Transcranial Direct Current Stimulation (tDCS) for major depression - Interim analysis of cloud supervised technical data from the DepressionDC trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) of prefrontal cortex regions has been reported to exert antidepressant effects, though large scale multicenter trials in major depressive disorder (MDD) supporting this notion are still lacking. Application of tDCS in multicenter settings, however, requires measurement, storage and evaluation of technical parameters of tDCS sessions not only for safety reasons but also for quality control. To address this issue, we conducted an interim analysis of supervised technical data across study centers in order to monitor technical quality of tDCS in an ongoing multicenter RCT in MDD (DepressionDC trial). METHODS: Technical data of 818 active tDCS sessions were recorded, stored in a data cloud, and analysed without violating study blinding. Impedance, voltage and current were monitored continuously with one data point recorded every second of stimulation. RESULTS: Variability of impedance was considerable (1,42 kΩ, to 8,23 kΩ), inter-individually and even more intra-individually, but did not significantly differ between the study centre in Munich and all other sites. CONCLUSION: Measurement, centralized data storage via data cloud and remote supervision of technical parameters of tDCS are feasible and proposed for future RCTs on therapeutic tDCS in multiple settings.

Predicting patient outcomes in psychiatric hospitals with routine data: a machine learning approach.

BACKGROUND: A common problem in machine learning applications is availability of data at the point of decision making. The aim of the present study was to use routine data readily available at admission to predict aspects relevant to the organization of psychiatric hospital care. A further aim was to compare the results of a machine learning approach with those obtained through a traditional method and those obtained through a naive baseline classifier. METHODS: The study included consecutively discharged patients between 1st of January 2017 and 31st of December 2018 from nine psychiatric hospitals in Hesse, Germany. We compared the predictive performance achieved by stochastic gradient boosting (GBM) with multiple logistic regression and a naive baseline classifier. We tested the performance of our final models on unseen patients from another calendar year and from different hospitals. RESULTS: The study included 45,388 inpatient episodes. The models' performance, as measured by the area under the Receiver Operating Characteristic curve, varied strongly between the predicted outcomes, with relatively high performance in the prediction of coercive treatment (area under the curve: 0.83) and 1:1 observations (0.80) and relatively poor performance in the prediction of short length of stay (0.69) and non-response to treatment (0.65). The GBM performed slightly better than logistic regression. Both approaches were substantially better than a naive prediction based solely on basic diagnostic grouping. CONCLUSION: The present study has shown that administrative routine data can be used to predict aspects relevant to the organisation of psychiatric hospital care. Future research should investigate the predictive performance that is necessary to provide effective assistance in clinical practice for the benefit of both staff and patients.

Follow-up magnetic resonance imaging/3D-magnetic resonance cholangiopancreatography in patients with primary sclerosing cholangitis: challenging for experts to interpret.

BACKGROUND: In patients with primary sclerosing cholangitis follow-up magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is performed by many centres, particularly for the early detection of biliary malignancies and strictures. Clinically meaningful MRI-based definitions of primary sclerosing cholangitis related complications are, however, lacking. AIM: To investigate how primary sclerosing cholangitis experts interpret follow-up MRI/MRCP with a focus on conclusions that may impact clinical decision-making in primary sclerosing cholangitis. METHODS: Within the International Primary Sclerosing Cholangitis Study Group, an online survey on 16 real-life primary sclerosing cholangitis cases including clinical and biochemical information as well as a T2-weighted liver MRI/3D-MRCP was conducted. The interpretation of images and subsequent recommendations were assessed using a multiple-choice questionnaire. An inter-rater reliability calculation (Fleiss' kappa) was performed and factors potentially affecting the interpretation of magnetic resonance images were analysed using generalised linear mixed-effect models. RESULTS: Forty-four members/associates of the International Primary Sclerosing Cholangitis Study Group (median experience in the care of primary sclerosing cholangitis patients: 14 years) completed the survey. The MRI interpretation significantly varied among the participants. The lowest agreement was found with respect to the indication to perform subsequent endoscopic retrograde cholangiopancreatography (ERCP; Κ = 0.12, 95%CI 0.11-0.14). Elevated total bilirubin was the variable with the strongest effect on the rate of suspected dominant strictures, cholangiocarcinoma or ERCP recommendations. Liver cirrhosis did not prevent participants from recommending ERCP. Overall, the survey participants' recommendations contrasted the real-life management and outcome. CONCLUSIONS: In primary sclerosing cholangitis, the interpretation of follow-up MRI/3D-MRCP significantly varies even among experts and seems to be primarily affected by bilirubin levels. Generally accepted MRI-based definitions of primary sclerosing cholangitis-related complications are urgently needed.

Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

[Guideline-conform inpatient psychiatric psychotherapeutic treatment of chronic depression: Normative personnel requirements]. / Leitlinienentsprechende stationäre psychiatrisch-psychotherapeutische Behandlung der chronischen Depression : Normative Personalbedarfsermittlung.

BACKGROUND: Chronic depression is a frequent mental disorder representing a significant subjective and economic burden. Effective disorder-specific treatment of chronic depression presupposes sufficient funding of treatment resources. OBJECTIVE: Definition of normative needs of personnel resources for guideline-compliant and evidence-based inpatient treatment of chronic depression based on treatment duration and intensity. The personnel resources determined were compared to the resources provided on the basis of the existing reimbursement system (Psych-PV) in Germany. MATERIAL AND METHODS: Resources determined according to national treatment guidelines and empirical evidence were compared to personnel resources dictated by the German Psych-PV reimbursement algorithm. RESULTS: The current funding algorithm greatly underestimates the resources needed for a guideline-compliant and evidence-based treatment program, even if healthcare providers received 100 % reimbursement of the sum determined by the Psych-PV algorithm. DISCUSSION: The results clearly show that even in the case of a full coverage of the current German reimbursement algorithm, funding allocation for evidence-based inpatient treatment of chronic depression is insufficient. In addition, the difficulties of specific coding of chronic depression in the ICD-10 system generates a major problem in the attempt to measure the current resources needed for sufficient treatment.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

[Where is convergence of psychiatry budgets leading to? A comparison of staffing regulations and actual personnel resources]. / Wohin führt die Konvergenz der Psychiatriebudgets? Ein Vergleich von Psych-PV-Vorgaben und tatsächlichen Personalressourcen.

BACKGROUND: Staffing regulations have determined the number of qualified staff required for sufficient, appropriate and economical inpatient mental health care in Germany since 1991. This minimum level of structural quality will probably be abolished in the context of the convergence of hospital budgets starting in 2019. AIMS AND OBJECTIVES: The aim of this study was to analyze the current fulfilment of staffing regulations in terms of time per patient in a large nationwide sample. MATERIAL AND METHODS: The required minutes of staff time as defined by staffing regulations were calculated for each patient using the treatment classifications provided by a large nationwide database. The actual use of staff time was calculated on the basis of average costs published by the German Institute for Hospital Reimbursement. Both figures were compared to calculate the fulfilment of staffing regulations. RESULTS: The study included approximately 95,000 inpatient episodes from 46 psychiatric hospitals and departments with a total length of stay of almost 2.5 million days. On average, the weekly use of staff resources per patient was 190 min (10 %) below the requirements of the staffing regulations. The largest gap in absolute terms was found in nursing staff where the weekly time per patient was 189 min (14 %) below the requirements of the staffing regulations. CONCLUSION: The convergence of psychiatric hospital budgets starts in 2019 below a level of funding required to fulfil staffing regulations. This would perpetuate inadequately funded structures and should initially be opposed with a demand for complete fulfilment of staffing regulations. Thereafter, a normative consent should be reached to define the resources required for current inpatient mental health care.

[Resource use and financing of guideline-adherent psychotherapeutic inpatient care]. / Aufwand und Finanzierung leitliniengerechter, psychotherapeutischer Behandlung im Krankenhaus.

BACKGROUND: The financing of psychiatric psychotherapeutic care in Germany is determined by the German psychiatric staffing regulations which are unchanged since 1991. Psychotherapy was established after 1991 as an effective and indispensable treatment of mental and behavioral disorders. AIMS AND OBJECTIVES: The aim of this study was to empirically investigate the use of psychiatrists' and psychologists' working time for psychotherapy in guideline-adherent hospital care. A further aim was to compare these results to the resources defined by the German psychiatric staffing regulations and in the new prospective payment system for psychiatry and psychosomatics in Germany. MATERIAL AND METHODS: University hospitals for psychiatry and psychotherapy were asked to retrospectively provide data of patients for which guideline-adherent care was possible. Participating institutions provided both data describing the staff time utilization of psychotherapeutic services provided by psychiatrists and psychologists and patient classifications according to the German psychiatric staffing regulations and the new prospective payment system for psychiatry and psychosomatics. RESULTS: Resources defined by the German psychiatric staffing regulations covered a mean of only 71 min of psychotherapy per patient and week while the actual mean intensity of psychotherapeutic care provided by the participating hospitals was 194 min per patient and week. The associated use of staff time was 102 min per patient and week. Both figures increased during an inpatient episode. The resources defined by the German psychiatric staffing regulations covered only 70 % of medical and psychological personnel. The current configuration of the new prospective payment system for psychiatry and psychosomatics covered only 59 % of staff time. CONCLUSION: The results of this study provide another unambiguous recommendation to adjust the out-dated German psychiatric staffing regulations to the current evidence and S3 guidelines for psychiatric psychotherapeutic hospital care. In particular, more resources are required for the provision of psychotherapeutic care.

[Guideline-adherent psychiatric-psychotherapeutic hospital care: Normative definition of staff required using the example of depression]. / Leitliniengerechte psychiatrisch-psychotherapeutische Krankenhausbehandlung : Normative Personalermittlung am Beispiel Depression.

BACKGROUND: Unipolar depression is of high relevance in German inpatient treatment. An effective psychiatric psychotherapeutic hospital treatment also requires sufficient staff for carrying out psychotherapeutic treatment. AIMS AND OBJECTIVES: The aim of this study was to define the staff requirements for guideline-adherent psychiatric-psychotherapeutic inpatient treatment of depression on the basis of a weekly treatment schedule for a 5-week admission period. A further aim was to compare the staff required with the resources defined by the German psychiatric staffing regulations (Psych-PV). MATERIAL AND METHODS: The weekly schedule was normatively defined on the basis of the current evidence for treatment efficacy and effectiveness. The staff required was calculated on the basis of the weekly schedule. The time for psychotherapy defined by the Psych-PV was calculated using the treatment classification provided by a large nationwide database. RESULTS: Regarding psychotherapy, 280 min per week is regarded as necessary and usually sufficient according to the current evidence. The results showed clearly higher requirements of working time of psychiatrists and psychologists than those defined by the Psych-PV. In particular, the Psych-PV allows only 72 min for psychotherapy per patient and week and only a limited amount of direct patient contact with psychiatrists. CONCLUSION: The figures provided impressively show that the Psych-PV does not allow effective guideline-adherent hospital treatment within a reasonable length of hospital stay. Despite its evidential effectiveness, psychotherapeutic treatment cannot be sufficiently provided under the current financing circumstances.

Cost drivers of inpatient mental health care: a systematic review.

Aims. New reimbursement schemes for inpatient mental health care are imminent in the UK and Germany. The shared intention is to reflect cost differences between patients in reimbursement rates. This requires understanding of patient characteristics that influence hospital resource use. The aim of this review was to show which associations between mental health care per diem hospital costs and patient characteristics are supported by current evidence. Methods. A systematic review of the literature published between 1980 and 2012 was carried out. The search strategy included electronic databases and hand-searching. Furthermore, reference lists, citing articles and related publications were screened and experts were contacted. Results. The search found eight studies. Dispersion in per diem costs was moderate, as was the ability to explain it with patient characteristics. Six patient characteristics were identified as the most relevant variables. These were (1) age, (2) major diagnostic group, (3) risk, (4) legal problems, (5) the ability to perform activities of daily living and (6) presence of psychotic or affective symptoms. Two non-patient-related factors were identified. These were (1) day of stay and (2) treatment site. Conclusions. Idiosyncrasies of mental health care complicated the prediction of per diem hospital costs. More research is required in European settings since transferability of results is unlikely.

Autoimmune hepatitis 2013 and beyond.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease leading to cirrhosis and its complications if left untreated. Clinical features include elevated transaminases, elevated immunoglobulin G and the presence of autoantibodies. A liver biopsy is necessary for the establishment of the diagnosis. If treated properly and timely, prognosis of AIH is excellent. Standard treatment today consists of azathioprine and prednisolone and leads to remission in the vast majority of patients. Intolerance to standard treatment or incomplete remission as well as special patient groups such as pregnant patients or elderly patients require second- or sometimes even third-line treatments. For those patients, a number of effective drugs are available off-label and induction of remission will be possible in the vast majority of patients. Choice of drug regimen is important as drug-drug-interactions, concomitant diseases, age and gender of the patients have to be taken into account to achieve a tolerable side effect profile and good quality of life in patients. Mycophenolate mofetil is the drug of first choice in azathioprine intolerance. Other treatments may include the use of cyclosporine, tacrolimus, cyclophosphamide or biologicals such as rituximab or infliximab. Close monitoring of the patients will be necessary as side effects may occur.

Acute liver failure following minocycline treatment - a case report and review of the literature.

We present the case of a 23-year-old female patient with acute liver failure following intake of minocycline. This patient had severe hypereosinophilia and massively increased IgE levels. Experimental studies in this case revealed elevated IFN-γ-, as well as TNF-α-producing CD4+ and CD8+ T-cells after in vitro stimulation with minocycline, indicating a type I/IgE-mediated as well as type II/cytotoxic reaction in the pathogenesis of minocycline-induced liver failure. Although mild forms of liver involvement are well known side effects of minocycline, only 8 cases with acute liver failure have been reported, and we present a review of all cases.

[Options, limits and ethics of pharmacological neuroenhancement]. / Möglichkeiten und Grenzen des pharmakologischen Neuroenhancements.

Pharmacological neuroenhancement is an attempt to increase cognitive performance in healthy humans. Learning and memory, attention and vigilance or mood and social interaction are targeted by a modulation of brain plasticity. Firstly, an analysis of the current state of research shows that, until now, clinical trials of neuroenhancing drugs have demonstrated only limited efficacy and long-term side effects remain largely unexplored. Secondly, we argue that, from an ethical perspective, neuroenhancement differs from socially mediated methods of learning. Pharmacological neuroenhancement is based on notions of efficacy and control that threaten to undermine other important aspects of mental capacities.

[Autoimmune liver diseases]. / Autoimmunerkrankungen der Leber.

Autoimmune hepatitis (AIH) can occur in all age groups. AIH affects women more commonly than men (3:1). Clinical presentation may be an acute hepatitis up to fulminant liver failure, but can also be asymptomatic. AIH is characterized by lymphoplasmacellular infiltrates on liver biopsy, elevated liver enzymes in serum and the absence of active viral markers. Patients characteristically present with hypergammaglobulinemia, elevated serum levels of IgG and autoantibodies. Corticosteroids are the drug of choice for induction of remission, azathioprine the drug of choice for maintenance of remission. Rapid response to immunosuppressive treatment supports the diagnosis and leads to a good long-term prognosis.Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are immune mediated diseases affecting bile ducts. While PBC has a slow progression to cirrhosis and complications mostly will be limited to complications of cirrhosis, PSC additionally carries a high risk of developing cholangiocellular carcinoma. The treatment of choice in PBC and PSC is oral ursodeoxycholic acid which may slow progression of liver disease and may ameliorate lab findings.

[The etiopathogenesis of unipolar depression. Neurobiological and psychosocial factors]. / Atiopathogenese der unipolaren Depression. Neurobiologische und psychosoziale Faktoren.

Despite its clinical and socio-economic relevance, surprisingly little is known on the etiology of depression. A multitude of neurobiological and psychosocial hypotheses have been postulated but most lack empirical validity or cannot be integrated into comprehensive pathophysiological models. In neurobiological research, most evidence supports a contribution of genetic factors in the causation of depression. However, it seems that only the susceptibility for the disorder is inherited which ultimately causes the onset of depressive symptoms by interacting with psychosocial adversity. More recent research suggests an important role for altered stress responses and disturbed neuroplasticity in the etiopathogenesis of depression. From a psychosocial point of view, the different approaches prioritize different aspects. Psychoanalytical approaches assume a fragile self-worth system developed in early childhood as a decisive vulnerability factor for later depression. Behavioral-cognitive theories focus on dysfunctional cognitions coupled with learned helplessness and behavioural deficits as well as a failing in positive reinforced activities as predisposing factors for affective disorders. Interpersonal theories, however, postulate that the psychosocial and interpersonal context is most important for the development and course of depression. With regard to the etiopathogenesis of the so called difficult-to-treat chronic depression, especially early traumata as well as preoperational patterns of thinking seem to play a decisive role. In conclusion, only bio-psycho-social models which integrate neurobiological and psychosocial vulnerabilities and stressors have the potential to contribute to a better understanding of the etiology of depression.

Mouse models of liver fibrosis.

Liver fibrosis is the final common pathway in a variety of liver diseases. To model liver fibrosis in mice is important as mechanisms not only of fibrogenesis, but also of fibrolysis, need to be clearly defined. Also, small rodents present a possibility to test potential treatments in vivo. Today, there are several mouse models of liver fibrosis available--induced by administration of hepatotoxins, by bile duct ligation or by immunological mechanisms--and, more and more widespread, transgenic animal models elucidating pathogenesis and common pathways in liver fibrosis. These different mouse models are complementary as they represent different pathways to fibrosis--as also seen in human disease. Recently, several promising treatment methods interfering with cytokine signaling have been published, offering new potential therapeutic interventions. This review seeks to summarize the different methods of fibrosis induction as well as to briefly review some promising new treatment options for fibrosis in the mouse model.

Initial treatment of severe acute psychosis with fast orally disintegrating risperidone tablets.

INTRODUCTION: Although the use of atypical antipsychotics is the standard of care in the maintenance treatment of psychosis, most clinicians still rely on conventional neuroleptics to treat acutely agitated psychotic patients. The objective of this study was to evaluate the effectiveness and safety of a fast orally disintegrating tablet formulation of risperidone in the initial treatment of a large sample of very acutely ill psychotic patients. METHODS: In this multi-center, prospective, open-label observational trial, 191 schizophrenic patients were treated upon admission to hospital with fast orally disintegrating risperidone tablets for up to seven days. Co-medication was per usual clinical practice and at physician's discretion. Psychopathology was rated at baseline, 2, 24 and 48 hours and 4 and 7 days after initiation of therapy. RESULTS: A mean PANSS total score of 114.3+/-23.4 at baseline reflected a severely exacerbated patient population. The PANSS total score was significantly reduced to 83.6+/-26.8 (p<0.0001) and the CGI from 5.6+/-0.7 to 4.5+/-1.1 (p<0.0001) after 7 days. The median time to calmness was 70 min and the associated PANSS item 4 (excitation) dropped two hours after the first intake of the study medication from 4.3+/-1.5 to 3.1+/-1.5 (p<0.0001). A total of 172 patients (90.1%) out of 191 completed the study. The median risperidone dose was 2 mg/d at the initiation of therapy and 4 mg/d after one week. CONCLUSION: Oral treatment of acutely exacerbated schizophrenic patients with fast orally disintegrating risperidone tablets, alone or in combination with benzodiazepines, was associated with a rapid onset of action and a significant and clinically relevant improvement of acute symptoms.

Serum levels of substance P and response to antidepressant pharmacotherapy.

Substance P (SP) is possibly involved in the etiopathology of affective disorders. Here we investigated the relationship of SP serum levels and response to antidepressant drug therapy. SP serum levels were determined before and during a 9-week drug trial in 40 depressed patients treated with paroxetine in combination with either lamotrigine (n = 20) or placebo (n = 20). Responders (n = 18) and non-responders (n = 22) significantly differed in SP serum levels: responders started with higher SP levels that decreased during drug therapy, whereas non-responders had lower SP levels that increased at the beginning. There were no differences between patients with adjunct lamotrigine or placebo. These preliminary data indicate that SP serum levels might be related to response to antidepressant drug therapy. Further studies have to substantiate this finding.

[Neurobiological principles of bipolar affective disorders].

The neurobiology of bipolar affective illness can be described in a model with structural and functional components, which also address the role of stressors, coping mechanisms, and psychophysical disposition. More data exist on depressive than on manic patients or on patients switching from one clinical pole to the other. Structural and functional chronobiological alterations appear to play a major role in the pathophysiology of bipolar illness. From an anatomical view, neurobiological abnormalities are primarily confined to limbic-striatal-pallidal-thalamocortical circuits. The whole cascade of neural signaling is changed starting from neurotransmitters and neuromodulators to receptor-mediated intracellular signal transduction targeting nuclear gene expression. Transnosological factors such as suicidal tendency appear to essentially modulate those changes. Replicated data on decisive neurobiological differences between bipolar and unipolar affective disorders are currently not yet available.