In particular, the early phase of the illness, and how people evolve from ostensibly normal in their premorbid phase to meet DSM criteria for schizophrenia and related psychotic disorders, is incompletely characterized and poorly understood. Extensive evidence indicates that schizophrenia is a complex neurodevelopmental disorder reflecting the interplay of genetics and the environment. It is also highly likely that there may be multiple different etiologies that phenotypically converge to induce the symptoms of schizophrenia. Therapeutic pessimism historically colored perspectives on the prognoses and treatment of schizophrenia, but more recent studies in the s and early 21st century of first episode and early stage of illness patients revealed that symptom remission and recovery are possible if patients receive prompt, appropriate treatment.
Treatment response and outcome were significantly affected by the duration of active illness prior to treatment. Longer duration of psychotic symptoms prior to treatment intervention is associated to longer time to, and lower rates of, symptom remission. This body of research led to efforts to develop innovative treatment strategies for patients in the early stages of psychotic disorders designed to reduce the duration of untreated illness and promote engagement in sustained treatment and reduce non-adherence and relapse.
Our methods for case identification are insufficiently specific, and we do not know what are the optimal treatments for people approaching or at the incipient stage of their illness. Therefore, we risk mislabeling and treating them, possibly unnecessarily, to alleviate their attenuated psychotic symptoms and prevent the onset of schizophrenia.
An Introduction to Schizophrenia and Other Psychotic Disorders
To advance our knowledge of psychotic disorders and improve the methodology for early detection and intervention in the pre-syndromal phase of schizophrenia, we developed a pathophysiologic model that characterizes the progression of schizophrenia from the premorbid through the prodromal stages to syndromal psychosis. This model posits dysregulation of glutamate neurotransmission occurring in the CA1 region of the hippocampus which elevates neuronal activity reflected in metabolism and blood flow, and in doing so elicits attenuated psychotic symptoms and initiates the prodromal stage of schizophrenia.
As this persists, it drives the transition process to the later prodromal stage and subsequently syndromal psychosis. As the incipient illness progresses, this dysfunction expands to projection fields within and external to the hippocampus and frontal cortex, and causes an atrophic process in which the neuropil of hippocampal cells is reduced and interneurons are lost. The evidence supporting this model is substantial, consistent and derives from numerous investigators.
Our aim was to elucidate the pathophysiologic mechanism leading to the onset of schizophrenia and develop a pharmacologic intervention. We began by developing a biomarker to facilitate the diagnosis of people at clinical high risk for psychotic disorders.
We focused on the hippocampus because previous neuroimaging research has demonstrated structural volume reduction, shape anomalies and functional abnormalities increased metabolism measured by blood flow and glucose metabolism in the medial temporal lobe structures of patients with schizophrenia specifically the CA1 and subiculum sub-regions of the anterior hippocampus. However, as these findings came from different studies with separate patient samples, their concordance within subjects was unknown. Moreover, the temporal sequence of these pathologic features and whether they are progressive was unclear.
Nineteen control subjects were also recruited. All subjects were medically healthy. All adult subjects provided written informed consent and minors provided written assent, with written informed consent given by one or both parents.shop.reborn.mk/el-retorno-de-la-expatriada.php
Creating A Thesis Statement For A Research Paper On Schizophrenia
In addition to clinical ratings of psychopathology with the structured interview for psychosis risk syndromes SIPS , subjects were assessed with MRI measures of structure and function using gadolinium a paramagnetic contrast agent to provide high-resolution maps of the spatial and temporal pattern of hippocampal metabolism and structure 19 , 35 , 36 and followed for 2 years or conversion to a psychotic disorder at which time they were reassessed with the same measures as at study entry. Subjects were reassessed 2 years of follow-up after their initial scan or sooner if they developed a syndromal psychotic disorder.
Forty percent of the initial cohort or 10 of 25 of the baseline sample converted to a syndromal psychosis over the course of the follow-up period mean time to conversion days; median days. We examined longitudinal changes in CBV between baseline and follow-up assessments, and found that: 1 CA1—CBV, which was higher in high-risk subjects compared to healthy volunteers, and in high-risk subjects who converted to psychosis compared to those that did not convert to psychosis, did not increase from baseline but remained elevated in relation to the healthy comparison group; 2 in subjects who developed psychotic disorders, CBV increased from baseline to conversion in the subiculum; no significant change in CBV occurred from time 1 to time 2 in other hippocampal sub-regions including entorhinal cortex, dentate gyrus, and CA3.
Medication exposure had no effect on CBV values in this analysis. The hippocampal volume of high-risk subjects who subsequently developed psychotic disorders declined. Relationship hippocampal CBV and atrophy. Hypermetabolism and atrophy of the hippocampus were strongly associated in anterior regions of the CA1 region but not in posterior or mid-regions. These associations were not found in the posterior or mid body subfields. None of these changes were related to medication exposure. We hypothesized that the pathophysiology driving the anatomically concordant hypermetabolism and associated atrophy was caused by a dysregulation of glutamate neurotransmission and increased extracellular glutamate.
Numerous case studies and anecdotal reports of the psychotomimetic effects of NMDA receptor blockers ketamine and phencyclidine showed that ketamine produces a behavioral syndrome that recapitulates the full spectrum of schizophrenia symptoms. Studies of NMDA receptor blockade on limbic metabolic activity produced homologous findings in rodents and humans, and provided a translational framework in which to examine the pathogenic mechanisms underlying the psychosis-related hippocampal CA1 hypermetabolism we had observed in patients.
Clinical studies of 1H MRS have found increased glutamate levels in prodromal and patients with schizophrenia in the hippocampus have found elevated levels in the hippocampus compared to healthy control subjects and associated with hypermetabolism in different brain regions of interest in patients with schizophrenia 28 , 29 , 48 , 49 , 50 and including in some instances correlated with hippocampal atrophy.
Because of its importance as an excitatory neurotransmitter and potential for neurotoxicity, glutamate is tightly regulated by a group of enzymes distributed in astrocytes and neurons 51 , 52 —including glutamate dehydrogenase; glutaminase; glutamine synthetase; glutamic acid decarboxylase; GABA transaminase; and aspartate and alanine aminotransferases. It is therefore possible, that alterations in this group of enzymes might occur genetically, either directly, by genes encoding these enzymes; 53 secondarily, by genetic links to the glutamatergic system 54 , 55 , 56 or via environmental stressors and risk factors.
To examine this possibility, we used microarray to profile gene-expression levels of postmortem tissue collected from the CA1 subfield from the brains with schizophrenia and the age-matched controls, and the entorhinal cortex, a neighboring sub region of the hippocampal formation that was found to be differentially unaffected in schizophrenia.
GLUD1 is expressed primarily in astrocytes where it is one of the main enzymes that degrades glutamate, and its deficiency might account for glutamate elevations.
outline of schizophrenia research paper | Schizophrenia | Mental Disorder
CBV was measured using the same high-resolution contrast-based fMRI methods used in the clinical high-risk subjects. The sub region in which the ketamine challenge had the greatest effect on glutamate was CA1, a finding consistent with our previous study using the same CBV variant, suggesting that the CA1 region is specifically sensitive to alterations in glutamate. Regional patterns of increased metabolic activity in hippocampus of patients with schizophrenia a , c and induced by acute ketamine in mice BD. The pattern induced by ketamine with greatest deviation in CA1, then SUB, and non-significant in other regions.
Adapted from data in Schobel et al.
Together, these experiments established that increases in extracellular glutamate can drive increases in metabolic activity within the hippocampal CA1 region and that can be mitigated by pharmacologic agents that inhibit glutamate. LY co pre -treatment blocks the increase in basal CBV c1 and relative loss of hippocampal volume c2 produced by repeated ketamine exposure. Parvalbumin expressing neurons in dorsal hippocampus of the mouse. Hippocampal volume loss correlates with increases in CBV.
With these findings demonstrating a link between glutamate dysregulation, CA1 hypermetabolism and hippocampal volume reduction, we next aimed to understand the pathological impact of the hyperglutamatergic-hypermetabolic events on hippocampal circuits. These cells provide the major inhibitory input to glutamate secreting excitatory projection neurons of the hippocampus, tightly controlling their excitability and ultimately the output signal of the hippocampus.
We postulated that the repeated ketamine challenges produced a series of events in which a surge in extracellular glutamate drives metabolic demand. By limiting evoked glutamate efflux, the LY treatment mitigated this pathogenic process. The natural history of schizophrenia, characteristically evolves from a premorbid phase in which the clinical phenotype is not, or only partially, expressed through a series of stages culminating in the syndromal manifestation of symptoms meeting diagnostic criteria and constituting a first episode of a psychotic disorder.
The subsequent course varies markedly based on illness severity, adequacy of treatment and environmental, including social, factors. Numerous prior postmortem and neuroimaging studies have demonstrated early pathological involvement of the hippocampal formation in schizophrenia as reviewed above.
These findings implicate the fundamental relationship of the hippocampus to the onset and early course of schizophrenia as reflected by measures of its metabolism and structure.
Our longitudinal study of clinical high-risk patients revealed a specific spatiotemporal pattern of hippocampal dysfunction that progresses in the transition from attenuated psychotic symptoms to syndromal psychosis. During pre-syndromal stages or attenuated psychotic symptoms, increased glutamate levels and hypermetabolism of hippocampal neurons selectively occurs in the CA1 sub-region.
Those patients who progress go through the prodromal stage to syndromal psychosis, this pathologic process spreads from CA1 to the subiculum and likely beyond the hippocampus and leads to hippocampal volume reduction in a precise spatially concordant manner.
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We tested this pathophysiological hypothesis in a rodent model with three experiments. First, we found that ketamine-evoked increases in extracellular glutamate in mice mirrored the evoked fMRI pattern, with maximal changes found in the CA1 and subiculum hippocampal sub regions. Second, we demonstrated that the ketamine induced effects described were associated with and presumably caused atrophy in a spatial-temporally concordant manner. Third, we established a mechanistic link by pre-treating with an agent that inhibited or blocked ketamine-induced extracellular glutamate efflux, hypermetabolism and spatio-temporally concordant atrophy in the hippocampus.
Finally, we extended this acute experiment longitudinally over 1 month and found that by inhibiting extracellular glutamate efflux with therapeutic agents prior to intermittent ketamine administration, sustained basal hypermetabolism and hippocampal atrophy were reduced or prevented. Numerous studies by other investigators and from other laboratories support the hypothesis that glutamate neurotransmission plays a critical role in mediating the cognitive and behavioral disturbances of psychosis.
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Differential regional vulnerability to the effects of NMDA receptor blockade within the hippocampal circuit may be mediated at a molecular level by increased density of NMDA and AMPA receptors in CA1 relative to the CA3 subfield, dentate gyrus and entorhinal cortex; 79 and AMPA receptors may play an important role in the consequent synaptic and hemodynamic state.
In addition to clarifying mechanisms of disease onset, the aforementioned studies indicate that measures of increases of extracellular glutamate in CA1, may serve as a state-specific biomarker of prodromal psychotic disorders. By showing that hypermetabolism occurs before atrophy, our results reinforce this concept, because reversing functional defects are likely easier before the development of structural brain pathology.
In addition, these results suggest that reducing extracellular glutamate is a valid target for preventing or ameliorating the onset of illness and limiting hippocampal atrophy, one of the first regions of the brain to show volumetric loss in schizophrenia. It is possible, therefore, to design a study in subjects at high risk for psychotic disorders to test whether these drugs normalize hippocampal hypermetabolism and prevent progression to psychosis, and hippocampal atrophy.
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Although the source of glutamate dysregulation awaits further exploration, the imaging studies summarized earlier suggest that glutamate elevation itself is a valid drug target and that glutamate-reducing agents might be effective for therapeutic intervention. An important implication of the imaging studies is that these agents should be given during prodromal stages of disease, before its imaging correlate of atrophy and the loss of interneurons occurs.
Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci ; 6 : — Benes FM.