Ten year longitudinal study of neuropsychological functioning subsequent to a first episode of schizophrenia.

We previously reported relative stability in neuropsychological functions over a 4- to 5-year period after the onset of a first episode of schizophrenia, with patients demonstrating less improvement than controls on some functions [Hoff, A.L., Sakuma, M., Wieneke, M., Horon, R., Kushner, M., DeLisi, L.E., 1999. A longitudinal follow-up study of neuropsychological functioning subsequent to a first-episode of schizophrenia. American Journal of Psychiatry 156, 1336-1341.]. The current study was conducted to extend follow-up evaluations through 10 years of illness to determine whether neuropsychological functions remain stable or deteriorate over a longer time period. Twenty-one first episode patients and 8 controls were re-evaluated 10 years after an initial evaluation on neuropsychological and clinical measures. Repeated measures analyses demonstrated no differences between patients and controls in degree of change over this time period nor was change in symptoms reliably associated with improvement or deterioration in cognitive abilities. However, baseline level of cognitive functioning was correlated with the degree of change. Thus, when the baseline level of functioning was controlled for in the analyses, less or lack of improvement was seen in the patients compared with controls in verbal intellectual functioning, delayed verbal and nonverbal recall, and cognitive inhibition (Stroop Color Word Test). In no test did patients deteriorate significantly more than controls. We conclude that most first episode patients have had considerable cognitive decline by the time of their first hospitalization and that it remains relatively stable through at least 10 years of illness. Most cognitive change takes place early in this illness, prior to the first hospitalization, but its exact timing still remains unknown.

Failure to find progressive temporal lobe volume decreases 10 years subsequent to a first episode of schizophrenia.

The present study used magnetic resonance imaging to examine the volumes of the temporal lobe and the superior temporal gyrus in a 10-year follow-up study of 27 patients with schizophrenia and 10 controls. No change over time was observed in these structures when patients were compared with controls. These results do not support the notion that progressive temporal lobe deterioration occurs in schizophrenia.

Familial cognitive deficits in schizophrenia.

Susceptibility to schizophrenia is considered familial, but the mechanism for transmission has not been found. Since widespread cognitive deficits have been found in patients with schizophrenia, several of these have been proposed as candidate familial endophenotypes that may or may not be predictive of who develops the illness. The current study examines these candidates in individuals from 32 families with at least 2 members having the diagnosis of chronic schizophrenia and normal comparison subjects using an extensive neuropsychological battery. Consistent with previous literature, family members with schizophrenia were significantly impaired on all measures compared with controls. Well relatives demonstrated significantly worse performance on a measure of verbal learning, delayed visual recall, perceptual-motor, and pure motor speed. Expressive and receptive language, but not other functions, were highly correlated within both concordant for schizophrenia and discordant sibling pairs, suggesting that they are familial vulnerability endophenotypes, but not predictive of whom becomes ill. On the other hand, some measures of perceptual-motor, pure motor speed, and frontal/executive functioning were significantly correlated in concordant, but not discordant pairs. These latter correlations suggest that some cognitive measures may be genetically related to the illness.

Severity of neuropsychological impairment in cocaine and alcohol addiction: association with metabolism in the prefrontal cortex.

We used exploratory and confirmatory statistical approaches to study the severity of neuropsychological (NP) impairment in 42 crack/cocaine addicted subjects and in 112 comparison subjects (40 alcoholics and 72 controls). Twenty neuropsychological test indices most reliably defining predetermined cognitive domains were submitted to exploratory factor analysis. A four-dimensional model of neurocognitive function was derived: Verbal Knowledge, Visual Memory, Verbal Memory, and Attention/Executive functioning accounted for 63% of the variance. We then examined this model's association with resting glucose metabolism in the brain reward circuit measured with 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography. Results revealed that (1) cocaine addicted individuals had a generalized mild level of neurocognitive impairment (<1 S.D. below control mean); and (2) controlling for age and education, relative metabolism in the dorsolateral prefrontal cortex significantly predicted the Visual Memory and Verbal Memory factors and relative metabolism in the anterior cingulate gyrus significantly predicted the Attention/Executive factor. Nevertheless, it remains to be determined whether metabolic changes in these regions are associated with addiction. Our results also suggest that compared to cocaine, alcohol has a more detrimental effect on Attention/Executive functioning, as assessed with traditional NP measures. We conclude that relative to other psychopathological disorders (such as schizophrenia), the severity of neuropsychological impairment in cocaine addiction is modest, albeit not indicative of the absence of neurocognitive dysfunction. The impact of such small differences in performance on quality of life, and possibly on craving and relapse, may be substantial. Tasks that simulate real-life decision-making or that target specific putative cognitive-behavioral or motivational-emotional mechanisms might offer greater sensitivity in characterizing the changes that accompany addiction to drugs. Obtaining valid estimates of alcohol use in cocaine addicted subjects is essential in characterizing neurocognitive functioning in individuals addicted to drugs.

Correlates of cognitive deficits in first episode schizophrenia.

OBJECTIVE: The presence of cognitive dysfunction in schizophrenia has been well documented, but questions remain about whether there are relationships between this dysfunction and clinical symptomatology. If present, such relationships should be most clearly observable in patients with first episode schizophrenia; that is, before the effects of chronic illness, institutionalization, or treatment might confound them. METHOD: 307 schizophrenia subjects in their first episode of illness were recruited to participate in a clinical trial comparing the long-term efficacy of haloperidol and risperidone. The psychopathology, cognitive functioning, early treatment history, and duration of untreated psychosis of these subjects were assessed prior to their assignment to randomized, double-blind treatment. Approximately two-thirds of the subjects were receiving antipsychotic treatment at the time of assessment; however, the duration of treatment was limited to 12 weeks or less. RESULTS: The severity of negative symptoms at the time of assessment was associated with deficits in memory, verbal fluency, psychomotor speed and executive function. Positive symptoms were not associated with cognitive deficits. Also, the duration of untreated illness (DUI) prior to assessment was not significantly associated with cognitive impairment. CONCLUSIONS: The results of this study of first episode schizophrenia patients suggest that a relationship exists between negative symptoms and cognitive dysfunction. However, that relationship accounts for only a minor portion of the variance (i.e., 10-15%) in the severity of cognitive dysfunction after controlling for a number of potentially confounding factors. This finding provides support for the theory that the neurobiological processes that give rise to symptomatology and cognitive dysfunction in schizophrenia are partially overlapping.

Cerebral ventricular change over the first 10 years after the onset of schizophrenia.

Whether the brain structural abnormalities seen in schizophrenia are progressive is controversial. We previously reported on a longitudinal study of 50 first-episode patients with schizophrenia and 20 controls who had serial MRI scans during the first 5 years of illness. Greater enlargement of lateral ventricles and reduction of hemispheric volume was observed over time in the patients compared with controls. The present study obtained MRI scans from 26 of these patients and 10 controls at a follow-up 10 years subsequent to their first evaluations. The initial, 4-5th and 10th year scans were examined for the degree of change in ventricular and hemispheric volume. Significantly greater ventricular enlargement during the second 5 years was detected in the patient cohort compared with controls (P<0.05) with nine of the patients having ventricular enlargement (as measured by percent change) occurring at a rate exceeding that of any of the controls from years 1 through 10. The rate of ventricular change during the first 5 years was significantly correlated with age at first hospitalization, and ventricular enlargement in years 5-10 was correlated with the amount of time spent in hospital. Paradoxically, greater change in ventricles over time was correlated with better, not worse, outcome at the 10th year of follow-up with regard to the presence of symptoms. These data suggest heterogeneity in the course of brain change whereby some patients may exhibit active structural brain change only early in their illness or not at all after their first episode, while others continue to exhibit ventricular change spanning the decade subsequent to their first episode. Despite these differences among patients, the present study fails to detect any relationship of ventricular enlargement to poorer outcome as has been reported by other investigators.

Folic acid supplementation in dementia: a preliminary report.

Recent work on high plasma homocysteine levels in patients at risk for developing Alzheimer's disease has led to the hypothesis that folic acid supplementation might reduce risk in such patients. The authors report on the effects of folic acid 10 mg/day versus placebo on 11 patients (only 7 completers) with dementia and low-normal folic acid levels. This is the first study evaluating folic acid or placebo in patients with dementia. Subjects had low-normal baseline folic acid levels. The magnitude of change between baseline and second testing was not statistically significant between the 2 groups. However, there was a trend for the folate group to perform worse on two specific cognitive measures, suggesting a possible trend toward worsening of some cognitive abilities after the folic acid. The folic acid in very high doses was well tolerated. Larger studies are necessary before empirically administering folic acid to patients already suffering from dementia.

Sex differences in the corpus callosum of patients with schizophrenia.

The corpus callosum (CC) has been of interest in schizophrenia research because of its possible role in reduced lateralization and because of its sexually dimorphic characteristics. The literature has been replete with structural brain studies that have yielded equivocal results because of failure to address sex differences, handedness, and overall reductions in total brain volume (TBV) associated with schizophrenia. We performed midsagittal corpus callosum area MRI measurements on 71 chronically ill patients with schizophrenia (52 males, 19 females) and 67 controls (49 males, 18 females) using a semiautomated analytic technique subdividing the corpus callosum into five segments. Consistent with a meta-analysis [J. Neurol., Neurosurg. Psychiatry 58 (1995) 457], reductions in total CC area (after controlling for TBV and age) were found in schizophrenia patients relative to controls. However, our effect size, though not statistically significant, was -0.33 compared to -0.18 for the meta-analysis, indicating greater reductions in total CC area in our group of patients. Statistical significance was achieved only in male patients versus male controls (effect size=-0.50). The effect size remained the same when only right-handers were included in the analysis; thus, handedness did not account for this result. CC size was not related to psychiatric symptoms nor cognitive functioning in this group of patients.

Does cognitive function improve with quetiapine in comparison to haloperidol?

Recent evidence suggests that schizophrenia patients taking atypical antipsychotic medications may perform better on some tests of cognitive function than those treated with older antipsychotics. The current study compared the effects of quetiapine and haloperidol on measures of executive function, memory and attention. Subjects were 58 stable outpatients with schizophrenia (DSM III-R) who received a battery of cognitive tests as part of a randomized, double-blind, multi-site clinical efficacy study conducted by AstraZeneca Pharmaceuticals. Cognitive assessments were conducted prior to randomization when patients were receiving < or =30 mg haloperidol or equivalent (mean: 9.2mg/day haloperidol equivalents), and again after 24 weeks of fixed-dose treatment with either quetiapine 600 or 300 mg/day or haloperidol 12 mg/day. Analyses of covariance with planned comparisons were used to compare scores on cognitive measures at the end of 24 weeks by treatment group with baseline cognitive function scores used as covariates. Patients receiving quetiapine 600 mg/day improved to a greater extent than patients receiving haloperidol on overall cognitive function (p<0.02). Specific differences were found for executive function (Verbal Fluency Test, p<0.04), attention (Stroop Color Word Test, p<.03) and verbal memory (Paragraph Recall Test, p<0.02). Treatment group differences were not solely due to benztropine use, medication side effects, or changes in symptomatology. Treatment with quetiapine at higher doses (600 mg/day) relative to haloperidol appears to have a positive impact on important domains of cognitive performance that have been found to predict role function and community outcomes in patients with schizophrenia.