Making bubbles: Targeting VPS41 induces vacuolization and methuosis.

In this issue of Cell Chemical Biology, Liu et al. describe the natural product DMBP as the first tool compound for VPS41. Treatment with DMBP induced vacuolization and methuosis and inhibited autophagic flux in lung and pancreatic cancer cell lines, validating VPS41 as a potential therapeutic target.

Substance use in a large sample of patients with schizophrenia or related disorders and co-morbid obsessive-compulsive symptoms.

OBJECTIVE: The aim of this study was to examine the relationship between obsessive-compulsive symptoms (OCS) and substance use in patients with a non-affective psychotic disorder. METHOD: The data were derived from the Genetic Risk and Outcome of Psychosis study. Using the Yale-Brown Obsessive Compulsive Scale, three groups of in- and outpatients with non-affective psychotic disorder (76.6% male, mean age 27.7 years, mean duration of illness 4.5 years) were distinguished: patients without OCS (N = 777), patients with mild OCS (N = 143) and patients with more severe OCS (N = 85). These three groups were compared using various substance use variables, including quantitative substance use variables and severity of substance use [Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) misuse disorders]. RESULTS: We found no statistically significant differences in smoking and other substance use variables between the three patients groups according to the severity of OCS. CONCLUSIONS: Our large study sample and detailed comparison of substance use rates strongly adds to the evidence that schizophrenia patients with OCS do not differ in prevalence of substance use compared to patients without OCS. This suggests that in clinical practice, enquiring into (problematic) substance use is relevant in both schizophrenia patients with co-morbid OCS and patients without OCS.

Craving for cannabis in patients with psychotic disorder, their non-affected siblings and healthy controls: psychometric analysis of the obsessive compulsive drug use scale.

Cannabis use is more common in individuals with non-affective psychotic disorder and their siblings compared to healthy controls. As cannabis use is associated with a greater risk to develop psychotic disorder and an adverse outcome in those who already developed psychosis, it is important to know the role of craving in continued cannabis use and relapse in these vulnerable subjects. Therefore, we examined the validity of the Obsessive Compulsive Drug Use Scale for cannabis (OCDUS-CAN) in patients with non-affective psychotic disorder, their siblings, and healthy controls who all used cannabis in the past year. Simultaneous component analysis (SCA) was used to determine component weights that optimally explained the (co)variance of the OCDUS-CAN variables in these different populations simultaneously. A three-component SCA solution explained 74.2 % of the total variance, and consisted of well-interpretable subscales that could be best described as craving/urge, resistance, and impact. Reliability of the subscales was good. The three subscales significantly discriminated between frequent and infrequent cannabis users. Patients scored higher on the craving/urge and impact scale than siblings and controls, which could be related to primary and secondary symptoms of their disorder. The OCDUS-CAN is well suitable for people with or without vulnerability for psychotic disorder.

Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine.

Substance abuse and psychotic disorders have a high rate of comorbidity. Both disorders are associated with changes in the dopaminergic transmission in the mesocorticolimbic pathways of the brain. Since antipsychotic medications interact with the dopamine receptors in these pathways, these medications could affect craving for substances. In the current study, the effect of clozapine (n = 27, mean dosage 350 mg), risperidone (n = 54, mean dosage 3.46 mg) and olanzapine (n = 60, mean dosage 13.78 mg) on subjective craving for cannabis was compared in 123 patients with cannabis dependence and psychotic disorder. Patients treated with risperidone reported significantly more craving compared with patients treated with clozapine (Z = -3.19, p = .001) or olanzapine (Z = -2.24, p = .025). No significant differences in craving between clozapine and olanzapine were found. These results are in concordance with findings in the literature on this subject and could be explained by differences in three dopamine mediated mechanisms of these compounds: 1) occupancy rate of dopamine D(2) receptors, 2) dissociation rate of dopamine D(2) receptors, 3) D(1)/D(2) occupancy ratio. Risperidone and clozapine show a maximal difference in D(2) receptor occupancy rate, dissociation rate and D(1)/D(2) ratio. Olanzapine is intermediate between risperidone and clozapine in these characteristics.

White matter connectivity and psychosis in ultra-high-risk subjects: a diffusion tensor fiber tracking study.

This study assessed with diffusion tensor imaging (DTI) whether ultra-high-risk subjects who later develop a psychotic disorder (UHR-P) show abnormalities in association white matter fiber tracts as compared to UHR subjects who do not convert to psychosis (UHR-NP) and healthy controls. Participants comprised 17 male UHR subjects and 10 male healthy controls, who received baseline DTI scans before clinical follow-up. The uncinate and arcuate fasciculi, anterior and dorsal cingulate, and subdivisions of the corpus callosum were calculated and visualized, and tract-specific measurements were performed. At 24-month follow-up seven UHR subjects had developed a first psychotic episode. Fractional anisotropy in baseline DTI scans, including left-right asymmetry measures, did not differ between the groups. Thus, DTI measures of these association white matter tracts were not biological markers of psychosis in our UHR sample. Abnormalities of these fiber tracts may develop around or after onset of psychosis. However, further DTI studies in UHR subjects are needed in larger samples.

Cannabis use and callosal white matter structure and integrity in recent-onset schizophrenia.

Adolescent-onset cannabis use, compared with adult-onset use, has been associated with a higher risk for developing symptoms of schizophrenia-like psychotic disorders. To test the hypothesis that onset of cannabis use in early adolescence in male schizophrenia patients is associated with abnormalities in white matter structure and integrity, we used high resolution structural and diffusion tensor brain images to compare three groups of patients: those who started regular use of cannabis (1) before the age of 15 years (early-onset cannabis users, n = 10) or (2) at the age of 17 years or later (late-onset cannabis users, n = 8), and (3) those who were cannabis naïve (n = 8). To verify patient findings, we also compared white matter integrity of the three patient groups with that of a healthy control group (n = 10). Cannabis naïve patients showed reduced white matter density and reduced fractional anisotropy, an indicator for white matter integrity, in the splenium of the corpus callosum compared with patients with early-onset cannabis use. In the same brain area, cannabis naïve patients showed reduced fractional anisotropy compared with healthy controls. Our results suggest that the age of onset of cannabis use is not an identifying characteristic for white matter abnormalities in schizophrenia patients; however, our results might indicate a more vulnerable brain structure in cannabis naïve schizophrenia patients.

White matter fibertracking in first-episode schizophrenia, schizoaffective patients and subjects at ultra-high risk of psychosis.

There is increasing evidence of white matter pathology in schizophrenia. The aim of this study was to examine whether white matter abnormalities found with diffusion tensor imaging (DTI) in previous schizophrenia studies are present in the early phase of the illness. DTI was performed at 3 T on 10 male patients with a first (n = 8) or second (n = 2) psychotic episode of schizophrenia or schizoaffective disorder, 10 male patients at ultra-high risk of psychosis with (pre)psychotic symptoms and 10 healthy controls. Fibertracts found to be abnormal in other DTI studies (uncinate and arcuate fasciculus, anterior and dorsal cingulum, subdivisions of the corpus callosum) were calculated and visualized; tract-specific measurements (fractional anisotropy and trace) were performed. No differences were found between the healthy subjects and the 2 patient groups. These preliminary findings suggest that there is no white matter pathology of these association tracts detectable with DTI in the early stages of schizophrenic illness in males. Our findings are in contrast with DTI abnormalities found in some other first-episode studies. This discrepancy in findings may be related to differences in subject characteristics and DTI methodology. Possible effects of age, gender, level of education and illicit substance use on DTI findings in schizophrenia are discussed.

Cessation of cannabis use by patients with recent-onset schizophrenia and related disorders.

BACKGROUND: Cannabis abuse has been found to be a component risk factor for the onset and poor outcome during the early course of schizophrenia and related disorders. Cannabis use has become a target for prevention and treatment of schizophrenia patients. Therefore, knowledge of factors that influence continuation and cessation of cannabis use is crucial. However, little is known about factors associated with cessation of cannabis use in young schizophrenia patients. SAMPLING AND METHODS: We examined medical records of 206 consecutively admitted young patients with schizophrenia or related disorders, to explore factors associated with cessation of cannabis use. RESULTS: Of all patients that had used cannabis (167) in the past, more than half (87) ceased the use of cannabis before they were admitted to our clinic. Most patients ceased the use of cannabis after they became psychotic and after their first contact with psychiatric services. According to the urinalysis, only five patients seemed to have lied about their time of cessation. No differences in patient characteristics were found between patients that ceased their use of cannabis and patients that continued their use. CONCLUSIONS: The results suggest that the start of treatment for psychosis is related to the cessation of cannabis use, at least in part of the patients.