Johan Lundberg

Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorder (MDD). The antidepressive effect of ECT relies on an induced generalized seizure. ECT is given under general anesthesia, even though most anesthetic drugs increase the seizure threshold. This could diminish the therapeutic effect of ECT. No trial has addressed the impact of anesthetic dose on treatment outcome with ECT for MDD. In this pilot for a randomized controlled, double blind, clinical trial 30 hospitalized patients with MDD for which ECT is indicated are randomized 1:1 to anesthesia with either a low or high dose thiopental during ECT. A blinded rater asesses severity of depressive symptoms with Montgomery-Åsberg Depression Rating Scale (MADRS) and subjective cognitive dysfunctions before ECT and after six ECTs. After this, patients are given treatment as usual and are followed with register data up till one year after ECT, to compare the lengths of the ECT series, memory function six months after ECT, and risk of MDD relapse in the low versus high thiopental dose group. Patients will be recruited 2024-2025. Based on the pilor study data we will plan for a national RCT. The main purpose of the study is to test if ECT reduces MADRS scores more effectively with a low thiopental dose compared to a high thiopental dose for anesthesia. Optimized treatment effect of ECT has great clinical value, with more rapid alleviation of severe depression and reduced length of hospital stay.

A third of those who get cancer also develop it Depression. Despite the special circumstances of these patients, with concomitant cancer treatment, reduced quality of life and often expected shortened lifespan related to the cancer itself, there is no specific antidepressant treatment introduced in care. A single dose of psilocybin has shown a rapid (within days) and long-term (months to years) antidepressant effect in several small studies in which different cancer groups included. There is still a lack of good studies to introduce the treatment in clinical practice. There is also a lack of knowledge about which patients benefit of this particular treatment. 100 patients with cancer and depression are randomized to treatment with pslicybin or placebo i four different regions in Sweden during 2024-2025. We are investigating the antidepressant effect as well side effects 6 weeks after treatment and after six months. All patients submit blood samples and undergoes EEG examination before and six weeks after the treatment. The 25 patients participating in The Stockholm region is also examined with three other more demanding methods, MEG, fMRI and PET, to be able to create a simple measure where we can predict which patients with the help of blood tests and EEG who benefit most from psliocybin even before treatment. All this information will be used to carry out a so-called phase three study of psilocybin in cancer-related depression, where we also can refine the prognostic tool, blood tests and EEG, to see which patients benefit the most the treatment. After that, this treatment, together with the prognosis tool, can be introduced in usual clinical care. We think it can happen in 2031.

While the selective serotonin reuptake inhibitors (SSRIs) are first line of treatment of depression, 30% of patients do not respond adequately. Adding an atypical antipsychotic agent to the SSRI may lead to a marked response in these cases, this having become a recommended strategy. Antipsychotic drugs are, however, marred by serious side effects, such as motor impairment, apathy, and the metabolic syndrome. OSU6162 is a dopamine stabilizer developed by Nobel prize winner Arvid Carlsson which bears pharmacological similarities to atypical antipsychotics, but which, according to experimental and clinical studies (where it has been tested mainly for the treatment of fatigue), is more activating than these, and entirey devoid of their side effects. A network of clinicians in Gothenburg, Kungälv, Lund, Stockholm, and Uppsala will now perform a randomized, 5-center, placebo-controlled trial aiming to assess the efficacy and tolerability of OSU6162 as add-on (flexible dose

6 weeks of treatment

n=80 per group) in patients who have not responded to six weeks of treatment with an SSRI or a serotonin and noradrenaline reuptake inhibitor (SNRI). Mixed model statistics will be used to compare the groups with respect to the sum score for 6 core items of the Hamilton Depression Rating Scale at week 6. First patient first visit: Q1/2023

last patient last visit: Q4/2025. Patient benefit: an effective and tolerable treatment for SSRI-resistant depression is an important unmet medical need.

Background: The age standardised rate of yearly new cancer cases is 190/100 000 globally, by WHO. 30-40% of these will develop depression. There is currently no specific antidepressant treatment regime implemented in the cancer population. This is in spite of the specific needs given by concurrent cancer treatments, limited quality of life from the cancer per se and the often limited life expectancy from a cancer disease. A single dose of psilocybin combined with 3 hours of psychological support has shown rapid (within days) and long term (months or years) antidepressant effect in several small studies in different cancer populations. Large, well designed RCTs are still lacking, as is response predictors for treatment guidance. I am PI of the first RCT of psilocybin treament of depression in Sweden, expected to end randomisation in june 2022. CAPSI: 100 patients with cancer and depression will be randomised to psilocybin or active placebo (2:1) at 4 different regions in Sweden during 2024-2025. Primary end point is depressive symptoms 6 weeks post dose and follw up is 6 months. All subjects will undergo EEG and blood sampling, a subsample (n=50) will also undergo MEG and fMRI, and 25 of them also PET, in order to develop a EEG proxy response signature. Together with markers in blood we will develop a predictor model for psilocybin treatment response. All data will be used to motivate a phase three study with the same PICO and further development of the response markers.