Early Intervention and a Direction of Novel Therapeutics for the Improvement of Functional Outcomes in Schizophrenia: A Selective Review

Abstract

BackgroundA recent review reported that the median proportion of patients recovering from schizophrenia was 13.5% and that this did not change over time. Various factors including the duration of untreated psychosis, cognitive impairment, negative symptoms, and morphological changes in the brain influence the functional outcome of schizophrenia. The authors herein reviewed morphological changes in the brain of schizophrenia patients, effects of early intervention, and a direction of developing novel therapeutics to achieve significant improvement of the functional outcome.MethodsA selective review of the literature including studies from our department was performed.ResultsLongitudinal structural neuroimaging studies on schizophrenia revealed that volume reductions in the peri-Sylvian regions (e.g., superior temporal gyrus and insula), which are related to positive psychotic symptoms, progress around the onset (critical stage) of schizophrenia, but become stable in the chronic stage. On the other hand, morphological changes in the fronto-thalamic regions and lateral ventricle, which are related to negative symptoms, neurocognitive dysfunction, and the functional outcome, progress during both the critical and chronic stages. These changes in the peri-Sylvian and fronto-thalamic regions may provide a pathophysiological basis for Crow’s two-syndrome classification. Accumulated evidence from early intervention trials suggests that the transition risk from an at-risk mental state (ARMS) to psychosis is approximately 30%. Differences in the cognitive performance, event-related potentials (e.g., mismatch negativity), and brain morphology have been reported between ARMS subjects who later developed psychosis and those who did not. Whether early intervention for ARMS significantly improves the long-term recovery rate of schizophrenia patients remains unknown. With respect to the development of novel therapeutics, animal models of schizophrenia based on the N-methyl-d-aspartate receptor hypofunction hypothesis successfully mimicked behavioral changes associated with cognitive impairments characteristic of the disease. Furthermore, these animal models elicited histological changes in the brain similar to those observed in schizophrenia patients, i.e., decreased numbers of parvalbumin-positive interneurons and dendritic spines of pyramidal neurons in the frontal cortex. Some antioxidant compounds were found to ameliorate these behavioral and histological abnormalities.ConclusionEarly intervention coupled with novel therapeutics may offer a promising approach for substantial improvement of the functional outcome of schizophrenia patients.

Brain morphologic changes in early stages of psychosis: Implications for clinical application and early intervention

“…98 Taken together with the findings from other groups, 11 our results suggest a period of intense gray matter reduction during the early phases of schizophrenia, especially in the lateral temporal and insular regions, which is likely to underlie the severity and early course of clinical symptoms in a region-specific manner but could be ameliorated with antipsychotic medication. Given that the STG, which includes the primary auditory and neocortical language regions, 99 is also involved in social cognition in concert with the insular cortex, a component of the limbic integration cortex, and other limbic © 2018 The Authors Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology regions, 100,101 these longitudinal findings are in line with a hypothesized perisylvian pathology of schizophrenia 37 where excessive dopamine transmission in the STG and insula causes positive symptoms (e.g., delusions, hallucinations, and disorganized speech) that are responsive to antipsychotic treatment. However, it is also reported that higher doses of antipsychotics (especially typical ones) may contribute to more progressive gray matter loss in schizophrenia.…”

“…Glutamatergic excess due to hypofunction of the N ‐methyl‐ d ‐aspartate receptors on corticolimbic gamma‐aminobutyric acidergic interneurons may also lead to adverse neurotoxic effects in the early stages of psychosis . While these potential mechanisms may partly explain histological changes observed in the cortical regions of schizophrenia patients, such as decreased numbers of parvalbumin‐positive interneurons and dendritic spines of pyramidal neurons (see review by Kurachi et al …”

“…9,10 Glutamatergic excess due to hypofunction of the Nmethyl-D-aspartate receptors on corticolimbic gammaaminobutyric acidergic interneurons may also lead to adverse neurotoxic effects in the early stages of psychosis. 106,107 While these potential mechanisms may partly explain histological changes observed in the cortical regions of schizophrenia patients, such as decreased numbers of parvalbumin-positive interneurons and dendritic spines of pyramidal neurons (see review by Kurachi et al 37 ), further work would be required to integrate microscopic changes in the molecular/cellular levels and in vivo imaging findings in order to understand the etiological and pathophysiological meanings of MRI findings in schizophrenia.…”

“…Schizophrenia is thought to have clinical and biological heterogeneities, 37 with a large variability in regional brain volumes, 36 and there is also a considerable overlap between schizophrenia patients and healthy subjects in each anatomical variable, even for brain regions where patients have significant change with a large effect size (e.g., left STG; Cohen's d = −1.25). 84 Nevertheless, we have demonstrated that a combination of brain anatomical variables 138 or a pattern of disease-related anatomical changes 139 could differentiate patients with schizophrenia from healthy subjects with a favorable classification accuracy even for first-episode patients.…”

“…28 There have also been attempts to examine the clinical applicability of structural neuroimaging data to the classification of psychiatric disorders (e.g., diagnosis 29,30 and prediction of treatment response 31 in schizophrenia). However, there are still practical problems, such as rather low disease specificity of the brain changes in schizophrenia 32,33 and the clinical/biological heterogeneity of schizophrenia itself, [34][35][36][37] that prevent clinical application of these neuroimaging research findings.…”