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Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine.Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS.26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group.In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.

In a previous single center study we found that a standardized drug treatment algorithm (ALGO) was more cost effective than treatment as usual (TAU) for inpatients with major depression. This report aimed to determine whether this promising initial finding could be replicated in a multicenter study.Treatment costs were calculated for two time periods: the study period (from enrolment to exit from study) and time in hospital (from enrolment to hospital discharge) based on daily hospital charges. Cost per remitted patient during the study period was considered as primary outcome.266 patients received ALGO and 84 received TAU. For the study period, ALGO costs were significantly lower than TAU (ALGO: 7 848 ± 6 065 €; TAU: 10 033 ± 7 696 €; p = 0.04). For time in hospital, costs were not different (ALGO: 14 734 ± 8 329 €; TAU: 14 244 ± 8 419 €; p = 0.617). Remission rates did not differ for the study period (ALGO: 57.9%, TAU: 50.0%; p=0.201). Remission rates were greater in ALGO (83.3%) than TAU (66.2%) for time in hospital (p = 0.002). Cost per remission was lower in ALGO (13 554 ± 10 476 €) than TAU (20 066 ± 15 391 €) for the study period (p0.001) and for time in hospital (ALGO: 17 582 ± 9 939 €; TAU: 21 516 ± 12 718 €; p = 0.036).Indirect costs were not assessed. Different dropout rates in TAU and ALGO complicated interpretation.Treatment algorithms enhance the cost effectiveness of the care of depressed inpatients, which replicates our prior results in an independent sample.

Background Approximately 20–30% of patients with Major depressive disorder (MDD) develop a chronic course of their disease. Chronic depression is associated with increased health care utilisation, hospitalisation and a higher disease burden. We identified clinical correlates and differences in treatment response of chronic MDD (cMDD) patients compared with non-chronic episodic depression in a huge sample of depressive inpatients. Methods Data were collected from 412 inpatients who had been diagnosed with a major depressive episode (MDE; according to ICD-10) and scored 15 or higher on the 21-item Hamilton Depression Rating Scale (HRSD-21). All subjects were participants in the German Algorithm Project, phase 3 (GAP3). Patients who were diagnosed with a MDE within the last two years or longer (herein referred to as CD) were compared with non-chronic depressive patients (herein referred to as non-CD). CD and non-CD patients were assessed for the following: psychosocial characteristics, symptom reduction from hospital admission to discharge, symptom severity at discharge, remission and response rates, and pharmacological treatment during inpatient treatment. The primary outcome measure was the HRSD-21. Results 13.6% ( n =56) of patients met the criteria for chronic depression. Compared with non-CD patients, patients with CD showed increased axis I comorbidities (74% vs. 52%, χ 2 (1)=7.31, p =.02), a higher level of depressive symptoms at baseline and discharge, increased duration of inpatient treatment (64.8 vs. 53.3 days; t =2.86, p =.03) and lower response (HRSD: 60.0% vs. 72.0%; χ 2 (1)=3.61, p χ 2 (1)=3.56, p =.04) and remission rates (BDI 17.9.% vs. 29.7%; χ 2 (1)=3.42, p =.05. However, both groups achieved a comparable symptom reduction during inpatient treatment. The prescribed pharmacological strategy had no significant influence on treatment outcome in patients with CD. Conclusion Inpatients with CD show higher symptom severity, lower response and remission rates and a longer duration of inpatient treatment, although they achieve comparable symptom reduction during treatment. These findings support the need to recognise CD and its defining characteristics as a distinct subclass of depression.

Introduction Transcranial direct current stimulation (tDCS) has been proposed as novel treatment for major depressive disorder (MDD), based on clinical pilot studies as well as randomized controlled monocentric trials. Methods The DepressionDC study investigates efficacy and tolerability of prefrontal tDCS used as an additive therapy to an antidepressant medication (SSRI) as treatment for major depression in a double-blinded, randomized, placebo-controlled multicenter trial [1] . There is a consensus on parameters like electrical current (1–2 mA) and the critical impedance values are known from safety-studies, but the in vivo stability of these technical parameters over the stimulation period has not been investigated yet. For the DepressionDC study a novel system for recording and monitoring of technical data has been established in order to continuously control tDCS quality and allow posthoc analysis of technical data in conjunction with clinical outcome criteria. Here, we present a blind analysis of the technical data of 280 active tDCS sessions from multiple centers in order to monitor tDCS quality at this stage of the study. The descriptive analysis showed high homogeneity and stability of the technical parameters over the time of the tDCS session in 120 active stimulations from a single center, as well as in 160 active stimulations across different study sites. To determine tDCS-affected brain areas we leveraged the freely available Simnibs 2.0.1. software to develop subject-specific head model based on MRI data and calculate electric fields (and current density) induced by tDCS. Calculating the electric field, the peak electric field strength as well as activation graduation by percentiles in every single subject, revealed stable and homogenous activation patterns in all participants. Online recording of technical parameters across centers and individual e-field modelling for defining tDCS dosage at target sites are promising deliverables from the DepressionDC trial for further clinical applications.

We conducted a randomized, sham-controlled repetitive transcranial magnetic stimulation (rTMS) study in chronic schizophrenia in-patients ( n =35) to evaluate the therapeutic efficacy of 10 Hz stimulation. Patients, who were on stable antipsychotic treatment, were randomly assigned to the active or sham condition. In the active rTMS group, ten sessions with a total of 10,000 stimuli were applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. The sham group received corresponding sham stimulation. Clinical improvement was measured by the Clinical Global Impression scale (primary outcome measure), the Global Assessment of Functioning Scale (GAF) and the Positive and Negative Symptom Scale (PANSS; secondary outcome measures). Between-group comparisons revealed no significant differences in clinical outcome variables. Only a subgroup of patients with pronounced negative symptoms developed some clinical improvement as indicated by significant changes in the GAF-scale. Besides there is some evidence for a more favourable clinical outcome within this subgroup after rTMS in the CGI-S and PANSS negative scale, too. In line with earlier investigations, our results suggest a moderate — potentially clinically relevant — treatment effect of prefrontal 10 Hz rTMS stimulation in chronic patients. However, in our study this beneficial effect was restricted to subjects with pronounced negative symptoms. Clinical trial registration information ClinicalTrial.gov Identifier: NCT00169689, http://www.clinicaltrials.gov.

Background Gray matter reduction and ventricular enlargement belong to the best replicated findings in schizophrenia. Brain morphologic changes were also found in non-schizophrenic family members (FM). The intention of this study was to examine whether non-psychotic first-degree relatives reveal similar morphologic changes as schizophrenic patients and how state of genetic loading contribute to these abnormalities. Methods Forty-nine schizophrenic patients, 71 non-schizophrenic FM and 48 control subjects took part in this volumetric MRI study. All subjects were between 18 and 59 years old. Dependent variables were gray matter, white matter and total cerebrospinal fluid (CSF) volume, determined by SPM99 segmentation algorithm. As an important part of CSF lateral ventricle volume was determined manually by removing surrounding CSF areas. Results In schizophrenic patients compared to controls and non-schizophrenic FM total CSF volumes and lateral ventricles were increased. Gray and, to a lesser degree, white matter volumes were decreased as well. For CSF, gray and white matter there was no significant difference between uni- and multiple affected families. CSF correlated significantly negative with gray matter (r = −0.78) and, less intensive, with white matter (r = −0.40). There were negative correlations between gray and white matter volume as well (r = −0.26). These correlations were not significantly different between the diagnostic groups. Conclusion CSF enlargement and gray matter reductions in schizophrenic patients compared to controls and non-affected FM seem to be interdependent findings. However, this correlation is independent of the factor diagnosis and is therefore not specific for schizophrenia.

Introduction Chronic tinnitus is a frequent disease accompanied in many cases by high morbidity and reduction in quality of life. Despite its high incidence, treatment remains elusive. Aggregated research over the last years has contributed to a deeper understanding of the neurobiological basis of chronic tinnitus and point to the involvement of auditory and non-auditory brain areas. Repetitive transcranial magnetic stimulation (rTMS) is able to non-invasively modulate brain activity. Pilot studies indicate a potential therapeutic effect of rTMS in tinnitus patients, however, sample sizes were small so far. The aim of this study was to evaluate the efficacy and safety of rTMS in tinnitus in a large patient sample. Methods 7 study centers participated in this randomized, placebo-controlled trial. From February 2008 until May 2011 a total of 154 patients were enrolled and received 10 sessions of either verum or sham 1 Hz-rTMS over the left primary auditory cortex. Effects on tinnitus and accompanying psychiatric symptoms were evaluated using a variety of standardized rating scales (tinnitus questionnaire (TQ), tinnitus handicap inventory (THI), beck depression inventory, etc.). Results and conclusions rTMS treatment was well tolerated in all patients. In the primary outcome (change of the TQ-score baseline vs. day 12) no significant difference between both study arms was observed. During the follow-up period, a trend to superiority of verum rTMS could be observed, which did not reach statistical significance. This study shows, that 1 Hz-rTMS over the left primary auditory cortex is not superior to placebo treatment. Therefore, more effective treatment protocols are needed and combined treatment regimes focusing on auditory and non-auditory brain regions may be better as recent studies have demonstrated.