Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls.

BACKGROUND: Patients suffering from schizophrenic psychosis show reduced synaptic connectivity compared to healthy individuals. Furthermore, the use of cannabis often precedes the onset of schizophrenic psychosis. Therefore, we investigated whether consumption of cannabis has an impact on the methylation pattern of schizophrenia candidate genes concerned with the development and preservation of synapses and synaptic function. METHODS: Fifty blood samples of outpatients affected by treatment-resistant schizophrenic psychosis were collected in the outpatient department of Ch Ste Anne/INSERM (Paris, France). Extracted DNA was sent to the LMN/MHH (Hanover, Germany) where DNA samples were bisulfite converted. The methylation patterns of the promoter region of neuregulin 1 (NRG1), neurexin (NRXN1), disrupted in schizophrenia 1 (DISC1), and microtubule-associated-protein tau (MAPT) were then analysed by sequencing according to Sanger. RESULTS: In NRXN1 the group of non-consumer patients showed a methylation rate slightly lower than controls. In patients with preliminary use of tetrahydrocannabinol (THC) the NRXN1 promoter turned out to be methylated almost two times higher than in non-consumer patients. In MAPT, non-consumer patients showed a significant lower mean methylation rate in comparison to controls. In THC-consuming patients the difference compared with controls became less. NRG1 and DISC1 showed no significant differences between groups, whereas DISC1 appeared to be not methylated at all. CONCLUSION: In MAPT and NRXN1 mean methylation rates were lower in non-consumer patients compared with controls, which seems to be a compensatory mechanism. With consumption of THC, mean methylation rates were increased: in the case of MAPT compared with controls, and in NRXN1 even significantly beyond that. Methylation of NRG1 and DISC1 seems not to be affected by the psychiatric disorder or by consumption of THC.

Severe hair loss associated with psychotropic drugs in psychiatric inpatients-Data from an observational pharmacovigilance program in German-speaking countries.

BACKGROUND: The study aimed to investigate severe hair loss related to psychotropic drugs (PDs) by using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie (AMSP). METHODS: Data on PD utilization and reports of severe PD-related hair loss were collected in 83 psychiatric hospitals in Austria, Germany and Switzerland during the period 1993-2013. RESULTS: Out of 432,215 patients under surveillance, 404,009 patients were treated with PDs for the main indications of depression, schizophrenic disorder, neurosis, mania, and organic psychosis. Severe hair loss related to PD treatment was reported in 43 cases (0.01%). The rates of hair loss under antipsychotic drugs were slightly lower than the mean rates of all PDs and antidepressant drugs. Valproic acid was related to the highest risk. In 6 of the 43 cases, hair loss was imputed to multiple drugs, with 4 cases imputed to double drug combinations and 2 cases to triple combinations. Rates of severe hair loss under valproic acid (VPA) and lithium salts were distinctly lower as compared with the overall rates reported in literature. Severe hair loss under PD treatment was reported significantly more often in female patients than in male patients (p < 0.01). CONCLUSION: The rate of severe PD-related hair loss was very low in the present survey. The large number of patients included in this multicentre study allows for assessment and comparison of hair loss rates related to different PDs and groups of PDs and provides new and supplementary information on PD-related hair loss.

Cortical electroconvulsive stimulation alleviates breeding-induced prepulse inhibition deficit in rats.

In patients with medical-refractory schizophrenia electroconvulsive therapy (ECT), i.e., the induction of therapeutic seizures via cortical surface electrodes, is effectively used. Electroconvulsive stimulation (ECS) in rodents simulates ECT in humans and is applied to investigate the mechanisms underlying this treatment. Experimentally-induced reduced prepulse inhibition (PPI) of the acoustic startle response (ASR), i.e., the reduction of the startle response to an intense acoustic stimulus when this stimulus is shortly preceded by a weaker not-startling stimulus, serves as an endophenotype for neuropsychiatric disorders that are accompanied by disturbed sensorimotor gating, such as schizophrenia. Here we used rats selectively bred for high and low PPI to evaluate whether bifrontal cortical ECS would affect PPI. For this purpose, cortical screw electrodes were stereotactically implanted above the frontal cortex. After recovery ECS was applied for five consecutive days with stimuli of 1 ms pulse-width, 100 pulses/s, 1 s duration, ranging from 5.5 mA to 10 mA. PPI of ASR was measured one day before ECS, and on days 1, 7, and 14 after the last ECS. In rats with breeding-induced low PPI ECS increased PPI one week after stimulation. In contrast, ECS decreased PPI in rats with high PPI on the first day after stimulation. The reaction to the startle impulse was reduced by ECS without difference between groups. This work provides evidence that rats with breeding-induced high or low PPI could be used to further investigate the underlying mechanisms of ECT in neuropsychiatric disorders with disturbed sensorimotor gating like schizophrenia.

Decreased galanin serum levels are associated with alcohol-craving during withdrawal.

BACKGROUND: The hypothalamic galanin expression has been associated with increased intake of carbohydrates and fats in preclinical studies. The appetite stimulating effect of galanin is thought to underlie the positive association between alcohol consumption and hypothalamic galanin expression observed in preclinical studies. METHODS: In this pilot study we investigated alterations in galanin serum levels (33 male patients) in alcohol-dependent patients during alcohol withdrawal (days 1, 7 and 14) in comparison to healthy controls (19 male controls). In order to assess the putative association between appetite regulation, galanin serum levels and alcohol consumption we additionally investigated the serum levels of insulin, glucose and triglycerides. RESULTS: The galanin serum levels on day 1 of alcohol withdrawal were significantly reduced in the alcohol-dependent patients (T=-3.302, p=0.002) and increased significantly from day 1 to day 14 of alcohol withdrawal (F=6.437, p=0.002). We found a significant negative association between the galanin serum levels and alcohol craving measured by the Obsessive Compulsive Drinking Scale (OCDS) (r=-0.449, p=0.009) and the obsessive subscale of the OCDS (r=-0.521, p=0.002) on day 1 of alcohol withdrawal. There was no association between the galanin serum levels and the parameters of energy homeostasis (triglycerides, cholesterol, insulin, and glucose) investigated. CONCLUSIONS: Acute alcohol withdrawal was associated with decreased galanin serum levels in this pilot study. There was no association between the galanin serum levels and the parameters of energy homeostasis. Further research of galanin serum levels in active drinkers will be necessary to clarify the putative association between galanin serum levels, appetite regulation and alcohol consumption.

Neuropathological and Reelin deficiencies in the hippocampal formation of rats exposed to MAM; differences and similarities with schizophrenia.

BACKGROUND: Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied. PRINCIPAL FINDINGS: Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged. CONCLUSIONS: Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.