Michael Parrella

Cognitive decline in late-life schizophrenia: A longitudinal study of geriatric chronically hospitalized patients

BACKGROUND Geriatric schizophrenic patients with a chronic course of institutionalization manifest cognitive and functional impairments that implicate decline at some time point after the onset of illness. The rate of change in cognitive and functional status in these patients has not yet been identified with a longitudinal study. METHODS Three hundred and twenty-six schizophrenic patients entered a 30-month follow-up study with two separate assessments of the patients. Overall functional and cognitive status was indexed with the Clinical Dementia Rating (CDR). Survival analysis was used to examine changes in cognitive and functional status, including worsening for the less impaired patients and improvements on the part of more impaired patients. RESULTS Approximately 30% of the patients who had baseline scores in the less impaired range manifested a worsening of their CDR ratings to a score of 2.0 (moderate) or more severe, whereas only 7% of the sample with lower scores at baseline appeared to improve in their functioning. Several characteristics of the patients at baseline assessment predicted increased risk for cognitive and functional decline, including lower levels of education, older age, and more severe positive symptoms. CONCLUSIONS Cognitive and functional decline can be detected in a short-term follow-up in a subset of geriatric long-stay patients with schizophrenia. This decline appears distributed across patients and not due to the presence of progressive degenerative dementing conditions. Later research will have to identify the causes of this decline, possibly on the basis of the risk factors identified in this study.

A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia

BACKGROUND Despite the beneficial effects of atypical antipsychotics on cognition, these improvements will not return most schizophrenic patients to normative standards of cognitive functioning. Therefore, other treatments need to be considered. Subtle changes in cholinergic function in schizophrenic patients provide the rationale to test the effectiveness of cholinesterase inhibitors in treating cognitive impairment in schizophrenia. METHODS Given this, a 12-week, double-blind, placebo-controlled trial of donepezil (5 mg and 10 mg) as adjunctive treatment to risperidone was conducted in a total of 36 schizophrenic patients. RESULTS Neither the 5-mg nor 10-mg dose of donepezil produced significant improvements in any cognitive measure compared with placebo. CONCLUSIONS It is possible that nicotinic receptor desensitization produced by chronic tobacco use in these patients rendered their nicotinic receptors refractory to the effects of increased agonist activity produced by donepezil. An alternative treatment is the allosterically potentiating ligands, which enhance the activity of (sensitize) nicotinic receptors in the presence of acetylcholine.

Cognitive impairment and negative symptoms in geriatric chronic schizophrenic patients : a follow-up study

Cognitive impairment is increasingly recognized as an important aspect of schizophrenia. Since cognitive impairment has many features in common with the negative symptoms of the illness, it is possible that some of the characteristics attributed to negative symptoms are due to an association with cognitive impairments. In order to test this hypothesis, 174 chronically hospitalized geriatric schizophrenic patients were examined twice at a 1-year follow-up with ratings of the severity of their symptoms (using the Positive and Negative Syndrome Scale: PANSS) and assessments of cognitive functions with the Mini-Mental State Examination and a brief neuropsychological battery aimed at the typical impairments seen in dementia. Positive symptoms were unassociated with any of the cognitive variables, while negative symptom severity was correlated with each of the cognitive measures. In the cross-temporal analyses, cognitive impairments were more stable over time than negative symptom scores, but cognitive impairment did not predict the severity of any negative symptom over time. At each assessment, however, cognitive impairment was strongly correlated with each of the seven negative symptoms studied. These data indicate that cognitive impairments and negative symptoms are related, but discriminable, features in schizophrenia and that the considerable overlap between some negative symptoms and estimates of cognitive function may suggest a rethinking of the definition of some of these symptoms.

Convergence of cognitive and adaptive decline in late-life schizophrenia

Cognitive impairment has proven to be a major predictor of overall functional deficit in schizophrenia. Despite the significant impairments seen on the part of many patients with schizophrenia that implicate decline at some point in time, there have been no longitudinal studies of adaptive decline in patients with schizophrenia. In this study, 57 geriatric patients with chronic schizophrenia were examined with measures of clinical symptoms, cognitive impairments, and adaptive functioning while living in a chronic psychiatric hospital and followed up an average of two and a half years after their referral to nursing home care. Cognitive functioning and adaptive functioning both declined over the follow-up period, whereas there was no change in schizophrenic symptoms. Changes in cognitive functioning accounted for 25% of the variance in adaptive decline, whereas the baseline severity of cognitive impairment and schizophrenia symptoms were uncorrelated with adaptive decline. These data indicate that cognitive decline may predict deterioration in overall functional status and imply that treatment of cognitive impairment might have a beneficial effect on global functional status.

Guanfacine treatment of cognitive impairment in schizophrenia

Norepinephrine plays a significant role in the working memory functions of the prefrontal cortex by its actions at alpha-2a noradrenergic receptors. Guanfacine has demonstrated efficacy in reversing working memory deficits in non-human primate. In the present study the effect of guanfacine adjunctive treatment to neuroleptics on the cognitive performance of schizophrenic patients was investigated in a four week, placebo-controlled, double-blind, parallel design trial. The primary analyses revealed no significant differences between guanfacine and placebo treatment; however, exploratory non-parametric statistics revealed some significant and some trend differences between guanfacine and placebo on spatial working memory test performance and CPT reaction time in those subjects treated with atypical neuroleptics.

The longitudinal relationship of clinical symptoms, cognitive functioning, and adaptive life in geriatric schizophrenia

Cognitive dysfunction is increasingly being recognized as a major contributor to the adaptive impairment seen in most patients with schizophrenia. Reported here is a prospective longitudinal evaluation of the relationship between cognitive and adaptive functioning in elderly patients with schizophrenia. It was hypothesized that baseline cognitive and negative, but not positive symptoms, would be predictive of cross-sectional impairment and longitudinal outcome. Subjects were 168 elderly patients with schizophrenia, free of major neurological disorders, who were residents of a long-term psychiatric facility. Subjects were assessed at baseline and again an average of 15months later. The PANSS was used to assess the severity of symptoms of schizophrenia. Cognitive symptoms were assessed using the components of the CERAD cognitive battery. Social and adaptive functioning was assessed using the SAFE scale. Spearman correlations were determined among clinical variables, and the rank ordering of prediction of SAFE scale scores at follow-up was determined using a stepwise regression procedure. At follow-up, adaptive life skills correlated with cognitive performance and negative symptoms (Spearman rho values 0. 41-0.57, all p values <0.0001), but not positive symptoms (r=0.09, n. s.). Among cognitive tasks, verbal learning and memory were most highly correlated with adaptive skills at follow-up. These results confirm and extend previous studies that indicate that cognitive impairments are predictive, both cross-sectionally and longitudinally, of adaptive life skills in persons with schizophrenia. Negative symptoms, but not positive symptoms, were correlated with impaired adaptive skills. Taken together, these results underscore the need to develop more effective treatments for cognitive and negative symptoms in schizophrenia.

The course of functional decline in geriatric patients with schizophrenia: cognitive-functional and clinical symptoms as determinants of change.

OBJECTIVE Authors sought to use a cognitive assessment instrument validated for assessing low-functioning patients to broaden knowledge about the rate and correlates of functional decline. METHODS Patients were examined across a wide range of baseline cognitive and functional status, and changes in cognitive and functional status were examined. A group of 424 elderly patients with schizophrenia were followed up over a 6-year period; 280 of these manifested severe cognitive impairment at baseline. Patients were examined with an instrument designed for cognitive and functional assessment of severe cognitive impairment: the Alzheimers Disease Assessment Scale-Late (ADAS-L). RESULTS Patients with higher and lower baseline scores manifested equivalent declines in the ADAS-L cognitive subscale, but differences in decline on basic activities of daily living. Random-effects regression analysis indicated that functional changes were significantly correlated with cognitive changes for the sample as whole and that cognitive changes were the best predictor of changes in functional status over time. Baseline cognitive status was not a statistically significant covariate for functional change, nor was the course of negative symptoms over the follow-up period. CONCLUSIONS Cognitive change appears very similar in magnitude across older, poor-outcome patients with different baselines of cognitive impairment. In contrast, functional decline was limited to patients with lower levels of functioning at baseline. These findings suggest that cognitive thresholds for impairments in different aspects of functional status may exist in patients with schizophrenia. Basic activities of daily living decline only in patients with very low levels of baseline cognitive functioning.

Assessment of dementia in elderly schizophrenics with structured rating scales

Although a number of elderly institutionalized schizophrenic patients appear to suffer from dementia, little is known about the characteristics of the cognitive impairment or its prevalence in this population. In order to answer these questions it is necessary to first reliably and validly assess dementia in elderly schizophrenic patients. This paper reports the results of a study examining the reliability of assessments of the severity of dementia in schizophrenia using scales designed for other dementing conditions and examining the convergence of ratings of the severity of dementia generated from all available sources of information (patient, caregiver, and chart) versus the chart alone. It was found that the interrater reliability of these ratings was very high. On the other hand ratings generated from the hospital chart alone, without contact with either the patient or caregiver, manifested a systematic bias toward overestimation of the severity of dementia. These results suggest that dementia assessment in schizophrenia does not require different instrumentation from that used in other conditions but that relying on the medical chart alone would induce a systematic bias in the results.

The Effects of Hypertension and Body Mass Index on Cognition in Schizophrenia

OBJECTIVE In recent years there has been a greater appreciation of the elevated prevalence of cardiovascular risk factors in the schizophrenia population and the liability some treatments have for their development. These vascular risk factors are in turn important risk factors in the development of dementia and more subtle cognitive impairments. However, their impact on the cognitive functions of patients with schizophrenia remains underexplored. The authors investigated whether vascular risk factors influence the cognitive impairments of schizophrenia and whether their effects on cognition in schizophrenia are different from those observed in nonpsychiatric comparison subjects. METHOD The authors compared 100 patients with schizophrenia and 53 comparison subjects on cognitive test performance in 2×2 matrices composed of individual vascular risk factors and group (schizophrenia patients and comparison subjects). RESULTS Hypertension exerted a significant negative effect on immediate delayed and recognition memory in both groups. Patients with schizophrenia and hypertension were adversely affected in recognition memory, whereas comparison subjects were not. A body mass index above 25 was associated with negative effects on delayed memory in both groups, although the association fell short of statistical significance. CONCLUSIONS Given that patients with schizophrenia have a higher prevalence of vascular risk factors than the general population and are undertreated for them, treatment of these risk factors may significantly improve cognitive outcome in schizophrenia.

A Pilot Study of Adjunctive Atomoxetine Treatment to Second-Generation Antipsychotics for Cognitive Impairment in Schizophrenia

Relationships between altered prefrontal cortical dopamine, norepinephrine, and some of the cognitive impairments of schizophrenia support an approach for pharmacological remediation of cognitive symptoms through manipulations of prefrontal cortical dopamine and norepinephrine. Atomoxetine, a selective norepinephrine reuptake inhibitor, produces a widespread increase in brain norepinephrine and a secondary and selective increase in prefrontal dopamine. Given this, we evaluated atomoxetines cognitive effects in a pilot placebo-controlled trial in patients with schizophrenia. Moreover, a functional magnetic resonance imaging investigation was undertaken to assess the neural mechanisms underlying the cognitive effects of atomoxetine. Twenty participants with schizophrenia were randomized to treatment with placebo or atomoxetine 80 mg daily for an 8-week parallel-designed treatment trial. Cognitive performance was assessed with the Brief Assessment of Cognition in Schizophrenia. No significant cognitive improvement was associated with atomoxetine treatment. However, atomoxetine treatment was associated with significantly greater increases in working memory-related activation of the left dorsolateral prefrontal and left posterior cingulate cortices. The negative results of this study conflict with the effectiveness of amphetamine in enhancing the cognitive abilities of schizophrenic patients and may be related to the differential pattern of cortical activation and deactivation produced by amphetamine.