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.     

Neuropsychological functioning among non-psychotic siblings and parents of schizophrenic patients

Several studies have shown subtle neuropsychological deficits in healthy relatives of schizophrenic patients. However, older relatives and parents have been less frequently assessed than younger adult relatives and siblings. Furthermore, some areas of neuropsychological functioning such as memory and learning have been little studied. Thirty-seven 22-70-year-old non-psychotic parents and siblings of schizophrenic patients were compared to 37 healthy control subjects on a battery of neuropsychological tests (Trail Making, parts A and B, verbal fluency, Wisconsin Card Sorting Test, and four subtests of the Wechsler Memory Scale-Revised: logical memory, design reproduction, verbal paired associates and digit span). Relatives did not differ from control subjects on Wisconsin Card Sorting Test performance and on visual memory, but were significantly impaired on verbal fluency; more subtle deficits were found on Trail Making, part B, digit span and paired associates. A higher proportion of relatives than control subjects showed impairment on verbal fluency and verbal memory. These neuropsychological weaknesseswere present as much in siblings as in parents of schizophrenic patients, and age did not cancel differences between relatives and control subjects. Thus, these subtle deficits seem to be potential phenotypic markers of schizophrenia.     

Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia

The early course of neuropsychological dysfunction in schizophrenia and the impact of treatment on these deficits need to be better specified. A sample of 45 patients with schizophrenia underwent five neuropsychological evaluations from prior to treatment with antipsychotic treatment through a 2-year follow-up period. A comparison sample of 33 matched healthy individuals underwent neuropsychological evaluations at similar time points. At baseline, a generalized deficit across cognitive domains was evident for the schizophrenia sample. After 6 weeks of treatment, patients showed modest improvements in visual memory and visual perception, but a decline in verbal memory. Verbal memory performance returned to baseline levels by the 6-month follow-up while deficits in other neuropsychological domains persisted throughout the 2-year period. Relatively static and generalized neuropsychological dysfunction, evident from illness onset, is consistent with neurodevelopmental rather than neurodegenerative models of schizophrenia.     

Frontal release signs among patients with schizophrenia, their first-degree biological relatives, and non-psychiatric controls

BACKGROUND: Frontal release signs (FRS) are a subset of neurological soft signs that are overrepresented among patients with schizophrenia and their unaffected relatives and may be correlated with neuropsychological functioning and chronicity of illness. This study sought to explore FRS and their associations with verbal memory and symptoms of schizophrenia in an African American sample of patients, and FRS and their associations with verbal memory and schizotypal features among first-degree relatives and non-psychiatric controls. METHOD: FRS, verbal memory, schizophrenia symptoms (in patients), and schizotypal features (in relatives and controls) were assessed in 63 patients with schizophrenia and related disorders, 33 of their unaffected first-degree relatives, and 51 controls. RESULTS: Patients and their relatives displayed greater FRS than controls. Among relatives and controls, greater FRS were related to greater self-reported disorganized and interpersonal features of schizotypal personality disorder. FRS were not associated with patients' schizophrenia symptoms in the expected direction. In the entire sample, greater FRS were associated with poorer verbal working memory. CONCLUSIONS: Because they are easy to assess, may be correlated with neuropsychological functioning, and appear to covary with level of genetic diathesis for schizophrenia, the study of FRS may shed light on the neurodevelopmental processes that underlie schizophrenia.     

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

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

Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics

The synaptosomal-associated protein of 25 kDa (SNAP-25) is part of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment receptor (SNARE), which mediates synaptic neurotransmission. In earlier studies a possible involvement of this protein in schizophrenia has been shown. As neurocognitive impairment is a core feature in the pathology of schizophrenia and considered to be a putative endophenotype according to genetic studies we investigated the influences of different SNAP-25 polymorphisms on neuropsychological test results before and during treatment with atypical antipsychotics. A total of 104 schizophrenic patients treated with atypical antipsychotics were genotyped for three different polymorphisms of the SNAP-25 gene (MnlI, TaiI and DdeI in the 3'-UTR). Cognitive function was assessed at baseline, week 4 or 6 and week 8 or 12. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index. The MnlI and TaiI polymorphisms showed no associations to deficits on neuropsychological test results. In contrast, we observed a significant relation between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions. Homozygote T/T allele carriers of the DdeI polymorphism showed significant better neuropsychological test results in cognitive domains verbal memory and executive functions than those with the combined T/C and C/C genotypes (P < 0.01) at all three time points, but no differences in response to treatment with atypical antipsychotics. Additionally, TT carriers exhibited significantly better results in a general cognitive index (P < 0.05). As we observed an association between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions of schizophrenic patients our finding suggests that the SNAP-25 gene could play a role in the pathophysiology of neurocognitive dysfunctions in schizophrenia but is not predictive for treatment response with atypical antipsychotics.     

Neuropsychological functioning of first-episode schizophreniform patients.

OBJECTIVE AND METHOD: This study compared 32 consecutively admitted first-episode schizophreniform patients, 26 patients with chronic schizophrenia according to the DSM-III-R criteria, and 25 normal comparison subjects on a comprehensive battery of neuropsychological tests to determine the degree of cognitive impairment existing at the onset of schizophrenic illness. Patients were tested within 2 weeks of admission to the hospital, after their medication had been stabilized. RESULTS: With age and education controlled, the first-episode and chronic patients performed significantly worse than the normal subjects on neuropsychological summary measures of executive function, verbal memory, spatial memory, concentration/speed, and global cognitive function and on left and right hemisphere function scales. The first-episode patients were as cognitively impaired as the chronic patients on all summary scales and many of the individual tests. Both groups showed relatively greater left than right hemisphere dysfunction. CONCLUSIONS: These findings suggest that substantial cognitive deficits, comparable to those of chronic patients, are present early in the course of psychotic illness.     

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.     

Relationship between psychopathology and cognitive functioning in schizophrenia

The purpose of this study was to delineate the relationship between positive, negative, cognitive, depressive, and excitement symptom dimensions of schizophrenia and cognitive functioning. Fifty-eight patients with schizophrenia (DSM-IV criteria) were assessed using the Positive and Negative Syndrome Scale (PANSS) and a battery of neuropsychological tests (executive function/abstraction, verbal and spatial working memory, verbal and nonverbal memory/learning, attention, visuospatial ability, and psychomotor speed). The cognitive symptom dimension correlated with executive functions, attention, verbal memory, and spatial ability. Severity of the negative symptom dimension was related to impairment in the structure of the semantic knowledge system, verbal memory, and auditory attention. In contrast, severity of the positive symptom dimension correlated only with impairment in the structure of the semantic knowledge system, and psychomotor speed. Finally, severity of the depressive and excitement symptom dimension was not associated with cognition. Correlations between symptom dimensions and cognitive measures were at best modest. Severity of cognitive and negative symptoms was mainly correlated with deficits on executive functions, semantic memory, and verbal memory, while positive symptoms only with semantic memory. These correlations were modest, suggesting that psychopathology and cognitive deficits in schizophrenia are caused, at least partially, by distinct pathophysiological processes.     

Neurobehavioral deficits in young adult offspring with heightened risk for psychosis who developed schizophrenia-spectrum disorder

Neurobehavioral deficits in neuromotor function, verbal memory, executive function and attention found in patients with schizophrenia and their relatives have been suggested to be liability indicators or predictors of schizophrenia. It remains uncertain which of these neurobehavioral deficits are components of the illness itself or characteristics associated with genetic risk for it. The purpose of this study was to investigate the relation between these neurobehavioral deficits and schizophrenia-spectrum disorder in young adults at genetic risk for psychosis. A 93%-effective follow-up (total n=166, mean 22.4 yr of age) of a sample longitudinally investigated since fetal age provided complete data for mental disturbance, neuropsychological performance and neurological abnormality for 74 offspring at increased risk for psychosis (38 offspring of mothers with schizophrenia and 36 offspring of mothers with affective psychosis) and 88 normal-risk offspring. Abnormal glabella reflex and deficits in verbal memory, attention and complex executive functions seem specifically to be related to schizophrenia-spectrum disorder (primarily Cluster A personality disorders) among offspring at genetic risk for psychosis, while neurobehavioral deficits in general characterized offspring at heightened (vs. normal) genetic risk for psychosis, with no relation to schizophrenia-spectrum disorders. The two patterns of neurobehavioral deficits observed here may possibly reflect different causes and different aspects of a deviant neurodevelopmental process, and potentially contribute to a more nuanced version of this all-pervasive (but often non-specific) "model" of schizophrenia's development.     

Executive functioning and verbal memory in young patients with unipolar depression and schizophrenia

Although neuropsychological studies have consistently reported executive deficits in schizophrenia, studies of executive functions in depression have produced equivocal results. The aim of this study was to examine the profile and the specificity of the executive impairment and its association with memory performance in young patients with unipolar depression. We compared patients with depression to normal control subjects and schizophrenics. Twenty young inpatients with unipolar depression, 14 schizophrenics and 20 age-, education- and IQ-matched control subjects were assessed with a neuropsychological battery including: (1) verbal memory task; (2) frontal tasks (WCST, Cognitive Estimate, Verbal fluency, verbal and visuo-spatial span) and a new complex sorting test (Delis test). Depressed patients and schizophrenics exhibited executive deficits. Unlike schizophrenics, depressed patients did not show memory impairment. Deficits in several 'higher-level' functions combined to produce executive impairments in patients with depression including complex integration for concept formation, spontaneous cognitive flexibility and initiation ability. Impaired functions in schizophrenia and in depressed patients were similar but were differently related to clinical variables. The pattern of memory failure in our schizophrenics is believed to reflect retrieval and encoding deficits. Our findings highlight the heterogeneity of skills grouped under the term 'executive functions' that are vulnerable in depression or schizophrenia.     

Severe Episodic Memory Impairment in a Patient With Clinical Features Compatible With Corticobasal Degeneration

Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder characterized by asymmetric parkinsonism associated with apraxia, cortical sensory loss, and alien-limb phenomenon. Neuropsychological testing in patients with CBD typically shows deficits in executive functions, praxis, language, and visuospatial functioning, but not in memory. We report a CBD patient with severely impaired memory function but relatively mild motor symptoms. Detailed neuropsychological assessment showed significant verbal and visual memory deficits accompanied by frontal executive dysfunctions. Our observations indicate that CBD can in rare cases present with severe episodic memory impairment associated with frontal executive dysfunctions in the early stage of illness.     

Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks

Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia.     

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

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

Problems in remembering to carry out future actions in first-episode schizophrenia: Primary or secondary impairment?

Prospective memory (PM) is the ability to remember to carry out intended actions in the future. Empirical evidence suggests that PM deficits exist in individuals with chronic schizophrenia. However, it is unclear whether PM deficits in first-episode schizophrenia exist independently from other neuropsychological deficits. Moreover, prior research using patients with first-episode has been limited to small inpatient samples. We aimed to clarify the nature and extent of PM deficits in individuals with first-episode schizophrenia, using a large outpatient sample. Participants were 91 clinically stable outpatients with first-episode schizophrenia and 83 healthy controls. PM was assessed using both a subjective self-reported checklist and a laboratory-based task capturing time- and event-based PM. A battery assessing verbal and visuo-spatial working memory, as well as executive functions was also administered. ANOVA analyses showed that patients with first-episode schizophrenia performed significantly poorer than healthy controls in time- and event-based PM. Stepwise linear regression analyses suggested that cognitive flexibility predicted time- and event-based PM; and working memory predicted event-based PM. Subgroup analyses showed that “cognitive-preserved” patients with first-episode schizophrenia tended to perform poorer in time-based PM deficit than healthy controls who were matched in IQ and other neuropsychological functions. Overall, our results provide substantial evidence to support that time-based PM deficits in first-episode schizophrenia are apparent and not entirely attributable to other neuropsychological deficits. PM may constitute a neuropsychological marker for schizophrenia.     

Concurrent validation of schizotaxia: a pilot study.

BACKGROUND: Many first-degree relatives of patients with schizophrenia show deficits in clinical, neuropsychological, neurobiological and social domains, in the absence of psychosis. We recently reformulated Meehl's concept of schizotaxia to conceptualize the liability to schizophrenia, and we proposed preliminary criteria based on the presence of negative symptoms and neuropsychological deficits. Here we investigate the concurrent validity of schizotaxia by comparing a group of subjects who met criteria for schizotaxia with a group who did not on independent measures of clinical function, and on lifetime rates of selected comorbid psychiatric disorders. METHODS: Twenty-seven adults who were first-degree, biological relatives of patients with schizophrenia were evaluated for schizotaxia based on our predetermined criteria involving negative symptoms and neuropsychological deficits. Subjects also received portions of the Diagnostic Interview for Genetic Studies, the Structured Interview for Schizotypy, the Family Interview for Genetic Studies, the DSM-IV Global Assessment of Functioning, the Physical Anhedonia Scale, the Social Adjustment Scale and the Symptom Checklist-90-Revised. Subjects who met criteria for schizotaxia were compared with those who did not on each of the clinical measures, and on their rates of comorbid DSM-IV psychiatric diagnoses. RESULTS: Eight subjects met criteria for schizotaxia, and 19 did not. Subjects with schizotaxia showed significantly lower levels of function on each of the clinical scales. Differences in comorbid psychiatric diagnoses were not significant, although the rate of lifetime substance abuse diagnoses in the schizotaxic group (50%) approached levels that are often seen in schizophrenia. CONCLUSIONS: These findings provide the first evidence of concurrent validation for a proposed syndrome of schizotaxia. They are also consistent with the view that the vulnerability to schizophrenia may be defined, at least partially, although larger studies to assess both the concurrent and predictive validity of schizotaxia will be required to confirm these results.     

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

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

Comparative study of neuropsychological correlates in schizophrenia with onset in childhood, adolescence and adulthood

Childhood onset schizophrenia (COS) patients have marked neuropsychological deficits in areas of attention, working memory and executive functions. Similar deficits have been found in studies on Adolescent onset (AdOS) and Adult onset schizophrenia (AOS). In this study we compared the neuropsychological profile of COS with AdOS and AOS to test the hypothesis that earlier the onset greater is the severity of illness and greater are the neuropsychological deficits. A sample of 15 patients of COS was compared with 20 patients each of AdOS and AOS group. Assessment of neuropsychological profile was done using standard neuropsychological battery for Indian population. Nahor Benson Test and Bender Visual Motor Gestalt Test were used to assess perceptuomotor functioning. COS patients showed significantly greater deficits on scales of IQ, memory and perceptuomotor skills as compared to AdOS that in turn had greater deficits than AOS. The persistence of differences across the three groups inspite of controlling for education and age suggest that these deficits may have been present even before the onset of illness and was not the result of poor academic achievements. These findings also point towards a brain damage in schizophrenia that occurs on a continuum of severity with COS being the most virulent, AOS being the least and AdOS falling in between these two extremes.     

A longitudinal analysis of memory in patients with schizophrenia

Memory deficits are widely reported in patients with schizophrenia, but uncertainties remain about the extent and the longitudinal course of these deficits. Twenty-eight patients with a DSM-IV diagnosis of schizophrenia were tested on multiple aspects of memory at baseline, 9- and 18-month follow-up. Measures included: digit span, the Rivermead Behavioural Memory test (RBMT) battery, the Graded Naming Test (GNT) and several computerized memory tests from the Cambridge Automated Neuropsychological Testing Battery (CANTAB). A group of healthy controls (N=17) was tested on the CANTAB battery at baseline and 9-month follow up. The patients performed significantly poorer than controls on all CANTAB measures; however, there was no difference in change between groups over a 9-month period. Within-group patient comparisons revealed that symptoms reduced significantly over the study period, but had no association with memory. Significant improvements were observed for patients on two verbal memory tasks: the GNT and digit span, but not on any other measure. Interestingly, these were the only two tests on which patients were within normal limits at baseline. This study shows that patients with schizophrenia have deficits in multiple aspects of memory which remain stable over long periods of time. In addition, patients showed a tendency to improve on memory tasks which contained a verbal component.