Impact of Untreated Major Depressive Disorder on Cognition and Daily Function

Larry Culpepper, MD, MPH

From the Department of Family Medicine, Boston University School of Medicine, Boston, Massachusetts

The impact of MDD on cognition is a relatively new area of clinical focus, both in primary care and specialty practices. Cognitive deficits may reflect an underlying pathology that occurs not only during episodes but also may precede the first episode and continue during interepisode periods of remission,1,2 even when other symptoms have responded to treatment. Such long-term cognitive deficits have the potential to decrease patients’ family, social, and occupational functioning.3 To optimize functional outcomes, clinicians must recognize cognitive symptoms in their patients with MDD, assess these symptoms and their impact on functioning throughout the course of the disorder, and manage treatment accordingly.

Impact of MDD on Cognition

Cognition can be divided into the concepts of cold cognition (emotion-independent) and hot cognition (emotion-laden).4 These interrelate and influence how patients with MDD think and respond to their environment, circumstances, and social interactions.

Cold cognition deficits. For patients with MDD, the most replicated cold cognition deficits occur in the domains of executive function, attention, working memory, and general and psychomotor processing speed.5 Executive function enables people to form concepts, focus on a set of information, shift between sets of information, plan, self-monitor, and divide attention between activities.5 Between 20% and 30% of people with MDD have deficits in executive function (1 SD below the normative mean).5 The attention domain dictates the mental energy necessary to organize and complete cognitive tasks.

Within the cognitive domain of memory are subtypes related to general (semantic memory) and specific memories (episodic memory), for example, city streets in general versus a specific event on a certain street, in addition to various forms of memory (eg, visual and verbal). Working memory supports the temporary storage and management of information required to carry out complex cognitive tasks such as learning, reasoning, and planning. Processing speed controls how efficiently people monitor and process cognitive and sensory data (such as motor accuracy).

Hot cognition deficits. Problems in hot cognition associated with MDD include a cognitive bias toward negative information and a misinterpretation of social cues.4 Cognitive bias, with its increased focus on negative over positive stimuli, is a significant component of depressive illness.4 For example, fMRI studies6,7 comparing unmedicated participants with MDD with healthy controls found that the participants with MDD showed greater brain response to sad facial expressions than to happy ones, while the brains of control subjects responded more to happy faces. Negative bias in patients with MDD may contribute to dysfunction in their thoughts and social interactions with resultant impact on functioning, but positive bias can develop with antidepressant treatment.7,8

Cognition impairment severity. The severity of cognitive symptoms may differ by subjective experience and objective measures. That is, people with depression may perceive a different level of cognitive impairment than objective tests demonstrate.

A study9 of subjective experience measured with the BC-CCI found that about 27% of depressed participants felt that they were moderately cognitively impaired, while only about 2% of healthy control participants perceived this level of impairment (AV 1).9 Participants in a focus group study10 reported a variety of cognitive symptoms related to depression, including lack of focus and clear thought, memory problems, and difficulty with word finding, divided attention, decision making, thinking quickly, and learning new things.

AV 1. Perceived Cognitive Impairments by Patients With Depression and Healthy Control Subjects (00:30)

Data from Iverson and Lam9

A number of neurocognitive tests (eg, WCST, TMT, CANTAB) are available to objectively measure performance in various domains.5 For more on neurocognitive tests, see “Components of Cognitive Functioning and Their Measurement.”One study11 measured cognitive performance in 5 domains (memory, psychomotor speed, reaction time, attention, and cognitive flexibility) in patients with GAD, MDD, and bipolar disorder compared with healthy control participants. Patients had no other conditions that might affect cognition. Only 4% of healthy controls scored more than 2 SD below the mean (which is clinically meaningful) on 2 or more cognitive domains, but 21% of patients with depression did so.11


Occurrence of Cognitive Symptoms Throughout the Course of MDD

Cognitive impairment may be present in individuals before their first episode, during episodes, and between episodes. Clinicians should assess and address cognitive symptoms early before they become a chronic problem.

Before and during initial episodes. Cognitive impairment can precede an initial depressive episode. A population-based study1 assessed nondepressed adults (N=708). At 3-year follow up, the presence of MDD was associated with baseline impairments in episodic memory, indicating that low episodic memory performance may be a premorbid indicator of depression.1

For individuals experiencing their initial depressive episode, cognitive impairments may differ based on depression type and severity. For example, a study12 comparing adults with MDD, dysthymia, mixed anxiety-depressive disorder, or minor depression and healthy subjects found that performance on a variety of cognitive tasks was not impaired in the group with minor depression. However, the MDD and mixed anxiety–depressive disorder groups showed substantial memory dysfunction, while the dysthymia group displayed pronounced impairment in mental flexibility.12

During subsequent episodes. In patients experiencing subsequent depressive episodes, cognitive impairment may become more severe. For example, patients with more past depressive episodes have shown a more severe clinical level of psychomotor retardation on neurocognitive tests (d2 Test of Attention, TMT).13 In a study of 8,229 outpatients with MDD, Gorwood and colleagues14 tested delayed recall, a memory function related to hippocampal integrity. Results showed that, at presentation with depression, the severity of the current episode was the major determinant of delayed recall performance. After treatment, the number and length of previous depressive episodes became more significant to memory performance than current symptoms. Imaging findings consistently reveal atrophy of the hippocampus in patients with MDD, indicating a toxic link between depression and cognition. The authors concluded that, for each depressive episode (up to 4), memory performance is impaired an additional 2% to 3%, and hippocampal atrophy is probably involved in this cognitive decline.14

Between episodes. Not only are cognitive impairments present before and during depressive episodes, but they also may persist after remission of mood symptoms. A meta-analysis15 of cognitive impairment in depression found moderate deficits in executive function and attention and small-to-moderate deficits in memory that persisted in remitted patients. Another meta-analysis16 examined 27 studies comparing euthymic adults with MDD (N=895) with healthy control subjects (N=997) and found poorer cognitive function in the MDD patients, especially among those with late-onset depression.

A 3-year prospective study2 assessed patients (N=267) during depressive episodes and intervals of remission. Cognitive problems were present 94% of the time during depressive episodes and 44% of the time between episodes. Because cognitive symptoms are present almost half of the time even in periods of remission, clinicians must identify and treat these symptoms to improve patients’ daily function (AV 2).

AV 2. Assessing Cognitive Impairment in a Patient With Depression (02:10)

Impact of Cognitive Deficits on Daily Function

As Judd and colleagues17 reported almost 20 years ago, individuals with depressive symptoms have a higher risk of household and financial strain, social irritability, physical and job limitations, bed days, and health problems. More recently, connections have been made between functional deficits and cognitive impairments associated with depression. One study18 reported baseline and 6-month neurocognitive deficits in hospitalized patients with MDD (N=48). While baseline deficits did predict functionality at 6-month follow up, contemporaneous neurocognitive performance was strongly associated with function at 6 months, even after controlling for residual depression. A European study19 that surveyed over 21,000 adults examined activity limitations and role functioning in the past 30 days and depression in the past 12 months. Following multivariate adjustment of other factors, cognition (concentration and attention problems) was most strongly associated with role functioning, and along with embarrassment were the only 2 significant factors that contributed to the role of MDD in impaired role functioning, especially work performance. Together they accounted for about half of this impact.

Withall and colleagues20 assessed severely depressed patients (aged 20 to 60 years) at admission and 3 months after remission and discharge. Patients with more errors on the shortened WCST (which measures concept formation, abstraction, working memory, shifting set, and the ability to use feedback) and prospective memory problems (affecting planning, monitoring both self and output, and retention of task and relevant cues) at admission had worse social and occupational outcomes at follow up. This study demonstrates that clinicians should assess cognitive impairment to help predict social and occupational impairment, which may occur even after patients achieve remission.

For severely depressed nondemented patients, in a study by McCall and colleagues,21 cognitive deficits, rather than depression severity or age, most closely predicted impairments in instrumental activities of daily living, such as managing finances and medication, shopping and preparing meals, communicating by telephone and other devices, using transportation, and maintaining a home. However, this study did not account for the physical health of the patients.

Recently, McIntyre and colleagues22 assessed workplace adjustment in adults with depression. They found that workplace performance was explained to a greater extent by subjective measures of cognitive dysfunction than by depression symptom severity, although the latter was important to global measures of disability. They note that assessment of cognition and attention to use of antidepressants that do not have a deleterious effect on cognitive function may be important in successfully returning depressed patients to work.

A recent systematic review23 of the relationship between cognitive and psychosocial functioning concluded that although the literature is limited, neurocognitive deficits are significant and clinically important factors related to the quality of life and level of social and occupational functioning of individuals with MDD.

Finally, one key issue to consider regarding the evidence base for cognitive and psychosocial functioning is that most studies report comparisons of the means of depressed and nondepressed group scores. While this demonstrates that a large portion of depressed patients have ongoing moderate cognitive impairments, it may obscure that some clinically important subgroups of patients have large depression-related deficits. For instance, high-performing individuals prior to depression may not be considered impaired when compared to a population average, even though they are significantly impaired when assessed relative to their own pre-depression performance.


Cognitive symptoms are common in patients with depression, affecting domains including executive function, memory, attention, and processing speed. Another aspect of cognition, negative bias, can contribute to low mood symptoms. Both patient reports and objective measures demonstrate moderate cognitive symptoms in about one-fourth of patients with depression. These symptoms may be present before the first depressive episode, during episodes, and between episodes and have been shown to affect social and occupational functioning. In addition to monitoring mood symptoms, clinicians must assess cognitive symptoms to improve their patients’ functioning.

Clinical Points

  • Understand the cognitive domains that may be impaired in your patients with MDD, especially areas of executive function, memory, attention, and processing speed
  • Realize that cognitive symptoms may be present before an initial depressive episode, during episodes, and between episodes
  • Assess your patients’ social and occupational functioning to see if cognitive symptoms are hindering their daily lives


BC-CCI = British Columbia Cognitive Complaints Inventory

CANTAB = Cambridge Neuropsychological Test Automated Battery

fMRI = functional magnetic resonance imaging

GAD = generalized anxiety disorder

MDD = major depressive disorder

SD = standard deviation

TMT = Trail Making Test

WCST = Wisconsin Card Sorting Test

Take the online posttest.


  1. Airaksinen E, Wahlin A, Forsell Y, et al. Low episodic memory performance as a premorbid marker of depression: evidence from a 3-year follow-up. Acta Psychiatr Scand. 2007;115(6):458–465. PubMed
  2. Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41(6):1165–1174. PubMed
  3. Godard J, Baruch P, Grondin S, et al. Psychosocial and neurocognitive functioning in unipolar and bipolar depression: a 12-month prospective study. Psychiatry Res. 2012;196(1):145–153. PubMed
  4. Roiser JP, Sahakian BJ. Hot and cold cognition in depression. CNS Spectr. 2013;18(3):139–149. PubMed
  5. McIntyre RS, Cha DS, Soczynska JK, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30(6):515–527. PubMed
  6. Victor TA, Furey ML, Fromm SJ, et al. The extended functional neuroanatomy of emotional processing biases for masked faces in MDD. PLoS One. 2012;7(10):e46439. PubMed
  7. Victor TA, Furey ML, Fromm SJ, et al. Relationship between amygdala responses to masked faces and mood state and treatment in MDD. Arch Gen Psychiatry. 2010;67(11):1128–1138. PubMed
  8. Harmer CJ, O’Sullivan U, Favaron E, et al. Effect of acute antidepressant administration on negative affective bias in depressed patients. Am J Psychiatry. 2009;166(10):1178–1184. PubMed
  9. Iverson GL, Lam RW. Rapid screening for perceived cognitive impairment in major depressive disorder. Ann Clin Psychiatry. 2013;25(2):135–140. PubMed
  10. Fehnel SE, Forsyth BH, Dibenedetti DB, et al. Patient-centered assessment of cognitive symptoms of depression [published online ahead of print September 25, 2013]. CNS Spectr. doi:10.1017/S1092852913000643. PubMed
  11. Gualtieri CT, Morgan DW. The frequency of cognitive impairment in patients with anxiety, depression, and bipolar disorder: an unaccounted source of variance in clinical trials. J Clin Psychiatry. 2008;69(7):1122–1130. Full Text
  12. Airaksinen E, Larsson M, Lundberg I, et al. Cognitive functions in depressive disorders: evidence from a population-based study. Psychol Med. 2004;34(1):83–91. PubMed
  13. Gorwood P, Richard-Devantoy S, Bayle F, et al. Psychomotor retardation is a scar of past depressive episodes, revealed by simple cognitive tests. Eur Neuropsychopharmacol. 2014;24(10):1630–1640. PubMed
  14. Gorwood P, Corruble E, Falissard B, et al. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J Psychiatry. 2008;165(6):731–739. PubMed
  15. Rock PL, Roiser JP, Riedel WJ, et al. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44(10):2029–2040. PubMed
  16. Bora E, Harrison BJ, Yücel M, et al. Cognitive impairment in euthymic MDD: a meta-analysis. Psychol Med. 2013;43(10):2017–2026. PubMed
  17. Judd LL, Paulus MP, Wells KB, et al. Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population. Am J Psychiatry. 1996;153(11):1411–1417. PubMed
  18. Jaeger J, Berns S, Uzelac S, et al. Neurocognitive deficits and disability in MDD. Psychiatry Res. 2006;145(1):39–48. PubMed
  19. Buist-Bouwman MA, Ormel J, de Graaf R, et al. Mediators in the association between depression and role functioning. Acta Psychiatr Scand. 2008;118(6):451–458. PubMed
  20. Withall A, Harris LM, Cumming SR. The relationship between cognitive function and clinical and functional outcomes in MDD. Psychol Med. 2009;39(3):393–402. PubMed
  21. McCall WV, Dunn AG. Cognitive deficits are associated with functional impairment in severely depressed patients. Psychiatry Res. 2003;121(2):179–184. PubMed
  22. McIntyre RS, Soczynsky JZ, Woldeyohannes HO, et al. The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project. Compr Psychiatry. 2015;56:279–282. PubMed
  23. Evans VC, Iverson GL, Yatham LN, et al. The relationship between neurocognitive and psychosocial functioning in major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75(12):1359–1370. Full Text