EMDR versus waiting list in individuals at clinical high risk for psychosis with post-traumatic stress symptoms: A randomized controlled trial.

BACKGROUND: Post-traumatic stress disorder (PTSD) is highly prevalent in the individuals at clinical-high risk for psychosis (CHR). The aim of this study was to examine the efficacy and safety of Eye Movement Desensitization and Reprocessing (EMDR) in individuals at CHR with comorbid PTSD or subthreshold PTSD in a randomized controlled trial. METHODS: Fifty-seven individuals at CHR with PTSD or subthreshold PTSD formed the study sample. The eligible participants were randomly assigned to a 12 weeks EMDR treatment (N = 28) or a waiting list condition (WL, N = 29). The structured interview for psychosis risk syndrome (SIPS), the clinician administered post-traumatic stress disorder scale (CAPS) and a battery of self-rating inventories covering depressive, anxiety and suicidal symptoms were administered. RESULTS: Twenty-six participants in the EMDR group and all the participants in the WL group completed the study. The analyses of covariance revealed greater reduction of the mean scores on CAPS (F = 23.2, Partial η2 = 0.3, P < 0.001), SIPS positive scales (F = 17.8, Partial η2 = 0.25, P < 0.001) and all the self-rating inventories in the EMDR group than in the WL group. Participants in the EMDR group were more likely to achieve remission of CHR compared to those in the WL group at endpoint (60.7 % vs. 31 %, P = 0.025). CONCLUSIONS: EMDR treatment not only effectively improved traumatic symptoms, but also significantly reduced the attenuated psychotic symptoms and resulted in a higher remission rate of CHR. This study highlighted the necessity of adding a trauma-focused component to the present approach of early intervention in psychosis.

[Nitrogen and Phosphorus Leaching Characteristics and Adsorption Properties of Hardwood Biochar in Stormwater Runoff].

At present, the fillers used in bioremanent systems are limited by problems such as unstable leaching and adsorption of nitrogen and phosphorus. To assess the feasibility of using hardwood biochar as a filter filler material in bioretention systems, it was compared to traditional filter filler materials, namely coconut chaff, compost, ceramsite, and volcanic stone. Experiments and tests were conducted to study the physico-chemical properties, leaching, and adsorption characteristics of hardwood biochar, and to explore the optimizing effect and mechanism of hardwood biochar in bioretention systems. Hardwood biochar created through high temperature pyrolysis was found to be porous and loose, with a saturated moisture content of 195.65% and good water retention capacity. After pyrolysis, the nitrogen and phosphorus elements on the hardwood biochar surface were converted into stable compounds. In a batch leaching experiment, the quantity of leached nitrogen was low, and the leaching speed was fast; phosphorus leaching was slow, although the linear negative value increased during artificial rainwater runoff leaching, and the adsorption effect was stable. When exposed to typical nitrogen and phosphorous concentrations in rainwater runoff (2 mg·L-1 of NH4+ and 2 mg·L-1 of PO43-), hardwood biochar adsorbed 34.6 mg·kg-1 NH4+ and 59.5 mg·kg-1 PO43-, showing outstanding comprehensive adsorption capacity. After reaching adsorption equilibrium, the average desorption rates of the hardwood biochar in deionized water were 21.23% and 17.43%, proving that the adsorption effect was stable. In conclusion, the application of hardwood biochar can mitigate excessive leaching of nutrients from fillers, as it has a better adsorption capacity for nitrogen and phosphorus. Therefore, hardwood biochar can be used as the filler material in bioretention systems, to reduce pollution associated with rainwater runoff.

Classification of First-Episode Schizophrenia, Chronic Schizophrenia and Healthy Control Based on Brain Network of Mismatch Negativity by Graph Neural Network.

Mismatch negativity (MMN) has been consistently found deficit in schizophrenia, which was considered as a promising biomarker for assessing the impairments in pre-attentive auditory processing. However, the functional connectivity between brain regions based on MMN is not clear. This study provides an in-depth investigation in brain functional connectivity during MMN process among patients with first-episode schizophrenia (FESZ), chronic schizophrenia (CSZ) and healthy control (HC). Electroencephalography (EEG) data of 128 channels is recorded during frequency and duration MMN in 40 FESZ, 40 CSZ patients and 40 matched HC subjects. We reconstruct the cortical endogenous electrical activity from EEG recordings using exact low-resolution electromagnetic tomography and build functional brain networks based on source-level EEG data. Then, graph-theoretic features are extracted from the brain networks with the support vector machine (SVM) to classify FESZ, CSZ and HC groups, since the SVM has good generalization ability and robustness as a universally applicable nonlinear classifier. Furthermore, we introduce the graph neural network (GNN) model to directly learn for the network topology of brain network. Compared to HC, the damaged brain areas of CSZ are more extensive than FESZ, and the damaged area involved the auditory cortex. These results demonstrate the heterogeneity of the impacts of schizophrenia for different disease courses and the association between MMN and the auditory cortex. More importantly, the GNN classification results are significantly better than those of SVM, and hence the EEG-based GNN model of brain networks provides an effective method for discriminating among FESZ, CSZ and HC groups.

The Impact of Smoking, Sex, Infection, and Comedication Administration on Oral Olanzapine: A Population Pharmacokinetic Model in Chinese Psychiatric Patients.

BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting. METHODS: A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate. RESULTS: Typical estimates for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h-1, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model's performance was good, stable, and precise. CONCLUSION: This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.

This study included a total of 1546 serum olanzapine concentrations from 354 Chinese adult psychiatric patients that were analyzed by a complex mathematical model. The goal was to explore how oral olanzapine is eliminated from the body in Chinese psychiatric patients and how to personalize its dosing. Prior studies using similar complex mathematical models only studied the effects of sex and smoking on olanzapine elimination. This study also investigated the influence of co-occurrence of infection and comedications, including dangguilonghui tablets. This is a Chinese herbal medicine used to treat constipation, including constipation secondary to olanzapine treatment. Olanzapine elimination was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine elimination was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. This study contributes to the improvement of oral olanzapine dosing personalization, but further studies are needed to verify the effects of infection and comedications, including valproate and dangguilonghui.

Prepulse inhibition in first-degree relatives of schizophrenia patients: A systematic review.

BACKGROUND: Prepulse inhibition (PPI) is a measure of sensorimotor gating used to identify deficits in early-stage information processing and inhibitory function defects. Many studies support the presence of PPI deficits in schizophrenia patients. However, very few studies have explored PPI levels among first-degree relatives (FDR) of schizophrenia patients, and the results have been inconsistent. This review article explored PPI levels in FDR of schizophrenia patients. METHODS: We performed a systematic literature review using the PubMed, Cochrane, Embase, EBSCO and Chinese databases from inception to January 2020. A series of related factors (eg, PPI paradigm, heritability and sample characteristics) and outcomes were summarized from the literature that met the inclusion criteria. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. RESULTS: A total of eight studies were eligible for systematic review after screening. A meta-analysis of the selected studies was not conducted due to the limitations of quantity and paradigm heterogeneity. A majority of the studies' subjects were siblings of schizophrenia patients and different paradigms were applied. Most of the included studies reported no difference in PPI values between FDR of schizophrenia patients and healthy controls. CONCLUSION: Contrary to traditional certainty that unaffected FDR of schizophrenia patients have PPI defects, our review found no sufficient evidence supporting that the PPI level in FDR of schizophrenia patients was lower than in healthy controls. A prospective cohort study focusing on different outcomes such as developing schizophrenia is required to explore PPI levels in FDR of schizophrenia patients.

Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples: They Ranged Between 2% and 13.

PURPOSE/BACKGROUND: Clozapine clearance is influenced by sex, smoking status, ethnicity, coprescription of inducers or inhibitors, obesity, and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 SDs beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalence of PMs and UMs using data from 4 already published Asian samples. Three samples were East Asian (Beijing 2, Taipei, and Seoul); one was from South India (Vellore). FINDINGS/RESULTS: The prevalence of phenotypical PMs ranged from 2% to 13%, but inflammation was not excluded. The prevalence was 7% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypic PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0% to 1.6% but may be partly explained by lack of adherence. A Vellore phenotypic UM appeared to be associated with induction through high coffee intake. IMPLICATIONS/CONCLUSIONS: Approximately 10% of Asians may be clozapine PMs and may need only 50 to 150 mg/d to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation, and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings, and multiple serum concentrations.

Impact of childhood trauma on sensory gating in patients with first-episode schizophrenia.

BACKGROUND: Childhood trauma (CT) has been found to contribute to the onset of schizophrenia and auditory sensory gating deficit is a leading endophenotype for schizophrenia. However, the association between the CT and sensory gating in first-episode schizophrenia remains elusive. METHODS: Fifty-six patients and 49 age and sex-matched healthy controls were assessed using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) for CT and Positive and Negative Syndrome Scale (PANSS) for symptoms severity. Sensory gating was tested using the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS-PPI), and the perceived spatial co-location PPI (PSC-PPI or classical PPI). RESULTS: Comparing with healthy controls, the patients had significantly higher score on sexual abuse (t = 2.729, p < 0.05), lower PSS- PPI, % (ISI = 120 ms and ISI = 60 ms) (t = - 3.089, - 4.196, p < 0.05). Univariate analysis revealed the absence of a significant correlation among CT, PPI paradigms and symptoms. However, multiple linear regression analyses demonstrated the CTQ-SF total was negatively associated with PSS PPI (ISI = 120 ms) (p = 0.018). CONCLUSION: The current study illustrates that the impact of CT on sensory gating in patients with first-episode schizophrenia, and thus we conclude that CT may be a risk factor to the occurrence of schizophrenia through its impact on sensory gating.

Impact of childhood trauma on sensorimotor gating in Chinese patients with chronic schizophrenia.

We investigated the relationship between childhood trauma (CT) and sensorimotor gating in Chinese patients diagnosed with chronic schizophrenia. Seventy-five patients were assessed with the Childhood Trauma Questionnaire-Short Form (CTQ-SF), and then the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS PPI) and the perceived spatial co-location PPI (PSC PPI or classical PPI) were applied to test sensorimotor gating. Startling stimuli (90 dB) were presented either alone or preceded by discrete prepulse stimuli of 4 dB in a background 60-dB noise level. Associations between CT and various PPI paradigms were statistically analyzed. Univariate analysis revealed the absence of a significant correlation between CT and PPI paradigms (p > 0.05). However, multiple linear regression analyses revealed that sexual abuse and the positive and negative syndrome scale (PANSS) score were negatively correlated with PSS PPI (p = 0.029 and 0.008, respectively). On the other hand, female sex and history of smoking were positively correlated with PSS PPI (p = 0.044 and 0.043, respectively). In conclusion, the results of this study suggest that CT can be a predisposing factor that affects sensorimotor gating in schizophrenia patients.

Peony-Glycyrrhiza Decoction for Antipsychotic-Related Hyperprolactinemia in Women With Schizophrenia: A Randomized Controlled Trial.

OBJECTIVES: An herbal preparation called peony-glycyrrhiza decoction (PGD) may have the potential in reducing antipsychotic-related hyperprolactinemia (hyperPRL). This double-blind, randomized placebo-controlled study aimed to reevaluate the efficacy of PGD against antipsychotic-related hyperPRL. METHODS: Ninety-nine schizophrenic women who were under antipsychotic therapy and had symptomatic hyperPRL were randomly assigned to additional treatment with placebo (n = 50) or PGD (n = 49, 45 g/d) for 16 weeks. The severity of hyperPRL, psychosis, and abnormal involuntary movements was assessed at baseline and weeks 8 and 16 using standard instruments including the Prolactin Related Adverse Event Questionnaire. Blood levels of prolactin (PRL) and related pituitary and sex hormones were measured at the same time points. RESULTS: Peony-glycyrrhiza decoction treatment produced a significantly greater reduction of the Prolactin Related Adverse Event Questionnaire score at weeks 8 and 16 and a greater improvement on abnormal involuntary movements at end point compared with placebo, without altering the severity of psychosis. The group treated with PGD showed significantly higher proportion of having overall improvement on hyperPRL symptoms (χ = 4.010, P = 0.045) and menstrual resumption (χ = 4.549, P = 0.033) at week 8 than placebo. Serum PRL levels were similar in the 2 groups. CONCLUSIONS: Peony-glycyrrhiza decoction is effective in reducing antipsychotic-related hyperPRL and abnormal involuntary movement symptoms, but no reduction in blood PRL concentrations was observed. The underlying mechanisms of PGD's effects need further investigation (trial registration of NCT01852331 at www.clinicaltrials.gov).

Peony-Glycyrrhiza Decoction, an Herbal Preparation, Inhibits Clozapine Metabolism via Cytochrome P450s, but Not Flavin-Containing Monooxygenase in In Vitro Models.

Our previous studies have shown the therapeutic efficacy and underlying mechanisms of Peony-Glycyrrhiza Decoction (PGD), an herbal preparation, in treating antipsychotic-induced hyperprolactinemia in cultured cells, animal models, and human subjects. In the present study, we further evaluated pharmacokinetic interactions of PGD with clozapine (CLZ) in human liver microsomes (HLM), recombinantly expressed cytochrome P450s (P450s), and flavin-containing monooxygenases (FMOs). CLZ metabolites, N-demethyl-clozapine and clozapine-N-oxide, were measured. PGD, individual peony and glycyrrhiza preparations, and the two individual preparations in combination reduced production of CLZ metabolites to different extents in HLM. While the known bioactive constituents of PGD play a relatively minor role in the kinetic effects of PGD on P450 activity, PGD as a whole had a weak-to-moderate inhibitory potency toward P450s, in particular CYP1A2 and CYP3A4. FMOs are less actively involved in mediating CLZ metabolism and the PGD inhibition of CLZ. These results suggest that PGD has the capacity to suppress CLZ metabolism in the human liver microsomal system. This suppression is principally associated with the inhibition of related P450 activity but not FMOs. The present study provides in vitro evidence of herb-antipsychotic interactions.

An epidemiological study of concomitant use of Chinese medicine and antipsychotics in schizophrenic patients: implication for herb-drug interaction.

BACKGROUND: Herb-drug interactions are an important issue in drug safety and clinical practice. The aim of this epidemiological study was to characterize associations of clinical outcomes with concomitant herbal and antipsychotic use in patients with schizophrenia. METHODS AND FINDINGS: In this retrospective, cross-sectional study, 1795 patients with schizophrenia who were randomly selected from 17 psychiatric hospitals in China were interviewed face-to-face using a structured questionnaire. Association analyses were conducted to examine correlates between Chinese medicine (CM) use and demographic, clinical variables, antipsychotic medication mode, and clinical outcomes. The prevalence of concomitant CM and antipsychotic treatment was 36.4% [95% confidence interval (95% CI) 34.2%-38.6%]. Patients using concomitant CM had a significantly greater chance of improved outcomes than non-CM use (61.1% vs. 34.3%, OR = 3.44, 95% CI 2.80-4.24). However, a small but significant number of patients treated concomitantly with CM had a greater risk of developing worse outcomes (7.2% vs. 4.4%, OR = 2.06, 95% CI 2.06-4.83). Significant predictors for concomitant CM treatment-associated outcomes were residence in urban areas, paranoid psychosis, and exceeding 3 months of CM use. Herbal medicine regimens containing Radix Bupleuri, Fructus Gardenia, Fructus Schisandrae, Radix Rehmanniae, Akebia Caulis, and Semen Plantaginis in concomitant use with quetiapine, clozapine, and olanzepine were associated with nearly 60% of the risk of adverse outcomes. CONCLUSIONS: Concomitant herbal and antipsychotic treatment could produce either beneficial or adverse clinical effects in schizophrenic population. Potential herb-drug pharmacokinetic interactions need to be further evaluated.

A randomized, crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia.

Hyperprolactinemia is a common adverse effect that occurs as a result of antipsychotic therapies, which often results in discontinuation. Empirical evidence has shown that some herbal medicines have suppressive effects on prolactin (PRL) hyperactivities. This study was designed to compare the herbal preparation called Peony-Glycyrrhiza Decoction (PGD) with bromocriptine (BMT), a dopamine agonist widely used for PRL-secreting disorders, in the treatment of risperidone-induced hyperprolactinemia. Twenty schizophrenic women who were under risperidone maintenance treatment, diagnosed with hyperprolactinemia (serum PRL levels >50 mug/L), and currently experiencing oligomenorrhea or amenorrhea were selected for the study. Subjects were randomized to additional treatment with PGD (45 g/d) followed by BMT (5 mg/d) or BMT followed by PGD at the same doses for 4 weeks each, with an interval of 4-week washout period between 2 treatment sessions. The severity of psychotic symptoms, adverse events, serum PRL, estradiol, testosterone, and progesterone levels were examined at baseline and end point. Peony-Glycyrrhiza Decoction treatment produced a significant baseline-end point decrease in serum PRL levels, without exacerbating psychosis and changing other hormones, and the decreased amplitudes were similar to those of BMT (24% vs 21%-38%). Moreover, there was a significantly greater proportion of patients during PGD treatment than BMT treatment showing improvements on adverse effects associated with hyperprolactinemia (56% vs 17%, P = 0.037). These results suggest that the herbal therapy can yield additional benefits while having comparable efficacy in treating antipsychotic-induced hyperprolactinemia in individuals with schizophrenia.