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Objective: Neurocognitive impairment was found to be heritable in individuals with schizophrenia and their relatives. However, the heritability of neurocognitive measures in families with and without schizophrenia has not been directly compared. In this study, we examined the genetic structure of clinical and neurocognitive measures in sibling pairs with and without schizophrenia to test the hypothesis that the familial aggregation of such measures may be altered by having schizophrenia., Method: A total of 278 subjects including patients with schizophrenia and their non-psychotic full siblings, healthy controls, and their full siblings were recruited. Heritability was estimated for working memory, episodic memory, executive function and attention, as well as clinical features, such as positive, negative and disorganization symptoms., Results: Many clinical and cognitive domains were impaired in subjects with schizophrenia and their non psychotic siblings. Negative symptoms, working memory, episodic memory and executive function, but not positive, disorganization symptoms and attention, were found to be significantly heritable in all sibling pairs. However, the heritability of working memory function was significantly (chi(2)((d.f.=6))=13.9, p=.031) decreased in proband sibling pairs (h(2)=.38) as compared to control sibling pairs (h(2)=.95). Significant genetic correlations were observed between negative symptoms and the cluster of working memory, episodic memory and executive function., Conclusions: Several neurocognitive measures were heritable in sibling pairs with and without schizophrenia. However, schizophrenia reduced the heritability of working memory, perhaps due to disease-related environmental or genetic factors. Evidence for potential pleiotropy will inform future phenotypic studies.

Background: Progressive decreases in cortical gray matter volume have been reported in schizophrenia. However, studies of progressive change in deep brain nuclei and hippocampal-amygdala formation have not yielded consistent findings., Methods: Two high-resolution, T1-weighted magnetic resonance images were collected 2 years apart in 56 schizophrenia and 62 control subjects. Large-deformation high-dimensional brain mapping was used to generate surfaces for deep brain nuclei and hippocampal-amygdala formation at baseline and follow-up. Repeated-measures analysis of variance was used to test for longitudinal changes in volume and shape., Results: The pattern of progressive changes in the deep brain nuclei and hippocampal-amygdala formation in schizophrenia and control subjects was variable. Of the structures that receive direct projections from the cortex, the thalamus, caudate nucleus, nucleus accumbens, and hippocampus showed changes specific to subjects with schizophrenia, and changes in the amygdala and putamen were similar in both groups. Although different at baseline, no progressive change was observed in the globus pallidus, which does not receive direct projections from the cortex., Conclusions: These findings suggest that the disease process of schizophrenia is associated with progressive effects on brain structure and that brain structures that receive direct, excitatory connections from the cortex may be more likely to show progressive changes, compared with brain structures that receive indirect, inhibitory connections from the cortex. These findings are also somewhat consistent with the hypothesis that overactivity of excitatory pathways in the brain may contribute to the neural degeneration that occurs in at least a subgroup of individuals with schizophrenia.

Background and Methods: In vivo neuroimaging studies have provided evidence of decreases in the gray matter volume of the cingulate gyrus in subjects with schizophrenia as compared to healthy controls. To investigate whether these changes might be related to heritable influences, we used high-resolution magnetic resonance imaging and labeled cortical mantle distance mapping to measure gray matter volume, as well as thickness and the area of the gray/white interface, in the anterior and posterior segments of the cingulate gyrus in 28 subjects with schizophrenia and their non-psychotic siblings, and in 38 healthy control subjects and their siblings., Results: There was a significant effect of group status on posterior cingulate cortex (PCC) gray matter volume (p=0.02). Subjects with schizophrenia and their non-psychotic siblings showed similar reductions of gray matter volume (approximately 10%) in the PCC compared to healthy control subjects and their siblings. In turn, trend level effects of group status were found for thickness (p=0.08) and surface area (p=0.11) of the PCC. In the combined group of schizophrenia subjects and their siblings, a direct correlation was observed between PCC gray matter volume and negative symptoms. However, the reduction in PCC gray matter volume in schizophrenia subjects and their siblings was proportionate to an overall reduction in whole cerebral volume, i.e., the effect of group on the volume of the PCC became non-significant when cerebral volume was included as a covariate (p=0.4). There was no significant effect of group on anterior cingulate cortex volume, thickness, or area., Conclusions: Our findings suggest that decreases in the gray matter volume of the PCC occur in schizophrenia subjects and their siblings. The presence of such decreases in the non-psychotic siblings of schizophrenia subjects suggests that heritable factors may be involved in the development of cortical abnormalities in schizophrenia.

Deficits in the volume of the thalamus have been observed in both individuals with schizophrenia and their nonpsychotic relatives. However, no studies to date have examined the underlying pattern of thalamic shape change in relatives of individuals with schizophrenia. This study examined the volume and shape of the thalamus in schizophrenia subjects, their siblings, and healthy control individuals. T1-weighted magnetic resonance scans were collected in a group of young subjects with schizophrenia (mean age, 23 years) and their nonpsychotic siblings (n = 25 pairs), and control subjects and their siblings (n = 40 pairs). Thalamic surfaces were generated using high-dimensional brain mapping. A canonical weighting function was derived from the contrast between schizophrenia and control subjects and then used to generate a canonical shape score for all subjects. Maps of the estimated surface displacement between groups were also created to visualize the thalamic shape differences between groups. The thalamic canonical scores of the siblings of the schizophrenia probands were intermediate between the probands and healthy control subjects. These siblings also displayed an intermediate degree of the inward surface deformation of the anterior and posterior thalamus that was present between schizophrenia probands and controls. There was no main effect of group status on thalamic volume and no significant correlations of the structural measures with measures of psychopathology or cognitive function. Our results indicate that thalamic shape abnormalities are present in relatively young individuals with schizophrenia and their siblings. Inward deformation of the anterior and posterior regions of the thalamus represents a potential neuroanatomical endophenotype of schizophrenia.

Objective and Methods: Abnormalities of the neuroanatomy of the gray matter of the cingulate gyrus, especially its anterior segment, have been suggested to be an important characteristic of schizophrenia. In this study, T1-weighted magnetic resonance scans were collected in 53 individuals with schizophrenia and 68 comparison subjects matched for age, gender, race and parental socioeconomic status. We applied Labeled Cortical Mantle Distance Mapping to assess the volume, surface area and thickness of the cortical mantle within the anterior (AC) and posterior (PC) segments of the cingulate gyrus, excluding the paracingulate gyrus, and related these anatomical measures to measures of psychopathology and illness duration., Results: After covarying for total cerebral volume, individuals with schizophrenia showed smaller AC gray matter volume (p=0.024), thickness (trend, p=0.081), but not surface area (p=0.16), than comparison subjects. Similar group differences were found for PC gray matter volume (p=0.0005) and thickness (trend, p=0.055), but not surface area (p=0.15). Across both groups, there was a significant L>R asymmetry in thickness of the AC, and a significant L>R asymmetry in the surface area of the PC. However, there were no significant group-by-hemisphere interactions. In the individuals with schizophrenia, thinning of the AC, but not the PC, was correlated with a longer duration of illness and a greater severity of psychotic symptoms., Conclusions: Individuals with schizophrenia showed smaller gray matter volumes across the entire cingulate gyrus, mostly due to a reduction in cortical mantle thickness. However, structural measures of the AC were more closely related to clinical features of the illness.

Schizotypal traits and cognitive disturbances are known to be present in first-degree relatives of people with schizophrenia. However, there is little understanding of how these endophenotypes are related to each other. We explored the nature of this relationship in individuals with schizophrenia, their full siblings, community controls, and their siblings. All participants were assessed in the domains of working memory, attention, episodic memory, and executive function, as well as in their level of positive, negative, and disorganization symptoms. Schizophrenia probands were significantly impaired on all cognitive domains, as compared with the other 3 groups, and displayed the highest levels of positive, negative, and disorganization symptoms. Proband siblings performed significantly worse than controls on tasks of working memory, episodic memory, and executive function, and they displayed significantly more positive and negative symptoms as compared with controls. Poorer task performance across all 4 cognitive domains was most strongly correlated with increased negative symptoms. Mediation analyses revealed that working memory, episodic memory, and executive function deficits partially mediated increases in negative symptoms among proband siblings. Negative symptoms fully mediated deficits in working memory and episodic memory but only partially mediated deficits in executive function. Results suggest that there is a complex relationship between cognitive and clinical factors in this high-risk population.

Objective: Postmortem and neuroimaging studies of schizophrenia have reported deficits in the volume of the thalamus and its component nuclei. However, the pattern of shape change associated with such volume loss has not been investigated. In this study, alterations in thalamic volume, shape, and symmetry were compared in subjects with and without schizophrenia., Method: T(1)-weighted magnetic resonance scans were collected in 52 schizophrenia and 65 comparison subjects matched for age, gender, race, and parental socioeconomic status. High-dimensional (large-deformation) brain mapping was used to assess thalamic morphology., Results: Significant differences in thalamic volume, deformities of thalamic shape at the anterior and posterior extremes of the structure, and a significant exaggeration of thalamic asymmetry (i.e., left smaller than right) were found in the schizophrenia subjects. After covarying for total cerebral volume, the difference in thalamic volume became insignificant. When information about thalamic shape was combined with previously collected information about hippocampal shape, the discrimination between schizophrenia patients and comparison subjects was improved., Conclusions: Thalamic volume was smaller than normal in schizophrenia patients, but only proportionate to reductions in reduced total cerebral volume. The presence of changes in thalamic shape and asymmetry suggest greater pathologic involvement of individual nuclei at its anterior and posterior extremes of the thalamic complex.

Background: Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study., Method: Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study., Results: Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium., Conclusion: Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation.

Objective: The age at onset of schizophrenia for males has usually but not always been reported to be less than that for females. Early onset has also been associated with poor response to neuroleptic treatment and worse long-term outcome. The authors compared age at onset in neuroleptic-resistant and -responsive schizophrenic patients to determine whether the gender difference in age at onset is related to response to neuroleptic treatment., Method: The subjects were 322 patients with schizophrenia or schizoaffective disorder who were consecutively admitted to a university hospital-based research program., Results: Analysis of variance showed significant relationship between age at onset and both gender and longterm responsivity to neuroleptic drugs. The mean ages at onset in the neuroleptic-responsive men (mean = 21.2 years, SD = 6.1, N = 75), neuroleptic-resistant men (mean = 19.4 years, SD = 4.7, N = 119), and neuroleptic-resistant women (mean = 20.1 years, SD = 6.3, N = 77) were fairly similar, whereas that of the neuroleptic-responsive women (mean = 24.2 years, SD = 8.7, N = 51) was significantly greater than for all other groups. A simple effects model indicated that male and female neuroleptic-resistant patients did not differ significantly in mean age at onset, whereas male and female neuroleptic-responsive patients did. The effect of gender and neuroleptic responsivity on age at onset was related to schizophrenic subtype., Conclusions: These results confirm previous data indicating neuroleptic resistance is associated with early onset. The finding that the difference in age at onset between males and females is smaller in neuroleptic-resistant patients than in neuroleptic-responsive patients suggests that neuroleptic-resistant patients differ premorbidly as well as after onset of illness.

Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic--resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

The densities of dopamine-D4 receptors were determined in postmortem samples of caudate nucleus from patients with schizophrenia (n = 9) and age-matched controls (n = 10). D4 receptor binding was defined as the difference between binding sites labeled by [3H]YM-09151-2 (D2 + D3 + D4 receptors) and those by [3H]raclopride, in the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p) (D2 + D3 receptors). D4 receptor binding was measurable in all the subjects with schizophrenia (mean = 3.8 pmol/g tissue) but only in 3/10 controls. To determine the specificity of these findings for schizophrenia, D4 receptor binding was also measured in the caudate nucleus of suicide victims with major depression (n = 6) and age-matched controls (n = 6). A small amount of D4 binding was noted in some of the controls + depressed subjects and there was no significant difference between controls and patients with major depression. The addition of 200 microM Gpp(NH)p to the assay significantly increased the amount of specific binding of [3H]raclopride in control tissues, but not in tissues from subjects with schizophrenia, suggesting an abnormality in the G-protein component coupled to the D2 receptor. [3H]Raclopride binding was also significantly increased by Gpp(NH)p in subjects with major depression. These results confirm a previous report of Seeman et al. (1993) and suggest that measurable D4 receptor binding in the caudate nucleus is more frequent in patients with schizophrenia as compared with normal controls and subjects with major depression and that guanine nucleotides do not enhance [3H]raclopride binding in schizophrenia.(ABSTRACT TRUNCATED AT 250 WORDS)

The Brief Psychiatric Rating Scale (BPRS) is an 18-item rating scale frequently used to assess change in psychopathology in schizophrenic patients in antipsychotic drug trials. BPRS items may be rated by the use of either a 1 to 7 or 0 to 6 scaling system, with the 1 or 0 rating indicating no pathology, respectively. When percent change in BPRS total score is used as an index of change, measurement considerations indicate that the 0 to 6 scaling system is preferable. Furthermore, when the 1 to 7 scaling system is used, patients whose initial BPRS values fall at the lower end of the range are classified as responders at a lower rate than are patients with higher initial scores. The adoption of the 0 to 6 scaling system for the BPRS and other rating scales, such as the Positive and Negative Syndrome Scale, is advocated.

Cognitive dysfunction may underlie some of the psychopathology of schizophrenia as well as contribute to impaired social and vocational function in this disorder. Chronic treatment with typical neuroleptics has been reported to produce only minimal improvement in and may impair cognitive function in schizophrenia. We have studied the effect of clozapine, an atypical antipsychotic drug, on cognitive function in 36 patients with treatment-resistant schizophrenia. In addition, patients with non-treatment-resistant schizophrenia were randomly assigned to clozapine (N = 24) or typical neuroleptics (N = 23). Cognitive function in the treatment-resistant schizophrenia group was studied after 6 weeks and 6 months of treatment, while the non-treatment-resistant patients were also studied at 12 months of treatment. Clozapine treatment improved several domains of cognitive function, especially attention and verbal fluency in both treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. On the other hand, typical neuroleptic treatment produced minimal improvement in cognitive function. The effect of clozapine on some tests of attention and verbal fluency was significantly greater than that of typical neuroleptic treatment in non-treatment-resistant schizophrenia. These data suggest that clozapine treatment was superior to typical neuroleptics in improving cognitive function in schizophrenia. The possibility that this is related to normalization of dopaminergic function by clozapine is discussed.

Neuroendocrine challenge studies are frequently used to make inferences about the pathophysiology of psychiatric illness or about the effects of chronic psychotropic drug treatment on brain monoamine function. The outcome of these exploratory neuroendocrine tests, however, may be influenced by the effects of confounding variables, such as specific stress effects and variations in basal hormone levels. The inclusion of a placebo control condition minimizes the variability due to these variables. A number of recent neuroendocrine studies have omitted the placebo control condition. Based on experimental data, it can be shown that failure to include a placebo control condition may result in both Type I and Type II errors of inference. These results suggest a placebo control condition should be included in exploratory neuroendocrine challenge studies.

Objective: The goal of this study was to determine whether clozapine is a cost-effective treatment for treatment-resistant schizophrenia., Method: Data were collected on 96 treatment-resistant patients with schizophrenia for 2 years before they entered a clozapine treatment study and for at least 2 years after they entered the study. Information about the cost of inpatient and outpatient treatment, housing costs, other costs, and family burden through direct interview or questionnaire of these patients and their families were available for 47 of the 96 patients. Data on lost income and Social Security disability insurance were also obtained. Outcome measures included psychopathology, quality of life, global functioning, work function, and rehospitalization., Results: The cost of treatment was significantly decreased in the patients who continued clozapine treatment for at least 2 years. This was primarily due to a dramatic decrease in the frequency and cost of rehospitalization. Costs were nonsignificantly lower in patients who dropped out of treatment. The estimated total 2-year cost for the 59 patients who continued clozapine treatment, the 34 patients who dropped out, and the three who interrupted treatment decreased from $7,390,206 to $5,719,463, a savings of $8,702/year per patient. There was a decrease in total costs of $22,936/year for the 37 patients who continued clozapine treatment for whom cost data were available. There were no significant changes in lost income or Social Security disability insurance payments in either group. Clozapine produced a marked improvement in Brief Psychiatric Rating Scale total scores as well as positive negative symptom scores, Global Assessment Scale scores, Quality of Life Scale scores, work functioning, capacity for independent living, and rehospitalization rates., Conclusions: Clozapine is a cost-effective treatment for treatment-resistant schizophrenic patients. Cost savings result almost exclusively from the reduced cost of hospitalization.