2026 ECNP Congress

PS01-1186

The PRIME-D trial: improving recovery in depression through pro-cognitive pharmacological enhancement of cognitive behavioral therapy

Nanna Svart — S. Olsen, E.S. Høgsted, A. Fuglsang-Damgaard, V. Garre, S.V. Larsen, A. Sankar, V.G. Frokjaer, V.H. Dam · Copenhagen University Hospital Rigshospitalet, Neurobiology Research Unit and BrainDrugs, Copenhagen, Denmark

2026 ECNP Congress

Background

Cognitive behavioral therapy (CBT) is a first-line treatment for major depressive disorder (MDD) in Danish outpatient care. However, cognitive impairments, which are common and often underrecognized in MDD [1], may interfere with therapy outcome [2,3]. There are currently no established interventions targeting cognitive functioning in MDD. The serotonin 4 receptor (5-HT4R) agonist prucalopride has shown short-term pro-cognitive effects particularly for memory and learning [4]. In this trial, we investigate whether adjunctive prucalopride treatment can improve cognitive and mood symptoms when combined with CBT.

Trial hypothesis

Adjunctive treatment targeting the 5-HT4R will enhance clinical response to CBT and improve cognitive function in patients with MDD.

Study Design

In the PRIME-D trial, we will include 106 patients aged 18-50 years with a moderate-to-severe depressive episode. Patients must be medication-free for at least two months prior to inclusion. In a double-blind randomized clinical trial design, patients will be allocated to either placebo (n=53) or 2 mg prucalopride (n=53) during the first 8 weeks of a 13-week group CBT program. Discontinuing the intervention at week 8 allows us to distinguish sustained therapeutic effects from those dependent on ongoing pharmacological action. Patients will be assessed at seven time points: at baseline, 3h after prucalopride/placebo intervention, after 1, 4, 8, and 13 weeks of treatment as well as long-term follow-up after 6 months.

Patients will complete a comprehensive neuropsychological test battery at baseline and at week 8 including measures of verbal, visuospatial and working memory; processing and psychomotor speed; emotion processing; and social cognition. Patients will also complete a shorter battery at week 1, 4, and 13 assessing memory functioning. Biological stress markers will be assessed with salivary cortisol awakening response measures at baseline and week 8. In addition, questionnaire data on personality, daily functioning, thinking patterns, mood, distress, and quality of life, and functioning will be collected. Clinical symptom severity will be assessed with Hamilton Depression Rating Scale 17 (HDRS-17) at all visits. To assess potential non-CBT related effects, we record CBT manual adherence, therapeutic alliance, and observe one session to assess the quality of the group as a therapeutic community.

Study outcomes and analysis plan

The trial has two primary estimands assessing baseline-adjusted differences in i) depressive symptom severity indexed by HDRS-6 scores and ii) verbal memory performance indexed with the Verbal Affective Memory Task 24 (VAMT-24) at week 8 between patients randomized to adjunctive prucalopride versus placebo. Analyses will follow both intention-to-treat (primary) and per-protocol (secondary) principles. Outcomes will be analyzed using constrained linear mixed models with a common baseline mean and group-specific follow-up means, accounting for within-subject differences. All models will be controlled for age, sex, hormonal contraceptive use (women-only) and education. Multiplicity will be controlled using the Hochberg procedure.

Expected impact

The PRIME-D trial will: a) evaluate whether a new adjunctive 5-HT4R drug can improve treatment outcomes including cognitive symptoms and daily life for patients with MDD as well as b) advance our understanding of how 5-HT4R agonism as a pro-cognitive strategy might affect outcomes of CBT in MDD.

References

  1. Dam, V.H., Stenbæk, D.S., Köhler-Forsberg, K., Ip, C., Ozenne, B., Sahakian, B.J., Knudsen, G.M., Jørgensen, M.B., Frokjaer, V.G., 2021. Hot and cold cognitive disturbances in antidepressant-free patients with major depressive disorder: a NeuroPharm study. Psychol. Med. 51 (14), 2347–2356.
  2. Tanev, K.S., Federico, L.E., Greenberg, M.S., et al., 2020. Baseline cognitive performance and treatment outcomes from cognitive behavioral therapies for posttraumatic stress disorder: a naturalistic study. J. Neuropsychiatry Clin. Neurosci. 32 (3), 286–293.
  3. Wild, J., Gur, R.C., 2008. Verbal memory and treatment response in posttraumatic stress disorder. Br. J. Psychiatry 193 (3), 254–255.
  4. Murphy, S.E., Wright, L.C., Browning, M., Cowen, P.J., Harmer, C.J., 2019. A role for 5‑HT4 receptors in human learning and memory. Psychol. Med. 1–9.