Summary: “Brain fog”, the memory loss and lack of focus that affects up to 90% of people with major depressive disorder, has long been thought to be a warning sign of future relapse. However, a major study has turned this assumption on its head.
After tracking 1,800 participants, researchers found that for those with a history of depression, higher cognitive performance was actually linked to a greater risk of relapse. This “confounding” result suggests that the relationship between how we think and how we feel is far more complex than previously believed.
Key Facts
- The Study Group: Researchers used data from the UK Biobank, matching 1,800 participants who had previously experienced depression with healthy controls.
- The Expectation: Scientists hypothesized that “brain fog” (cognitive impairment) would act as a predictor for future depressive episodes.
- The Relapse Rate: 33% of participants with a history of depression relapsed during the follow-up period, compared to only 13% of the control group experiencing a first-time episode.
- The Paradox: In healthy controls, poor cognitive scores did predict a first episode of depression. But for those with a history of depression, the pattern flipped: those with the highest cognitive scores were the most likely to relapse.
- Potential Reasonings: Researchers suggest that higher cognitive functioning might be necessary for patients to actually “recognize” their symptoms and seek help, or that high-performing individuals may face different social pressures that contribute to relapse.
Source: University of Birmingham
Experiences of cognitive problems such as memory loss or difficulty concentrating, known as ‘brain fog’, may not predict relapse in depression according to a new study that has confounded researchers’ expectations.
In a new paper published today (7 May) in the BMJ Mental Health, a research team led by Dr Angharad de Cates from the University of Birmingham, along with researchers from the University of Oxford, studied data from 1,800 UK participants who had previously had an episode of depression. Participants were matched for age and sex with a control; and recruited as part of the UK Biobank.
The study was funded by the Guarantors of Brain and National Institute for Health and Care Research (NIHR) through the NIHR Biomedical Research Centre: Oxford Health.
The research team tested the idea that decline in some elements of cognition such as memory and attention, which affect between 70-90% of patients with major depressive disorder (MDD), might be associated with a greater risk of relapse.
With 40% of MDD patients having persistent cognitive impairment, the team looked to see whether cognitive decline could, therefore, help clinicians predict who is more likely to have further depressive episodes.
Participants were invited to take part in a series of cognitive tests and have structural and functional MRI imaging to look at whether there were any structural changes to their brains. Tests include a snap-card game to test reaction times, a numerical memory game, a word-pairing game and others.
These tests looked at different areas of cognitive performance. The researchers also pooled data across the battery of tasks to generate a measure of general cognitive functioning.
The research team found that one third (33%) of participants who had previously had depression experienced at least one depressive relapse in the years following their study visit, compared to 13% of control participants having their first episode of depression.
However, the study also found that patients with previous depression who had the lowest performance across the battery of cognitive tests were less likely to relapse compared to those with the highest cognitive scores.
This was contrary to expected findings, and also results seen for control participants, where worse performance on cognitive tests was associated with higher risk of depression during the follow up period.
Dr Angharad de Cates from the University of Birmingham and corresponding author of the paper said: “We expected poorer cognitive performance to be associated with a higher risk of future depression in both participants with a history of depression and matched controls.
“However, the results were more nuanced than expected. Among people with previous depression, those with higher cognitive scores were more likely to experience a further depressive episode than those with lower scores—the opposite pattern to that observed in controls.”
“We think this finding points to a range of social and residual factors related to cognition that warrant further investigation in both research and clinical practice.
“One possible explanation is that better cognitive functioning may be needed to recognise symptoms and seek help, highlighting the importance of optimising cognition in those with previous depression to support early intervention.”
What about healthy controls?
Participants from the healthy control group who took part in the study also took cognitive tests and had fMRI scans, and the results suggested that participants who performed poorly in terms of cognitive performance were at a higher risk of having an initial depressive episode.
While only 13% of participants who had no previous history of depression had an episode during the study period, fairly low in absolute terms, the lowest cognitive performing participants were 40% more likely to have had a first depressive episode compared to the baseline.
Dr Anya Topiwala from the University of Oxford and senior author of the paper said:
“People often think of memory problems as simply a consequence of depression, but our findings suggest the relationship is more complex. Among people with a history of depression, those with better cognitive performance were actually more likely to experience future depressive symptoms.
This highlights that remitted depression remains a high-risk state, and that relapse risk may not look the same across different individuals. Understanding these differences could help us design more personalised approaches to prevention and follow-up care.”
The research team are part of the Midlands Mental Health Mission, supported by NIHR Biomedical Research Centre: Oxford Health and are continuing to research ways to address cognitive loss, which is prevalent among people with major depressive disorders, and can affect short- and long-term memory, attention and focus.
Key Questions Answered:
A: Not necessarily. Cognitive impairment is still a major burden for 70-90% of patients. What this study suggests is that cognitive scores alone aren’t a reliable “early warning system” for relapse in the way they might be for a first-time diagnosis.
A: One theory from the researchers is that people with higher cognitive function have more “mental bandwidth” to introspect, notice their symptoms, and report them. Another possibility is that higher cognitive performance is linked to more demanding social or professional environments that create more opportunities for stress-induced relapse.
A: No. Recovery of cognitive function is a key goal of therapy. The takeaway here is for clinicians: they shouldn’t assume that a patient is “out of the woods” just because their memory and focus have returned. Remitted depression remains a high-risk state regardless of how well you score on a memory test.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Cognition and depression research news
Author: Tim Mayo
Source: University of Birmingham
Contact: Tim Mayo – University of Birmingham
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Cognition and Future Depression: Associations with Risk in Those With and Without a History of Depression” by Angharad N. de Cates, Angeline Lee, Laura Winchester, Klaus P. Ebmeier, Paris Lalousis, Rachel Upthegrove, Susannah E. Murphy, Catherine J. Harmer, Thomas Nichols, and Anya Topiwala. BMJ Mental Health
DOI:10.1136/bmjment-2025-302332
Abstract
Cognition and Future Depression: Associations with Risk in Those With and Without a History of Depression
Background
Cognitive impairments are common in depression and often persist beyond mood resolution. However, the relationship between cognitive performance, its neurological underpinnings, and future depression risk is unclear, limiting strategies for primary and secondary prevention.
Objective
Our objective was to determine whether cognition associates with subsequent depression, both relapse and first-episode occurrences.
Methods
1862 UK Biobank participants with a history of International Classification of Diseases (ICD)-10-defined depression in remission (RD) (mean (SD) age: 52.7 (7.13) years) were age-matched and sex-matched to 1862 participants without depression history or current antidepressant use.
Cognitive scores were compared between groups at the composite (z-score), domain and task levels. MRI-derived phenotypes assessed brain network structure and functional connectivity. Longitudinal associations with future depression were assessed using logistic regression models and a Cox proportional hazards model controlling for key confounders.
Findings
Participants with RD had a higher risk of future depression (33%) than controls (13%), including when we accounted for temporal differences in longitudinal assessment (HR=3.16 (95% CI 2.71 to 3.67), global proportional hazard assumption p=0.07). Composite cognitive performance in controls was inversely associated with future depression risk (risk estimated marginal means: 0.25% at −1SD, 0.20% at mean, 0.15% at +1 SD). In RD, this relationship was reversed (0.74% at −1SD, 0.90% at mean, 1.10% at +1 SD).
Executive functioning, processing speed and reasoning task scores all contributed. Higher grey matter in default mode network regions was associated with better concurrent cognitive performance across all participants, but not with future depression risk. Other MRI findings were limited.
Conclusions
RD carried a threefold higher risk of future depression than controls. Cognitive performance was a risk marker for future depression in both groups but in opposing directions. Neuroimaging metrics provided little predictive value.
Clinical implications
Personalised risk factor assessment for depression is likely to be dependent on depression history. Those without previous history of diagnosed depression are at higher risk of future depression when cognitive performance is lower at baseline. RD is a high-risk group for future depression, and those with relatively higher cognitive performance may be more likely to report future depressive symptoms.
