When the Fog Doesn’t Lift: Targeting Cognitive Dysfunction in Depression

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SPECIAL REPORT: COGNITION

Clinical Vignette

“Sarah,” a 42-year-old marketing executive, presented with a major depressive episode of moderate severity. After 6 months of treatment with sertraline, her mood had significantly improved. She was sleeping well, had regained her appetite, and reported feeling much more positive about life. However, during follow-up, she expressed ongoing concerns about things at work.

“I can’t seem to keep up anymore,” she explained. “I make mistakes I never used to make, and I can’t focus during important meetings. Even though I do not feel as depressed, my mind feels foggy, and I am forgetting important details.”

Despite achieving remission of core depressive symptoms, Sarah’s persistent cognitive difficulties were threatening her career advancement and contributing to diminished self-esteem. Her case illustrates the common challenge of residual cognitive dysfunction even after successful treatment of mood symptoms in depression.

Incomplete Remission

Cognitive symptoms affect between 85% and 94% of patients with major depressive disorder (MDD), making them nearly ubiquitous in the clinical presentation.¹ Despite this prevalence, cognitive dysfunction often remains undertreated and inadequately addressed in routine clinical practice. Growing evidence suggests that problems with cognition are a distinct clinical dimension of depression that are independent from mood symptoms and that may need targeted clinical management.

While diagnostic manuals emphasize problems in concentration, depression is associated with impairments across a much broader range of cognitive domains, including executive function, memory, processing speed, and attention.² The degree of cognitive dysfunction has been shown to be associated with several clinical features, including severity of depression, age of onset, psychiatric comorbidity, educational background, and number of previous episodes. Cognitive dysfunction has been shown to be more pronounced in patients with recurrent depression.^3,4

A particularly concerning aspect of depression treatment is the high rate of incomplete remission, especially regarding cognitive symptoms. Evidence shows that over 70% of patients who respond to selective serotonin reuptake inhibitor (SSRI) treatment continue to experience significant cognitive impairments, even when their mood symptoms have improved.⁵ These residual symptoms, particularly in domains of memory, concentration, attention, and executive function, present a substantial clinical challenge.

The consequences of untreated cognitive dysfunction are far-reaching. Ongoing cognitive problems are known to be a risk factor for subsequent relapse.⁶ These symptoms also significantly impact patients’ psychosocial functioning, often presenting greater barriers to occupational recovery than mood symptoms alone. Quality of life measures consistently show that cognitive difficulties interfere with workplace performance, social relationships, and daily functioning, even in patients whose emotional symptoms have improved with treatment.^7,8

Current Pharmacological Approaches

Current treatments for depression, whether medication or therapy, produce only minimal improvements in cognitive function. A recent review highlighted that 95% of cognitive problems show little or no meaningful improvement after treatment.⁹ While a patient’s mood might get better, their ability to think clearly, remember information, and focus on tasks often remains impaired. This analysis also highlighted that with each episode of depression, some cognitive problems may worsen. Like scratches on a record, these scar effects are particularly noticeable in areas like sustained attention and verbal memory. This suggests that early intervention might be crucial in preventing long-term cognitive decline.

There is currently a lack of pharmacological treatments approved by the US Food and Drug Administration (FDA) to treat the cognitive symptoms of depression. SSRIs, while demonstrating reliable efficacy for core depressive symptoms, have shown limited impact on cognitive dysfunction. Meta-analyses of SSRI trials typically demonstrate small effect sizes for cognitive improvement.^10,11 However, most benefits appear secondary to mood improvement rather than direct procognitive effects, and many studies do not appropriately control for nonspecific effects that can affect cognitive task performance, such as practice and learning. One large-scale study with a healthy control group (to control for nonspecific effects of repeated testing) reported no significant effect of 8 weeks of antidepressant treatment with sertraline, venlafaxine, or escitalopram on standardized assessments of cognition.¹² Taken together, this evidence suggests that traditional SSRI treatment may be insufficient to address the full spectrum of cognitive deficits in MDD.

The multimodal antidepressant vortioxetine appears to have a more direct effect on cognitive symptoms and is the only medicine indicated by the FDA for the treatment of cognition in depression. As well as inhibiting serotonin reuptake, vortioxetine directly modulates serotonin modulator activity (acting as an antagonist at 5-HT_3A, 5-HT₇, and 5-HT_1D receptors, a partial agonist at 5-HT_1B receptors, and a full agonist at 5-HT_1A receptors). Clinical trials have demonstrated vortioxetine’s ability to improve executive function and learning and memory, with particularly well-replicated effects on the Digit Symbol Substitution Test (a general measure of cognitive impairment that is not specific to any one cognitive domain).^13,14 Importantly, path analyses suggest that vortioxetine’s cognitive benefits are, in part, independent of its antidepressant effects, suggesting direct procognitive properties. The magnitude of these effects appears more robust than those observed with conventional SSRIs, although head-to-head comparisons have suggested that its clinical superiority in the treatment of cognitive symptoms is marginal at best.^15,16

Beyond serotonin, there is some evidence that modulators of dopamine (eg, bupropion, modafinil), glutamate (eg, ketamine), and acetylcholine (eg, donepezil) may have some positive effects on cognition in individuals with depression, although the extent to which these effects are independent from broader symptomatic improvements is not clear.¹⁷

Future Treatment of Symptoms

The development of treatments that effectively target both mood and cognitive symptoms is now recognized as essential for achieving successful long-term remission and functional recovery in depression. More selective targeting of specific serotonin receptors may hold promise in the development of novel treatments. In particular, there is ongoing interest in the potential of selective agonists of the 5-HT_1A and 5-HT₄ and selective antagonists of the 5-HT₆ and 5-HT₇ receptors. While there is promising evidence of this potential from animal studies and healthy volunteer studies, clinical evidence is still sparse. There are also some promising novel treatment targets in the pipeline, but they have not yet been tested in placebo-controlled randomized clinical trials in patients, including creatine, α₂-adrenergic receptor antagonists, glucagon-like peptide-1 agonists, GABA_B receptor agonists, and histamine H₃ receptor antagonists.¹⁷ Finally, there are a range of nonpharmacological approaches to the treatment of cognition that may hold utility as stand-alone or adjunctive treatment approaches, including neurostimulation (transcranial magnetic stimulation, transcranial direct-current stimulation), cognitive remediation, and physical exercise.¹⁸ With renewed interest in this area, and a growing recognition of cognition as a neurobiologically and clinically distinct feature of MDD, there is genuine potential for improving the treatment of cognitive impairment in depression in the future.

Dr Murphy is an associate professor in the Department of Psychiatry at the University of Oxford. Murphy has received consultancy fees from Zogenix, Sumitomo Dainippon Pharma, UCB Pharma, and Janssen Pharmaceuticals. She holds grant income from UCB Pharma, Janssen Pharmaceuticals, and ADM.

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