Depressive Episode

The proposed project will investigate the neurobiological mechanisms of accelerated intermittent Theta Burst Stimulation (iTBS) in major depressive disorder (MDD) using an advanced multimodal imaging approach. This single-arm, within-subject study will deliver one week of accelerated iTBS and use pre-/post-treatment PET/MRI to quantify changes in synaptic density, functional connectivity, and microstructural integrity. We will combine \[¹⁸F\]SynVesT-1 PET with functional, neurochemical and anatomical MRI, such as resting-state fMRI, magnetic resonance spectroscopy (MRS) and neurite orientation dispersion and density imaging (NODDI), to capture treatment-related plasticity. This integrated design will link molecular and network-level mechanisms to clinical improvement, providing an unprecedented mechanistic map of how accelerated iTBS restores brain function in depression.

Evidence-based treatments for depression, such as antidepressive medication, usually have a latency of 4 to 6 weeks before they achieve a therapeutic effect. Chronotherapy is a group of non-pharmacological interventions that presumably act on the circadian system to achieve a rapid-onset clinical effect and better long-term effects and has been shown efficient to improve depressive symptoms. Interventions include sleep deprivation, sleep-phase advancement and stabilization, and light therapy. There are few studies testing the effectiveness of combining these three chronotherapeutic techniques in the initial phase of treatment of depression in a mental health care clinic. The investigators aim to test the effects and safety of chronotherapy in addition to TAU compared to TAU alone, with the primary outcome being self-reported depressive symptoms at 1 week following randomization. The study is a randomized controlled trial with 76 patients with a depressive episode who initiate treatment at Nidaros DPS, St. Olavs University Hospital. Participants will be allocated 1:1 to either chronotherapy + treatment as usual (TAU) or to TAU alone.

In this triple-blind randomized controlled trial, we ask if targeting intermittent theta burst stimulation (iTBS) based on individual resting state connectivity improves treatment outcomes in major depressive disorder (MDD). For the trial, we will recruit 210 patients with major depressive disorder. Each patient will undergo a 30-40-minute MRI scan, after which they will receive a 6-week standard iTBS treatment. Participants will be randomized to receive iTBS either to the standard neuronavigated target (a technique for treatment location targeting, based on group-average connectivity) or to a personalized connectivity-guided target selected based on individual functional connectivity scans. The main outcome of this trial is response rate as determined by ≥ 50% reduction in Grid HRSD-17 scores. Secondary outcomes include remission rate, change in depression, anxiety and anhedonia symptoms, quality of life, and biological measures of heart rate variability, objective sleep measures and daily activity as a proxy of anhedonia - defined as a reduced ability to experience pleasure.

The goal of this clinical trial is to compare three different treatments for depression in patients with moderate depression in General Practice, aged 18-65 years. We wish to investigate the effect of the treatment approaches, and 171 patients will be included in the trial. The participants will be randomised to one of the following three treatments: 1. Standard treatment provided by a general practitioner (i.e. the general practitioner treats the patient as he/she would normally do, when treating a patient with depression). 2. Standard treatment provided by a psychologist in the form behavioural therapy (i.e. the psychologist treats the patient as he/she would normally do, when treating a patient with depression). 3. A step-by-step treatment plan carried out by a general practitioner. The plan includes pre-determined follow-ups and a pre-determined, structured plan for which medications to use and when to increase dose or switch medication. The hypothesis is that a structured and step-by-step treatment approach regarding patients with depression, treated in general practice, is more effective than standard treatment provided by a general practitioner and a psychologist. All the participants will: 1. Receive one of the three treatments for 12 weeks. 2. Have meetings with the project staff every 4 weeks (week 0, 4, 8 and 12) were rating scales will be completed, e.g. a rating scale to measure progress or deterioration in the participant's depression.

We propose to test the hypothesis that bezafibrate, a pan-PPAR agonist, may be effective and safe for bipolar depression with the following specific aims: Aim #1. Proof-of-Concept Safety and Tolerability Aim: To assess the safety and tolerability of bezafibrate added to anti-manic medication for bipolar depression, especially with regard to worsening manic symptoms and suicidal ideation. We will conduct a phase IIa, 8-week, open pilot trial of bezafibrate added to FDA-approved anti-manic medication in 30 participants with bipolar depression. We will monitor changes in manic symptoms (Young Mania Rating Scale), suicidal ideation, cognitive functioning specifically in attention and verbal memory, and treatment emergent adverse events (SAFTEE). We will also monitor changes in the Framingham Cardiovascular Risk Score. Aim #2. Preliminary Assessment of Efficacy: To assess the antidepressant efficacy of bezafibrate added to anti-manic medication for acute bipolar I major depressive episodes. Hypothesis: The bezafibrate group will have a statistically significant decrease in the Montgomery Asberg Rating Scale (MADRS) Scores over 8 weeks. The results of this proof-of concept phase IIa study will help us to plan a placebo-controlled randomized trial. In summary, we propose an 8-week, proof-of-concept open pilot trial of an adjunctive pan-PPAR agonist, bezafibrate, for 30 patients with an acute bipolar I major depressive episode. The study may have a profound impact on the development of a novel treatment consistent with the mitochondrial dysregulation hypothesis of bipolar disorder and, to the best of our knowledge, will be the first proof-of-concept trial to assess a pan-PPAR agonist for bipolar disorder.

This is a randomised, placebo-controlled, parallel-group trial comparing OSU6162 at flexible dosage with placebo as add-on to treatment with an SSRI/SNRI in patients with depression that have not responded to treatment with an SSRI/SNRI per se for at least 6 weeks. The study will last for 6 weeks, after which those not having responded will leave the trial and those having responded will be offered to continue treatment without unblinding for another 4 weeks. Optional Substudy 1 and 2: Baseline and treatment-associated change in reward-related striatal activity per fMRI-assessment. (Substudy 1). Brain signal variability per fMRI-assessment. (Substudy 1). Probabilistic Reward Task (PRT). (Substudy 2). While assessment of the efficacy and safety of OSU6162 is the main objective of this study, possible differences between the two treatment groups with respect to a number of biomarkers in serum will also be explored. Multicenter trial: Multiple sites four Gothenburg, Lund, Stockholm and Uppsala.

This is a prospective, longitudinal, single-center observational study of data from the medical records of patients hospitalized after a characterized depressive episode and reviewed three months after hospital discharge, as part of a normally scheduled evaluation.

The POKAL-PSY project is a study that monitors participants for five years. The goal of the study is to identify distinguishable subtypes of depression on the basis of biomarkers and to gain insight into their prognostic significance.