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Comparing trajectories of cognitive functioning in treatment-resistant and non-resistant depression: a multicentre linear mixed-effects analysis.

Viktor T H Wahner·Toni Lange·Inga Stonner·Pasquale Paribello·Martina Contu·Marco Pinna·Dobrochna Kopeć·Ewa Ferensztajn-Rochowiak·Filip Rybakowski·Mara Dierssen·Massimo Gennarelli·Mirko Manchia·Alessandra Minelli·Marie-Claude Potier·Claudia Pisanu·Ferran Sanz·Alessio Squassina·Júlia Perera-Bel·Silke Jörgens·PROMPT consortium·Bernhard T Baune
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Abstract

BACKGROUND: Impaired cognitive functioning is a severe symptom in major depressive disorder (MDD). Recent evidence suggests it may be a central characteristic in its treatment resistant form (TRD), potentially constituting a clinical marker for treatment resistance and a target amenable to intervention. To date, cognitive functioning in TRD remains poorly understood and longitudinal investigations are scarce. METHODS: This observational prospective cohort study, including 320 patients diagnosed with MDD from the multicentre PROMPT study, examined differences in cognitive functioning between 118 TRD and 202 non-TRD patients over a period of twelve weeks in a real-world setting, using linear mixed modelling. Patients that failed to respond to at least two prior antidepressants trials at baseline were classified as TRD. RESULTS: TRD patients showed significantly poorer baseline performances than non-TRD patients in attention/processing speed (β = -0.45; 95%CI[-0.70, -0.19]; FDR-p = 0.003) and verbal memory (β = -0.45; 95%CI[-0.72, -0.18]; FDR-p = 0.003). Significant time × group interactions were observed in motor speed and verbal fluency tasks. Post-hoc-analyses revealed stagnation in TRD patients and significant improvement in non-TRD patients. Across all other tasks improvement was observed in both groups, and random effects showed large heterogeneity between patients, indicating notable individual differences in cognitive performances. CONCLUSIONS: The results suggest distinct recovery patters between non-TRD and TRD patients, and diminished functioning in TRD patients at the domain level. However, intact and diminished performances likely occur in both groups, warranting further investigation of cognitive heterogeneity. These short-term findings highlight the need for more comprehensive longitudinal research on cognition in TRD.

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HumansMajor Depressive DisorderDepressive Disorder, Treatment-ResistantFemaleMaleCognitionProspective StudiesMiddle AgedAdultAntidepressive AgentsProcessing SpeedNeuropsychological TestsAttentionLinear ModelsLongitudinal StudiesCognitive functioningDifficult-to-treat depressionLinear mixed modelMajor depressive disorderTreatment-resistant depressionJournal ArticleMulticenter StudyObservational StudyComparative Study

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Viktor T H Wahner, Toni Lange, Inga Stonner, Pasquale Paribello, Martina Contu, Marco Pinna, Dobrochna Kopeć, Ewa Ferensztajn-Rochowiak, Filip Rybakowski, Mara Dierssen, Massimo Gennarelli, Mirko Manchia, Alessandra Minelli, Marie-Claude Potier, Claudia Pisanu, Ferran Sanz, Alessio Squassina, Júlia Perera-Bel, Silke Jörgens, PROMPT consortium, Bernhard T Baune. 2026-08-15. Comparing trajectories of cognitive functioning in treatment-resistant and non-resistant depression: a multicentre linear mixed-effects analysis.. https://doi.org/10.1016/j.jad.2026.122380

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Adult subjectAntidepressive Agents subjectAttention subjectCognition subjectCognitive functioning subjectComparative Study subjectDepressive Disorder, Treatment-Resistant subjectFemale subjectHumans subjectJournal Article subjectLongitudinal Studies subjectMajor Depressive Disorder subjectMale subjectMiddle Aged subjectMulticenter Study subjectNeuropsychological Tests subject

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