Neurocognitive performance in subjects at ultrahigh risk for schizophrenia: a comparison with first-episode schizophrenia

Objective

The aim of the present study was to explore the neurocognitive performance of patients at ultrahigh risk (UHR) compared with patients with first-episode (FE) schizophrenia and healthy control (HC) subjects.

Method

Twenty-seven subjects at UHR for schizophrenia, 25 patients in their FE of schizophrenia, and 33 HCs were included. All participants completed a neurocognitive battery, including tests of general intelligence, attention and working memory, executive function, and verbal and visual memory.

Results

Of the 3 groups, the FE subjects performed poorest at all neurocognitive tests, encompassing the broad range of impairments. The UHR subjects had a similar pattern of neuropsychological dysfunction but less severe than that of FE patients. The UHR subjects were particularly impaired on measures of attention and working memory, executive function, and verbal memory compared with the HCs.

Conclusion

These findings are consistent with the view that the neurocognitive impairments of schizophrenia are neurodevelopmental in nature and, although less severe, those impairments are mostly in place before the onset of the first frank psychotic episode. Neurocognitive impairments may play an important role in the pathogenesis of early psychosis and could help to clarify individuals at UHR for schizophrenia.     

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

BACKGROUND: Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome. METHODS: Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders. RESULTS: At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic. CONCLUSIONS: Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.     

Early recognition and disease prediction in the at-risk mental States for psychosis using neurocognitive pattern classification

Background: Neuropsychological deficits predate overt psychosis and overlap with the impairments in the established disease. However, to date, no single neurocognitive measure has shown sufficient power for a prognostic test. Thus, it remains to be determined whether multivariate neurocognitive pattern classification could facilitate the diagnostic identification of different at-risk mental states (ARMS) for psychosis and the individualized prediction of illness transition. Methods: First, classification of 30 healthy controls (HC) vs 48 ARMS individuals subgrouped into 20 "early," 28 "late" ARMS subjects was performed based on a comprehensive neuropsychological test battery. Second, disease prediction was evaluated by categorizing the neurocognitive baseline data of those ARMS individuals with transition (n = 15) vs non transition (n = 20) vs HC after 4 years of follow-up. Generalizability of classification was estimated by repeated double cross-validation. Results: The 3-group cross-validated classification accuracies in the first analysis were 94.2% (HC vs rest), 85.0% (early at-risk subjects vs rest), and, 91.4% (late at-risk subjects vs rest) and 90.8% (HC vs rest), 90.8% (converters vs rest), and 89.0% (nonconverters vs rest) in the second analysis. Patterns distinguishing the early or late ARMS from HC primarily involved the verbal learning/memory domains, while executive functioning and verbal IQ deficits were particularly characteristic of the late ARMS. Disease transition was mainly predicted by executive and verbal learning impairments. CONCLUSIONS: Different ARMS and their clinical outcomes may be reliably identified on an individual basis by evaluating neurocognitive test batteries using multivariate pattern recognition. These patterns may have the potential to substantially improve the early recognition of psychosis.     

Subjective quality of life in subjects at risk for a first episode of psychosis: a comparison with first episode schizophrenia patients and healthy controls

The concept of quality of life (QoL) is of growing relevance in schizophrenia research. However, there is to date no information on subjective QoL in subjects at risk for a first episode of psychosis in comparison to first episode schizophrenia patients (FE) or healthy controls (HC). Therefore 45 subjects in a putatively early initial prodromal state (EIPS), 40 FE and 45 HC were assessed on demographics, symptoms and subjective QoL as measured by the Modular System for Quality of Life. Results indicated that in most areas HC experienced the highest QoL scores followed in hierarchical order by EIPS and FE. EIPS and FE experienced significantly lower QoL than HC in 5 and 6 of 7 QoL domains. EIPS experienced the lowest ratings in affective QoL. Thus the data demonstrates that subjective QoL in subjects at risk for a first episode of psychosis is substantially reduced when compared with HC and suggests that subjective QoL is already compromised prior to the onset of first positive schizophrenia symptoms. These findings support the notion that subjects at risk for a first episode of psychosis constitute a clinical population for which further service and intervention research is indicated.     

A longitudinal study of neurocognitive function in individuals at-risk for psychosis

INTRODUCTION: Clinically defined prodromal diagnostic criteria identify at-risk individuals with a 35-40% likelihood of developing a psychotic disorder within a year. The time course and predictive value of cognitive deficits in the development of psychosis has not been established. METHODS: A comprehensive neurocognitive battery and clinical assessments were administered to 37 subjects meeting Criteria of Prodromal States (COPS) criteria for being at risk for psychosis, and two comparison groups: 59 first episode and 47 healthy subjects. Subjects were also evaluated at 6-month and 1-year follow-up periods. Primary analyses used a neurocognitive composite score derived from individual neurocognitive measures, including measures of vigilance, verbal memory, working memory, and processing speed. RESULTS: At-risk subjects performed more poorly than healthy subjects (t=2.93, P=0.01), but better than first episode subjects (t=4.72, p<0.0001). At-risk subjects were particularly impaired on measures of vigilance and processing speed. Cognitive composite scores were significantly lower in at-risk subjects who progressed to psychosis (N=11; z=-1.2), while those at-risk subjects who did not progress to psychosis (N=17) performed better (z=-0.5), and not significantly different from controls. Poor CPT performance combined with better WAIS-R digit symbol performance predicted progression to psychosis. Severity of neurocognitive deficits was not related to duration of prodrome or to time to development of psychosis and neurocognitive function improved in all subjects except those who progressed to psychosis. CONCLUSION: Neurocognitive impairment emerges early in the course of psychotic illness. Performance on tests of neurocognition may prove to be an early risk predictor for subsequent development of psychotic disorders.     

Neurocognitive function and outcome in first-episode schizophrenia: a 10-year follow-up of an epidemiological cohort

The natural history of neurocognitive impairments in schizophrenia is unclear. We aimed to characterise this in an epidemiological first-episode cohort and relate it to long-term outcome. All but 1 of 112 first-episode psychosis cases ascertained from a geographical catchment area were traced at 10-12 years. Neurocognitive and multi-dimensional outcome assessments were made at interview in 49 cases with schizophrenia and related disorders. Twenty-four of these had completed the same neurocognitive battery at index admission. Comparisons with normative data showed impaired executive function in a proportion of the first episode (FE) sample at baseline. Significant deterioration was seen over the follow-up period in three of nine sub-tests: object assembly, picture completion and memory for designs. Neurocognitive impairments at outcome, but not baseline, correlated with clinical outcome. Poor outcome was associated with a decline in performance on visuo-spatial tasks and a failure to improve on frontal-temporal tasks during the follow-up period. Executive deficits may be present in the FE, but do not progress over 10-12 years. Visuo-spatial function is spared in the FE but may deteriorate over time. Changes in both these patterned deficits are predictive of clinical outcome.     

Neurocognitive functioning in patients with first-episode schizophrenia 1 year from onset in comparison with patients 5 years from onset

Objective. The course of neurocognitive deficits in schizophrenia has not yet been established. Therefore, we followed patients with first-episode schizophrenia to verify the course of these deficits. Methods. In Study 1, tests of neurocognitive functioning were administered to patients with first-episode schizophrenia (FE group) every 6 months. Of the 26 patients who completed the baseline assessment, 19 completed a 6-month follow-up, and 13 completed a 1-year follow-up. In Study 2, 19 patients in FE group at 6-months when the neuropsychological measures was less influenced by psychotic symptoms and other patients who experienced schizophrenia 5-years earlier (5-year group) were compared. Results. In Study 1, verbal memory, motor speed, and executive functions significantly improved at the 1-year follow-up. In Study 2, patients in 5-year group performed worse in verbal memory and executive functions than patients in FE at 6-month group, but marginally but significantly better in verbal fluency. Conclusions. Verbal memory, executive functions, and verbal fluency were significantly different between 5-year group and FE at 6-month group, and may indicate progression of schizophrenia. Executive functions may reflect the state of psychosis. Working memory and processing speed which did not change significantly from onset are needed to verify the course in further research.     

Social cognition and neurocognition as independent domains in psychosis

Patients with psychosis display alterations in social cognition as well as in the realm of neurocognition. It is unclear, however, to what degree these cognitive domains represent two separate dimensions of liability or the pleiotropic expression of a single deficit. The purpose of the present study was to investigate (i) to what extent alterations in social cognition represent an independent area of vulnerability to psychosis, separate from neurocognitive deficits and (ii) whether social cognition is one construct or can be divided into several subcomponents. Five social cognition and three neurocognitive tasks were completed by 186 participants with different levels of vulnerability for psychosis: 44 patients with psychotic disorder; 47 subjects at familial risk; 41 subjects at psychometric risk and 54 control subjects. The social cognition tasks covered important basic subcomponents of social cognition, i.e. mentalisation (or theory of mind), data gathering bias (jumping to conclusions), source monitoring and attribution style. Neurocognitive tasks assessed speed of information processing, inhibition, cognitive shifting and strategy-driven retrieval from semantic memory. The results of factor analysis suggested that neurocognition and social cognition are two separate areas of vulnerability in psychosis. Furthermore, the social cognition measures lacked significant overlap, suggesting a multidimensional construct. Cognitive liabilities to psychosis are manifold, and include key processes underlying basic person-environment interactions in daily life, independent of cognition quantified by neuropsychological tests.     

Social functioning in young people at risk for schizophrenia

Deficits in social functioning are potential risk factors for schizophrenia. Social functioning was assessed in 55 individuals "at risk" for schizophrenia, 16 first episode patients with schizophrenia and 45 normal comparison subjects. The Social Adjustment Inventory for Children and Adolescents (SAICA) was administered to adolescents <18 and the Social Adjustment Scale (SAS-SR) to young adults >17. The at risk and first episode groups significantly differed from the normal subjects on measures of social functioning in the domains of peer, family, work and school relationships. Individuals at risk for schizophrenia have significant functional deficits which may be potential indicators of increased vulnerability for psychosis.     

Neurocognitive deficits in adolescents with schizophrenia: longitudinal stability and predictive utility for short-term functional outcome

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.     

Neuropsychological Profiles in Different At-Risk States of Psychosis: Executive Control Impairment in the Early—and Additional Memory Dysfunction in the Late—Prodromal State

Impairments in neuropsychological functioning have been described in subjects clinically at high risk for psychosis, but the specific cognitive deficits in different clinical high-risk groups remain to be elucidated. The German Research Network on Schizophrenia employs a heuristic 2-stage model: a putatively late prodromal state (LPS), characterized by the onset of attenuated positive or brief psychotic symptoms, and an early prodromal state (EPS), mainly characterized by the presence of basic symptoms, which are predictive for psychosis within the next 10 years.A total of 205 subjects met the criteria for either an EPS or an LPS of psychosis and were assessed with a comprehensive neuropsychological test battery. Neurocognitive profiles of high-risk groups were compared with data of 87 healthy controls comparable with regard to gender, age, and premorbid verbal IQ.Patients in the LPS were impaired in all neurocognitive domains (memory/learning, executive control/processing speed, and working memory) examined, with memory being the worst. Deficits were less pronounced in patients in the EPS, with a specific deficit in the executive control/processing speed domain. Consistent with a progressive neurodevelopmental disorder, some cognitive abilities were already impaired in patients in the EPS, followed by further deterioration in the LPS. Specifically, deficits in executive control functioning were related to the presence of basic symptoms, indicating a vulnerability for psychosis. Memory deficits were associated with the onset of psychotic symptoms indicating further disease progression in the trajectory to psychosis and, thus, may be useful in predicting psychosis and targeting early intervention.     

Cognitive functioning in young people with first episode psychosis: relationship to diagnosis and clinical characteristics

OBJECTIVE: To examine the extent and nature of neuropsychological deficits in adolescents and young people with first episode psychosis (FEP), and to determine whether the pattern and extent of neuropsychological deficits varied according to diagnosis. METHOD: A total of 83 FEP subjects aged 13-25 years, and 31 healthy controls completed a comprehensive battery of neuropsychological tests, grouped into 10 cognitive domains. First episode psychosis subjects were stratified into three diagnostic groups (schizophrenia, affective disorders, substance-induced psychosis) and differences in cognitive profiles were examined. The contribution of demographic and clinical characteristics to cognitive performance was also explored. RESULTS: The schizophrenia group demonstrated significantly worse performance on tasks of verbal learning and memory than the affective disorders group. Compared to healthy controls, the schizophrenia group also demonstrated global impairment across the majority of cognitive domains. The substance-induced group's performance lay between that of the schizophrenia and affective disorders groups. Analyses of differential deficits revealed that verbal learning, verbal memory and current intellectual functioning were selectively impaired in the schizophrenia group, whereas the affective disorders group demonstrated a selective deficit in speeded processing. Premorbid intellectual functioning, negative symptomatology and medication levels were the strongest predictors of cognitive performance in FEP subjects. CONCLUSIONS: Verbal memory deficits differentiate individuals with schizophrenia from those with psychotic affective disorders. Although significant cognitive deficits are evident across all diagnostic FEP groups, individuals with schizophrenia appear to have more generalized impairment across a broad array of cognitive functions than other psychotic diagnoses. Lower premorbid intellectual functioning does not appear to contribute to greater cognitive deterioration following onset of psychosis, but severity of illness may be a more important factor than levels of mood disturbance.     

Neurocognitive indicators for a conversion to psychosis: comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis

The study aims to identify potential neurocognitive indicators of an enhanced risk for developing psychosis. N=44 patients meeting clinical inclusion criteria for initial prodromal states (IPS) who developed psychosis within a median interval of 10 months were compared to N=39 IPS patients not developing psychosis within a minimum interval of 1 year (median 36 months), and to N=44 healthy controls on a comprehensive neuropsychological test battery (pattern recognition, divided and sustained attention, spatial and verbal working memory, verbal/visual memory, speed of processing, executive and intellectual functions). IPS patients who converted to psychosis performed worse than healthy controls on all broad neurocognitive domains. They were more impaired than IPS patients not developing psychosis on the Subject Ordered Pointing Task (SOPT; working memory), verbal memory functions, verbal executive, verbal IQ and speed of processing tests. After a Bonferroni-Holms adjustment for multiple testing differences on SOPT, Digit-Symbol Test, and verbal IQ remained significant (effect sizes d=0.54-0.88). Neurocognitive predictors had a sensitivity of 0.75 and a specificity of 0.79. Results support several cognitive domains as indicators of vulnerability to psychosis, and additionally suggest that subtle deficits in verbal abilities (working and long-term memory, executive and intellectual functions) and decreased speed of processing may help to predict conversion to psychosis in a clinically defined IPS group.     

The course of neurocognition and social functioning in individuals at ultra high risk for psychosis

OBJECTIVE: This study evaluates longitudinal neuropsychological performance and its association with clinical symptomatology and psychosocial outcome in individuals identified as ultra high risk (UHR) for psychosis. METHODS: Thirty-five UHR individuals completed neurocognitive, clinical, and social/role functioning assessments at baseline and, on average, 8.3 months later. RESULTS: UHR subjects showed significant cognitive deficits at baseline and 2 distinct profiles of cognitive change over time. On average, 50% demonstrated improvement in social and role functioning over the follow-up period, while the other half showed either stability or decline in functioning. Functional improvement was associated with improved processing speed and visual memory, as well as improvement in clinical symptoms over the follow-up period. In contrast, patients who did not improve functionally showed stable clinical symptoms and cognitive performance over time. CONCLUSIONS: Although the degree of neurocognitive deficit at baseline in UHR patients does not predict psychosocial outcome, the course of neurocognitive change over the first 8 months of follow-up does differentiate patients with good and poor functional outcomes.     

Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia

BACKGROUND: Although a deficit in social cognition is regarded as an early indicator of schizophrenia, few studies have investigated social cognition in ultra-high-risk (UHR) individuals. METHODS: Our investigation involved subjects at UHR for psychosis (N=33) and an age- and IQ-matched healthy control (HC) group (N=36). Two types of theory of mind (ToM) tasks and a neuropsychological test battery were measured. RESULTS: Compared to the HC group, the UHR group performed significantly worse for ToM tasks, with the effect size at an intermediate level (0.64-0.68). Furthermore, the UHR group showed impaired performance in the executive and working memory tests, but not verbal memory tests. These deficits for ToM tests observed in the UHR group were significantly correlated with set-shifting tasks. CONCLUSIONS: Deficits in social cognition may be modest at the prodromal stage of schizophrenia and may be attributed to prefrontal dysfunction. To prevent or delay transition to psychosis, there is a need for specific preventive strategies targeting social functioning for the UHR group.     

Neurocognitive predictors of functional outcome two to 13 years after identification as ultra-high risk for psychosis

Background and aim

Little is known about the relationship between neurocognitive performance and functional outcome before the onset of frank psychosis. This longitudinal study aimed to investigate neurocognitive predictors of poor functional outcome in a group identified as ultra-high risk (UHR) for psychosis between two and 13 years prior.

Method

Individuals (N = 230) identified as UHR for psychosis at the PACE Clinic in Melbourne completed assessment of psychopathology, functioning and neurocognition at baseline and follow-up. The mean length of follow-up was 7.26 years (SD 3.05).

Results

Forty-one individuals with the poorest functional outcome were identified. Only 48.8% of this group had transitioned to psychosis. Poor functional outcome was associated with reduced performance at baseline in the specific neurocognitive domains of verbal learning and memory, processing speed and attention, and verbal fluency, but not global cognitive impairment. Reduced performance on a verbal story recall task, in combination with higher negative symptoms at baseline, was the best predictor of later poor outcome. Baseline positive psychotic symptoms and GAF scores were not associated with later poor outcome.

Discussion

To date, this is the longest follow-up study of an UHR sample. Poor functional outcome was associated with specific neurocognitive decrements, regardless of transition to psychosis. The detection of individuals with poor functioning at follow-up, against a background of previously identified risk factors for psychotic disorder, may yield a valid group in which to study biomarkers and treatment of schizophrenia.     

The relative influences of symptoms, insight, and neurocognition on social adjustment in schizophrenia and schizoaffective disorder

Impaired insight and neurocognitive deficits are commonly seen in schizophrenia. No study to date, however, has documented the relative influences of insight deficits, neurocognitive functioning, and psychotic symptoms on overall social adjustment in this population. This was done in a cohort of individuals recovering from acute exacerbations. Forty-six individuals with schizophrenia or schizoaffective disorder were recruited upon discharge from an inpatient unit. Symptom levels, neurocognitive functioning (information processing, memory, and executive functioning), and symptom awareness were documented, and social adjustment was assessed in three domains: treatment compliance, social behavior, and subjective quality of life. Cross-sectional data from initial assessments are reported. Sequential linear regression analyses identified differential associations between illness characteristics and outcome domains. Treatment compliance was most influenced by insight; social behavior deficits were associated with thought disorder and neurocognitive (working memory and visuo-spatial) impairments; and quality of life was associated with mood disturbances. Outcome is multidimensional in schizophrenia, and there are differential patterns of associations between illness characteristics and domains of social adjustment. Studies such as this can guide clinicians in determining the most appropriate treatments for specific individuals and should also guide researchers in efforts to clarify the processes that underlie treatment response and recovery in schizophrenia.     

Risk Factors for Psychosis: Impaired Social and Role Functioning

Objectives: Risk for psychosis is currently defined primarily on the basis of attenuated positive symptoms (APS), with no inclusion of the functional deficits characteristic of schizophrenia. Impaired social and role functioning have been of interest for reflecting poor outcome but far less is known about the developmental impact of these deficits as vulnerability or risk factors. Methods: Age-appropriate social and role functioning were prospectively assessed in 100 individuals at clinical high risk (CHR) for psychosis included in the 8-site North American Prodromal Longitudinal Study database. A nested case-control design was used to compare changes in social and role functioning in 26 individuals converting to psychosis shortly after baseline assessment and 24 converting over a year later. Individuals in each converter subgroup were directly matched to a non-converter at the same site, controlling for time to conversion, age, gender, and severity of baseline symptoms. Results: At baseline, CHR subjects who later became psychotic were significantly more likely to be impaired socially than matched non-converters. Onset of psychosis did not further disrupt social difficulties. Role functioning showed some of the same trends, but the overall pattern was not as consistent as for the social domain. Controlling for neurocognition did not change the pattern of group differences. Conclusions: Early impaired social functioning appears to be a risk factor for psychosis and, added to APS, could potentially contribute to accurate identification of CHR individuals and provide a new direction for early intervention to reduce long-term disability.     

Neuropsychological functioning in adolescents and young adults at genetic risk for schizophrenia and affective psychoses: results from the Harvard and Hillside Adolescent High Risk Studies

Siblings and offspring of persons with schizophrenia carry elevated genetic risk for the illness and manifest attentional and memory impairments. Because less is known about other neuropsychological functions and their specificity in adolescents, we conducted a genetic high-risk (HR) study of schizophrenia (HR-SCZ) and affective psychosis (HR-AFF). Participants (ages 12-25) were from the Harvard Adolescent High-Risk and Hillside Family studies, including 73 HR-SCZ, 18 HR-AFF, and 84 community controls (CCs) recruited in metropolitan Boston and New York. Groups were compared on overall neurocognitive functioning, 6 domains, and 13 test scores, controlling for age, parental education, and correlated data within families. The HR-SCZ group was significantly impaired overall, while the HR-AFF group demonstrated a trend toward overall impairment. HR-SCZ subjects showed significantly lower Verbal Ability (d = .73) and Executive Functioning/Working Memory (d = .47) than CCs. HR-AFF subjects showed reduced Verbal Ability (d = .64) compared to CCs. Excluding 12 CCs with a parental history of depression (without psychosis) led to larger differences between HR and CC groups across domains. Moreover, HR-SCZ and CC group differences in Verbal Memory (d = .39) and Visual-Spatial (d = .34) became statistically significant. There were no significant differences between HR-SCZ and HR-AFF groups. Data support a modest neuropsychological deficit in persons at genetic HR for psychosis, with a broader range of deficits in HR-SCZ. Future work should assess the relationship of neurocognition to adaptive functioning and possible onset of psychosis in HR samples. Ascertainment criteria for controls may markedly influence results and interpretation of group differences.     

Do schizotypal symptoms mediate the relationship between genetic risk for schizophrenia and impaired neuropsychological performance in co-twins of schizophrenic patients?

BACKGROUND: Neurocognitive deficits and symptoms of schizotypal personality disorder are both elevated in the first-degree relatives of schizophrenic patients, but their relationship to each other and their potential common genetic source remain unclear. METHODS: Fifty unaffected co-twins of schizophrenic patients and 123 control twins were assessed with a neuropsychological battery and structured clinical interviews. RESULTS: Working memory was influenced by genetic risk for schizophrenia but not schizotypal symptoms. Nearly all other domains were influenced by schizotypy symptoms but only in the co-twins of schizophrenic patients. Schizotypy symptoms in the absence of a family history did not seem to be related to impaired neurocognitive functioning. CONCLUSIONS: Schizotypy symptoms in those with genetic risk for schizophrenia are associated with increased risk for cognitive deficits. Some neurocognitive deficits might covary with subpsychotic symptoms due to a shared genetic factor. Community-ascertained schizotypal individuals might not be appropriate for modeling underlying genetic risk for schizophrenia.