Modeling Approach with Therapeutic Drug Monitoring Data to Describe Time Course of Clozapine Exposure and Positive and Negative Syndrome Scale Scores.

OBJECTIVE: The Positive and Negative Syndrome Scale (PANSS) is commonly used to assess the severity of the clinical symptoms of schizophrenia (SCZ). This study aimed to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model based on therapeutic drug monitoring (TDM) data to characterize the relationship between clozapine exposure and the PANSS scores in patients with SCZ. METHODS: TDM data for clozapine and PANSS scores from 45 patients with SCZ were included in this modeling analysis using NONMEM. Based on published data, intensive PK sampling data collected up to 12 hours postdose from 23 patients was incorporated into the PK data set to improve the fitting of absorption and disposition. For PD model development, the PANSS score was assessed at baseline, followed by 8 and 18 weeks after the initiation of clozapine dosing. Visual predictive check plots, the precision of parameter estimates, and decreases in the minimum objective function values were used for the model evaluation. RESULTS: A 2-compartment model with an absorption lag and a combined error model adequately described the PK of clozapine. The implementation of disease progression with placebo and drug effects improved the model's ability to describe the time course of the PANSS scores. In the final PK/PD model, Weibull and maximum effect (E max ) models were selected as disease progression models for the placebo and drug effect models, respectively. The model evaluation results supported the adequacy of the final model. CONCLUSIONS: A clozapine PK/PD model based on clinical settings adequately described the PANSS time course in patients with SCZ. These findings may aid the development of treatment strategies for patients with SCZ.

Surface Passivation of Layered MoSe2 via van der Waals Stacking of Amorphous Hydrocarbon.

Development of efficient surface passivation methods for semiconductor devices is crucial to counter the degradation in their electrical performance owing to scattering or trapping of carriers in the channels induced by molecular adsorption from the ambient environment. However, conventional dielectric deposition involves the formation of additional interfacial defects associated with broken covalent bonds, resulting in accidental electrostatic doping or enhanced hysteretic behavior. In this study, centimeter-scaled van der Waals passivation of transition metal dichalcogenides (TMDCs) is demonstrated by stacking hydrocarbon (HC) dielectrics onto MoSe2 field-effect transistors (FETs), thereby enhancing the electric performance and stability of the device, accompanied with the suppression of chemical disorder at the HC/TMDCs interface. The stacking of HC onto MoSe2 FETs enhances the carrier mobility of MoSe2 FET by over 50% at the n-branch, and a significant decrease in hysteresis, owing to the screening of molecular adsorption. The electron mobility and hysteresis of the HC/MoSe2 FETs are verified to be nearly intact compared to those of the fabricated HC/MoSe2 FETs after exposure to ambient environment for 3 months. Consequently, the proposed design can act as a model for developing advanced nanoelectronics applications based on layered materials for mass production.

Longitudinal symptom network structure in first-episode psychosis: a possible marker for remission.

BACKGROUND: Network approach has been applied to a wide variety of psychiatric disorders. The aim of the present study was to identify network structures of remitters and non-remitters in patients with first-episode psychosis (FEP) at baseline and the 6-month follow-up. METHODS: Participants (n = 252) from the Korean Early Psychosis Study (KEPS) were enrolled. They were classified as remitters or non-remitters using Andreasen's criteria. We estimated network structure with 10 symptoms (three symptoms from the Positive and Negative Syndrome Scale, one depressive symptom, and six symptoms related to schema and rumination) as nodes using a Gaussian graphical model. Global and local network metrics were compared within and between the networks over time. RESULTS: Global network metrics did not differ between the remitters and non-remitters at baseline or 6 months. However, the network structure and nodal strengths associated with positive-self and positive-others scores changed significantly in the remitters over time. Unique central symptoms for remitters and non-remitters were cognitive brooding and negative-self, respectively. The correlation stability coefficients for nodal strength were within the acceptable range. CONCLUSION: Our findings indicate that network structure and some nodal strengths were more flexible in remitters. Negative-self could be an important target for therapeutic intervention.

The relationship between grey matter volume and striatal dopamine function in psychosis: a multimodal 18F-DOPA PET and voxel-based morphometry study.

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.

Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis.

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as Kicer value using [18F]DOPA PET before and 6 weeks after antipsychotic discontinuation. The D2/3 receptor availability was measured as BPND using [11C]raclopride PET after antipsychotic discontinuation. Healthy controls also underwent PET scans according to the corresponding schedule of the patients. Patients were monitored for psychotic relapse during 12 weeks after antipsychotic discontinuation. 40% of the patients showed psychotic relapse after antipsychotic discontinuation. The change in Kicer value over time significantly differed between relapsed, non-relapsed patients and healthy controls (Week*Group: F = 4.827, df = 2,253.193, p = 0.009). In relapsed patients, a significant correlation was found between baseline striatal Kicer values and time to relapse after antipsychotic discontinuation (R2 = 0.518, p = 0.018). BPND were not significantly different between relapsed, non-relapsed patients and healthy controls (F = 1.402, df = 2,32.000, p = 0.261). These results suggest that dysfunctional dopamine autoregulation might precipitate psychotic relapse after antipsychotic discontinuation in FEP. This finding could be used for developing a strategy for the prevention of psychotic relapse related to antipsychotic discontinuation.

Distinct neural networks associated with obsession and delusion: a connectome-wide association study.

BACKGROUND: Obsession and delusion are theoretically distinct from each other in terms of reality testing. Despite such phenomenological distinction, no extant studies have examined the identification of common and distinct neural correlates of obsession and delusion by employing biologically grounded methods. Here, we investigated dimensional effects of obsession and delusion spanning across the traditional diagnostic boundaries reflected upon the resting-state functional connectivity (RSFC) using connectome-wide association studies (CWAS). METHODS: Our study sample comprised of 96 patients with obsessive-compulsive disorder, 75 patients with schizophrenia, and 65 healthy controls. A connectome-wide analysis was conducted to examine the relationship between obsession and delusion severity and RFSC using multivariate distance-based matrix regression. RESULTS: Obsession was associated with the supplementary motor area, precentral gyrus, and superior parietal lobule, while delusion was associated with the precuneus. Follow-up seed-based RSFC and modularity analyses revealed that obsession was related to aberrant inter-network connectivity strength. Additional inter-network analyses demonstrated the association between obsession severity and inter-network connectivity between the frontoparietal control network and the dorsal attention network. CONCLUSIONS: Our CWAS study based on the Research Domain Criteria (RDoC) provides novel evidence for the circuit-level functional dysconnectivity associated with obsession and delusion severity across diagnostic boundaries. Further refinement and accumulation of biomarkers from studies embedded within the RDoC framework would provide useful information in treating individuals who have some obsession or delusion symptoms but cannot be identified by the category of clinical symptoms alone.

In vivo gamma-aminobutyric acid-A/benzodiazepine receptor availability and genetic liability in asymptomatic individuals with high genetic loading of schizophrenia: A [11C]flumazenil positron emission tomography study.

OBJECTIVES: Whilst reduced signalling and gene expression related to gamma-aminobutyric acid (GABA) play a role in the presumed pathophysiology of schizophrenia, its origin is unclear. Studying asymptomatic individuals with high genetic liability to schizophrenia (AIs) would provide insights. Therefore, this study aimed to investigate the role of genetic liability in GABAergic dysfunction of schizophrenia by exploring in vivo GABA-A/benzodiazepine receptor (GABAR) availability in AIs. METHODS: A total of 10 AIs with multiple relatives diagnosed as schizophrenia and 11 healthy controls underwent [11C]flumazenil positron emission tomography and neurocognitive function tests. RESULTS: There was no significant difference in [11C]flumazenil availability based on the groups. GABAR availability in caudate nuclei had positive correlations with genetic liability of AIs. GABAR availability in caudate nuclei and verbal memory measures of AIs revealed positive correlations. Only the correlation between right caudate and short-term verbal memory survived multiple-comparison correction (p = 0.030). CONCLUSIONS: This study, for the first time, reports correlations between the genetic liability of schizophrenia and GABAR availability. Correlations between [11C]flumazenil binding in caudate of individuals with high genetic liability to schizophrenia suggests that the GABAergic dysfunction may arise from shared genetic factors and also that it may be responsible for cognitive impairment of AIs.

Occurrence of metabolic diseases associated with antipsychotic use among Korean patients with schizophrenia.

OBJECTIVE: Metabolic side effects of antipsychotics significantly affect adherence to medication. We aimed to identify factors associated with the occurrence of metabolic diseases among Korean patients with schizophrenia (SCZ) from the national health insurance system database. We evaluated the frequency of antidiabetic and antihyperlipidemic use after diagnosis of SCZ according to typical or atypical antipsychotic use. MATERIALS AND METHODS: Among the 43,800 patients diagnosed with SCZ between 2008 and 2012, 29,591 patients who had no metabolic diseases before the diagnosis were included in the analysis to investigate the occurrence of metabolic diseases associated with antipsychotic use. The associations between the development of metabolic diseases and patient characteristics were evaluated using logistic regression analysis. RESULTS: Use of both typical and atypical antipsychotics (multivariate-adjusted odds ratio (OR), 1.2513; 95% confidence interval (CI), 1.0953 - 1.4294) was associated with higher incidence of metabolic diseases than without their use. Among the atypical antipsychotics, use of clozapine (multivariate-adjusted OR, 1.1959; 95% CI, 1.0086 - 1.4179) and quetiapine (multivariate-adjusted OR, 1.1284; 95% CI, 1.0446 - 1.2189) showed higher incidence of metabolic diseases compared to that without their use. Among the patients using ≥ 1 type of antidiabetic or antihyperlipidemic agents within 6 years after diagnosis of SCZ, the proportion of patients using only atypical antipsychotics was greater than those using only typical antipsychotics. CONCLUSION: The use of both typical and atypical antipsychotics, and clozapine and quetiapine treatment, may be associated with the occurrence of metabolic diseases in patients with SCZ. Additional prospective studies with accurate dosage information are needed to validate our findings.

A Prospective Study for Prediction of Psychotic Relapse Using the Korean Early Signs Scale in Patients With Schizophrenia.

INTRODUCTION: A psychotic relapse of schizophrenia is commonly preceded by nonpsychotic behavioral symptoms and signs, and detection of these early signs may enable prevention of relapse of schizophrenia. This study aimed to test the predictive validity of a Korean version of Early Signs Scale (K-ESS) for psychotic relapse for detecting the early signs. MATERIALS AND METHODS: In this multicenter noninterventional 52-week prospective study, outpatients diagnosed as having schizophrenia within 5 years were recruited. The K-ESS and Clinical Global Impression-Severity (CGI-S) scale were administered monthly until the end of the study or the relapse. The primary objective was to determine an optimal cutoff point of K-ESS score for prediction of psychotic relapse. The secondary objective was to assess the concurrent validity of the K-ESS using CGI-S scale. RESULTS: Among the 162 included patients, 14 (8.6%) relapsed during the 52-week study period. The optimal cutoff score of K-ESS was 15 with a sensitivity of 71.43% and a specificity of 52.70%, indicating poor predictive accuracy of K-ESS. A lower cutoff K-ESS score of 3 and a higher cutoff score of 28 were found in the subgroups with milder (CGI-S = 1-2) and severer (CGI-S = 3-4) symptom severity, respectively, with fair to good predictive accuracy. The K-ESS showed acceptable concurrent validity with CGI-S and concordance rate between self-rated and informant-rated scores. DISCUSSION: The predictive accuracy of K-ESS was limited by evaluation interval of a month. At least fortnightly follow-up would be needed for detection of early signs to prevent a psychotic relapse in schizophrenia.

Defect-Induced Gas-Sensing Properties of a Flexible SnS Sensor under UV Illumination at Room Temperature.

Tin sulfide (SnS) is known for its effective gas-detecting ability at low temperatures. However, the development of a portable and flexible SnS sensor is hindered by its high resistance, low response, and long recovery time. Like other chalcogenides, the electronic and gas-sensing properties of SnS strongly depend on its surface defects. Therefore, understanding the effects of its surface defects on its electronic and gas-sensing properties is a key factor in developing low-temperature SnS gas sensors. Herein, using thin SnS films annealed at different temperatures, we demonstrate that SnS exhibits n-type semiconducting behavior upon the appearance of S vacancies. Furthermore, the presence of S vacancies imparts the n-type SnS sensor with better sensing performance under UV illumination at room temperature (25 °C) than that of a p-type SnS sensor. These results are thoroughly investigated using various experimental analysis techniques and theoretical calculations using density functional theory. In addition, n-type SnS deposited on a polyimide substrate can be used to fabricate high-stability flexible sensors, which can be further developed for real applications.

Frontostriatal functional connectivity and striatal dopamine synthesis capacity in schizophrenia in terms of antipsychotic responsiveness: an [18F]DOPA PET and fMRI study.

BACKGROUND: Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine. METHODS: Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans. RESULTS: No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups. CONCLUSIONS: The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

Higher serotonin transporter availability in early-onset obsessive-compulsive disorder patients undergoing escitalopram treatment: A [11 C]DASB PET study.

OBJECTIVE: Early-onset obsessive-compulsive disorder (EOCD) and late-onset obsessive-compulsive disorder (LOCD) are distinct subtypes of obsessive-compulsive disorder (OCD). OCD patients are treated with serotonin reuptake inhibitors, but the difference in serotonin transporter (SERT) availability between medicated EOCD and LOCD is unexplored yet. METHODS: Six EOCD and 6 LOCD patients were enrolled. They underwent serial [11 C]DASB positron emission tomography scans during maintenance therapy with escitalopram, and their plasma concentration of escitalopram was measured simultaneously with the scan. Then, the drug-free binding potential of SERT was calculated by pharmacokinetic-pharmacodynamic modelling. RESULTS: In comparison with LOCD patients, SERT availability was significantly higher in the putamen of EOCD patients (U = 4, p = .026), but not in the caudate nucleus (U = 14, p = .589), thalamus (U = 16, p = .818), and dorsal raphe nucleus (U = 7, p = .093). Binding potential of putamen showed a negative correlation (r = -.580, p = .048) with age of onset of the disease, but not with the Yale-Brown Obsessive Compulsive Scale scores. CONCLUSIONS: These findings indicate that the earlier the age of onset of OCD, the less serotonergic pathology there is and that this difference remains even after long-term serotonin reuptake inhibitor treatment. Clinically, it might suggest that nonserotonergic treatments would be a better option for EOCD patients.

Efficient strategy for obtaining reliable pharmacokinetic parameters in population compartmental approaches.

OBJECTIVE: This study aimed to suggest efficient strategies for obtaining reliable pharmacokinetic (PK) parameters in population compartmental approach (PCA) a early-phase or resource-limited clinical trials with limited data. METHODS: This study employed plasma concentration of olanzapine, an antipsychotic drug, from a bioequivalence study. To assess bias and precision of PK parameters that were estimated from limited data, this study utilized simulations with the generation of small-size datasets (SSD) and minimal-sampling datasets (MSD) that consisted of limited volunteers and PK samplings per volunteer, respectively. RESULTS: Clearance (CL) estimates were the most robust, volume of the central (Vc) and peripheral compartment (Vp) were moderately affected, and absorption rate constant (Ka) and intercompartmental clearance (Q) were very sensitive with limited dataset. MSD had more impact on the bias and precision of PK parameter estimation than SSD. CONCLUSIONS: Performance of PK parameter estimation evaluated by bias and precision from simulation datasets was better in SSD than MSD. This finding implies that collecting more PK samplings is a more efficient strategy than recruiting more volunteers in order to obtain informative results in performing PCA.

Exploring the Relationships Between Antipsychotic Dosage and Voice Characteristics in Relation to Extrapyramidal Symptoms.

OBJECTIVE: Extrapyramidal symptoms (EPS) are common side effects of antipsychotic drugs. Despite the growing interest in exploring objective biomarkers for EPS prevention and the potential use of voice in detecting clinical disorders, no studies have demonstrated the relationships between vocal changes and EPS. Therefore, we aimed to determine the associations between voice changes and antipsychotic dosage, and further investigated whether speech characteristics could be used as predictors of EPS. METHODS: Forty-two patients receiving or expected to receive antipsychotic drugs were recruited. Drug-induced parkinsonism of EPS was evaluated using the Simpson-Angus Scale (SAS). Participants' voice data consisted of 16 neutral sentences and 2 second-long /Ah/utterances. Thirteen voice features were extracted from the obtained voice data. Each voice feature was compared between groups categorized based on SAS total score of below and above "0.6." The associations between antipsychotic dosage and voice characteristics were examined, and vocal trait variations according to the presence of EPS were explored. RESULTS: Significant associations were observed between specific vocal characteristics and antipsychotic dosage across both datasets of 1-16 sentences and /Ah/utterances. Notably, Mel-Frequency Cepstral Coefficients (MFCC) exhibited noteworthy variations in response to the presence of EPS. Specifically, among the 13 MFCC coefficients, MFCC1 (t=-4.47, p<0.001), MFCC8 (t=-4.49, p<0.001), and MFCC12 (t=-2.21, p=0.029) showed significant group differences in the overall statistical values. CONCLUSION: Our results suggest that MFCC may serve as a predictor of detecting drug-induced parkinsonism of EPS. Further research should address potential confounding factors impacting the relationship between MFCC and antipsychotic dosage, possibly improving EPS detection and reducing antipsychotic medication side effects.

Edge-Rich 3D Structuring of Metal Chalcogenide/Graphene with Vertical Nanosheets for Efficient Photocatalytic Hydrogen Production.

Constructing pertinent nanoarchitecture with abundant exposed active sites is a valid strategy for boosting photocatalytic hydrogen generation. However, the controllable approach of an ideal architecture comprising vertically standing transition metal chalcogenides (TMDs) nanosheets on a 3D graphene network remains challenging despite the potential for efficient photocatalytic hydrogen production. In this study, we fabricated edge-rich 3D structuring photocatalysts involving vertically grown TMDs nanosheets on a 3D porous graphene framework (referred to as 3D Gr). 2D TMDs (MoS2 and WS2)/3D Gr heterostructures were produced by location-specific photon-pen writing and metal-organic chemical vapor deposition for maximum edge site exposure enabling efficient photocatalytic reactivity. Vertically aligned 2D Mo(W)S2/3D Gr heterostructures exhibited distinctly boosted hydrogen production because of the 3D Gr caused by synergetic impacts associated with the large specific surface area and improved density of exposed active sites in vertically standing Mo(W)S2. The heterostructure involving graphene and TMDs corroborates an optimum charge transport pathway to rapidly separate the photogenerated electron-hole pairs, allowing more electrons to contribute to the photocatalytic hydrogen generation reaction. Consequently, the size-tailored heterostructure showed a superior hydrogen generation rate of 6.51 mmol g-1 h-1 for MoS2/3D graphene and 7.26 mmol g-1 h-1 for WS2/3D graphene, respectively, which were 3.59 and 3.76 times greater than that of MoS2 and WS2 samples. This study offers a promising path for the potential of 3D structuring of vertical TMDs/graphene heterostructure with edge-rich nanosheets for photocatalytic applications.

Clinical, cognitive, and functional characteristics of recent-onset psychosis with autistic features: A 2-year longitudinal study.

Though categorized as separate illnesses, schizophrenia and autism are known to exhibit shared characteristics. This study explored the distinctions in clinical, cognitive, and functional characteristics among individuals with recent-onset psychosis, considering the severity of their autistic symptoms, involving longitudinal examinations. We analyzed 671 patients with recent-onset psychosis from Korean Early Psychosis Cohort Study (KEPS), and used the PANSS Autism Severity Score (PAUSS) to categorize patient into 'autistic', 'moderate', and 'non-autistic' groups. The autistic group had the highest rate of schizophrenia diagnosis, and the lowest incidence of comorbid psychiatric disorders. Schizophrenia diagnosis predicted membership of the autistic group. More severe autistic symptoms correlated with worse overall symptoms and functional outcomes, which significantly predicted membership of the autistic group. Cognitive impairments and emotional recognition difficulties increased with the severity of autistic symptoms. 2-year longitudinal assessments demonstrated that group differences in autistic features and overall symptoms, and functional outcomes remained consistent, and membership of the autistic group significantly predicted symptomatic remission and functional recovery. In conclusion, the presence of autistic symptoms has a significant impact on the overall symptomatology and functional capabilities. They are enduring attributes rather than temporary state variables, and serve as a significant predictor for both symptomatic and functional recovery.

The characteristics and clinical outcomes of a pluripotent high-risk group with the potential to develop a diverse range of psychiatric disorders.

BACKGROUND: Recent studies have indicated that clinical high risk for psychosis (CHR-P) is highly specific for psychotic disorders other than pluripotential to various serious mental illnesses. However, not all CHR-P develop psychotic disorder only, and psychosis can occur in non-psychotic disorders as well. Our prospective cohort study aims to investigate the characteristics and clinical outcomes of a pluripotent high-risk group with the potential to develop a diverse range of psychiatric disorders. METHODS: The SPRIM study is a prospective naturalistic cohort program that focuses on the early detection of those at risk of developing serious mental illness, including psychosis (CHR-P), bipolar (CHR-B), and depressive disorder (CHR-D), as well as undifferentiated risk participants (UCHR). Our study has a longitudinal design with a baseline assessment and eight follow-up evaluations at 6, 12, 18, 24, 30, 36, 42, and 48 months to determine whether participants have transitioned to psychosis or mood disorders. RESULTS: The SPRIM sample consisted of 90 CHR participants. The total cumulative incidence rate of transition was 53.3% (95% CI 32.5-77.2). CHR-P, CHR-B, CHR-D, and UCHR had cumulative incidence rates of 13.7% (95% CI 3.4-46.4), 52.4% (95% CI 28.1-81.1), 66.7% (95% CI 24.6-98.6) and 54.3% (95% CI 20.5-93.1), respectively. The cumulative incidence of psychosis, bipolar, and depressive disorder among all participants was 3.3% (95% CI 0.8-11.5), 45.7% (95% CI 24.4-73.6), and 11.2% (95% CI 3.1-36.2), respectively. CONCLUSIONS: Our study suggests that the concept of pluripotent high-risk for a diverse range of psychiatric disorders is an integrative approach to examining transdiagnostic interactions between illnesses with a high transition rate and minimizing stigma.

Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: Focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.

Efficacy and Safety of Lurasidone vs. Quetiapine XR in Acutely Psychotic Patients With Schizophrenia in Korea: A Randomized, Double-Blind, Active-Controlled Trial.

OBJECTIVE: This study was performed to evaluate the efficacy and safety of lurasidone (160 mg/day) compared to quetiapine XR (QXR; 600 mg/day) in the treatment of acutely psychotic patients with schizophrenia. METHODS: Patients were randomly assigned to 6 weeks of double-blind treatment with lurasidone 160 mg/day (n=105) or QXR 600 mg/day (n=105). Primary efficacy measure was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions severity (CGI-S) score. Adverse events, body measurements, and laboratory parameters were assessed. RESULTS: Lurasidone demonstrated non-inferiority to QXR on the PANSS total score. Adjusted mean±standard error change at week 6 on the PANSS total score was -26.42±2.02 and -27.33±2.01 in the lurasidone and QXR group, respectively. The mean difference score was -0.91 (95% confidence interval -6.35-4.53). The lurasidone group showed a greater reduction in PANSS total and negative subscale on week 1 and a greater reduction in end-point CGI-S score compared to the QXR group. Body weight, body mass index, and waist circumference in the lurasidone group were reduced, with significantly lower mean change compared to QXR. Endpoint changes in glucose, cholesterol, triglycerides, and low-density lipoprotein levels were also significantly lower. The most common adverse drug reactions with lurasidone were akathisia and nausea. CONCLUSION: Lurasidone 160 mg/day was found to be non-inferior to QXR 600 mg/day in the treatment of schizophrenia with comparable efficacy and tolerability. Adverse effects of lurasidone were generally tolerable, and beneficial effects on metabolic parameters can be expected.