Barbara L. Schwartz

A revised excitotoxic hypothesis of schizophrenia : Therapeutic implications

A revision of an “excitotoxic hypothesis” of schizophrenia is summarized. The hypothesis suggests that in, at least, a subtype of patients with schizophrenia, progressive excitotoxic neuronal cell death in hippocampal and cortical areas occurs via “disinhibition” of glutamatergic projections to these areas. Patients who have excitotoxic damage would be expected to have poor outcomes characterized, perhaps, by anatomic evidence of progressive neurodegeneration, pronounced negative symptoms and cognitive deficits, and profound psychosocial deterioration. Disinhibited glutamatergic activity could result from inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission and a consequent failure to stimulate inhibitory gamma-aminobutyric acid (GABA)–ergic interneurons, and/or anatomic degeneration of inhibitory GABAergic interneurons. The result of these hypothesized mechanisms is excessive stimulation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate class of glutamate receptor complexes. In turn, this excessive stimulation of AMPA/kainate receptors could lead to disruption of ionic gradients, depletion of energy reserves expended in an attempt to restore and maintain the ionic disequilibrium across neuronal membranes, generation of reactive oxygen species, and cell death from apoptotic and other mechanisms. The postulated existence of disinhibited glutamatergic neurotransmission and the subsequent cascade of excitotoxic events resulting from NMDA receptor hypofunction (NRH), anatomic degeneration of inhibitory GABAergic interneurons, or a combination of the two has suggested a diverse variety of experimental therapeutic interventions for schizophrenia. These interventions include facilitation of NMDA receptor-mediated neurotransmission, potentiation of GABAergic neurotransmission, antagonism of AMPA/kainate receptors, and “quenching” of locally generated reactive oxygen species. In fact, several of these approaches have already been pursued or are proposed as part of a systematic clinical investigation of the revised excitotoxic hypothesis of schizophrenia.

Memory for temporal order in Schizophrenia

Memory for temporal order information was examined in patients with chronic schizophrenia using the recency discrimination task. In this task, subjects were shown a pair of previously studied words and were asked to choose which one of the two words they had seen more recently. In addition, subjects performed the Wisconsin Card Sorting Test (WCST). The results showed that schizophrenic patients differed from normal control subjects in their performance on the recency discrimination task. In addition, for schizophrenic patients, performance on the recency discrimination task was inversely related to the number of perseverative errors on the WCST. These results provide further evidence of prefrontal-type cognitive deficits in schizophrenia.

Fluoxetine's effects on cognitive performance in patients with traumatic brain injury.

Objective: There are preclinical data showing that fluoxetine stimulated expression of Brain Derived Neurotrophic Factor (BDNF) and its specific tyrosine kinase receptor, and caused neuritic elongation and increased dendritic branching density of CA3 hippocampal pyramidal cell neurons in rodents. The latter effect of fluoxetine has been referred to as neuronal remodeling. In view of this preclinical data, we wondered if specific cognitive measures could serve as novel therapeutic targets for fluoxetine in head-injured patients. Theoretically, fluoxetine-induced “neuronal remodeling” might improve cognition, independently of a primary effect on mood. Method: In an open-label pilot investigation, fluoxetine hydrochloride (Prozac; 20–60 mg/day) was administered to a heterogeneous group of five head-injured patients with either no or moderate depression for a period of eight months. These patients had no histories of prior treatment with antidepressant medications. They were administered cognitive and memory tests at baseline and after eight months of treatment on fluoxetine. Results: The preliminary results showed that fluoxetine improved mood, in addition to improving performance on the Trail Making Test Part A, an attentional-motor speed task, and the letter-number sequencing subtest of the WAIS-III, a measure reflecting “working memory.” Conclusions: Although fluoxetine had beneficial effects on some measures of cognition, more work is needed to connect these improvements with neuronal remodeling.

Limits of the processing view in accounting for dissociations among memory measures in a clinical population

In three experiments, we examined the performance of patients with schizophrenia on implicit and explicit memory tests that have been shown to involve predominantly data-driven or predominantly conceptually driven processes. In Experiment 1, we compared the implicit tests of category production (conceptually driven)and word identification (data driven) and found that schizophrenic patients’ performance on these tests did not differ from that of normal subjects. In Experiment 2, a comparison of the category-production and explicit cued-recall tests, both of which involve conceptual processes, showed that schizophrenic patients were impaired on the cued-recall test but not on the category-production test. In Experiment 3, a comparison of the word-identification and explicit graphemic cued-recall tests, both of which involve data-driven processes, showed that patients were impaired on the cued-recall test but not on the word-identification test. The results of both Experiments 2 and 3 revealed a dissociation between implicit and explicit test performance under conditions in which the two tests involve similar- types of processes. These results support theoretical views that distinguish implicit from explicit modes of retrieval.

A quantitative measure of postural sway deficits in schizophrenia

Clinicians rely on observational methods to assess obvious signs of postural abnormalities in schizophrenia, yet subtle signs of postural deficits may go unnoticed. Posture is controlled, in large part, by the cerebellum, which has been implicated in numerous reports of structural and functional deficits in schizophrenia. Given the possibility of an underlying disruption of cerebellar function in schizophrenia, this study used an objective, quantitative measure to assess the magnitude of postural stability in this disorder. A total of 36 schizophrenia patients and 36 non-psychiatric age-matched controls stood on a pressure-sensitive platform that recorded shifts in weight (body sway) through pressure points in the feet. Patients demonstrated more postural sway than did healthy controls (p<0.01). When patients with noticeable signs of tardive dyskinesia were removed from analyses, group differences remained (p<0.01). There was no significant correlation between neuroleptic medication level and degree of postural sway (r=0.16, p=0.37). These results indicate that patients with schizophrenia have subtle, yet quantifiable, disturbances in the control of posture and balance. Quantitative measures of postural sway may provide a more sensitive means of detecting disturbances of movement than do standard clinical observations alone.

Implicit Learning of Visuospatial Sequences in Schizophrenia

The authors examined whether patients with schizophrenia learned sequential patterns in a probabilistic serial response time task in which pattern trials alternated with random ones. Patients showed faster and more accurate responses to pattern trials than to random trials, but controls showed greater sensitivity to patterns. The highest level of regularity learned in both groups was information about runs of 3 events. Pattern learning occurred largely outside of awareness, as participants could not describe patterns. Controls with higher memory spans learned the sequential pattern better than those with lower memory spans, suggesting that working memory influences implicit pattern learning. Pathology in motor sequencing systems and poor working memory may lead to deficits in learning sequence structure in schizophrenia.

Effects of aging on priming and skill learning.

This study examined the effects of aging on 2 kinds of implicit memory; repetition priming and skill learning. In Experiment 1, older adults showed less improvement in the skill of reading inverted words than did young adults, but priming performance did not differ for the 2 age groups. Similarly, in Experiment 2, in a partial-word identification task, skill learning was observed only for young adults, whereas there was no age difference in priming. Experiments 1a and 2a, however, showed that when older adults were presented with more perceptual information than were young adults, the age deficit in skill learning was eliminated. These results indicate that skill learning is impaired under data-limited conditions, whereas priming is unaffected under these conditions. It is proposed that the age deficit in skill learning is related to a deficit in perceptual organization and reorganization.

Configural processing in face recognition in schizophrenia

Introduction. There is currently substantial literature to suggest that patients with schizophrenia are impaired on many face-processing tasks. This study investigated the specific effects of configural changes on face recognition in groups of schizophrenia patients. Methods. In Experiment 1, participants identified facial expressions in upright faces and in faces inverted from their upright orientation. Experiments 2 and 3 examined recognition memory for faces and other non-face objects presented in upright and inverted orientations. Experiment 4 explored recognition of facial identity in composite images where the top half of one face was fused to the bottom half of another face to form a new face configuration. Results. In each experiment, the configural change had the same effect on face recognition for the schizophrenia patients as it did for control participants. Recognising inverted faces was more difficult than recognising upright faces, with a disproportionate effect of inversion on faces relative to other objects. Recognition of facial identity in face-halves was interfered with by the formation of a new face configuration. Conclusion. Collectively, these results suggest that people with schizophrenia rely on configural information to recognise photographs of faces.

Clock drawing in the screening assessment of cognitive impairment in an ambulatory care setting: A preliminary report

In an exploratory study to assess the utility of clock drawing as a screening test for cognitive impairment in medical/surgical outpatients, clock drawing and the 6-item Orientation-Memory-Concentration Test (OMCT) were administered to over 400 randomly selected ambulatory patients over the age of 55 in a busy inner-city hospital. The clock drawing test was completed by 431 patients, and 471 completed the OMCT. Clock drawing errors suggestive of moderate-to-severe cognitive impairment were found in 42.7% of patients; OMCT errors suggestive of moderate-to-severe cognitive impairment were found in 35.4% of the population tested. The clock drawing test might represent a quick-screen for cognitive impairment in an older general medical/surgical outpatient population, and might help identify patients not otherwise recognized as potentially unable to fully understand treatment recommendations.

Topiramate improves deficit symptoms in a patient with schizophrenia when added to a stable regimen of antipsychotic medication

Topiramate was shown to attenuate the severity of negative symptoms (e.g., emotional withdrawal) in a patient with schizophrenia when added to his stable regimen of antipsychotic medication. Topiramate was administered for a period of 12 weeks; during the first 4 weeks, dosage was adjusted to the maximal tolerated dose (i.e., 175 mg/d), and, thereafter, this dosage was maintained for 8 weeks. Topiramate was studied because of recent data and hypotheses suggesting that N-methyl-D-aspartate receptor hypofunction, dampened GABAergic inhibition, and excessive stimulation of the kainic acid (KA)/&agr;-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) class of glutamate receptors occur in at least some patients with schizophrenia, especially those with persistent negative symptoms and progressive psychosocial deterioration. Topiramate is a recently approved and marketed medication for the treatment of seizure disorders, whose mechanism of action includes potentiation of GABAergic neurotransmission and antagonism of KA/AMPA glutamate receptors. This case is presented because of the dramatic response of negative symptoms to the addition of topiramate. The severity of negative symptoms was assessed formally with the Negative Scale of the Positive and Negative Syndrome Scale. The negative symptoms of schizophrenia are usually resistant to most behavioral and pharmacologic interventions.