Use and safety of antiepileptic drugs in psychiatric inpatients-data from the AMSP study.

The psychiatric utilization patterns and risks of antiepileptic drugs (AEDs) were assessed by using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie over the time period 1993-2013. In a total of 432,215 patients, the main indications for AED use were acute mania, schizoaffective disorder, and schizophrenic and organic psychoses. Valproic acid (VPA) was the most common substance across all of those groups, reaching administration rates of up to 50% since 2005, at which time carbamazepine (CBZ) administration consistently dropped below a rate of 10%. Lamotrigine (LTG) and pregabalin (PGB) increased in relevance after 2005 and 2010, respectively (with administration rates of up to 9%), whereas oxcarbazepine (OXC) was least prevalent (<3%). The mean rates of severe adverse drug reactions (ADRs) ranged from 6 cases per 1000 patients treated (VPA) to 19/1000 (OXC) and were significantly lower with treatment with VPA compared to OXC and CBZ. Hyponatremia was the leading ADR during treatment with OXC; severe allergic skin reactions were most often observed during treatment with CBZ and LTG, and severe oedema was most common during treatment with PGB. Severe hyponatremia induced by OXC was observed significantly more often in female patients than in male patients.

Elevated methylation and decreased serum concentrations of BDNF in patients in levomethadone compared to diamorphine maintenance treatment.

Brain-derived neurotrophic factor (BDNF) appears to play a crucial role in the reward response to drugs such as heroin. The primary objective of the present study was to examine epigenetic changes and serum levels of BDNF in patients undergoing different opiate-based maintenance treatments. We compared patients receiving treatment with either levomethadone (n = 55) or diamorphine (n = 28) with a healthy control group (n = 51). When comparing all subjects (patients and controls), BDNF serum levels showed a negative correlation with the BDNF IV promoter methylation rate (r = -0.177, p = 0.048). Furthermore, BDNF serum levels negatively correlated with Beck's Depression Inventory measurements (r = -0.177, p < 0.001). Patients receiving diamorphine maintenance treatment showed slightly decreased BDNF serum levels compared to healthy controls, whereas patients on levomethadone maintenance treatment with or without heroine co-use showed a pronounced decrease (analysis of covariance: control vs. levomethadone with and without heroine co-use: p < 0.0001, diamorphine vs. levomethadone with heroine co-use: p = 0.043, diamorphine vs. levomethadone without heroine co-use: p < 0.0001). According to these findings, methylation of the BDNF IV promoter showed the highest level in patients receiving levomethadone without heroine co-use (linear mixed model: control vs. levomethadone group without heroine co-use: p = 0.008, with heroin co-use: p = 0.050, diamorphine vs. levomethadone group with heroine co-use: p = 0.077 and without heroine co-use: p = 0.015.). For the first time, we show an epigenetic mechanism that may provide an explanation for mood destabilization in levomethadone maintenance treatment.

Joint Effects of the Epigenetic Alteration of Neurotrophins and Cytokine Signaling: A Possible Exploratory Model of Affective Symptoms in Alcohol-Dependent Patients?

AIMS: Neurotrophins have been linked to the symptomatology of alcohol dependence. We aimed to investigate a possible association between the methylation of the promoters of both neurotrophins, the serum levels of the cytokines and core symptoms of alcohol dependence as withdrawal severity and anxiety. METHODS: In this study we investigated a possible association between alterations in the methylation of the BDNF IV/NGF I gene promoter and the cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in 55 male alcohol-dependent patients. RESULTS: Mean methylation of the promoter of the BDNF gene was significantly associated with the TNF-α serum levels and the CIWA-score during withdrawal (P < 0.001). Moreover, mean methylation of the NGF I promoter was significantly associated with the IL-6 serum levels and STAI-I score during withdrawal (P < 0.001). CONCLUSION: Our results suggest an association between the epigenetic regulation of both neurotrophins, BDNF and NGF, cytokine release and the symptomatology of alcohol dependence. They imply that changes in the methylation of neurotrophins may contribute to the symptomatology of alcohol dependence by affecting relevant downstream signaling cascades.

BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy.

We examined potential changes in brain-derived neurotrophic factor (BDNF) serum levels and promoter methylation of the BDNF gene in 11 patients with treatment-resistant major depressive disorder during a series of electroconvulsive therapy (ECT). Blood samples were taken before, 1 and 24 h after ECT treatment sessions 1, 4, 7 and 10. Patients remitting under ECT had significantly lower mean promoter methylation rates, especially concerning the exon I promoter, compared to non-remitters (both p < 0.002). These findings may point to a depression subtype in which ECT is particularly beneficial.

Aripiprazole for the treatment of Tourette syndrome: a case series of 100 patients.

OBJECTIVE: Aripiprazole is an atypical neuroleptic with agonistic and antagonistic dopaminergic and serotonergic effects. Because preliminary data obtained from uncontrolled studies suggest that aripiprazole may be effective in the treatment of tics, we performed a retrospective study with a large group of patients with Tourette syndrome. METHODS: One hundred patients (78 men and 22 women; mean ± SD age, 27.1 years (± 11.5) years) who had been treated with daily doses of 5 to 45 mg (mean, 17.0 ± 9.6 mg) aripiprazole at our specialized Tourette syndrome outpatient clinic were included. Ninety-five patients with insufficient pretreatment (one or more neuroleptics) were switched to aripiprazole. RESULTS: Eighty-two patients exhibited a considerable reduction in tic severity. In 48 patients, effective treatment lasted for more than 12 months. Five patients reported additional beneficial effects on behavioral comorbidities such as depression, anxiety, and autoaggression. Altogether, 31 patients (31%) dropped out of the treatment owing to inefficacy (n = 7), adverse effects (n = 15: drowsiness, agitation, weight gain, and sleep disturbances), both (n = 4) or other reasons (n = 5). CONCLUSION: This is the largest case series on the treatment of tics with aripiprazole so far. Overall, our results corroborate previous data suggesting that aripiprazole is effective and safe in most patients. In particular, our data confirm effectiveness in adult patients and clarify that beneficial effects sustain. However, in contrast to previous data, in 1 of 3 of our highly selected patients, aripiprazole was ineffective or not well tolerated. Optimal dose seems to be individually different and may range from 5 to 45 mg.

Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy.

OBJECTIVES: To determine the possible interactions between levodopa therapy and plasma levels of B vitamins in patients with advanced idiopathic Parkinson's disease (IPD) in the context of either oral levodopa therapy or levodopa/carbidopa intestinal gel (LCIG). Secondly, to determine the prevalence of neuropathy and its relation to plasma levels of B vitamins and homocysteine. METHODS: Medication doses, neurographies, and serum levels of pyridoxine, cobalamin, folate, and homocysteine of eight LCIG and 13 orally treated advanced IPD patients matched for age, Hoehn & Yahr stage, and UPRDS III were collected. This data was analyzed for correlation with daily levodopa dose (LDD). RESULTS: LICG patients had a longer disease duration and higher LDD. All LCIG patients and most orally treated patients had sensorimotor axonal polyneuropathy. Of all plasma vitamin levels, pyridoxine was decreased most and significantly lower in the LCIG group. Cobalamin and folate, however, were within the lower reference range, and homocysteine highly elevated, all without any significant difference between both groups. LDD correlated significantly with pyridoxine deficiency (p = .02) irrespective of the route of application and with hyperhomocysteinemia in the LCIG group (p = .03). At LDDs above 2,000 mg, pyridoxine deficiency was almost always detectable. CONCLUSIONS: Pyridoxine deficiency and hyperhomocysteinemia are dependent on the daily levodopa/carbidopa dose, while levels of cobalamin and folate are not. The mode of application of levodopa/carbidopa has no impact on B-vitamin levels. Neuropathy is very frequent in advanced IPD; however, it remains to be investigated further whether neuropathy is more frequent in LCIG than in orally levodopa/carbidopa-treated advanced IPD patients.

Behavioral differences of male Wistar rats from different vendors in vulnerability and resilience to chronic mild stress are reflected in epigenetic regulation and expression of p11.

Outbred rat lines such as Wistar rats are commonly used for models of depressive disorders. Such rats arise from random mating schedules. Hence, genetic drift occurs in outbred populations which could lead to genotypic and phenotypic heterogeneity between rats from different vendors. Additionally, vendor specific rearing conditions could contribute to intrastrain variability. In the present study differences in behavioral responses to the chronic mild stress (CMS) model of depression within Wistar rat strains from different vendors are described. DNA methylation studies and mRNA expression analysis of p11 revealed that the behavioral differences between the substrains are reflected at the epigenetic and genetic level. The results suggest that there are breeder-dependent differences in vulnerability to stress in the CMS model of depression, which might bear on the validity of the model and contribute to contradictory findings and difficulties of replication between laboratories. P11 mRNA expression seems to be differently regulated depending on the quality of the stress response evoked by CMS exposure.

Psychopharmacological treatment of 1650 in-patients with acute mania-data from the AMSP study.

BACKGROUND: Several studies have analyzed prescription patterns for bipolar disorder, but few have for acute mania. Treatment strategies in this complex domain change over time and do not always follow evidence-based guidelines. METHODS: Prescription data of in-patients suffering from acute mania in the time period from 2005 to 2012 were obtained from the database of the Drug Safety Program in Psychiatry (Institut für Arzneimittelsicherheit in der Psychiatrie; AMSP). Data were collected on two index dates per year. Changes over time were analyzed comparing the time periods 2005/06 and 2011/12. RESULTS: Among 1650 patients (mean ±SD; age: 48.9±14.91 years; 53.1% females) 54.1% received anticonvulsants, 74.5% second-generation antipsychotics (SGAs), 17.8% first-generation antipsychotics (FGAs), 29.1% lithium, 44.1% benzodiazepines and 14.5% antidepressants. Prescription of SGAs increased from 70% to 79% (p=0.005), while prescription of FGAs and anticonvulsants decreased from 19% to 13% (p<0.05) and 59% to 46% (p<0.001), respectively. Only 30% of patients received monotherapy with one mood stabilizer. We observed an impact of gender, age and psychotic symptoms on treatment strategy. 36.8% of the women≤40 years received valproate. LIMITATIONS: Follow-up data are missing and no differentiation between acute and maintenance treatments could be made due to the cross-sectional design. Additionally, our findings do not necessarily translate to outpatients or to other countries. CONCLUSIONS: Combination therapies represent standard clinical practice. Though many results reflect clinical necessity, the high number of antidepressant prescriptions or valproate use in women of child-bearing age should be judged critically. Further prospective studies should focus on real-world prescription practice in acute mania to evaluate efficacy and safety of common practice. This paper is dedicated to Prof. Dr. Hanns Hippius on the occasion of his 90th birthday.

Do changes in the BDNF promoter methylation indicate the risk of alcohol relapse?

The neurotrophic growth factor brain derived neurotrophic factor (BDNF) was linked to the risk of alcohol relapse in clinical studies. In this study we investigated alterations in the methylation of the BDNF gene during alcohol withdrawal (day 1, 7 and 14) in 99 male alcohol-dependent patients compared to age matched healthy males (n=33). In particular, we aimed to investigate a possible association between the BDNF promoter methylation and the self-reported duration of alcohol abstinence before relapse. Mean methylation of the BDNF promoter was significantly increased in alcohol-dependent patients compared to the healthy controls (F=10.014, p<0.001) and decreased significantly during alcohol-withdrawal (F=10.014, p<0.001). Moreover, mean methylation was associated with depressive (F=2.014, p<0.001) and anxious symptoms in the alcohol-dependent patients (F=2.228, p<0.001). On day 14 of alcohol-withdrawal we found significantly higher methylation rates in those patients who abstained longer before relapse compared to those patients who abstained shorter (F=9.938, p<0.001). Our results suggest an association between BDNF expression and the symptomatology of alcohol withdrawal and imply that changes in the methylation of the BDNF IV gene may contribute to alcohol consumption.

Psychiatric symptoms in patients with Shiga toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome.

BACKGROUND: In May 2011 an outbreak of Shiga toxin-producing enterohaemorrhagic E. coli (STEC) O104:H4 in Northern Germany led to a high number of in-patients, suffering from post-enteritis haemolytic-uraemic syndrome (HUS) and often severe affection of the central nervous system. To our knowledge so far only neurological manifestations have been described systematically in literature. AIM: To examine psychiatric symptoms over time and search for specific symptom clusters in affected patients. METHODS: 31 in-patients suffering from E. coli O104:H4 associated HUS, were examined and followed up a week during the acute hospital stay. Psychopathology was assessed by clinical interview based on the AMDP Scale, the Brief Symptom Inventory and the Clinical Global Impressions Scale. RESULTS: At baseline mental disorder due to known physiological condition (ICD-10 F06.8) was present in 58% of the examined patients. Patients suffered from various manifestations of cognitive impairment (n = 27) and hallucinations (n = 4). Disturbances of affect (n = 28) included severe panic attacks (n = 9). Psychiatric disorder was significantly associated with higher age (p<0.0001), higher levels of C-reactive protein (p<0.05), and positive family history of heart disease (p<0.05). Even within the acute hospital stay with a median follow up of 7 days, symptoms improved markedly over time (p <0.0001). CONCLUSIONS: Aside from severe neurological symptoms the pathology in E.coli O104:H4 associated HUS frequently includes particular psychiatric disturbances. Long term follow up has to clarify whether or not these symptoms subside.