Effects of add-on Celecoxib treatment on patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame): study design and methodology of a multicentre randomized, placebo-controlled trial.

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The "Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)" is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration: http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044.

Severe serotonin syndrome under duloxetine in a patient with coeliac disease — Is there a connection? A case report

Background and objectives: Serotonin Syndrome (SS) is a rare but severe drug side effect of serotonergic substances. The various symptoms of SS are the result of excess serotonin on the central and enteric nervous system. Monotherapy with serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine induce the syndrome very rarely. It has been shown that patients with coeliac disease (CD) per se have significantly increased serum serotonin levels.MethodsWe report the case of a 41-year-old white male who developed an unusual severe SS under monotherapy with duloxetine. Remarkably, the patient was also diagnosed with CD shortly before.ResultsAfter all other possible causes have been excluded by intensive diagnostics the clinical diagnosis of a serotonergic syndrome was made.ConclusionTo our knowledge, this case is the first report of such a severe serotonin syndrome under duloxetine monotherapy, which might be boosted trough the patient’s coeliac disease. We suspect that the serotonin level of the patient could already have been significantly increased due to his CD and therefore jointly responsible for the fulminant serotonin syndrome under duloxetine. (AU)

rTMS and tDCS for the treatment of catatonia: A systematic review.

BACKGROUND: Catatonia is a potentially life threatening syndrome in various psychiatric disorders. As first line treatment, benzodiazepines and electroconvulsive therapy (ECT) are recommended. In some cases, benzodiazepines are ineffective and ECT is not available or contraindicated. Therefore, the search for new and alternative treatment strategies is of great importance. OBJECTIVE: To review the evidence for alternative neurostimulation treatment strategies (rTMS and tDCS) for catatonia according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. METHOD: We performed a systematic literature search in several electronic databases. We also searched the WHO International Clinical Trials Registry Platform (ICTRP) and the ClinicalTrials.gov database to detect registered studies. RESULTS: We identified nine publications on rTMS treatment and four publications on tDCS in catatonia. Most of the publications reported clinically relevant improvement of catatonic symptoms. Only two publications reported insufficient improvement. The available Bush-Francis Catatonia Rating Scale scores showed statistical significant improvement following rTMS and tDCS. We could not identify any finished clinical studies or case series, dedicated to this topic. We also could not identify any publications that compared first line treatment options with rTMS or tDCS. CONCLUSIONS: Based on the case report literature, rTMS and tDCS might be promising alternative treatment strategies for patients who do not respond to benzodiazepines or in case ECT is not available or contraindicated. There are even hints that rTMS or tDCS might be an option in patients who respond to ECT but need long-term treatment to control catatonic symptoms. Further clinical trials are needed to allow for an evidence-based evaluation of potential risks and benefits of rTMS and tDCS for catatonia.

Add-on spironolactone as antagonist of the NRG1-ERBB4 signaling pathway for the treatment of schizophrenia: Study design and methodology of a multicenter randomized, placebo-controlled trial.

BACKGROUND: Preclinical studies recently showed that the mineralocorticoid antagonist spironolactone acts also as an antagonist of the NRG1-ERBB4 signaling pathway and improves schizophrenia-like behaviour in Nrg1 transgenic mouse model. As this signaling pathway is critically linked to the pathophysiology of schizophrenia, especially in the context of working-memory dysfunction, spironolactone may be a novel treatment option for patients with schizophrenia targeting cognitive impairments. AIMS: To evaluate whether spironolactone added to an ongoing antipsychotic treatment improves cognitive functioning in schizophrenia. METHODS: The add-on spironolactone for the treatment of schizophrenia trial (SPIRO-TREAT) is a multicenter randomized, placebo-controlled trial with three arms (spironolactone 100 mg, spironolactone 200 mg and placebo). Schizophrenia patients are treated for three weeks and then followed-up for additional nine weeks. As primary outcome, we investigate changes in working memory before and at the end of the intervention phase. We will randomize 90 patients. Eighty-one patients are intended to reach the primary endpoint measure at the end of the three-week intervention period. Secondary endpoints include other measures of cognition, psychopathology, safety measures and biological measures. CONCLUSIONS: SPIRO-TREAT is the first study evaluating the efficacy of the mineralocorticoid receptor antagonist spironolactone to improve cognitive impairments in schizophrenia patients targeting the NRG1-ERBB4 signaling pathway. With SPIRO-TREAT, we intend to investigate a novel treatment option for cognitive impairments in schizophrenia that goes beyond the established concepts of interfering with dopaminergic neurotransmission as key pathway in schizophrenia treatment. CLINICAL TRIAL REGISTRATION: International Clinical Trials Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE.

Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms - Results from an exploratory re-analysis.

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.