Managing Cognitive Disturbances in Major Depression: An Unmet Need

Major depression

Major depression is characterized by mood symptoms, disturbances in sleep, appetite, energy, psychomotor function and suicidality. Cognitive disturbances like problems with learning and episodic memory while an integral part of major depression have been relatively neglected until recently primarily because the available treatments have shown little efficacy in improving these symptoms. Only 35% of patients with MDD achieved remission on monotherapy with citalopram in the STAR-D trial and even after four levels of treatment almost 40% of patients had not achieved remission. Moreover the rates of relapse and recurrence were extremely high over a one year follow up period even in those who achieved remission.


Clinicians need to be educated about an adequate trial of antidepressants before seeing response and remission and deciding about switching or augmenting antidepressants. The need for adequate maintenance treatment also needs to be emphasized.

Even though cognitive disturbances are easier to measure objectively than the other symptoms of major depression they are seldom measured in clinical practice. There are two major types of cognitive deficits in MDD. “Hot” cognitive deficits or negative emotional bias or “cold” cognitive deficits. Patients with major depression have problems with explicit verbal and visual memory while implicit memory appears to be relatively unaffected. They are also have difficulties with attention and processing speed. Deficits in executive functioning are also common in depression, particularly in severe depression and are associated with relapses and readmissions. In contrast to patients with mania who have difficulty inhibiting behavioral responses patients with depression have difficulties in shifting the focus of attention.

Several studies have looked at the correlation of severity of depression and cognitive disturbances. Nine studies have found no correlation while 11 studies have demonstrated a positive correlation. Some authors have suggested based on the specific cognitive deficits in patients with depression that they may have difficulties with “effortful” versus “automatic” tasks. This may also explain the relative sparing of implicit memory in contrast to explicit memory in patients with depression. Investigators have also studied the relationship of the subtype of major depression to cognitive deficits and found that patients with endogenous depression are more impaired compared to those with non-endogenous depression.

Lack of motivation which may be related to anhedonia which is commonly seen in patients with depression is one of the cognitive behavioral paradigms put forward to explain cognitive deficits in depression. Lack of response to financial incentive in testing paradigms which is often seen in depressed patients and is referred to as a “response bias” is another explanation put forward. Finally the negative cognitive set that is present in depressed patients may also contribute to cognitive disturbances.

One of the important clinical questions is whether the cognitive deficits are enduring even in the presence of recovery or remission. Even though there are methodological limitations to the studies including differing definitions of recovery, lack of control for medication status and the definitions of cognitive normalization most studies have found that deficits can persist even in patients who are in remission. This could be a function of the inadequacies of the existing treatments for major depression. In fact some of the treatments like the SSRI’s can impair cognition by causing apathy and impairing memory. One of the confounding variables could be age.

Cognitive function declines with age even in normal individuals. There is also a correlation of microvascular disease in the brain and late onset depression (“vascular depression”) which can also contribute to cognitive deficits in elderly depressed patients. White matter hyperintensities have been correlated with late onset depression and cognitive deficits.

Even though neurocognitive testing in depressed patients has its limitations because of the confounding variable of depression combined with the practice effects and reinforcing feedback in some tests like the WCST one way to address this issue is to give a comprehensive battery of tests for cognitive dysfunction to depressed patients before and after treatment to examine the relationship and persistence.


From a neuroanatomical standpoint the anterior cingulate (ACC) and the subgenual region of the prefrontal cortex have been implicated in major depression as a result of neuroimaging studies.

We now believe that cognitive deficits are intrinsic expressions of brain changes in depression and not merely epiphenomena.

Even though when the symptoms of depression improve with the currently available antidepressants like the SSRI’s and SNRI’s some of the cognitive disturbances may improve many may still persist. Hot cognition improves with all antidepressant treatments but cold cognition does not. Studies have found that only verbal memory improves consistently with monotherapy with antidepressants.

Keefe et al reviewed 43 studies (15 placebo controlled) looking at the cognitive effects of pharmacotherapy ( both monotherapy and adjunctive therapy) in major depression. Studies varied widely in size ( median number of participants was 50), duration ( median duration was 8 weeks). Only a minority ( 12% ) of analyzed measures improved with pharmacotherapy compared to placebo or untreated healthy controls. The effect size for improvement in verbal memory was 0.1 for monotherapy and effect sizes were 0.1-0.4 for adjunctive therapy for visual memory, visual processing, processing speed, executive function and cognitive control. These were the only measures that reached statistical significance.

Newer antidepressants with different mechanisms of action may offer the potential to improve cognitive deficits along with the other depressive symptoms thereby potentially improving the long terms outcomes in patients with major depression.

In at least three studies vortioxetine has improved cognitive function in patients with major depression compared to placebo or duloxetine whereas duloxetine the active reference in 2 studies did not show the same efficacy particularly on the DSST. Also the direct effects of vortioxetine on cognition were greater than the indirect effects whereas that was not true with duloxetine. ( 76% direct effect for vortioxetine vs 49% for duloxetine in one study).

Studies particularly in elderly patients who are at high risk for cognitive disturbances and head to head comparisons against existing antidepressants will help identify such agents and their potential role in treating depression and fulfilling the unmet needs.

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