficits of patients with schizophrenia has been appreciated, there is increasing evidence suggesting the existence of disturbed functional connectivity within brain networks subserving domain-specific components of working memory in schizophrenia. This functional deficit may result from dysfunctional neurotransmitter systems, of which the dopaminergic system has been best characterized, and/or white matter abnormalities which have been shown to be a consistent pathological finding in brains of schizophrenia patients. Working memory deficits in schizophrenia can be somewhat relieved by antipsychotics and various cognitive rehabilitation approaches. Atypical, but not typical, antipsychotics have shown some promise for relieving working memory deficits in patients with schizophrenia. Cognitive rehabilitation, an alternative to pharmacological treatment of cognitive deficits in patients with schizophrenia, also shows promise, but further work needs to be done to optimize this approach. Developing effective treatments for working memory impairments in schizophrenia patients remains an important therapeutic goal.
... It has been shown through a dense body of evidence that, in schizophrenia, there is an impairment of working memory (WM) 1 , as a result of altered neural mechanisms which underlie its function 2 . The extent of this impairment is associated with both the level of adaptive functioning of patients and the age of onset of the symptoms [3][4][5] . Furthermore, individuals sharing genetic components of vulnerability to schizophrenia, yet not affected by it, also show WM impairment 6 . ...
... Many studies show that WM is related to functionality in schizophrenia 4,39 ; however, although significant, the LUT and WUT show only a low correlation with the functional outcome measures. ...
... It has been shown through a dense body of evidence that, in schizophrenia, there is an impairment of working memory (WM) 1 , as a result of altered neural mechanisms which underlie its function 2 . The extent of this impairment is associated with both the level of adaptive functioning of patients and the age of onset of the symptoms [3][4][5] . Furthermore, individuals sharing genetic components of vulnerability to schizophrenia, yet not affected by it, also show WM impairment 6 . ...
... Many studies show that WM is related to functionality in schizophrenia 4,39 ; however, although significant, the LUT and WUT show only a low correlation with the functional outcome measures. ...
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Objective This study describes the development of two updating measures of working memory (WM): Letter Updating Test (LUT) and Word Updating Test (WUT). Methods In stage 1, items were created and the instruments were assessed by experts and laymen. In stage 2, tests were given to 15 patients with schizophrenia and 15 paired controls. All were able to understand and respond to the instruments. In stage 3, 141 patients with schizophrenia and 119 healthy controls aged 18 to 60 took part; they were assessed on WM, processing speed (PS) and functional outcome. Results The results showed adequate rates of internal consistency for both measures developed, for both the total sample and each group separately, as well as evidence of convergent validity, discriminant validity and sensitivity to differentiate performance among the groups. Principal component analysis yielded two components, one for updating tests and other for PS measures, indicating factorial validity. Positive and significant, yet low, correlations were found with functionality measures. Conclusion These results provide adequate psychometric parameters for the measures developed, applicable to cognitive research settings in schizophrenia.
... Working memory is a finite and temporary short term memory store, which involves perceptual attention for encoding, active maintenance, and manipulation of novel informative stimuli in a readily accessible form (Klink et al. 2017). In schizophrenia, greater severity of working memory impairment is predictive of positive psychosis symptom severity (Jenkins et al. 2018;Panov et al. 2023) and functional outcomes (Cervellione et al. 2007;Shamsi et al. 2011). In humans and non-human primates, the cingulo-prefrontal network has been implicated as having a major role in working memory function, with increased engagement of these regions during working memory processes and increased activation of excitatory pyramidal neurones (Owen et al. 2005;Chein et al. 2011;Medalla and Barbas 2012). ...
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Rationale Working memory impairment is a prominent feature of schizophrenia which predicts clinical and functional outcomes. Preclinical data suggest histamine-3 receptor (H3R) expression in cortical pyramidal neurons may have a role in working memory, and post-mortem data has found disruptions of H3R expression in schizophrenia. Objectives We examined the role of H3R in vivo to elucidate its role on working memory impairment in schizophrenia. Methods We used positron emission tomography (PET) with the selective H3R radioligand [¹¹C]MK-8278 to measure H3R availability, and employed a task during functional magnetic resonance imaging (fMRI) to assess working memory-evoked brain activation and cognitive task performance, in patients with schizophrenia (n = 12) and matched healthy volunteers (n = 12). We assessed the relationship between H3R availability and both task performance and working memory-evoked brain activation in regions of interest (ROIs), including the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). Results Patients with schizophrenia showed a strong positive correlation, after corrections for multiple comparisons, between ACC H3R availability and task performance (rho = 0.73, p = 0.007), which was absent in the control group (rho = 0.03, p = 0.94). Further ROI analysis did not find a significant relationship between H3R availability and working memory-evoked brain activation. Conclusions These results provide support for the role of H3R on working memory processes in patients with schizophrenia.
... A major cause of these functional deficits in daily activities in patients with SCZ is cognitive impairment [4]. Patients with more severe cognitive impairment experience a much greater decline in self-care [5]. Cognitive deficits, which include impairments in attention, general intelligence, executive function, working memory, and verbal dysfunction, emerge during the prodromal phase of psychosis and persist even after clinical symptoms have subsided [6]. ...
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Functional deficits including cognitive impairment and social dysfunction are the core symptoms of schizophrenia (SCZ), and sensory gating (SG) deficits may be involved in the pathological mechanism of functional deficits in SCZ. This study was to investigate the relationship between defective P50 inhibition and functional deficits in first-episode drug naïve (FEDN) SCZ patients. A total of 95 FEDN SCZ patients and 53 healthy controls (HC) were recruited. The Chinese version of UCSD Performance-Based Skills (UPSA), MATRICS Consensus Cognitive Battery (MCCB), and EEG system were used to assess the social function, cognitive performance, and P50 inhibition, respectively. The MCCB total score and eight domain scores were significantly lower in patients with FEDN SCZ than those in HC (all p < 0.05). The UPSA total score and financial skills scores were also significantly lower in SCZ patients than that in the HC (all p < 0.05). Compared with HC, patients with FEDF SCZ had a higher P50 ratio (all p < 0.05). There was no correlation between P50 components and MCCB scores in patients with FEDF SCZ. However, there was only a correlation between the P50 ratio and UPSA financial skills, communication skills, or total score in patients (all p < 0.05). Defective P50 inhibition in FEDN SCZ patients may be associated with social dysfunction but not cognitive impairment, suggesting that the social dysfunction and cognitive impairment of patients with FEDN SCZ may have different pathogenic mechanisms.
... Schizophrenia, one of the most disabling brain disorders, is characterized by positive symptoms (e.g., hallucinations and delusions), negative symptoms (e.g., affective blunting, asociality, and avolition), and deficits in cognitive domains (including speed of processing, attention, working memory, visual learning and memory, verbal learning and memory, and problem solving) (Green et al., 2000;Nam et al., 2009;Lin et al., 2013;Jeganathan and Breakspear, 2021). Importantly, cognitive dysfunction has been regarded as a core feature of schizophrenia and the main determinant for functional outcome of patients with schizophrenia (Cervellione et al., 2007;Nam et al., 2009;Zanelli et al., 2019;Lin et al., 2022). Further, cognitive functions decline during the illness course of the patients with schizophrenia (Zanelli et al., 2019). ...
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Background: Impaired antioxidant defense is implicated in the pathophysiology of schizophrenia; and superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) are three first-line endogenous antioxidants. Various cognitive functions decline differently during schizophrenia course. The characteristic roles of the three antioxidants in clinical and cognitive profiles in acute and chronic phases of schizophrenia require study. Methods: We recruited 311 patients with schizophrenia, including 92 acutely exacerbated patients who had been off antipsychotics for at least 2 weeks and 219 chronic patients who had been stable on medication for at least 2 months. Blood SOD, CAT, and GSH, clinical symptoms, and nine cognitive tests were measured. Results: Blood CAT levels were higher in the acute patients than in the chronic patients, while SOD and GSH levels were similar between them. Higher CAT levels were correlated with less positive symptoms, better working memory and problem solving in the acute phase, and less negative symptoms, less general psychopathology, better global assessment of function (GAF), and better cognitive function (in speed of processing, attention, problem solving) in the chronic period. Higher SOD levels were correlated with better GAF in the acute phase, and better speed of processing, working memory, and verbal learning and memory in the chronic period. GSH influenced neither clinical nor cognitive manifestations. Conclusions: This study showed that blood CAT affected different clinical and cognitive domains between acute and chronic stages of schizophrenia, SOD influenced cognitive functions in chronic state, but GSH impacted none. Further studies are needed to explore the underlying mechanisms.
... Nonetheless, this result might be important as verbal memory is a significant predictor of long-term functioning in EOS patients, who are at major risk of poor functional outcomes. [43][44][45] At baseline, the EOS group had a similar cognitive profile compared to the AOS group in all cognitive domains, including a selective deficit in VLM. This is in line with previous meta-analyses and reviews showing a similar degree of cognitive impairment in EOS compared to AOS. [23][24][25] However, there is also evidence suggesting that verbal memory is especially impaired in EOS. ...
Article
Background: Developmental stages characterized by greater neural plasticity might be critical periods during which the effects of cognitive training (CT) could theoretically be maximized. However, experiencing a first episode of schizophrenia during childhood or adolescence (ie, early-onset schizophrenia [EOS]) may reduce the brain's ability to benefit from CT. This study examined the effects of EOS versus onset at > 18 years of age (ie, adult-onset schizophrenia [AOS]) as a predictor of response to CT and the relationship between duration of illness and cognitive improvements. Methods: This study is a secondary analysis of data from 2 randomized trials that examined the cognitive effects of neuroscience-informed auditory training (AT) exercises in 84 outpatients with schizophrenia (26 EOS, 58 AOS, recruited between 2004 and 2014). Results: There was a significant effect of time in all cognitive domains (F > 10.22, P < .002). The effect of EOS was significant only for verbal learning and memory (F = 5.79, P = .018). AOS increased the mean change score by 5.70 points in this domain, whereas EOS showed no change (t = -2.280, P = .025). However, the difference between AOS and EOS was no longer statistically significant after control for multiple comparisons. Shorter duration of illness was associated with greater improvement in problem solving in the AOS group (r = -0.27, P = .040). Conclusions: Auditory training is effective in improving cognition in both EOS and AOS. Treatment effects in all cognitive domains were similar, with the exception of verbal learning and memory. This result requires replication. Cognitive training provided earlier in the course of the illness results in greater improvements in executive functions. Trial registration: ClinicalTrials.gov identifiers: NCT00312962, NCT00694889 .
... A decline in cognitive performance during adolescent years has been associated with schizophrenia and psychosis more broadly (MacCabe et al., 2013) and may be predictive of risk even when occurring prior to prodromal symptoms (Gur et al., 2014;Kendler et al., 2016). Generally, cognitive deficits are modestly improved with antipsychotic treatment but often persist despite improvements in psychotic symptoms or functioning (Cervellione et al., 2007). Although treatment with atypical antipsychotic medications can significantly and rapidly alleviate positive and disorganized symptoms, neurocognitive symptoms may take longer to recover, and some deficits may remain despite effective antipsychotic treatment (Emsley et al., 2006). ...
Article
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Objective To assess cognitive functioning in adolescents (12–17 years old) with schizophrenia during open-label treatment with paliperidone extended-release (pali ER). Methods In this exploratory analysis, adolescents treated with pali ER (oral, flexibly dosed, 1.5–12 mg/day) underwent cognitive assessments at baseline and month 6 using a battery of cognitive tests validated in adolescents. Correlation analysis was used to explore the relationship between cognitive assessments and clinical symptoms (Positive and Negative Syndrome Scales [PANSS] and factors) and functionality (Children Global Assessment Scale [CGAS]) at baseline and at 6 months. Results A total of 324 of 393 patients had evaluable neurocognitive data. Changes in cognition function tests from baseline to endpoint were generally small to modest, with improvement noted for most cognitive domains (motor speed, attention/working memory, verbal learning and memory, social cognition, speed of processing, executive functioning). No improvement was noted for visual learning and memory. At baseline, there were modest negative correlations between disorganized thoughts and most cognitive domains; these correlations persisted at 6 months. Other significant negative correlations at 6 months were between speed of processing and PANSS total score, positive symptoms, negative symptoms and uncontrolled hostility (p < 0.05). At 6 months, higher CGAS scores (improved functioning) positively correlated with speed of processing and executive functioning, especially among pali ER responders. Conclusions In this large sample of adolescents with schizophrenia, frank cognitive deficits across multiple domains were observed. Treatment with pali ER over 6 months did not worsen neurocognitive functioning and was possibly associated with positive improvement in certain domains.
... 5 Working memory: an overall composite T score including 2 domains (Backward digit span, WMS-III, Spatial span) was calculated by standardizing the sum of T scores. 6 WAIS-III, Wechsler adult intelligence scale, 3 rd version. 7 WMS-III, Wechsler memory scale, 3 rd version. ...
Article
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Schizophrenia’s pathogenesis remains elusive. Cognitive dysfunction is the endophenotype and outcome predictor of schizophrenia. The LIM and SH3 domain protein (LASP1) protein, a component of CNS synapses and dendritic spines, has been related to the N-methyl-D-aspartate receptor (NMDAR) dysfunction hypothesis and schizophrenia. A single-nucleotide polymorphism (rs979607) in the LASP1 gene promoter region has been also implicated in schizophrenia susceptibility. The aim of this study was to investigate the role of the LASP1 rs979607 polymorphism in the cognitive functions of patients with schizophrenia. Two hundred and ninety-one Han Taiwanese patients with schizophrenia were recruited. Ten cognitive tests and two clinical rating scales were assessed. The scores of cognitive tests were standardized to T-scores. The genotyping of the LASP1 rs979607 polymorphism was performed using TaqMan assay. Among the 291 patients, 85 were C/C homozygotes of rs979607, 141 C/T heterozygotes, and 65 T/T homozygotes, which fitted the Hardy-Weinberg equilibrium. After adjusting age, gender, and education with general linear model, the C/C homozygotes performed better than C/T heterozygotes in overall composite score (p = 0.023), Category Fluency test (representing processing speed and semantic memory) (p = 0.045), and Wechsler Memory Scale (WMS)-III backward Spatial Span test (p = 0.025), albeit without correction for multiple comparisons for the latter two individual tests. To the best of our knowledge, this is the first study suggesting that the genetic variation of LASP1 may be associated with global cognitive function, category verbal fluency, and spatial working memory of patients with schizophrenia. The finding also lends support to the NMDAR dysfunction hypothesis of schizophrenia. More studies with longitudinal designs are warranted.
... With regard to finger tapping speed as measured by Tap Count, performance seems to peak around the same time (both genders). GPT scores at age 15 years are slightly better in our data set relative to those reported in the other two same-age samples (Cervellione, Burdick, Cottone, Rhinewine, & Kumra, 2007;Skranes et al., 2007). ...
... Cognitive deficits are a hallmark characteristic of schizophrenia and these deficits predict global functioning, including the extent of social and occupational impairment (Cervellione et al. 2007;Heinrichs et al. 2008). In particular, deficits in WM have received considerable empirical attention. ...
Article
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Psychiatric illness has been acknowledged for as long as people were able to describe behavioral abnormalities in the general population. In modern times, these descriptions have been codified and continuously updated into manuals by which clinicians can diagnose patients. None of these diagnostic manuals have attempted to tie abnormalities to neural dysfunction however, nor do they necessitate the quantification of cognitive function despite common knowledge of its ties to functional outcome. In fact, in recent years the National Institute of Mental Health released a novel transdiagnostic classification, the Research Domain Criteria (RDoC), which utilizes quantifiable behavioral abnormalities linked to neurophysiological processes. This reclassification highlights the utility of RDoC constructs as potential cognitive biomarkers of disease state. In addition, with RDoC and cognitive biomarkers, the onus of researchers utilizing animal models no longer necessitates the recreation of an entire disease state, but distinct processes. Here, we describe the utilization of constructs from the RDoC initiative to forward animal research on these cognitive and behavioral processes, agnostic of disease. By linking neural processes to these constructs, identifying putative abnormalities in diseased patients, more targeted therapeutics can be developed.
... In addition to the most prominent clinical features, including hallucinations, delusions, thought disorders, and flat affect [1], a wide range of cognitive deficits, such as attentional problems [2], impaired working memory (WM) [3][4][5][6][7], and abnormal executive functioning [8], also characterize the disorder. These cognitive deficits are important, as they affect sufferers' social problem-solving abilities and disturb everyday life [9][10][11][12]. ...
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Impaired working memory (WM) is a core cognitive deficit in schizophrenia. Nevertheless, past studies have reported that patients may also benefit from increasing salience of memory stimuli. Such efficient encoding largely depends upon precise perception. Thus an investigation on the relationship between perceptual processing and WM would be worthwhile. Here, we used biological motion (BM), a socially relevant stimulus that schizophrenics have difficulty discriminating from similar meaningless motions, in a delayed-response task. Non-BM stimuli and static polygons were also used for comparison. In each trial, one of the three types of stimuli was presented followed by two probes, with a short delay in between. Participants were asked to indicate whether one of them was identical to the memory item or both were novel. The number of memory items was one or two. Healthy controls were more accurate in recognizing BM than non-BM regardless of memory loads. Patients with schizophrenia exhibited similar accuracy patterns to those of controls in the Load 1 condition only. These results suggest that information contained in BM could facilitate WM encoding in general, but the effect is vulnerable to the increase of cognitive load in schizophrenia, implying inefficient encoding driven by imprecise perception.
... However, participants who were female, older, unemployed, and less educated, were of low SES, and stayed at healthcare institutions were less capable of self-care than others. Age correlated negatively with cognitive functioning, which is linked to self-care, activities of daily living, and functional performance [19,[32][33][34][35]. Moreover, participants of middle to low SES were less educated and had more severe schizophreniainduced impairment than those of average SES. ...
Article
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Schizophrenia is a common mental disorder characterized by deficits in multiple domains of functioning. This study is arguably the first of its kind in Taiwan to examine, in a multifaceted and objective manner, the disability of patients with schizophrenia and the factors affecting it. A cross-sectional design was adopted to gather data from 24,299 patients with schizophrenia who were listed in the Taiwan Databank of Persons with Disabilities. The level of disability in these patients was measured using the World Health Organization Disability Assessment Schedule 2.0. Statistical analyses were conducted through the χ² statistic and Poisson regression. The highest level of disability was in participation and the lowest was in self-care. An analysis of disability in all six domains of functioning on the basis of sex, age, type of residence, and socioeconomic status (SES) showed significant differences (P < 0.05). Significant factors (P < 0.05) affecting disability in these domains were female gender, age, educational attainment, SES, type of residence, and employment status. The overall degree of disability in schizophrenia patients was moderate. Six domains were measured in this study. The degrees of disability in mobility and self-care were mild while cognition, getting along, life activities, and participation were moderate. Moreover, female gender, an age of 45 or older, low educational attainment, middle to low SES, staying at healthcare institutions, and unemployment were crucial factors affecting disability of the participants. Preventive and rehabilitation programs should be developed to delay disability and functional degeneration in schizophrenic patients with these characteristics.
... Working memory, an important cognitive function that underlies diverse aspects of thought and action (Baddeley, 1992), is impaired in individuals with schizophrenia (Lee and Park, 2005) and is contributory to the degree of social and occupational impairment that may result (Heinrichs and Zakzanis, 1998;Cervellione et al., 2007). Thus a further understanding of this impairment is important, allowing for directed and novel treatment approaches to optimize potential outcomes. ...
Article
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Schizophrenia is associated with a deficit in working memory, with the degree of working memory impairment related to the level of social and occupational functioning. This study tests the hypothesis that the working memory deficits in individuals with schizophrenia can be explained by slow processing of visual stimuli, as measured by the attentional blink (AB) task. Individuals with schizophrenia (SC) and controls (HC) were recruited from an early intervention service for psychosis and the local community. Data from 16 SC (11M/5F, mean = 26.4 yo) and 20 age-matched HC (11M/9F, mean = 25.8 yo) were analyzed. Each subject performed an AB task to determine their AB duration, defined as the lag to reach their plateau performance (ltpp). As expected, mean AB duration in the SC group (575 ms) was significantly slower than HC (460 ms; p = 0.007). Recall accuracy of the SC group on a working memory task, a 6-item probed serial recall task (PSR), was reduced compared to the HC group at a standard interstimulus interval (ISI) (p = 0.002). When the individual's AB duration was then used to adjust the ISI on the PSR task to three relative ISI rates (Slow (2 × ltpp), Medium (ltpp) and Fast (1/2 × ltpp)), performance on the PSR task was affected by group, position and ISI and qualified by an ISI ∗ position (p = 0.001) and a trend to a triple interaction (p = 0.054). There was main effect of group at all ISIs, but group ∗ position interaction only at Slow ISI (p = 0.01). Our interpretation of the results is that absolute ISI, rather than ISI relative to AB duration, affected performance.
... This longitudinal pattern appears to be different from the changes seen in children with ADHD (?ie et al., 2010). However, another follow-up study did not find evidence for declining verbal memory over a 2-year period (Cervellione et al., 2007). ...
Chapter
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Clinically defined psychotic disorders such as schizophrenia are rare in children and adolescents while psychotic symptoms are surprisingly common. Psychotic disorders such as schizophrenia can inflict serious disability when the onset is in childhood and adolescence. Understanding the epidemiology, clinical features, pathophysiology and the natural course of schizophrenia is essential for the provision of adequate clinical care for patients with early-onset schizophrenia. In this chapter we provide an overview of the clinical presentation of schizophrenia and related psychotic syndromes in children and adolescents, with an overview of up-to-date information regarding the pathophysiological underpinnings of psychosis. An outline for clinical assessment is also provided along with a summary of evidence-based treatment options that aim to reduce the morbidity associated with this group of severe mental illnesses.
... For many patients, schizophrenia is a lifelong disease and those with schizophrenia take themselves as having minimal competence, social value or self-efficacy [3,4]. Generally, schizophrenia is characterized by abnormal social behavior and cognitive impairment [5], including those in psychomotor speed, attention, memory, and executive functions, which are thought to underlie the severe functional disability associated with this illness [6][7][8]. Environmental and genetic factors are known to influence the risk of suffering from schizophrenia, however, the mechanistic basis for these gene-environment interactions remains unrevealed. ...
Article
Objective: Schizophrenia is a mental disorder and characterized by abnormal social behavior and failure to recognize what is real. The current study was to explore the long-term effects of cognitive rehabilitation training on schizophrenia. Methods: Eighty six cases of hospitalized patients with schizophrenia were randomly divided into study group and control group. The relapse and employment (attending school) rates were used as indicators to assess the treatment effect. All patients were followed up by 2 years. Kaplan-Meier survival analysis was conducted with relapse and employment (attending school) rates. Results: The rates of relapse in the study group and the control group were 18% and 41%, and relapse free survival time was 22.22 months and 18.55 months; the rates of employment (attending school) were 64% and 43%, and not employment (attending school) time were 10.68 months and 15.74 months, respectively. There was significant difference between the two groups (P<0.05). Conclusions: We found that the cognitive rehabilitation training could significantly reduce schizophrenic relapse rate, prolong the time of patients without relapse, improve the employment (attending school) rate, and shorten the discharged time, which is a powerful treatment method to improve social competence in schizophrenia patients.
... Both dimensions have an important value for prognosis and outcome as they are known to influence outcome (Crumlish et al., 2005;Bowie et al., 2006;Petkari et al., 2011) and treatment choice and/or response (Addington et al., 1998;Peralta and Cuesta, 2008). Finally, there is increasing evidence of the validity of a cognitive dimension in psychosis spectrum disorders and its utility to predict functional abilities (Green et al., 2004;McClure et al., 2007;Heinrichs et al., 2010;Cervellione et al., 2007;Ibanez-Casas et al., 2013a,b). ...
... However, the current finding may be valid per se in its showing emotion identification to be independent of EOSS clinical dimensions. This view is in line with the absence of positive correlations between positive or negative symptoms in EOS and specific neuroimaging structural anomalies or neuropsychological impairment (Banaschewski et al., 2000;Cervellione et al., 2007;Frangou et al., 2008;Jepsen et al., 2010;Greenstein et al., 2012). ...
Article
Recognition of emotional expressions plays an essential role in children's healthy development. Anomalies in these skills may result in empathy deficits, social interaction difficulties and premorbid emotional problems in children and adolescents with schizophrenia. Twenty-six subjects with early onset schizophrenia spectrum (EOSS) disorders and twenty-eight matched healthy controls (HC) were instructed to identify five basic emotions and a neutral expression. The assessment entailed presenting visual, auditory and congruent cross-modal stimuli. Using a generalized linear mixed model, we found no significant association for handedness, age or gender. However, significant associations emerged for emotion type, perception modality, and group. EOSS patients performed worse than HC in uni-and cross-modal emotional tasks with a specific negative emotion processing impairment pattern. There was no relationship between emotion identification scores and positive or negative symptoms, self-reported empa-thy traits or a positive history of developmental disorders. However, we found a significant association between emotional identification scores and nonverbal communication impairments. We conclude that cumulative dys-functions in both nonverbal communication and emotion processing contribute to the social vulnerability and morbidity found in youths who display EOSS disorder.
... Both dimensions have an important value for prognosis and outcome as they are known to influence outcome (Crumlish et al., 2005;Bowie et al., 2006;Petkari et al., 2011) and treatment choice and/or response (Addington et al., 1998;Peralta and Cuesta, 2008). Finally, there is increasing evidence of the validity of a cognitive dimension in psychosis spectrum disorders and its utility to predict functional abilities (Green et al., 2004;McClure et al., 2007;Heinrichs et al., 2010;Cervellione et al., 2007;Ibanez-Casas et al., 2013a,b). ...
Article
Introduction Since the early description of paranoia, nosology of delusional disorder has always been controversial. The idea of ??unitary psychosis is old but has now taken on new value from the dimensional continuum model of psychosis. Aims 1. To study the psychopathological dimensions of the schizophrenia spectrum. 2. To explore the relationship between the dimensions obtained and the categorical diagnoses. 3 To compare the different diagnoses of the psychosis from a psychopathological and functional point of view. Material and Methods an observational study with 550 patients was conducted. 373 patients with schizophrenia, 137 patients with delusional disorder, 40 patients with schizoaffective disorder. PANSS was used to assess the psychopathology and GAF for global functioning. Exploratory and confirmatory factor analysis of the PANSS items was performed in order to obtain a dimensional model. The relationship between diagnostic categories and dimensions was subsequently studied with ANOVA tests. Results 5 Factors,-manic, negative symptoms, depression, positive symptoms and cognition-, similar in composition to other models were obtained. The model yielded the 57.27% of the total variance. The dimensional model obtained was able to explain the differences and similarities between the different categories of the schizophrenia spectrum and the validity of the categories was questioned. The value of the model in order to help establish the diagnosis, prognosis and treatment decision-making was postulated.
... For many patients, schizophrenia is a lifelong disease and those with schizophrenia take themselves as having minimal competence, social value or self-efficacy [3,4]. Generally, schizophrenia is characterized by abnormal social behavior and cognitive impairment [5], including those in psychomotor speed, attention, memory, and executive functions, which are thought to underlie the severe functional disability associated with this illness678. Environmental and genetic factors are known to influence the risk of suffering from schizophrenia, however, the mechanistic basis for these gene-environment interactions remains unrevealed. ...
Article
Background: Schizophrenia is a mental disorder and characterized by abnormal social behavior and failure to recognize what is real. The current study was to explore the long-term effects of cognitive rehabilitation training on schizophrenia. Methods: Eighty six cases of hospitalized patients with schizophrenia were randomly divided into study group and control group. The relapse and employment (attending school) rates were used as indicators to assess the treatment effect. All patients were followed up by 2 years. Kaplan-Meier survival analysis was conducted with relapse and employment (attending school) rates. Results: The rates of relapse in the study group and the control group were 18% and 41%, and relapse free survival time was 22.22 months and 18.55 months; the rates of employment (attending school) were 64% and 43%, and not employment (attending school) time were 10.68 months and 15.74 months, respectively. There was significant difference between the two groups (P<0.05). Conclusion: We found that the cognitive rehabilitation training could significantly reduce schizophrenic relapse rate, prolong the time of patients without relapse, improve the employment (attending school) rate, and shorten the discharged time, which is a powerful treatment method to improve social competence in schizophrenia patients.
... Cognitive impairment is a core feature of schizophrenia [4,16], and deficits affecting processing speed, attention/vigilance, working memory, and executive function correlate with poor functional outcomes [3,19,29]. Antipsychotic agents significantly control clinical symptoms, especially positive symptoms. ...
Article
Individual-level Cognitive Remediation Therapy (CRT) has been shown to be effective for cognitive improvement and social function amelioration. Here, we aimed to test the efficacy of group-based CRT in Chinese subjects with schizophrenia. One-hundred and four inpatients were randomly assigned to either 40 sessions of small-group CRT therapy or therapeutic contact-matched Musical and Dancing Therapy (MDT). Cognitive and social functioning, as well as clinical symptoms, were evaluated over the course of treatment. Specifically, cognitive function was evaluated using a battery of cognitive measurements, clinical symptoms were evaluated using the Positive and Negative Syndrome Scale, and social function was evaluated using the Nurse's Observation Scale for Inpatient Evaluation-30. All patients were evaluated pre- and post-treatment. Forty-four individuals in the CRT group and 46 in the MDT group completed all of the planned treatments and analyses. Cognitive functions, especially cognitive flexibility and memory, showed significant improvement in the CRT group over the course of the study. The MDT group also showed improvement in several cognitive flexibility assessments, but the degree of improvement was significantly greater in the CRT group. Several social-function factors exhibited a significant improvement in the CRT group, but not in the MDT group. Cognitive function improvement correlated positively with social function without predicting social function change. We conclude that group-based CRT is an effective and promising therapy.
... However, the current finding may be valid per se in its showing emotion identification to be independent of EOSS clinical dimensions. This view is in line with the absence of positive correlations between positive or negative symptoms in EOS and specific neuroimaging structural anomalies or neuropsychological impairment (Banaschewski et al., 2000;Cervellione et al., 2007;Frangou et al., 2008;Jepsen et al., 2010;Greenstein et al., 2012). ...
... This finding is important in that it is consistent with the consideration that working memory impairment is a key feature of schizophrenia (Goldman-Rakic, 1994, 1999, and associated with multiple neural mechanisms (Barch, 2005). Indeed, some literature suggests that working memory deficits are a unique predictor of multiple aspects of community functioning in schizophrenia (Cervellione et al., 2007;Heinrichs et al., 2008). Thus, our examination of verbal working memory extends this work by implicating it as more proximal to functioning than other neurocognitive abilities. ...
... • Non-schizophrenia diagnosis 39,87,92,103 • Better premorbid adjustment 108,110 • Lack of abnormal premorbid personality traits 108 • Better baseline executive functioning, 109 visuomotor processing, 109 motor coordination, 109 working memory, 109 and verbal learning 110 • Being in a romantic relationship negatively associated with a schizophrenia diagnosis (versus acute psychosis) and discharge against medical advice from index hospitalization 21 Occupational/ educational functioning Better occupational/educational functioning predicted by: ...
Article
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Given the global burden of psychotic disorders, the identification of patients with early-onset psychosis (EOP; that is, onset before the age of 18) at higher risk of adverse outcome should be a priority. A systematic search of Pubmed, Embase, and PsycInfo (1980 through August 2014) was performed to identify longitudinal observational studies assessing correlates and/or predictors of clinical, functional, cognitive, and biological outcomes in EOP. Seventy-five studies were included in the review. Using multivariate models, the most replicated predictors of worse clinical, functional, cognitive, and biological outcomes in EOP were premorbid difficulties and symptom severity (especially of negative symptoms) at baseline. Longer duration of untreated psychosis (DUP) predicted worse clinical, functional, and cognitive outcomes. Higher risk of attempting suicide was predicted by greater severity of psychotic illness and of depressive symptoms at the first episode of psychosis. Age at onset and sex were not found to be relevant predictors of outcome in most multivariate models, whereas studies using bivariate analyses yielded inconsistent results. Lower intelligence quotient at baseline predicted lower insight at follow-up, worse functional outcomes, and a diagnostic outcome of schizophrenia. Biological predictors of outcome in EOP have been little studied and have not been replicated. Lower levels of antioxidants at baseline predicted greater brain volume changes and worse cognitive functioning at follow-up, whereas neuroimaging markers such as regional cortical thickness and gray matter volume at baseline predicted remission and better insight at follow-up, respectively. EOP patients with poorer premorbid adjustment and prominent negative symptoms at initial presentation are at risk of poor outcome. They should therefore be the target of careful monitoring and more intensive interventions to address whether the disease course can be modified in this especially severely affected group. Early intervention strategies to reduce DUP may also improve outcome in EOP.
... K. Cervellione и соавт. [25] в исследовании подростков с диагнозом «шизофрения» привели подробные данные о состоянии когнитивной сферы по показателям теста Векслера и ряда соответствующих тестов (рабочая память, показатели внимания, «сенсорная моторика», вербальное научение и др.). Авторы отметили «генерализованное» нейрокогнитивное снижение у обследованных больных на 0,6-2,2 стандартного отклонения, подчеркнув, что относительно сохранной остается моторная сфера. ...
Article
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Objective: To explore cognitive disorders in children and adolescents with schizophrenia from the perspective of cognitive dysontogenesis concept, assess severity and specificity of cognitive deficits and identify variants of the dynamics and types of cognitive development. Material and methods: Three diagnostic groups of patients were studied: 1) childhood onset schizophrenia, 2) schizotypal disorder, and 3) other types of schizophrenia. RESULTS AND СONCLUSION: There was a predomination of cognitive development types, named cognitive dysontogenesis, which structure was determined by a combination of the dynamics of cognitive development and severity of cognitive deficits. Severity and type of the dynamics of cognitive deficits were associated with the diagnosis and cognitive process.
Article
В обзоре рассматриваются подходы к понятию дефекта при эндогенной психической патологии у детей и подростков. Пред- ставлена информация об истории вопроса, выделены медицинский (психиатрический) и психологический подходы к изучению проблемы дефекта. Показана связь дефекта, дефицита и дизонтогенеза. Выделен когнитивный компонент анализируемых по- нятий. Обозначены трудности научного изучения данной проблемы в возрастном аспекте применительно к детскому и подрост- ковому возрасту. Обсуждаются возможности квалификации и типологии дефекта при психической патологии в сопоставлении взрослых, детей и подростков, рассматриваются пути клинических и клинико-психологических исследований, подводящих к проблеме формирования дефекта при расстройствах из круга шизофрении у детей и подростков.
Article
Background: The translin-associated factor X (TSNAX) gene, located adjacent to the DISC1 gene, has been implicated in schizophrenia. While cognitive impairment determines long-term the functional outcome of schizophrenia, the role of TSNAX in cognitive dysfunction of schizophrenia patients remains elusive. This study aimed to explore the genetic effect of TSNAX on cognitive functions of schizophrenia. Methods: We recruited 286 chronic schizophrenia patients who had been stabilized with antipsychotics for at least 2 months and genotyped three TSNAX SNPs (rs1630250, rs766288, rs6662926). Clinical symptoms and seven cognitive domains were assessed. The score of cognitive tests was standardized to T score. Results: Clinical symptoms were similar among genotypes of all the three SNPs. The GLM analysis demonstrated that TSNAX genetic polymorphisms influenced cognitive function of schizophrenia patients after adjustment for gender, age, and education. The patients with the rs1630250 C/G genotype performed better than the G/G homozygotes in the Trail Making A (p = 0.034). Those with the rs766288 G/T genotype also performed better than the G/G homozygotes in the Trail Making A (p = 0.012). The patients with the G/G genotype of rs6662926 also performed better than the C/C homozygotes in verbal learning and memory test (p = 0.044). Conclusions: This study suggests that the TSNAX gene variation may influence the cognitive functions of the patients with schizophrenia.
Article
Исследуется влияние фармакотерапии на состояние памяти и внимания у детей и подростков, больных эндогенными психическими заболеваниями. Три группы больных (N = 86) с разными диагнозами (F20 – шизофрения, детский тип; F21 – шизотипическое расстройство; Fxx – прочие диагнозы в рамках этой рубрики) обследовались дважды: в начале лечения и спустя 20–60 дней. Показана специфичность изменений в состоянии когнитивных процессов по отношению к диагнозу. Больные шизофренией демонстрируют более выраженные улучшения в состоянии памяти, а больные шизотипическим расстройством – в состоянии внимания.
Article
Objective To investigate cardiometabolic effects and its predictors in youth with first-episode psychosis (FEP) treated with quetiapine-extended release (ER) vs. aripiprazole. Method Youths with FEP aged 12-17 years were randomized to quetiapine-ER or aripiprazole in the 12-week, double-blinded, Tolerability and Efficacy of Antipsychotics (TEA) trial. Primary outcome was change in body weight; secondary outcomes were changes in body mass index (BMI) and waist circumference (WC), blood pressure (BP), heart rate, and lipid and glucose metabolism parameters. Possible predictors of cardiometabolic changes were examined. Results Altogether, 113 patients (schizophrenia-spectrum disorders=93%, age (mean±SD): 15.7±1.4 years, male participants=30.1%), were randomized to quetiapine-ER (n=55) or aripiprazole (n=58). Quetiapine-ER led to significant increases in body weight (4.88 kg, 95% confidence interval (CI): 3.92-5.83, p<.0001), BMI z-score (0.43, 95%CI= 0.33-0.53, p<0.0001) and WC z-score (0.97, CI=0.7-1.23, p<0.0001). Changes were significantly smaller with aripiprazole (all between-group p-values p<0.0001): body weight: 1.97 kg (CI=0.97-2.97, p=0.0001), BMI z-score: 0.10 (CI: -0.01-0.20, p=0.0646) and WC z-score: 0.18 (CI: -0.09-0.45, p=0.1968). Lipid and glucose metabolism parameters increased significantly at week 4 and 12 only with quetiapine-ER (p-range: 0.0001-0.037). Quetiapine-ER was associated with an increased occurrence of obesity, elevated blood lipids and hyperinsulinemia (p-range=0.004-0.039). Early weight gain, obesity or type 2 diabetes in the family significantly predicted weight and BMI gain at week 12. Conclusion In youth with FEP, quetiapine-ER was associated with significantly greater weight gain and adverse changes in metabolic outcomes than aripiprazole. Early weight gain must be addressed and family lifestyle factors taken into consideration when treating youth with antipsychotics.
Article
Brain-derived neurotrophic factor (BDNF) may be related to the pathophysiology of schizophrenia. This study aims to examine the relation between plasma BDNF levels and the cognition of patients with schizophrenia. We recruited 31 patients with chronic schizophrenia, 34 first-episode patients, and 35 healthy control subjects. We examined the MATRICS Consensus Cognitive Battery (MCCB) and the plasma BDNF levels in all groups. The schizophrenic symptoms were assessed using the positive and negative syndrome scale. The BDNF levels of schizophrenic patients were remarkably lower than those of the controls. The cognitive MCCB global composite scores and part index scores of schizophrenic patients were remarkably lower than those of the controls. Moreover, remarkable correlations were observed between BDNF levels and partial cognitive dimensions, such as visual learning, memory, and processing speed. Therefore, BDNF may be involved in the pathophysiology and cognitive impairment of schizophrenia.
Article
The present follow-up study examines the associations between cognition and parent-rated internalizing problems among adolescents with early-onset schizophrenia (EOS) at baseline (T1) and self-rated internalizing problems 13 years later (T2). Twelve individuals (8 male/4 female) with EOS and 30 healthy controls (16 male/14 female) were included in the study. All were between 12 and 18 years of age at T1. Internalizing problems were measured with the Achenbach System of Empirically Based Assessment Internalizing Scale. Cognition was examined with a neuropsychological test battery measuring auditory attention/working memory, visuomotor processing, cognitive flexibility and verbal memory. Compared to healthy controls, the EOS group had significant cognitive deficits and more internalizing problems both at T1 and T2. There was no correlation between parent-rated internalizing problems at T1 and self-rated internalizing problems at T2 in the EOS group. However, deficits in auditory attention/working memory at T1 were significantly associated with internalizing problems at T2. A focus on improving the treatment of cognitive impairments may be important in preventing the development of internalizing problems in young patients with schizophrenia. The small sample size of the study is a limitation and further research is recommended.
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Supplementary information 1 - Predictors of functional recovery in first-episode psychosis: A systematic review and meta-analysis of longitudinal studies
Article
Cognitive and functional deficits are commonly seen in people with schizophrenia. The profile of these impairments has a resemblance to the cognitive changes seen in healthy aging. In specific, many of the cognitive ability domains that change the most with aging in healthy people are the most salient of these deficits seen in people with schizophrenia, including prominent deficits in processing speed, working memory, and episodic memory. Functional deficits seen in schizophrenia are also similar to those seen in healthy aging. There is a relationship between multiple psychotic relapses and treatment resistance and longitudinal cognitive and functional changes in schizophrenia, with this relationship starting early in the course of illness. Cognitive performance in people with schizophrenia may be consistent with accelerated or premature aging. People with schizophrenia perform similarly to healthy people who are 3 or more decades older on indices of both cognition and their everyday functional skills. Some people with schizophrenia show exaggerated cognitive changes as well. Cognitive and functional performance worsens at the outset of the illness in schizophrenia compared to premorbid functioning, meaning that these deficits are not due to development disabilities. There are multiple medical and substance abuse comorbidities in schizophrenia and although these comorbidities affect cognitive functioning, they are not completely responsible for age-related changes.
Thesis
The impact of mental disorders on somatic health is an issue of major importance. Youths with psychotic disorders suffer from debilitating symptoms, stigmatization from peers and social isolation, and their disabilities have major consequences for their level of daily functioning. To add insult to injury, both the abovementioned problems as well as the pharmacological treatment of the psychotic symptoms significantly increase the risk of developing metabolic and cardiovascular diseases, which, in turn, is a major contribution to the decrease in life expectancy of up to twenty years that patients with psychotic disorders face. Nonetheless, antipsychotic medications are essential in the treatment of these patients, even though the efficacy is limited and youths endure more severe adverse effects than adults. Balancing the beneficial and harmful effects of these drugs is adamant for optimal treatment, but we still know too little concerning the cardiometabolic risk of most antipsychotic agents when prescribed to this age group. In the present PhD study, we have examined the cardiometabolic risk factors in 113 youths with psychosis before and during treatment with quetiapine extended release (ER) versus aripiprazole in the setting of an independently funded, multi-center, randomized, controlled trial (RCT). We found that patients already at entry into the trial had significantly higher waist circumference (WC) and plasma lipids than the matched, healthy controls. We also found that a family history with type 2 diabetes or dyslipidemia was associated with higher cardiometabolic risk in psychotic youth. Our results from the 12 week intervention period revealed statistically and clinically significant increases in weight, WC, body mass index (BMI), insulin resistance, plasma lipids and corrected QT interval during treatment with quetiapine ER, while aripiprazole was associated with smaller, yet still clinically relevant, increases in weight, BMI and WC.
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Objective: The purpose of the present study was to assess the relationship between various domains of cognitive functions, the intensity of psychopathological symptoms, and the general functional outcome in adolescents with early-onset schizophrenia. Method: 33 adolescents with early-onset schizophrenia (EOS) were investigated in their partial symptom remission period. The control group consisted of 30 healthy adolescents. Schizophrenia was diagnosed on the basis of ICD-10 criteria. Psychopathological symptoms were assessed with the use of the PANSS (Positive and Negative Symptoms Scale) scale. General functioning was evaluated with the use of the CGAS (Children's Global Assessment Scale) scale. Results: Significant dysfunctions of various aspects of working memory, executive functions, and verbal memory were found in the group of EOS adolescents, as compared to the control group. Working memory and executive function deficits were significantly more severe in patients with a greater intensity of negative schizophrenia symptoms. EOS patients with a familial burden of psychosis presented greater cognitive deficits than patients without such a burden. Conclusions: These data suggest that visual working memory and verbal memory deficits with a higher intensity of negative and positive symptoms proved to be significant predictors of poor functioning. Limitations of the study are discussed.
Article
Objective: Treatment of early-onset schizophrenia spectrum psychosis (EOS) is hampered by limited data on clinical presentation and illness course. We aimed to systematically review the clinical characteristics, diagnostic trajectories, and predictors of illness severity and outcomes of EOS. Methods: We conducted a systematic PubMed, PsycINFO, and Embase literature review including studies published from January 1, 1990 to August 8, 2014 of EOS patients with 1) ≥50% nonaffective psychosis cases; 2) mean age of subjects <19 years; 3) clinical samples recruited through mental health services; 4) cross-sectional or prospective design; 5) ≥20 participants at baseline; 6) standardized/validated diagnostic instruments; and 7) quantitative psychotic symptom frequency or severity data. Exploratory analyses assessed associations among relevant clinical variables. Results: Across 35 studies covering 28 independent samples (n = 1506, age = 15.6 years, age at illness onset = 14.5 years, males = 62.3%, schizophrenia-spectrum disorders = 89.0%), the most frequent psychotic symptoms were auditory hallucinations (81.9%), delusions (77.5%; mainly persecutory [48.5%], referential [35.1%], and grandiose [25.5%]), thought disorder (65.5%), bizarre/disorganized behavior (52.8%), and flat or blunted affect/negative symptoms (52.3%/50.4%). Mean baseline Positive and Negative Syndrome Scale (PANSS)-total, positive, and negative symptom scores were 84.5 ± 10.9, 19.3 ± 4.4 and 20.8 ± 2.9. Mean baseline Clinical Global Impressions-Severity and Children's Global Assessment Scale/Global Assessment of Functioning (CGAS/GAF) scores were 5.0 ± 0.7 and 35.5 ± 9.1. Comorbidity was frequent, particularly posttraumatic stress disorder (34.3%), attention-deficit/hyperactivity and/or disruptive behavior disorders (33.5%), and substance abuse/dependence (32.0%). Longer duration of untreated psychosis (DUP) predicted less CGAS/GAF improvement (p < 0.0001), and poor premorbid adjustment and a diagnosis of schizophrenia predicted less PANSS negative symptom improvement (p = 0.0048) at follow-up. Five studies directly comparing early-onset with adult-onset psychosis found longer DUP in EOP samples (18.7 ± 6.2 vs. 5.4 ± 3.1 months, p = 0.0027). Conclusions: EOS patients suffer substantial impairment from significant levels of positive and negative symptoms. Although symptoms and functioning improve significantly over time, pre-/and comorbid conditions are frequent, and longer DUP and poorer premorbid adjustment is associated with poorer illness outcome.
Article
This chapter considers the relationship of disorders to brain function. It begins by defining executive functions and their importance to prosocial behavior and independent functioning. It then describes how these functions develop concomitantly with prefrontal brain growth through childhood and adolescence and decline in late life. Next it reviews specific mental disorders that arise during these developmental windows and the executive dysfunctions common to those disorders. The disorders considered include attention deficit hyperactivity disorder, schizophrenia, depression, generalized anxiety disorder, Huntington's disease, Parkinson's disease, and possibly Alzheimer's disease. The chapter concludes by highlighting the importance of imaging and biomarkers, methods that will continue to elucidate brain-behavior relationships and so aid early detection, prognosis, and treatment.
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The discovery of dopamine in 1957-8 was one of the seminal events in the development of modern neuroscience, and has been extremely important for the development of modern therapies of neurological and psychiatric disorders. Dopamine has a fundamental role in almost all aspects of behavior — from motor control to mood regulation, cognition and addiction and reward — and dopamine research has been unique within the neurosciences in the way it has bridged basic science and clinical practice. Over the decades, research into the role of dopamine in health and disease has been at the forefront of modern neuroscience.
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This publication provides an overview of plenary symposia of the XVI World Psychiatry Congress (14–18 September, 2014, Madrid, Spain) and the 27th European College of Neuropsychopharmacology (18–21 October, Berlin, Germany) concerning some important issues of bipolar affective disorder and includes: 1) personalized medicine (Sophia Frangou, Eduard Vieta, Thomas Schulze); 2) staging model (Flavio Kapczinski, Jan Scott, Fiametta Cosci). Key words: bipolar affective disorder; personalized medicine; staging model; early interventions эпизодов;
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Cognitive functions are important determinants of outcome in schizophrenia. Psychiatric hospitalization and intensive treatment in the early-onset psychosis may reduce the severity of psychotic symptoms and improve cognitive functions. It is not clear if after discharge improvement or further deterioration of cognition is observed. The aim of the current study is the evaluation of executive functioning in early onset schizophrenia (EOS) across stages of illness. Two groups of EOS patients: hospitalized subjects with first episode (FES, n=16) at the introduction of pharmacotherapy (T1) and after mean 7 weeks (T2) and stable outpatients group (SO, n=24) were assessed with the Wisconsin Card Sorting Test (WCST) the Positive and Negative Syndrome Scale. Matched healthy (n=32) controls were assessed with WCST. All patients performed significantly worse in WCST than healthy controls. Subjects in acute psychotic episode (FES T1) presented more pronounced executive impairment and psychopathological symptoms than after the resolution of psychotic symptoms (FES T2). No differences in executive function between FES T2 and SO group were observed. In all assessments perseverative errors correlated with negative symptoms. Cognitive impairment is present at the onset of EOS and persists in attenuated but stable form after the resolution of psychotic symptoms.
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Using experimentally validated tests to measure the vigilance/alerting, orienting and executive control attention networks, we have developed a novel, theoretically driven battery for measuring attentional abilities, called the Dalhousie Computerized Attention Battery (DalCAB). The current study sought to examine the factor structure of the DalCAB as preliminary evidence for its validation as an assessment tool for the above-named attention networks. One hundred young, healthy adult participants (18 to 31 years) completed the DalCAB (simple reaction time, choice reaction time, dual task, go/no-go, visual search, vertical flanker, and item memory tasks). Exploratory factor analysis of task performance with promax rotation highlighted a 9-factor model, accounting for 54.66% of the shared variance. Factors 1, 2, and 5 are associated with measures reflecting the vigilance/alerting network (response speed, maintenance/preparation and consistency, respectively), Factor 3 is associated with the orienting network (searching measures). Factors 4, 6, 7, and 8 are associated with different aspects of the executive control network including: inhibition, working memory, filtering, and switching. The final factor is associated with vigilance/alerting (fatigue) and executive control (proactive interference). Our model provides preliminary evidence for the validation of our interpretation of the DalCAB as a measure of vigilance/alerting, orienting, and executive control attentional abilities, and contributes to the previously reported evidence for the validation of these tasks for measuring different aspects of attention. We also demonstrate the importance of each of the specific measures derived from the DalCAB tasks, and our results provide further behavioral evidence of the existence of multiple attention-related networks. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
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The neurocognitive literature on test performance in schizophrenia is reviewed quantitatively. The authors report 22 mean effect sizes from 204 studies to index schizophrenia versus control differences in global and selective verbal memory, nonverbal memory, bilateral and unilateral motor performance, visual and auditory attention, general intelligence, spatial ability, executive function, language, and interhemispheric tactile-transfer test performance. Moderate to large raw effect sizes (d > .60) were obtained for all 22 neurocognitive test variables, and none of the associated confidence intervals included zero. The results indicate that schizophrenia is characterized by a broadly based cognitive impairment, with varying degrees of deficit in all ability domains measured by standard clinical tests.
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Neuropsychological impairments are well documented in schizophrenia and are important targets of treatment. Information about the severity and pattern of deficits after treatment for the first psychotic episode and about relationships between these deficits and syndromal characteristics remains limited. Comprehensive neuropsychological assessments including 41 individual tests were given to 94 patients with first-episode schizophrenia after initial stabilization of psychosis and to a comparison group of 36 healthy volunteers. Profiles of neuropsychological deficits and the relationship of deficits to sex and handedness were examined. Correlations of neuropsychological deficit with a broad range of historical and clinical characteristics, including outcome, were explored. Patients had a large generalized neuropsychological deficit (1.5 standard deviations compared to healthy volunteers). Patients also had, superimposed on the generalized deficit, subtle relative deficits (less than 0.5 standard deviation compared to their own average profile) in memory and executive functions. Learning/memory dysfunction best distinguished patients from healthy individuals; after accounting for this difference, only motor deficits further distinguished the groups. Patients with higher neuropsychological ability had only memory deficits, and patients with lower ability had both memory and executive deficits. No sex differences were observed beyond the normal advantage for men in motor speed. Dextral patients had less severe generalized deficit. Severity of residual symptoms was associated with greater generalized deficit. Executive and attentional deficits were most linked to global functional impairment and poor outcome. The results document a large generalized deficit, and more subtle differential deficits, in clinically stabilized first-episode patients. Learning/memory deficits were observed even in patients with less severe generalized deficit, but the pattern was unlike the amnestic syndrome and probably reflects different mechanisms. Executive and attentional deficits marked the more severely disabled patients, and may portend relatively poor outcome. Failure to develop typical patterns of cerebral dominance may increase the risk for greater generalized deficit.
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Neurocognitive impairments have been documented in adolescents with early-onset schizophrenia (EOS; onset by age 18) and are important treatment targets. Information concerning the severity, pattern, and clinical correlates of these deficits in EOS remains limited. Tests assessing motor skills, attention, memory, visuospatial abilities and executive functioning were administered to 54 clinically stabilized adolescents with EOS and 52 age- and sex-matched healthy controls. Childhood-onset patients (onset by age 13) were compared to those with an adolescent onset of illness. Patients' neurocognitive profiles were compared to those of controls. Relationships between neurocognitive deficits and demographic and clinical characteristics were explored. Neurocognitive profiles did not differ between childhood- and adolescent-onset participants. Patients showed a generalized neurocognitive deficit of 2.0 SDs compared to controls, with relative deficit in executive functioning and relative sparing of language and visuospatial abilities. Degree of generalized neurocognitive impairment was associated with premorbid adjustment and negative symptom severity (Adjusted R(2) = .39). Results document both a significant generalized deficit and a relative deficit of executive functioning in adolescents with EOS. The overall pattern is similar to that observed in severely ill first-episode adult patients. The impairments across multiple neurocognitive domains suggest widespread brain dysfunction in EOS.
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Neurocognitive enhancement therapy (NET), which involves computerized cognitive training and other methods, has been shown to improve working memory and executive function in schizophrenia. In the present study, 145 outpatients with diagnoses of schizophrenia or schizoaffective disorder recruited from a Department of Veterans Affairs mental hygiene clinic and from a community mental health center were ran domized to 6 months of paid work therapy (WT) or to NET+WT. Mixed random effects analyses revealed significant increase in hours worked and money earned over time for both conditions (p < 0.0001). NET+WT worked more hours than WT (p < 0.03), with differences emerging after rehabilitation. Responders to NET+WT worked the most during follow-up and tended to have more competitive-wage employment. Results indicate that work outcomes were enhanced by NET training. Effects were greatest for NET responders. Findings support the efficacy of cognitive training when it is integrated into broader rehabilitation programs.
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Cognitive impairment associated with schizophrenia (CIAS) includes neuropsychological deficits in attention, working memory, verbal learning, and problem solving. These deficits have been shown to be linked to impairment in functional status (eg, social behavior, work performance, and activities of daily living) among patients with schizophrenia in cross-sectional studies. Less is known about the relationship between cognitive and functional change over time, such as potential functional implications of treatment-related improvement in CIAS. The purpose of this review is to summarize research on the association between change in CIAS and change in functional status, to discuss responsiveness of functional outcomes measures, and to provide recommendations for future research and measure development. Nine longitudinal studies were located on the link between CIAS and functional status, and 8 functional outcomes measures were used across these studies. The 9 studies offer initial support for a link between change in cognitive function and change in functional status. However, inconsistent findings across studies indicate that available research is preliminary, and substantial questions remain unanswered. Shortcomings of functional status measures are noted: most instruments were not developed for the target population, and none have demonstrated responsiveness to cognitive change among schizophrenic patients. It is recommended that new functional outcome measures be developed that are specifically designed to be responsive to change in cognition, with domains previously shown to be related to cognitive ability. When creating new functional outcomes measures for assessment of patients with schizophrenia, responsiveness to change in CIAS should be evaluated as part of the development and validation process.
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Both early (i.e., pre- and perinatal periods) and late (i.e., adolescent period) neurodevelopmental processes are thought to participate in the etiology and pathophysiology of schizophrenia. However, whether markers of these processes would be expected to predict an imminent onset of psychosis, as is hoped in the current generation of prodromal research programs, depends on whether their disruptions result from genetic factors shared by patients and some of their unaffected relatives, nongenetic factors specific to those who manifest the illness phenotype, or combinations of these sets of influences. Here we present recent work deriving primarily from high-risk and family-study (i.e., "genetic high-risk") designs, which provide a framework for investigating the neural changes that may occur proximally to the initial onset of psychosis. This work indicates that some of the alterations in brain function and structure in schizophrenia are primarily genetically mediated and also appear in some of patients' unaffected first degree relatives, while other alterations are present in individuals who manifest the illness phenotype but not in relatives at genetic risk (Cannon et al. 2002a, 2002c; Van Erp et al. 2002). Whereas the primarily genetically mediated deficits shared by at-risk but nonsymptomatic relatives are not likely to show differential change in the premorbid period and may be necessary but clearly not sufficient for the development of psychotic symptoms, the deficits specific to patients who manifest the illness phenotype are good candidates for marking the neurobiological processes associated with the emergence of psychotic symptoms at the time of schizophrenia onset. Preliminary results from longitudinal studies of individuals ascertained initially in a prodromal (i.e., "clinical high-risk") state appear to be interpretable within this framework. A number of questions arising from this line of inquiry need to be addressed in the current generation of prodromal research programs: To what extent do the neural systems affected by early and late neurodevelopmental influences overlap? Is there likely to be a schizophrenia-related disturbance in the processes associated with adolescent brain maturation, or are these maturational processes themselves intact, participating in psychosis onset only indirectly, by promoting a neurobiological context in which the early neurodevelopmental disturbances can be expressed in psychotic symptoms? What pattern of changes observable from in vivo imaging studies is consistent with a reduction in neuropil volume? We develop a framework for addressing these questions and evaluating their implications for understanding the roles of early and late neurodevelopmental influences in the etiology and pathophysiology of schizophrenia.
Article
Background: Recent research on schizophrenia indicates that cognitive deficits in this illness are important predictors of functional outcome, highlighting the need for treatments that have a positive impact on cognitive function. Here we explore the hypothesis that acute administration of D-amphetamine can improve cognitive function in individuals with schizophrenia who are well-treated with typical antipsychotics, as well as in healthy controls performing under dual task conditions designed to elicit performance deficits analogous to those found in schizophrenia. Methods: Ten individuals with schizophrenia taking haldol or prolixin and 22 healthy controls performed spatial working memory, language production, and Stroop tasks under both placebo and 0.25 mg/kg of D-amphetamine. Results: D-Amphetamine improved reactions times on the spatial working memory and Stroop tasks for both individuals with schizophrenia and controls, and improved working memory accuracy in schizophrenia. In addition, D-amphetamine improved language production for both individuals with schizophrenia and controls. Conclusions: These results provide support for the hypothesis that the adjunctive administration of dopamine agonist can improve cognitive in individuals with schizophrenia taking typical antipsychotics. The results are discussed in terms of their implications for understanding the nature of working memory deficits in schizophrenia, and potential future avenues for cognitive enhancement in this illness. (c) 2005 Elsevier B.V. All rights reserved.
Article
There has been a surge of interest in the functional consequences of neurocognitive deficits in schizophrenia. The published literature in this area has doubled in the last few years. In this paper, we will attempt to confirm the conclusions from a previous review that certain neurocognitive domains (secondary verbal memory, immediate memory, executive functioning as measured by card sorting, and vigilance) are associated with functional outcome. In addition to surveying the number of replicated findings and tallying box scores of results, we will approach the review of the studies in a more thorough and empirical manner by applying a meta-analysis. Lastly, we will discuss what we see as a key limitation of this literature, specifically, the relatively narrow selection of predictor measures. This limitation has constrained identification of mediating variables that may explain the mechanisms for these relationships.
Article
The assessment of functional impairment has become increasingly important in the ascertainment of psychopathology in clinical practice, as well as in epidemiological research. It is no longer adequate for case ascertainment merely to detect those individuals who meet symptomatic criteria for one or more psychiatric disorders; it is equally important to assess the degree to which those individuals are dysfunctional or impaired. The determination of "caseness" requires a method for assessing impairment attributable to psychiatric morbidity as a fundamental element of case detection. This chapter addresses the following topics: the domains of functional impairment, the assessment of "caseness" and functional impairment in recent epidemiological research, and measures to assess functional impairment (measures of symptom-specific impairment, Children's Global Assessment Scale, Columbia Impairment Scale, Social Adjustment Inventory for Children and Adolescents, Child and Adolescent Functional Assessment Scale). (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Presents the SANS, which was developed to facilitate evaluation of 5 symptoms frequently observed in core schizophrenia: affective flattening, alogia, avolition, anhedonia, and attentional impairment. Each of the measures is defined and broken down in observable behavioral components that are rated on a 6-point scale. The rating of each of the behavioral components is followed by an item that describes the patient's subjective evaluation of the symptom as a whole. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
The NART is a new word-reading test which was specifically designed for use with adults: the 50 words were selected in order to assess familiarity with words rather than the ability to phonetically decode unfamilar words, i.e. for each word intelligent guesswork alone would not result in a correct response. The results from a group of patients with cortical atrophy and a control group demonstrated the superiority of the NART over the best previously available word list (the Schonell GWRT) in enabling higher and more accurate levels of intelligence to be predicted. The evidence implied that the reading of the NART words was not significantly affected by the dementing processes in the patients with cortical atrophy, and therefore that the NART reading score can provide an accurate estimate of premorbid intelligence levels in these patients.
Article
Fifty-nine patients with DSM-III-R early onset (mean, 13.9 years) psychoses of schizophrenia (N = 30) or bipolar disorder (N = 23) were seen at follow-up (mean interval, 5 years; mean age, 19 years). About 50% of the variance in outcome was predictable using stepwise multiple correlation, which has the advantage of eliminating redundancy among variables and giving a quantitative estimate for each predictor. Abnormal premorbid adjustment/personality and degree of recovery after initial hospitalization were the substantial predictors in schizophrenia, whereas in bipolar disorder, they were premorbid adjustment and IQ. Other items such as diagnosis (bipolar or schizophrenia), symptoms, and gender predicted at too low a level to be useful clinically. Though psychosis is necessary for diagnosis, premorbid personality abnormality may be an indicator of an early onset, developmental type schizophrenia with poor prognosis.
Article
The Premorbid Adjustment Scale (PAS) is a rating scale which was developed to be applicable in a research setting. It is designed to evaluate the degree of achievement of developmental goals at each of several periods of a subject's life before the onset of schizophrenia. A description of the scale and its use is presented, along with a discussion of psychometric properties. The PAS has been found to be useful in identifying patients likely to become chronically hospitalized or at high risk for readmission. It may also serve as a possible predictor of patients with brain abnormalities on a computerized tomography (CT) scan.
Article
To describe the psychometric properties of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL) interview, which surveys additional disorders not assessed in prior K-SADS, contains improved probes and anchor points, includes diagnosis-specific impairment ratings, generates DSM-III-R and DSM-IV diagnoses, and divides symptoms surveyed into a screening interview and five diagnostic supplements. Subjects were 55 psychiatric outpatients and 11 normal controls (aged 7 through 17 years). Both parents and children were used as informants. Concurrent validity of the screen criteria and the K-SADS-PL diagnoses was assessed against standard self-report scales. Interrater (n = 15) and test-retest (n = 20) reliability data were also collected (mean retest interval: 18 days; range: 2 to 36 days). Rating scale data support the concurrent validity of screens and K-SADS-PL diagnoses. Interrater agreement in scoring screens and diagnoses was high (range: 93% to 100%). Test-retest reliability kappa coefficients were in the excellent range for present and/or lifetime diagnoses of major depression, any bipolar, generalized anxiety, conduct, and oppositional defiant disorder (.77 to 1.00) and in the good range for present diagnoses of posttraumatic stress disorder and attention-deficit hyperactivity disorder (.63 to .67). Results suggest the K-SADS-PL generates reliable and valid child psychiatric diagnoses.
Article
The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness. Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed. Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group. Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.
Article
To examine the course and outcome of early-onset psychotic disorders. These are data from a longitudinal, prospective study of youths with psychotic disorders. Standardized diagnostic and symptom rating measures were used. Fifty-five subjects with the following disorders have been recruited: schizophrenia (n = 18), bipolar disorder (n = 15), psychosis not otherwise specified (n = 15), schizoaffective disorder (n = 6), and organic psychosis (n = 1). Follow-up assessments were obtained on 42 subjects at year 1 and 31 subjects at year 2. Youths with schizophrenia had more chronic global dysfunction, whereas subjects with bipolar disorder overall had better functioning, with a cyclical course of illness. However, according to results of a regression model, premorbid functioning and ratings of negative symptoms, but not diagnosis, significantly predicted the highest level of functioning over years 1 and 2. Course and level of functioning differentiated bipolar disorder from schizophrenia. However, premorbid functioning and ratings of negative symptoms were the best predictors of functioning over the follow-up period. These findings are consistent with the adult literature, and they further support that psychotic illnesses in young people are continuous with the adult-onset forms.
Article
There has been a surge of interest in the functional consequences of neurocognitive deficits in schizophrenia. The published literature in this area has doubled in the last few years. In this paper, we will attempt to confirm the conclusions from a previous review that certain neurocognitive domains (secondary verbal memory, immediate memory, executive functioning as measured by card sorting, and vigilance) are associated with functional outcome. In addition to surveying the number of replicated findings and tallying box scores of results, we will approach the review of the studies in a more thorough and empirical manner by applying a meta-analysis. Lastly, we will discuss what we see as a key limitation of this literature, specifically, the relatively narrow selection of predictor measures. This limitation has constrained identification of mediating variables that may explain the mechanisms for these relationships.
Article
In our previous study we demonstrated that, in 80 schizophrenia subjects, verbal ability, verbal memory and executive functioning were significantly associated with social problem solving. The objective of this present study was to assess the longitudinal stability of the relationship between social and neurocognitive functioning in schizophrenia. This 2.5 year longitudinal cohort study re-assessed community functioning, social problem solving and symptoms in 65 of the 80 original subjects to determine the predictive ability of neurocognitive functioning. Neurocognition was not re-assessed at this follow-up. Positive and negative symptoms were assessed with the Positive and Negative Syndrome Scale. Social functioning was assessed using the Social Functioning Scale, the Quality of Life Scale, and the Assessment of Interpersonal Problem-Solving Skills (AIPSS). Verbal ability, verbal memory and vigilance were significant predictors of social problem solving as assessed by the AIPSS. Results suggest that the association between neurocognition and social functioning remains consistent over time.
Article
Childhood neurobehavioral deficits in offspring of schizophrenic, affectively ill, and psychiatrically normal parents were evaluated as predictors of schizophrenia-related psychoses in adulthood. The offspring were tested with neurobehavioral measures at 7-12 years of age and assessed in mid-adulthood for axis I diagnoses. The relationships of childhood deficits in attention, verbal memory, and gross motor skills to adulthood schizophrenia-related psychoses were examined in separate path analyses by using logistic regression equations. Sensitivity and specificity were determined for each of the childhood dysfunctions. For the offspring of schizophrenic parents, childhood deficits in verbal memory, gross motor skills, and attention identified 83%, 75%, and 58%, respectively, of the subjects with schizophrenia-related psychoses; 50% were identified by all three variables combined. False positive rates in subjects who did not develop schizophrenia-related psychoses ranged from 18% for those with deficits in attention during childhood to 28% for those with deficits in memory. The three variables had low deficit rates in the offspring of the other two parental groups and were not associated with other psychiatric disorders in any group. Schizophrenia-related psychoses in adulthood are distinguished in subjects at risk for schizophrenia by childhood deficits in verbal memory, gross motor skills, and attention. The findings suggest that deficits in these variables are relatively specific to schizophrenia risk and may be indicators of the genetic liability to schizophrenia.
Article
The goal of the study was to establish the predictive validity of a diagnosis of schizophrenia in childhood and early adolescence by examining diagnostic continuity into adult life and comparing social and symptomatic outcomes of child- and adolescent-onset schizophrenia with those of nonschizophrenic psychoses. A total of 110 consecutive patients with first-episode child- or adolescent-onset psychosis (mean age at onset=14.2 years) presenting to the Maudsley Hospital in London between 1973 and 1991 were followed up an average of 11.5 years after first contact. Ninety-three (84.5%) of 110 patients were successfully followed-up, 51 with a first-episode diagnosis of DSM-III-R schizophrenia and 42 with nonschizophrenic psychoses. Consensus best-estimate DSM-III-R diagnoses were made at follow-up, and course and outcome were assessed blind to first-episode diagnosis. Diagnostic stability was high for child- and adolescent-onset DSM-III-R schizophrenia (positive predictive value=80%) and affective psychoses (positive predictive value=83%) but much lower for schizoaffective and atypical psychoses. Compared with other psychoses, child- or adolescent-onset schizophrenia was associated with significantly worse symptomatic and social outcomes, which were characterized by a chronic illness course and severe impairments in social relationships and independent living. The diagnosis of DSM-III-R schizophrenia in childhood and adolescence has good predictive validity. The high level of diagnostic stability suggests etiological continuity with adult schizophrenia, with onset in childhood and adolescence associated with a particularly malignant course and outcome.
Article
Neuropsychological deficits in schizophrenia appear to predate clinical symptoms of the disease and become more pronounced at illness onset, but controversy exists about whether and when further neuropsychological progression may occur. To identify and characterize any subset of patients who evidenced progressive neuropsychological impairment, we compared the longitudinal stability of neuropsychological functioning in schizophrenic outpatients and normal comparison subjects. One hundred forty-two schizophrenic outpatients and 206 normal comparison subjects were given annually scheduled comprehensive neuropsychological evaluations during an average of 3 years (range, 6 months to 10 years). Clinically and demographically defined subgroups were compared, and test-retest norms were used to identify individual patients who showed unusual worsening over time. The schizophrenic group was neuropsychologically more impaired than the normal comparison subjects but showed comparable test-retest reliability and comparable neuropsychological stability over both short (mean, 1.6 years) and long (mean, 5 years) follow-up periods. No significant differences in neuropsychological change were found between schizophrenic subgroups defined by current age, age at onset of illness, baseline level of neuropsychological impairment, improvement or worsening of clinical symptoms, and occurrence of incident tardive dyskinesia. Norms for change also failed to show neuropsychological progression in individuals with schizophrenia. Neuropsychological impairment in ambulatory persons with schizophrenia appears to remain stable, regardless of baseline characteristics and changes in clinical state. Our results may not be generalizable to the minority of institutionalized poor-outcome patients.
Article
Neuropsychological function has been little studied early in the course of adolescent onset schizophrenia. The present study investigated cognitive function in adolescents with recent onset schizophrenia (n=20) and healthy controls (n=21), employing a comprehensive battery of intelligence, memory and executive function paradigms. Relative to the control group, the patients showed significant or near-significant deficits in more than half of the cognitive variables we examined. A substantial proportion of this broadly based neuropsychological deficit could be accounted for, at least in part, by a mild decrement in general intellectual ability. However, deficits in general and verbal memory remained highly significant after co-varying for IQ.
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Several clinical and research applications require an estimation of therapeutic dose equivalence across antipsychotic medications. Since the advent of the newer atypical antipsychotics, new dose equivalent estimations have been needed. The reported minimum effective dose was identified for each newer atypical antipsychotic medication and for haloperidol across all available fixed-dose placebo-controlled studies. Reported minimum effective dose equivalence ratios to haloperidol were then converted to chlorpromazine equivalents using the "2 mg of haloperidol equals 100 mg of chlorpromazine" convention. To identify the fixed-dose studies, the following sources were searched until June 2002: MEDLINE, the bibliographies of identified reports, published meta-analyses and reviews, Cochrane reviews, Freedom of Information Act material available from the Food and Drug Administration, and abstracts from several scientific meetings from 1997 to 2002. Doses equivalent to 100 mg/day of chlorpromazine were 2 mg/day for risperidone, 5 mg/day for olanzapine, 75 mg/day for quetiapine, 60 mg/day for ziprasidone, and 7.5 mg/day for aripiprazole. These equivalency estimates may be useful for clinical and research purposes. The source of the dose equivalency estimation is evidence-based and consistent across medication.
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A critical review of randomized, controlled trials of extended programs of neurocognitive rehabilitation for the cognitive deficits characteristic of schizophrenia conducted between the years 2000 to 2002 was completed. Over the past several years, two models of cognitive rehabilitation have emerged. In one model, labeled "cognitive remediation," cognitive deficits are treated directly through repeated practice and acquisition of compensatory strategies on cognitive exercises designed to engage underfunctioning brain systems. In a second model, labeled "cognitive adaptation," neurocognitive deficits are addressed through modification of the patients' environment to allow patients to bypass their deficits. Results revealed that a range of cognitive remediation strategies varying widely along dimensions of duration, intensity, method, target of behavioral intervention, and clinical status of participants produced improvements on measures of working memory, emotion perception, and executive function distinct from those trained during remediation. No effects were evident in secondary verbal or nonverbal memory. Results of two pilot studies using functional magnetic resonance imaging to assess changes in task-evoked brain activation have revealed that these interventions may produce changes in several functionally relevant neural systems in a subset of patients. Results from studies of standardized cognitive adaptation interventions have indicated that these treatments can produce improvements in symptoms, psychosocial status, and relapse rates. A variety of approaches for future research are also discussed.
Article
This paper examines whether neuropsychological profiles of youth with early onset psychotic disorders predicted diagnostic or clinical status. Youth with schizophrenia (n=27), bipolar disorder (n=22), and psychosis NOS (n=20) were included. Subjects received an extensive neuropsychological evaluation, including measures of general cognition, attention, memory, and executive functioning. Medication status was not controlled. No statistically significant neurocognitive differences across diagnostic groups were found. Compared to standardized norms, youth with schizophrenia demonstrated deficits in general cognition, verbal learning, recall, sustained effort, and social knowledge. Subjects with bipolar disorder and psychosis NOS exhibited deficits on measures of verbal learning, recall, and sustained effort similar to those of youth with schizophrenia. Neurocognitive deficits in memory and attention appeared to be common among youth with psychotic illnesses, regardless of diagnosis. Those with schizophrenia may have greater global cognitive deficits and problems with social knowledge. Across diagnoses, subjects demonstrated relative strengths on tests that provided them with immediate feedback, and performed most poorly on tests requiring delayed recall.
Article
To assess changes in cognitive function in stable outpatients with schizophrenia switched to ziprasidone from conventional antipsychotics (n = 108), olanzapine (n = 104), or risperidone (n = 58) because of suboptimal efficacy or poor tolerability. In three separate 6-week trials, patients received ziprasidone 40 mg b.i.d. for 2 days, followed by 20-80 mg b.i.d. for the next 40 days. Before switching, and at endpoint, patients were evaluated with tests of working and secondary verbal memory, vigilance, visuomotor speed, verbal fluency, and executive functioning. Principal components factor analysis was performed to test for clustering of cognitive variables. Significant improvements were seen at endpoint in secondary verbal memory (in all three groups), vigilance (in patients switched from conventional antipsychotics or risperidone), executive function (in patients switched from conventional antipsychotics or risperidone), and verbal fluency. Factor analysis on baseline scores suggested reduction of the cognitive variables to three factors: verbal skills, attention and short-term memory, and executive functioning. Analysis of z-transformed mean change in factor scores showed significant improvement in verbal skills and global score following the switch from conventional antipsychotics, olanzapine, or risperidone. Patients requiring a change in antipsychotic therapy may exhibit cognitive improvement following a switch to ziprasidone.
Article
It is generally accepted that cognitive deficits in schizophrenia are related to functional outcome. However, support for longitudinal relationships between cognition and functional outcome has not been as well documented. The current paper presents a review of 18 recently published longitudinal studies (minimum 6-month follow up) of the relationships between cognition and community outcome in schizophrenia. Results from these studies reveal considerable support for longitudinal associations between cognition and community outcome in schizophrenia. These studies demonstrate that cognitive assessment predict later functional outcome and provide a rationale for psychopharmacological interventions for cognitive deficits in schizophrenia. Although the relationships between cognition and community outcome are well-supported, it is clear that community functioning is also affected by a host of factors apart from cognition that are usually not considered in clinical trial studies (e.g., psychosocial rehabilitation and educational/vocational opportunities). In the second part of the paper, we consider intervening steps between cognitive performance measures and community outcome. These steps are apt to have important implications for clinical trials of cognition-enhancing agents in schizophrenia.