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Introduction Precision medicine in psychiatry is still in its infancy. To establish patient-tailored treatment, adequate indicators predicting treatment response are required. Electroconvulsive therapy (ECT) is considered one of the most effective options for pharmacoresistant major depressive disorder (MDD), yet remission rates were reported to be below 50%. Methods Since epigenetics of the stress response system seem to play a role in MDD, we analyzed the DNA methylation (DNAm) of genes encoding the glucocorticoid receptor (NR3C1) and proopiomelanocortin (POMC) through Sanger Sequencing. For analysis, blood was taken before and after the first and last ECT from MDD patients (n=31), unmedicated depressed controls (UDC; n=19, baseline), and healthy controls (HC; n=20, baseline). Results Baseline DNAm in NR3C1 was significantly lower in UDCs compared to both other groups (UDC: 0.014(±0.002), ECT: 0.031(±0.001), HC: 0.024(±0.002); p Discussion Our findings indicate that both genes might play a role in the chronification of depression and NR3C1 may be relevant for ECT response prediction.

The significance of neurological soft signs (NSS) in major depressive disorder (MDD) remains unclear and the stability of NSS in relation to antidepressant treatment has never been investigated. We hypothesized that NSS are relatively stable trait markers of MDD. We thus predicted that patients show more NSS than healthy controls, irrespective of illness duration and antidepressant treatment. To test this hypothesis, NSS were assessed in chronically depressed, medicated MDD patients before (n = 23) and after (n = 18) a series of electroconvulsive therapy (ECT). In addition, NSS were assessed once in acutely depressed, unmedicated MDD patients (n = 16) and healthy controls (n = 20). We found that both chronically depressed, medicated MDD patients and acutely depressed, unmedicated MDD patients showed more NSS than healthy controls. The degree of NSS in both patient groups did not differ. Importantly, we found no change in NSS after on average eleven sessions of ECT. Thus, the manifestation of NSS in MDD seems to be independent of illness duration and pharmacological and electroconvulsive antidepressant treatment. From a clinical perspective, our findings corroborate the neurological safety of ECT.

Autoimmune encephalitis (AE) can rarely manifest as a predominantly psychiatric syndrome without overt neurological symptoms. This study’s aim was to characterize psychiatric patients with AE; therefore, anonymized data on patients with suspected AE with predominantly or isolated psychiatric syndromes were retrospectively collected. Patients with readily detectable neurological symptoms suggestive of AE (e.g., epileptic seizures) were excluded. Patients were classified as “probable psychiatric AE (pAE),” if well-characterized neuronal IgG autoantibodies were detected or “possible pAE” (e.g., with detection of nonclassical neuronal autoantibodies or compatible cerebrospinal fluid (CSF) changes). Of the 91 patients included, 21 (23%) fulfilled our criteria for probable (autoantibody-defined) pAE and 70 (77%) those for possible pAE. Among patients with probable pAE, 90% had anti-NMDA receptor (NMDA-R) autoantibodies. Overall, most patients suffered from paranoid-hallucinatory syndromes (53%). Patients with probable pAE suffered more often from disorientation (p p = 0.001) than patients with possible pAE. Immunotherapies were performed in 69% of all cases, mostly with high-dose corticosteroids. Altogether, 93% of the patients with probable pAE and 80% of patients with possible pAE reportedly benefited from immunotherapies (p = 0.251). In summary, this explorative, cross-sectional evaluation confirms that autoantibody-associated AE syndromes can predominantly manifest as psychiatric syndromes, especially in anti-NMDA-R encephalitis. However, in three out of four patients, diagnosis of possible pAE was based on nonspecific findings (e.g., slight CSF pleocytosis), and well-characterized neuronal autoantibodies were absent. As such, the spectrum of psychiatric syndromes potentially responding to immunotherapies seems not to be limited to currently known autoantibody-associated AE. Further trials are needed.

This study investigated the recently reported association between alcohol dependence and accelerated ageing and the potential effects of abstinence and relapse on DNA methylation status using Levine's epigenetic clock to estimate DNA methylation age in two independent cohorts. The first sample comprised 88 (15 female) detoxified patients with alcohol use disorder (AUD) and 32 (5 female) healthy control (CON) subjects (NCT02615977), and the second included 69 (10 female) AUD patients that were followed up for 12 months with respect to relapse (n = 38, 4 female) and abstinence (n = 31, 6 female) (NCT01679145). To account for the different aspects of ageing captured by various clocks, we performed additional analyses of the first-generation Horvath clock and next-generation Zhang clock. To account for the genetic liability of AUD and its potential influence on DNA methylation, we calculated a polygenic risk score for alcohol dependence. We found that ageing was accelerated by 3.64 years in AUD patients compared with the CON group according to Levine's DNAm PhenoAge. Furthermore, in a second longitudinal sample, we found that abstaining AUD patients displayed a decrease in DNAm PhenoAge by 3.1 years, but we found an over proportional increase by 2.7 years in those who relapsed. Polygenic risk did not affect epigenetic ageing within our sample. These results confirm the age acceleration associated with AUD and provide the first evidence for a recovery of this effect upon abstinence from alcohol.

Die umfassende Neubearbeitung des Handbuches liefert kompakte und klare Informationen zu allen in Deutschland, Österreich und der Schweiz erhältlichen Psychopharmaka. Die Einteilung der Psychopharmaka erfolgt nach dem jeweiligen Anwendungsbereich. So werden u.a. Antidepressiva, Antipsychotika, Anxiolytika, Hypnotika, Phasenprophylaktika, Substanzen zur Behandlung der ADHS und des Substanzmissbrauchs, Antidementiva, missbräuchlich verwendete Substanzen und triebdämpfende Arzneimittel in all ihren psychopharmakologischen Eigenschaften und Wechselwirkungen dargestellt. Im Buch wird mit verschiedenen Icons zu Indikationen und Kontraindikationen, Dosierung, Pharmakokinetik, unerwünschten Arzneimittelwirkungen, Absetzphänomenen, Hinweisen für die Pflege, Wechselwirkungen etc. gearbeitet. Leserinnen und Leser des Handbuches können dadurch schnell die für sie relevanten Informationen zu einem bestimmten Psychopharmakon auffinden. Auch nichtpharmakologische Therapieverfahren wie die Repetitive Transkranielle Magnetstimulation oder die Lichttherapie werden ausführlich behandelt. Zusätzlich zum Handbuch werden über 90 Seiten Patienteninformationen über häufig angewendete Psychopharmaka zur Verfügung gestellt, die nach erfolgter Registrierung von der Hogrefe Website heruntergeladen und den Patientinnen und Patienten mit nach Hause gegeben werden können. Dank der Übersichtlichkeit und leichten Zugänglichkeit der Informationen stellt das Handbuch ein praxisorientiertes und aktuelles Nachschlagewerk für alle im psychiatrischen Bereich tätigen Berufsgruppen dar.

Viral encephalitis often presents with severe illness, headache, fever, behavioral changes, altered level of consciousness, and focal neurologic deficits. One of the most feared kind of virus encephalitis is herpes simplex encephalitis; however, other central virus infections are also capable of presenting with psychiatric symptoms. Here, we report the case of a 22-year-old woman with first time visual and auditory hallucinations due to an acute enterovirus encephalitis with no cerebrospinal fluid abnormalities but a positive PCR result for enterovirus (ECHO). During treatment, the symptoms deteriorated, and she hat to be shifted to the sheltered ward because of imperative suicidal auditory hallucinations. Under treatment with risperidone and olanzapine, symptoms suddenly stopped and did not reoccur under subsequent reduction of the antipsychotic medication.

Objectives Drug-induced liver injury (DILI) has been associated with various antipsychotic drugs (APDs). Comparative studies between individual APDs are largely not available. Methods Antipsychotic drug utilisation data and reports of severe antipsychotic DILI were assessed by using data from an observational pharmacovigilance programme-Arzneimittelsicherheit in der Psychiatrie (AMSP)-during the period 1993-2016. Results Of the 333,175 patients treated with APDs, a total of 246 (0.07%) events of severe DILI were identified. Phenothiazines were associated with significantly higher rates of severe DILI (0.03%, 95% CI = 0.02-0.04) than thioxanthenes (0.01%, 95% CI = 0.00-0.02) or butyrophenones (0.01%, 95% CI = 0.00-0.01). Among individual drugs, olanzapine (0.12%, 95% CI = 0.10-0.16), perazine (0.09%, 95% CI = 0.05-0.15) and clozapine (0.09%, 95% CI = 0.10-0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more APDs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe DILI while older patients (≥65 years old) were significantly less often affected. Conclusions In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual APDs associated with severe DILI.

Alcohol use disorder is one of the most disabling diseases worldwide. Glial-cell derived neurotrophic factor (Gdnf) shows promising results concerning the inhibition of alcohol consumption in rodent models. We investigated the epigenetic regulation of Gdnf following ethanol consumption and withdrawal in a rat model. 32 Wistar rats underwent 7 weeks of intermittent access to alcohol in a 2-bottle choice (IA2BC). Whole blood, Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA) were collected immediately after the last 24 h of an alcohol-drinking session (alcohol group, AG) or 24 h after withdrawal (withdrawal group, WG). MRNA levels were measured using real-time quantitative PCR. Bisulfite-conversion of DNA and capillary sequencing was used to determine methylation levels of the core promoter (CP) and the negative regulatory element (NRE). The CP of the AG in the NAc was significantly less methylated compared to controls (p 0.05). In the NAc, mRNA expression was significantly higher in the WG (p 0.05). In the WG, mRNA expression levels in the VTA were significantly lower (p 0.05) and showed significantly less methylation in the NRE in the VTA (p 0.001) and the NAc (p 0.01) compared to controls. Changes in the cerebral mRNA expression correspond to alterations in DNA methylation of the Gdnf promoter in a rodent model. Our results hold clinical relevance since differences in Gdnf mRNA expression and DNA methylation could be a target for pharmacological interventions.

Obesity is often accompanied by major depressive disorder (MDD), and vice versa. Latest research findings suggest the body mass index (BMI) to play a role in antidepressant treatment response in general. Our study aims to examine whether adiposity-related parameters such as BMI, glucose homeostasis, or serum lipids are associated with remission to electroconvulsive therapy (ECT). A pilot study (PS, n = 9) and a glucose study (GS, n = 29) were conducted. Blood was withdrawn directly before and 15 min (GS) as well as 1 h (PS) after the first ECT and directly before the last one (usually an ECT series comprised up to twelve sessions). BMI was associated with remission in the PS (remitters: M = 28, SD = 2.5; non-remitters: M = 22, SD = 2.08; t(7) = 3.325, p d = 0.24) but not in the GS or when pooled together. Glucose and insulin levels increased significantly after a single ECT session (GS: glucose: F (2,25.66) = 39.04, p F (2,83) = 25.8, p F (2,25.87) = 3.97, p

We examined potential changes in catecholamine plasma levels and cortisol serum levels in 29 patients with treatment-resistant Major Depressive Disorder (MDD) during a course of electroconvulsive therapy (ECT). Blood samples were taken at three different time points: directly before (T1) and 15 min after (T2) the first ECT, and directly before the last one (T3). Patients responding to ECT had a significant decrease of the intraindividual epinephrine plasma level when both first time points (Δ T1-T2) were compared (χ2 (1) = 10.05, p = 0.002). This finding encourages further investigation in the understanding of the catecholamine-metabolism including its release and uptake in patients with treatment-resistant MDD receiving ECT.

The aim of the study was to assess rates of severe parkinsonism related to different antipsychotic drugs (APDs) using data from an observational pharmacovigilance programme in German-speaking countries—Arzneimittelsicherheit in der Psychiatrie (AMSP). Data on APD utilization and reports of severe APD-induced parkinsonism were collected in 99 psychiatric hospitals in Austria, Germany and Switzerland during the period 2001–2016. Of 340,099 patients under surveillance, 245,958 patients were treated with APDs for the main indications of schizophrenic disorders, depression, mania and organic mental disorders. A total of 200 events of severe APD-induced parkinsonism were identified (0.08%). First-generation low-potency APDs were significantly less often implicated (0.02%) than second-generation APDs (0.07%) and first-generation high-potency APDs (0.16%). Among the second-generation APDs, amisulpride and risperidone ranked highest. The phenothiazines were associated with significantly lower rates of severe parkinsonism (0.02%) than those of the butyrophenones (0.11%) and thioxanthenes (0.12%). In 71 cases (35.5%), more than 1 drug was considered responsible for the induction of severe parkinsonism. In 44 patients (22.0%), the symptoms were extremely severe, leading to complete immobility and/or massive complications such as pneumonia and severe injuries due to falls. Higher age (> 60 years) was associated with significantly higher rates of severe parkinsonism, as were the diagnoses of schizophrenic disorder or mania. The large number of patients included in the present survey allows for the comparison of severe parkinsonism rates related to different APD classes and single APDs. The first-generation low-potency APDs had significantly reduced risk of severe parkinsonism compared not only to high potency but also to second-generation APDs.

Objectives: The study aimed to assess seizure rates related to different antipsychotic drugs (APDs) in a clinical setting using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie (AMSP).Methods: Psychotropic drug use data and reports of APD-related seizures were collected in 89 psychiatric hospitals in Austria, Germany and Switzerland from 1993 to 2015.Results: Of 475,096 patients under surveillance, 320,383 patients were treated with APDs for the main indications of schizophrenic disorders, mood disorders and organic disorders. A total of 144 APD-related tonic clonic seizures were identified (0.04%). The butyrophenones ranked slightly lower (0.03%) compared to the phenothiazines, thioxanthenes and second-generation APDs (0.05% each). No significant differences were observed when comparing first- and second-generation APDs. Clozapine was related to the highest seizure rate (0.18%). In 107 cases (74.3%), more than one drug was considered responsible for seizure induction....

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal–fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal–fetal transfer of Contactin-associated protein-like 2, N-methyl-d-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

Background Major depressive disorder (MDD) represents a serious global health concern. The urge for efficient MDD treatment strategies is presently hindered by the incomplete knowledge of its underlying pathomechanism. Despite recent progress (highlighting both genetics and the environment, and thus DNA methylation, to be relevant for its development), 30–50% of MDD patients still fail to reach remission with standard treatment approaches. Electroconvulsive therapy (ECT) is one of the most powerful options for the treatment of pharmacoresistant depression; nevertheless, ECT remission rates barely reach 50% in large-scale naturalistic population-based studies. To optimize MDD treatment strategies and enable personalized medicine in the long- term, prospective indicators of ECT response are thus in great need. Because recent target-driven analyses revealed DNA methylation baseline differences between ECT responder groups, we analyzed the DNA methylome of depressed ECT patients using next-generation sequencing. In this pilot study, we did not only aim to find novel targets for ECT response prediction but also to get a deeper insight into its possible mechanism of action. Results Longitudinal DNA methylation analysis of peripheral blood mononuclear cells isolated from a cohort of treatment-resistant MDD patients (n = 12; time points: before and after 1st and last ECT, respectively) using a TruSeq-Methyl Capture EPIC Kit for library preparation, led to the following results: (1) The global DNA methylation differed neither between the four measured time points nor between ECT responders (n = 8) and non-responders (n = 4). (2) Analyzing the DNA methylation variance for every probe (=1476812 single CpG sites) revealed eight novel candidate genes to be implicated in ECT response (protein-coding genes: RNF175, RNF213, TBC1D14, TMC5, WSCD1; genes encoding for putative long non-coding RNA transcripts: AC018685.2, AC098617.1, CLCN3P1). (3) In addition, DNA methylation of two CpG sites (located within AQP10 and TRERF1) was found to change during the treatment course. Conclusions We suggest ten novel candidate genes to be implicated in either ECT response or its possible mechanism. Because of the small sample size of our pilot study, our findings must be regarded as preliminary.

Major Depressive Disorder (MDD) is a major contributor to the global burden of disease. Approximately 30–50% of depressed patients fail to reach remission with standard treatment approaches. Electroconvulsive therapy (ECT) is one of the most effective options for these patients. Its exact therapeutic mechanism remains elusive, and reliable predictors of response are absent in the routine clinical practice. To characterize its mode of action and to facilitate treatment decision-making, we analyzed ECT's acute and chronic effects on various immune cell subsets. For this purpose, blood was withdrawn from depressed patients (n=21) directly before and 15 min after the first and last ECT session, respectively. After isolating peripheral blood mononuclear cells, we investigated defined populations of immune cells and their proportional changes upon ECT treatment using flow cytometry. By these means, we found ECT remitters (R; n=10) and non-remitters (NR; n=11) to differ in their relative proportion of putative immunoregulatory CD56highCD16–/dim and cytotoxic CD56dimCD16+ natural killer (NK) cells (CD56highCD16–/dim/CD56dimCD16+: R=0.064(±0.005), NR=0.047(±0.005), p

Current treatment guidelines for major depressive disorders (MDD) recommend the use of antidepressive drugs. Today, the decision on specific drugs is mainly driven by trial and error, as no markers are at hand that can guide this decision. Resulting response and remission rates are therefore unsatisfactorily low. We and others have shown that epigenetic biomarkers based on DNA methylation status of specific gene promoter regions can predict the individual susceptibility toward monoaminergic drugs, psychotherapy, or electroconvulsive therapy, making it possible to provide clinicians and patients with a specific recommendation toward a certain treatment. Further potential epigenetic markers include specific histone modifications, chromatin structure, and also small RNA species. For example, specific alterations of the DNA methylation of the gene encoding the brain-derived neurotrophic factor (BDNF) predicted nonresponsiveness to monoaminergic drugs such as citalopram, or even lithium, in two independent trials of antidepressant treatments. Use of these epigenetic biomarkers will increase the proportion of patients receiving an adequate therapy initially, reduce the time until depressive symptoms decrease, and ultimately help prevent chronic courses of the disorder.

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.

Background Suicidal ideations, suicide attempts, and fatal suicides are rare adverse drug reactions to antidepressant drugs, but they essentially are clinically relevant. Drawing on a larger dataset of the European drug surveillance program, the present naturalistic study updates a previous contribution (Stübner et al., 2010). Methods First an analysis of the comprehensive data collected in 81 psychiatric hospitals from 1993 to 2014 by the European drug surveillance program Arzneimittelsicherheit in der Psychiatrie was made. All documented single cases of suicidal ideations or behavior judged as adverse drug reactions to antidepressant drugs were carefully assessed as to their clinical features and drug prescriptions. Results Among 219,635 adult hospitalized patients taking antidepressant drugs under surveillance, 83 cases of suicidal adverse drug reactions occurred (0.04%): 44 cases of suicidal ideation, 34 attempted suicides, and 5 committed suicides were documented. Restlessness was present in 42 patients, ego-dystonic intrusive suicidal thoughts or urges in 39 patients, impulsiveness in 22 patients, and psychosis in 7 patients. Almost all adverse drug reactions occurred shortly after beginning antidepressant drug medication or increasing the dosage. Selective serotonin reuptake inhibitors caused a higher incidence of suicidal ideation and suicidal behavior as adverse drug reactions than noradrenergic and specific serotonergic antidepressants or tricyclic antidepressants, as did monotherapy consisting of one antidepressant drug, compared to combination treatments. Conclusions The study supports the view that antidepressant drug-triggered suicidal ideation and suicidal behavior (primarily with selective serotonin reuptake inhibitors) are rare. Special clinical features (restlessness, ego-dystonic thoughts or urges, impulsiveness) may be considered as possible warning signs. A combination therapy might be preferable to antidepressant drug monotherapy when beginning treatment.

Background. Electroconvulsive therapy (ECT) is one of the most effective treatment options for refractory depressed patients. To date, there are only a few predictors of response. Aim. The aim was to identify predictive biomarkers of remission to ECT on a molecular level. Methods. 11 patients suffering from a major depressive episode—according to the Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)—underwent 10 ECT sessions. Blood samples were taken, and the depression severity was assessed before, one hour and 24 hours after sessions 1, 4, 7, and 10 using the Montgomery Asberg Depression Rating Scale (MADRS). A MADRS total score Results. Patients remitting under ECT had significantly higher homocysteine (p<0.001), S100B (p<0.001), and procalcitonin (PCT) (p=0.027) serum levels. On the contrary, serum levels of vitamin B12 (p<0.001) and folic acid (p=0.007) were significantly lower in remitters compared to those in nonremitters. Levels remained unchanged throughout the whole ECT course. Conclusions. Our findings indicate that lower levels of vitamin B12 and folic acid associated with higher levels of homocysteine, S100B, and PCT point to a subgroup of depressed patients sensitive to ECT. Due to the limited sample size, further studies are required to replicate our findings.

Epigenetic alterations are increasingly implicated in the pathophysiology of anorexia nervosa (AN) but are as yet poorly understood. We investigated possible associations between the leptin gene (LEP) and the leptin receptor gene (LEPR) DNA promoter methylation and (1) a diagnosis of AN and (2) outcome after a 10 months psychotherapeutic outpatient treatment. 129 (LEPR: n = 135) patients with AN were investigated during the large scale psychotherapeutic Anorexia Nervosa Treatment Outpatient Study (ANTOP) trial, compared to 117 (LEPR: n = 119) age and height matched, normal-weight healthy controls. Blood samples were taken at baseline, the end of therapy (40 weeks) and the 12-months follow-up and compared to controls. Methylation was measured in whole blood via bisulfite sequencing. Within the promoter region 32 (LEP) and 39 CpG sites (LEPR) were analyzed. Two key findings were observed. First, LEP and LEPR methylation at baseline were lower in patients compared to controls (LEP: [%] AN: 30.94 ± 13.2 vs. controls: 34.53 ± 14.6); LEPR ([%] AN: 3.73 ± 5.4 vs. controls: 5.22 ± 8.3, mixed linear models: both P < 0.001). Second, lower DNA methylation of the LEP promoter, with a dynamic upregulation during treatment, was associated with a full recovery in AN patients (% change from baseline to follow-up in full recovery patients: +35.13% (SD: 47.56); mixed linear model: P < 0.0001). To test for potential predictive properties of mean LEP DNA methylation a LEP DNA methylation cut-off (31.25% DNA methylation) was calculated, which significantly discriminated full recovery vs. full syndrome AN patients. This cut-off was then tested in a group of previously unclassified patients (missing follow-up data of the Structured Interview for Anorexic and Bulimic disorders; n = 33). Patients below the cut-off (31.25% LEP DNA methylation) showed an increase in BMI over time, while those above the cut-off had a decrease in BMI (ANOVA at the 12-months follow-up: P = 0.0142). To our knowledge, this is the first study investigating epigenetic alterations in AN over time. Our findings indicate that LEP DNA methylation might be involved in the disease course of AN.

Major problems of current antidepressant pharmacotherapy are insufficient response rates and difficulties in response prediction. We recently provided preliminary evidence in a small study that patients with major depressive disorder (MDD) with a hypomethylation of the CpG-87 site of the promoter IV region of the brain-derived neurotrophic factor (BDNF) gene are less likely to benefit from antidepressants. Here, we aimed at replicating this finding in a secondary analysis of 561 MDD patients (mean age 40.0 ± 11.9 years, 56% female) included into the Early Medication Change study (EMC). We measured BDNF exon IV promoter and p11 gene methylation at Baseline (BL) as well as BDNF-plasma-levels (pBDNF) at BL and day 14 and related them to treatment outcome. Although we were not able to replicate the predictor function of hypomethylation of the BDNF exon IV promoter, a subgroup of patients with severe depression (Hamilton Depression Rating Scale [HAMD-17] ≥ 25) (n = 199) and hypermethylation at CpG-87 of the BDNF exon IV promoter had significantly higher remission rates than patients without a methylation (p = 0.032). We also found that 421 (75%) of 561 patients showed an early improvement (≥ 20% HAMD-17 reduction after 2 weeks), which was associated with a 4.24-fold increased likelihood to remit at study end compared to the 140 patients without early improvement. However, specificity of response prediction of early improvement was low (34%) and false positive rate high (66%). The combination of early improvement with a pBDNF increase between BL and day 14, however, increased the specificity of response prediction from 34 to 76%, and the combination with methylation of the CpG-87 site of the BDNF exon IV promoter from 34 to 62%. Thus, the combined markers reduced false positives rates from 66 to 24% and 38%, respectively. Methylation at other sites or p11 promoter methylation failed to increase specificity of early improvement prediction. In sum, the results add to previous findings that BDNF, BDNF promoter methylation and the combination of clinical and biological markers may be interesting candidates for therapy response prediction which has to be confirmed in further studies. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00974155, identifier: NCT00974155.

Chronic granulomatous disease (CGD) is a rare genetic immunodeficiency which is characterized by recurrent severe bacterial and fungal infections caused by a defect in phagocytic cells due to loss of superoxide production. The disease usually manifests within the first years of life. Early diagnosis allows therapeutic intervention to improve the limited life expectancy. Nevertheless, only half of the patients exceed the age of 25. Here, we present the case of a 41-year old female patient who presented with an extensive spinal cord infection and atypical pneumonia mimicking tuberculosis. The medical history with recurrent granulomatous infections and microbiological findings with multiple unusual opportunistic pathogens was the key to the diagnosis of chronic granulomatous disease which is exceptionally rare first diagnosed in patients in the fifth decade of life. The late diagnosis in this case was likely to the lack of knowledge of the disease by the treating teams before but not because the patient did not have typical CDG infections along her life. The extensive progressive developing granulomas in our patient with fatal outcome raise the question of early immunosuppressive therapy in addition to anti-infectious treatment. We recommend appropriate CGD diagnostics in adult patients with unclear granulomatous diseases of the nervous system.

Although electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Thus, there is a need for markers reliably predicting ECT non/response. In our study, we have taken a novel translational approach for discovering potential biomarkers for the prediction of ECT response. Our hypothesis was that the promoter methylation of p11, a multifunctional protein involved in both depressive-like states and antidepressant treatment responses, is differently regulated in ECT responders vs. nonresponders and thus be a putative biomarker of ECT response. The chronic mild stress model of MDD was adapted with the aim to obtain rats that are resistant to conventional antidepressant drugs (citalopram). Subsequently, electroconvulsive stimulation (ECS) was used to select responders and nonresponders, and compare p11 expression and promoter methylation. In the rat experiments we found that the gene promoter methylation and expression of p11 significantly correlate with the antidepressant effect of ECS. Next, we investigated the predictive properties of p11 promoter methylation in two clinical cohorts of patients with pharmacoresistant MDD. In a proof-of-concept clinical trial in 11 patients with refractory MDD, higher p11 promoter methylation was found in responders to ECT. This finding was replicated in an independent sample of 65 patients with pharmacoresistant MDD. This translational study successfully validated the first biomarker reliably predicting the responsiveness to ECT. Prescreening of this biomarker could help to identify patients eligible for first-line ECT treatment and also help to develop novel antidepressant treatment procedures for depressed patients resistant to all currently approved antidepressant treatments.

Objectives: Executive dysfunctions are frequently seen in patients with major depressive disorder (MDD) and normalise in many cases during effective antidepressant therapy. This study investigated whether a normalisation of executive dysfunctions during antidepressant treatment correlates with or can be predicted by clinical parameters or levels of brain-derived neurotrophic factor (BDNF). Methods: In 110 MDD patients with executive dysfunctions (percentile Results: Eighty patients (73%) experienced a normalisation of executive dysfunctions, while 30 (27%) suffered from persistent dysfunctions until day 56. Patients with persistent dysfunctions had significantly higher HAMD scores at days 14 and 56, and lower plasma BDNF levels at each time point than patients with a normalisation of dysfunctions (F1= 10.18; P = 0.002). This was seen for verbal fluency, but not processing speed. BDNF exon IV and p11 promoter methylation was not associated with test performance. Conclusions: Our results corroborate a concomitant amelioration of executive dysfunctions with successful antidepressant therapy and support a role of BDNF in the neural mechanisms underlying the normalisation of executive dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96

Aims: The nerve growth factor (NGF) and the vascular endothelial growth factor-A (VEGF-A) may be of importance for psychiatric diseases including substance use disorders. The aim of the study was to identify differences in the regulation of both neuropeptides via the DNA-methylation status of the promotor regions of NGF and VEGF-A in different forms of maintenance therapy for opioid dependence and the related stress regulation via the hypothalamic-pituitary-adrenal axis. Methods: We compared methylation levels of opioid-dependent patients receiving treatment with diamorphine (n = 28) or levomethadone (n = 54) and similar levels in a healthy control group (n = 72). Results: There was a significantly higher methylation of VEGF-A in opioid-maintained patients with levomethadone compared to that in the control group (estimated marginal means [EMM] [SE]): 0.036 [0.003] vs. 0.020 [0.003]; p < 0.001). We performed a cluster analysis for NGF, splitting up the results in 4 clusters. We found significant changes in methylation rates of the opioid-maintained patients compared to the controls in cluster I ([EMM] [SE]: 0.064 [0.005] vs. 0.084 [0.006]; p = 0.03), cluster II ([EMM] [SE]: 0.133 [0.013] vs. 0.187 [0.014]; p < 0.001) and cluster III ([EMM] [SE]: 0.190 [0.014] vs. 0.128 [0.016]; p < 0.001). Conclusions: The results are of importance, as they indicate that long-term changes in stress regulation regulated by neurotrophines are a crucial part of the symptomatology of opioid dependence, thus influencing drug consumption and the different forms of opioid-maintenance therapies.

Die Altersdepression oder auch „Late-Life-Depression“ stellt insbesondere aufgrund des hoheren Ruckfallrisikos eine Herausforderung fur die psychiatrische Praxis dar. Eine aktuelle Metaanalyse liefert nun weitere Erkenntnisse zur Unterstutzung der Hypothese einer vaskularen Genese.

Nur 30 % der depressiven Patienten spricht ausreichend auf das erste Antidepressivum an. Die Datenlage zum besten therapeutischen Vorgehen in diesem Fall ist heterogen. Nach S3-Leitlinie wird die Kombination, ein Substanzwechsel oder eine Augmentation empfohlen. Die vorliegende Studie untersuchte die verschiedenen Vorgehensweisen methodisch hochwertig — und zeigte nur moderate Effekte.