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Abstract Background The symptom severity of a substantial group of schizophrenia patients (30–40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood–brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia. Methods/design In total, 90 subjects aged 18–70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted. Discussion It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. Trial registration ClinicalTrials.gov , NCT02949232 and NCT03340909 . Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014–000520-14 and 2017–000163-32.

Introduction Gait difficulties are common in Parkinson’s disease (PD) and cause significant disability. These symptoms are often resistant to treatment. Spinal cord stimulation (SCS) has been found to improve gait, including freezing of gait, in a small number of patients with PD. The mechanism of action is unclear, and some patients are non-responders. With this double-blind, placebo-controlled efficacy and feasibility clinical and imaging study, we aim to shed light on the mechanism of action of SCS and collect data to inform development of a scientifically sound clinical trial protocol. We also aim to identify clinical and imaging biomarkers at baseline that could be predictive of a favourable or a negative outcome of SCS and improve patient selection.Methods and analysis A total of 14 patients will be assessed with clinical rating scales and gait evaluations at baseline, and at 6 and 12 months after SCS implantation. They will also receive serial 18F-deoxyglucose and 18FEOBV PET scans to assess the effects of SCS on cortical/subcortical activity and brain cholinergic function. The first two patients will be included in an open pilot study while the rest will be randomised to receive active treatment or placebo (no stimulation) for 6 months. From this point, the entire cohort will enter an open label active treatment phase for a subsequent 6 months.Ethics and dissemination This study was reviewed and approved by the Committee on Health Research Ethics, Central Denmark RM. It is funded by the Danish Council for Independent Research. Independent of outcome, the results will be published in peer-reviewed journals and presented at national and international conferences.Trial registration number NCT05110053; ClinicalTrials.gov Identifier.