Yusuke Iwata

Glutamate-mediated excitotoxicity in schizophrenia: A review

Findings from neuroimaging studies in patients with schizophrenia suggest widespread structural changes although the mechanisms through which these changes occur are currently unknown. Glutamatergic activity appears to be increased in the early phases of schizophrenia and may contribute to these structural alterations through an excitotoxic effect. The primary aim of this review was to describe the possible role of glutamate-mediated excitotoxicity in explaining the presence of neuroanatomical changes within schizophrenia. A Medline(®) literature search was conducted, identifying English language studies on the topic of glutamate-mediated excitotoxicity in schizophrenia, using the terms schizophreni and glutam and ((MRS or MRI or magnetic resonance) or (computed tomography or CT)). Studies concomitantly investigating glutamatergic activity and brain structure in patients with schizophrenia were included. Results are discussed in the context of findings from preclinical studies. Seven studies were identified that met the inclusion criteria. These studies provide inconclusive support for the role of glutamate-mediated excitotoxicity in the occurrence of structural changes within schizophrenia, with the caveat that there is a paucity of human studies investigating this topic. Preclinical data suggest that an excitotoxic effect may occur as a result of a paradoxical increase in glutamatergic activity following N-methyl-D-aspartate receptor hypofunction. Based on animal literature, glutamate-mediated excitotoxicity may account for certain structural changes present in schizophrenia, but additional human studies are required to substantiate these findings. Future studies should adopt a longitudinal design and employ magnetic resonance imaging techniques to investigate whether an association between glutamatergic activity and structural changes exists in patients with schizophrenia.

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials

Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=−0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=−0.03 to 0.11) (n=367–940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

Lifetime History of Depression Predicts Increased Amyloid-β Accumulation in Patients with Mild Cognitive Impairment.

Mounting evidence associates a lifetime history of major depression (LMD) with an increased risk for Alzheimers disease (AD). Studies have shown that major depression (MD) is strongly linked to pathophysiological markers of AD, such as cortical amyloid-β (Aβ) burden. However, no imaging studies have shown in vivo whether an LMD is linked to increased Aβ accumulation in patients with mild cognitive impairment (MCI) in four cortical regions that have been highly associated with increased Aβ deposition in previous literature: frontal, cingulate, parietal, and temporal. Drawing from the ADNI database, we found that patients with amnestic MCI (aMCI) and an LMD (n = 39) had significantly higher 18F-Florbetapir standardized uptake value ratios, a surrogate measure of Aβ deposition, mainly in the bilateral frontal cortex, compared to patients with aMCI without an LMD (n = 39) (p = 0.02). This difference was not explained by current depressive symptoms, vascular risk factors, or the use of different PET scanners. The results were reliable employing two independent methods for analysis: region-of-interest and voxel-based analyses. Increased Aβ in the bilateral frontal lobes may be a biomarker of depressive symptomology in aMCI patients. Further studies should test whether higher Aβ predicts future conversion into AD in this population.

Neuroimaging findings in treatment-resistant schizophrenia: A systematic review Lack of neuroimaging correlates of treatment-resistant schizophrenia

BACKGROUNDnRecent developments in neuroimaging have advanced the understanding of biological mechanisms underlying schizophrenia. However, neuroimaging correlates of treatment-resistant schizophrenia (TRS) and superior effects of clozapine on TRS remain unclear.nnnMETHODSnSystematic search was performed to identify neuroimaging characteristics unique to TRS and ultra-resistant schizophrenia (i.e. clozapine-resistant [URS]), and clozapines efficacy in TRS using Embase, Medline, and PsychInfo. Search terms included (schizophreni*) and (resistan* OR refractory OR clozapine) and (ASL OR CT OR DTI OR FMRI OR MRI OR MRS OR NIRS OR PET OR SPECT).nnnRESULTSn25 neuroimaging studies have investigated TRS and effects of clozapine. Only 5 studies have compared TRS and non-TRS, collectively providing no replicated neuroimaging finding specific to TRS. Studies comparing TRS and healthy controls suggest that hypometabolism in the prefrontal cortex, hypermetabolism in the basal ganglia, and structural anomalies in the corpus callosum contribute to TRS. Clozapine may increase prefrontal hypoactivation in TRS although this was not related to clinical improvement; in contrast, evidence has suggested a link between clozapine efficacy and decreased metabolism in the basal ganglia and thalamus.nnnCONCLUSIONnExisting literature does not elucidate neuroimaging correlates specific to TRS or URS, which, if present, might also shed light on clozapines efficacy in TRS. This said, leads from other lines of investigation, including the glutamatergic system can prove useful in guiding future neuroimaging studies focused on, in particular, the frontocortical-basal ganglia-thalamic circuits. Critical to the success of this work will be precise subtyping of study subjects based on treatment response/nonresponse and the use of multimodal neuroimaging.

Reduced Insulin Sensitivity Is Related to Less Endogenous Dopamine at D2/3 Receptors in the Ventral Striatum of Healthy Nonobese Humans

Background: Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [11C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity. Methods: Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [11C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion. Results: Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36). Conclusion: In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities.

Total syntheses of lactonamycin and lactonamycin Z with late-stage A-ring formation and glycosylation.

and inhibition of drug-resistant influenza virus neuraminidase using anthraquinone-sialic acid hybrids, photodegradation of HIV-1 protease and inhibition of HIV-1 replication in living cells by designed fullerene-sugar hibrids, evaluation of molecular probes based on the 9-methylstreptimidone derivative DTCM-glutarimide, a boron-doped diamond electrode mediated by methoxy radicals, Angew. iodination and one-pot arylation by on/off switching of electric current, Application of electrochemically generated hypervalent iodine oxidant to natural products synthesis, Electrochemistry, in press. a toxic matalloendopeptidase from the tropical toadstool,

Synthetic studies on lactonamycins: synthesis of the model BCDEF aglycon.

The lactonamycin model aglycon 4 was synthesized from the trihalogenated benzene derivative 10. Ethynyltetraol 6 was prepared from 10 via carbon elongations, oxidative demethylation, a cycloaddition reaction with the diene derived from homophthalic anhydride, and dihydroxylation. Final E- and F-ring constructions from 6 were realized via a palladium-catalyzed cyclization-methoxycarbonylation, a stereoselective methanol addition, and lactonization, leading to the production of 4.

Cortical Amyloid β Deposition and Current Depressive Symptoms in Alzheimer Disease and Mild Cognitive Impairment

Depressive symptoms are frequently seen in patients with dementia and mild cognitive impairment (MCI). Evidence suggests that there may be a link between current depressive symptoms and Alzheimer disease (AD)-associated pathological changes, such as an increase in cortical amyloid-β (Aβ). However, limited in vivo studies have explored the relationship between current depressive symptoms and cortical Aβ in patients with MCI and AD. Our study, using a large sample of 455 patients with MCI and 153 patients with AD from the Alzheimer’s disease Neuroimaging Initiatives, investigated whether current depressive symptoms are related to cortical Aβ deposition. Depressive symptoms were assessed using the Geriatric Depression Scale and Neuropsychiatric Inventory-depression/dysphoria. Cortical Aβ was quantified using positron emission tomography with the Aβ probe 18F-florbetapir (AV-45). 18F-florbetapir standardized uptake value ratio (AV-45 SUVR) from the frontal, cingulate, parietal, and temporal regions was estimated. A global AV-45 SUVR, defined as the average of frontal, cingulate, precuneus, and parietal cortex, was also used. We observed that current depressive symptoms were not related to cortical Aβ, after controlling for potential confounds, including history of major depression. We also observed that there was no difference in cortical Aβ between matched participants with high and low depressive symptoms, as well as no difference between matched participants with the presence and absence of depressive symptoms. The association between depression and cortical Aβ deposition does not exist, but the relationship is highly influenced by stressful events in the past, such as previous depressive episodes, and complex interactions of different pathways underlying both depression and dementia.

Depressive symptoms and small hippocampal volume accelerate the progression to dementia from mild cognitive impairment

Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimers Disease Neuroimaging Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (pu200a=u200a0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non-converters over the 2-year period (pu200a=u200a0.003, pu200a=u200a0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia.

Kynurenic Acid in Schizophrenia: A Systematic Review and Meta-analysis

Kynurenic acid (KYNA) is an endogenous antagonist of N-methyl-D-aspartate and α7 nicotinic acetylcholine receptors that is derived from astrocytes as part of the kynurenine pathway of tryptophan degradation. Evidence suggests that abnormal KYNA levels are involved in the pathophysiology of schizophrenia. However, this has never been assessed through a meta-analysis. A literature search was conducted through Ovid using Embase, Medline, and PsycINFO databases (last search: December 2016) with the search terms: (kynuren* or KYNA) and (schizophreni* or psychosis). English language studies measuring KYNA levels using any method in patients with schizophrenia and healthy controls (HCs) were identified. Standardized mean differences (SMDs) were calculated to determine differences in KYNA levels between groups. Subgroup analyses were separately performed for nonoverlapping participant samples, KYNA measurement techniques, and KYNA sample source. The influences of patients age, antipsychotic status (%medicated), and sex (%male) on study SMDs were assessed through a meta-regression. Thirteen studies were deemed eligible for inclusion in the meta-analysis. In the main analysis, KYNA levels were elevated in the patient group. Subgroup analyses demonstrated that KYNA levels were increased in nonoverlapping participant samples, and centrally (cerebrospinal fluid and brain tissue) but not peripherally. Patients age, %medicated, and %male were each positively associated with study SMDs. Overall, KYNA levels are increased in patients with schizophrenia, specifically within the central nervous system. An improved understanding of KYNA in patients with schizophrenia may contribute to the development of novel diagnostic approaches and therapeutic strategies.