Schizophrenia pathophysiology

Fendri C., Mechri A., Khiari G., Othman A., Kerkeni A., and Gaha L. (2006). Implication du stress oxydant dans la physiopathologie de la schizophrenic revue de la litterature [Oxidative stress involvement in schizophrenia pathophysiology a review], L Encephale 32 244-252. 

Lawrie SM, Hall J, McIntosh AM, Cunningham-Owens DG, Johnstone EC. 2008. Neuroimaging and molecular genetics of schizophrenia Pathophysiological advances and therapeutic potential. Brit J Pharmacol 153 S120-S124. 

Explain the pathophysiologic mechanisms that are thought to underlie schizophrenia. 

Schizophrenia is a chronic, complex psychiatric disorder affecting approximately 1% of the population worldwide. The chronic nature of the illness, in addition to the early age of onset, results in direct and indirect health care expenditures in the U.S., which amount to approximately 30 to 64 billion dollars per year [4]. It is perhaps the most devastating of psychiatric disorders, with approximately 10% of patients committing suicide. The dopamine hypothesis of schizophrenia postulates that overactivity at dopaminergic synapses in the central nervous system (CNS), particularly the mesolimbic system, causes the psychotic symptoms (hallucinations and delusions) of schizophrenia. Roth and Meltzer [5] have provided a review of the literature and have concluded a role for serotonin as well in the pathophysiology and treatment of schizophrenia. The basic premise of their work stems from the known interaction between the serotonergic and dopaminergic systems. 

The D2 antagonist activity of current antipsychotics led to the "dopamine hypothesis," which states that the pathophysiology of schizophrenia is due to excessive dopaminergic neurotransmission and dysfunctional D2 signaling [6]. This hypothesis has prevailed for nearly 60 years however, it falls short as a complete explanation due to the deficiencies current antipsychotics exhibit against negative and cognitive symptoms. 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

Our understanding of the pathophysiology of schizophrenia has advanced remarkably over the last decade through... 

Harrison, P. J. and Owen, M. J. Genes for schizophrenia Recent findings and their pathophysiological implications. The Lancet 361 417-419, 2003. 

Nemeroff CB, Musselman DL, Nathan KI, et al. Pathophysiological basis of psychiatric disorders focus on mood disorders and schizophrenia. In Tasman A, Kay J, Lieberman JA (eds), Psychiatry, Volume 1. Philadelphia WB Saunders, 1997, pp 258-311. 

Glutamate systems have long been implicated in the pathophysiology of schizophrenia. Strong if circumstantial evidence comes from the psychosis associated with phencyclidine (PGP) administration PGP blocks of the ion channel the glutamate/NMDA receptor. Psychosis due to PGP and other noncompetitive NMDA antagonists includes the development of negative as well as positive symptoms and therefore is considered a better model of schizophre-... 

Several lines of evidence have implicated NMDA receptor hypofunction in the pathophysiology of schizophrenia. The administration of certain, but not all, uncompetitive NMDA receptor antagonists exacerbates psychotic symptoms in schizophrenics and mimics schizophrenia in non-psychotic subjects (Coyle et al. 2003 Konradi and Heckers 2003). 

A major h) othesis concerning the pathophysiology of schizophrenia is centred on the membrane composition and functional perturbations associated with the disease. Therefore, P MRS has been utilized extensively... 

Lieberman JA, Koreen AR, Chakos M, et al Factors influencing treatment response and outcome of first-episode schizophrenia implications for understanding the pathophysiology of schizophrenia. J Clin Psychiatry 57 (suppl 9) 5-9, 1996... 

Lieberman JA, Sheitman B, Chakos M, et al The development of treatment resistance in patients with schizophrenia a clinical and pathophysiologic perspective. J Clin Psychopharmacol 18 (2, suppl 1) 20S-24S, 1998... 

Similar observations can be made with regard to the antidepressants introduced in the last 15 years or so. Both SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) represent some quantitative progress from the earlier antidepressants in that they are less toxic, cause fewer medically significant adverse events and support treatment compliance. As is the case for antipsychotics and schizophrenia, the development of these newer antidepressants was not based on fundamentally new insights into the pathophysiology of affective disorders. 

Another hypothesis (Crow, 1982) involves a division of schizophrenias into two types Type I corresponds to acute schizophrenia or schizophreniform disorder in which one observes more positive symptoms of hallucinations and delusions with a good prognosis and excellent response to neuroleptics... Type II represents chronic schizophrenia with affective flattening, poverty of speech and loss of drive, the so-called negative symptoms of schizophrenia. Type II patients respond less well to neuroleptics... (Snyder, 1982). Type I patients would fit into the dopamine hypothesis whereas a pathophysiological basis other than dopaminergic hyperactivity must be assumed for type II patients. However, as pointed out by Snyder (1982). "one should be cautious about drawing such a distinction. ... 

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