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Treatment Resistant Depression / Major Depressive Disorder / Depressive Disorder, Treatment Resistant · Journal article
Journal of Affective Disorders · August 15, 2026
Encouraging direction, but not yet definitive.
This 12-week observational study found that treatment-resistant depression patients demonstrated significantly poorer baseline cognitive performance in attention/processing speed and verbal memory compared to non-resistant patients, with divergent trajectories in motor speed and verbal fluency (stagnation in TRD, improvement in non-TRD). The findings suggest cognitive impairment may characterise TRD but require longer-term investigation and confirmation, particularly given substantial individual heterogeneity within both groups.
Multicentre prospective observational cohort study. 320 patients with major depressive disorder enrolled in the multicentre PROMPT study; 118 classified as treatment-resistant (≥2 failed antidepressant trials) and 202 as non-resistant.. Intervention: Cognitive assessment (attention/processing speed, verbal memory, motor speed, verbal fluency, and other cognitive domains) conducted at baseline and over 12-week period.. Compared with: Treatment-resistant depression (TRD) versus non-treatment-resistant depression (non-TRD). n = 320. Multicentre (specific number of centres and countries not stated in abstract).
TRD patients showed significantly poorer baseline attention/processing speed than non-TRD (β = -0.45; 95%CI[-0.70, -0.19]; FDR-p = 0.003) TRD patients showed significantly poorer baseline verbal memory than non-TRD (β = -0.45; 95%CI[-0.72, -0.18]; FDR-p = 0.003) Significant time × group interactions in motor speed and verbal fluency revealed stagnation in TRD and improvement in non-TRD patients
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Clinicians should recognise that cognitive impairment in attention, processing speed, and verbal memory may characterise treatment-resistant depression and warrants direct assessment. However, the 12-week timeframe and substantial individual variation suggest that cognitive status should not yet be used as a sole marker for treatment resistance; longer-term studies and investigation of cognitive heterogeneity are needed before clinical implementation.
A well-designed observational cohort study with adequate sample size and rigorous statistical method (linear mixed modelling) reporting clear differences in cognitive trajectories between TRD and non-TRD patients, but limited to 12 weeks and requiring confirmation in longer-term, interventional designs.
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Quoted from the source exactly as published.
Clinicians should recognise that cognitive impairment in attention, processing speed, and verbal memory may characterise treatment-resistant depression and warrants direct assessment. However, the 12-week timeframe and substantial individual variation suggest that cognitive status should not yet be used as a sole marker for treatment resistance; longer-term studies and investigation of cognitive heterogeneity are needed before clinical implementation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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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