HONOLULU— “‘Dementia of schizophrenia’ is not an official diagnostic term, but it’s a very illustrative term,” said Soo Borson, MD. In her address at the American Association for Geriatric Psychiatry’s annual meeting, Dr. Borson examined the relationship between cognitive impairments of schizophrenia, Alzheimer’s disease, and other primary neurodegenerative dementias in order to “consider informative commonalties.” She is a Professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

COMPARING DEMENTIAS

Schizophrenia has an early onset, with late progression of cognitive impairment in some people; Alzheimer’s disease has a late onset but early progression of impairment in all, Dr. Borson said as she set the stage for her discussion. There are no universally accepted genetic causes of schizophrenia, and the neuropathology of cognitive disorders in schizophrenia and schizophrenia itself is very obscure, she added, while in Alzheimer’s disease, there are certain genes that cause the disease and others that increase risk, and the neuropathology is definitive.

Likewise, imaging studies of schizophrenia reveal deficits in the front parts of the brain and changes in temporal regions, but imaging studies in Alzheimer’s disease show posterior brain deficits with characteristic temporal deficits. “So there are considerable differences in clinical features and in underlying factors,” she said, “but cognitive dysfunction in both Alzheimer’s disease and schizophrenia is a powerful predictor of functional disability.”

COGNITION IN COMMON

Cognition marks the most basic shared ground between schizophrenia and Alzheimer’s disease. “In both diseases, depression, positive and negative symptoms, and extrapyramidal signs confer excess disability,” Dr. Borson said, but cognitive dysfunction is the principal source of disability after disease onset.

Yet, even within this shared space there are differences. “In Alzheimer’s disease, premorbid cognition and social functioning are normal in people who go on to develop Alzheimer’s disease, at least until they have mild cognitive impairment or prodromal dementia. This is not the case, at least in general, in schizophrenia, where there are abnormalities in individuals who later become schizophrenic,” Dr. Borson related.

DEFINING BY DEFICIT

“So let’s look at the cognitive deficits we see in schizophrenia and compare those to the cognitive performance in normal individuals and patients with Alzheimer’s disease,” Dr. Borson invited. She described a study of 198 older adults matched for age and education and divided into three groups: healthy individuals, patients with Alzheimer’s disease, and patients with schizophrenia. The groups were matched for Mini-Mental State Examination scores and compared across different cognitive domains, including verbal learning, delayed verbal recall, naming, and the ability to reproduce four different designs.

“For verbal learning, the controls did considerably better than the other two groups and learned well; their performance improved with three trials. That was not the case for patients with either schizophrenia or Alzheimer’s disease. Their baseline performance was worse and their learning was markedly impaired,” she related.

For delayed recall, “the healthy individuals remembered about 80% of what they had learned, whereas patients with schizophrenia remembered only about 30% and those with Alzheimer’s disease, a little less than 20%.” For naming, the deficits were less prominent in Alzheimer’s disease and schizophrenia, Dr. Borson said, but still worse than in controls. “Finally, copy drawing was also impaired, with Alzheimer’s disease patients actually performing somewhat better than patients with schizophrenia. These are interesting findings that cross a wide variety of cognitive domains,” she observed.

Summarizing the idea of dementia in schizophrenia and its relationship with Alzheimer’s disease at the clinical neuropsychological level, Dr. Borson noted that “the cognitive impairments in schizophrenia differ from those of Alzheimer’s disease to a degree, but both differ strongly from normal. Both forms of dementia cause disability and dependency; however, progression is the rule in Alzheimer’s disease, whereas it’s the exception in schizophrenia.”

FROM DEMENTIA TO PSYCHOSES

Dr. Borson commented on the psychotic features in schizophrenia and Alzheimer’s disease, and how they differ. “In schizophrenia, psychosis is the major cause of hospitalization, but many patients are also admitted because of failure of community adjustment and complications of social deterioration. The latter are the result of negative symptoms more often than they are of positive symptoms,” she said. “Psychosis is a significant cause of nursing home placement in schizophrenia. Treatment has to be effective without causing further cognitive impairment because cognition is already impaired.”

Where does psychosis come from in the dementing diseases? she asked. “Though we don’t know as much as we’d like to know about the pathogenesis of psychosis in neurodegenerative dementias, we know more about its prevalence.” The Cache County study showed that in Alzheimer’s disease, delusions were present in 22% of patients in a cross-sectional study, hallucinations in 13%. In the same study, 13% of patients with vascular dementia had delusions and 16% had hallucinations.

For diffuse Lewy body dementia, however, the situation is different. “Some studies have shown rates of psychosis over 50% and hallucinations over 75% in patients in whom Lewy body pathology was by autopsy,” Dr. Borson said. Dr. Borson cited a recently published study looking at choline acetyltransferase in postmortem brain tissue of healthy adults, patients with mild Alzheimer’s disease, and patients with mild Lewy body dementia. In the superior temporal regions, both the patients with mild Alzheimer’s disease and those with mild Lewy body dementia had significant reductions compared with controls in the activity of choline acetyltransferase (taken as a proxy for how much acetylcholine is produced). In the inferior parietal areas, patients with Alzheimer’s disease showed a reduction compared to controls, but reductions in patients with Lewy body dementia were markedly greater than those of both the controls and the patients with Alzheimer’s disease. Similar findings were made in the midfrontal regions. “Levels this low that are seen in mild Lewy body dementia aren’t seen until very late in the course of Alzheimer’s disease,” Dr. Borson observed.

ANTIPSYCHOTICS, COGNITION, AND PSYCHOSIS

The cognitive effects of antipsychotic medications have become a major focus of interest in recent years. In an eight-week comparison study of olanzapine versus risperidone for the treatment of schizophrenia and schizoaffective disorder in older adults, the two drugs were compared across a range of cognitive measures, Dr. Borson related. “There were statistically significant improvements in executive function, memory, and verbal fluency in the risperidone group. Changes in the olanzapine group reached statistical significance for certain areas of memory overall but not for executive function or verbal fluency.”

If atypical antipsychotics improve cognition, how might they do this, she asked. “One approach to understanding these effects is the clinical model. In this formulation, atypical antipsychotics can be seen as improving cognition because they reduce cognitive interference from psychotic symptoms—particularly because they reduce negative symptoms, which we’ve seen are strongly associated with cognitive dysfunction in schizophrenia.

“Another approach uses a neurotransmitter and pathway neuroscience model. Here, it’s possible that by blocking a limbic hyperdopaminergic state, appropriate inhibitory controls, normally exerted by the frontal lobes downward, are restored, allowing better integration of cognition and behavior. There is some evidence from animal studies that atypical antipsychotics activate cortical acetylcholine release,” she added.

ACETYLCHOLINESTERASE INHIBITORS FOR PSYCHOSIS

We know acetylcholinesterase inhibitors have broad-spectrum benefits for cognition and behavior, Dr. Borson said. “This is a drug class effect not unique to a specific medication and has been reported in studies of outpatients and nursing home patients across the spectrum of dementia severity. We also have learned in the last several years that the effect of cholinesterase inhibitors is not diagnosis dependent. They can help in Alzheimer’s disease, Lewy body dementia, vascular dementia, possibly multiple sclerosis, and potentially, attention-deficit/ hyperactivity disorder as well as other conditions. But is there a specific antipsychotic effect of these drugs that may be mediated through improving cholinergic tone in the brain?”

For that, Dr. Borson offered, it is helpful to look at schizophrenia. “Carefully designed single case studies and an open-label trial in a group of 15 patients with schizophrenia reported significant improvement in cognition. A cholinesterase inhibitor was added to a stable antipsychotic regimen. Donepezil plus risperidone improved well-being, cognition, and verbal fluency in one patient. Added to olanzapine in a functional MRI study, donepezil treatment was associated with activation of the prefrontal cortex and basal ganglia that was associated with improved cognition. Galantamine improved treatment-resistant negative symptoms in another patient.”

In the open-label trial, the results were similar, Dr. Borson said, but extended to manual dexterity, visual and verbal memory, and visual-processing speed. However, “there was no measurable effect on psychosis. More recently, results of the first randomized, placebo-controlled trial of donepezil were reported. In that study, donepezil did not appear to improve cognition or psychosis in a group of schizophrenic patients stably treated with antipsychotics. What remains to be seen is whether a subgroup of patients—perhaps older adults or patients with greater cognitive deficits—might benefit,” she noted.

A COMMON ROAD TO COGNITIVE IMPROVEMENT?

“Integrating these disparate lines of evidence to create a testable model is our next task,” Dr. Borson said. “There are several different diseases, but they share some common features. We have several drugs, but here, too, some mechanisms may be shared: Both atypical antipsychotics and cholinesterase inhibitors are thought to increase available acetylcholine in specific brain regions. As a consequence, both classes of drugs might stimulate nicotinic receptors as a consequence. Such an action, in turn, increases the output of critical neurotransmitters from several kinds of widely projecting neurons in the brain.

“Atypical antipsychotics increase cortical acetylcholine release in prefrontal regions as determined in animal studies and cholinesterase inhibitors increase cortical acetylcholine action.” The net effect, Dr. Borson said, “is improvement in memory, in thinking, and in behavior, and perhaps in some aspects of psychosis. The mechanisms suggest the potential for high-level therapeutic synergy for the benefit of our patients,” she concluded.

—C. Justin Romano

Suggested Reading
Leroi I, Voulgari A, Breitner JC, Lyketsos CG. The epidemiology of psychosis in dementia. Am J Geriatr Psychiatry. 2003;11:83-91.

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