Pharmacoepidemiological studies on depression : treatments, treatment-resistance and consequences

Today, a large proportion of patients with depression do not get satisfactory effect from the recommended treatments. If there is no adequate response after two treatment attempts, this is often referred to as treatment-resistant depression (TRD), estimated to occur in around 30% of patients with depression. There is limited knowledge on certain potential consequences of TRD, and on the effect of electroconvulsive therapy (ECT) in TRD. Disturbed sleep is a common symptom of depression and may indicate worse outcomes. Still, there are no clear recommendations regarding hypnotic drugs in depression treatment guidelines, and observational studies have found risks associated with hypnotics use. There is little previous knowledge on hypnotics use in depression, or on factors associated with long-term hypnotics use in patients with depression starting hypnotic treatment. The overarching aim of this project was to improve our understanding of depression and its treatments using pharmacoepidemiologic methods for national registers, focusing particularly on treatment-resistant patients and those using hypnotic drugs. In Study I, the consequences of TRD on health care utilisation (HCU) were investigated. We observed that patients with TRD had a two- to-fourfold higher use of inpatient and outpatient healthcare compared to matched non-TRD patients. The increase in HCU appeared most pronounced during the first year, but also persisted over the entire follow-up period. Study II compared response rates after ECT for unipolar depression in patients with TRD and non-TRD. Response and remission rates were somewhat lower in patients with TRD. ECT response rates increased with higher age and more severe depression symptoms. Study III examined risks of major adverse cardiovascular events (MACE) in patients with TRD or severe depression and in matched comparators. No overall risk increase was seen in patients with TRD or severe depression, yet hazards were increased specifically for cardiovascular death in patients with TRD, and for MACE in young patients with severe depression. In Study IV we found that hypnotic drugs were commonly used in patients with depression, the most drug class used the most was Z-drugs, followed by propiomazine, melatonin, and BZD hypnotics. During the study period, trends were found of decreasing use of Z-drugs and BZD hypnotics, and a sharply increased use of melatonin. Study V investigated factors associated with long-term use of hypnotic drugs in patients with depression starting any hypnotic drug. Long-term use was associated with older age, a range of clinical factors including comorbidities and certain concurrent medications, and most prominently with the number of AD trials in the last year. List of scientific papers I. Philip Brenner, Adam Nygren, David Hägg, Mikael Tiger, Marguerite O'Hara, Lena Brandt & Johan Reutfors Health care utilisation in treatment-resistant depression: a Swedish population-based cohort study International Journal of Psychiatry in Clinical Practice, 2022, Vol. 26, No. 3, p. 251-258 https://doi.org/10.1080/13651501.2021.2003405 Il. Adam Nygren, Johan Reutfors, Lena Brandt, Robert Boden, Axel Nordenskjold and Mikael Tiger Response to electroconvulsive therapy in treatment-resistant depression: nationwide observational follow-up study B JPsych Open, 2023, Vol. 9, p. 1-7 https://doi.org/10.1192/bjo.2023.5 III. Adam Nygren, Johan Reutfors, Pär Karlsson, Mikael Tiger, Jonas Faxén, Philip Brenner Risk of major adverse cardiovascular events in treatment-resistant or severe depression Journal of Affective Disorders, 2025, Vol. 386, p. 119419 https://doi.org/10.1016/j.jad.2025.119419 IV. Adam Nygren, Philip Brenner, Lena Brandt, Pär Karlsson, Sandra Eloranta, Johan Reutfors Trends in hypnotic drug use in depression 2007-2017: A Swedish population-based study Journal of Sleep Research, 2025, Vol. 34, p. e14267 https://doi.org/10.1111/jsr.14267 V. Adam Nygren, Pär Karlsson, Mikael Tiger, Philip Brenner, Karin Gembert, Zhiheng Zhang, Ying Qu, Jari Tiihonen, Heidi Taipale, Johan Reutfors Factors associated with long-term hypnotics use in depression [Submitted]