Branched-chain amino acids prevent obesity by inhibiting the cell cycle in an NADPH-FTO-m6A coordinated manner.

Obesity has become a major health crisis in the past decades. Branched-chain amino acids (BCAA), a class of essential amino acids, exerted beneficial health effects with regard to obesity and its related metabolic dysfunction, although the underlying reason is unknown. Here, we show that BCAA supplementation alleviates high-fat diet (HFD)-induced obesity and insulin resistance in mice and inhibits adipogenesis in 3T3-L1 cells. Further, we find that BCAA prevent the mitotic clonal expansion (MCE) of preadipocytes by reducing cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2) expression. Mechanistically, BCAA decrease the concentration of nicotinamide adenine dinucleotide phosphate (NADPH) in adipose tissue and 3T3-L1 cells by reducing glucose-6-phosphate dehydrogenase (G6PD) expression. The reduced NADPH attenuates the expression of fat mass and obesity-associated (FTO) protein, a well-known m6A demethylase, to increase the N6-methyladenosine (m6A) levels of Ccna2 and Cdk2 mRNA. Meanwhile, the high m6A levels of Ccna2 and Cdk2 mRNA are recognized by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), which results in mRNA decay and reduction of their protein expressions. Overall, our data demonstrate that BCAA inhibit obesity and adipogenesis by reducing CDK2 and CCNA2 expression via an NADPH-FTO-m6A coordinated manner in vivo and in vitro, which raises a new perspective on the role of m6A in the BCAA regulation of obesity and adipogenesis.

mRNA m5C inhibits adipogenesis and promotes myogenesis by respectively facilitating YBX2 and SMO mRNA export in ALYREF-m5C manner.

Although 5-methylcytosine (m5C) has been identified as a novel and abundant mRNA modification and associated with energy metabolism, its regulation function in adipose tissue and skeletal muscle is still limited. This study aimed at investigating the effect of mRNA m5C on adipogenesis and myogenesis using Jinhua pigs (J), Yorkshire pigs (Y) and their hybrids Yorkshire-Jinhua pigs (YJ). We found that Y grow faster than J and YJ, while fatness-related characteristics observed in Y were lower than those of J and YJ. Besides, total mRNA m5C levels and expression rates of NSUN2 were higher both in backfat layer (BL) and longissimus dorsi muscle (LDM) of Y compared to J and YJ, suggesting that higher mRNA m5C levels positively correlate with lower fat and higher muscle mass. RNA bisulfite sequencing profiling of m5C revealed tissue-specific and dynamic features in pigs. Functionally, hyper-methylated m5C-containing genes were enriched in pathways linked to impaired adipogenesis and enhanced myogenesis. In in vitro, m5C inhibited lipid accumulation and promoted myogenic differentiation. Furthermore, YBX2 and SMO were identified as m5C targets. Mechanistically, YBX2 and SMO mRNAs with m5C modification were recognized and exported into the cytoplasm from the nucleus by ALYREF, thus leading to increased YBX2 and SMO protein expression and thereby inhibiting adipogenesis and promoting myogenesis, respectively. Our work uncovered the critical role of mRNA m5C in regulating adipogenesis and myogenesis via ALYREF-m5C-YBX2 and ALYREF-m5C-SMO manners, providing a potential therapeutic target in the prevention and treatment of obesity, skeletal muscle dysfunction and metabolic disorder diseases.

Metformin combats obesity by targeting FTO in an m6A-YTHDF2-dependent manner.

Obesity has become a health threat and hard enough to deal with. Evidences show that metformin could inhibit adipogenesis and combat obesity, while its mechanisms remain to be elucidated more comprehensively. In this study, we found that administration of metformin could combat obesity of mice induced by high-fat diet (HFD), indicated by strikingly decreased body weight and weight of inguinal white adipose tissue (iWAT) and epidydimal white adipose tissue (eWAT) compared with the control group. Mechanically, we revealed that metformin could inhibit protein expression of FTO, leading to increased m6A methylation levels of cyclin D1 (Ccnd1) and cyclin dependent kinase 2 (Cdk2), two crucial regulators in cell cycle. Ccnd1 and Cdk2 with increased m6A levels were recognised by YTH m6A RNA binding protein 2 (YTHDF2), causing an YTHDF2-dependent decay and decreased protein expressions. In consequence, mitotic clonal expansion (MCE) process was blocked and adipogenesis was inhibited.

DHA alleviates diet-induced skeletal muscle fiber remodeling via FTO/m6A/DDIT4/PGC1α signaling.

BACKGROUND: Obesity leads to a decline in the exercise capacity of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. Dietary intervention has been shown to be an important measure to regulate skeletal muscle function, and previous studies have demonstrated the beneficial effects of docosahexaenoic acid (DHA; 22:6 ω-3) on skeletal muscle function. At the molecular level, DHA and its metabolites were shown to be extensively involved in regulating epigenetic modifications, including DNA methylation, histone modifications, and small non-coding microRNAs. However, whether and how epigenetic modification of mRNA such as N6-methyladenosine (m6A) mediates DHA regulation of skeletal muscle function remains unknown. Here, we analyze the regulatory effect of DHA on skeletal muscle function and explore the involvement of m6A mRNA modifications in mediating such regulation. RESULTS: DHA supplement prevented HFD-induced decline in exercise capacity and conversion of muscle fiber types from slow to fast in mice. DHA-treated myoblasts display increased mitochondrial biogenesis, while slow muscle fiber formation was promoted through DHA-induced expression of PGC1α. Further analysis of the associated molecular mechanism revealed that DHA enhanced expression of the fat mass and obesity-associated gene (FTO), leading to reduced m6A levels of DNA damage-induced transcript 4 (Ddit4). Ddit4 mRNA with lower m6A marks could not be recognized and bound by the cytoplasmic m6A reader YTH domain family 2 (YTHDF2), thereby blocking the decay of Ddit4 mRNA. Accumulated Ddit4 mRNA levels accelerated its protein translation, and the consequential increased DDIT4 protein abundance promoted the expression of PGC1α, which finally elevated mitochondria biogenesis and slow muscle fiber formation. CONCLUSIONS: DHA promotes mitochondrial biogenesis and skeletal muscle fiber remodeling via FTO/m6A/DDIT4/PGC1α signaling, protecting against obesity-induced decline in skeletal muscle function.

FTO knockout in adipose tissue effectively alleviates hepatic steatosis partially via increasing the secretion of adipocyte-derived IL-6.

OBJECTIVE: Adipose dysfunction affects the secretion of adipokines and mediates the hepatic physiological changes. Fat mass and obesity associated protein (FTO) plays a crucial part in fat deposition but the crosstalk between FTO-mediated secretion of adipokines and hepatic steatosis is not clear. METHODS: Firstly, adipose-selective FTO knockout (FTOAKO) and control (FTOflox/flox) mice were induced by high fat diet (HFD). Then qRT-PCR assay was performed to analyze the expressions of hepatic lipid metabolism genes and adipocytokines gene of inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT). Afterwards, 3T3-L1 cells were knocked out IL-6 and co-cultured with AML12 cells (3T3-L1 siIL-6/AML12) and the expressions of hepatic lipid lipolysis genes were measured. Finally, we detected the hepatic lipid metabolism genes expressions in AML12 cells with the medium from 3T3-L1 cells or IL-6 treatment. RESULTS: FTOAKO effectively alleviated HFD-induced hepatic steatosis in mice and improved the transcription level of genes involved in hepatic lipolysis. Further investigation demonstrated that FTO knockout increased level of IL-6 in adipose tissues and 3T3-L1 cells. Compared to 3T3-L1/AML12, our results showed lipolysis-related genes expressions were dramatically inhibited in 3T3-L1 siIL-6/AML12. Finally, both depletion of FTO in adipocytes and IL-6 supplement led to increased lipolysis genes expressions in AML12 cells. CONCLUSIONS: FTO knockout in adipose tissue alleviated hepatic steatosis via targeting adipocyte-derived IL-6.

m6A methylation promotes white-to-beige fat transition by facilitating Hif1a translation.

Obesity mainly results from a chronic energy imbalance. Promoting browning of white adipocytes is a promising strategy to enhance energy expenditure and combat obesity. N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an important role in regulating adipogenesis. However, whether m6A regulates white adipocyte browning was unknown. Here, we report that adipose tissue-specific deletion of Fto, an m6A demethylase, predisposes mice to prevent high-fat diet (HFD)-induced obesity by enhancing energy expenditure. Additionally, deletion of FTO in vitro promotes thermogenesis and white-to-beige adipocyte transition. Mechanistically, FTO deficiency increases the m6A level of Hif1a mRNA, which is recognized by m6A-binding protein YTHDC2, facilitating mRNA translation and increasing HIF1A protein abundance. HIF1A activates the transcription of thermogenic genes, including Ppaggc1a, Prdm16, and Pparg, thereby promoting Ucp1 expression and the browning process. Collectively, these results unveil an epigenetic mechanism by which m6A-facilitated HIF1A expression controls browning of white adipocytes and thermogenesis, providing a potential target to counteract obesity and metabolic disease.

mRNA m5C controls adipogenesis by promoting CDKN1A mRNA export and translation.

5-Methylcytosine (m5C) is a type of RNA modification that exists in tRNAs and rRNAs and was recently found in mRNA. Although mRNA m5C modification has been reported to regulate diverse biological process, its function in adipogenesis remains unknown. Here, we demonstrated that knockdown of NOL1/NOP2/Sun domain family member 2 (NSUN2), a m5C methyltransferase, increased lipid accumulation of 3T3-L1 preadipocytes through accelerating cell cycle progression during mitotic clonal expansion (MCE) at the early stage of adipogenesis. Mechanistically, we proved that NSUN2 directly targeted cyclin-dependent kinase inhibitor 1A (CDKN1A) mRNA, a key inhibitory regulator of cell cycle progression, and upregulated its protein expression in an m5C-dependent manner. Further study identified that CDKN1A was the target of Aly/REF export factor (ALYREF), a reader of m5C modified mRNA. Upon NSUN2 deficiency, the recognition of CDKN1A mRNA by ALYREF was suppressed, resulting in the decrease of CDKN1A mRNA shuttling from nucleus to cytoplasm. Thereby, the translation of CDKN1A was reduced, leading to the acceleration of cell cycle and the promotion of adipogenesis. Together, these findings unveiled an important function and mechanism of the m5C modification on adipogenesis by controlling cell cycle progression, providing a potential therapeutic target to prevent obesity.

Curcumin prevents obesity by targeting TRAF4-induced ubiquitylation in m6 A-dependent manner.

Obesity has become a major health problem that has rapidly prevailed over the past several decades worldwide. Curcumin, a natural polyphenolic compound present in turmeric, has been shown to have a protective effect on against obesity and metabolic diseases. However, its underlying mechanism remains largely unknown. Here, we show that the administration of curcumin significantly prevents HFD-induced obesity and decreases the fat mass of the subcutaneous inguinal WAT (iWAT) and visceral epididymal WAT (eWAT) in mice. Mechanistically, curcumin inhibits adipogenesis by reducing the expression of AlkB homolog 5 (ALKHB5), an m6 A demethylase, which leads to higher m6 A-modified TNF receptor-associated factor 4 (TRAF4) mRNA. TRAF4 mRNA with higher m6 A level is recognized and bound by YTHDF1, leading to enhanced translation of TRAF4. TRAF4, acting as an E3 RING ubiquitin ligase, promotes degradation of adipocyte differentiation regulator PPARγ by a ubiquitin-proteasome pathway thereby inhibiting adipogenesis. Thus, m6 A-dependent TRAF4 expression upregulation by ALKBH5 and YTHDF1 contributes to curcumin-induced obesity prevention. Our findings provide mechanistic insights into how m6 A is involved in the anti-obesity effect of curcumin.

Effect of citalopram on hippocampal volume in first-episode schizophrenia: Structural MRI results from the DECIFER trial.

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.

Association of Aripiprazole With Reduced Hippocampal Atrophy During Maintenance Treatment of First-Episode Schizophrenia.

PURPOSE/BACKGROUND: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. METHODS/PROCEDURES: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). FINDINGS/RESULTS: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. IMPLICATIONS/CONCLUSIONS: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.

Effect of DAOA genetic variation on white matter alteration in corpus callosum in patients with first-episode schizophrenia.

D-amino acid oxidase activator (DAOA) gene, which plays a crucial role in the process of glutamatergic transmission and mitochondrial function, is frequently linked with the liability for schizophrenia. We aimed to investigate whether the variation of DAOA rs2391191 is associated with alterations in white matter integrity of first-episode schizophrenia (FES) patients; and whether it influences the association between white matter integrity, cognitive function and clinical symptoms of schizophrenia. Forty-six patients with FES and forty-nine healthy controls underwent DTI and were genotyped for DAOA rs2391191. Psychopathological assessments were performed by Brief Psychiatric Rating Scale (BPRS) and Scale for Assessment of Negative Symptoms (SANS). Cognitive function was assessed by MATRICS Consensus Cognitive Battery (MCCB). Schizophrenia patients presented lower fractional anisotropy (FA) and higher radial diffusivity (RD), mainly spreading over the corpus callosum and corona radiata compared with healthy controls. Compared with patients carrying G allele, patients with AA showed lower FA in the body of corpus callosum, and higher RD in the genu of corpus callosum, right superior and anterior corona radiata, and left posterior corona radiata. In patients carrying G allele, FA in body of corpus callosum was positively correlated with working memory, RD in genu of corpus callosum was negatively associated with the speed of processing, working memory, and the composite score of MCCB, while no significant correlations were found in AA homozygotes. In our study, patients with FES presented abnormal white matter integrity in corpus callosum and corona radiata. Furthermore, this abnormality was associated with the genetic variation of DAOA rs2391191, with AA homozygotes showing less white matter integrity in the corpus callosum. Our findings possibly provide further support to the evidence that DAOA regulates the process of glutamatergic neurotransmission and mitochondrial function in the pathophysiological mechanism of schizophrenia.

Air pollution and hippocampal atrophy in first episode schizophrenia.

Air pollution has recently been linked to central nervous system (CNS) diseases, possibly mediated by inflammation and oxidative stress. Hippocampal atrophy in individuals with first episode schizophrenia (FES) has also been associated with biomarkers of inflammation and oxidative stress, whereas hippocampal atrophy was not observed in matched healthy controls with similar biomarker levels of inflammation and oxidative stress. Fine particulate matter (PM2.5), one component of air pollution, is most strongly implicated in CNS disease. The present study examined the association between PM2.5 and hippocampal volume in individuals with FES who participated in a 52-week placebo-controlled clinical trial of citalopram added to clinician-determined antipsychotic treatment at four sites in the US and China. Left hippocampal volumetric integrity (LHVI; inversely related to atrophy) was measured at baseline and week 52 using an automated highly-reliable algorithm. Mean annual PM2.5 concentrations were obtained from records compiled by the World Health Organization. The relationships between baseline LHVI and PM2.5 and change in LHVI and PM2.5 were evaluated using regression analyses. 89 participants completed imaging at baseline and 46 participants completed imaging at week 52. Mean annual PM2.5 was significantly associated with both baseline LHVI and change in LHVI after controlling for age, sex, baseline LHVI, duration of untreated psychosis and baseline antipsychotic medication dose. Air pollution may contribute to the progression of hippocampal atrophy after a first episode of illness, but these findings should be considered preliminary since other unmeasured factors may have differed between cities and contributed to the observed effect.

Parietal memory network and default mode network in first-episode drug-naïve schizophrenia: Associations with auditory hallucination.

Atypical spontaneous activities in resting-state networks may play a role in auditory hallucinations (AHs), but networks relevant to AHs are not apparent. Given the debating role of the default mode network (DMN) in AHs, a parietal memory network (PMN) may better echo cognitive theories of AHs in schizophrenia, because PMN is spatially adjacent to the DMN and more relevant to memory processing or information integration. To examine whether PMN is more relevant to AHs than DMN, we characterized these intrinsic networks in AHs with 59 first-episode, drug-naïve schizophrenics (26 AH+ and 33 AH-) and 60 healthy participants in resting-state fMRI. We separated the PMN, DMN, and auditory network (AN) using independent component analysis, and compared their functional connectivity across the three groups. We found that only AH+ patients displayed dysconnectivity in PMN, both AH+ and AH- patients exhibited dysfunctions of AN, but neither patient group showed abnormal connectivity within DMN. The connectivity of PMN significantly correlated with memory performance of the patients. Further region-of-interest analyses confirmed that the connectivity between the core regions of PMN, the left posterior cingulate gyrus and the left precuneus, was significantly lower only in the AH+ group. In exploratory correlation analysis, this functional connectivity metric significantly correlated with the severity of AH symptoms. The results implicate that compared to the DMN, the PMN is more relevant to the AH symptoms in schizophrenia, and further provides a more precise potential brain modulation target for the intervention of AH symptoms.

Anterior Hippocampal-Cortical Functional Connectivity Distinguishes Antipsychotic Naïve First-Episode Psychosis Patients From Controls and May Predict Response to Second-Generation Antipsychotic Treatment.

BACKGROUND: Converging evidence implicates the anterior hippocampus in the proximal pathophysiology of schizophrenia. Although resting state functional connectivity (FC) holds promise for characterizing anterior hippocampal circuit abnormalities and their relationship to treatment response, this technique has not yet been used in first-episode psychosis (FEP) patients in a manner that distinguishes the anterior from posterior hippocampus. METHODS: We used masked-hippocampal-group-independent component analysis with dual regression to contrast subregional hippocampal-whole brain FC between healthy controls (HCs) and antipsychotic naïve FEP patients (N = 61, 36 female). In a subsample of FEP patients (N = 27, 15 female), we repeated this analysis following 8 weeks of second-generation antipsychotic treatment and explored whether baseline FC predicted treatment response using random forest. RESULTS: Relative to HC, untreated FEP subjects displayed reproducibly lower FC between the left anteromedial hippocampus and cortical regions including the anterior cingulate and insular cortex (P < .05, corrected). Anteromedial hippocampal FC increased in FEP patients following treatment (P < .005), and no longer differed from HC. Random forest analysis showed baseline anteromedial hippocampal FC with four brain regions, namely the insular-opercular cortex, superior frontal gyrus, precentral gyrus, and postcentral gyrus predicted treatment response (area under the curve = 0.95). CONCLUSIONS: Antipsychotic naïve FEP is associated with lower FC between the anterior hippocampus and cortical regions previously implicated in schizophrenia. Preliminary analysis suggests that random forest models based on hippocampal FC may predict treatment response in FEP patients, and hence could be a useful biomarker for treatment development.

Citalopram in first episode schizophrenia: The DECIFER trial.

Antidepressants are frequently prescribed in first episode schizophrenia (FES) patients for negative symptoms or for subsyndromal depressive symptoms, but therapeutic benefit has not been established, despite evidence of efficacy in later-stage schizophrenia. We conducted a 52 week, placebo-controlled add-on trial of citalopram in patients with FES who did not meet criteria for major depression to determine whether maintenance therapy with citalopram would improve outcomes by preventing or improving negative and depressive symptoms. Primary outcomes were negative symptoms measured by the Scale for Assessment of Negative Symptoms and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia; both were analyzed by an intent-to-treat, mixed effects, area-under-the-curve analysis to assess the cumulative effects of symptom improvement and symptom prevention over a one-year period. Ninety-five patients were randomized and 52 (54%) completed the trial. Negative symptoms were reduced with citalopram compared to placebo (p = .04); the effect size of citalopram versus placebo was 0.32 for participants with a duration of untreated psychosis (DUP) of <18 weeks (median split) and 0.52 with a DUP >18 weeks. Rates of new-onset depression did not differ between groups; improvement in depressive symptoms was greater with placebo than citalopram (p = .02). Sexual side effects were more common with citalopram, but overall treatment-emergent side effects were not increased compared to placebo. In conclusion, citalopram may reduce levels of negative symptoms, particularly in patients with longer DUP, but we found no evidence of benefit for subsyndromal depressive symptoms.

Association between catechol-O-methyltransferase genetic variation and functional connectivity in patients with first-episode schizophrenia.

Dopamine in the prefrontal cortex (PFC) plays an important role in cognitive performance and regulates by catechol-O-methyltransferase (COMT) expression. To clarify the effect of COMT genotype on cognitive function in patients with schizophrenia, we performed DNA genotyping, cognitive evaluations, and functional magnetic resonance imaging (fMRI) in antipsychotic-naïve patients with first-episode schizophrenia (FES) and matched healthy control subjects. We found that all cognitive domains were impaired in patients with FES compared with healthy subjects. Moreover, COMT genotype influenced the verbal learning performance in healthy subjects, but not in patients with FES. Resting-state fMRI data revealed that patients with FES exhibited higher functional connectivity degree centrality in the medial PFC and lower degree centrality in the parietal-occipital junction than healthy subjects. Furthermore, patients with FES who were COMT Met allele carriers had higher degree centrality in the medial PFC than those with the Val/Val genotype. In contrast, in healthy controls, Met allele carriers exhibited higher degree centrality than healthy controls with the Val/Val genotype in the left hippocampus and left amygdala. There was a negative correlation between the degree centrality value in medial PFC and score of the Hopkins Verbal Learning Test-Revised (HVLT-R) in FES patients with the Met allele. Our findings suggest that COMT genotype differentially influences pathways related to cognitive performance in patients with FES versus healthy individuals, providing an important insight into schizophrenia pathophysiology.

Association of Hippocampal Atrophy With Duration of Untreated Psychosis and Molecular Biomarkers During Initial Antipsychotic Treatment of First-Episode Psychosis.

Importance: Duration of untreated psychosis (DUP) has been associated with poor outcomes in schizophrenia, but the mechanism responsible for this association is not known. Objectives: To determine whether hippocampal volume loss occurs during the initial 8 weeks of antipsychotic treatment and whether it is associated with DUP, and to examine molecular biomarkers in association with hippocampal volume loss and DUP. Design, Setting, and Participants: A naturalistic longitudinal study with matched healthy controls was conducted at Shanghai Mental Health Center. Between March 5, 2013, and October 8, 2014, 71 medication-naive individuals with nonaffective first-episode psychosis (FEP) and 73 age- and sex-matched healthy controls were recruited. After approximately 8 weeks, 31 participants with FEP and 32 controls were reassessed. Exposures: The participants with FEP were treated according to standard clinical practice with second-generation antipsychotics. Main Outcomes and Measures: Hippocampal volumetric integrity (HVI) (an automated estimate of the parenchymal fraction in a standardized hippocampal volume of interest), DUP, 13 peripheral molecular biomarkers, and 14 single-nucleotide polymorphisms from 12 candidate genes were determined. Results: The full sample consisted of 71 individuals with FEP (39 women and 32 men; mean [SD] age, 25.2 [7.7] years) and 73 healthy controls (40 women and 33 men; mean [SD] age, 23.9 [6.4] years). Baseline median left HVI was lower in the FEP group (n = 57) compared with the controls (n = 54) (0.9275 vs 0.9512; difference in point estimate, -0.020 [95% CI, -0.029 to -0.010]; P = .001). During approximately 8 weeks of antipsychotic treatment, left HVI decreased in 24 participants with FEP at a median annualized rate of -.03791 (-4.1% annualized change from baseline) compared with an increase of 0.00115 (0.13% annualized change from baseline) in 31 controls (difference in point estimate, -0.0424 [95% CI, -0.0707 to -0.0164]; P = .001). The change in left HVI was inversely associated with DUP (r = -0.61; P = .002). Similar results were found for right HVI, although the association between change in right HVI and DUP did not achieve statistical significance (r = -0.35; P = .10). Exploratory analyses restricted to the left HVI revealed an association between left HVI and markers of inflammation, oxidative stress, brain-derived neurotrophic factor, glial injury, and markers reflecting dopaminergic and glutamatergic transmission. Conclusions and Relevance: An association between longer DUP and accelerated hippocampal atrophy during initial treatment suggests that psychosis may have persistent, possibly deleterious, effects on brain structure. Additional studies are needed to replicate these exploratory findings of molecular mechanisms by which untreated psychosis may affect hippocampal volume and to determine whether these effects account for the known association between longer DUP and poor outcome.

Reduced γ-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk.

Altered γ-aminobutyric acid (GABA), glutamate (Glu) levels, and an imbalance between GABAergic and glutamatergic neurotransmissions have been involved in the pathophysiology of schizophrenia. However, it remains unclear how these abnormalities impact the onset and course of psychosis. In the present study, 21 drug-naïve subjects at ultrahigh risk for psychosis (UHR), 16 drug-naïve patients with first-episode schizophrenia (FES), and 23 healthy controls (HC) were enrolled. In vivo GABA and glutamate+glutamine (Glx) levels in the medial prefrontal cortex were measured using proton magnetic resonance spectroscopy. Medial prefrontal GABA and Glx levels in FES patients were significantly lower than those in HC and UHR, respectively. GABA and Glx levels in UHR were comparable with those in HC. In each group, there was a positive correlation between GABA and Glx levels. Reduced medial prefrontal GABA and Glx levels thus may play an important role in the early stages of schizophrenia.

Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment.

BACKGROUND: Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent. METHOD: Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8 weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons. RESULTS: At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018). CONCLUSIONS: White matter deficits were validated in the present study by a relatively large sample of medication naïve and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may provide clues to the mechanism of antipsychotic response and provide a biomarker for clinical studies.

Prolonged cortical silent period among drug-naive subjects at ultra-high risk of psychosis.

BACKGROUND: Deficits in gamma-aminobutyric acid (GABA) inhibitory neurotransmission have been associated with pathophysiological mechanisms underlying schizophrenia. However, little is known about whether these deficits occur before or after the onset of psychosis. METHOD: We recruited 16 drug-naive subjects at ultra-high risk of psychosis (UHR), 17 schizophrenia patients and 28 healthy controls. Cortical inhibition was determined using transcranial magnetic stimulation (TMS) over the left primary motor cortex. TMS markers such as short-interval cortical inhibition (SICI), cortical silent period (CSP) and intracortical facilitation (ICF) were obtained from each subject. While SICI can reflect GABA type A (GABAA) mediated inhibition, CSP is thought to indicate GABA type B (GABAB) mediated inhibitory circuits. RESULTS: As compared with healthy controls, UHR subjects showed a prolonged CSP with no change in SICI, whereas schizophrenia patients demonstrated both a prolonged CSP and a reduced SICI. No group differences were found for ICF. CSP in schizophrenia patients also had a positive correlation with positive symptom score of the positive and negative symptom scale (PANSS). CONCLUSIONS: Cortical inhibitory deficits among UHR subjects were relatively limited compared to those among schizophrenia patients. Alterations might occur in some subgroup of GABA-mediated neurotransmitter systems before the onset of psychosis, while alterations in both GABAA and GABAB networks might contribute to full-blown psychosis.