Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression: a pragmatic, open-label, parallel-group, randomised controlled superiority trial in the UK
Anthony J. Cleare, Jess Kerr‐Gaffney, Kimberley Goldsmith, Zohra Zenasni, Nahel Yaziji, Huajie Jin, Alessandro Colasanti, John Geddes, David Keßler, R. Hamish McAllister‐Williams, Allan H. Young, Álvaro Barrera, Lindsey Marwood, R. Taylor, Helena Tee, James Rucker, Ryan Williams, Camilla Day, Ilia Bountouni, Mario Juruena, Luke Jelen, Allison Edwards, Carol Kan, Chaitra Jairaj, Lauren Waterman, Robert McCutcheon, Romayne Gadelrab, Rashmi Patel, Patrick McLoughlin, Elana Day, Rupal Shah, Joseph Cattell, Valeria De Angel, Emma Incecik, Anda Ancane, Emmanuella Oprea, Andrea Ulrichsen, Viktoriya Nikolova, Tim Mantingh, Dimosthenis Tsapekos, Andrew Pickles, Daniel Deitch, Rebecca Strawbridge, Kirsty James, Renee Romeo, Rachel Holland, Stuart Watson, Hossam Marey, Niraj Ahuja, Eman Arebi, Daniel Armstrong, Dheeraj Buruju, Afamefuna Emechebe, Oghenefejiro Esi, Jayne Healicon, Selma Osman, William Stageman, Neeti Sud, Vineet Raj, Jennifer Burgess, Jake Hutchinson, Kimberley Nortey, Susan Wilson, Wendy Hall, Joe Swift, Rosie Carr, Jahnese Hamilton, Joe Reilly, Rajesh Nair, Philip Cowen, Michael Browning, Lucas McKeown, Sarah Mather, Jen Potts, Chris Millar, Sarah Hollingsworth, Rebecca Dean, Ceri Morgan, Jade Harvey, Fay Davies, Andrea Cipriani, Mary-Jane Attenburrow, Jonathan Evans, Jonathan Davies, Rwth Leach, Catherine Roiz de S'a, Joanna Pooley, Guy Emery, Serena Gregory
Abstract
BACKGROUND: Lithium and quetiapine are first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. We aimed to assess whether quetiapine augmentation therapy is more clinically effective and cost-effective than lithium for patients with treatment-resistant depression over 12 months. METHODS: We did this pragmatic, open-label, parallel-group, randomised controlled superiority trial at six National Health Service trusts in England. Eligible participants were adults (aged ≥18 years) with a current episode of major depressive disorder meeting DSM-5 criteria, with a score of 14 or higher on the 17-item Hamilton Depression Rating Scale at screening who had responded inadequately to two or more therapeutic antidepressant trials. Exclusion criteria included having a diagnosis of bipolar disorder or current psychosis. Participants were randomly assigned (1:1) to the decision to prescribe lithium or quetiapine, stratified by site, depression severity, and treatment resistance, using block randomisation with randomly varying block sizes. After randomisation, pre-prescribing safety checks were undertaken as per standard care before proceeding to trial medication initiation. The coprimary outcomes were depressive symptom severity over 12 months, measured weekly using the Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation. Economic analyses compared the cost-effectiveness of the two treatments from both an NHS and personal social services perspective, and a societal perspective. Primary analyses were done in the intention-to-treat population, which included all randomly assigned participants. People with lived experience were involved in the trial. The trial is completed and registered with the International Standard Randomised Controlled Trial registry, ISRCTN16387615. FINDINGS: Between Dec 5, 2016, and July 26, 2021, 212 participants (97 [46%] male gender and 115 [54%] female gender) were randomly assigned to the decision to prescribe quetiapine (n=107) or lithium (n=105). The mean age of participants was 42·4 years (SD 14·0 years) and 188 (89%) of 212 participants were White, seven (3%) were of mixed ethnicity, nine (4%) participants were Asian, four (2%) were Black, three (1%) were of Other ethnicity, and ethnicity was not recorded for one (1%) participant. Participants in the quetiapine group had a significantly lower overall burden of depressive symptom severity than participants in the lithium group (area under the between-group differences curve -68·36 [95% CI -129·95 to -6·76; p=0·0296). Time to discontinuation did not significantly differ between the two groups. Quetiapine was more cost-effective than lithium. 32 serious adverse events were recorded in 18 participants, one of which was deemed possibly related to the trial medication in a female participant in the lithium group. The most common serious adverse event was overdose, occurring in three (3%) of 107 participants in the quetiapine group (seven events) and three (3%) of 105 participants in the lithium group (five events). INTERPRETATION: Results of the trial suggest that quetiapine is more clinically effective than lithium as a first-line augmentation option for reducing symptoms of depression in the long-term management of treatment-resistant depression, and is probably more cost-effective than lithium. FUNDING: National Institute for Health and Care Research Health Technology Assessment programme.