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Background and Hypothesis Meta-analyses have shown that the majority of patients with schizophrenia who have not improved after 2 weeks of treatment with an antipsychotic drug are unlikely to fully respond later. We hypothesized that switching to another antipsychotic with a different receptor binding profile is an effective strategy in such a situation. Study Design In total, 327 inpatients with an acute exacerbation of schizophrenia were randomized to double-blind treatment with either olanzapine (5–20 mg/day) or amisulpride (200–800 mg/day). Those patients who had not reached at least 25% Positive-and-Negative-Syndrome-Scale (PANSS) total score reduction from baseline after 2 weeks (the “non-improvers”) were rerandomized double-blind to either staying on the same compound (“stayers”) or to switching to the other antipsychotic (“switchers”) for another 6 weeks. The primary outcome was the difference in the number of patients in symptomatic remission between the combined “switchers” and the “stayers” after 8 weeks of treatment, analyzed by logistic regression. Study Results A total of 142 nonimprovers were rerandomized at week two. 25 (45.5 %) of the ‘stayers' compared to 41 (68.3 %) of the “switchers” reached remission at endpoint (p = .006). Differences in secondary efficacy outcomes were not significant, except for the PANSS negative subscore and the Clinical-Global-Impression-Scale. “Switchers” and “stayers” did not differ in safety outcomes. Conclusions Switching “non-improvers” from amisulpride to olanzapine or vice-versa increased remission rates and was safe. The superiority in the primary outcome was, however, not paralleled by significant differences in most secondary efficacy outcomes and the effect was only apparent at the last visit making replications of longer duration necessary.

Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field.The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations.Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

Background: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. Methods: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. Findings: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94–1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ 2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. Interpretation: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. Funding: Lundbeck and Otsuka.

Zusammenfassung Hintergrund Für die Behandlung von Menschen mit Schizophrenien wird vorrangig antipsychotische Monotherapie empfohlen. Antipsychotische Polypharmazie (APP) wird dennoch oft eingesetzt und dient als Qualitätsindikator. Ziel der Arbeit Das Auftreten von APP an 9 psychiatrischen Kliniken des LVR zu untersuchen und die Nutzbarkeit als Qualitätsindikator zu diskutieren. Material und Methoden Es wurden Behandlungsdaten von stationären und teilstationären Fällen mit der Hauptdiagnose ICD-10 F20.x im Zeitraum 6/2016 bis 6/2017 hinsichtlich der APP-Rate analysiert. Ergebnisse Bei 6788 Behandlungsfällen wurde eine APP-Rate von 55,5 % ermittelt. Männliches Geschlecht, längere Verweildauer, keine Zwangsunterbringung und der Standort der Klinik waren mit APP assoziiert. Diskussion Die APP-Rate ist im Vergleich bisherigen Ergebnissen hoch und weist erhebliche Unterschiede zwischen den Kliniken auf. Die Verwendung des Qualitätsindikators APP wird diskutiert.

Background This study addresses the question of whether psychosocial functioning measured by the Personal and Social Performance (PSP) Scale is related to various psychopathological measures in a cohort of patients with schizophrenia. Methods The ‘Neuroleptic Strategy Study’ (NeSSy) performed at 14 German hospitals between 2010 and 2013 compared two treatment strategies instead of individual drugs. Secondary end-points were the two PSP scales as well as measures of quality of life (SF-36) and the Positive and Negative Syndrome Scale (PANSS). Results 149 patients were randomised. There was no difference between the two treatment strategies (first-generation versus second-generation antipsychotics) with regard to the PSP. There were differences in doctors’ assessments regarding psychosocial functioning compared with patients’ own assessments. Furthermore, there were relationships between the PSP and quality of life, level of skills (ICF), and severity of disease (PANSS), level of sexual activities and poor well-being under antipsychotic medication but not with cognitive changes. Conclusions The findings on psychosocial functioning of patients with schizophrenia related to severity and skill level could be confirmed. Further findings were the correlation between psychosocial functioning and quality of life, well-being under treatment, and sexuality what emphasizes the substantial importance of a reduced psychosocial functioning.

Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy.A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20.Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment).The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered.German Federal Ministry of Education and Research.

Introduction/Objective. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and safe brain stimulation method for the treatment of therapy resistant depression in adulthood. The German S3 guideline for unipolar depression recommends the use of high frequency rTMS of the left dorsolateral prefrontal cortex for depressive patients who did not respond primarily to antidepressant pharmacotherapy. Although a number of meta-analyses demonstrated its antidepressant efficacy on a high evidence level, rTMS is rarely offered to patients with mental disorders in German psychiatric hospitals. Methods. We introduced a questionnaire-based survey examining patients? (n = 122) and medical students? (n = 53) attitude towards rTMS. The questionnaire consisted of 10 questions with a 5-point Likert-scale. When testing for group differences, we conducted ?2 tests. Results. The majority of students and patients are not aware of rTMS as a psychiatric treatment of depression, with more patients than students not being aware (?2(1) = 9.462, p = 0.002; 39.3% vs. 17%). However, participants wish to be informed in more detail about rTMS. In general, positive attitudes cover the assumption of safety, while negative attitudes show concerns regarding the efficacy and a lack of trust in the method, mainly due to the fear of irreversible brain damage. Most participants would rather take psychiatric medication than rTMS. rTMS was assumed to be a helpful [?2(2) = 16.710, p < 0.001 (patients: 32.8% vs. students: 5.7%)] and well-tolerated treatment [?2(1) = 9.110, p = 0.003 (36.1% vs. 15.1%)] significantly more often by patients than by students. Conclusion. Our results show a clear need for more information on rTMS as a psychiatric treatment for patients and medical students to fight present prejudices and negative assumptions so that this treatment method with fewer side effects than medication may be used more often.

Objective It is well established that long-term hypothyroidism is associated with cognitive deficits. Based on recent literature, we hypothesized that pharmacologically induced euthyroidism would lead to improved cognitive performance compared to a hypothyroid state. Methods We analyzed data from 14 nondepressed thyroidectomized female patients after differentiated thyroid carcinoma during hypothyroidism (due to a four-week withdrawal of thyroid hormone, T1) and euthyroidism brought about by substitution with L-thyroxine (T2). At both measurement points, patients completed a cognitive test battery as our dependent measure and Beck’s Depression Inventory to control depressive states. Results A Wilcoxon signed-rank tests revealed a significant improvement in the Rey–Osterrieth complex figure test (cognitive reproduction), Z = −3.183, p = 0.001, and the D2 concentration score, Z = −1.992, p = 0.046 in euthyroidism compared to hypothyroidism. Conclusions Our results confirm that hormone replacement therapy with L-thyroxine promotes cognitive reproduction and concentration in thyroidectomized female patients after differentiated thyroid carcinoma.

Background Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). Methods An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. Results In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. Conclusions Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

PURPOSE/BACKGROUND The present study was conducted to investigate the difference in attitudes toward psychiatric drugs, long-term medication, and depot formulations between psychiatric patients and patient-related groups and the German general public. METHODS/PROCEDURES Different groups (n = 50 patients, n = 34 relatives of patients, n = 42 psychiatrists, n = 70 medical students, and n = 58 psychiatric nursing professionals) were surveyed using a questionnaire to investigate their attitude toward depot medication and compared with matched participants from the German general public. FINDINGS/RESULTS Patients did not differ from their matched controls regarding their attitude toward potential reasons to reject a depot, whereas psychiatrists (P = 0.002) and nursing staff (P = 0.003) were more concerned about patients fearing an injection than their matched controls. IMPLICATIONS/CONCLUSIONS Psychiatrists and psychiatric nurses were significantly more concerned about giving an (intragluteal) injection because of concerns about patients' fears of this administration method than their matched controls. In contrast, patients' concerns about receiving an injection did not differ from their matched controls. Furthermore, we found that psychiatrists tended to believe that giving an injection might be time-consuming than giving oral medication. These results may emphasize the fact that the low rate of depot medication use is derived from subjective reservations of medical staff rather than actual negative attitudes or fears of patients.

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.

Background Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions. Methods Using data from the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia. Results 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found. Conclusion These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period.

Antipsychotics are the cornerstone in the treatment of schizophrenia and are primarily recommended as monotherapy by evidence-based guidelines. Nevertheless, antipsychotic polypharmacy (APP) is prevalent in routine practice and APP is also used as a quality indicator since 2016 in quality management programs.Based on routine data of nine psychiatric hospitals of the Landschaftsverband Rheinland (LVR)/Germany the prevalence of APP was determined and correlated with factors of routine healthcare in order to monitor the adoption of APP and to discuss its feasibility as a quality indicator.All cases with schizophrenia (ICD-10 F20.x; ≥ 18 years) discharged between June 1st, 2016, and June 1st, 2017, (in-patient and day clinic) were extracted from an established research database shared by all nine hospitals and analyzed regarding APP prevalence at the time of discharge.Based on 6,788 cases, the prevalence of APP was 55.5 % with an average of 2.4 antipsychotics (SD = 0.6) administered simultaneously. In multivariate analyses, significant predictors for APP were: gender (male female), the number of days in hospital (long short), involuntary treatment (no yes) and the location of the hospital.We found a high proportion of polypharmacy in inpatient schizophrenia patients and significant differences between hospitals. The use of the results as a quality indicator (criteria ≥ 2 antipsychotics) remains dependent on the background of the individual treatment courses, which cannot be adequately represented by the existing routine data. The LVR has been using the quality indicator of ≥ 3 antipsychotics since 2018, which is discussed as a more appropriate approach for future evaluations.Für die Behandlung von Menschen mit Schizophrenien wird vorrangig antipsychotische Monotherapie empfohlen. Antipsychotische Polypharmazie (APP) wird dennoch oft eingesetzt und dient als Qualitätsindikator.Das Auftreten von APP an 9 psychiatrischen Kliniken des LVR zu untersuchen und die Nutzbarkeit als Qualitätsindikator zu diskutieren.Es wurden Behandlungsdaten von stationären und teilstationären Fällen mit der Hauptdiagnose ICD-10 F20.x im Zeitraum 6/2016 bis 6/2017 hinsichtlich der APP-Rate analysiert.Bei 6788 Behandlungsfällen wurde eine APP-Rate von 55,5 % ermittelt. Männliches Geschlecht, längere Verweildauer, keine Zwangsunterbringung und der Standort der Klinik waren mit APP assoziiert.Die APP-Rate ist im Vergleich bisherigen Ergebnissen hoch und weist erhebliche Unterschiede zwischen den Kliniken auf. Die Verwendung des Qualitätsindikators APP wird diskutiert.

Objectives: Biological strategies to improve treatment efficacy in clozapine-treated patients are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) merits consideration as intervention for patients with persistent auditory hallucinations (AH) or negative symptoms (NS) not responding sufficiently to clozapine treatment. Methods: Data from 10 international RCTs of rTMS for patients being treated with clozapine were pooled. Two levels of symptomatic response were defined: improvement of >= 20% and >= 50% on study-specific primary endpoint scales. Changes in the positive and negative syndrome scale (PANSS) from baseline to endpoint assessment were also analysed. Results: Analyses of 131 patients did not reveal a significant difference for >= 20% and >= 50% response thresholds for improvement of AH, negative or total symptoms between active and sham rTMS groups. The number needed to treat (NNT) for an improvement in persistent AH was nine following active rTMS. PANSS scores did not improve significantly from baseline to endpoint between active and sham groups in studies investigating NS and AH. Conclusions: rTMS as a treatment for persistent symptoms in clozapine-treated patients did not show a beneficial effect of active compared to sham treatment. For AH, the size of the NNTs indicates a possible beneficial effect of rTMS.

ZusammenfassungAufgrund der hohen Wirksamkeit der Elektrokonvulsionstherapie (EKT) in der leitliniengerechten Behandlung therapieresistenter depressiver Episoden und der klinischen Bedeutung kognitiver Beeinträchtigungen ist eine Optimierung des Nebenwirkungsmanagements notwendig. Da kognitive Nebenwirkungen des Verfahrens in Verbindung mit krankheitsbedingten Beeinträchtigungen das soziale Funktionsniveau und das subjektive Wohlbefinden reduzieren können, sollten eine umfassende Aufklärung und ein spezifisches Monitoring potenzieller kognitiver Nebenwirkungen erfolgen. Diese Übersichtsarbeit stellt die klinische Relevanz und die Messverfahren kognitiver Nebenwirkungen dar, die bei einer EKT-Behandlung auftreten können. Es wird diskutiert, welche patientenindividuellen, technischen und pharmakologischen Faktoren die Auswirkung der EKT auf die Kognition moderieren können. Ferner werden die Empfehlungen hinsichtlich des Monitorings kognitiver Nebenwirkungen in nationalen und internationalen Leitlinien zusammengefasst. Bei der EKT werden Beeinträchtigungen der globalen Kognition sowie anterograde und retrograde Gedächtnisstörungen beobachtet. In den ersten beiden Bereichen scheinen diese nur vorübergehend von Bedeutung zu sein, wohingegen das Ausmaß der retrograden Gedächtnisdefizite, darunter vor allem das des autobiografischen Gedächtnisses, nach aktuellem Kenntnisstand nicht klar definiert ist und potenziell länger anhaltend beeinträchtigt sein kann. Ein kontroverses Thema ist diesbezüglich auch die Frage nach geeigneten Testverfahren zur Erfassung dieser Funktionen, um die Dauer möglicher Leistungsabfälle und den Schweregrad ermitteln zu können. Im klinischen Kontext finden hierbei unterschiedliche Verfahren Verwendung, teilweise wird eine Symptomgraduierung aufgrund von Zeitmangel oder methodischer Unsicherheit nicht durchgeführt. Die vorliegenden nationalen und internationalen Leitlinien machen sehr unterschiedliche Vorgaben, wie die kognitiven Beeinträchtigungen im Laufe der Therapie beobachtet und dokumentiert werden sollen. Im deutschen Sprachraum werden keine konkreten Handlungsempfehlungen zur Erfassung von kognitiven Nebenwirkungen erteilt. In diesem Zusammenhang wird eine Überarbeitung der aktuellen Leitlinien empfohlen sowie weiterer Forschungsbedarf identifiziert, um die Erfassung und das Monitoring der Nebenwirkungen zu verbessern und Patienten mit einer erhöhten Anfälligkeit zu identifizieren.

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.

Auditory verbal hallucinations (AH) are core symptoms of schizophrenia. They are often severely distressing and refractory to therapy. Their perception is associated with increased activity in temporoparietal areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) can reduce focal brain hyperactivity and has been shown to ameliorate AH. However, controlled multicenter clinical trials are still missing, effect sizes are moderate, and the treatment with rTMS is time consuming. Continuous theta burst stimulation (cTBS) is a quicker and potentially more effective technique to reduce cortical hyperactivity. First case and pilot studies indicate effectiveness in the treatment of AH. In this randomized, sham-controlled, double-blind multicenter clinical trial, 86 patients with schizophrenia spectrum disorder will be randomized to either cTBS or sham to the left and right temporoparietal cortex during three consecutive weeks (15 sessions totally). In each session, both hemispheres will be stimulated sequentially. The order in the first session (left-right or right-left, respectively) will be determined by randomization and alternated in all following sessions. Primary outcome is the reduction of mean PSYRATS-AH score after cTBS as compared to sham treatment. Follow-up measurements will be performed 1, 3 and 6 months after the end of the treatment. Statistical analysis will be based on the intention-to-treat population including all randomized patients using an analysis of covariance. This multicenter-controlled clinical trial will be able to provide decisive evidence for the efficacy of cTBS in the treatment of AH. The results will be suitable to clarify the role of this innovative, pathophysiology-based therapeutic approach in treatment guidelines for AH.ClinicalTrials.gov identifier: NCT02670291.

Patients with schizophrenia are at increased risk of diabetes, cardiovascular disease (CVD) and associated mortality versus the general population. Increased intra-abdominal and pericardial adipose tissue are associated with elevated CVD and mortality in the general population, but little is known about these in patients with schizophrenia. This study examined pericardial and intra-abdominal adipose tissue in schizophrenia and compared this to healthy controls. Thirty-one patients with schizophrenia (mean age 41.2 years, 76% males) and 30 healthy volunteers (CTRL) were examined in this study. The primary outcomes were the volumes of pericardial adipose tissue and intra-abdominal adipose tissue, measured using magnetic resonance imaging. Secondary outcomes included diabetes and cardiac event risk assessed by established instruments. Volumes of pericardial adipose tissue were increased in male and female patients with schizophrenia compared to healthy controls after the adjustment of age, sex and body mass index (P

Background Chronic tinnitus is a frequent, difficult to treat disease with high morbidity. Objective This multicenter randomized, sham-controlled trial investigated the efficacy and safety of 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal cortex in patients with chronic tinnitus. Methods Tinnitus patients were randomized to receive 10 sessions of either real or sham 1-Hz-rTMS (2000 stimuli, 110% motor threshold) to the left temporal cortex. The primary outcome was the change in the sum score of the tinnitus questionnaire (TQ) of Goebel and Hiller from baseline to end of treatment. Results A total of 163 patients were enrolled in the study (real rTMS: 75; sham rTMS: 78). At day 12, the baseline mean of 43.1 TQ points in 71 patients assigned to real rTMS changed by −0.5 points; it changed by 0.5 points from a baseline of 42.1 in 75 patients randomized to sham rTMS (adjusted mean difference between groups: −1.0; 95.19% confidence interval: −3.2 to 1.2; p = 0.36). All secondary outcome measures including measures of depression and quality of life showed no significant differences either (p > 0.11). The number of participants with side-effects or adverse events did not differ between groups. Conclusion Real 1-Hz-rTMS over the left temporal cortex was well tolerated but not superior compared with sham rTMS in improving tinnitus severity. These findings are in contrast to results from studies with smaller sample sizes and put the efficacy of this rTMS protocol for treatment of chronic tinnitus into question. Trial Registration Controlled Trials: http://www.isrctn.com/ISRCTN89848288 .

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Zusammenfassung Anliegen Der Einsatz antidepressiver Kombinationsbehandlungen wurde bisher nur in wenigen Studien untersucht. Methode Die Verschreibungspraxis antidepressiver Kombinationstherapien wurde am LVR-Klinikum Düsseldorf bei Patienten mit schwerer depressiver Episode (ICD-10 F32.2 und F33.2) retrospektiv untersucht. Ergebnis Von 1198 stationären und teilstationären Fällen erhielten 25,1 % eine Kombination aus zwei oder mehr Antidepressiva. Schlussfolgerung Kombinationstherapien werden häufig eingesetzt, was einem geringen Empfehlungsgrad der Behandlungsleitlinie gegenübersteht.

Due to the efficacy of electroconvulsive therapy (ECT) in the guideline-based treatment of therapy-resistant depressive episodes and the clinical significance of cognitive impairments, it is necessary to optimize the management of potential side effects. As cognitive side effects of the treatment combined with impairments resulting from the depression may lead to a reduction in the ability to function in social contexts and reduce subjective wellbeing, comprehensive information about and monitoring of potential side effects is essential. In this review we present the clinical relevance and measurement of cognitive side effects that may occur during electroconvulsive therapy. The individual characteristics of the patient as well as the technical and pharmacological parameters that influence the effect of ECT on cognition will be discussed. Furthermore, the recommendations of national and international treatment guidelines for the monitoring of cognitive side effects will be summarized.After ECT, impairments of global cognition, and anterograde as well as retrograde amnesia may occur. While the first two side effects appear to be transient, the extent of retrograde amnesia, particularly for autobiographical information, is not yet well understood and may potentially be present for a longer period. A controversial issue in this context is the question whether there are appropriate instruments for the monitoring of reduction in cognitive performance. In clinical context, a number of different measures are used, and in many cases, monitoring is omitted due to lack of time and methodological uncertainty. Current national and international guidelines make very different suggestions about the monitoring of cognitive side effects during ECT and in German-speaking regions no concrete recommendations are available. In this context, we recommend a revision of current guidelines and identify future areas of research that would further our understanding of the effects of ECT on cognition. These may enable us to keep an eye on these deficiencies better as well as allow us to identify patients that may have a higher risk of developing such impairments.Aufgrund der hohen Wirksamkeit der Elektrokonvulsionstherapie (EKT) in der leitliniengerechten Behandlung therapieresistenter depressiver Episoden und der klinischen Bedeutung kognitiver Beeinträchtigungen ist eine Optimierung des Nebenwirkungsmanagements notwendig. Da kognitive Nebenwirkungen des Verfahrens in Verbindung mit krankheitsbedingten Beeinträchtigungen das soziale Funktionsniveau und das subjektive Wohlbefinden reduzieren können, sollten eine umfassende Aufklärung und ein spezifisches Monitoring potenzieller kognitiver Nebenwirkungen erfolgen. Diese Übersichtsarbeit stellt die klinische Relevanz und die Messverfahren kognitiver Nebenwirkungen dar, die bei einer EKT-Behandlung auftreten können. Es wird diskutiert, welche patientenindividuellen, technischen und pharmakologischen Faktoren die Auswirkung der EKT auf die Kognition moderieren können. Ferner werden die Empfehlungen hinsichtlich des Monitorings kognitiver Nebenwirkungen in nationalen und internationalen Leitlinien zusammengefasst. Bei der EKT werden Beeinträchtigungen der globalen Kognition sowie anterograde und retrograde Gedächtnisstörungen beobachtet. In den ersten beiden Bereichen scheinen diese nur vorübergehend von Bedeutung zu sein, wohingegen das Ausmaß der retrograden Gedächtnisdefizite, darunter vor allem das des autobiografischen Gedächtnisses, nach aktuellem Kenntnisstand nicht klar definiert ist und potenziell länger anhaltend beeinträchtigt sein kann. Ein kontroverses Thema ist diesbezüglich auch die Frage nach geeigneten Testverfahren zur Erfassung dieser Funktionen, um die Dauer möglicher Leistungsabfälle und den Schweregrad ermitteln zu können. Im klinischen Kontext finden hierbei unterschiedliche Verfahren Verwendung, teilweise wird eine Symptomgraduierung aufgrund von Zeitmangel oder methodischer Unsicherheit nicht durchgeführt. Die vorliegenden nationalen und internationalen Leitlinien machen sehr unterschiedliche Vorgaben, wie die kognitiven Beeinträchtigungen im Laufe der Therapie beobachtet und dokumentiert werden sollen. Im deutschen Sprachraum werden keine konkreten Handlungsempfehlungen zur Erfassung von kognitiven Nebenwirkungen erteilt. In diesem Zusammenhang wird eine Überarbeitung der aktuellen Leitlinien empfohlen sowie weiterer Forschungsbedarf identifiziert, um die Erfassung und das Monitoring der Nebenwirkungen zu verbessern und Patienten mit einer erhöhten Anfälligkeit zu identifizieren.

Background Treatment of schizophrenia with depot medication has advantages compared with oral medication, and among these include an improved compliance. Despite such advantages, prescription rates in many European countries are lower than 20%. The aim of this survey was to study the attitudes toward depot medication among the German general population. To the best of our knowledge, only selective samples have been investigated up until now. Methods A representative sample of 754 people were interviewed via telephone by a professional market research and polling organization. The questionnaire queried demographic characteristics, experience with medication, and the treatment of mental disorders. Subjects' attitudes toward medication in general, long-term medication, and depot medication were surveyed. Results Most (66.7%) of the subjects stated that they would be willing to receive depot medication. Subjects who experienced the treatment of mental disorders were more likely to be willing to receive depot medication. Among the reasons for not using depot medication, "fear of injection" (66.3%) and "more self-control when taking medication as tablets" (48.9%) were stated as the most frequent reasons. Conclusions This study found a good acceptance of antipsychotic depot medication among the German general population in terms of willingness to receive such treatment. We argue that the clinical practitioners' assumptions that depot formulations would be refused by many patients are unsubstantiated.

Cognitive impairment represents a core feature of schizophrenia. Uncertainty about demonstrable benefits of available antipsychotics on cognition remains an important clinical question relevant to patients’ quality of life. The aim of our multi-center, randomized, double-blind “Neuroleptic Strategy Study” (NeSSy) was to compare the effectiveness of selected antipsychotics, conventionally classified as second- (SGAs) (haloperidol, flupentixol) and first generation antipsychotics (FGAs) (aripiprazole, olanzapine, quetiapine), on quality of life in schizophrenia. The effects on cognitive deficits represented a secondary outcome. We used an innovative double randomization for assignment of treatment group, and followed the patients with a neurocognitive test-battery upon six and 24 weeks of treatment. Psychopathology and quality of life were assessed using CGI, PANSS and SF-36. Assessment of cognitive performance was conducted in 114 of the 136 randomized patients. The SGA group (N = 62) showed beneficial effects of small to moderate effect size on cognition during the initial six weeks of treatment (executive functions, verbal fluency) and at 24 weeks (executive functions, working memory). In contrast, the FGA group (N = 52) showed moderately improved executive function, but a decline in verbal fluency at six weeks, with significant declines of moderate to large effect size in executive function, verbal learning and memory, and verbal fluency at 24 weeks. Our study indicates that SGAs present an advantage over FGAs regarding cognitive function during a medium-term treatment for schizophrenia. The results further emphasize a distinction between progression to detrimental effects of FGAs with prolonged treatment in contrast to more persistent cognitive benefits with SGA treatment.

Weight gain among psychiatric inpatients is a widespread phenomenon. This change in body mass index (BMI) can be caused by several factors. Based on recent research, we assume the following factors are related to weight gain during psychiatric inpatient treatment: psychiatric medication, psychiatric diagnosis, sex, age, weight on admission and geographic region of treatment.876 of originally recruited 2328 patients met the criteria for our analysis. Patients were recruited and examined in mental health care centres in Nigeria (N=265), Japan (N=145) and Western-Europe (Denmark, Germany and Switzerland; N=466).There was a significant effect of psychiatric medication, psychiatric diagnoses and geographic region, but not age and sex, on BMI changes. Geographic region had a significant effect on BMI change, with Nigerian patients gaining significantly more weight than Japanese and Western European patients. Moreover, geographic region influenced the type of psychiatric medication prescribed and the psychiatric diagnoses. The diagnoses and psychiatric medication prescribed had a significant effect on BMI change.In conclusion, we consider weight gain as a multifactorial phenomenon that is influenced by several factors. One can discuss a number of explanations for our findings, such as different clinical practices in the geographical regions (prescribing or admission strategies and access-to-care aspects), as well as socio-economic and cultural differences.

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.

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS.

Physical activity (PA) may be therapeutic for people with severe mental illness (SMI) who generally have low PA and experience numerous life style-related medical complications. We conducted a meta-review of PA interventions and their impact on health outcomes for people with SMI, including schizophrenia-spectrum disorders, major depressive disorder (MDD) and bipolar disorder. We searched major electronic databases until January 2018 for systematic reviews with/without meta-analysis that investigated PA for any SMI. We rated the quality of studies with the AMSTAR tool, grading the quality of evidence, and identifying gaps, future research needs and clinical practice recommendations. For MDD, consistent evidence indicated that PA can improve depressive symptoms versus control conditions, with effects comparable to those of antidepressants and psychotherapy. PA can also improve cardiorespiratory fitness and quality of life in people with MDD, although the impact on physical health outcomes was limited. There were no differences in adverse events versus control conditions. For MDD, larger effect sizes were seen when PA was delivered at moderate-vigorous intensity and supervised by an exercise specialist. For schizophrenia-spectrum disorders, evidence indicates that aerobic PA can reduce psychiatric symptoms, improves cognition and various subdomains, cardiorespiratory fitness, whilst evidence for the impact on anthropometric measures was inconsistent. There was a paucity of studies investigating PA in bipolar disorder, precluding any definitive recommendations. No cost effectiveness analyses in any SMI condition were identified. We make multiple recommendations to fill existing research gaps and increase the use of PA in routine clinical care aimed at improving psychiatric and medical outcomes.

ZusammenfassungAls transkranielle Magnetstimulation (TMS) wird ein Verfahren bezeichnet, bei dem ein Stimulator über eine Spule kurze elektromagnetische Pulse mit einer Flussdichte von bis zu 2 Tesla induziert, welche die Schädelkalotte mit wenig Abschwächung durchdringen und zu einer Depolarisierung neuronaler Zellverbände führen. Die Stromdichte am Stimulationsort wird von einer Vielzahl physikalischer und biologischer Parametern bestimmt: Spulengeometrie sowie -positionierung, der Abstand der Spule zum Kortex, die Pulsform, die Intensität, Frequenz und das Muster der Stimulation sowie die dreidimensionale Orientierung der stimulierten neuronalen Strukturen im Verhältnis zur Geometrie des Magnetfeldes. Bei der repetitiven transkraniellen Magnetstimulation (rTMS) werden mehrere elektromagnetische Einzelstimuli als Reizserien mit konstanter Wiederholungsrate appliziert. Mithilfe dieser repetitiven TMS können Veränderungen der neuronalen Aktivität induziert werden, die über die eigentliche Stimulationsdauer hinweg andauern. Im vorliegenden Themenheft wird die Datenlage zu etablierten und potenziellen therapeutischen Anwendungen der repetitiven transkraniellen Magnetstimulation in psychiatrischen Indikationsgebieten zusammengefasst. Eine Empfehlung mit Evidenzgrad A kann für die hochfrequente rTMS-Behandlung des linken dorsolateralen präfrontalen Kortex (DLPFC) bei depressiven Störungen ausgesprochen werden. Empfehlungen mit dem Evidenzgrad B bestehen für niederfrequente rTMS des rechten DLPFC bei der Behandlung depressiver Störungen und für hochfrequente rTMS des linken DLPFC bei depressiver Symptomatik von Patienten mit Parkinson-Syndrom. Wahrscheinlich besteht ein additiver Effekt von rTMS des DLPFC zu einer antidepressiven Pharmakotherapie. Eine Empfehlung mit dem Evidenzgrad C kann folgenden rTMS-Paradigmen zugesprochen werden: hochfrequente rTMS des linken DLPFC bei Patienten mit schizophrener Negativsymptomatik (trotz einer großen negativen Multicenterstudie), niederfrequente rTMS des linken TPC bei chronischem Tinnitus und akustischen Halluzinationen (trotz vieler Publikationen eher niedriges Evidenzniveau), hochfrequente rTMS des rechten DLPFC bei Patienten mit posttraumatischer Belastungsstörung und hochfrequente rTMS des linken DLPFC bei Nikotinabhängigkeit. Gerade bei der Behandlung von Patienten mit chronischem und therapieresistentem Erkrankungsverlauf ist zu erwarten, dass dem gesamten Bereich neurostimulatorischer Methoden eine steigende Bedeutung zukommen wird. Es bleibt zu hoffen, dass vor dem Hintergrund innovativer technischer Entwicklungen und verbesserter Studienmethodologie die transkranielle Magnetstimulation in der nahen Zukunft ihr volles therapeutisches Potenzial entfalten wird.

Background Schizophrenia is a mental disorder with significant socioeconomic burden. Although current pharmacological treatments are effective for treating positive symptoms, medications have little-to-no effect in the treatment of negative symptoms. Objective To assess the efficacy of non-invasive brain stimulation (NIBS) for negative symptoms in schizophrenia in randomized clinical trials (RCTs). Methods A systematic review in Medline and Cochrane Library databases was performed up to May 31, 2017. The primary outcome was Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I 2 and χ 2 tests. Publication bias was assessed using Begg's funnel plot. Results 31 RCTs ( n = 1272) were included, most with small-to-modest sample sizes. Both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were superior to sham (Hedges' g = 0.19; 95% CI 0.07–0.32; and 0.5; 0.02–0.97, respectively). Only one study evaluated the use of transcutaneous auricular vagus nerve stimulation (taVNS). The funnel plot and Eggers test showed that the risk of publication bias was low. In relation to heterogeneity, we found an I 2 of 0% (p = 0.749) and 51.3% (0.055) for rTMS and tDCS, respectively. Conclusion Both rTMS and tDCS were superior to sham stimulation for ameliorating negative symptoms in schizophrenia. We found no considerable heterogeneity or publication bias in our analysis, corroborating the strength of our findings. Not enough studies on other NIBS techniques, such as taVNS, were found for an isolated analysis. Further RCTs with larger sample sizes are needed to clarify the specific impact of NIBS on negative symptoms in schizophrenia.

Background: The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS. Methods: We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a >= 20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction. Results: Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern. Conclusions: Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.

Objective Facial affect recognition, a basic building block of social cognition, is often impaired in schizophrenia. Poor facial affect recognition is closely related to poor functional outcome; however, neither social cognitive impairments nor functional outcome are sufficiently improved by antipsychotic drug treatment alone. Adjunctive repetitive transcranial magnetic stimulation (rTMS) has been shown to enhance cognitive functioning in both healthy individuals and in people with neuropsychiatric disorders and to ameliorate clinical symptoms in psychiatric disorders, but its effects on social cognitive impairments in schizophrenia have not yet been studied. Therefore, we evaluated the effects of sham-controlled rTMS on facial affect recognition in patients with chronic schizophrenia. Method Inpatients (N = 36) on stable antipsychotic treatment were randomly assigned to double-blind high-frequency (10 Hz) rTMS or sham stimulation for a total of ten sessions over two weeks. In the verum group, each session consisted of 10 000 stimuli (20 trains of 5 s) applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. Facial affect recognition was assessed before (T0) and after (T1) the ten sessions. Results Facial affect recognition improved significantly more after rTMS (accuracy change: mean = 8.9%, SD = 6.0%) than after sham stimulation (mean = 1.6%, SD = 3.5; Cohen's d = 1.45). There was no correlation with clinical improvement. Conclusion Our results indicate that prefrontal 10 Hz rTMS stimulation may help to ameliorate impaired facial affect recognition in schizophrenia.

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.

Background: Treatment algorithms are considered as key to improve outcomes by enhancing the quality of care. This is the first randomized controlled study to evaluate the clinical effect of algorithm-guided treatment in inpatients with major depressive disorder. Methods: Inpatients, aged 18 to 70 years with major depressive disorder from 10 German psychiatric departments were randomized to 5 different treatment arms (from 2000 to 2005), 3 of which were standardized stepwise drug treatment algorithms (ALGO). The fourth arm proposed medications and provided less specific recommendations based on a computerized documentation and expert system (CDES), the fifth arm received treatment as usual (TAU). ALGO included 3 different second-step strategies: lithium augmentation (ALGO LA), antidepressant dose-escalation (ALGO DE), and switch to a different antidepressant (ALGO SW). Time to remission (21-item Hamilton Depression Rating Scale

ObjectiveMajor depressive disorder (MDD) is associated with an estimated fourfold risk for premature death, largely attributed to cardiovascular disorders. Pericardial adipose tissue (PAT), a fat compartment surrounding the heart, has been implicated in the development of coronary artery disease. An unanswered question is whether people with chronic MDD are more likely to have elevated PAT volumes versus acute MDD and controls (CTRL).MethodsThe study group consists of sixteen patients with chronic MDD, thirty-four patients with acute MDD, and twenty-five CTRL. PAT and adrenal gland volume were measured by magnetic resonance tomography. Additional measures comprised factors of the metabolic syndrome, cortisol, relative insulin resistance, and pro-inflammatory cytokines (interleukin-6; IL-6 and tumor necrosis factor-α, TNF-α).ResultsPAT volumes were significantly increased in patients with chronic MDD > patients with acute MDD > CTRL. Adrenal gland volume was slightly enlarged in patients with chronic MDD > acute MDD > CTRL, although this difference failed to reach significance. The PAT volume was correlated with adrenal gland volume, and cortisol concentrations were correlated with depression severity, measured by BDI-2 and MADRS. Group differences were found concerning the rate of the metabolic syndrome, being most frequent in chronic MDD > acute MDD > CTRL. Further findings comprised increased fasting cortisol, increased TNF-α concentration, and decreased physical activity level in MDD compared to CTRL.ConclusionOur results extend the existing literature in demonstrating that patients with chronic MDD have the highest risk for developing cardiovascular disorders, indicated by the highest PAT volume prevalence of metabolic syndrome. The correlation of PAT with adrenal gland volume underscores the role of the hypothalamus-pituitary-adrenal system as mediator for body-composition changes. Metabolic monitoring, health advices and motivation for the improvement of physical fitness may be recommended in depressed patients, in particular in chronic depression.

Background: The ‘gold standard’ for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians’ preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types. Methods: The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients’ needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia. Results: In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians’ preferences for specific drugs used for the respective patients were analysed. Conclusion: The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient–drug interaction, this design should prove particularly useful.

Bei schweren psychischen Erkrankungen besteht eine erhohte kardiometabolische Morbiditat und eine gegenuber der Allgemeinbevolkerung erhohte Mortalitat. Daher ist die kardiometabolische Vertraglichkeit einer psychopharmakologischen Behandlung bei psychisch Kranken bedeutsam, insbesondere wenn eine kardiometabolische Grunderkrankung vorliegt. Relativ haufige Nebenwirkungen einer psychopharmakologischen Therapie sind Veranderungen des Fett- und Glukosestoffwechsels, des Korpergewichts und des QTc-Intervalls. Je nach Praparat und individueller Vulnerabilitat des Patienten treten diese Nebenwirkungen in unterschiedlicher Haufigkeit auf. Daher ist ein regelmasiges Monitoring unter Einschluss von EKG-Kontrollen empfehlenswert. Daruber hinaus sind bei psychisch und kardiometabolisch Erkrankten Arzneimittelwechselwirkungen zu beachten, die zu einer Erhohung oder Erniedrigung der Medikamentenspiegel fuhren konnen. Vor Beginn einer psychiatrischen Pharmakotherapie ist eine stabile kardiologisch-medikamentose Einstellung empfehlenswert, ebenso wie die interdisziplinare Zusammenarbeit beim Management komorbider Patienten.

This study was designed to investigate whether a preventive weight management program (WMP) reduces weight gain during olanzapine (OLZ) treatment. Moreover, we examined the effects of intervention on metabolic parameters.Patients (N = 100) with schizophrenia or schizoaffective disorder (DSM-IV) who had commenced treatment with OLZ were recruited. Following a run-in period of 4 weeks, 74 patients who had gained at least 1.5 kg body weight were randomized to receive either 12 bi-weekly WMP sessions (prevention group (PG), n = 36), or usual care (control group (CG), n = 38). Anthropometric and metabolic parameters were assessed after the 24-week intervention phase and a 24-week follow-up.Forty-two percent of 74 participants (PG: 36.1%, CG: 47.4%) finished the 24-week intervention phase while 34% of them (PG: 30.6%, CG: 36.8%) completed the 48-week study. There was no significant difference in weight gain between groups (PG: + 3.4 ± 4.2 kg vs. CG: + 4.5 ± 6.1 kg, P = 0.184) after 24 weeks. Nevertheless, PG showed a significantly smaller increase in waist circumference than CG (PG: + 4.6 ± 8.3 cm, CG: + 10.1 ± 7.3 cm, P = 0.019) after 48 weeks. Furthermore, PG showed a significantly smaller increase in fasting glucose (P = 0.031) and 2-h glucose after oral glucose load (P = 0.018) than CG.These results suggest that preventive WMP may reduce the risk of abdominal obesity and deterioration of glucose metabolism in OLZ-treated patients.

Aims Prevalence of metabolic syndrome (MetS) in men and women who use alcohol has been inconsistent in the literature. The aim of this study is to compare the prevalence of MetS in patients with a diagnosis of alcohol dependence who are currently abstinent in a controlled environment, and in control subjects followed in primary care from a similar region in Northern Germany. Design Cross-sectional study. Setting In-patient cognitive behavioural therapy. Participants One hundred and ninety-seven men and women with alcohol dependence during behavioural treatment in a controlled environment were compared to 1158 subjects from primary care from a similar region in northern Germany. Measurements We used the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHBLI) criteria to determine the rate of MetS and each single criterion of MetS in both groups. Findings The prevalence of MetS was almost twice as high in men and women with alcohol dependence compared to control subjects (30.6% versus 17.0%). With respect to the single criteria, elevations were found for fasting glucose and blood pressure in both genders and for triglycerides in women only. High density lipoprotein (HDL)-cholesterol was higher in men and women with alcohol dependence. Conclusions Our results demonstrate an increased rate of MetS, increased blood pressure and dysregulation of glucose and lipid metabolism in alcohol-dependent patients. Whether high HDL-cholesterol has cardioprotective effects in this context remain doubtful.

Objective The objective of this study was to explore the prevalence of anxious depression in an inpatient population, to describe its clinical and sociodemographic correlates, and to compare treatment outcomes between patients with anxious and nonanxious depression. Furthermore, the efficacy of algorithm-guided treatment versus treatment as usual in patients with anxious versus nonanxious depression was evaluated. Method Data were collected on 429 inpatients with the diagnosis of a depressive episode (according to ICD-10) and a score of ≥ or = 15 on the 21-item Hamilton Depression Rating Scale (HDRS-21). The German Algorithm Project, phase 3 (GAP3), was conducted between 2000 and 2005 in 10 psychiatric departments throughout Germany. A baseline HDRS-21 anxiety/somatization factor score of ≥ or = 7 was considered indicative of anxious depression. Remission was defined as an HDRS-21 score or ≤ = 9. To evaluate the efficacy of algorithm-guided treatment, patients were randomly assigned into 3 groups: 2 different treatment algorithms or treatment as usual. Results The prevalence of anxious depression was 49%. Patients with anxious depression were more likely than those with nonanxious depression to be older (mean ± SD = 45.3 ± 12.8 vs 42.9 ± 12.0 years, odds ratio [OR] = 1.02 [95% CI, 1.00-1.03], P = .046), retired (70% vs 30%, OR = 3.09 [95% CI, 1.70-5.62], P = .000), without school qualification (74% vs 26%, OR = 3.11 [95% CI, 1.09-8.83], P = .035), more severely depressed (mean ± SD HDRS-21 score = 20.1 ± 5.0 vs 18.5 ± 4.4, OR = 1.08 [95% CI, 1.03-1.12], P = .001), and more likely to have a longer duration of the current episode (mean ± SD = 20.9 ± 26.2 vs 13.7 ± 14.3 weeks, OR = 1.02 [95% CI, 1.01-1.03], P = .011). Patients with anxious depression were more likely to display a variety of melancholic features. In patients with anxious depression compared to those with nonanxious depression, remission was less likely to be achieved (48.6% vs 61.5%, OR = 0.63 [95% CI, 0.42-0.92], P = .018) and took longer to occur (mean ± SD = 44 ± 3.4 vs 30 ± 2.8 days, HR = 0.65 [95% CI, 0.50-0.85], P = .001). There was no significant interaction with the treatment mode with regard to remission (Wald = 0.20, P = .890). Conclusions Anxious depression is common in patients diagnosed with depression. The poorer treatment outcome in patients with anxious depression demonstrates the need to address the issue of specific treatment strategies for this subgroup. However, anxious depression has no moderating effect on the efficacy of algorithm-guided treatment. Trial registration http://www.germanctr.de/ Identifier: DRKS00000161.

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 Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. Methods In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. Results In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS. Discussion This secondary analysis of the RESIS trials has several limitations. First of all, the analysis of the primary endpoint was negative [24] and all subsequent secondary analyses showing a positive effect of the intervention (here: change in PANSS excitement factor) are of limited statistical power and therefore subject to uncertainty. On the other hand, our analyses confirm the negative finding of the original publication extends this finding to a broader negative symptom definition. Moreover, the new analysis provides a possible, but hypothetical explanation for the previously described effect of active rTMS on PANSS positive subscale. Of course, many other PANSS factor models are available and in pharmacological research the Marder factors [23, 35] have particular significance. However, the here used five-factor consensus model [21] includes the Marder factor results and our negative symptom factors overlaps with those factors. Another limitation is that it may be possible that our sham stimulation (coil tilted over one wing at an angle of 45°[24]) may still have been slightly biologically active as discussed elsewhere [24].