Schizophrenia

__**Schizophrenia (SZ) **__


 * Root Cause of disease: **

Schizophrenia (SZ) is a devastating psychiatric illness affecting approximately 1% of the world population. Its prevalence is independent of ethnic, economical, and cultural boundaries, suggesting that the disorder has no simple, nor single etiological factor (fig. #1). An array of loci exhibit connections to SZ, the majority of which are found on chromosomes 1, 6, and 22.1 Familial investigations have illustrated that the risk of developing SZ is larger in family members than the general population, the risk being highest in the monozygotic twin of an affected individual. However, investigations of monozygotic twins show that the concordance rate for schizophrenia is only approximately 48%, though twins share 100% of their genes.1 These findings suggest that though there is a strong genetic component to schizophrenia, non-genetic factors (environmental or experience related) also play a role. The identification of a single common environmental factor, or any genes and loci increasing proclivity to schizophrenia remains elusive. The structures of proteins coded by SZ genes lack discrete understanding, leaving a serious information gap for researchers toward understanding the underlying effects of missense mutations and single nucleotide polymorphisms (SNPs) that have been linked to susceptibility to disease.2 Neurocognition is variably impaired in schizophrenics (moderate to severe), and nearly all patients demonstrate noticeable decline from expected levels of cognitive function. Cognitive deficits represent a core pathophysiological feature of the illness and appear to have a stronger correspondence with poor outcome than does psychiatric symptom severity.3


 * Affected cell types/tissues/organs/systems: **

Alterations in the excitatory neurotransmitter glutamate system involving N-methyl-d-aspartate (NMDA) receptor function have emerged as a promising pathophysiological model for SZ. Glutamatergic constructs such as the NMDA receptor hypofunction model have considerable explanatory ability, and may integrate the early and late developmental deviations, the role of dopamine, as well as the post-illness onset deteriorative processes that occur in SZ.4 Again, stress must be placed on the idea that the exact mechanism by which SZ operates is not completely deduced, though it is clear that neurotransmitters responsible for stable neurocognitive ability are under stress in individuals who have the disease. Figure #1, again, shows the vast array of SZ symptoms and their origins.




 * Figure #1—Extant model of schizophrenia that encompasses known etiological & pathophysiological factors of the disease. The elephant serves as an allegory that combines the immense amount of individual theories into one large model, demonstrating the idea that schizophrenia cannot be traced to one single factor. **


 * Historical Backround of Schizophrenia: **

The term “schizophrenia” (coined by Swiss phychiatrist Eugen Bleuler in 1911) did not exist just over 100 years ago, though the discrete mental illness that it defines was discovered in 1887 by German scientist Dr. Emile Kraepelin. Several notable individuals who have been diagnosed with SZ are Eduard Einstein (son of Albert Einstein), Syd Barret (bassist from Pink Floyd), and John Nash (Nobel Prize winning Mathematician—protagonist of the motion picture “A Beautiful Mind”). The oldest written documents that seem to identify SZ were traced to ancient Egypt and dated to circa 2000 BC. Roman and Greek literature show awareness of psychotic disorders, though no criteria existed for diagnosis.5


 * Common Symptoms: **

The symptoms of SZ are divided into two categories, encompassing cognitive defecits and psychiatric impairment. Positive symptoms (cognitive defecits, i.e. hallucination and delusion) of are prevalent among individuals with neurological diseases other than SZ, but are expressed to a much higher degree in those afflicted with the disorder itself. Negative symptoms (psychiatric inadequacies, i.e. social withdrawal and apathy) are more strongly observed in SZ-affected individuals, but are present among those affected with other neurological impairments.1,6


 * Standard Treatments: **

Predominant treatments for SZ revolve around antipsychotic drugs. Antipsychotics are divided into first- and second-generation categories. Previous studies have demonstrated that first-generation antipsychotics (FGAs) have little benefit in treating the cognitive impairments of SZ patients. More recent trials and analyses have reported that second-generation antipsychotics (SGAs) enhance cognitive improvement to a higher degree than FGAs. Previous studies, however, had been limited by small sample sizes, short duration of treatment, and almost exclusive use of haloperidol as the first-generation comparator creating an unfair comparison because of the increased risk of sedation, extrapyramidal symptoms, and need for anticholinergic treatment, which may further impair cognition.3


 * Current Research: **

Only positive symptoms of SZ can be treated by antipsychotics; the socially debilitating negative symptoms continue to be elusive to effective medications. Though SGAs have exhibited traits that enhance cognitive improvement in individuals with SZ, new studies are emerging that focus directly on GlyT1. RG1678 is a GlyT1 inhibitor currently undergoing clinical testing that, when combined with SGAs, shows reduction of the ever-elusive negative symptoms associated with SZ. Thus, restoration of normal NMDA function may potentially represent a novel mechanism for the treatment of SZ. One approach involves elevation of the levels of extracellular glycine by inhibition of the glycine transporter-1 (GlyT1), which is co-expressed with the NMDA receptor, thereby enhancing NMDA receptor function while normalizing glutamate neurotransmission.6


 * References: **

Rowley, M., Bristow, L., J., Hutson, P., H. (2001). Current and Novel Approaches to the Drug Treatment of Schizophrenia. Journal of Medicinal Chemistry 44 (4): 477-501

<span style="font-family: 'Times New Roman',Times,serif; font-size: 140%;">Soares, D., C., Carlyle, B., C., Bradshaw, N., J., Porteous, D., J. (2011). DISC1: Structure, Function, and Therapeutic Potential for Major Mental Illness. Journal of American Chemical Society—Neuroscience 2: 609-632

<span style="font-family: 'Times New Roman',Times,serif; font-size: 140%;">Guoa, X., Zhaib, J., Weic, Q., Twamleyd, E., W., Jin, H., Fange, M., Hua, M., Zhaoa, J. (2011). Neurocognitive effects of first- and second-generation antipsychotic drugs in early-stage schizophrenia: A naturalistic 12-month follow-up study. Neuroscience Letters 503: 141-146

<span style="font-family: 'Times New Roman',Times,serif; font-size: 140%;">Keshavana, M., S., Nasrallahb, H., A., Tandonc, R. (2011). Moving ahead with the schizophrenic concept: From the elephant to the mouse. Schizophrenic Research 127: 1-3

<span style="font-family: 'Times New Roman',Times,serif; font-size: 140%;">Hopkins, C., R. (2011). ACS chemical neuroscience molecule spotlight on RG1678. Journal of American Chemical Society—Neuroscience 2: 685-686

<span style="font-family: 'Times New Roman',Times,serif; font-size: 140%;">http://www.schizophrenia.com/history