Association of estrogen levels with neuropsychological performance in women with schizophrenia.

OBJECTIVE: This study sought to determine the relationship of estrogen levels with psychiatric symptoms and neuropsychological function in female patients with schizophrenia. METHOD: Psychiatric symptoms were assessed and average estrogen and progesterone levels from four consecutive weekly blood samples were measured in 22 female inpatients with schizophrenia who were also administered a neuropsychological battery. RESULTS: There were strong positive correlations between average estrogen level and cognitive function, especially measures of global cognitive function, verbal and spatial declarative memory, and perceptual-motor speed. Correlations of hormone levels with psychiatric symptoms were nonsignificant. CONCLUSIONS: Higher estrogen levels in female patients with schizophrenia are associated with better cognitive ability. These results may have implications for potential treatment of cognitive dysfunction with adjunctive estrogen in female patients with schizophrenia.

Lack of association between duration of untreated illness and severity of cognitive and structural brain deficits at the first episode of schizophrenia.

OBJECTIVE: The purpose of the study was to determine whether the duration of illness before antipsychotic drug treatment for schizophrenia was associated with the severity of cognitive deficits and volumetric brain structure anomalies observed in some patients with a first episode of schizophrenia. METHOD: Duration of psychotic symptoms and of other symptoms marking a behavioral change was estimated from structured interviews with 50 patients who had a first episode of schizophrenia and their family members. Interviews were conducted within a month of the patients' hospitalization. Duration of untreated psychotic symptoms and of behavioral change was correlated with neuropsychological summary scores from a comprehensive cognitive battery and with measurements of lateral ventricular, temporal lobe, and cerebral hemispheric volumes. RESULTS: No significant correlations were observed between measures of untreated illness and the severity of either cognitive or structural brain deficits at baseline. CONCLUSIONS: The duration of untreated symptoms of schizophrenia, for which an association with an uncontrolled toxic brain process has been proposed, is unlikely to explain why first-episode patients with schizophrenia have widespread deficits in cognitive functioning and have detectable ventricular enlargement and some loss of cortical mass.

Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia.

OBJECTIVE: The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness. METHOD: Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed. RESULTS: Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group. CONCLUSIONS: Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.

P300 amplitude is related to clinical state in severely and moderately ill patients with schizophrenia.

BACKGROUND: Relationships between illness severity and neurobiologic abnormalities in schizophrenia were studied in subpopulations varying in clinical severity. METHODS: Auditory ERPs were collected from 28 severely ill, chronically hospitalized schizophrenic men from a state hospital; 29 moderately ill inpatient and outpatient schizophrenic men from a veterans hospital; and 30 healthy male subjects from the community as controls. Clinical symptoms were evaluated in patients using the Brief Psychiatric Rating Scale (BPRS). RESULTS: Both schizophrenic patient groups had smaller P300 amplitude than the control subjects. Severely ill patients had smaller P300s than moderately ill patients and scored higher on three BPRS factor scores as well as BPRS Total. Among severely ill patients, P300 amplitude was unrelated to clinical symptoms. Among moderately ill patients, P300 was related to Withdrawal/Retardation, Anxiety/Depression, and BPRS Total. After combining patients, Thinking Disturbance emerged as an additional correlate of P300. Group differences in P300 could not be accounted for by group differences in symptom severity using analysis of covariance. CONCLUSIONS: Reduced P300 amplitude marks the diagnosis of schizophrenia, but also reflects individual differences in severity, including positive symptoms. Previous failures to find relationships between positive symptoms and P300 may have been due to a restricted range of clinical severity.

Severity of schizophrenia and magnetic resonance imaging abnormalities: a comparison of state and veterans hospital patients.

BACKGROUND: The relationship between illness severity and neuroanatomical abnormalities in schizophrenia remains unclear. The purpose of this study was to test whether the pattern and extent of brain volume abnormalities differed between two patient groups, distinguished by their overall severity and clinical course of schizophrenia. METHODS: Subjects were 56 severely ill, chronically hospitalized schizophrenic men from Napa State Hospital (SH-SZ), 44 moderately ill, acutely hospitalized schizophrenic men from the Palo Alto Veterans Administration Health Care System (VA-SZ), and 52 healthy male control subjects. Temporolimbic, ventricular, and frontoparietal volumes, quantified from 3-mm coronal spin-echo magnetic resonance images and adjusted for cerebral volume and age, were compared using analysis of variance. RESULTS: Compared to control subjects, both SZ groups had smaller (p < .05) temporal lobe and frontoparietal gray matter volumes and larger ventricles and temporal sulci. Whereas SH-SZ had more pronounced cerebrospinal fluid and frontoparietal abnormalities relative to VA-SZ; VA-SZ had greater temporal lobe gray matter deficits. Neither patients group had hippocampal or cerebral volume deficits relative to control subjects. There were no differences between diagnostic subtypes. CONCLUSIONS: The magnitude of volume abnormalities in schizophrenia varies with respect to disease severity and to brain region, but disease severity is not associated with anatomically distinct subgroups.

Sex differences in neuropsychological functioning of first-episode and chronically ill schizophrenic patients.

OBJECTIVE: The purpose of this study was to determine whether men and women with schizophrenia demonstrate differences in cognitive abilities. METHOD: Two cohorts of patients with schizophrenia, an acute first-episode and a chronically hospitalized group, were evaluated with a neuropsychological battery and compared with a normal group of subjects. RESULTS: After adjustment for age, age at onset, and premorbid IQ, male chronic patients performed worse than female chronic patients on measures of visual memory. These differences were eliminated after control for symptom severity. No other differences were found in cognitive function between men and women in either cohort. CONCLUSIONS: Sex differences in cognitive function in schizophrenic patients are not robust findings.

A profile of cortical gray matter volume deficits characteristic of schizophrenia.

Quantitative magnetic resonance imaging (MRI) studies from our laboratory have reported that patients with schizophrenia show a widespread cortical gray matter volume deficit, which is especially pronounced in the prefrontal and anterior superior temporal cortices. The present study compared two separate samples of schizophrenic patients -- 71 men from a Veterans Administration (VA) hospital and a sample of 57 severely ill men from a state hospital (SH) -- in an effort to test whether the pattern of brain volume abnormalities previously observed in VA schizophrenic patients can be generalized to other groups of schizophrenic patients. MRI-derived brain volumes of gray matter, white matter and sulcal cerebrospinal fluid (CSF) in six cortical regions, and CSF in the lateral and third ventricles were computed. All MRI volumes were adjusted for normal variation in head size and age and were expressed as standardized Z-scores, which also permitted structures of different sizes to be compared directly. The two schizophrenic groups displayed similar patterns of volume abnormalities: cortical gray matter but not white matter volume deficits that were widespread but especially notable in the prefrontal and temporal regions. The regional gray matter deficits in the SH group were generally greater than those in the VA group, particularly in the prefrontal and posterior superior temporal regions. Both schizophrenic groups had abnormally large volumes of the cortical sulci and lateral and third ventricles; however, the SH group showed greater enlargements, the most prominent occurring in the ventricles and temporal sulci. The overlapping patterns of cortical gray matter deficits in the two groups provide evidence for generality of this pattern of regional brain volume abnormalities in schizophrenia.

No neuropathologic evidence for an increased frequency of Alzheimer's disease among elderly schizophrenics.

BACKGROUND: There is currently controversy as to the frequency of Alzheimer's disease (AD) in elderly persons with schizophrenia. Several studies have reported an increased frequency of AD in elderly schizophrenics, whereas others have found no increase. This issue is important because it has been hypothesized that medications used to treat schizophrenia may exacerbate AD histopathology. METHODS: We examined autopsy cases from a state psychiatric hospital and a Veterans Affairs medical center. Charts were reviewed on 166 subjects to determine if the history warranted a DSM-IV diagnosis of schizophrenia. All subjects had complete gross and microscopic neuropathologic evaluations, which were reviewed for evidence of Alzheimer's disease. RESULTS: Retrospective chart review identified 51 subjects over the age of 55 who met DSM-IV criteria for schizophrenia (mean age = 71.7 years, SD = 8.6, range 56-95 years). Of these 51, only I met neuropathologic criteria for AD, a frequency of 2%. CONCLUSIONS: The frequency of subjects meeting neuropathologic criteria for Alzheimer's disease in our sample of schizophrenics was equal to or less than that found in the general population. Because institutionalized populations may contain an excess of elderly schizophrenic patients with severe behavioral pathologies, which may in turn reflect the presence of neurodegenerative processes such as Alzheimer's disease, our results may actually overestimate the frequency of Alzheimer's in the entire schizophrenic population. The frequency of Alzheimer's disease in the elderly with schizophrenia may be less than that in the general population.

Structural magnetic resonance imaging abnormalities in men with severe chronic schizophrenia and an early age at clinical onset.

BACKGROUND: Early age at onset of schizophrenia often signifies a more severe form of the illness. However, the relationship between age at onset and brain abnormalities has not been established. We assessed temporal-limbic morphometry in severely ill men with chronic schizophrenia who had a relatively early onset of illness and examined the relationships among regional brain volumes, clinical symptoms, and age at illness onset. METHOD: Temporal lobe, superior temporal gyrus, hippocampus, temporal horn, lateral ventricles, third ventricle, and frontoparietal volumes were measured on magnetic resonance imaging data from 56 schizophrenic men (mean [SD] age at illness onset, 16.6 [4.2] years) recruited from a state hospital and 52 age- and range-matched healthy control men. RESULTS: Patients had significantly smaller gray matter volumes in the temporal lobe, superior temporal gyrus, and frontoparietal regions; smaller temporal lobe white matter volumes; and larger cerebrospinal fluid volumes for temporal lobe sulci and the 3 ventricular measures. There were no group differences in hippocampal volumes. Psychotic symptom subscores from the Brief Psychiatric Rating Scale were selectively correlated with smaller left posterior superior temporal gyrus gray matter volumes. None of the brain measurements were significantly correlated with age at illness onset. CONCLUSIONS: Data from this unique sample of severely ill schizophrenic men emphasize a pattern of structural abnormalities involving the cortex, but not the hippocampus, in schizophrenia. Furthermore, these data support theories suggesting that superior temporal gyrus abnormalities contribute selectively to psychotic symptoms and that the extent of structural abnormalities is unrelated to age of clinical symptom onset.

Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia.

Brain structural deviation is known to be present in chronic patients with schizophrenia when compared with normal age-matched individuals. While the assumption is that these differences are based on a neurodevelopmental disturbance, whether they are static or continue to change throughout the disease process remains unknown. The following report describes a prospective follow-up study of first episode cases of schizophrenic illness. Analyses of MRI evaluations on an approximate annual basis for a minimum of four years are presented on 50 patients and 20 controls. Computer-assisted image analysis measuring the volume of several brain regions, using the program ANALYZE (Mayo Clinic), was performed on all scans. Patients were compared with controls for the rate of change over time in size of structures. No differences were found for the volumes of the caudate nucleus, temporal lobes, or hippocampus; and no changes in the degree of cerebral laterality were detected. However, there was a significant difference in the rate of change in the overall volumes of left and right hemispheres (P < 0.0004 and 0.001, respectively), right cerebellum (P < 0.02) and area of the isthmus of the corpus callosum (P < 0.05). The left cerebral ventricle had significantly greater enlargement over time when measured on coronal slice sequences (P < 0.02), but was not detected by axial views. These findings suggest that a subtle active brain process may be continuing through the first few years of a schizophrenic illness causing greater than the normal adult cortical deterioration. Further studies using other methods of image analysis and over a longer period of time are needed to determine the course and nature of this biologic process.

Language processing and memory in ill and well siblings from multiplex families affected with schizophrenia.

The present study was designed to extend the investigation of genetic factors for schizophrenia to cognitive and linguistic signs of central nervous system dysfunction. Of 51 siblings studied from 19 schizophrenia multiplex families, 37 had a DSM-III-R diagnosis of schizophrenia or related schzophrenia spectrum disorder and 14 were well. Controls were 17 unrelated healthy individuals within the same social class and age range. Subjects were tested on measures of memory, attention, reading and expressive language ability. Schizophrenic and spectrum disorder siblings were significantly more impaired in tests of auditory discrimination and memory than their well siblings or controls and displayed significantly reduced syntactic complexity to their speech. While well siblings did not differ from controls on most measures, some aspects of language complexity were reduced. A familial effect was observed for tests of reading ability, attention, some syntactic measures, and short-term memory, although these were not the measures that distinguished patients from controls in this cohort, the scores were not correlated among the ill sibling pairs, and poorer scores did not segregate with schizophrenia within these families. Thus, while some measures of language, memory and attention are deviant in patients with schizophrenia, they may not be heritable and directly related to the genetics of the disorder. Instead, they may be a manifestation of, rather than a vulnerability to, the illness.

Anomalous cerebral asymmetry and language processing in schizophrenia.

Reversal or reduction of normal structural cerebral asymmetries may be related to the pathogenesis of schizophrenia, but this relationship remains controversial. We review the literature and describe a further study designed to detect whether anomalous asymmetries are present early in the illness (at the first episode), whether they predict deficits in language processing, and whether they may be related to a genetic predisposition for schizophrenia. Asymmetries of brain widths and segments of the sylvian fissure were assessed in a magnetic resonance imaging study of 87 patients with a first episode of schizophrenia and 52 normal controls. These asymmetries were correlated with specific measures of language processing, memory, and hand skill. An independent group of 14 pairs of siblings with schizophrenia were also evaluated for evidence of heritability to cerebral asymmetries. Width asymmetries were reduced in patients compared with controls in the posterior (p = 0.02) and occipital (p = 0.05) regions. Brain horizontal length, on the other hand, was significantly more asymmetrical in patients (left > right; p = 0.04). For sylvian fissure measurements, asymmetries in controls (left > right) were greatest for the horizontal component; this asymmetry tended to detect differences in patients by comparison with controls (p < 0.06). In a range of tests of language and memory, few significant correlations between performance and cerebral asymmetries were detected either in patients or controls, although patients consistently scored poorer than controls in the majority of tests. In 14 pairs of psychotic siblings, within-pair correlations for the horizontal sylvian fissure asymmetry were significantly greater than between-pair correlations. These findings are consistent with the early presence (possibly genetic) of anomalous cerebral asymmetry. However, the functional correlates of reduced asymmetry remain obscure.

Functional asymmetries in schizophrenia and their relationship to cognitive performance.

Previous accounts of cerebral dominance in schizophrenic patients have been conflicting. While many studies report decreased patterns of functional laterality in schizophrenic subjects, others report increases or no differences. Conceptual differences in the definition of laterality and its effects on behavior may be a reason for the poor concordance among studies. The present report addresses some of these problems and examines the hypothesis that schizophrenia may be associated with an alteration in normal patterns of functional laterality. In addition, the relationship between patterns of laterality and cognitive functioning was assessed. Twenty-one schizophrenic patients and 24 control subjects, all right-handed, were compared on two neuropsychological batteries, one designed to test cerebral dominance and the other, cognitive performance. Cerebral dominance was measured by two dichotic listening tests (verbal and nonverbal) and three motoric tests. Cognitive ability was assessed with a comprehensive neuropsychological battery. Schizophrenic and control subjects differed significantly in performance on laterality measures, but they did not differ in patterns of functional laterality when performance was taken into account. In addition, it was shown that the relationship between cognitive ability and laterality is complex, with some aspects of laterality appearing to be beneficial to cognitive ability.

The effects of clozapine on symptom reduction, neurocognitive function, and clinical management in treatment-refractory state hospital schizophrenic inpatients.

Thirty chronically hospitalized, refractory schizophrenic patients were evaluated while on typical neuroleptics and again after 12 weeks of clozapine treatment. Patients demonstrated small but statistically significant reductions in total Brief Psychiatric Rating Scale (BPRS) symptoms, need for seclusion and restraint, and PRN medications, and they frequently were transferred to a less restrictive treatment environment. Neuropsychological test data from a subset of patients suggested improvement on measures of verbal fluency and graphomotor speed, but deterioration on measures of visual memory and executive/frontal ability. Clozapine's different effects on multiple neurotransmitter systems may be responsible for its mixed effects on cognitive abilities. No significant relationships were found between symptom reduction, cognitive improvement, and transfer to a less restrictive environment.

Gray matter deficits in young onset schizophrenia are independent of age of onset.

This study examined whether the degree of brain dysmorphology observable in adulthood was related to onset age of schizophrenic symptoms. Brain magnetic resonance imaging (MRI) scans were acquired in 57 men with schizophrenia, whose age at MRI was 19-53 years, and whose symptom onset ranged from age 7 to 29 years; all were inpatients in a state hospital. Volumes of intracranial space, cortical gray matter (GM) and white matter (WM), and cerebrospinal fluid (CSF) in lateral and third ventricles and cortical sulci were derived from MRI scans and corrected by regression analysis for variations attributable to age and head size, quantified in a control sample of healthy community volunteers. The schizophrenic patients had larger volumes of cortical and ventricular CSF and smaller volumes of cortical GM but not WM than age-matched controls, whether or not volumes were adjusted for head size and age norms. Age of onset did not correlate with any of the five age-adjusted brain measures. Neither current age, length of illness, nor symptom severity correlated with age-normalized volumes of cortical GM, sulcal CSF, or ventricular CSF. These observations are consistent with the theory that brain structure deficits 1) first develop prior to symptom onset (perhaps during the prenatal and/or early childhood process of GM development); 2) probably establish a vulnerability to subsequent dysfunctionality; but 3) are nonprogressive.

A neuropsychological study of early onset schizophrenia.

Characterizing a pattern of cognitive dysfunction in early onset schizophrenic patients may illuminate neurodevelopmental contributions to the illness. A cohort of chronically institutionalized schizophrenic patients with a variable range of age of onset (range 7-29 years) was administered a comprehensive battery of neuropsychological tests that included the Luria-Nebraska Neuropsychological Test Battery. After statistical control of age, parental socioeconomic class (SES) effects, and thorazine equivalents, age of illness onset was positively correlated with performance on measures of motor ability, perceptual motor and pure motor speed, receptive and expressive speech, and overall cognition function, and inversely related to severity of negative symptoms; that is, earlier age of onset was associated with worse cognitive performance and an increase in negative symptoms. This study demonstrates that an early age of onset in schizophrenic illness is associated with impairment on tasks which involve motor and language abilities, functions linked to the frontal, temporal, and subcortical regions of the brain. This association is not due to the effects of medication, negative symptoms, or duration of illness.

Effects of crack cocaine on neurocognitive function.

Because crack cocaine appears to have a preferential effect on the metabolic and electrophysiological activity of the frontal and temporal regions of the brain (Pascual-Leone et al., 1991a, 1991b; Volkow, 1992), we hypothesized that cognitive measures of those regions would be impaired in crack cocaine users relative to measures in normal volunteers. We used logistic regression to determine the relationship of cocaine usage to neuropsychological test performance. We compared 38 patients with an average of 3.6 (SD = 2.5) years of crack cocaine use and 24.5 (SD = 28.1) days of abstinence to 54 normal volunteers on a battery of neuropsychological tests. Statistical adjustments were made for the effects of age, education, socioeconomic class, and level of depression. Our findings were mixed with regard to purported measures of executive/frontal functioning, with worse performance associated with cocaine usage on the Booklet Categories Test, but better performance associated on others (number of categories on the Wisconsin Card Sorting Test, Controlled Oral Word Association). Cocaine usage was associated with impairment on measures of spatial, but not verbal memory, confrontation naming, and Trail-making Test, Part B, a measure of perceptual-motor speed and cognitive flexibility. In summary, it appears that continuous crack cocaine use produces a dissociative pattern in neuropsychological test performance with improvement on some measures, but deterioration on others. The permanence of these effects remains to be determined with longitudinal studies.

A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings.

Brain morphological abnormalities have been reported in several independent investigations of chronic schizophrenic patients. The present study is a prospective 4-year follow-up of first-episode schizophrenic patients to determine whether some of these abnormalities may be a consequence of regional brain structural change over time after the onset of a first psychotic episode. Whole hemisphere, temporal lobes, superior temporal gyrus, hippocampus, caudate, corpus callosum, and lateral ventricles were measured in a series of MRI scans taken over a 4-year period in 20 patients and five controls. Total volume reduction was noted in both hemispheres to a greater degree in patients than controls. When adjusted for total brain size, left ventricular enlargement occurred in patients, but not controls, over time. These preliminary data suggest that subtle cortical atrophy may be occurring over time after the onset of illness.

Gender differences in corpus callosum size in first-episode schizophrenics.

Previous studies indicate differences between schizophrenics and normals in thickness and overall size of the corpus callosum, particularly in female subjects. The present study compares the area of the corpus callosum as measured by magnetic resonance imaging (MRI) in men and women experiencing first-episode cases of schizophrenia. The corpus callosum area is also correlated with measures of neuropsychological function. The results of this study suggest that women who are first-episode schizophrenic patients have a smaller total corpus callosum area than female controls, with no difference noted for men. In normal controls, a larger corpus callosum was associated with better cognitive function, whereas in schizophrenics, no such relationship emerged.

Asymmetries in the superior temporal lobe in male and female first-episode schizophrenic patients: measures of the planum temporale and superior temporal gyrus by MRI.

Schizophrenia has been hypothesized to be associated with an underlying brain developmental anomaly, specifically affecting normal brain asymmetries. The most pronounced asymmetries are present on the superior surface of the temporal lobes, the left plane, as measured along the sylvian fissure (planum temporale) being longer than the right in the majority of normal individuals. These asymmetries encompass Wernicke's area, the anatomical substrate for language, and have been found to be less pronounced in individuals with developmental language problems, i.e. dyslexia. Since disordered language is one of the hallmarks of schizophrenia, the present study focuses on the planum temporale and related superior temporal gyrus. Eighty-five first-episode schizophrenic patients and 40 controls had measurements of the sylvian fissure taken from coronal slices. The pattern of asymmetry in controls was for the right length to be longer than the left in anterior slices, and for left to be longer than right in posterior slices (corresponding to the planum temporale). Schizophrenic patients as a group demonstrated less asymmetry (R > L) in anterior slices, and female patients showed a trend for less (L > R) asymmetry in posterior slices. In contrast to the report of Barta et al. (1990), the volume of the anterior superior temporal gyrus did not differ from controls in first-episode schizophrenic patients. Neither the presence of formal thought disorder nor auditory hallucinations defined a subgroup of patients with reduced size or lateralization of the planum temporal or superior temporal gyrus.