Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis

BACKGROUND: Schizophrenia is characterized by a generalized cognitive impairment with pronounced deficits in the domains of verbal memory, executive functioning and attention. AIM: To investigate whether cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. METHOD: A meta-analytic review of the published literature on cognitive performance between relatives of schizophrenic patients and healthy controls. RESULTS: The meta-analyses yielded nine weighted effect sizes from 37 studies comprising 1639 relatives of schizophrenia patients and 1380 control subjects. The largest differences were found on verbal memory recall (d=0.54, 95% CI=0.43-0.66) and executive functioning (d=0.51, 0.36-0.67). Attentional functioning showed smaller effect sizes (d=0.28, 0.06-0.50). These effect sizes are in the moderate range. CONCLUSION: Cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. This finding is consistent with the idea that certain cognitive deficiencies in relatives are caused by familial predisposition to schizophrenia and that these deficiencies might be putative endophenotypes for schizophrenia. However, our results do not address genetic causes directly. Further work is needed to determine whether certain cognitive traits are familial and whether there is co-inheritance of these traits with schizophrenia within families.     

Brain volumes in relatives of patients with schizophrenia: a meta-analysis

CONTEXT: Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent. OBJECTIVE: To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. DATA SOURCES: A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected. STUDY SELECTION: Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes. DATA EXTRACTION: For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors (H.B.M.B. and A.A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model. DATA SYNTHESIS: Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d = 0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d = 0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d = 0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects. CONCLUSION: Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.     

Social cognition in first-degree relatives of people with schizophrenia: A meta-analysis

Social cognition is affected in people with schizophrenia, but whether this is the case for healthy relatives of these patients is less clear. The presence of social cognition impairments in relatives would suggest a potential genetic role of social cognition in schizophrenia. To determine whether social cognition is affected in first-degree relatives of people with schizophrenia and examine the impact of potential moderator variables, a meta-analysis of studies investigating at least one domain of social cognition (mentalizing, emotional processing, social perception, social knowledge and/or attributional style) in adult first-degree relatives of patients with schizophrenia was performed. Our inclusion criteria were satisfied by 29 studies, of which 11 evaluated mentalizing, 20 emotional processing, and two social perception. Moderate mean effect sizes were obtained for these three components. Across all studies, effect sizes were significantly correlated with IQ and age differences between groups, calling for careful group matching for future studies. Overall, the results from this meta-analysis highlight that social cognition is globally affected in first-degree relatives of people with schizophrenia, suggesting that social cognition deficits in schizophrenia may be related to a genetic vulnerability for the disorder.     

Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis

Poor performance on the antisaccade (AS) task has been interpreted as a potential indicator of genetic liability that may enhance the power of linkage studies of a multidimensional phenotype for schizophrenia. Every study has replicated the finding of significantly worse performance in schizophrenia patients regardless of which specific antisaccade paradigm was employed. In some studies involving a standard version of the antisaccade task, relatives of schizophrenia patients made an increased number of errors, but in other studies that used this same paradigm, relatives of schizophrenia patients did not differ from controls. In this paper, we report the results of a meta-analysis on studies that used the standard antisaccade paradigm. The meta-analysis shows that those studies that reported large effect sizes and statistically significant differences between relatives of schizophrenia patients and controls used inclusion/exclusion criteria that were not symmetrical between the two groups, whereas those studies that reported small and nonsignificant differences between relatives of schizophrenia patients and controls used symmetrical inclusion/exclusion criteria. Specifically, studies that applied stricter psychopathology exclusion criteria to controls than to relatives of schizophrenia patients had larger effect sizes than studies that applied comparable exclusion criteria to both groups, suggesting that antisaccade performance is compromised by psychopathology in general rather than by schizophrenia per se. Since symmetrical inclusion/exclusion criteria between relatives of schizophrenia patients and controls are essential for a genetic analysis, and those studies that did apply symmetrical criteria had small effect sizes, the available data suggest that poor antisaccade performance is unlikely to be useful in identifying clinically unaffected carriers of genes for schizophrenia.     

Cancer incidence in patients with schizophrenia and their first-degree relatives - a meta-analysis

Objective: Controversy concerning cancer incidence in schizophrenia exists because of heterogeneous study findings. Method: A meta‐analysis was performed on standardized incidence ratios (SIR) of cancer in patients with schizophrenia and first‐degree relatives and compared with general population samples. Results: The pooled overall cancer incidence in patients was not significantly increased (SIR = 1.05, CI 0.95–1.15). Lung cancer incidence was slightly increased (SIR = 1.31, CI 1.01–1.71), but was reduced after adjusting for smoking prevalence. The incidence of several cancers unrelated to smoking was reduced in patients. Breast cancer rates were significantly increased in female patients. The pooled overall cancer incidence in siblings (SIR = 0.89, CI 0.84–0.94) and parents (SIR = 0.90, CI 0.88–0.93) was significantly reduced. A meta‐regression detected a significant relationship between cancer risk in the general population and relative risk in patients. Conclusion: The meta‐analysis aided exploration of inconsistent study findings. There is a discrepancy between cancer risk exposure and cancer incidence in schizophrenia consistent with a protective effect.     

A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives

Bundy H, Stahl D, MacCabe JH. A systematic review and meta‐analysis of the fertility of patients with schizophrenia and their unaffected relatives. Objective: We aimed to systematically evaluate the empirical evidence for the commonly held view that the reduced reproductive output in patients with schizophrenia is compensated for by an increased fitness in unaffected relatives. Secondary aims were to quantify the magnitude of the fertility disadvantage and the apparent gender difference in fertility of patients with schizophrenia. Method: We carried out a systematic review and meta‐analysis of studies investigating the fertility of patients with schizophrenia, their siblings, their parents and the general population. Results: Patients with schizophrenia had reduced fertility compared with the general population, [Fertility Ratio (FR) = 0.39 (95% Confidence Interval (CI) = 0.35–0.44)]. Siblings of patients with schizophrenia had somewhat fewer offspring than the general population (FR = 0.96, 95% CI = 0.93–1.00). Parents of patients with schizophrenia had fertility similar to the general population (FR = 1.17, 95% CI = 0.94–1.46). Men had a greater impairment in fertility than women, both in patients (FR = 0.54, 95% CI = 0.50–0.57) and in their unaffected siblings (FR = 0.81, 95% CI = 0.71–0.92). Conclusion: Compensatory fitness advantage in siblings and parents cannot explain the maintenance of schizophrenia in the population. Alternative explanations include mutation‐selection balance and the role of quantitative traits.     

Declarative memory in unaffected adult relatives of patients with schizophrenia: a systematic review and meta-analysis

Despite evidence for diverse neuropsychological impairment in schizophrenia, verbal declarative memory has emerged as a core deficit in the disorder. Similar but less marked impairments have been demonstrated in unaffected biological relatives of patients with schizophrenia, but the nature and extent of the memory impairment in relatives compared to controls is unclear. We have conducted a systematic review and meta-analysis of the literature investigating declarative memory in unaffected biological relatives of schizophrenics and controls, with the aim of quantifying memory deficits in relatives. The standardised mean difference between groups was calculated for nine measures of declarative memory and two measures of intellectual ability, based on 21 studies of several hundred relatives of schizophrenics and controls. Unaffected relatives showed poorer performance relative to controls on all tests of memory examined. Small to moderate effect sizes, with overlapping 95% confidence intervals, were greatest on immediate (trial 1) list recall (0.65), followed by immediate (0.53) and delayed story recall (0.52). Verbal and general IQ showed smaller standardised mean differences as the latter tests, while the smallest standardised mean difference was shown on delayed visual recall (0.32). Results suggest greater deficits on tests of increasing memory load or which place demands on effective encoding processes but more studies with these tasks are needed. Investigation of sub-groups within these cohorts (e.g. age groups within or beyond the maximum age of risk) is recommended in order to identify deficits specific to the disease process.     

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.     

Emotional experience in patients with schizophrenia revisited: meta-analysis of laboratory studies

Our understanding of the emotion deficits in schizophrenia is limited. Findings from studies employing trait emotion instruments suggest that patients have attenuated levels of positive emotion (ie, anhedonia) and increased levels of negative emotion. Conversely, patients and controls have not statistically differed in their subjective reactions to positive or negative valenced stimuli in most laboratory studies to date. Further obfuscating this issue is the fact that many of these laboratory studies are underpowered and a handful of emotion induction studies have found evidence of anhedonia. We conducted a meta-analysis of 26 published studies employing laboratory emotion induction procedures in patients with schizophrenia and healthy controls. Patients did not differ from controls when strictly rating their subjective hedonic reactions to the stimuli. However, they reported experiencing relatively strong aversion to both positive and neutral stimuli (Hedges D = .72 and .64, respectively). These findings were not the result of demonstrable sample or methodological differences across studies. Patients' ability to experience hedonic emotion is preserved, although they also show relatively strong, simultaneously occurring aversive emotion when processing laboratory stimuli considered by others to be pleasant or neutral.     

Dyskinesia and parkinsonism in antipsychotic-naive patients with schizophrenia, first-degree relatives and healthy controls: a meta-analysis

Background: Several studies have reported the presence of dyskinesia and parkinsonism in antipsychotic-naive patients with schizophrenia as well as in their first-degree relatives. These movement disorders may therefore form an integral part of the illness and its (genetic) liability. Method: A systematic search was conducted in the Medline, EMBASE, and PsychINFO databases to identify studies reporting on dyskinesia and parkinsonism assessed in antipsychotic-naive patients with schizophrenia (n = 213) and controls (n = 242) and separately in nonill first-degree relatives (n = 395) and controls (n = 379). Effect sizes were pooled using random-effect models to calculate odds ratios (ORs) to compare the risk of these movement disorders among patients and healthy relatives each with matched controls. Results: Antipsychotic-naive schizophrenia was found to be strongly associated with dyskinesia (OR: 3.59, 95% confidence interval [CI]: 1.53–8.41) and parkinsonism (OR: 5.32, 95% CI: 1.75–16.23) compared with controls. Dyskinesia and parkinsonism were also significantly more prevalent in healthy first-degree relatives of patients with schizophrenia as compared with healthy controls (OR: 1.38, 95% CI: 1.06–1.81, and OR: 1.37, 95% CI: 1.05–1.79, respectively).Conclusion: The results suggest that movement disorders, and by inference abnormalities in the nigrostriatal pathway, are not only associated with schizophrenia itself but may also be related to the (genetic) risk of developing the disease.     

Neuropsychological correlates of P50 sensory gating in patients with schizophrenia

Impaired inhibition of P50 cerebral evoked response is one of the best validated endophenotypes in schizophrenia. There are controversial data on the relationship between P50 evoked potential deficit and measures of cognitive function in schizophrenia. A comprehensive clinical and neurocognitive assessment plus an evaluation of P50 sensory gating was performed in 160 schizophrenia patients and 64 controls. Neurocognitive scores from each cognitive domain were converted to demographically-adjusted T-scores (age, gender, and years of education) for all study participants. The relationship between P50 and neurocognitive variables was assessed via parametric and nonparametric correlations and categorical strategies: we compared neuropsychological test scores in patients and controls in the lowest P50 quartile vs. the highest. Controls had better performance than schizophrenia patients in all cognitive domains. Schizophrenia patients had significantly higher P50 ratios than controls, and no significant correlation was found between P50 gating measures and neuropsychological test scores in schizophrenia patients or healthy controls. Moreover, no differences in neurocognitive performance were found between subjects in the lowest P50 ratio quartile vs. the highest in healthy controls or patients with schizophrenia. We concluded that there is no evidence of an association between P50 ratio and cognitive measures in schizophrenia patients, and this seems to be also the case in healthy controls.     

Structural brain abnormalities among relatives of patients with schizophrenia: implications for linkage studies

Several studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit structural brain abnormalities that may be manifestations of genes that predispose to schizophrenia. In this work, we examine the utility of such measures for linkage analyses. Subjects were 45 nonpsychotic first-degree adult relatives of schizophrenic patients and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3D magnetic resonance images of the entire brain were acquired on a 1.5-T magnet. We used factor analysis to derive MRI-based phenotypes for analysis. The factor analyses produced three factors that significantly discriminated relatives from controls. We used a linear combination of the three factor scores to derive an MRI phenotype. A receiver operating characteristic (ROC) analysis of this phenotype estimated an area under the curve (AUC) statistic of 0.85. The phenotype also discriminated nonpsychotic relatives having two schizophrenic relatives from those having only one. The nonpsychotic relatives of schizophrenic patients show deviant values on MRI measures of brain structure and the distribution of these deviations among relatives and controls suggests that if these results can be replicated, an MRI-derived phenotype could be useful for genetic linkage and association analyses.     

Association of cognitive and P50 suppression deficits in chronic patients with schizophrenia

ObjectiveCognitive deficits are core symptoms of schizophrenia; however, their pathophysiological mechanisms are still unclear. A sensory gating deficit, as reflected by P50 suppression, has been repeatedly shown in schizophrenia patients, which may be associated with cognitive deficits in this disorder. The present study was to examine the relationship between the P50 suppression and cognitive deficits in patients with schizophrenia, which is still under-investigated.MethodWe recruited 38 chronic schizophrenia patients and 32 matched healthy controls, and assessed their cognition with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and P50 suppression with the electroencephalography system.ResultsThe total and its 4 index scores (all p < 0.05) except for the visuospatial/ constructional index of RBANS were significantly lower in patients compared with healthy controls. However, only the language and attention passed Bonferroni corrections. Patients displayed a significantly higher P50 ratio, higher S2 amplitude, and lower S1 amplitude (all p < 0.05) than healthy controls. Interestingly, only in the patients, the S1 amplitude was associated with both language and attention, and the S2 amplitude with both visuospatial/ constructional and language (all p < 0.05), although all of these significances did not pass the Bonferroni corrections. The P50 ratio was not associated with any of the RBANS scores (all p > 0.05).ConclusionsOur results suggest the P50 suppression deficits in Chinese patients with schizophrenia, which may be associated with cognitive impairments of this illness. Moreover, the amplitude of S1 and the amplitude of S2 may be involved in the different cognitive domain deficits in schizophrenia patients.SignificanceThis study suggests that the P50 components may possibly be effective biomarkers for cognitive deficits in patients with schizophrenia.     

Sex differences in cognition among persons with schizophrenia and healthy first-degree relatives

Previous research suggests differences between women and men in the clinical features of schizophrenia, but studies examining sex differences in neuropsychological functioning have reached inconsistent results. In the present study, sex differences in cognition and clinical features were investigated in population-based samples of participants with schizophrenia (n = 218), their healthy first-degree relatives (n = 438) and controls (n = 123). Sex differences in illness features were small; nevertheless, women with schizophrenia had less negative symptoms and lived independently more often than men. The schizophrenia group had impairments in all studied neuropsychological domains, and the relatives were impaired in processing speed and set-shifting. In all groups, women performed better than men in processing speed, set-shifting and verbal episodic memory, whereas men outperformed women in visual working memory. The group-by-sex interaction was significant in two variables: women outperformed men in the relatives group in immediate verbal reproduction and in the use of semantic clustering as a learning strategy, while there was no sex difference in the schizophrenia group. In conclusion, sex differences in cognition are mostly similar in schizophrenia to those among controls, despite sex differences in illness features. The preservation of sex differences also in first-degree relatives supports the conclusion.     

The P50 auditory evoked potential in violent and non-violent patients with schizophrenia

BACKGROUND: Emotionally driven violence is facilitated by increased arousal. It may be a consequence of an information-processing deficit and the cognitive attributions for the stimuli given by the subject. The aim of this study was to compare the P50 evoked potential responses of violent patients with schizophrenia with non-violent patients with schizophrenia and healthy controls. METHOD: Patients were classified into violent and non-violent in accordance to the Overt Aggression Scale. P50 auditory evoked potentials of 32 unmedicated patients with schizophrenia (violent=14, non-violent=18) and 17 healthy controls were recorded during five runs of 30 click pairs. RESULTS: Healthy controls exhibited a lower S2/S1 ratio when compared to violent (p<0.001) and non-violent (p=0.04) patients. Using a cutoff point of 0.50 for S2/S1 ratio to define abnormal gating a significant proportion of violent patients did not show P50 suppression (71.4%) in comparison to non-violent patients (38.9%) and healthy controls (23.5%) (p=0.02). CONCLUSIONS: Violent behavior in patients with schizophrenia could be associated with a disturbed information sensory gating. Violence in patients with schizophrenia may be facilitated by an increased arousal which may in turn be the result of an information-processing deficit.     

Cognitive functioning in patients with affective disorders and schizophrenia: A meta-analysis

There is considerable evidence for cognitive dysfunction in schizophrenia and affective disorders, but the pattern of potential similarities or differences between diagnostic groups remains uncertain. The objective of this study was to conduct a quantitative review of studies on cognitive performance in schizophrenia and affective disorders. Relevant articles were identified through literature search in major databases for the period between January 1980 and December 2005. Meta-analytic treatment of the original studies revealed widespread cognitive deficits in patients with schizophrenia and affective disorders in intellectual ability and speed of information processing, in encoding and retrieval, rule discovery and in response generation and response inhibition. Differences between diagnostic groups were quantitative rather than qualitative.