New role of platelets in schizophrenia:predicting drug response

Background Elevated platelet count(PLTc)is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis.However,the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear.Aims We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables.Methods A total of 2985 patients with schizophrenia were randomised into seven groups.Each group received one of seven antipsychotic treatments and was assessed at 2,4 and 6 weeks.Clinical symptoms were evaluated using the positive and negative syndrome scale(PANSS).Additionally,we measured blood cell counts and metabolic parameters,such as blood lipids.Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes,while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes.Results PLTc significantly increased in patients treated with aripiprazole(F=6.00,p=0.003),ziprasidone(F=7.10,p<0.001)and haloperidol(F=3.59,p=0.029).It exhibited a positive association with white blood cell count and metabolic indicators.Higher baseline PLTc was observed in non-responders,particularly in those defined by the PANSS-negative subscale.In the structural equation model,PLTc,white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores.Moreover,higher baseline PLTc was observed in individuals with less metabolic change,although this association was no longer significant after accounting for baseline metabolic values.Conclusions Platelet parameters,specifically PLTc,are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia.Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation.Given PLTc’s easy measurement and clinical relevance,it warrants increased attention from psychiatrists.Trial registration number ChiCTR-TRC-10000934.

GABAergic Abnormalities Associated with Sensorimotor Corticostriatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naive Patients with Schizophrenia

The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia.We used prepulse inhibition(PPI)and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls.Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions.Concurrently,we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in firstepisode treatment-naı¨ve schizophrenic patients(n=117)and in age-and sex-matched healthy controls(n=86).We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia.Significant correlations between gray matter volumes(GMVs)in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice.Furthermore,these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients.The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients.Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation,providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.

Testing the role of genetic variation of the MC4R gene in Chinese population in antipsychotic-induced metabolic disturbance

Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.

Interaction Between Variations in Dopamine D2 and Serotonin 2A Receptor is Associated with Short-Term Response to Antipsychotics in Schizophrenia

Dear Editor,Schizophrenia is a chronic and debilitating brain disorder,which has a strong genetic component with heritability ranging from 66%to 85%[1,2].Currently,antipsychotic drugs remain the most effective treatment for the psychotic symptoms of schizophrenia[3].Because of the severe sideeffects of first-generation antipsychotics(FGAs),secondgeneration antipsychotics(SGAs)have become more widely used in the treatment of schizophrenia.

Genes in the serotonin pathway are associated with bipolar affective disorder in a Han Chinese population

Serotonin plays an important role in mood regulation, but the involvement of serotonin pathway genes in the development of bipolar I disorder. （BP-I）, a mood disorder, is not clear. We selected 21 single- nucleotide polymorphisms （SNPs） within the HTR2A gene, 8 within the SLC6A4 gene and 23 within the TPH2 gene for genotyping using the GoldenGate genotyping assay. A total of 375 patients with BP-I and 475 normal controls were recruited. Two out of 21 SNPs （rs1475196 and rs9567747） in the HTR2A gene and 1/23 SNPs （rs17110566） in the TPH2 gene were significantly associated with BP-I, both genotype-wise and allele-wise. Furthermore, a specific haplotype in the HTR2A gene showed a significant association with BP-I. Our results indicate that the HTR2A and TPH2 genes in the serotonin pathway play important roles in susceptibility to BP-I.

Disrupted association between structural and functional coupling of the supplementary motor area and neurocognition in major depressive disorder

To the Editor:Major depressive disorder(MDD)is a common mood disorder that contributes considerably to disability worldwide.Abnormalities in either structural connectivity or functional connectivity in the brains of patients with MDD have been widely reported,which greatly extends our knowledge of the pathophysiology of MDD.