Search tips
Search criteria 


Logo of schbulOxford JournalsContact UsMy BasketMy AccountSchizophrenia BulletinAbout this JournalContact this JournalSubscriptionsCurrent IssueArchiveSearch
Schizophr Bull. 2008 July; 34(4): 743–759.
Published online 2008 April 29. doi:  10.1093/schbul/sbn027
PMCID: PMC2632447

Neurocognitive Allied Phenotypes for Schizophrenia and Bipolar Disorder


Psychiatric disorders are genetically complex and represent the end product of multiple biological and social factors. Links between genes and disorder-related abnormalities can be effectively captured via assessment of phenotypes that are both associated with genetic effects and potentially contributory to behavioral abnormalities. Identifying intermediate or allied phenotypes as a strategy for clarifying genetic contributions to disorders has been successful in other areas of medicine and is a promising strategy for identifying susceptibility genes in complex psychiatric disorders. There is growing evidence that schizophrenia and bipolar disorder, rather than being wholly distinct disorders, share genetic risk at several loci. Further, there is growing evidence of similarity in the pattern of cognitive and neurobiological deficits in these groups, which may be the result of the effects of these common genetic factors. This review was undertaken to identify patterns of performance on neurocognitive and affective tasks across probands with schizophrenia and bipolar disorder as well as unaffected family members, which warrant further investigation as potential intermediate trait markers. Available evidence indicates that measures of attention regulation, working memory, episodic memory, and emotion processing offer potential for identifying shared and illness-specific allied neurocognitive phenotypes for schizophrenia and bipolar disorder. However, very few studies have evaluated neurocognitive dimensions in bipolar probands or their unaffected relatives, and much work in this area is needed.

Keywords: neurocognition, schizophrenia, endophenotype, bipolar disorder


Revisiting the classification of schizophrenia and bipolar disorder as separate clinical entities with distinct etiology and pathophysiologies has gained momentum recently. Infusion of a growing literature has drawn attention to shared aspects of psychopathology, neurobiology, and treatment efficacy across the 2 disorders. Linkage findings offer a substantial challenge to the traditional Kraepelinian model of the 2 disorders as having fully discrete underlying disease processes. Empirical support for similar pathoetiology in these disorders comes from genetic studies demonstrating shared genetic susceptibility. Yields from linkage studies indicate several loci that may represent risk genes for schizophrenia and bipolar disorder including 18p11.2, 13q32, 22q11–13, and 10p14.14 Candidate association studies have specified several genes (eg, G72/G30, BDNF, DISC1, COMT, neuregulin 1, and dysbindin) that appear to confer risk for both disorders. Importantly, these shared genetic factors appear to be more common in psychotic bipolar patients and their family members, suggesting that there may be common causes for psychosis across bipolar disorder and schizophrenia.58

Although differences between the disorders are established, especially the relatively specific familial aggregation of the disorders,9 shared deficits in neuropsychology,1013 neurophysiology,1416 gross brain anatomy,17 and responsivity of both disorders to antipsychotic medications are consistent with the view that these disorders may share aspects of pathophysiology. Genetic models considering both common and unique genetic features of the disorders are of interest, for they bear on fundamental questions about the causes and interrelationship of the 2 most common, serious mental illnesses in adult psychiatry.

Unraveling the role of numerous contributing genetic factors to disease risk, including commonalities and differences across clinical syndromes, requires novel linkage strategies. The allied phenotype approach attempts to break down complex genetic disorders into their component parts by isolating intermediate expression/effects of individual genes. This approach is based on the premise that genetic determination of neurobiological alterations linked to illnesses may be more readily tracked than the genetic causes of overt expression of disorders. Relative to the clinical expression of psychiatric syndromes, this might be due to either an enhanced ability to resolve illness heterogeneity or a more direct genetic determination of specific biological traits. As in other medical disorders, this strategy in psychiatric genetics is based on the hope that improved understanding of the genetic causes of variation in allied phenotype expression will accelerate progress in understanding the genetics of complex psychiatric disorders. Given the possibility that schizophrenia and bipolar disorder share overlapping etiologic determinants, the endophenotypic approach may be helpful for delineating shared and unique causal pathways from genetic variation, to altered neural systems and neurobehavioral function, to the overt clinical expression of both disorders.

Useful allied phenotypes help to resolve questions about etiology in part by helping track down illness-related gene variants and also by filling gaps in the causal chain between gene expression and clinical expression. Consistent with suggested criteria for identification of endophenotypic markers,1820 allied phenotypes should be: (1) heritable, (2) associated with the illness, (3) stable traits that can be reliably assessed, (4) cosegregated within families, and (5) higher in prevalence for unaffected relatives compared with the general population.

Based on current knowledge of both schizophrenia and bipolar disorder, genetic influence is likely to impact both structural and functional aspects of brain systems in ways that increase risk for the disorder. Atypical patterns in the organization of brain anatomy can be neurodevelopmental in origin,2123 resulting in a cascade of events that manifest across a wide range of neurocognitive and affective abilities such as attention, executive function, working memory, affect regulation, affect-cognition integration, declarative memory, spatial processing, and psychomotor function. Consequently, neuropsychological measures are promising allied phenotypes, as are neurophysiological assessments of brain systems that subserve specific neurocognitive processes. The established heritability of cognitive abilities24,25 and the availability of highly reliable procedures for assessment of most cognitive skills highlight the potential of neurocognitive performance measures as candidate allied phenotypes for schizophrenia and bipolar disorder. To date, the allied phenotype approach has been used much more widely in studies of schizophrenia than bipolar disorder. Yet, patient studies with schizophrenia and bipolar patients have begun to show interesting patterns of separate and overlapping abnormalities in putative allied phenotypes.

The present review was organized to illustrate promising neuropsychological and neurocognitive candidate allied phenotypes with an eye toward guiding future work by identifying potential confounds and other critical factors that highlight areas where more work is needed. To this end, we review neurodevelopmental accounts of schizophrenia and bipolar disorder and the implications for allied phenotype research. Next, we examine the pediatric bipolar disorder and early-onset schizophrenia literatures for indicators of neurodevelopmental disruption, which may represent core allied phenotypic deficits. Finally, we review promising approaches from clinical cognitive and affective neuroscience research that have been used in studies of probands with schizophrenia and bipolar disorder and to a much more limited degree with their family members.


Both schizophrenia and bipolar disorder are associated with neurodevelopmental abnormalities that often manifest themselves early in life. Available evidence suggests that neurodevelopmental disturbances are generally more severe and disabling in schizophrenia. Indeed, relative to bipolar disorder, schizophrenia has been associated with higher rates of pre- and perinatal complications; more frequent developmental cognitive, motor, and language problems; and greater maturational abnormalities in brain regions such as the hippocampus.2628

One neurodevelopmental model has proposed that the greater neuroanatomical and neuropsychological abnormalities in schizophrenia, relative to bipolar disorder, stem from a core set of related genetic risks but that additional susceptibility genes and/or environmental pre- or perinatal insults lay the foundation for a more severe illness expression in schizophrenia.29 The mechanisms through which neurodevelopmental disturbances might contribute to increased risk for later illness expression, in either schizophrenia or bipolar disorder, are not yet clear. However, various manifestations of neurodevelopmental disturbances may provide promising allied phenotypes for both disorders. Many genetic causes of brain dysmaturation are being identified in basic developmental neurobiological research, and illness expression in the form of cognitive, motor, and social function is often evident well before illness onset during childhood and adolescence.

The time course of the emergence of neurocognitive deficits in schizophrenia and bipolar disorder is variable and not fully understood. However, retrospective studies of schizophrenia patients before illness onset,30,31 and studies of unaffected family members,3234 indicate that at least some cognitive deficits are present before illness onset and thus may represent intermediate cognitive phenotypes. Neurodevelopmental models of schizophrenia have been considered for some time and have been investigated in animal models.35,36 While less developed for bipolar disorder, the growing recognition of pediatric bipolar disorder as a common clinical condition highlights the need for parallel modeling of brain dysmaturation associated with bipolar disorder.37

Proband Studies

Early-Onset Schizophrenia.

Similar to adult schizophrenia studies, neuropsychological studies of childhood-onset schizophrenia have revealed impairments across a broad array of cognitive functions.38 Generalized cognitive deficits include areas of learning and abstraction as well as attention, which are commonly impaired in adult patients with schizophrenia. Neuropsychological deficits in childhood-onset schizophrenia appear to be greater than those associated with adult-onset patients, particularly in the areas of working memory, perceptual-motor skills, and overall intellectual abilities.39

Pediatric Bipolar Disorder.

Impairments in attentional set-shifting, visuospatial memory, verbal memory, working memory, and executive functions have been documented in pediatric bipolar disorder, regardless of medication status or illness state.37,40,41 Affective modulation of cognition has been investigated more extensively in pediatric bipolar disorder than in early-onset schizophrenia. Children with pediatric bipolar disorder misinterpret affective expression of sad, happy, and fearful child faces.42 Further, children with bipolar disorder display impairments in the identification of emotionally intense happy and sad facial expressions, tending to misjudge extreme facial expressions as being moderate to mildly intense.43 Whereas cognitive problems are more severe in early-onset schizophrenia, pediatric-onset bipolar disorder is associated with greater impairments in emotion processing. The pattern of more severe neurocognitive deficits in cases with early-onset highlights the potential importance of brain maturational factors in both disorders.

Family Studies

Early-Onset Schizophrenia.

Psychomotor speed, working memory, and executive function difficulties are seen in unaffected parents of children with schizophrenia.44 Offspring of schizophrenia, followed from birth to adolescence, showed motor and sensory dysfunction by 1 year of life, perceptual and motor difficulties by school age, and additional attention difficulties and social cognitive difficulties by adolescence.45 Studies that examined offspring in the high-risk period for illness onset (16–25 years of age) have shown impaired development of intellectual abilities, executive function, perceptual-motor speed, verbal learning, and memory.46 Other studies of genetically high-risk samples revealed impairments across a wide range of cognitive areas including executive function, information processing speed, motor speed, working memory, sustained attention, verbal fluency, and verbal memory across.4751

Pediatric Bipolar Disorder.

The few studies examining cognitive function in children at familial risk for bipolar disorder have reported decreased academic achievement and lower verbal intellectual abilities.52,53

Based on existing studies of early-onset schizophrenia and bipolar disorder, commonly affected cognitive domains across both disorders include attention, working memory, verbal memory, and executive function in probands and their families, while motor problems may be more specifically associated with schizophrenia. There is a strong tradition of cognitive research in schizophrenia and affective research in bipolar disorder, with limited overlap. This is a major limitation as affective problems in schizophrenia and cognitive problems in bipolar disorder are now both well established. To address issues of overlap and maximize the utility of the allied phenotypic approach, it will be important to assess cognitive and affective allied phenotypes in both disorders.

More importantly, adopting methods that map cognitive deficits to specific neural systems will be a critical step in tracing neurocognitive changes back to regional neural dysfunction and from there back to genetic variation. Paradigms from cognitive and affective neuroscience that are used in both human and animal models often can be more directly linked to neuroanatomy, neurotransmitter systems, and gene expression than standard clinical neuropsychological tests. Neurodevelopmental models need to specify growth trajectories and the relationships between genotype and neurocognitive development to further clarify how brain dysmaturation impacts cognitive development and potential illness expression.

Neuropsychological Impairments in Adulthood

Proband Studies

Neuropsychological deficits, typically ranging from moderate to marked, have been established in schizophrenia across a wide range of cognitive abilities and are recognized as a “generalized deficit.”54,55 Impairments are present during the first episode of psychosis and endure with minimal change in the early years after clinical stabilization with pharmacological treatment. Cognitive performance often does not change dramatically, even during acute episodes of psychosis.5457 Heretofore, a wide array of cognitive abnormalities have been associated with bipolar disorder,14,58 yet meta-analytic studies have indicated less pronounced impairments compared with schizophrenia samples.10

Over time, neuropsychological performance appears to be more stable in schizophrenia relative to bipolar disorder.59 Level of acute psychopathology may be linked to cognitive performance and long-term deficits in bipolar disorder.60 Additional reports of improved performance following clinical stabilization for bipolar patients (in the areas of nonverbal memory, executive function, and sustained attention) support this hypothesis.6163 Symptomatology in schizophrenia, on the other hand, appears to be relatively independent of cognitive performance as deficits persist after clinical stabilization in first-episode patients.64 However, the presence of psychotic symptoms may play a key role in the severity and stability of cognitive deficits in bipolar and other affective disorders.56

The most commonly observed cognitive deficits in bipolar disorder have been in the areas of attention, executive function, and to a lesser extent verbal memory and spatial working memory.65 Meta-analysis revealed worse performance for schizophrenia than bipolar patients in 9 of 11 cognitive domains.10 However, a subsample of bipolar patients with psychotic symptoms displayed a neuropsychological profile that was qualitatively more similar to the profile of schizophrenia patients.66 Indeed, several recent investigations have reported that psychosis in affective disorders is associated with more severe neuropsychological dysfunction compared with patients with no history of psychosis. For example, psychotic bipolar groups show more severe executive function impairments67 and differentially impaired spatial working memory68 when compared with nonpsychotic bipolar samples. Findings of more severe dysfunction have also been associated with psychosis in the context of unipolar depression.56,69 Overall, a lifetime presence of psychosis appears to be a key contributor to cognitive dysfunction, independent of affective symptoms, and some have suggested that psychotic disorders should be conceptualized as being on a continuum rather than as a group of categorically distinct illnesses.70,71 This pattern of results is consistent with data indicating a stronger genetic similarity between bipolar disorder with psychosis and schizophrenia.58 The degree to which risk for psychosis accounts for greater genetic similarity and overlapping patterns of neuropsychological dysfunction across these disorders needs to be addressed in future research.

Family Studies

Efforts to uncover the patterns of neuropsychological dysfunction shared among adults with schizophrenia and their unaffected relatives are plentiful.3234,7276 Although cognitive deficits are now well established in bipolar patients, there have been few studies using neuropsychological tasks in family studies of bipolar disorder. Many existing studies are an extension of the schizophrenia literature inasmuch as cognitive performance in bipolar probands and their family members have been collected for comparison with schizophrenia probands and their family members.66

Table 1 was designed to illustrate allied phenotype studies in psychotic probands and their unaffected relatives. The sparse citations for family and proband studies in bipolar disorder highlight the strong bias for work in this area focused on schizophrenia. To identify studies reporting significant neuropsychological findings in bipolar probands and their relatives as well as relatives of schizophrenia patients, the title, abstract, and key word fields of Medline were searched using the terms “bipolar” or “schizophrenia”; “neuropscyh*,” “neurocognit*,” or “cognit*”; and “famil*,” “relative,” or “twin.” The search was limited to English language articles available between 1980 and January 2008. Abstracts and titles were used to determine whether the references might be relevant to this review, and full texts of potentially relevant articles were retrieved to assess for inclusion in the table. Finally, reference lists of relevant articles were also checked for additional citations not identified during the database search. Cited articles were nonreview papers reporting significant heritability estimates or performance deficits, in bipolar probands or schizophrenia/bipolar familial samples (n > 10), on one or more neuropsychological tests. Reports of neuropsychological dysfunction in schizophrenia probands were excluded from the table given the large number of relevant studies and the generally accepted profile of diffuse neuropsychological deficits in schizophrenia.

Table 1.
Studies Reporting Significant Impairment or Heritability on Neuropsychological Tests in Bipolar Probands and Relatives of both Schizophrenia and Bipolar Probands


Episodic memory impairment may be an indicator of disrupted temporal lobe/hippocampal function. Studies of both high-risk adolescents and unaffected family members of schizophrenia patients have reported episodic memory dysfunction.46,77 A meta-analysis of family studies in schizophrenia also indicated moderate verbal memory deficits in unaffected relatives.78 Neuroanatomical findings of decreased temporal lobe and hippocampal volume in unaffected relatives77,7981 support these neuropsychological findings and suggest a genetic/neurodevelopmental component.

There is also strong support for a familial pattern of deficits in prefrontally mediated cognitive processes such as working memory, attention, abstraction, reasoning, and planning in unaffected relatives of schizophrenia patients.82 Working memory, the ability to hold information “online” for planning future behavior, is a critical component of many higher order cognitive skills, and deficits in this area may thus have widespread effects on other cognitive processes. Working memory deficits have been well documented in schizophrenia probands8385 and in offspring, monozygotic and dizygotic twins, and other unaffected relatives.32,8688 Spatial working memory deficits appear to increase in family members as genetic similarity to schizophrenia probands increases.33 Using a unique approach to identifying phenotypically homogeneous groups, a cluster analysis of several common neuropsychological tests resulted in 3 groups, comprised of both probands and family members, separated primarily by level of overall dysfunction.89 The authors proposed that multiple allied phenotypic measures may be helpful in characterizing genetic homogeneity among mixed samples of probands and unaffected family members.

Bipolar Disorder.

Unaffected monozygotic co-twins of bipolar patients display impaired face memory, verbal learning and memory, and working memory.90 Findings have been mixed among the few studies directly comparing schizophrenia and bipolar disorder probands and their unaffected relatives, but some deficits for verbally mediated tasks seem to be shared across the disorders. For example, delayed verbal memory deficits were observed in unaffected siblings of both bipolar and schizophrenia patients, whereas unaffected siblings of bipolar patients did not show impairments in general intelligence, working memory, verbal fluency, reasoning, or abstraction.91 Bipolar patients and their unaffected relatives were comparable to healthy controls on several executive function tests with the exception of response inhibition, as measured by the Stroop test, which was impaired in the relatives of both schizophrenia and bipolar patients.92 The latter finding suggests that susceptibility to interference and reduced inhibitory processing could be intermediate cognitive markers for similar or related familial vulnerability. McIntosh et al12 reported memory impairments in schizophrenia and bipolar probands as well as their unaffected relatives. In a Finnish twin study, bipolar probands and their unaffected co-twins did not differ from controls on measures of working memory; however, schizophrenia probands showed impaired verbal and spatial working memory while their unaffected twins displayed poor spatial working memory.13 Finally, meta-analysis in first-degree relatives of bipolar patients indicated small but significant effect sizes for a familial pattern of impairment for executive function and verbal memory.93

In summary, the schizophrenia literature offers more data suggesting that cognitive deficits may provide allied phenotypic markers indicative of liability to illness, and findings generally point to a familial pattern of neurocognitive dysfunction involving working memory, episodic memory, attention, and executive function. In contrast, there are relatively few family studies of neurocognitive function in the bipolar literature. This may reflect that until recently, systems neuroscience frameworks have not had the same level of impact in mood disorder research as in schizophrenia research. The few existing studies of bipolar disorder typically have small sample sizes, and findings are not yet consistent across studies. This is further complicated because factors such as clinical state and presence/history of psychosis in probands may be related to neuropsychological performance and result in greater heterogeneity in family studies of bipolar disorder. Despite the limitations of the bipolar literature, some cognitive domains (eg, working memory, verbal memory) appear to be affected in individuals with schizophrenia and bipolar disorder and in some of their relatives, thereby pointing to several potential allied neuropsychological phenotypes for future family genetic research.

Cognitive Oculomotor Paradigms

Cognitive abilities have traditionally been assessed using neuropsychological tests. However, performance on neuropsychological measures is not often strongly linked to specific functional brain systems affected by neuropsychiatric disorders and their treatment. Oculomotor paradigms have the advantages of being based on well-developed animal models that have characterized the neural systems supporting performance on different tasks in nonhuman primates,94 focal brain lesion studies,95 and functional brain imaging studies of healthy individuals.96

Two commonly used cognitive oculomotor tasks are the antisaccade task97 and the oculomotor delayed response task.98 During the antisaccade task, subjects are instructed to inhibit the natural tendency to look toward the appearance of a peripheral target but rather to immediately look to the opposite, mirror location. Prefrontal systems are known to support performance on such response suppression tasks. The oculomotor delayed response task requires subjects to remember the location of a briefly presented peripheral target and then to look to the remembered target location after a delay period. Accurate performance on this task reflects the ability to maintain information in spatial working memory, an ability that is also believed to reflect executive function.

Proband Studies


Thus far, oculomotor research with neuropsychiatric populations has mostly focused on schizophrenia patients and their family members. Medicated, unmedicated, chronic, and first-episode schizophrenia samples all consistently show higher error rates on antisaccade tasks than do healthy individuals.99105 However, some findings with this test have been inconsistent, perhaps due to methodological issues.106 For example, some studies found prolonged latencies to initiate context appropriate responses in schizophrenia patients,100,103,107 while others found no impairment.102,108 Longer antisaccade latencies were observed in treatment-naive but not previously treated first-episode patients, so treatment status may affect response latencies on this task.101 However, others found no differences between unmedicated and medicated chronic patients,109 no change in initially neuroleptic naive patients after treatment,110 and improved but consistently longer latencies compared with healthy participants in first-episode initially medication-naive patients up to 1 year after treatment initiation.99

Working memory studies with schizophrenia patients using the oculomotor delayed response task have consistently shown performance deficits compared with healthy individuals.111 These impairments have been reported in cross-sectional investigations of medicated and untreated patients109,110,112116 as well as never-treated first-episode patients.85,117 These deficits may be greater with longer delay periods during which spatial information needs to be maintained in working memory.85 Longitudinal studies of treatment-naive first-episode patients also reported impaired working memory performance, but these were restricted to longer delay periods during which spatial information had to be maintained in working memory. After 6 weeks of treatment with atypical antipsychotic medications, patients exhibited an exacerbation of baseline deficits reflected in uniformly inaccurate performance at all delay periods.85

Bipolar Disorder.

Although few studies have used cognitive saccade tasks with bipolar patients, antisaccade deficits have been reported in both bipolar disorder and schizophrenia.16,118,119 In a recent comparison of treatment-naive first-episode psychosis patients, antisaccade error rates were elevated in both bipolar and schizophrenia patients.120

There have also been few studies investigating working memory performance in bipolar patients using the oculomotor delayed responding task. Findings generally indicated no impairments for chronic, medicated bipolar disorder patients relative to healthy individuals,84,116,118,121 suggesting that spatial working memory deficits, as assessed by oculomotor delayed responding tasks, may be relatively specific to schizophrenia.

Family Studies

Studies with unaffected first-degree relatives of schizophrenia patients have reported increased rates of antisaccade abnormalities.102 While some consider this deficit to be a promising phenotype of genetic risk for schizophrenia,122 large-scale family studies are needed to clarify performance patterns in unaffected relatives and their relation to genotypes. Studies of working memory using oculomotor delayed response paradigms have reported deficits in individuals at high risk for schizophrenia,123 as have investigations of unaffected family members of schizophrenia probands.88,124

In summary, cognitive deficits for response inhibition and working memory are present on oculomotor tasks in both schizophrenia and bipolar patient populations. Available findings indicate a familial pattern in schizophrenia, but little family data are available in bipolar families. Further investigations are needed to assess the usefulness of neurophysiology studies of oculomotor paradigms as allied phenotypes for tracking down independent and overlapping genetic risks for schizophrenia and bipolar disorder.

Affective/Social Cognition Studies

Proband Studies

Emotion Perception.

Facial emotion matching125 is impaired schizophrenia and perhaps less so in bipolar patients. Individuals with schizophrenia consistently show deficits in the perception of facial affect126129 beyond general impairments of face perception. Significant deficits in the interpretation of emotional prosody in individuals with schizophrenia have also been reported.130,131 The literature in bipolar disorder with regard to perceived facial emotion is mixed, with euthymic patients generally showing no impairments132 and manic patients showing significant impairments.133 However, one study found deficits in facial affect matching in a euthymic sample.134 Direct comparison of emotion perception in schizophrenia and bipolar samples reported no difference in eye movements when visually scanning facial stimuli.135


While anhedonia, or decreased experience of positive emotion, has long been considered a core characteristic of schizophrenia,136 deficits in this area have not been observed consistently.137142 In particular, most studies assessing emotional responses at the moment of exposure to stimuli have found similar emotional responses for schizophrenia patients and healthy controls. The one study comparing anhedonia in schizophrenia and bipolar disorder reported less anhedonia in the bipolar group.137 Differentiating and measuring affective disturbances in schizophrenia and bipolar disorder, and their utility as endophenotypes, remain largely unexplored.

Stress Reactivity.

Individuals with schizophrenia can show intense responses to stressful situations, including family interactions with high levels of critical comments. High levels of criticism from relatives predict relapse of illness143 and increasing speech disorganization,144 while frequent contact with positively perceived relatives has been associated with longer periods without psychotic exacerbation.145 Similarly, individuals with bipolar disorder demonstrate higher levels of relapse when home environments include a highly critical relative146,147 and more disordered speech in response to negative situations.147 Thus, heightened social stress reactivity appears to be a common feature of both disorders, but its prevalence in family members has not been systematically explored.

Social Competence.

Individuals with schizophrenia and bipolar disorder often have significant difficulty in effectively managing interpersonal situations. In schizophrenia, this social impairment is known to be present prior to onset of psychotic illness and is characterized by fewer and less satisfactory social relationships.148 Although both disorders are associated with poor premorbid social functioning in adolescence, premorbid adjustment difficulties typically appear earlier and are more debilitating in schizophrenia.149 However, recent findings suggest minimal differences between the 2 disorders for participation in social activities or frequency of social relations150 after illness onset. This observation highlights the growing recognition of significant functional disturbances in bipolar disorder, even during euthymic periods.

Social Cognition.

Although few studies have compared social cognitive abilities in schizophrenia and bipolar disorders, available findings indicate that both disorders show similar impairments in social knowledge151 and social problem solving.152

Family Studies

There are few studies of emotion perception in family members of individuals with schizophrenia and fewer in family members of bipolar patients. Findings have been mixed with regard to deficits in affect perception in relatives of schizophrenia probands. Whereas one study reported no differences among probands, family members, and healthy controls in recognition of basic emotions,145 2 recent studies showed impaired emotion recognition among unaffected siblings.153,154 Similarly, inconsistent findings have been reported for social judgment. One study reported a mixed pattern of no deficits for facial affect recognition or social judgment but impaired nonverbal behavior sensitivity in unaffected family members.155 In contrast, recent reports have indicated impaired social judgment in unaffected first-degree relatives, albeit less severe than in schizophrenia probands.156 Disturbances in affect perception were reported for facial, vocal, and combined modalities in unaffected siblings.157

Studies assessing emotional experience, to our knowledge, have been limited to relatives of schizophrenia probands. Two studies158,159 found significantly more self-reported physical anhedonia, and a third study160 found more social anhedonia in unaffected relatives of schizophrenia patients. However, observational studies of emotion-modulated startle have not found differences among schizophrenia probands, their unaffected relatives, and healthy controls.138

Although social competence is rarely assessed in relatives of patients, studies using measures of schizotypy have reported social dysfunction and social-interpersonal deficits in unaffected relatives of schizophrenia probands.161 Direct comparison of relatives of both schizophrenia and bipolar probands using schizotypy ratings indicated not only very minimal group differences but also a significant intrafamilial resemblance for social behavior (lack of close friends, constricted affect, excessive social anxiety) in both groups.162

Overall, schizophrenia probands display greater levels of dysfunction than their bipolar counterparts in the expression of anhedonia as well as when decoding facial expression or emotional cues in the prosody of speech. However, similar levels of dysfunction have been reported for response to interpersonal stressors, social activity, and social cognition. Oddly, given the cardinal clinical characteristics of the disorders, there has been much more laboratory research on emotional deficits in schizophrenia than in bipolar probands. Moreover, the discrepancy is even greater for studies of family members where there has been little quantitative laboratory assessment of emotional characteristics in the unaffected relatives of bipolar probands. Studies of affective processes, and their neural substrate, may provide important endophenotypes for studies of both bipolar disorder and schizophrenia. With the emergence of affective neuroscience as a field, and the parallel emergence of neurophysiological and neuroimaging tools to study emotional brain systems, significant progress in this area is likely in coming years, especially in family studies of bipolar disorder.


The allied phenotype approach has garnered much enthusiasm owing, in part, to the assumption of a more direct association between related genetic characteristics and both neurophysiological measures and narrowly parsed psychological processes, compared with the overt expression of clinical disorders. Support for this approach remains indirect, based on its success in other medical disorders rather than a compelling track record in psychiatric genetics. For psychiatric disorders, it remains unclear whether more detailed phenotyping or gathering much larger samples will ultimately prove the best strategy for unraveling the genetic contributions of complex psychiatric disorders. Experience in unraveling the genetics of neurological disorders such as epilepsy and dementias may prove useful in this regard. There, phenotypic delineation of subtypes of syndromes has been crucial to unraveling their genetic basis. The value of extensive laboratory phenotyping for psychiatric genetics may also depend on the utility of allied phenotypes for resolving the heterogeneity of the broadly defined syndromes of schizophrenia and bipolar disorder into subgroups of patients with more homogeneous etiopathology.

The potential value of the allied phenotype approach has recently been challenged on theoretical grounds.163 Reflecting on findings from a meta-analysis of the effect of COMT on promising allied phenotypes, these investigators caution that allied phenotypes and disease phenotypes may both reflect many genes of small effect.163 The notion that the allied phenotypes currently being used in proband and family studies are genetically complex has merit, yet the allied phenotype approach may have value if the genetics of allied phenotypes are significantly simpler than that of the disorder.

The genetic complexity of allied phenotypes notwithstanding, this approach also has the advantage of providing more reliable and objective laboratory assessments for large multisite family genetic studies. This can potentially help define homogeneous etiological groups and detect biomarkers of illness susceptibility that can help guide earlier diagnosis and intervention. Also, the intermediate phenotype approach can potentially contribute to enhanced understanding of disease pathophysiology from gene to protein expression to biochemistry to neurophysiology to behavior that will ultimately provide better theoretical models for understanding the neurobiology of serious mental disorders, both those unique and common to currently defined clinical syndromes.

Cognitive Epidemiology

Distinguishing potential genetic effects from normative aging, sex, and education effects is critical for identifying and using allied phenotypes in family genetic research. Often, it is unclear whether the variability in patient performance can be attributed to specific genes or to complex population stratification effects. Normative data provide a means for equitable comparison among test takers relative to well-defined performance expectations. In this respect, the clinical neuropsychological approach to assessing cognition is promising due to its standardized procedures and published normative data. However, the drawback to using neuropsychological measures is the complexity of the tests and therefore the high likelihood that the determination of test performance itself has a high-level genetic complexity. Tests that isolate discrete neurocognitive processes or neurophysiological measures are likely to have less genetic variance and more apt to link with specific genes. Despite all these advantages, it remains fair to say that many of the most intriguing allied phenotype measures have not yet proved their value in associating specific genes with discreet neurocognitive processes in schizophrenia or bipolar disorder research.

Part of this issue may be related to the need for better and more refined allied phenotypes. Outside the “usual suspects” (eg, P3, P50, global eye tracking performance, and the Wisconsin Card Sorting Test), there is very little family data with newer neurocognitive tests, newly defined neural systems, or new cognitive neuroscience constructs to guide their selection for use in larger family studies. The fields of experimental cognitive and affective neuroscience are rapidly evolving. Research in this area typically focuses on ever changing tools to investigate the most current theoretical frameworks. The same test is rarely used in subsequent studies, tests are often developed with difficulty levels suitable for undergraduate populations, and psychometric properties are rarely established or even examined. As these fields mature, a critical step forward will be developing standardized testing procedures for the most useful measures complete with well-developed psychometric exploration. Systematic assessment of normative parameters in diverse samples from various geographical regions across varied age and educational levels will be essential for establishing the utility of newer phenotypes in large-scale family genetic studies.

Concluding Remarks

Can progress in molecular genetics lay the framework for major advances in psychiatric genetics? Advances in the development and utilization of allied phenotypes have generally lagged behind, but developments in cognitive and affective neuroscience provide a framework for substantial progress in this area over the coming decade. Revised and refined paradigms will be needed for clinical studies; base rates of deficits must be established for patient studies and followed by adequately powered family studies to evaluate the prevalence of deficits in family members as well as association with subclinical illness manifestations. Refocusing our efforts systematically will inevitably proceed more slowly than advances in molecular genetic methodologies, yet there is considerable potential for efforts to dissect clinical syndromes into neurobiologically discrete subgroups. In this manner, the field can begin to more effectively define the underlying causes of polygenetic disorders such as schizophrenia and bipolar disorder.

Importantly, this approach may be useful for bipolar disorder as well as schizophrenia. To date, a variety of factors have led to far more investigation of potential allied phenotypes in schizophrenia compared with bipolar disorder. Yet, as the field of affective neuroscience proceeds, and as persistent cognitive deficits and functional deficits even during euthymic states are recognized in bipolar patients, especially those with a history of psychosis, one can expect a significant increase in the use of the allied phenotype approach in investigations of bipolar disorder. This work may have considerable impact in reframing understanding of the boundaries and overlaps between schizophrenia and bipolar disorder in ways that may have considerable impact on clinical practice.

At first glance, neurocognitive dysfunction in bipolar probands and their unaffected relatives appear less severe than the impairments associated with schizophrenia. However, the level of cognitive deficit is more similar for individuals with schizophrenia and bipolar disorder patients with a history of psychotic symptoms. Moreover, differences in the 2 disorders with respect to severity of impairments in specific cognitive domains may vary in ways that are yet to be fully specified. Deficits in affective processes and social cognition are important potential allied phenotypes that require considerably greater research attention as these may be even more useful for defining the boundaries of schizophrenia and bipolar disorder. To advance the use of the allied phenotype approach in family research, data are needed both to establish disorder-specific allied phenotypes and to evaluate the extent to which putative allied phenotypes are linked to shared or specific genetic risk factors.


This project was supported by the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) and the National Institutes of Health (NIMH: MH077862 and MH062134).


1. Berrettini WH. Are schizophrenic and bipolar disorders related? A review of family and molecular studies. Biol Psychiatry. 2000;48(6):531–538. [PubMed]
2. Bramon E, Sham PC. The common genetic liability between schizophrenia and bipolar disorder: a review. Curr Psychiatry Rep. 2001;3(4):332–337. [PubMed]
3. Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry. 2002;7(4):405–411. [PubMed]
4. Baron M. Genetics of schizophrenia and the new millennium: progress and pitfalls. Am J Hum Genet. 2001;68(2):299–312. [PubMed]
5. Craddock N, O'Donovan MC, Owen MJ. Phenotypic and genetic complexity of psychosis. Invited commentary on … schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry. 2007;190:200–203. [PubMed]
6. Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry. 2005;186:364–366. [PubMed]
7. Potash JB, Zandi PP, Willour VL, et al. Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder. Am J Psychiatry. 2003;160(4):680–686. [PubMed]
8. Levinson DF. The genetics of depression: a review. Biol Psychiatry. 2006;60(2):84–92. [PubMed]
9. Potash JB, Willour VL, Chiu YF, et al. The familial aggregation of psychotic symptoms in bipolar disorder pedigrees. Am J Psychiatry. 2001;158(8):1258–1264. [PubMed]
10. Krabbendam L, Arts B, van Os J, Aleman A. Cognitive functioning in patients with schizophrenia and bipolar disorder: a quantitative review. Schizophr Res. 2005;80(2–3):137–149. [PubMed]
11. Maier W, Zobel A, Wagner M. Schizophrenia and bipolar disorder: differences and overlaps. Curr Opin Psychiatry. 2006;19(2):165–170. [PubMed]
12. McIntosh AM, Harrison LK, Forrester K, Lawrie SM, Johnstone EC. Neuropsychological impairments in people with schizophrenia or bipolar disorder and their unaffected relatives. Br J Psychiatry. 2005;186:378–385. [PubMed]
13. Pirkola T, Tuulio-Henriksson A, Glahn D, et al. Spatial working memory function in twins with schizophrenia and bipolar disorder. Biol Psychiatry. 2005;58(12):930–936. [PubMed]
14. Sweeney JA, Luna B, Haas GL, Keshavan MS, Mann JJ, Thase ME. Pursuit tracking impairments in schizophrenia and mood disorders: step-ramp studies with unmedicated patients. Biol Psychiatry. 1999;46(5):671–680. [PubMed]
15. Rosenberg DR, Sweeney JA, Squires-Wheeler E, Keshavan MS, Cornblatt BA, Erlenmeyer-Kimling L. Eye-tracking dysfunction in offspring from the New York High-Risk Project: diagnostic specificity and the role of attention. Psychiatry Res. 1997;66(2–3):121–130. [PubMed]
16. Tien AY, Ross DE, Pearlson G, Strauss ME. Eye movements and psychopathology in schizophrenia and bipolar disorder. J Nerv Ment Dis. 1996;184(6):331–338. [PubMed]
17. Strasser HC, Lilyestrom J, Ashby ER, et al. Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: a pilot study. Biol Psychiatry. 2005;57(6):633–639. [PubMed]
18. Cannon TD, Keller MC. Endophenotypes in the genetic analyses of mental disorders. Annu Rev Clin Psychol. 2006;2:267–290. [PubMed]
19. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636–645. [PubMed]
20. Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry. 2006;60(2):93–105. [PubMed]
21. Bearden CE, Meyer SE, Loewy RL, Niendam TA, Cannon TD. The neurodevelopmental model of schizophrenia. In: Cicchetti D, Cohen DJ, editors. Developmental Psychopathology. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2006.
22. Keshavan MS, Gilbert AR, Diwadkar V. Neurodevelopmental theories. In: Lieberman JA, Scott ST, Perkins DO, editors. The American Psychiatric Publishing Textbook of Schizophrenia. Washington, DC: Psychiatric Publishing; 2006.
23. Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 2005;10(5):434–449. [PubMed]
24. Deary IJ, Spinath FM, Bates TC. Genetics of intelligence. Eur J Hum Genet. 2006;14(6):690–700. [PubMed]
25. Plomin R, Spinath FM. Intelligence: genetics, genes, and genomics. J Pers Soc Psychol. 2004;86(1):112–129. [PubMed]
26. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry. 2002;159(7):1080–1092. [PubMed]
27. Cannon M, Tarrant CJ, Hattunen MO, Jones PB. Childhood development and later schizophrenia: evidence from genetic high-risk and birth cohort studies. In: Murray RM, Jones PB, Susser E, Van Os J, Cannon M, editors. The Epidemiology of Schizophrenia. Cambridge, UK: Cambridge University Press; 2003.
28. Strakowski SM, DelBello MP, Sax KW, et al. Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry. 1999;56(3):254–260. [PubMed]
29. Murray RM, Sham P, van Os J, Zanelli J, Cannon M, McDonald C. A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophr Res. 2004;71(2–3):405–416. [PubMed]
30. Mittal VA, Tessner KD, Trottman HD, et al. Movement abnormalities and the progression of prodromal symptomatology in adolescents at risk for psychotic disorders. J Abnorm Psychol. 2007;116(2):260–267. [PubMed]
31. Walker EF. The role of endogenous and exogenous risk factors in the genesis of schizophrenia. In: McMahon RJ, Peters RD, editors. The Effects of Parental Dysfunction on Children. New York, NY: Kluwer Academic/Plenum Publishers; 2002.
32. Cannon TD, Huttunen MO, Lonnqvist J, et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet. 2000;67(2):369–382. [PubMed]
33. Glahn DC, Therman S, Manninen M, et al. Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry. 2003;53(7):624–626. [PubMed]
34. Wittorf A, Klingberg S, Wiedemann G. Secondary verbal memory: a potential endophenotype of schizophrenia. J Psychiatr Res. 2004;38(6):601–612. [PubMed]
35. Chen J, Lipska BK, Weinberger DR. Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models. Biol Psychiatry. 2006;59(12):1180–1188. [PubMed]
36. Thompson JL, Pogue-Geile MF, Grace AA. Developmental pathology, dopamine, and stress: a model for the age of onset of schizophrenia symptoms. Schizophr Bull. 2004;30(4):875–900. [PubMed]
37. Pavuluri MN, O'Connor MM, Harral EM, Moss M, Sweeney JA. Impact of neurocognitive function on academic difficulties in pediatric bipolar disorder: a clinical translation. Biol Psychiatry. 2006;60(9):951–956. [PubMed]
38. Kumra S, Wiggs E, Bedwell J, et al. Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified. Schizophr Res. 2000;42(2):135–144. [PubMed]
39. Biswas P, Malhotra S, Malhotra A, Gupta N. Comparative study of neuropsychological correlates in schizophrenia with onset in childhood, adolescence and adulthood. Eur Child Adolesc Psychiatry. 2006;15(6):360–366. [PubMed]
40. Doyle AE, Wilens TE, Kwon A, et al. Neuropsychological functioning in youth with bipolar disorder. Biol Psychiatry. 2005;58(7):540–548. [PubMed]
41. Dickstein DP, Treland JE, Snow J, et al. Neuropsychological performance in pediatric bipolar disorder. Biol Psychiatry. 2004;55(1):32–39. [PubMed]
42. McClure EB, Pope K, Hoberman AJ, Pine DS, Leibenluft E. Facial expression recognition in adolescents with mood and anxiety disorders. Am J Psychiatry. 2003;160(6):1172–1174. [PubMed]
43. Schenkel LS, Pavuluri MN, Herbener ES, Harral EM, Sweeney JA. Facial emotion processing in acutely ill and euthymic patients with pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(8):1070–1079. [PubMed]
44. Gochman PA, Greenstein D, Sporn A, et al. Childhood onset schizophrenia: familial neurocognitive measures. Schizophr Res. 2004;71(1):43–47. [PubMed]
45. Hans SL, Auerbach JG, Auerbach AG, Marcus J. Development from birth to adolescence of children at-risk for schizophrenia. J Child Adolesc Psychopharmacol. 2005;15(3):384–394. [PubMed]
46. Byrne M, Hodges A, Grant E, Owens DC, Johnstone EC. Neuropsychological assessment of young people at high genetic risk for developing schizophrenia compared with controls: preliminary findings of the Edinburgh High Risk Study (EHRS) Psychol Med. 1999;29(5):1161–1173. [PubMed]
47. Brewer WJ, Francey SM, Wood SJ, et al. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry. 2005;162(1):71–78. [PubMed]
48. Cannon M, Jones P, Huttunen MO, et al. School performance in Finnish children and later development of schizophrenia: a population-based longitudinal study. Arch Gen Psychiatry. 1999;56(5):457–463. [PubMed]
49. Cornblatt B, Obuchowski M, Roberts S, Pollack S, Erlenmeyer-Kimling L. Cognitive and behavioral precursors of schizophrenia. Dev Psychopathol. 1999;11(3):487–508. [PubMed]
50. Keefe RS, Perkins DO, Gu H, Zipursky RB, Christensen BK, Lieberman JA. A longitudinal study of neurocognitive function in individuals at-risk for psychosis. Schizophr Res. 2006;88(1–3):26–35. [PubMed]
51. Seidman LJ, Giuliano AJ, Smith CW, et al. 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. Schizophr Bull. 2006;32(3):507–524. [PMC free article] [PubMed]
52. Decina P, Kestenbaum CJ, Farber S, et al. Clinical and psychological assessment of children of bipolar probands. Am J Psychiatry. 1983;140(5):548–553. [PubMed]
53. McDonough-Ryan P, DelBello M, Shear PK, Ris DM, Soutullo C, Strakowski SM. Academic and cognitive abilities in children of parents with bipolar disorder: a test of the nonverbal learning disability model. J Clin Exp Neuropsychol. 2002;24(3):280–285. [PubMed]
54. Bilder RM, Goldman RS, Robinson D, et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry. 2000;157(4):549–559. [PubMed]
55. Saykin AJ, Shtasel DL, Gur RE, et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 1994;51(2):124–131. [PubMed]
56. Hill SK, Keshavan MS, Thase ME, Sweeney JA. Neuropsychological dysfunction in antipsychotic-naive first-episode unipolar psychotic depression. Am J Psychiatry. 2004;161(6):996–1003. [PubMed]
57. Hoff AL, Sakuma M, Wieneke M, Horon R, Kushner M, DeLisi LE. Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia. Am J Psychiatry. 1999;156(9):1336–1341. [PubMed]
58. Daban C, Martinez-Aran A, Torrent C, et al. Specificity of cognitive deficits in bipolar disorder versus schizophrenia. A systematic review. Psychother Psychosom. 2006;75(2):72–84. [PubMed]
59. Burdick KE, Goldberg JF, Harrow M, Faull RN, Malhotra AK. Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia. J Nerv Ment Dis. 2006;194(4):255–260. [PubMed]
60. Goldberg TE, Gold JM, Greenberg R, et al. Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery. Am J Psychiatry. 1993;150(9):1355–1362. [PubMed]
61. Liu SK, Chiu CH, Chang CJ, Hwang TJ, Hwu HG, Chen WJ. Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers. Am J Psychiatry. 2002;159(6):975–982. [PubMed]
62. Murphy FC, Sahakian BJ. Neuropsychology of bipolar disorder. Br J Psychiatry Suppl. 2001;41:s120–s127. [PubMed]
63. McGrath J, Scheldt S, Welham J, Clair A. Performance on tests sensitive to impaired executive ability in schizophrenia, mania and well controls: acute and subacute phases. Schizophr Res. 1997;26(2–3):127–137. [PubMed]
64. Hill SK, Schuepbach D, Herbener ES, Keshavan MS, Sweeney JA. Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naive patients with schizophrenia. Schizophr Res. 2004;68(1):49–63. [PubMed]
65. Quraishi S, Frangou S. Neuropsychology of bipolar disorder: a review. J Affect Disord. 2002;72(3):209–226. [PubMed]
66. Seidman LJ, Kremen WS, Koren D, Faraone SV, Goldstein JM, Tsuang MT. A comparative profile analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses. Schizophr Res. 2002;53(1–2):31–44. [PubMed]
67. Glahn DC, Almasy L, Blangero J, et al. Adjudicating neurocognitive endophenotypes for schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2007;144(2):242–249. [PubMed]
68. Glahn DC, Barrett J, Bearden CE, et al. Dissociable mechanisms for memory impairment in bipolar disorder and schizophrenia. Psychol Med. 2006;36(8):1085–1095. [PubMed]
69. Gomez RG, Fleming SH, Keller J, et al. The neuropsychological profile of psychotic major depression and its relation to cortisol. Biol Psychiatry. 2006;60(5):472–478. [PubMed]
70. Schretlen DJ, Cascella NG, Meyer SM, et al. Neuropsychological functioning in bipolar disorder and schizophrenia. Biol Psychiatry. 2007;62(2):179–186. [PMC free article] [PubMed]
71. Crow TJ. Schizophrenia as the price that homo sapiens pays for language: a resolution of the central paradox in the origin of the species. Brain Res Brain Res Rev. 2000;31(2–3):118–129. [PubMed]
72. Thompson JL, Watson JR, Steinhauer SR, Goldstein G, Pogue-Geile MF. Indicators of genetic liability to schizophrenia: a sibling study of neuropsychological performance. Schizophr Bull. 2005;31(1):85–96. [PubMed]
73. Winterer G, Coppola R, Goldberg TE, et al. Prefrontal broadband noise, working memory, and genetic risk for schizophrenia. Am J Psychiatry. 2004;161(3):490–500. [PubMed]
74. Snitz BE, MacDonald AW, III, Carter CS. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull. 2006;32(1):179–194. [PMC free article] [PubMed]
75. Szoke A, Schurhoff F, Mathieu F, Meary A, Ionescu S, Leboyer M. Tests of executive functions in first-degree relatives of schizophrenic patients: a meta-analysis. Psychol Med. 2005;35(6):771–782. [PubMed]
76. Whyte MC, McIntosh AM, Johnstone EC, Lawrie SM. Declarative memory in unaffected adult relatives of patients with schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2005;78(1):13–26. [PubMed]
77. Seidman LJ, Faraone SV, Goldstein JM, et al. Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch Gen Psychiatry. 2002;59(9):839–849. [PubMed]
78. Sitskoorn MM, Aleman A, Ebisch SJ, Appels MC, Kahn RS. Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophr Res. 2004;71(2–3):285–295. [PubMed]
79. Narr KL, van Erp TG, Cannon TD, et al. A twin study of genetic contributions to hippocampal morphology in schizophrenia. Neurobiol Dis. 2002;11(1):83–95. [PubMed]
80. van Erp TG, Saleh PA, Rosso IM, et al. Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. Am J Psychiatry. 2002;159(9):1514–1520. [PubMed]
81. van Erp TG, Saleh PA, Huttunen M, et al. Hippocampal volumes in schizophrenic twins. Arch Gen Psychiatry. 2004;61(4):346–353. [PubMed]
82. Kremen WS, Seidman LJ, Pepple JR, Lyons MJ, Tsuang MT, Faraone SV. Neuropsychological risk indicators for schizophrenia: a review of family studies. Schizophr Bull. 1994;20(1):103–119. [PubMed]
83. Keefe RS, Roitman SE, Harvey PD, et al. A pen-and-paper human analogue of a monkey prefrontal cortex activation task: spatial working memory in patients with schizophrenia. Schizophr Res. 1995;17(1):25–33. [PubMed]
84. Park S. Association of an oculomotor delayed response task and the Wisconsin Card Sort Test in schizophrenic patients. Int J Psychophysiol. 1997;27(2):147–151. [PubMed]
85. Reilly JL, Harris MS, Keshavan MS, Sweeney JA. Adverse effects of risperidone on spatial working memory in first-episode schizophrenia. Arch Gen Psychiatry. 2006;63(11):1189–1197. [PubMed]
86. Conklin HM, Curtis CE, Katsanis J, Iacono WG. Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task. Am J Psychiatry. 2000;157(2):275–277. [PubMed]
87. Egan MF, Goldberg TE, Gscheidle T, Weirich M, Bigelow LB, Weinberger DR. Relative risk of attention deficits in siblings of patients with schizophrenia. Am J Psychiatry. 2000;157(8):1309–1316. [PubMed]
88. Park S, Holzman PS, Goldman-Rakic PS. Spatial working memory deficits in the relatives of schizophrenic patients. Arch Gen Psychiatry. 1995;52(10):821–828. [PubMed]
89. Hoti F, Tuulio-Henriksson A, Haukka J, Partonen T, Holmstrom L, Lonnqvist J. Family-based clusters of cognitive test performance in familial schizophrenia. BMC Psychiatry. 2004;4:20. [PMC free article] [PubMed]
90. Gourovitch ML, Torrey EF, Gold JM, Randolph C, Weinberger DR, Goldberg TE. Neuropsychological performance of monozygotic twins discordant for bipolar disorder. Biol Psychiatry. 1999;45(5):639–646. [PubMed]
91. Keri S, Kelemen O, Benedek G, Janka Z. Different trait markers for schizophrenia and bipolar disorder: a neurocognitive approach. Psychol Med. 2001;31(5):915–922. [PubMed]
92. Zalla T, Joyce C, Szoke A, et al. Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res. 2004;121(3):207–217. [PubMed]
93. Arts B, Jabben N, Krabbendam L, van Os J. Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives. Psychol Med. October 9, 2007;1–15. doi:10.1017/S0033291707001675. [PubMed]
94. Bruce CJ, Goldberg ME. Primate frontal eye fields. I. Single neurons discharging before saccades. J Neurophysiol. 1985;53(3):603–635. [PubMed]
95. Pierrot-Deseilligny C. Saccade and smooth-pursuit impairment after cerebral hemispheric lesions. Eur Neurol. 1994;34(3):121–134. [PubMed]
96. Sweeney JA, Mintun MA, Kwee S, et al. Positron emission tomography study of voluntary saccadic eye movements and spatial working memory. J Neurophysiol. 1996;75(1):454–468. [PubMed]
97. Munoz DP, Everling S. Look away: the anti-saccade task and the voluntary control of eye movement. Nat Rev Neurosci. 2004;5(3):218–228. [PubMed]
98. Goldman-Rakic PS. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiatry. 1999;46(5):650–661. [PubMed]
99. Harris MS, Reilly JL, Keshavan MS, Sweeney JA. Longitudinal studies of antisaccades in antipsychotic-naive first-episode schizophrenia. Psychol Med. 2006;36(4):485–494. [PubMed]
100. Curtis CE, Calkins ME, Grove WM, Feil KJ, Iacono WG. Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives. Am J Psychiatry. 2001;158(1):100–106. [PubMed]
101. Hutton SB, Crawford TJ, Puri BK, et al. Smooth pursuit and saccadic abnormalities in first-episode schizophrenia. Psychol Med. 1998;28(3):685–692. [PubMed]
102. Clementz BA, McDowell JE, Zisook S. Saccadic system functioning among schizophrenia patients and their first-degree biological relatives. J Abnorm Psychol. 1994;103(2):277–287. [PubMed]
103. Fukushima J, Morita N, Fukushima K, Chiba T, Tanaka S, Yamashita I. Voluntary control of saccadic eye movements in patients with schizophrenic and affective disorders. J Psychiatr Res. 1990;24(1):9–24. [PubMed]
104. Clementz BA, McDowell JE, Zisook S. Saccadic system functioning among schizophrenia patients and their first-degree biological relatives. J Abnorm Psychol. 1994;103:277–287. [PubMed]
105. Fukushima J, Morita N, Fukushima AK, Chiba T, Tanaka S, Yamashita I. Voluntary control of saccadic eye movements in patients with schizophrenic and affective disorders. J Psychiatr Res. 1990;24:9–24. [PubMed]
106. Levy DL, O'Driscoll G, Matthysse S, Cook SR, Holzman PS, Mendell NR. Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis. Schizophr Res. 2004;71(1):113–125. [PubMed]
107. Sereno AB, Holzman PS. Antisaccades and smooth pursuit eye movements in schizophrenia. Biol Psychiatry. 1995;37(6):394–401. [PubMed]
108. Hutton SB, Joyce EM, Barnes TR, Kennard C. Saccadic distractibility in first-episode schizophrenia. Neuropsychologia. 2002;40(10):1729–1736. [PubMed]
109. Crawford TJ, Haeger B, Kennard C, Reveley MA, Henderson L. Saccadic abnormalities in psychotic patients. II. The role of neuroleptic treatment. Psychol Med. 1995;25(3):473–483. [PubMed]
110. Muller N, Riedel M, Eggert T, Straube A. Internally and externally guided voluntary saccades in unmedicated and medicated schizophrenic patients. Part II. Saccadic latency, gain, and fixation suppression errors. Eur Arch Psychiatry Clin Neurosci. 1999;249(1):7–14. [PubMed]
111. Lee J, Park S. Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol. 2005;114(4):599–611. [PubMed]
112. Broerse A, Crawford TJ, den Boer JA. Differential effects of olanzapine and risperidone on cognition in schizophrenia? A saccadic eye movement study. J Neuropsychiatry Clin Neurosci. 2002;14(4):454–460. [PubMed]
113. Ross RG, Olincy A, Harris JG, Sullivan B, Radant A. Smooth pursuit eye movements in schizophrenia and attentional dysfunction: adults with schizophrenia, ADHD, and a normal comparison group. Biol Psychiatry. 2000;48(3):197–203. [PubMed]
114. McDowell JE, Clementz BA. Ocular-motor delayed-response task performance among schizophrenia patients. Neuropsychobiology. 1996;34(2):67–71. [PubMed]
115. Crawford TJ, Haeger B, Kennard C, Reveley MA, Henderson L. Saccadic abnormalities in psychotic patients. I. Neuroleptic-free psychotic patients. Psychol Med. 1995;25(3):461–471. [PubMed]
116. Park S, Holzman PS. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry. 1992;49(12):975–982. [PubMed]
117. Reilly JL, Harris MSH, Khine TT, Keshavan MS, Sweeney JA. Antipsychotic drugs exacerbate impairment on a working memory task in first-episode schizophrenia. Biol Psychiatry. 2007;62:818–821. [PubMed]
118. Gooding DC, Tallent KA. The association between antisaccade task and working memory task performance in schizophrenia and bipolar disorder. J Nerv Ment Dis. 2001;189(1):8–16. [PubMed]
119. Katsanis J, Kortenkamp S, Iacono WG, Grove WM. Antisaccade performance in patients with schizophrenia and affective disorder. J Abnorm Psychol. 1997;106(3):468–472. [PubMed]
120. Hill SK, Reilly JL, Harris MS, Khine T, Sweeney JA. Oculomotor and neuropsychological effects of antipsychotic treatment for schizophrenia. Schizophr Bull. 2008;34(3):494–506. [PMC free article] [PubMed]
121. Park S, Holzman PS. Association of working memory deficit and eye tracking dysfunction in schizophrenia. Schizophr Res. 1993;11(1):55–61. [PubMed]
122. Calkins ME, Curtis CE, Grove WM, Iacono WG. Multiple dimensions of schizotypy in first degree biological relatives of schizophrenia patients. Schizophr Bull. 2004;30(2):317–325. [PubMed]
123. Diwadkar VA, Montrose DM, Dworakowski D, Sweeney JA, Keshavan MS. Genetically predisposed offspring with schizotypal features: an ultra high-risk group for schizophrenia? Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(2):230–238. [PubMed]
124. McDowell JE, Brenner CA, Myles-Worsley M, Coon H, Byerley W, Clementz BA. Ocular motor delayed-response task performance among patients with schizophrenia and their biological relatives. Psychophysiology. 2001;38(1):153–156. [PubMed]
125. Addington J, Addington D. Facial affect recognition and information processing in schizophrenia and bipolar disorder. Schizophr Res. 1998;32(3):171–181. [PubMed]
126. Herbener ES, Hill SK, Marvin RW, Sweeney JA. Effects of antipsychotic treatment on emotion perception deficits in first-episode schizophrenia. Am J Psychiatry. 2005;162(9):1746–1748. [PubMed]
127. Kohler CG, Bilker W, Hagendoorn M, Gur RE, Gur RC. Emotion recognition deficit in schizophrenia: association with symptomatology and cognition. Biol Psychiatry. 2000;48(2):127–136. [PubMed]
128. Mueser KT, Penn DL, Blanchard JJ, Bellack AS. Affect recognition in schizophrenia: a synthesis of findings across three studies. Psychiatry. 1997;60(4):301–308. [PubMed]
129. Salem JE, Kring AM, Kerr SL. More evidence for generalized poor performance in facial emotion perception in schizophrenia. J Abnorm Psychol. 1996;105(3):480–483. [PubMed]
130. Kucharska-Pietura K, David AS, Masiak M, Phillips ML. Perception of facial and vocal affect by people with schizophrenia in early and late stages of illness. Br J Psychiatry. 2005;187:523–528. [PubMed]
131. Murphy D, Cutting J. Prosodic comprehension and expression in schizophrenia. J Neurol Neurosurg Psychiatry. 1990;53(9):727–730. [PMC free article] [PubMed]
132. Harmer CJ, Grayson L, Goodwin GM. Enhanced recognition of disgust in bipolar illness. Biol Psychiatry. 2002;51(4):298–304. [PubMed]
133. Getz GE, Shear PK, Strakowski SM. Facial affect recognition deficits in bipolar disorder. J Int Neuropsychol Soc. 2003;9(4):623–632. [PubMed]
134. Bozikas VP, Tonia T, Fokas K, Karavatos A, Kosmidis MH. Impaired emotion processing in remitted patients with bipolar disorder. J Affect Disord. 2006;91(1):53–56. [PubMed]
135. Bestelmeyer PE, Tatler BW, Phillips LH, Fraser G, Benson PJ, St Clair D. Global visual scanning abnormalities in schizophrenia and bipolar disorder. Schizophr Res. 2006;87(1–3):212–222. [PubMed]
136. Bleuler E. Textbook of Psychiatry. New York: Macmillan Company; 1924. Translated by A.A Brill.
137. Blanchard JJ, Bellack AS, Mueser KT. Affective and social-behavioral correlates of physical and social anhedonia in schizophrenia. J Abnorm Psychol. 1994;103(4):719–728. [PubMed]
138. Curtis CE, Lebow B, Lake DS, Katsanis J, Iacono WG. Acoustic startle reflex in schizophrenia patients and their first-degree relatives: evidence of normal emotional modulation. Psychophysiology. 1999;36(4):469–475. [PubMed]
139. Herbener ES, Rosen C, Khine T, Sweeney JA. Failure of positive but not negative emotional valence to enhance memory in schizophrenia. J Abnorm Psychol. 2007;116(1):43–55. [PubMed]
140. Kring AM, Neale JM. Do schizophrenic patients show a disjunctive relationship among expressive, experiential, and psychophysiological components of emotion? J Abnorm Psychol. 1996;105(2):249–257. [PubMed]
141. Paradiso S, Andreasen NC, Crespo-Facorro B, et al. Emotions in unmedicated patients with schizophrenia during evaluation with positron emission tomography. Am J Psychiatry. 2003;160(10):1775–1783. [PubMed]
142. Taylor SF, Phan KL, Britton JC, Liberzon I. Neural response to emotional salience in schizophrenia. Neuropsychopharmacology. 2005;30(5):984–995. [PubMed]
143. Butzlaff RL, Hooley JM. Expressed emotion and psychiatric relapse: a meta-analysis. Arch Gen Psychiatry. 1998;55(6):547–552. [PubMed]
144. Docherty NM, Grosh ES, Wexler BE. Affective reactivity of cognitive functioning and family history in schizophrenia. Biol Psychiatry. 1996;39(1):59–64. [PubMed]
145. Bolte S, Poustka F. The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives. Psychol Med. 2003;33(5):907–915. [PubMed]
146. Miklowitz DJ, Goldstein MJ, Nuechterlein KH, Snyder KS, Mintz J. Family factors and the course of bipolar affective disorder. Arch Gen Psychiatry. 1988;45(3):225–231. [PubMed]
147. Rosenfarb IS, Miklowitz DJ, Goldstein MJ, Harmon L, Nuechterlein KH, Rea MM. Family transactions and relapse in bipolar disorder. Fam Process. 2001;40(1):5–14. [PubMed]
148. Erickson DH, Beiser M, Iacono WG, Fleming JA, Lin TY. The role of social relationships in the course of first-episode schizophrenia and affective psychosis. Am J Psychiatry. 1989;146(11):1456–1461. [PubMed]
149. Cannon M, Jones P, Gilvarry C, et al. Premorbid social functioning in schizophrenia and bipolar disorder: similarities and differences. Am J Psychiatry. 1997;154(11):1544–1550. [PubMed]
150. Dickerson FB, Sommerville J, Origoni AE, Ringel NB, Parente F. Outpatients with schizophrenia and bipolar I disorder: do they differ in their cognitive and social functioning? Psychiatry Res. 2001;102(1):21–27. [PubMed]
151. Cutting J, Murphy D. Impaired ability of schizophrenics, relative to manics or depressives, to appreciate social knowledge about their culture. Br J Psychiatry. 1990;157:355–358. [PubMed]
152. Bellack AS, Sayers M, Mueser KT, Bennett M. Evaluation of social problem solving in schizophrenia. J Abnorm Psychol. 1994;103(2):371–378. [PubMed]
153. Bediou B, Asri F, Brunelin J, et al. Emotion recognition and genetic vulnerability to schizophrenia. Br J Psychiatry. 2007;191:126–130. [PubMed]
154. Leppanen JM, Niehaus DJ, Koen L, Du TE, Schoeman R, Emsley R. Deficits in facial affect recognition in unaffected siblings of Xhosa schizophrenia patients: evidence for a neurocognitive endophenotype. Schizophr Res. 2007;99(1-3):270–273. [PubMed]
155. Toomey R, Seidman LJ, Lyons MJ, Faraone SV, Tsuang MT. Poor perception of nonverbal social-emotional cues in relatives of schizophrenic patients. Schizophr Res. 1999;40(2):121–130. [PubMed]
156. Baas D, Van't Wout M, Aleman A, Kahn RS. Social judgement in clinically stable patients with schizophrenia and healthy relatives: behavioural evidence of social brain dysfunction. Psychol Med. 2008;38(5):1–8. [PubMed]
157. Kee KS, Horan WP, Mintz J, Green MF. Do the siblings of schizophrenia patients demonstrate affect perception deficits? Schizophr Res. 2004;67(1):87–94. [PubMed]
158. Franke P, Maier W, Hardt J, Hain C. Cognitive functioning and anhedonia in subjects at risk for schizophrenia. Schizophr Res. 1993;10(1):77–84. [PubMed]
159. Thaker G, Moran M, Adami H, Cassady S. Psychosis proneness scales in schizophrenia spectrum personality disorders: familial vs. nonfamilial samples. Psychiatry Res. 1993;46(1):47–57. [PubMed]
160. Laurent A, Biloa-Tang M, Bougerol T, et al. Executive/attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives. Schizophr Res. 2000;46(2–3):269–283. [PubMed]
161. Kendler KS, McGuire M, Gruenberg AM, Walsh D. Schizotypal symptoms and signs in the Roscommon Family Study. Their factor structure and familial relationship with psychotic and affective disorders. Arch Gen Psychiatry. 1995;52(4):296–303. [PubMed]
162. Schurhoff F, Laguerre A, Szoke A, Meary A, Leboyer M. Schizotypal dimensions: continuity between schizophrenia and bipolar disorders. Schizophr Res. 2005;80(2–3):235–242. [PubMed]
163. Munafo MR, Thiselton DL, Clark TG, Flint J. Association of the NRG1 gene and schizophrenia: a meta-analysis. Mol Psychiatry. 2006;11(6):539–546. [PubMed]
164. Asarnow RF, Nuechterlein KH, Asamen J, et al. Neurocognitive functioning and schizophrenia spectrum disorders can be independent expressions of familial liability for schizophrenia in community control children: the UCLA family study. Schizophr Res. 2002;54(1–2):111–120. [PubMed]
165. Barrantes-Vidal N, Aguilera M, Campanera S, et al. Working memory in siblings of schizophrenia patients. Schizophr Res. 2007;95(1–3):70–75. [PubMed]
166. Hughes C, Kumari V, Das M, et al. Cognitive functioning in siblings discordant for schizophrenia. Acta Psychiatr Scand. 2005;111(3):185–192. [PubMed]
167. Niendam TA, Bearden CE, Rosso IM, et al. A prospective study of childhood neurocognitive functioning in schizophrenic patients and their siblings. Am J Psychiatry. 2003;160(11):2060–2062. [PubMed]
168. Davalos DB, Compagnon N, Heinlein S, Ross RG. Neuropsychological deficits in children associated with increased familial risk for schizophrenia. Schizophr Res. 2004;67(2–3):123–130. [PubMed]
169. Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR, Tsuang MT. Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatry. 2000;48(2):120–126. [PubMed]
170. Tuulio-Henriksson A, Haukka J, Partonen T, et al. Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia. Am J Med Genet. 2002;114(5):483–490. [PubMed]
171. Antila M, Tuulio-Henriksson A, Kieseppa T, et al. Heritability of cognitive functions in families with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2007;144(6):802–808. [PubMed]
172. Birkett P, Sigmundsson T, Sharma T, et al. Executive function and genetic predisposition to schizophrenia—the Maudsley Family Study. Am J Med Genet B Neuropsychiatr Genet. 2007 [PubMed]
173. Hallmayer JF, Kalaydjieva L, Badcock J, et al. Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet. 2005;77(3):468–476. [PubMed]
174. Toulopoulou T, Quraishi S, McDonald C, Murray RM. The Maudsley Family Study: premorbid and current general intellectual function levels in familial bipolar I disorder and schizophrenia. J Clin Exp Neuropsychol. 2006;28(2):243–259. [PubMed]
175. Christensen MV, Kyvik KO, Kessing LV. Cognitive function in unaffected twins discordant for affective disorder. Psychol Med. 2006;36(8):1119–1129. [PubMed]
176. Krabbendam L, Marcelis M, Delespaul P, Jolles J, van Os J. Single or multiple familial cognitive risk factors in schizophrenia? Am J Med Genet. 2001;105(2):183–188. [PubMed]
177. Asarnow RF, Nuechterlein KH, Subotnik KL, et al. Neurocognitive impairments in nonpsychotic parents of children with schizophrenia and attention-deficit/hyperactivity disorder. the University of California, Los Angeles Family Study. Arch Gen Psychiatry. 2002;59(11):1053–1060. [PubMed]
178. Egan MF, Goldberg TE, Gscheidle T, et al. Relative risk for cognitive impairments in siblings of patients with schizophrenia. Biol Psychiatry. 2001;50(2):98–107. [PubMed]
179. Gilvarry CM, Russell A, Hemsley D, Murray RM. Neuropsychological performance and spectrum personality traits in the relatives of patients with schizophrenia and affective psychosis. Psychiatry Res. 2001;101(2):89–100. [PubMed]
180. Harris JG, Adler LE, Young DA, et al. Neuropsychological dysfunction in parents of schizophrenics. Schizophr Res. 1996;20(3):253–260. [PubMed]
181. Hoff AL, Svetina C, Maurizio AM, Crow TJ, Spokes K, DeLisi LE. Familial cognitive deficits in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2005;133(1):43–49. [PubMed]
182. Keefe RS, Silverman JM, Roitman SE, et al. Performance of nonpsychotic relatives of schizophrenic patients on cognitive tests. Psychiatry Res. 1994;53(1):1–12. [PubMed]
183. Keri S, Gulyas B, Benedek G, Janka Z. Feature uncertainty: a novel test to probe prefrontal dysfunction in unaffected siblings of schizophrenia patients. Neurosci Lett. 2005;375(1):33–36. [PubMed]
184. Klemm S, Schmidt B, Knappe S, Blanz B. Impaired working speed and executive functions as frontal lobe dysfunctions in young first-degree relatives of schizophrenic patients. Eur Child Adolesc Psychiatry. 2006;15(7):400–408. [PMC free article] [PubMed]
185. Kuha A, Tuulio-Henriksson A, Eerola M, et al. Impaired executive performance in healthy siblings of schizophrenia patients in a population-based study. Schizophr Res. 2007;92(1–3):142–150. [PubMed]
186. Laurent A, Moreaud O, Bosson JL, et al. Neuropsychological functioning among non-psychotic siblings and parents of schizophrenic patients. Psychiatry Res. 1999;87(2–3):147–157. [PubMed]
187. Ma X, Wang Q, Sham PC, et al. Neurocognitive deficits in first-episode schizophrenic patients and their first-degree relatives. Am J Med Genet B Neuropsychiatr Genet. 2007;144(4):407–416. [PubMed]
188. Schubert EW, McNeil TF. Neurobehavioral deficits in young adult offspring with heightened risk for psychosis who developed schizophrenia-spectrum disorder. Schizophr Res. 2007;94(1–3):107–113. [PubMed]
189. Yurgelun-Todd DA, Kinney DK. Patterns of neuropsychological deficits that discriminate schizophrenic individuals from siblings and control subjects. J Neuropsychiatr Clin Neurosci. 1993;5(3):294–300. [PubMed]
190. Szoke A, Schurhoff F, Golmard JL, et al. Familial resemblance for executive functions in families of schizophrenic and bipolar patients. Psychiatry Res. 2006;144(2–3):131–138. [PMC free article] [PubMed]
191. Antila M, Tuulio-Henriksson A, Kieseppa T, Eerola M, Partonen T, Lonnqvist J. Cognitive functioning in patients with familial bipolar I disorder and their unaffected relatives. Psychol Med. 2007;37(5):679–687. [PubMed]
192. Appels MC, Sitskoorn MM, Westers P, Lems E, Kahn RS. Cognitive dysfunctions in parents of schizophrenic patients parallel the deficits found in patients. Schizophr Res. 2003;63(3):285–293. [PubMed]
193. Becker TM, Kerns JG, MacDonald AW, III, Carter CS. Prefrontal dysfunction in first-degree relatives of schizophrenia patients during a stroop task. Neuropsychopharmacology. 2008 [PubMed]
194. Sobczak S, Honig A, Schmitt JA, Riedel WJ. Pronounced cognitive deficits following an intravenous L-tryptophan challenge in first-degree relatives of bipolar patients compared to healthy controls. Neuropsychopharmacology. 2003;28(4):711–719. [PubMed]
195. Ross RG, Wagner B, Heinlein S, Zerbe GO. The stability of inhibitory and working memory deficits in children and adolescents who are children of parents with schizophrenia. Schizophr Bull. 2008;34(1):47–51. [PMC free article] [PubMed]
196. Delawalla Z, Barch DM, Fisher Eastep JL, et al. Factors mediating cognitive deficits and psychopathology among siblings of individuals with schizophrenia. Schizophr Bull. 2006;32(3):525–537. [PMC free article] [PubMed]
197. Faraone SV, Seidman LJ, Kremen WS, Pepple JR, Lyons MJ, Tsuang MT. Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. J Abnorm Psychol. 1995;104(2):286–304. [PubMed]
198. Pardo PJ, Knesevich MA, Vogler GP, et al. Genetic and state variables of neurocognitive dysfunction in schizophrenia: a twin study. Schizophr Bull. 2000;26(2):459–477. [PubMed]
199. Saoud M, d'Amato T, Gutknecht C, et al. Neuropsychological deficit in siblings discordant for schizophrenia. Schizophr Bull. 2000;26(4):893–902. [PubMed]
200. Toomey R, Faraone SV, Seidman LJ, Kremen WS, Pepple JR, Tsuang MT. Association of neuropsychological vulnerability markers in relatives of schizophrenic patients. Schizophr Res. 1998;31(2–3):89–98. [PubMed]
201. Wolf LE, Cornblatt BA, Roberts SA, Shapiro BM, Erlenmeyer-Kimling L. Wisconsin Card Sorting deficits in the offspring of schizophrenics in the New York High-Risk Project. Schizophr Res. 2002;57(2–3):173. [PubMed]
202. Frangou S, Haldane M, Roddy D, Kumari V. Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder. Biol Psychiatry. 2005;58(10):838–839. [PubMed]
203. Klimes-Dougan B, Ronsaville D, Wiggs EA, Martinez PE. Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders. Biol Psychiatry. 2006;60(9):957–965. [PubMed]
204. Staal WG, Hijman R, Hulshoff Pol HE, Kahn RS. Neuropsychological dysfunctions in siblings discordant for schizophrenia. Psychiatry Res. 2000;95(3):227–235. [PubMed]
205. Greenwood TA, Braff DL, Light GA, et al. Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry. 2007;64(11):1242–1250. [PubMed]
206. Gur RE, Nimgaonkar VL, Almasy L, et al. Neurocognitive endophenotypes in a multiplex multigenerational family study of schizophrenia. Am J Psychiatry. 2007;164(5):813–819. [PubMed]
207. D'Angelo EJ. Conceptual disorganization in children at risk for schizophrenia. Psychopathology. 1993;26(3–4):195–202. [PubMed]
208. Clark L, Sarna A, Goodwin GM. Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry. 2005;162(10):1980–1982. [PubMed]
209. Shear PK, DelBello MP, Lee RH, Strakowski SM. Parental reports of executive dysfunction in adolescents with bipolar disorder. Child Neuropsychol. 2002;8(4):285–295. [PubMed]
210. Trandafir A, Meary A, Schurhoff F, Leboyer M, Szoke A. Memory tests in first-degree adult relatives of schizophrenic patients: a meta-analysis. Schizophr Res. 2006;81(2–3):217–226. [PMC free article] [PubMed]
211. Donaldson S, Goldstein LH, Landau S, Raymont V, Frangou S. The Maudsley Bipolar Disorder Project: the effect of medication, family history, and duration of illness on IQ and memory in bipolar I disorder. J Clin Psychiatry. 2003;64(1):86–93. [PubMed]
212. Erlenmeyer-Kimling L, Rock D, Roberts SA, et al. Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project. Am J Psychiatry. 2000;157(9):1416–1422. [PubMed]
213. Groom MJ, Jackson GM, Calton TG, et al. Cognitive deficits in early-onset schizophrenia spectrum patients and their non-psychotic siblings: a comparison with ADHD. Schizophr Res. 2007 [PubMed]
214. Sitskoorn MM, Ebisch SJ, Appels M, Nuyen J, Kahn RS. Memory profiles in parents of patients with schizophrenia. Psychiatry Res. 2004;128(1):27–37. [PubMed]
215. Bearden CE, Glahn DC, Monkul ES, et al. Patterns of memory impairment in bipolar disorder and unipolar major depression. Psychiatry Res. 2006;142(2–3):139–150. [PubMed]
216. Bearden CE, Glahn DC, Monkul ES, et al. Sources of declarative memory impairment in bipolar disorder: mnemonic processes and clinical features. J Psychiatr Res. 2006;40(1):47–58. [PubMed]
217. Kieseppa T, Tuulio-Henriksson A, Haukka J, et al. Memory and verbal learning functions in twins with bipolar-I disorder, and the role of information-processing speed. Psychol Med. 2005;35(2):205–215. [PubMed]
218. Kremen WS, Faraone SV, Seidman LJ, Pepple JR, Tsuang MT. Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands. Psychiatry Res. 1998;79(3):227–240. [PubMed]
219. Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR, Tsuang MT. Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a 4-year follow-up study. J Abnorm Psychol. 1999;108(1):176–181. [PubMed]
220. Toulopoulou T, Morris RG, Rabe-Hesketh S, Murray RM. Selectivity of verbal memory deficit in schizophrenic patients and their relatives. Am J Med Genet B Neuropsychiatr Genet. 2003;116(1):1–7. [PubMed]
221. Toulopoulou T, Rabe-Hesketh S, King H, Murray RM, Morris RG. Episodic memory in schizophrenic patients and their relatives. Schizophr Res. 2003;63(3):261–271. [PubMed]
222. Whyte MC, Brett C, Harrison LK, et al. Neuropsychological performance over time in people at high risk of developing schizophrenia and controls. Biol Psychiatry. 2006;59(8):730–739. [PubMed]
223. Robles O, Blaxton T, Adami H, Arango C, Thaker G, Gold J. Nonverbal delayed recognition in the relatives of schizophrenia patients with or without schizophrenia spectrum. Biol Psychiatry. 2007 [PMC free article] [PubMed]
224. Schubert EW, McNeil TF. Neuropsychological impairment and its neurological correlates in adult offspring with heightened risk for schizophrenia and affective psychosis. Am J Psychiatry. 2005;162(4):758–766. [PubMed]
225. Conklin HM, Calkins ME, Anderson CW, Dinzeo TJ, Iacono WG. Recognition memory for faces in schizophrenia patients and their first-degree relatives. Neuropsychologia. 2002;40(13):2314–2324. [PubMed]
226. Ferrier IN, Chowdhury R, Thompson JM, Watson S, Young AH. Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disord. 2004;6(4):319–322. [PubMed]
227. Conklin HM, Curtis CE, Calkins ME, Iacono WG. Working memory functioning in schizophrenia patients and their first-degree relatives: cognitive functioning shedding light on etiology. Neuropsychologia. 2005;43(6):930–942. [PubMed]
228. Franke P, Gansicke M, Schmitz S, Falkai P, Maier W. Differential memory span–abnormal lateralization pattern in schizophrenic patients and their siblings? Int J Psychophysiol. 1999;34(3):303–311. [PubMed]
229. Johnson JK, Tuulio-Henriksson A, Pirkola T, et al. Do schizotypal symptoms mediate the relationship between genetic risk for schizophrenia and impaired neuropsychological performance in co-twins of schizophrenic patients? Biol Psychiatry. 2003;54(11):1200–1204. [PubMed]
230. Myles-Worsley M, Park S. Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau, Micronesia. Am J Med Genet. 2002;114(6):609–615. [PubMed]
231. Saperstein AM, Fuller RL, Avila MT, et al. Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction. Schizophr Bull. 2006;32(3):498–506. [PMC free article] [PubMed]
232. Bedwell JS, Esposito S, Miller LS. Accelerated age-related decline of visual information processing in first-degree relatives of persons with schizophrenia. Psychiatry Res. 2004;125(3):225–235. [PubMed]
233. MacQueen GM, Grof P, Alda M, Marriott M, Young LT, Duffy A. A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder. Bipolar Disord. 2004;6(5):374–378. [PubMed]
234. Irani F, Platek SM, Panyavin IS, et al. Self-face recognition and theory of mind in patients with schizophrenia and first-degree relatives. Schizophr Res. 2006;88(1–3):151–160. [PubMed]
235. Brunelin J, d'Amato T, Brun P, et al. Impaired verbal source monitoring in schizophrenia: an intermediate trait vulnerability marker? Schizophr Res. 2007;89(1–3):287–292. [PubMed]
236. Avila MT, Robles O, Hong LE, et al. Deficits on the Continuous Performance Test within the schizophrenia spectrum and the mediating effects of family history of schizophrenia. J Abnorm Psychol. 2006;115(4):771–778. [PubMed]
237. Birkett P, Sigmundsson T, Sharma T, et al. Reaction time and sustained attention in schizophrenia and its genetic predisposition. Schizophr Res. 2007;95(1–3):76–85. [PubMed]
238. Chen WJ, Liu SK, Chang CJ, Lien YJ, Chang YH, Hwu HG. Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry. 1998;155(9):1214–1220. [PubMed]
239. Chen WJ, Chang CH, Liu SK, Hwang TJ, Hwu HG. Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis. Biol Psychiatry. 2004;55(10):995–1000. [PubMed]
240. Keri S, Janka Z. Critical evaluation of cognitive dysfunctions as endophenotypes of schizophrenia. Acta Psychiatr Scand. 2004;110(2):83–91. [PubMed]
241. Laurent A, Saoud M, Bougerol T, et al. Attentional deficits in patients with schizophrenia and in their non-psychotic first-degree relatives. Psychiatry Res. 1999;89(3):147–159. [PubMed]
242. MacDonald AW, III, Pogue-Geile MF, Johnson MK, Carter CS. A specific deficit in context processing in the unaffected siblings of patients with schizophrenia. Arch Gen Psychiatry. 2003;60(1):57–65. [PubMed]
243. Michie PT, Kent A, Stienstra R, et al. Phenotypic markers as risk factors in schizophrenia: neurocognitive functions. Aust N Z J Psychiatry. 2000;34(suppl):S74–S85. [PubMed]
244. Tsuang HC, Lin SH, Liu SK, et al. More severe sustained attention deficits in nonpsychotic siblings of multiplex schizophrenia families than in those of simplex ones. Schizophr Res. 2006;87(1–3):172–180. [PubMed]
245. Wang Q, Chan R, Sun J, et al. Reaction time of the Continuous Performance Test is an endophenotypic marker for schizophrenia: a study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls. Schizophr Res. 2007;89(1–3):293–298. [PubMed]
246. MacDonald AW, III, Goghari VM, Hicks BM, Flory JD, Carter CS, Manuck SB. A convergent-divergent approach to context processing, general intellectual functioning, and the genetic liability to schizophrenia. Neuropsychology. 2005;19(6):814–821. [PubMed]

Articles from Schizophrenia Bulletin are provided here courtesy of Oxford University Press