Schizophrenia cognitive dysfunction

Roche for their inhibitor RG1678. This trial provides compelling evidence that GlyT-1 inhibitors show promise as a novel class of antipsychotics that are effective at ameliorating the negative symptoms and cognitive dysfunction associated with schizophrenia. 

The deficit of cortico-striatal innervation that is presumably responsible for reported losses of striatal glutamate uptake sites (Aparicio-Legarza et al., 1997 Simpson et al., 1992), is likely to contribute to the cognitive dysfunction of schizophrenia. These have been described as having similarities to the subcortical dementia (Pantelis et al., 1992) seen in a variety of neurodegenerative disorders disturbances of corticostriatal function are thought to underlie this pattern of cognitive deficits that include disturbances of attention, executive function and short-term memory. 

Glutamate was initially implicated in schizophrenia by studies of the behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., PCP, ketamine), which produce psychotic symptoms and cognitive dysfunction in healthy subjects and exacerbate psychotic, negative, and cognitive symptoms in patients with schizophrenia. Studies show that acute administration of NMDA antagonists causes NMDA receptor dysfunction, resulting in decreased inhibition of subcortical dopamine neurons and consequent increased mesolimbic dopamine release. Chronic administration produces decreased release, or hypoactivity, of dopamine in the prefrontal cortex (Davis and Lieberman, 2000). 

A basic ethical issue in several areas of psychiatric research is whether participants are able to provide informed consent, particularly for protocols entailing medication washout and/or placebo treatment. The majority of psychiatric patients who are asked to participate in clinical trials have adequate capacity to provide consent. Thus, in a study specifically designed to examine the capacity of schizophrenic patients to give informed consent, cognitive dysfunction and negative symptoms (apathy and avolition). but not psychotic symptoms (hallucinations, delusions), were found to be associated with impaired decisional capacity (Moser et al., 2002). These features are probably not unique to schizophrenia but are likely to apply to many other forms of illness. 

Schizophrenia is certainly not the only disorder with such impairments in cognition. Autism, poststroke dementia, Alzheimer s disease, and many other organic dementias (parkinsonian/Lewy body dementia, frontotemporal/Pick s dementia, etc.) are also associated with some cognitive dysfunctions similar to those seen in schizophrenia (Fig. 10—4). 

Friedman JI, Adler DN, Davis KL (1999) The role of norepinephrine in the pathophysiology of cognitive disorders potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer s disease. Biol. Psychiatry 46 1243-1252. 

Goldman-Rakic PS, Castner SA, Svensoon IH, Siever LJ, Williams GV Targeting the dopamine D1 receptor in schizophrenia insights for cognitive dysfunction. Psychopharmacology 2004 174 3-16. 

Castner SA, Goldman-Rakic PS, Williams GV. Animal models of working memory insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology 2004 174 111-125. 

Waddington, J. L., O Callaghan, E., Larkin, C., Kinsella, A. 1993, Cognitive dysfunction in schizophrenia organic vulnerability factor or state marker for tardive dyskinesia , Brain Cogn., vol. 23, no. 1, pp. 56-70. 

Krausz, M., Moritz, S., Naber, D., Lambert, M., Andresen, B. (1999). Neuroleptic-induced extrapyramidal symptoms are accompanied by cognitive dysfunction in schizophrenia. European Psychiatry, 14, 84-88. 

Waddington, J. L., 8c Youssef, H. A. (1986b). An unusual cluster of tardive dyskinesia in schizophrenia Association with cognitive dysfunction and negative symptoms. American Journal of Psychiatry, 143, 1162-1165. 

Ferreri F, Agbokou C, Gauthier S. 2006. Cognitive dysfunctions in schizophrenia Potential benefits of cholinesterase inhibitor adjunctive therapy. J Psychiatry Neurosci 31 ... 

Schizophrenia is a severe mental disorder associated with both a specific profile of symptoms and a complex pattern of neurocognitive dysfunction. The first effective treatment for schizophrenia was discovered fortuitously in the mid-1950s (Delay and Deniker, 1955) and subsequently shown in the mid-1970s to mediate their effects at dopamine D2 receptors (Seeman and Lee, 1975 Wong et al., 1986). The dopamine hypothesis has been the dominant neurochemical model of schizophrenia (Carlsson, 1988) and has proved heuristically valuable since that time. For example, all current treatments for schizophrenia mediate their effects via a blockade of the dopamine (D2) receptor. Further, certain forms of cognitive dysfunction may relate to impaired dopaminergic function within the prefrontal cortex (see Chapter 1.1 this volume). Nevertheless, over recent years, limitations of the dopamine hypothesis have become increasingly apparent, as has the need for alternative neurochemical conceptualizations of schizophrenia. 

This alternative model of schizophrenia, based upon actions of PCP and ketamine, was also proposed in the late 1980s (Olney, 1989 Olney et al., 1989), but focuses on a separate aspect of action of NMDA antagonists. In addition to producing cognitive dysfunction, NMDA antagonists were observed to produce neurode-generative changes in specific populations of cortical pyramidal neurons, particularly in frontal, posterior... 

Lewis DA, Moghaddam B. 2006. Cognitive dysfunction in schizophrenia Convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63 1372-1376. 

Sawada K, Barr AM, Nakamura M, Arima K, Young CE, et al. 2005. Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch Gen Psychiatry 62 ... 

Volk DW, Lewis DA. 2002. Impaired prefrontal inhibition in schizophrenia Relevance for cognitive dysfunction. Physiol Behav 77 501-505. 

Lewis DA, Cruz D, Eggan S, Erickson S. 2004. Postnatal development of prefrontal inhibitory circuits and the pathophysiology of cognitive dysfunction in schizophrenia. Ann NY Acad Sci 1021 64-76. 

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