Open Access

Intermittent theta burst stimulation (iTBS), a variant of repetitive transcranial magnetic stimulation (rTMS), is an established treatment for adults with major depressive disorder (MDD). Due to its favorable safety profile, iTBS is also a promising early intervention in the transition phase from adolescence to early adulthood, but this has not been systematically investigated to date. Thus, the EARLY-BURST trial investigates the efficacy and safety of iTBS over the left dorsolateral prefrontal cortex (lDLPFC) in treatment-seeking young patients (age 16–26 years) with depressive disorders (i.e. major depressive disorder, persistent depressive disorder, bipolar depression), allowing for relevant co-morbidities. Participants have not received antidepressant or antipsychotic medication during the last 12 months except for short-term (< 2 weeks) on-demand medication. The trial will employ a novel sequential Bayesian, randomized, double-blind, parallel-group, sham-controlled design. Up to 90 patients at two clinical sites (Munich, Augsburg) will be randomized 1:1 to the treatment groups, with sequential analyses starting after 26 patients in each group completed the treatment. The primary outcome will be the difference in depression severity at week 6 (post-treatment visit) between active iTBS and sham iTBS, assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). The trial is planned to be expanded towards a three-arm leapfrog design, contingent on securing additional funding. Thus, in addition to potentially providing evidence of iTBS’s efficacy in adolescents and young adults with depressive disorders, the EARLY-BURST trial aims at setting the stage for subsequent platform trials in this dynamic research field, where novel adaptive study designs are required to meet the need for rapidly testing promising new vs established rTMS protocols.

Background Quick symptomatic remission after the onset of psychotic symptoms is critical in schizophrenia treatment, determining the subsequent disease course and recovery. In this context, only every second patient with acute schizophrenia achieves symptomatic remission within three months of initiating antipsychotic treatment. The potential indication extension of clozapine—the most effective antipsychotic—to be introduced at an earlier stage (before treatment-resistance) is supported by several lines of evidence, but respective clinical trials are lacking. Methods Two hundred-twenty patients with acute non-treatment-resistant schizophrenia will be randomized in this double-blind, 8-week parallel-group multicentric trial to either clozapine or olanzapine. The primary endpoint is the number of patients in symptomatic remission at the end of week 8 according to international consensus criteria (‘Andreasen criteria’). Secondary endpoints and other assessments comprise a comprehensive safety assessment (i. e., myocarditis screening), changes in psychopathology, global functioning, cognition, affective symptoms and quality of life, and patients’ and relatives’ views on treatment. Discussion This multicentre trial aims to examine whether clozapine is more effective than a highly effective second-generation antipsychotics (SGAs), olanzapine, in acute schizophrenia patients who do not meet the criteria for treatment-naïve or treatment-resistant schizophrenia. Increasing the likelihood to achieve symptomatic remission in acute schizophrenia can improve the overall outcome, reduce disease-associated burden and potentially prevent mid- and long-term disease chronicity.

Background and Hypothesis Abnormal psychomotor behavior is a core schizophrenia symptom. However, assessment of motor abnormalities with expert rating scales is challenging. The Positive and Negative Syndrome Scale (PANSS) includes 3 items broadly related to hypokinetic motor behavior. Here, we tested whether a sum score of the PANSS items mannerisms and posturing (G5), motor retardation (G7), and disturbance of volition (G13) corresponds to expert ratings, potentially qualifying as a proxy-marker of motor abnormalities. Study Design Combining baseline datasets (n = 196) of 2 clinical trials (OCoPS-P, BrAGG-SoS), we correlated PANSS motor score (PANSSmot) and 5 motor rating scales. In addition, we tested whether the cutoff set at ≥3 on each PANSS motor item, ie, “mild” on G05, G07, and G13 (in total ≥9 on PANSSmot) would differentiate the patients into groups with high vs low scores in motor scales. We further sought for replication in an independent trial (RESIS, n = 102), tested the longitudinal stability using week 3 data of OCoPS-P (n = 75), and evaluated the validity of PANSSmot with instrumental measures of physical activity (n = 113). Study Results PANSSmot correlated with all motor scales (Spearman-Rho-range 0.19–0.52, all P ≤ .007). Furthermore, the cutoff set at ≥3 on each PANSS motor item was able to distinguish patients with high vs low motor scores in all motor scales except using Abnormal Involuntary Movement Scale (Mann-Whitney-U-Tests: all U ≥ 580, P ≤ .017). Conclusions Our findings suggest that PANSSmot could be a proxy measure for hypokinetic motor abnormalities. This might help to combine large datasets from clinical trials to explore whether some interventions may hold promise to alleviate hypokinetic motor abnormalities in psychosis.

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.