Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives

BACKGROUND: Clues to the causes of schizophrenia can be derived from studying first-degree relatives because they are genetically related to an ill family member. Abnormalities observed in nonpsychotic relatives are indicators of possible genetic vulnerability to illness, independent of psychosis. We tested 4 hypotheses: (1) that hippocampal volume is smaller in nonpsychotic relatives than in controls, particularly in the left hemisphere; (2) that hippocampi will be smaller in multiplex relatives as compared with simplex relatives, and both will be smaller than in controls; (3) that hippocampal volumes and verbal declarative memory function will be positively correlated; and (4) that hippocampi will be smaller in patients with schizophrenia than in their nonpsychotic relatives or in controls. METHODS: Subjects were 45 nonpsychotic adult first-degree relatives from families with either 2 people ("multiplex," n = 17) or 1 person ("simplex," n = 28) diagnosed with schizophrenia, 18 schizophrenic relatives, and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3-dimensional magnetic resonance images of the brain were acquired on a 1.5-T magnet. Volumes of the total cerebrum and the hippocampus were measured. RESULTS: Compared with controls, relatives, particularly from multiplex families, had significantly smaller left hippocampi. Verbal memory and left hippocampal volumes were significantly and positively correlated. Within families, hippocampal volumes did not differ between schizophrenic patients and their nonpsychotic relatives. CONCLUSIONS: Results support the hypothesis that the vulnerability to schizophrenia includes smaller left hippocampi and verbal memory deficits. Findings suggest that smaller left hippocampi and verbal memory deficits are an expression of early neurodevelopmental compromise, reflecting the degree of genetic liability to schizophrenia.     

Sustained and selective attention as measures of genetic liability to schizophrenia

We tested for a relationship between attention and genetic liability to schizophrenia. Samples of probands with DSM-IV schizophrenia (n=20), their well first-degree relatives (n=40) and healthy controls (n=82) were tested using measures of sustained attention (degraded-stimulus continuous performance test: DS-CPT) and selective attention (spatial negative priming task). Assuming a liability-threshold model, we predicted that probands would display greater attentional decrements than controls and that the relatives would show intermediate levels of decrement. We did not observe the predicted pattern of effect using either measure, although the probands showed a trend towards less negative priming. However, our results may have been affected by self-selection bias in probands and relatives and clinical heterogeneity among probands, which could have reduced our power to detect effects.     

Neural anomalies during visual search in schizophrenia patients and unaffected siblings of schizophrenia patients

Schizophrenia patients and their unaffected first-degree relatives exhibit performance deficits on attention tasks, perhaps indicating genetic influence over attentional abnormalities in schizophrenia. To identify anomalous brain function associated with attention in individuals who likely have unexpressed genetic liability for schizophrenia, we studied electrophysiological characteristics of unaffected siblings of schizophrenia patients during a visual serial search task. We gathered behavioral and electrophysiological data from 19 schizophrenia patients, 18 unaffected biological siblings of schizophrenia patients, and 19 nonpsychiatric control participants during performance of the Span of Apprehension (Span) task and a control task. Schizophrenia patients had lower Span task accuracy than the other two groups. Schizophrenia and sibling groups exhibited diminished late positive potentials (P300) over parietal brain regions during Span trials. Compared to control task stimuli, attentional demands of Span stimuli elicited augmented early negative potentials (N1, P2) over posterior brain regions. The degree of augmentation was reduced in schizophrenia patients but not in siblings compared to control subjects. Unaffected siblings of schizophrenia patients appear to modulate early attentional functions of posterior brain regions more effectively than schizophrenia patients but show later electrophysiological anomalies suggestive of abnormal updating of task-relevant information. While the latter may reflect neural mechanisms predisposing performance deficits on attentional tasks, the former may reflect compensatory processes present in unaffected relatives of schizophrenia patients.     

Working memory functioning in schizophrenia patients and their first-degree relatives: cognitive functioning shedding light on etiology

There is accumulating evidence for involvement of the prefrontal cortex (PFC) in the pathophysiology of schizophrenia. A primary function supported by the PFC is working memory (WM). Findings from WM studies in schizophrenia can provide insight into the nature of clinical symptoms and cognitive deficits associated with this disorder, as well as begin to suggest areas of underlying neuropathology. To date, studies have not adequately investigated different WM domains (e.g., verbal, spatial, or object) or processing requirements (e.g., maintenance, monitoring, or manipulation), shown to be associated with distinct patterns of neural activation, in schizophrenia patients and their well relatives. Accordingly, this study evaluated the performance of schizophrenia patients, their first-degree biological relatives, and nonpsychiatric controls on a comprehensive battery of WM tasks and investigated the association among WM deficits and schizophrenia-spectrum psychopathology. The findings indicate that schizophrenia patients are consistently impaired on WM tasks, irrespective of WM domain or processing requirements. In contrast, their unaffected relatives are only impaired on WM tasks with higher central executive processing requirements. This pattern of WM performance may further implicate DLPFC dysfunction in the liability for schizophrenia and has implications for future cognitive, genetic, and neurodevelopmental research.     

首发精神分裂症患者神经认知功能的遗传学分析

目的 探索精神分裂症患者及其亲属共同存在的神经认知功能损害,并对22号染色体上儿茶酚氧位甲基转移酶(COMT)基因和脯氨酸脱氢酶(PRODH)基因的5个候选单核苷酸多态性(SNP)位点进行相关的遗传学分析。方法 采用14个神经心理测验(共29项)对235例首发精神分裂症患者(患者组)、322名未患病亲属(亲属组)和133名正常对照(正常对照组)进行有关智力、注意、记忆、言语功能和执行功能等评定,比较各组间的神经认知功能有无差异,并对上述神经认知功能测验与COMT和PRODH基因的5个候选SNP进行定量性状的传递不平衡测试。结果 (1)患者组所有测验的成绩均差于正常对照组,差异有显著性(P<0.01和P<0.05),而亲属组的记忆、注意、言语功能和执行功能界于患者与正常对照之间;(2)PRODH1 195G/A与即刻逻辑记忆测验(P=0.03)、言语流畅性测验的正确数(P=0.03)和连线测验B的犯规数(P=0.01)相关,PRODH1945G/A与数字符号测验(P:0.01)、连线测验A的错误数(P:0.02)、HANOI塔测验的总分(P=0.01)、威斯康星卡片分类测验(WCST)的总错误数(P=0.01)、WCST的非持续错误数(P:0.02)和WCST的总分类数(P=0.02)相关。结论 精神分裂症患者在记忆、注意、言语功能和执行功能等方面存在广泛的神经认知功能损害,这种损害可能是精神分裂症的遗传“内表     

Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task

OBJECTIVE: The evidence for verbal working memory deficits in schizophrenia has been inconsistent. Few studies have evaluated verbal working memory in the first-degree relatives of schizophrenia patients, who likely share the genetic diathesis for schizophrenia but not the potential confounds associated with chronic mental illness. METHOD: The Wechsler Digit Span Task was used to investigate verbal working memory in 52 schizophrenia patients, 56 of their first-degree relatives, and 73 nonpsychiatric comparison subjects. RESULTS: The nonpsychotic relatives showed no impairment on the forward digit span task, a measure of general attention, but did show impairment on the backward digit span task, a measure of verbal working memory. Schizophrenia patients showed impairment on both the forward and backward digit span tasks. CONCLUSIONS: These results indicate that the forward and backward digit span tasks tap different cognitive abilities that are differentially associated with the diathesis for schizophrenia. Working memory deficits associated with schizophrenia appear to be generalized and not limited to the spatial modality.     

Self-face recognition and theory of mind in patients with schizophrenia and first-degree relatives

OBJECTIVE: The hypothesized relationship between theory of mind (ToM) and self-face recognition as well as its potential genetic associations has not been previously explored in patients with schizophrenia and in first-degree relatives with schizotypal personality traits. METHOD: Ten patients diagnosed with schizophrenia, 10 of their first-degree relatives and 10 healthy controls were included. To assess self-face recognition (SFR), participants were presented images of faces of themselves and others and asked to make rapid 'unfamiliar', 'familiar' and 'self' judgments. As a measure of ToM, subjects were administered the Revised Mind in the Eyes Test (MET [Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., and Plumb, I., 2001. The "Reading the Mind in the Eyes" Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry 42(2), 241-251.]). Schizotypal characteristics in relatives and controls were assessed using a modified version of the Schizotypal Personality Questionnaire (SPQ [Raine, A., 1991. The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophrenia Bulletin 17(4), 555-564.]). RESULTS: Patients took longer and were less accurate on the SFR task than their relatives who in turn performed worse than healthy controls. Specific ToM deficits in schizophrenia were replicated. There was a relationship between accuracy rates on the MET and SFR tasks. High levels of schizotypal traits such as social anxiety, constricted affect and no close friends were important for both tasks. CONCLUSIONS: Face recognition deficits and ToM deficits in schizophrenia are apparent. The critical influence of high levels of select schizotypal traits is also highlighted. A deficit in relatives of schizophrenia patients raises the possibility that ToM and face recognition deficits may be candidate endophenotypes for schizophrenia. Support for the hypothesized link between ToM and face recognition is provided.     

Facial emotion perception in Chinese patients with schizophrenia and non-psychotic first-degree relatives

Although there is a consensus that patients with schizophrenia have certain deficits in perceiving and expressing facial emotions, previous studies of facial emotion perception in schizophrenia do not present consistent results. The objective of this study was to explore facial emotion perception deficits in Chinese patients with schizophrenia and their non-psychotic first-degree relatives. Sixty-nine patients with schizophrenia, 56 of their first-degree relatives (33 parents and 23 siblings), and 92 healthy controls (67 younger healthy controls matched to the patients and siblings, and 25 older healthy controls matched to the parents) completed a set of facial emotion perception tasks, including facial emotion discrimination, identification, intensity, valence, and corresponding face identification tasks. The results demonstrated that patients with schizophrenia performed significantly worse than their siblings and younger healthy controls in accuracy in a variety of facial emotion perception tasks, whereas the siblings of the patients performed as well as the corresponding younger healthy controls in all of the facial emotion perception tasks. Patients with schizophrenia also showed significantly reduced speed than younger healthy controls, while siblings of patients did not demonstrate significant differences with both patients and younger healthy controls in speed. Meanwhile, we also found that parents of the schizophrenia patients performed significantly worse than the corresponding older healthy controls in accuracy in terms of facial emotion identification, valence, and the composite index of the facial discrimination, identification, intensity and valence tasks. Moreover, no significant differences were found between the parents of patients and older healthy controls in speed after controlling the years of education and IQ. Taken together, the results suggest that facial emotion perception deficits may serve as potential endophenotypes for schizophrenia.     

Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies.

BACKGROUND: Substantial evidence now shows that the genetic vulnerability to schizophrenia can be manifested clinically in first-degree relatives of people with schizophrenia, even without the full manifestations of the disorder. One pattern of problems observed involves the combination of negative symptoms and neuropsychological deficits. We have investigated whether a low dose of a novel antipsychotic medication, risperidone, could attenuate these clinical problems in non-psychotic, first-degree relatives, and report here findings from our first 4 cases. METHODS: Twelve adults who were first-degree relatives of patients with schizophrenia were evaluated for the presence of negative symptoms and neuropsychological deficits (in attention and working memory, long-term verbal memory and executive functions). Four subjects who met our predetermined criteria, and who did not demonstrate medical contraindications, were enrolled in a 6-week trial of risperidone. Clinical and medical measures were assessed before, during and after treatment. Doses of risperidone started at 0.25 mg and were increased to 1.0-2.0 mg/day. RESULTS: These subjects showed substantial reductions in negative symptoms, and one subject showed modest reductions. All four subjects showed substantial improvements on some tests of attention and working memory. Side effects of risperidone were temporary and mainly mild. CONCLUSIONS: These initial findings support two conclusions. First, clinical deficits in non-psychotic first-degree relatives of people with schizophrenia are identifiable, and to a significant extent, reversible. Second, risperidone may eventually serve as an effective treatment for people whose lives are impaired by similar or related problems.     

P50 sensory gating in multiplex schizophrenia families from a Pacific island isolate

OBJECTIVE: Multiplex schizophrenia families from Palau, Micronesia, were assessed with P50 sensory gating to 1) test for replication of the association between this inhibitory neurobiological trait and familial schizophrenia in non-Caucasian subjects and 2) evaluate the ability of the P50 trait to serve as an endophenotype in a genetic linkage study of these families. METHOD: A paired-stimulus auditory event- related potential paradigm was used to examine P50 sensory gating in 85 schizophrenia patients (56 medicated with typical antipsychotics and 29 unmedicated), 83 of their first-degree relatives (46 parents and 37 siblings), and 29 normal comparison subjects. RESULTS: Auditory sensory gating as measured by the P50 ratio was similarly impaired in medicated and unmedicated schizophrenia patients compared to the normal subjects, and medication dose had no significant effect on any P50 variable. This impairment extended to first-degree relatives, who also showed significantly higher P50 ratios than the normal subjects. Abnormal P50 ratios were found in 64.7% of the schizophrenia patients and 51.8% of their first-degree relatives but only 10.3% of the normal subjects. CONCLUSIONS: P50 sensory gating deficits were confirmed in Palauan schizophrenia families. Rates of abnormal P50 sensory gating in relatives versus normal subjects resulted in a risk ratio of 5.0. Impairment was independent of medication effects, indicating that the P50 paradigm measures a stable neurobiological trait unaffected by treatment with typical antipsychotics. These results suggest that this trait can fulfill the major criteria for an endophenotype for genetic liability to schizophrenia in these multiply affected Palauan families.     

Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives

OBJECTIVE: Performance on measures of saccadic inhibition and control was investigated in a large family study of schizophrenia to evaluate the utility of using antisaccade task performance as an endophenotypic marker of genetic liability for schizophrenia. METHOD: Ninety-five patients with acute schizophrenia and 116 of their first-degree biological relatives, 13 schizophrenia patients whose illness was in full remission, 35 patients with acute psychotic affective disorder, and 109 nonpsychiatric comparison subjects were administered antisaccade and prosaccade tasks. RESULTS: Both schizophrenia patient groups had a greater number of errors on the antisaccade task than did the first-degree relatives and the affective disorder group, which both had more errors than the comparison subjects. Among the first-degree relatives of the probands with acute schizophrenia, relatives of poor-performing patients performed worse on the antisaccade task than relatives of patients with good performance. Reflexive errors were not likely the result of interfering psychotic symptoms, medication, or medication side effects. Although the schizophrenia patients demonstrated other signs of saccadic abnormalities, these problems, which were not observed in their relatives even though they had high antisaccade error rates, seem unlikely to account for the higher antisaccade error rate of the schizophrenia patients. CONCLUSIONS: These findings suggest that saccadic disinhibition is strongly associated with the genetic liability for schizophrenia.     

Impaired working speed and executive functions as frontal lobe dysfunctions in young first-degree relatives of schizophrenic patients

The aim of the investigation was to detect neuropsychological markers, such as sustained and selective attention and executive functions, which contribute to the vulnerability to schizophrenia especially in young persons. Performance was assessed in 32 siblings and children of schizophrenic patients and 32 matched controls using Wisconsin Card Sorting Test, Colour-Word-Interference-Test, Trail Making Test, and d2-Concentration-Test. The first-degree relatives showed certain impairments on all four tests, in particular, slower times on all time-limited tests. These results suggest the need for more time when completing neuropsychological tasks involving selected and focused attention, as well as cognitive flexibility, as a possible indicator of genetic vulnerability to schizophrenia.     

Functional magnetic resonance imaging (fMRI) of attention processes in presumed obligate carriers of schizophrenia: preliminary findings

Background  

Presumed obligate carriers (POCs) are the first-degree relatives of people with schizophrenia who, although do not exhibit the disorder, are in direct lineage of it. Thus, this subpopulation of first-degree relatives could provide very important information with regard to the investigation of endophenotypes for schizophrenia that could clarify the often contradictory findings in schizophrenia high-risk populations. To date, despite the extant literature on schizophrenia endophenotypes, we are only aware of one other study that examined the neural mechanisms that underlie cognitive abnormalities in this group. The aim of this study was to investigate whether a more homogeneous group of relatives, such as POCs, have neural abnormalities that may be related to schizophrenia.     

Neural anomalies during sustained attention in first-degree biological relatives of schizophrenia patients.

BACKGROUND: A deficit in sustained attention might serve as an endophenotype for schizophrenia and therefore be a useful tool in understanding the genetic underpinnings of the disorder. We sought to detail functional brain abnormalities associated with sustained attention (i.e., vigilance) in individuals with genetic liability for schizophrenia. METHODS: We gathered electrophysiological data from 23 schizophrenia patients, 28 first-degree biological relatives of schizophrenia patients, and 23 nonpsychiatric control subjects while they performed a degraded-stimulus continuous performance task. Inclusion of sensory control trials allowed separation of target detection and vigilance effects on brain potentials. RESULTS: Schizophrenia patients, but not relatives, showed a behavioral deficit in sustained attention. During target detection, relatives exhibited diminished late positive amplitudes (P3b, i.e., P300) over parietal brain regions and augmented early posterior (P1) and right frontal (anterior N1) potentials. Electrophysiological anomalies were still evident after the exclusion of three relatives with histories of psychosis. CONCLUSIONS: Genetic liability for schizophrenia is associated with augmented early and diminished late brain potentials during sustained attention. Electrophysiological anomalies suggestive of right frontal-posterior parietal dysfunction might represent neural expression of genetic liability for schizophrenia. Electrophysiological indices also seem to be more sensitive than behavioral measures in assessing genetic liability for schizophrenia.     

Impaired automatization of a cognitive skill in first-degree relatives of patients with schizophrenia

We studied healthy, first-degree relatives of patients with schizophrenia to test the hypothesis that deficits in cognitive skill learning are associated with genetic liability to schizophrenia. Using the Weather Prediction Task (WPT), 23 healthy controls and 10 adult first-degree Relatives Of Schizophrenia (ROS) patients were examined to determine the extent to which cognitive skill learning was automated using a dual-task paradigm to detect subtle impairments in skill learning. Automatization of a skill is the ability to execute a task without the demand for executive control and effortful behavior and is a skill in which schizophrenia patients possess a deficit. ROS patients did not differ from healthy controls in accuracy or reaction time on the WPT either during early or late training on the single-task trials. In contrast, the healthy control and ROS groups were differentially affected during the dual-task trials. Our results demonstrate that the ROS group did not automate the task as well as controls and continued to rely on controlled processing even after extensive practice. This suggests that adult ROS patients may engage in compensatory strategies to achieve normal levels of performance and support the hypothesis that impaired cognitive skill learning is associated with genetic risk for schizophrenia.     

Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. METHODS: MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. RESULTS: We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). CONCLUSIONS: These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.     

Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report

OBJECTIVE: Patients with remitted bipolar disorder (BD) have persistent impairments in neuropsychological function, particularly in the domains of executive control and declarative memory [Br J Psychiatry 180 (2002) 293]. If these were the phenotypic expression of genetic vulnerability to BD, then healthy subjects with a genetic predisposition to BD would be expected to display the same deficits. This study, therefore, examined neuropsychological function in healthy first-degree relatives of patients with BD. METHOD: A cross-sectional design was employed to compare the performance of 17 unaffected first-degree relatives of BD patients and 17 demographically matched controls on a range of neuropsychological tests. RESULTS: Relatives were significantly impaired on Backward Digit Span, Spatial Span and on tasks of visuospatial declarative memory in comparison with controls. Psychomotor performance and verbal declarative memory were intact, as were non-working memory aspects of executive performance. CONCLUSION: The selective deficits in executive control and declarative memory exhibited by relatives in this study have previously been reported in euthymic BD patients suggesting they may be useful endophenotypic markers of genetic vulnerability to BD.     

An auditory processing abnormality specific to liability for schizophrenia

Abnormal brain activity during the processing of simple sounds is evident in individuals with increased genetic liability for schizophrenia; however, the diagnostic specificity of these abnormalities has yet to be fully examined. Because recent evidence suggests that schizophrenia and bipolar disorder may share aspects of genetic etiology the present study was conducted to determine whether individuals with heightened genetic liability for each disorder manifested distinct neural abnormalities during auditory processing. Utilizing a dichotic listening paradigm, we assessed target tone discrimination and electrophysiological responses in schizophrenia patients, first-degree biological relatives of schizophrenia patients, bipolar disorder patients, first-degree biological relatives of bipolar patients and nonpsychiatric control participants. Schizophrenia patients and relatives of schizophrenia patients demonstrated reductions in an early neural response (i.e. N1) suggestive of deficient sensory registration of auditory stimuli. Bipolar patients and relatives of bipolar patients demonstrated no such abnormality. Both schizophrenia and bipolar patients failed to significantly augment N1 amplitude with attention. Schizophrenia patients also failed to show sensitivity of longer-latency neural processes (N2) to stimulus frequency suggesting a disorder specific deficit in stimulus classification. Only schizophrenia patients exhibited reduced target tone discrimination accuracy. Reduced N1 responses reflective of early auditory processing abnormalities are suggestive of a marker of genetic liability for schizophrenia and may serve as an endophenotype for the disorder.     

Variability of ecological executive function in children and adolescents genetically at high risk for schizophrenia: a latent class analysis

Executive impairments have been observed both in patients with schizophrenia and in their unaffected first-degree relatives. Very few studies have investigated neurocognitive subgroups in unaffected first-degree relatives and in healthy participants using data-driven methods. The study included a high-risk group consisting of 100 unaffected young offspring and siblings of patients with schizophrenia and 198 healthy controls, all aged between 9 and 23 years. Executive function, victimization, and emotional and behavioral problems of participants were assessed by a series of self-report scales. Neurocognitive subgroups were investigated using latent class analysis of executive function measures. Four neurocognitive clusters were identified: a good performance cluster, a good self-control cluster, a low self-control cluster, and a severe impairment cluster. Participants in severe impaired executive function cluster reported a significantly higher level of victimization and had more prominent emotional and behavioral problems than the good performance cluster. Neurocognitive differences between high-risk young people and healthy controls were driven by individuals who have severe and global, rather than selective, executive deficits. Our results may provide clues to an explanation of the mechanisms behind executive impairments in young individuals at genetic risk and help to identify new targets for early interventions.

     

Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading.

BACKGROUND: We previously reported that the nonpsychotic relatives of schizophrenic patients exhibited disturbances in executive functioning, verbal and visual memory, auditory attention, mental control, and verbal ability. In a 4-year follow-up, we showed that the discriminating power of most of these tests was stable over time. METHODS: In this report we compare 41 nonpsychotic persons who have only one schizophrenic first-degree relative (simplex families) with 36 nonpsychotic persons who have two schizophrenic first-degree relatives (multiplex families). Our goal was to test a hypothesis that neuropsychologic deficits would be worse among the latter. RESULTS: Relatives from multiplex families differed significantly from controls on estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. In contrast, in comparisons with controls, relatives from simplex families only differed on immediate logical memories. Comparisons between relatives from multiplex and simplex families showed that the former group had significantly worse scores for estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. We also found group x gender interactions: the worse performance of the multiplex group was seen for females. CONCLUSIONS: These results are consistent with the idea that neuropsychologic deficits in relatives of schizophrenic patients reflect their degree of genetic predisposition to schizophrenia. They also suggest hypotheses about gender differences in the familial transmission of the disorder.