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Purpose:This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1/TSC2 or MTOR mutations.Patients and Methods:Patients with tumors with inactivating TSC1/TSC2 or activating MTOR mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations.Results:Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30), or MTOR (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%–22%]. Median progression-free survival was 2.3 months (95% CI, 1.8–3.7 months) and median overall survival (OS) was 7.3 months (95% CI, 4.5–12.7 months). There was no clear association between other genomic alterations and response. Of the 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of TSC1 and high tumor mutation burden, and the other had uterine carcinoma with biallelic TSC2-inactivating mutations and PEComa-like pathologic features.Conclusions:Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study.See related commentary by Kato and Cohen, p. 3807

Background A high level of insight in first episode psychosis (FEP) is positively correlated to important prognostic factors such as medication adherence and functional outcome but is associated with increased depression level and suicidal behavior. Aims This is the first study questioning the potential moderating role of cannabis use in the relationship between insight and depression one year after a FEP. Method In this prospective observational study, we enrolled 214 FEP patients who had provided informed consent and been referred to a specialized early psychosis program and followed for 36 months. A series of multivariate regression models were used. Baseline insight, medication adherence and cannabis use (level of use on a continuum) were entered as independent variables, while the PANSS (positive and negative), the MADRS and the SOFAS scores after one year were alternately selected as the dependent variable. Results We found a three-way interaction term between cannabis use, insight and medication adherence on depression level one year after the entry into the program. A high level of insight was significantly associated with higher MADRS scores in patients with high cannabis use, while depression decreased in high-insight patients with low cannabis use. Conclusions Cannabis use continuation during the year following a first episode psychosis may play a significant role in the development or the maintenance of post-psychotic depression in patients who present with high level of insight and adherence to medication, stressing the need for specific therapeutic strategies in this subgroup of patients.

Introduction The atypical antipsychotic quetiapine is known to induce weight gain and other metabolic complications. The underlying mechanisms are multifactorial and poorly understood with almost no information on the effect of dosage. Concerns were thus raised with the rise in low-dose quetiapine off-label prescription (i. e., Methods In this study, we evaluated the influence of quetiapine dose for 474 patients included in PsyMetab and PsyClin studies on weight and metabolic parameter evolution. Weight, blood pressure, lipid, and glucose profiles were evaluated during a follow-up period of 3 months after treatment initiation. Results Significant dose-dependent metabolic alterations were observed. The daily dose was found to influence weight gain and increase the risk of undergoing clinically relevant weight gain (≥7% from baseline). It was also associated with a change in plasma levels of cholesterol (total cholesterol, LDL cholesterol, and HDL cholesterol) as well as with increased odds of developing hypertriglyceridemia, as well as total and LDL hypercholesterolemia. No impact of a dose increase on blood pressure and plasma glucose level was observed. Discussion The dose-dependent effect highlighted for weight gain and lipid alterations emphasizes the importance of prescribing the minimal effective dose. However, as the effect size of a dose increase on metabolic worsening is low, the potential harm of low-dose quetiapine should not be dismissed. Prescriptions must be carefully evaluated and regularly questioned in light of side effect onset.

Background Not all patients respond well to early interventions for their psychosis. The present study's goal was to evaluate whether patients' responses in the first six months of treatment in a specialised three-year programme could predict final outcomes. Methods 206 early psychosis patients were assessed at baseline, using a large set of sociodemographic and clinical variables, and then monitored for 36 months. Among those variables, changes in their Global Assessment of Functioning (GAF) scores during the first six months were used to predict outcomes after three years. Results Changes in GAF scores during the first six months were the only variables that predicted every symptom of functional outcome. GAF scores were also always the first or second most important predictor for every outcome. This finding held for both high- and low-functioning patients at baseline. Conclusions Predicting poor long-term outcomes after only six months should help clinicians to improve treatments.

Background Service disengagement is a frequent problem in early intervention in psychosis. The goal of this study was to evaluate the rate and variables associated with service disengagement in a three year specialized program that allows treatment intensification on a case to case basis. Methods 328 early psychosis patients were assessed at baseline on a large set of socio-demographic and clinical variables and were followed-up over 36 months. Patients who left the program for reasons related to engagement with care were compared to patients who completed the program. Results Rates of disengagement were low (6.3%). Patients with lower socio-economic status, who committed offences during the program or with a diagnosis of Schizophreniform/brief psychotic disorder were more likely to disengage from the program. Conclusions The engagement strategies implemented in the context of our early intervention programs have allowed to keep disengagements to a relatively low level. In this context, only 3 variables emerged to guide adaptation of the intervention in order to improve this already good engagement rate.

Objectifs:Une proportion importante de patients présentant un premier épisode psychotique commettent des actes violents hétéro-agressifs. L’objectif de cette étude est d’explorer l’association entre insight et comportement violent (CV) et l’évolution de l’insight durant la période de suivi.Méthode:L’étude est conduite sur une cohorte prospective de 265 patients recrutés au sein du programme de traitement et d’intervention précoce dans les troubles psychotiques et suivis sur une période de 3 ans. L’évaluation de l’insight est basée sur une échelle d’insight en 3 points et l’item de l’insight à la Positive and Negative Syndrome Scale (PANSS). Les CV ont été évalués par les case-managers, par les informations provenant des services forensiques et par l’intermédiaire d’un relevé des CV en cours d’hospitalisation. Des analyses de régression logistique uni-variées et multi-variées, des tests-t et des corrélations ont été réalisés.Résultats:L’effet significatif de l’insight comme facteur associé aux CV trouvé dans les analyses uni-variées disparaît après avoir contrôlé l’effet des symptômes positifs, du diagnostic de dépendance aux substances, de l’impulsivité et de l’adhésion au traitement.Conclusion:Si la prise de conscience des patients à l’égard de leur maladie évolue positivement au cours du traitement, nos résultats suggèrent que le risque de survenue de CV n’est pas influencé par le degré d’insight. Il est par contre significativement lié à l’abus de substances et à l’impulsivité, impliquant de cibler ces deux dimensions dans les stratégies préventives. L’impact de l’insight sur le CV doit être l’objet d’analyses prospectives plus précises.

Early psychosis programs treat high ratios of migrants, given they display higher rates of psychosis. Studies on this topic are limited and less is known about outcomes. The aim of this study was to compare the premorbid, baseline and outcome profile of patients according to migration (M) and migration in psychosocial adversity (MA) in order to explore if there were differences suggesting particular needs in terms of treatment. 257 early psychosis patients aged 18-35 years old were followed-up over 36 months. MA (29.6%) and M (17.9%) were compared to patients who were born in Switzerland (NM). At entry to the program, MA patients had poorer functional levels and higher symptom intensity. MA patients were more likely to report past exposure to trauma. While M patients have similar outcome compared to NM patients, MA patients were less likely to reach symptom remission, displayed lower functioning and were more likely to relapse. Results suggests that migration in adversity is a potential determinant of functional impairment in early psychosis. While patients who migrated in other contexts have a better outcome, patients who experienced migration in adversity have specific needs considering they are less integrated and more likely to have been exposed to trauma.

Psychiatric patients are known to be at high risk of developing cardiovascular diseases (CVDs), leading to an increased mortality rate. To assess the CVD risk (presence of metabolic syndrome [MetS] and calculated 10-year CVD risk) in a Swiss psychiatric cohort taking weight gain-inducing psychotropic drugs, compare the findings to a Swiss population-based cohort, and evaluate the prevalence of participants treated for metabolic disruptions in both cohorts. Data for 1,216 psychiatric patients (of whom 634 were aged 35-75 years) were obtained between 2007 and 2017 from a study with metabolic parameters monitored during psychotropic treatment and between 2003 and 2006 for 6,733 participants from the population-based CoLaus|PsyCoLaus study. MetS as defined by the International Diabetes Federation (IDF) was identified in 33% of the psychiatric participants and 24.7% of the population-based subjects. Specifically, prevalence per the IDF definition was more than 3 times higher in the psychiatric cohort among women aged 35 to 49 years (25.6% vs 8.0%; P < 10-4). The psychiatric and population-based cohorts, respectively, had comparable predicted CVD risk (10-year risk of CVD event > 20%: 0% vs 0.1% in women and 0.3% vs 1.8% [P = .01] in men; 10-year risk of CVD death > 5%: 8.5% vs 8.4% [P = .58] in women and 13.4% vs 16.6% [P = .42] in men). No difference was observed among the proportion of participants with MetS treated for metabolic disturbances in the two cohorts, with the exception of women aged 35-49 years, for whom those in the psychiatric cohort were half as likely to receive treatment compared to participants in CoLaus|PsyCoLaus (17.8% vs 38.8% per the IDF definition; P = .0004). These findings emphasize the concern that psychiatric patients present an altered metabolic profile and that they do not receive adequate treatment for metabolic disruptions. Presence of metabolic disturbances should be routinely assessed, and adequate follow-up is needed to intervene early after illness onset.

Developmental clinical research in recent years has highlighted the value treating psychotic disorders at the earliest stage to reduce long-term morbidity. It is now suggested that treatment during the clinical high risk states (CHR), preceding by 1–4 years the onset of psychotic disorders, may delay or prevent the onset of psychosis, and contribute to a more positive prognosis. In this article, we wish to provide a rationale and clinical illustration of mentalization-based treatment (MBT) as an indicated preventive treatment for CHR. We will first review the notion of high-risk for psychosis, providing a trans-theoretical developmental framework for conceptualizing the clinical progression from sub-clinical towards clinical psychotic states. Second, we address the commonalities and differences between the constructs of mentalization and metacognition, and discuss their relevance in preventive psychotherapeutic treatment for CHR. Thirdly, we provide a clinical illustration of MBT to emerging psychosis. Finally, we conclude by discussing the specific contributions of MBT approach in youths at CHR, and the necessary research for evaluating its relevance in the context of risk for developing psychosis.

Palmitic acid (PA), a long-chain saturated fatty acid, might activate innate immune cells. PA plays a role in chronic liver disease, diabetes and Crohn&rsquo, s disease, all of which are associated with impaired intestinal permeability. We investigated the effect of PA, at physiological postprandial intestinal concentrations, on gut epithelium as compared to lipopolysaccharide (LPS) and ethanol, using an in vitro gut model, the human intestinal epithelial cell line Caco-2 grown on transwell inserts. Cytotoxicity and oxidative stress were evaluated, epithelial barrier integrity was investigated by measuring the paracellular flux of fluorescein, and through RT-qPCR and immunofluorescence of tight junction (TJ) and adherens junction (AJ) mRNAs and proteins, respectively. In PA-exposed Caco-2 monolayers, cytotoxicity and oxidative stress were not detected. A significant increase in fluorescein flux was observed in PA-treated monolayers, after 90 min and up to 360 min, whereas with LPS and ethanol, this was only observed at later time-points. Gene expression and immunofluorescence analysis showed TJ and AJ alterations only in PA-exposed monolayers. In conclusion, PA affected intestinal permeability without inducing cytotoxicity or oxidative stress. This effect seemed to be faster and stronger than those with LPS and ethanol. Thus, we hypothesized that PA, besides having an immunomodulatory effect, might play a role in inflammatory and functional intestinal disorders in which the intestinal permeability is altered.

Background The Clinical High Risk state (CHR) concept was implemented to promote the early detection of young help-seeking patients with higher risk of psychotic transition. This category is based on specific clinical criteria (EPA, 2015) and require narrow frequency/duration ratings of subclinical positive psychotic symptoms to allow its definition. Prevalence of CHR “category” appears nevertheless rare in help-seeking young people and the rate of psychotic transition of CHR state is lower than predicted by early studies. Therefore, the binary outcome of transition to psychosis proposed by the “CHR model” actually fails to be an efficient marker to stratify, in neurobiological studies, people with different psychopathological trajectories, notably those who develop psychosis from those who do not. In order to rely on a vulnerability model for schizophrenic psychosis more sensitive to psychosocial functioning and negative dimension, we study prospectively with three years of follow-up a population of help-seekers addressed for clinical suspicion of prodromal state of psychosis. We aimed here to identify subgroups of patients in a sample of subclinical psychotic states using psychological and cognitive outcomes as profiling criteria, focusing not only on transition but also on psychosocial functioning as main outcome. Methods A total of 32 help-seeking adolescents and young adults aged 14 to 35 were referred by health care providers for a specialized evaluation in case of suspicion of a prodromal psychotic state and/or detected by the French version of the Prodromal Questionnaire (PQ-16; cut-off 6/16). Their CHR status was assessed by the Structured Interview for Psychosis-Risk Syndromes (SIPS) and the Schizophrenia Proneness Instrument, Adult (SPI-A). Individuals included in the study presented either a CHR status, a subclinical CHR status or negative symptomatology. All subjects performed an additional neuropsychological battery and blood test for redox markers (Glutathione Peroxidase (GPx) and Glutathione Reductase (GR) activities) (Xin et al, 2016). Based on their clinical profile, we made a stratification of the patients using a Principal Component Analysis. Results Cognitive and psychological outcome stratification of all help-seekers revealed two subgroups (called group1 and group2) of patients with distinct profiles. Individuals in group1 (n=18) had greater levels of basic symptoms and general symptomatology. On the other hand, in group2 (n=14), individuals showed a weaker self-esteem and a lower rate of “living independently”. Cognitive scores for speed processing, attention, verbal learning and social cognition were significantly lower in group2 compared to group1. In addition, these cognitive outcomes were negatively correlated with negative symptoms only in group2. Analysis of redox markers revealed a positive correlation between GPx and GR activities in group1, a correlation disrupted in group2. Discussion Stratification of a cohort of young help-seekers with suspicion of prodromal psychosis, regardless of their CHR status, allowed us to distinguish two subgroups with different clinical profiles: group1 with higher levels of basic symptoms and general symptomatology, and group2 with weaker self-esteem, less autonomy and poorer neurocognition. In addition, analysis of redox markers revealed a redox dysregulation in patients with poorer cognitive profile. Considering the impact of neurocognitive impairment on functioning, special focus to patients of group2 is needed, mostly in clinical practice. Moreover, they might benefit of supplementation with antioxidant compounds such as NAC, which may improve cognitive deficits (Conus et al, 2018).

Background:While there is suggestion that early onset of psychosis is a determinant of outcome; knowledge regarding correlates of later onset age is more limited. This study explores the characteristics of patients developing psychosis after age 26, towards the end of the usual age range of early intervention programs, in order to identify potential specific needs of such patients.Methods:Two hundred and fifty-six early psychosis patients aged 18–35 were followed-up prospectively over 36 months. Patients with onset after 26 (“later onset”, LO) were compared to the rest of the sample.Results:LO patients (32% of the sample) had shorter DUP, were less likely to be male, had better premorbid functioning and were more likely to have been exposed to trauma. They had greater insight at presentation and less negative symptoms overall. The trajectories for positive and depressive symptoms were similar in both groups. Evolution of functional level was similar in both groups, but while LO patients recovered faster, they were significantly less likely to return to premorbid functional level.Conclusions:Later psychosis onset correlates with better premorbid functioning and higher rate of trauma exposure; the latter should therefore be a treatment focus in such patients. LO patients were less likely to return to premorbid functional level, which suggests that current treatment strategies may not be efficient to help patients maintain employment. The possibility of distinct illness mechanisms according to onset age and the more central role for trauma in patients with onset after age 26 needs to be further explored.

Background Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels. Objective This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development. Methods Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non–high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment. Results Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (≥5%) for TC, LDL-C, TG, and non-HDL-C and decrease (≥5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (≥30% TC, ≥40% LDL-C, ≥45% TG, ≥55% non-HDL-C increase, and ≥20% HDL-C decrease; sensitivity 70%–100%, specificity 53%–72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort ( P ≤ .03) as well as in a replication cohort (n = 79; P ≤ .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others ( P ≤ .01). Conclusion Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia.

In children and adolescents, psychotic disorders already represent one of the leading causes of disability-adjusted life years. During the past two decades, early detection of risk for psychosis has been intensively investigated, and in particular, predictive power for early signs of risk has been initiated and translated into clinical practice. In particular, the attenuated and transient positive symptoms of the ultra-high risk criteria, and the basic symptom criterion "cognitive disturbances", open promising routes to an indicated prevention and have recently been considered by the European Psychiatric Association (EPA) as diagnostic criteria of a psychosis-risk syndrome. The EPA recently provided evidence-based recommendations on the early detection of clinical high risk (CHR) for psychosis in patients with mental distress. In 2015, experts in the field of early detection conducted a meta-analysis reporting on studies examining conversion rates to psychosis in non-overlapping samples meeting at least one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria, examining the effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates. In the 42 identified samples, comprising more than 4000 CHR patients who had been mainly identified by means of UHR criteria and/or the basic symptom criterion 'cognitive disturbances' (COGDIS), conversion rates showed considerable heterogeneity. While UHR and COGDIS criteria were related to comparable conversion rates until a 2-year follow-up, rates for COGDIS were significantly higher for follow-up periods beyond 2 years. Differences in onset and frequency requirements of symptomatic UHR criteria, or in their different consideration of functional decline, substance use and co-morbidity, did not seem to have an impact on conversion rates. The 'genetic risk and functional decline' UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for the early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states. The EPA guidance on early intervention aimed to provide evidence-based recommendations on early intervention in CHR states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were also made by experts in the field of early intervention in psychoses and derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. In addition to analyses of treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n=1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional improvements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk status. Overall, age-related specificities and developmental transitions in the early detection and intervention in psychoses should be better accounted for in future research.

Aim In a survey conducted in the Lausanne catchment area in 2000, we could estimate on the basis of file assessment that first-episode psychosis (FEP) patients had psychotic symptoms for more than 2 years before treatment and that 50% did not attend any outpatient appointment after discharge from hospital. In this paper, we describe the implementation of a specialized programme aimed at improving engagement and quality of treatment for early psychosis patients in the Lausanne catchment area in Switzerland. Method The Treatment and Early Intervention in Psychosis Program-Lausanne is a comprehensive 3-year programme composed of (i) an outpatient clinic based on assertive case management; (ii) a specialized inpatient unit; and (iii) an intensive mobile team, connected for research to the Center for Psychiatric Neuroscience. Results Eight years after implementation, the programme has included 350 patients with a disengagement rate of 9% over 3 years of treatment. All patients have been assessed prospectively and 90 participated in neurobiological research. Based on this experience, the Health Department funded the implementation of similar programmes in other parts of the state, covering a total population of 540 000 people. Conclusion Programmes for early intervention in psychosis have a major impact on patients' engagement into treatment. While development of mobile teams and assertive case management with specific training are crucial, they do not necessitate massive financial support to be started. Inclusion of a research component is important as well, in terms of service planning and improvement of both quality of care and impact of early intervention strategies.

Background: CYC065 is a potent and selective inhibitor of CDK2 and CDK9. CDK2 drives cell cycle transition and activates major DNA double-strand break repair pathways; CDK9 regulates transcription of genes through phosphorylation of RNAP II. This first-in-human phase 1 study evaluates CYC065 administered by 4-hour infusion every 3 weeks in patients with advanced cancers. Methods: Dose escalation was 100% initially. Upon the occurrence of the first grade 2 drug-related toxicity, dose escalation decreased to 50% and then to 25% upon the occurrence of the first dose-limiting toxicity (DLT). Recommended phase 2 dose (RP2D) was MTD defined as highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Blood samples were taken in at pre-dose and up to 24 hours after the first dose of cycle 1 to assess pharmacokinetic (PK) and pharmacodynamic (PD) effects. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of Ser2 RNA polymerase II - a direct substrate of CDK9, and protein levels of downstream targets, such as Mcl-1, were determined in patient's PBMCs. Results: 26 patients were treated. The MTD was 192 mg/m2. DLTs are reversible neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, hypomagnesemia, white blood cell lysis syndrome and its associated electrolyte abnormalities and liver enzyme elevations. The most frequent adverse events (all cycles, regardless of causality) included constipation, diarrhea, decreased appetite, dehydration, fatigue, nausea, and vomiting, the majority mild to moderate in intensity. All patients participated in the PK/PD samplings. Exposure to CYC065 increased with dose. Average half-life ranged from 1.64 h to 3.9 h. Mcl-1 suppression, lasting at least 24 hours after a single dose, was observed in 11 out of 13 evaluable patients at the RP2D (192 mg/m2). Stable disease ≥ 6 cycles was observed in 6 patients, 5 of which treated at the RP2D: larynx neuroendocrine carcinoma (n=1), ovarian adenocarcinoma (n=2); uterine carcinosarcoma (1), parotid gland actinic cell carcinoma (n=1) and submandibular gland adenoid cystic carcinoma (n=1). Two patients with uterine and ovarian cancer are continuing on treatment having received 9 and 17 cycles respectively. Conclusion: CYC065 administered by 4-hour infusion is safe and demonstrated durable MCL-1 suppression at the RP2D. Durable stable diseases were observed. Additional dosing schedules to intensify dose density will be evaluated. Citation Format: Khanh T. Do, Nicole Chau, Andrew Wolanski, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Solida Pruitt-Thompson, Amber Scotton, Sheelagh Frame, Daniella I. Zheleva, David Blake, Judy Chiao, Geoffrey I. Shapiro. Phase I safety, pharmacokinetic and pharmacodynamic study of CYC065, a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT037.

Background Various strategies have been proposed to improve recruitment of “at risk mental state” patients; they may have an impact on the type of patients who reach such programs. We describe the clinical program for “at-risk” patients implemented in 2014 in Lausanne and the characteristics of referrals over the years. Methods Help seeking patients aged 14 to 35 were initially referred by health care providers for a specialized evaluation in case of suspicion of a potential “prodromal psychotic state” and more recently selected by PQ-16 (Ising et al. 2012) (cut-off: 6/16). At-Risk Mental State (ARMS) was defined according to the Basic Symptoms criterion (COPER-COGDIS criteria) from the Schizophrenia Proneness Instrument – Adult version (SPI-A) and to the Clinical High Risk criteria of the Structured Interview for Prodromal Syndromes (SIPS). ARMS patients underwent an extensive clinical evaluation (including Mini-SCID, SOFAS, MARDS, Yung Mania Scale, etc.) and were followed-up every 6 months over 3 years. Results Within a catchment area of 260 000 inhabitants, 110 patients have been referred to our center since 2014 and 100 completed the investigation. 29 (29%) fulfilled ARMS criteria, 52 (52%) didn’t and 19 (19%) were already psychotic. The proportion of true ARMS patients decreased progressively over the years from 45% in 2014 and 2015, to only 22 and 13.9 % in 2016 and 2017. In our sample of help-seekers, the group of patients ARMS- negative received mostly a schizophrenia spectrum diagnosis (26/52 patients, 50%), associated with low psychosocial functioning, even when not in the precise range of at-risk criteria. Discussion The global prevalence (29%) of ARMS patients in our sample over the 4 years is marginally lower than previous reports on similar tertiary centers, which ranges from 33 to 51 % (Kline E., 2014). Our lower prevalence of ARMS patients within the sample may be linked to the limited resources we had to conduct an information strategy and our focus on psychologists and psychiatrists working at our department. The introduction in 2016 of more intense screening strategy based on the use of the PQ-16 lead to an increase in referral numbers but decreased the rate of ARMS among referred patients. Our results confirm the influence of the recruitment strategy and information campaigns on the prevalence of at-risk patients within a population of help-seekers. The prevalence of schizophrenia spectrum diagnosis in our group of patients ARMS-negative also suggests that a larger “vulnerability” model for psychosis, more sensitive to functioning and negative symptoms and not narrowed on the focus of the risk of imminent acute psychosis, may better fit patients’ needs.

Aim To describe a large family with autosomal dominant parkinsonism. Background Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several multigenerational large families known with no identifiable mutation. Material and methods Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2 , SCA3 , UCHL1 , SNCA , LRRK2 , PINK1 , PRKN , PGRN , FMR1 premutation, and MAPT . The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. Results Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for α-synuclein. Conclusion Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.

Background: Both MEK and CDK4/6 have been investigated as therapeutic targets in preclinical models of RAS mutant solid tumors. Multiple mechanisms contribute to synergism including the development of MAP kinase-dependence in RAS mutant cells exposed to CDK4/6 inhibition, leading to increased apoptosis, as well as enhanced induction of senescence with combinatorial vs. monotherapy treatment. We conducted a Phase 1 study of combined palbociclib and PD-0325901 in patients with RAS mutant solid tumors to assess safety, tolerability, and MTD, as well as pharmacokinetic parameters, preliminary efficacy and effects on mutant RAS allelic burden in plasma. Methods: Patients with RAS mutant solid tumors were enrolled utilizing a 3 + 3 design. Palbociclib and PD-0325901 were given orally once and twice daily, respectively for three of every four weeks. The maximum planned administered doses were 125 mg palbociclib daily and 8 mg PD-025901 twice daily. Pharmacokinetic parameters were measured on cycle 1 day 21 and plasma samples to measure RAS allelic burden were serially collected. Results: Twenty-five patients (17 with KRAS mutant NSCLC) who received at least one dose of each study drug were enrolled over 5 dose levels including (palbociclib/PD-0325901) 75/2, 75/4, 100/4, 125/4 and 125/8. The maximum administered dose of 125 mg palbociclib daily and 8 mg twice daily PD-0325901 was tolerable. One DLT of pneumonitis occurred at the 100/4 dose level. The most frequent (>10%) drug-related toxicities were leukopenia (72%), anemia (72%), thrombocytopenia (72%), neutropenia (64%), acneiform rash (64%), diarrhea (52%), fatigue (44%), lower extremity edema (32%), vomiting (28%), nausea (28%), oral mucositis (24%), increased AST (20%), increased creatinine (12%), epistaxis (12%), and blurred vision (12%). The median number of cycles completed was 3 (range: 1 - 28+). Across all patients, 1 patient (4%) with KRAS mutant NSCLC achieved partial response and 18 (72%) had stable disease as the best response. Eleven patients were progression-free > 3 months, and 6 were progression-free > 6 months, including 5 with KRAS mutant NSCLC, two of whom received prior immune checkpoint blockade. Among patients with KRAS mutant NSCLC, clinical benefit was seen among those with tumors harboring KRAS mutation alone, as well as those with tumors demonstrating concomitant loss of TP53 or CDKN2AB. A dose-dependent decrease in plasma RAS allelic burden was observed across dose levels. Conclusions: Administration of combined palbociclib and PD-0325901 was tolerable and produced promising progression-free survival among patients with KRAS mutant NSCLC. Additional dose levels utilizing continuous MEK inhibition are being evaluated. Citation Format: Geoffrey I. Shapiro, John Hilton, Leena Gandi, Nicole Chau, James Cleary, Andrew Wolanski, Adrienne Anderson, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Elizabeth Downey, Joseph Gibson, Solida Pruitt-Thompson, Alona Muzikansky, Suzanne Barry, Nora Feeney, Cloud Paweletz, Geoffrey Oxnard, Jeffrey Supko, Pasi Jänne, Kwok-Kin Wong, Bruce Johnson. Phase I dose escalation study of the CDK4/6 inhibitor palbociclib in combination with the MEK inhibitor PD-0325901 in patients with RAS mutant solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT046. doi:10.1158/1538-7445.AM2017-CT046

Background: Although PARP inhibition is effective against HR repair-deficient cancers, efficacy is limited by HR proficiency, whether present de novo or as a result of acquired resistance, prompting HR disrupting strategies to sensitize tumor cells. Inhibition of CDK1 and CDK12 compromise HR by blocking BRCA1 phosphorylation, affecting recruitment to sites of DNA damage, and by reducing HR gene expression, respectively. Dinaciclib is a pan-CDK inhibitor that inhibits both CDK1 and CDK12 at nanomolar potency. We conducted a Phase 1 study combining dinaciclib and veliparib in patients with advanced solid tumors who are not germline BRCA carriers. Methods: A 3+3 design was utilized. Veliparib was administered twice daily continuously in 28-day cycles. Dinaciclib was administered intravenously on days 8 and 22. In part 1A, escalation followed a two-dimensional schema, utilizing doses of dinaciclib between 10 - 45 mg/m2 and veliparib between 20 - 120 mg. In part 1B, veliparib was escalated between 200 mg - 400 mg with dinaciclib maintained at 30 mg/m2. PK and PD assessments were performed at baseline, after veliparib, and after the combination. Preliminary Results: Sixty-three heavily pretreated patients were enrolled in part 1A (n = 39) and 1B (n = 24). Thirty-four patients had breast or gynecologic malignancies. The MTD was 400 mg twice-daily veliparib with dinaciclib at 30 mg/m2. DLTs included G4 neutropenia > 7 days (n =1), febrile neutropenia (n = 1), mucositis (n = 1) and fatigue (n = 1). Common drug-related toxicities were neutropenia (78%), nausea (75%), fatigue (67%), electrolyte abnormalities (59%), elevated liver function tests (57%), diarrhea (52%), lymphopenia (52%), anemia (43%), dehydration (37%), anorexia (30%), vomiting (29%), hypoalbuminemia (29%), dizziness (29%), headache (22%), mucositis (18%), elevated creatinine (16%), alopecia (16%), thrombocytopenia (14%), abdominal pain (13%), insomnia (13%), and dysgeusia (11%). The median number of cycles completed was 2 (r: 1 - 10). One patient with TNBC achieved complete resolution of axillary adenopathy lasting > 8 months. Twenty-four patients (38%) had stable disease as the best response, with 9 progression-free > 4 months (TNBC, gynecologic and thymic ca). Paired tumor biopsies from one patient demonstrated reduced Ki-67 and increased gamma-H2AX staining after combination treatment compared to after veliparib alone. Conclusions: Dinaciclib administered at doses known to produce PD effects is tolerable with full dose veliparib. Anti-tumor activity is limited in non-BRCA carriers, possibly related to intermittent administration of a CDK inhibitor with known short half-life. Additional patients are being enrolled utilizing dinaciclib in more dose-intense schedules. Citation Format: Geoffrey I. Shapiro, Khanh T. Do, Sara M. Tolaney, John F. Hilton, James M. Cleary, Andrew Wolanski, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Dongpo Cai, Elizabeth Downey, Solida Pruitt-Thompson, Suzanne M. Barry, Bose Kochupurakkal, Joseph Geradts, Christine Unitt, Alan D. D'Andrea, Alona Muzikansky, Richard Piekarz, L. Austin Doyle, Jeffrey Supko. Phase 1 dose-escalation study of the CDK inhibitor dinaciclib in combination with the PARP inhibitor veliparib in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT047. doi:10.1158/1538-7445.AM2017-CT047

Seventy-eight asymptomatic HIV-seropositive (aHIV) subjects were examined by means of an extensive neuropsychological test battery in comparison with 32 HIV-seronegative controls. They were also tested with regard to CD4+ and serum p24 antigen. Fifty-six of them completed a clinical follow-up of 12 up to 36 months and 35 also underwent a second session of neuropsychological, CD4+ and p24 antigen assessments at a 12- to 18-month interval from the first session. Results obtained lead to the following conclusions: (a) even among aHIV subjects there is a significant prevalence (28.2%) of cognitive abnormalities for which no cause other than HIV can be found, and therefore this suggests the possible development of HIV-related brain damage since the earliest stages of infection; (b) most sensitive to early HIV-related cognitive impairment are timed psychomotor tasks and memory tasks which require attention, learning and 'active' monitoring or retrieval of information; (c) during the early asymptomatic stages of HIV infection, there is no clear-cut evidence of a cross-sectional relationship between cognition and immunological/ virological markers (at least in the high ranges of CD4+ cell counts considered here); only in relatively more advanced stages does this relationship become evident in the subgroup of aHIV subjects with cognitive abnormalities; (d) the presence of cognitive abnormalities in early HIV infection is predictive of a further decrease in cognitive functioning and faster progression to AIDS-this latter reflected by a faster rate of decline in the number of CD4+ cells and by an increase in positivity of serum p24 antigen.

The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.

OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Context Intervention in the prodromal phase of psychosis remains controversial due to poor specificity of current criterion and ethical issues arising when developing interventions. There is less controversy regarding the need for specialist first episode psychosis intervention programs. Aims In the context of the implementation of an early intervention strategy in Lausanne, we focused on a first episode psychosis program and checked if need for an early detection program for UHR subjects would emerge over time. We recently structured a specialist At Risk Mental State (ARMS) clinic. Methods Help seeking patients aged 14–35, referred for a 'prodromal psychotic state” are assessed with: Mini-SCID; SPI-A; SIPS-PANSS; MARDS; Yung Mania scale and classified as ARMS on the basis of SPI-Cy (COPER and COGDIS criteria) and SIPS criteria (APS; BLIPS or Genetic Criterion). Results Since January 2014, twenty-four patients were addressed to our clinic, and diagnoses were: ARMS (33%); first episode psychosis (8%); schizotypal disorder (25%); other axis I or II diagnosis (13%); drop out before diagnosis (5%); still in investigation (16%). Conclusions Our data shows that there is a need for specialist ARMS clinic when developing early intervention programs. The proximity with a well implanted first episode program offers the possibility to treat patients who have already developed full blown psychosis or for those who make the transition. Ethically, it is our impression that having both structures is necessary in order to have adequate treatment to offer is patients develop full blown psychosis.

Differential display-polymerase chain reaction was used to compare gene expression between human chondrosarcoma cell lines and normal cartilage. A new gene, CSAGE, has been cloned and belongs to a gene family that includes the taxol resistance associated gene (TRAG)-3. CSAGE, like TRAG-3, does not confer resistance to taxol when transfected in vitro. Both genes have alternatively spliced variants. CSAGE and TRAG-3 are expressed in chondrosarcoma, melanoma, and cartilage and testis, but not in other normal tissues. TRAG-3 has been reported to be a cancer/testis antigen. Our results suggest that CSAGE belongs to the growing list of cancer/testis antigens as well. In all of the CSAGE positive samples, the melanoma antigen gene family was also expressed. This is the first report on the expression of cancer/testis antigens in chondrosarcoma.

Chondrosarcomas are alleged to be resistant to chemotherapy. A retrospective review of our experience primarily with dedifferentiated chondrosarcomas treated with chemotherapy was performed to reevaluate the efficacy of chemotherapy for this tumor. There were 18 patients: 14 stage IIB and four stage III. Seventeen patients had dedifferentiated chondrosarcoma. The median age at diagnosis was 57 years. Fourteen of the patients underwent wide excision of the tumor, two underwent amputation, and two had no surgery. The femur and the pelvis were the most common locations of the primary tumor. Chemotherapy for 11 of the patients consisted of cisplatin and doxorubicin. Survival was analyzed with the Kaplan-Meier method; the median survival was 12 months. The hypothesis that chondrosarcomas express P-glycoprotein was tested. Expression of P-glycoprotein was evaluated by immunostaining with use of the C494 and C219 antibodies on 41 benign and malignant cartilage tumors, six of which were from the patients in the chemotherapy group. Immunostaining revealed that 37 of 41 cartilage tumors expressed P-glycoprotein. The rate of survival of patients with high-grade chondrosarcoma treated with chemotherapy is poor. P-glycoprotein expression is common in benign and malignant cartilage lesions. The lack of response to chemotherapy may be related to the expression of P-glycoprotein.

The aim of the present study was to investigate the influence of focal cerebellar lesions on procedural learning. Eight patients with cerebellar lesions and six control subjects were tested in a serial reaction-time task. A four-choice reaction-time task was employed in which the stimuli followed (or not) a sequence repeated 10 times, with the subjects aware (or not) of the item sequence. Learning was manifested by the reduction in response latency over the sequential blocks. Acquisition of declarative knowledge of the sequence was also tested. Reaction times displayed by patients with cerebellar lesions, even though they tended to be longer than those of control subjects in all testing conditions, significantly differed from control subjects only when the stimuli were presented in sequence. The reaction times in sequential trials were still statistically significant when simple motor response times were taken into account. Cerebellar patients were also significantly impaired in detecting and repeating the sequence. On the other hand, when the sequence was learned before testing, motor performances were significantly improved in all subjects. These data indicate that cerebellar lesions induce specific impairment in the procedural learning of a motor sequence and suggest a role of the cerebellar circuitry in detecting and recognizing event sequences.

TPS2627 Background: Thioureidobutyronitrile, kevetrin, has demonstrated anti-tumor activity in several wild type and mutant p53 human tumor xenografts without evidence of genotoxicity. In wild type p53 models, kevetrin induces cell cycle arrest and apoptosis through activation and stabilization of wild type p53, resulting in increased expression of p53 target genes p21 and PUMA. Kevetrin also alters processivity of MDM2, and induces monoubiquitination of wild type p53, enhancing its stability (AACR 2011 abstract 4470). Mutant p53 is a complex target since it is an array of mutant proteins with oncogenic properties. Kevetrin induces degradation of oncogenic mutant p53 and induces apoptosis (AACR 2012 abstract 2874). Kevetrin therefore has the unique ability to target both wild type and mutant p53 tumors thereby controlling tumor growth in a wide range of preclinical tumor models. Methods: Adults with refractory locally advanced or metastatic solid tumors, acceptable liver and kidney function, and hematological status were eligible. Objectives include determination of DLT, MTD, recommended phase 2 dose, pharmacokinetics (PK), pharmacodynamics (PD), and evaluating preliminary evidence of antitumor activity. Kevetrin is given as a 1-hour intravenous infusion once weekly for 3 weeks in 28-day cycles. The starting dose was 10 mg/m2. In a 3+3 design, groups of 3-6 patients are evaluated for toxicity at each dose level. Dose escalation is based upon the number and intensity of adverse events in cycle 1. Kevetrin PK is characterized for the first and last doses given in cycle 1. Kevetrin induced expression of p21 in lymphocytes in preclinical studies; therefore p21 expression in peripheral blood mononuclear cells will be measured as a PD biomarker. Antitumor activity by RECIST 1.1 criteria and serum tumor markers will be assessed. The p53 status of tumors of selected patients will be determined. The second cohort is currently under evaluation. Conclusion: In preclinical models, Kevetrin has activity against tumors harboring both wild type and mutant p53 by diverse mechanisms. A first-in-human dose escalation trial is underway. Clinical trial information: NCT01664000.

In Parkinson's disease, a postural/kinetic tremor may occur in association with the classical resting tremor. According to the consensus statement of the Movement Disorder Society on tremor,1 this association is classified as type I (classical parkinsonian tremor) if the difference between the frequencies of postural/kinetic tremor and resting tremor is less than 1.5 Hz; and as type II if this difference is more than 1.5 Hz. In type I tremor, resting tremor and postural tremor share common pharmacological properties, responding to levodopa.2,3 Type II tremor (that is, a predominant postural/kinetic tremor associated with a resting tremor of a lower frequency) is considered to be a combination of essential tremor and parkinsonian tremor, and is reported in between 3% and 24% of the patients diagnosed as having Parkinson’s disease.3 Though postural/kinetic tremor and resting tremor may show some overlap in their electrophysiological properties in Parkinson’s disease, the postural/kinetic component does not respond to levodopa.3 Nevertheless, clinical criteria may be insufficient to differentiate between Parkinson’s disease and essential tremor. We report a case of a 70 year old patient affected by essential tremor and Parkinson's disease, in whom acute dopaminergic challenge tests allowed us to differentiate between the two components of severe bilateral arm tremor. Acute dopaminergic challenge tests, which are well accepted as a diagnostic tool in Parkinson’s disease, may be helpful in …

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia.