Cognitive deficits in depression often persist after SSRI treatment, research shows

A new study published in the Journal of Affective Disorders has found that adults with major depression show specific cognitive impairments. While many participants experienced mood improvements after taking antidepressants for eight weeks, their cognitive abilities did not improve to the same degree. These findings highlight an important gap in current depression treatment: antidepressants can help with emotional symptoms but may not fully address problems with memory, attention, and mental speed, at least after two months of treatment.

Depression is not just about feeling sad. It often comes with difficulties in thinking clearly, remembering things, or staying focused. These mental challenges—sometimes described as “brain fog”—can interfere with daily functioning, even when mood symptoms begin to lift.

Past studies have shown that people with depression tend to perform worse than others on tests of memory, attention, and mental flexibility. However, most of those studies included people who had other medical or psychiatric conditions, or who were already taking medications that could influence thinking. The current study aimed to isolate the effects of depression itself by focusing on people who were otherwise healthy and unmedicated.

“We want to better understand what specific cognitive functions are impaired in major depressive disorder and whether current antidepressant treatments address these deficits,” said study author Gwyneth W.Y Wu, a research scientist at the University of California, San Francisco.

“By identifying potential treatment gaps, we hope to contribute to more comprehensive and targeted therapeutic strategies. Additionally, most studies comparing cognitive impairments in individuals with depression to controls do not specifically focus on medically healthy, unmedicated individuals. Our study aimed to identify cognitive performance specifically associated with depression, rather than medication or other underlying illnesses.”

For their study, the researchers recruited 113 adults diagnosed with major depressive disorder and 88 adults without depression to serve as a comparison group. Everyone in the study was physically healthy and free of other psychiatric conditions, such as substance use disorders, bipolar disorder, or post-traumatic stress disorder. None of the participants were taking medications known to affect brain function including antidepressant, anti-anxiety, or mood stabilizing medication.

Depression diagnoses were confirmed through structured interviews, and participants completed a series of well-known cognitive tests that measured areas like processing speed, executive function, and both visual and verbal memory. These tests were given to everyone at the start of the study. A subgroup of 69 people with depression went on to complete eight weeks of treatment with a commonly prescribed selective serotonin reuptake inhibitor (SSRIs). At the end of those eight weeks, they repeated the cognitive tests.

At the beginning of the study, people with depression performed worse than those without depression on several key measures. They scored significantly lower on a test called the Symbol Digit Modalities Test, which measures how quickly someone can process information and match symbols to numbers. They also struggled more on parts of the Stroop Test, which assesses how well someone can focus attention and ignore distracting information, as well as on the Brief Visuospatial Memory Test, which measures how well people can remember visual patterns. Interestingly, differences between the groups were not seen on all tasks—especially those involving verbal memory or simpler forms of attention.

The researchers also looked at whether some people were more severely impaired than others. They defined clinical impairment as scoring more than 1.5 standard deviations below the population average. Compared to the healthy group, a larger portion of depressed participants showed this level of impairment in processing speed and visual memory.

“Our findings reinforce existing research, highlighting the link between cognitive deficits and major depressive disorder,” Wu told PsyPost. “We identified impairments in processing speed, visuospatial memory, and learning in unmedicated individuals with major depression. Additionally, we observed higher rates of clinical impairment in processing speed and both verbal and visual learning.”

“Our findings of impaired processing speed and visuospatial memory—without significant deficits in verbal memory or executive functioning—suggest that these cognitive abnormalities may be linked to dysfunction in specific structural or functional brain regions, but this requires further study. This highlights the possibility that depression-related cognitive impairment may affect certain domains more than others.”

After eight weeks of antidepressant treatment, the researchers reassessed cognitive function among the 69 treated participants. On the surface, the results seemed encouraging: people performed better on six of the thirteen cognitive tests, including measures of processing speed and visual memory. However, when the researchers dug deeper, they found that these improvements were not clearly linked to whether or not someone responded to antidepressants.

In fact, only one test—the Hopkins Verbal Learning Test, which assesses verbal memory—showed a meaningful difference between people whose depression symptoms improved and those whose symptoms did not. On that test, those who responded to medication showed improved verbal learning over time, while non-responders actually did slightly worse.

“While participants generally showed improved cognitive performance over the 8-week period, antidepressant response to SSRI treatment was not associated with cognitive gains,” Wu explained. “This underscores the need to consider cognition as an independent therapeutic target in the treatment of depression.”

The researchers also tested whether baseline cognitive scores could predict who would respond to antidepressants. They found no differences in initial cognitive performance between those who later responded to medication and those who did not. This means that measuring cognitive ability at the start of treatment was not helpful in predicting which patients would benefit from medication. Although earlier studies have suggested that slower thinking or poor memory might signal a lower chance of improvement, this study—using a carefully selected sample—did not support that idea.

Like all research, this study had limitations. The sample size was relatively large for this type of study, but it may still have been too small to detect subtle differences between responders and non-responders. The study also excluded people with other medical or psychiatric conditions, so the results may not apply to all patients with depression, especially those with more complex health profiles.

“Our study features a well-screened, relatively large cohort of unmedicated, physically healthy adults with major depressive disorder, free from substance use disorder or other comorbidities, along with a matched, never-depressed healthy control group,” Wu noted. “While these strict exclusion criteria strengthen the internal validity of our findings, they may limit the generalizability to broader populations, particularly those with comorbid physical or psychiatric conditions or those receiving pharmacological treatments.”

It’s also possible that different aspects of depression improve on different timelines, and that cognitive symptoms might take longer to respond to treatment. “It would be nice to retest after four or six months, in addition to the two months we did,” Wu said.

Still, the strengths of the study are notable. It is one of the few to examine cognitive function in unmedicated individuals with depression who are otherwise healthy. The researchers used a well-rounded set of cognitive tests and tracked changes over time, allowing them to compare baseline differences and treatment effects. They also confirmed that participants took their medication as prescribed by measuring drug levels in the blood.

The researchers hope their work can inform more targeted treatments in the future. Long-term, they aim to develop strategies that address both the emotional and cognitive symptoms of depression.

“While traditional depression treatments focus on alleviating mood symptoms, cognitive deficits often persist even after mood improvement,” Wu explained. “This dissociation between cognitive and depressive outcomes could have important clinical implications as even patients who respond symptomatically to SSRI treatment may still suffer from unaddressed cognitive deficits. Addressing this unmet need could lead to more comprehensive and functional patient outcomes.”

“Depression research is critical to advancing our understanding of this complex and pervasive condition. By exploring both the emotional and cognitive dimensions of depression, we can develop more effective and personalized treatments. Ongoing research not only improves clinical outcomes but also paves the way for innovative therapies that can enhance patients’ quality of life.”

The study, “Cognitive function in physically healthy, unmedicated individuals with major depression: Relationship with depressive symptoms and antidepressant response,” was authored by Anna Ou, Gwyneth W.Y Wu, Michelle T. Kassel, R. Scott Mackin, Ryan Rampersaud, Victor I. Reus, Synthia H. Mellon, and Owen M. Wolkowitz.