Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Longitudinal association between motor and obsessive compulsive symptoms in patients with psychosis and their unaffected siblings

Little is known about the co-prevalence of obsessive compulsive symptoms (OCS) and motor symptoms in patients with psychotic disorders. Cross-sectional associations between OCS and motor symptoms were assessed at baseline and at 3 years follow-up in patients (n = 726) with psychotic disorders and in their unaffected siblings (n = 761) from the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Furthermore, longitudinal associations between changes in OCS and motor symptoms were evaluated. At baseline, OCS was not associated with any motor symptom (akathisia, dyskinesia, parkinsonism or dystonia) in patients. At follow-up, patients with OCS reported significantly more akathisia. Dividing the patients into four groups-no OCS, OCS remission with OCS only at baseline, OCS de novo with OCS only at follow-up and a persistent OCS group-revealed that the OCS de novo group already reported more akathisia at baseline compared to the no-OCS group. At follow-up, both the OCS de novo and the persistent OCS group reported more akathisia. These results remained significant after correcting for relevant confounders clozapine, GAF score, PANSS-negative score and IQ. Motor symptoms at baseline were significantly associated with OCS at follow-up, but not the other way around. In siblings, OCS at baseline was associated with akathisia, but this association was lost at follow-up. Results suggest that motor symptoms might precede co-occurring OCS in patients with psychotic disorders. However, no inference can be made about causality, and further prospective research is needed to investigate this assumption.status: publishe

Osteocyte Apoptosis, Bone Marrow Adiposity, and Fibrosis in the Irradiated Human Mandible

Purpose: To assess the effect of radiation therapy on osteocyte apoptosis, osteocyte death, and bone marrow adipocytes in the human mandible and its contribution to the pathophysiology of radiation damage to the mandibular bone. Methods and Materials: Mandibular cancellous bone biopsies were taken from irradiated patients and nonirradiated controls. Immunohistochemical detection of cleaved caspase-3 was performed to visualize apoptotic osteocytes. The number of apoptotic osteocytes per bone area and per total amount of osteocytes, osteocytes per bone area, and empty lacunae per bone area were counted manually. The percentage fibrotic tissue and adipose tissue per bone marrow area, the percentage bone marrow of total area, and the mean adipocyte diameter (μm) was determined digitally from adjacent Goldner stained sections. Results: Biopsies of 15 irradiated patients (12 men and 3 women) and 7 nonirradiated controls (5 men and 2 women) were assessed. In the study group a significant increase was seen in the number of empty lacunae, the percentage of adipose tissue of bone marrow area, and the adipocyte diameter. There was no significant difference in bone marrow fibrosis nor apoptotic osteocytes between the irradiated group and the controls. Conclusions: Irradiation alone does not seem to induce excessive bone marrow fibrosis. The damage to bone mesenchymal stem cells leads to increased marrow adipogenesis and decreased osteoblastogenic potential. Early osteocyte death resulting in avital persisting bone matrix with severely impaired regenerative potential may contribute to the vulnerability of irradiated bone to infection and necrosis

clozapine Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or On behalf of: British Association for Psychopharmacology can be found at: Journal of Psychopharmacology Additional services and information for a

Abstract 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 ¼ 27, mean dosage 350 mg), risperidone (n ¼ 54, mean dosage 3.46 mg) and olanzapine (n ¼ 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 ¼ À3.19, p ¼ .001) or olanzapine (Z ¼ À2.24, p ¼ .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

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. © 2013 The Royal Australian and New Zealand College of Psychiatrists

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.status: publishe

Longitudinal association between motor and obsessive compulsive symptoms in patients with psychosis and their unaffected siblings

Little is known about the co-prevalence of obsessive compulsive symptoms (OCS) and motor symptoms in patients with psychotic disorders. Cross-sectional associations between OCS and motor symptoms were assessed at baseline and at 3 years follow-up in patients (n = 726) with psychotic disorders and in their unaffected siblings (n = 761) from the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Furthermore, longitudinal associations between changes in OCS and motor symptoms were evaluated. At baseline, OCS was not associated with any motor symptom (akathisia, dyskinesia, parkinsonism or dystonia) in patients. At follow-up, patients with OCS reported significantly more akathisia. Dividing the patients into four groups—no OCS, OCS remission with OCS only at baseline, OCS de novo with OCS only at follow-up and a persistent OCS group—revealed that the OCS de novo group already reported more akathisia at baseline compared to the no-OCS group. At follow-up, both the OCS de novo and the persistent OCS group reported more akathisia. These results remained significant after correcting for relevant confounders clozapine, GAF score, PANSS-negative score and IQ. Motor symptoms at baseline were significantly associated with OCS at follow-up, but not the other way around. In siblings, OCS at baseline was associated with akathisia, but this association was lost at follow-up. Results suggest that motor symptoms might precede co-occurring OCS in patients with psychotic disorders. However, no inference can be made about causality, and further prospective research is needed to investigate this assumption

Longitudinal association between motor and obsessive compulsive symptoms in patients with psychosis and their unaffected siblings

Little is known about the co-prevalence of obsessive compulsive symptoms (OCS) and motor symptoms in patients with psychotic disorders. Cross-sectional associations between OCS and motor symptoms were assessed at baseline and at 3 years follow-up in patients (n = 726) with psychotic disorders and in their unaffected siblings (n = 761) from the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Furthermore, longitudinal associations between changes in OCS and motor symptoms were evaluated. At baseline, OCS was not associated with any motor symptom (akathisia, dyskinesia, parkinsonism or dystonia) in patients. At follow-up, patients with OCS reported significantly more akathisia. Dividing the patients into four groups—no OCS, OCS remission with OCS only at baseline, OCS de novo with OCS only at follow-up and a persistent OCS group—revealed that the OCS de novo group already reported more akathisia at baseline compared to the no-OCS group. At follow-up, both the OCS de novo and the persistent OCS group reported more akathisia. These results remained significant after correcting for relevant confounders clozapine, GAF score, PANSS-negative score and IQ. Motor symptoms at baseline were significantly associated with OCS at follow-up, but not the other way around. In siblings, OCS at baseline was associated with akathisia, but this association was lost at follow-up. Results suggest that motor symptoms might precede co-occurring OCS in patients with psychotic disorders. However, no inference can be made about causality, and further prospective research is needed to investigate this assumption