Hostname: page-component-5d59c44645-jqctd Total loading time: 0 Render date: 2024-02-24T07:29:12.714Z Has data issue: false hasContentIssue false

Cognitive impairment in major depressive disorder

Published online by Cambridge University Press:  23 November 2018

Zihang Pan
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Caroline Park
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Elisa Brietzke
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil
Hannah Zuckerman
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
Carola Rong
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
Rodrigo B. Mansur
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Dominika Fus
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
Mehala Subramaniapillai
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
Yena Lee
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Roger S. McIntyre*
Mood Disorders Psychopharmacology Unit (MDPU), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
*Address for correspondence: Roger S. McIntyre, MD, FRCPC, Professor of Psychiatry and Pharmacology, University of Toronto, Head, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada. (Email:
Rights & Permissions [Opens in a new window]


Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues.

© Cambridge University Press 2018 


Major depressive disorder (MDD) is a highly prevalent and disabling mental disorder associated with significant morbidity and mortality.Reference Fagiolini, Forgione and Maccari 1 MDD affects approximately 350 million individuals worldwide and is projected to be a top contributor to global functional disability in the following decades. Lifetime prevalence of individuals with MDD comprises up to 15% of the general North American population.Reference Marcus, Yasamy, Ommeren, Chisholm and Saxena 2 By 2030, MDD is projected to become a leading cause of global disease burden according to the World Health Organization (WHO).Reference Collins, Patel and Joestl 3 In addition, the economic costs associated with MDD are immense. For example, in 2016 alone, decreased workplace productivity and impaired occupational functioning associated with MDD resulted in losses of $32.3 billion and $201.5 billion in Canada and the United States, respectively.Reference Cha, Carmona and Subramaniapillai 4

MDD is a syndrome of disturbances in mood, energy, metabolism, motivation, and cognition. Many studies have shown that cognitive dysfunction, in particular, is a powerful predictor of occupational and social functional impairment in adults with MDD.Reference Woo, Rosenblat, Kakar, Bahk and McIntyre 5 Reference McIntyre and Lee 7 Indeed, cognitive dysfunction is well established as a core diagnostic criterion of MDD according to the Research Domain Criteria (RDoC). The RDoC approach dissects MDD into domains of analyses with the aim of more easily identifying biological underpinnings of MDD (ie, understanding cognitive impairment) and predicting treatment outcomes.

A significant subpopulation of individuals with MDD does not achieve functional remission after treatment with multiple FDA-approved pharmacological agents. It is important to note that improvements in mood do not necessarily translate into improvements in function. Hitherto, only 2 antidepressants (ie, duloxetine and vortioxetine) have demonstrated direct, independent, and clinically relevant effects on cognitive dysfunction in MDD.Reference Rosenblat, Kakar and McIntyre 8 The persistence of cognitive deficits after remission of depressive symptoms has been shown to contribute to the failure in achieving full functional recovery in MDD.Reference Woo, Rosenblat, Kakar, Bahk and McIntyre 5 Vice versa, functional impairments can also contribute to the persistence of cognitive symptoms in MDD.Reference Pan, Grovu and Cha 9

Domain-specific cognitive deficits in learning and memory, executive function, processing speed, and attention and concentration are highly replicated findings in individuals with MDD presenting with a major depressive episode (MDE). Moreover, cognitive dysfunction in MDD has been proposed to be an endophenotype that worsens as a function of episode frequency.Reference Pan, Grovu and Cha 9 , Reference Rosenblat, Brietzke, Mansur, Maruschak, Lee and McIntyre 10 Other well-characterized symptoms in patients with MDD include anhedonia (the lack of interest) and depressed mood. The trifecta of cognitive dysfunction, anhedonia, and depressed mood is thought to be a critical mediator of MDD-related functional disability.Reference McIntyre, Cha and Soczynska 6 , Reference Carvalho, Berk, Hyphantis and McIntyre 11 These interconnected domains of depression contribute to self-perpetuating cycles of illness and impairment.

Multiple neurobiological mechanisms have been proposed to contribute to cognitive dysfunction observed in individuals with MDD. These mechanisms have been extensively reviewed elsewhere.Reference McIntyre, Cha and Soczynska 12 Neuroinflammatory pathways are postulated to play a key role in the pathoetiology of MDD. Indeed, individuals with inflammatory and metabolic comorbidities are at greater risks of mood disorders and cognitive dysfunction.Reference Jantaratnotai, Mosikanon, Lee and McIntyre 13 , Reference Mansur, Lee and Zhou 14 A derivative of the foregoing observation is that disturbances in cognitive function in individuals with MDD and/or persons with metabolic/inflammatory morbidity may exhibit improvement with multimodal treatment targeting inflammatory-metabolic systems. This article provides an overview of the determinants, substrates, and treatment approaches related to cognitive impairments in MDD.

Cognition: Glossary

A domain-based approach provides an opportunity to disambiguate the complex phenomenological features of cognition. Disturbances in concentration, executive function, decision-making, and learning and memory are part of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) items that determine whether an individual meets criteria for cognitive dysfunction in MDD.Reference McIntyre, Cha and Soczynska 6 Cognitive constructs have been further classified into typologies that are useful in different settings (eg, clinical versus research settings). For example, the 4 subdomains of executive function, learning and memory, attention and concentration, and processing speed are differentially operationalized in clinical and research practice.Reference Harrison, Lam, Baune and McIntyre 15 These interconnected and dissociable cognitive phenomena often share overlapping, yet discrete, neurobiological substrates. Disparate neurobiological systems, including, but not limited to, arousal, mood, impulsivity, reward, anhedonia, energy, fatigue, and suicidality, all contribute to cognitive changes in MDD.Reference McIntyre, Woldeyohannes and Soczynska 16 , Reference McIntyre, Xiao and Syeda 17

The current discourse on cognition is limited by the absence of consistent language delineating observable cognitive domains. In this regard, the concepts of “hot” and “cold” cognition are relevant. “Hot” cognition refers to cognitive functions that are emotionally valenced. In other words, “hot” cognitive processes are influenced by an individual’s emotional state.Reference Roiser and Sahakian 18 Examples of “hot” cognition include, but are not limited to, rumination, anticipatory anhedonia, negative attentional bias, and emotionally linked recall. Conversely, “cold” cognition refers to cognitive processes that are uncoupled from emotional valence.Reference Roiser and Sahakian 18 Prominent examples of “cold” cognition include the aforementioned subdomains of executive function, learning and memory, attention and concentration, and processing speed, which are uncoupled from emotional processing. Despite the foregoing typologies separating “hot” and “cold” cognition into distinct entities, a discrete separation between “hot” and “cold” cognition in neurobiological terms cannot be parsed.Reference McIntyre, Xiao and Syeda 17

Cognition: Neurobiology

Specific neurobiological mechanisms subserving cognitive function in MDD have not been fully elucidated. Notwithstanding, multiple levels of analysis (eg, genetic, molecular, cellular, circuit) have been implicated. Herein, the working hypothesis postulates that there is a disturbance in the structure, function, and interconnectivity of brain circuits and networks related to cognitive control and function.

The well-established monoamine abnormalities in MDD likely contribute to impaired cellular signaling and neurocircuit deficits.Reference Stahl 19 Peripheral inflammation and systemic activation of proinflammatory cytokines may also play a role in the pathogenesis of cognitive symptoms. For instance, the degree and severity of cognitive dysfunction has been shown to be mediated by the location of inflammation, neurotoxicity, and apoptosis.Reference Bortolato, Carvalho, Soczynska, Perini and McIntyre 20 Consequently, the amplification of inflammatory signals provides a compelling explanation for the emergence of cognitive symptoms in depressed individuals. The role of inflammation in the pathoetiology of MDD has been extensively reviewed elsewhere.Reference Pan, Grovu and Cha 9 , Reference Rosenblat, Cha, Mansur and McIntyre 21 , Reference Shariq, Brietzke, Rosenblat, Barendra, Pan and McIntyre 22

The structure, function, and chemical composition of fronto-temporal and fronto-subcortical circuitry have also been implicated in the emergence of cognitive symptoms in MDD.Reference Jiao, Ding and Lu 23 , Reference Pizzagalli 24 Nodal structures such as the hippocampus, amygdala, and the anterior cingulate cortex (ACC) have demonstrated susceptibility to volumetric and functional changes as a consequence of greater illness severity, episode frequency, and duration.Reference MacQueen, Campbell and McEwen 25 Neurochemical changes (eg, catecholaminergic disturbances) have also been implicated as a mediator of cognitive dysfunction in MDD.Reference Stahl, Zhang, Damatarca and Grady 26

Circuits of the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and the ACC are particularly relevant in the pathogenesis of MDD. Dorsal cognitive networks, formed by the dorsal ACC working in concert with the hippocampus and the DLPFC, have been implicated in deficits of executive function.Reference Kheirbek and Hen 27 Ventral affective networks, formed by the perigenual ACC, the amygdala, and the OFC, working in concert with the hippocampus, have also been shown to be important for a variety of cognitive processes such as establishing salience, mediating contextually appropriate responses, planning, working memory, and executive function.Reference Kheirbek and Hen 27

It is recognized that individuals with MDD exhibit a bilateral reduction in hippocampal volume. The foregoing reduction in hippocampal volume may be a consequence of decreased neuronal and dendritic density, and/or reduced size of neuronal soma.Reference Malykhin, Carter, Seres and Coupland 28 The reduction in hippocampal volume has also been shown to be proportional with the frequency of illness episodes. For example, the findings of one study demonstrated that performance in verbal memory decreases as a function of episode frequency in MDD.Reference Gorwood, Corruble, Falissard and Goodwin 29 In addition, individuals with MDD exhibit hypoactivity of the prefrontal cortex, which is associated with increase in activity of the ACC. Abnormalities in the connections between cortical and subcortical structures (ie, prefrontal cortical regions and the ACC) have been hypothesized to lead to poor functional outcomes in MDD.Reference Pizzagalli 24 , Reference Zeng, Shen and Liu 30 These observations may be mediated by domain-specific deficits in executive function, attention, learning, memory, and processing speed.

The cognitive impairments in individuals with MDD may also be explained by an increase in neural effort. The n-Back test is a validated measure of working memory in which subjects were asked to recall the previous stimuli that was observed. In one study, although performance on the n-Back test did not differ significantly between MDD subjects and healthy controls, differences were observed in the activation and deactivation of nodal substrates.Reference Harvey, Fossati and Pochon 31 Specifically, MDD subjects exhibited greater activation of working memory networks relative to healthy controls.Reference Harvey, Fossati and Pochon 31 These findings suggest that individuals with MDD require greater neural effort to achieve the same level of cognitive performance as healthy controls. One theory posits that abnormal activity in the medial prefrontal cortex may contribute to the requirement of increased neural effort in individuals with MDD.Reference Harvey, Fossati and Pochon 31

The neurobiological substrates underlying cognition are both integrated and segregated and rely on a system of reciprocity between integrated and segregated cognitive structures. For example, anti-correlation, which refers to the selective reciprocal activation and deactivation of various brain regions, is critical for proper cognitive functioning.Reference Hamilton, Furman, Chang, Thomason, Dennis and Gotlib 32 Dysregulation of the normal reciprocity between nodal structures within default mode networks, therefore, may be involved in substrate disturbances and suboptimal functional outcomes resulting from cognitive impairments and reduced cognitive efficiency observed in individuals with MDD.Reference Cha, De Michele and Soczynska 33

Mediators of aberrant neural circuitry, structure, and function are hypothesized to involve imbalances in hormonal regulation (ie, insulin resistance, glucocorticoid abnormalities), neurotrophin dysregulation (ie, brain-derived neurotrophic factor), immunoinflammatory activation, and oxidative stress.Reference Li, Soczynska and Kennedy 34 Reference McAfoose and Baune 37 There is wide recognition of reciprocal relationships between mood, cognition, and metabolic disorders.Reference McIntyre, Rasgon and Kemp 38 For example, evidence linking diabetes mellitus type 2 and insulin resistance with cognitive deficits in mood disorders is well-documented.Reference Baker, Cross, Minoshima, Belongia, Watson and Craft 39 Moreover, an imbalance in insulin and counterregulatory neurohormonal systems (ie, glucocorticoids) has been suggested to alter pro-apoptotic intracellular signaling cascades, resulting in loss of neuronal and glial cells as well as accelerated neurocognitive decline. In addition, metabolic syndrome and obesity have been consistently shown to negatively impact cognitive functions.Reference Hidese, Ota and Matsuo 40

In summary, the pathoetiology of cognitive dysfunction in MDD involves both structural and functional disturbances in neural circuits as well as disturbances in the connectivity of cognitive networks. Substrates that subserve cognition in MDD are discrete but may overlap functionally with other substrates that contribute to affective, metabolic, and inflammatory processes. Interventional strategies should, therefore, take into consideration these underlying pathophysiological changes subserving cognitive deficits in MDD.

Cognition: Implications of Function

In individuals with MDD, symptomatic remission does not always translate into functional recovery. The foregoing disconnect indicates that determinants of functional outcome are mediated by other factors, which are not adequately measured using standard clinical indicators of illness severity. For example, most of the questionnaires that are used clinically to measure the severity of depressive symptoms (eg, Hamilton Depression Rating Scale, Montgomery–Åsberg Depression Rating Scale) tend to underemphasize cognitive symptoms.Reference Buist-Bouwman, Ormel and de Graaf 41 In addition, it may be surmised that cognitive function is more indicative of self-reported health outcomes than measures of total depressive symptom severity.Reference McIntyre and Lee 7 Therefore, a holistic, domain-based approach that incorporates a dimensional measure of cognition may be superior in predicting functional outcomes. In this regard, cognition should be appropriately dimensionalized and integrated into larger composite measures of depressive symptom severity.

Cognition has been previously established as a principal mediator of health outcomes in MDD.Reference McIntyre, Soczynska and Woldeyohannes 42 Cognitive disturbances are more commonly observed in individuals with MDD compared to the general population. Individuals who are unemployed are more likely to exhibit decreases in cognitive performance and those who are employed will experience a greater loss of workplace productivity.Reference McIntyre and Lee 7 In addition, cognitive impairment predicted overall psychosocial function in individuals with MDD.Reference McIntyre, Cha and Soczynska 6 Results from the International Mood Disorders Collaborative Project (IMDCP), a collaborative effort between the University of Toronto and Cleveland Clinic, indicated that cognitive function is a greater determinant of overall workplace function than measures of depression severity among working adults with MDD. Moreover, evidence from a recent meta-analysis showed that reductions in cognitive function are predictive of poorer functional and metabolic outcomes.Reference Mansur, Lee and Zhou 14 Despite the foregoing evidence, current antidepressant regimens do not primarily target psychosocial impairments and workplace disability in MDD. Therefore, there is a need to target cognitive dysfunction in individuals with MDD to prospectively improve overall performance in occupational and functional domains.

Cognition: Treatment

One approach to treating cognitive symptoms observed in individuals with MDD involves modifying factors that contribute to and/or exacerbate these symptoms. For example, the management of underlying medical conditions, psychiatric comorbidities, and iatrogenic confounds may help reduce cognitive symptoms in MDD.

Nonpharmacological interventions

Psychosocial approaches such as cognitive remediation therapy (CRT) appear promising in treating cognitive dysfunction in MDD. CRT improves learning and enhances cognitive activation via strategy development, monitoring, and pruning. During CRT, individuals are instructed to complete a computerized task that stimulates neuroplastic processes in the brain. Regardless of changes in performance over time, the task ensures that users have relatively high success rates to elicit sustained motivation.Reference McIntyre and Cha 43 The ultimate goal of CRT is to develop useful strategies for overcoming cognitively challenging tasks with the support of social networks (eg, therapists and peers). “Far-transfer” is the final step in CRT where improvements in cognition and problem-solving are applied to challenges faced in daily life.Reference Medalia, Revheim and Herlands 44 To date, only the first step of CRT (ie, cognitive activation) has been applied to the treatment of cognitive dysfunction in MDD. Preliminary results suggest that adjunctive CRT may improve cognitive outcomes in individuals with MDD, when combined with pharmacotherapy.Reference Bowie, Gupta, Holshausen, Jokic, Best and Milev 45 Reference Porter, Bowie, Jordan and Malhi 47

Computerized working memory tasks have also shown efficacy to improve cognitive function. For example, Siegle et alReference Siegle, Thompson, Carter, Steinhauer and Thase 48 reported that use of the Paced Auditory Serial Addition Test (ie, which requires patients to add sequentially presented digits) increased cognitive skills, decreased maladaptive thoughts (ie, rumination), and improved depressive symptom severity in individuals with MDD.Reference Siegle, Thompson, Carter, Steinhauer and Thase 48 Furthermore, computer programs focused on sequencing mental arithmetic problems have been reported to improve full-scale intelligence quotient (IQ) in individuals with MDD. 49 Computerized working memory tasks have been shown to improve psychosocial and occupational functioning, as well as hippocampal and frontotemporal activation.Reference Mohlman, Deckersbach and Weissman 50 Notwithstanding the foregoing evidence, the specific efficacy of computerized measures of cognitive function in clinical populations remains elusive. Moreover, the implementation of such computational measures is a challenge. Nevertheless, the emergence of big data approaches and blockchain technologies may aid in the development of such computational tasks.Reference Lazar, Pan and Ragguett 51

Manualized psychotherapy approaches (eg, cognitive behavioral therapy [CBT] and mindfulness therapies) are effective in the acute treatment of cognitive symptoms in MDD.Reference Lam, Parikh and Ramasubbu 52 , Reference Parikh, Quilty and Ravitz 53 For example, CBT has shown to be effective in treating cognitive symptoms in ADHD, a disorder characterized by significant disturbances in executive function and attention.Reference Young, Khondoker and Emilsson 54 However, current psychotherapies primarily target “hot” cognitive deficits, and therefore effective strategies targeting “cold” cognition still require further investigation.

Studies have shown that brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) have procognitive effects in subpopulations with depression.Reference Serafini, Pompili and Belvederi Murri 55 For example, brain stimulation therapies have been associated with greater tolerability, reduced likelihood of cognitive impairment, and higher rates of remission in treatment-resistant individuals. As a result, brain stimulation therapies may be useful in targeting cognitive symptoms associated with treatment-resistant MDD.Reference Demirtas-Tatlidede, Vahabzadeh-Hagh and Pascual-Leone 56 Indeed, brain imaging studies in individuals with MDD have shown that rTMS may be a viable precognitive neuromodulatory strategy. 57

Aerobic exercise in combination with resistance training is another potential treatment avenue that is cost-effective and accessible. Aerobic exercise improves cognition, has negligible side effects, and is scalable (ie, has the potential to be a population-wide health intervention).Reference Smith, Blumenthal and Hoffman 58 For example, a recent review by Stanton and ReaburnReference Stanton and Reaburn 59 found that performing aerobic exercise 3–4 times a week for 9 weeks at moderate intensity is effective in alleviating depressive symptoms.Reference Stanton and Reaburn 59 Likewise, a recent study showed lower depression relapse rates in individuals partaking in an aerobic exercise regimen compared to individuals treated with sertraline, a selective-serotonin reuptake inhibitor (SSRI).Reference Mohlman, Deckersbach and Weissman 50 Both acute and regular aerobic exercise have been shown to improve cognitive functions such as memory. Acute physical activity (ie, single bout of exercise lasting between 10–30 minutes in duration) has been shown to have a positive impact on short- and long-term memory.Reference Hillman, Kamijo and Scudder 60 However, greater improvements in memory have also been observed with regular sustained exercise in individuals with mild cognitive impairments compared to individuals without cognitive impairments, suggesting that individuals with cognitive difficulties due to depressive disorders may be more sensitive to the procognitive effects of exercise.Reference Smith, Blumenthal and Hoffman 58 , Reference Stanton and Reaburn 59 , Reference Heyn, Abreu and Ottenbacher 61

Pharmacological interventions

Available evidence indicates that improvements in measures of cognitive function with the use of conventional antidepressants are associated with improvements in depressive symptom severity. However, it remains to be seen whether most conventional antidepressants exert direct and clinically significant effects on cognitive functions in individuals with MDD. There is currently a paucity of FDA-approved pharmacological agents and/or interventions that are efficacious, tolerable, and specifically target cognitive dysfunction associated with MDD. Several studies have examined the efficacy of various antidepressant agents in improving cognitive function in individuals with MDD. For example, bupropion and escitalopram have been reported to improve some aspects of verbal memory and delayed free recall. 49 , Reference Soczynska, Ravindran and Styra 62 Similarly, sertraline has been shown to improve psychomotor performance.Reference Constant, Adam, Gillain, Seron, Bruyer and Seghers 63 , Reference Schrijvers, Maas, Pier, Madani, Hulstijn and Sabbe 64

Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has been demonstrated to have procognitive effects compared to placebo.Reference Raskin, Wiltse and Siegal 65 In addition to improving general symptoms of depression, duloxetine improved verbal learning and memory. Both duloxetine and the multimodal antidepressant, vortioxetine, have been shown to improve learning, memory, and verbal recall as measured by scores on the Rey Auditory Verbal Learning Test (RAVLT). In addition, individuals on vortioxetine also showed significant improvements in acquisition time and delayed recall. While both duloxetine and vortioxetine improved measures of depressive symptom severity, vortioxetine demonstrated a larger direct effect on RAVLT recall and acquisition scores compared to duloxetine.Reference McIntyre, Lophaven and Olsen 66 Duloxetine was evaluated from the point of view of multiple domains of cognitive function identical to those evaluated in studies with vortioxetine. Duloxetine did not exhibit a statistically significant improvement when compared to placebo on composite measures of cognitive function in contradistinction to vortioxetine.Reference McIntyre, Harrison, Loft, Jacobson and Olsen 67 In addition, vortioxetine appears to improve a broader range of cognitive functions (ie, executive function, learning, memory, processing speed, concentration) than duloxetine, which has only been shown to improve measures of learning and memory.Reference McIntyre, Lophaven and Olsen 66 Currently, vortioxetine is the only FDA-approved antidepressant agent that has demonstrated direct and independent procognitive effects in individuals with MDD. Specifically, as of May 2018, the FDA has updated the product monograph for vortioxetine based on data from the FOCUS and CONNECT trials to mention that vortioxetine is capable of improving performance on the Digit Symbol Substitution Test (DSST), indicating improvement in processing speed in individuals with MDD.Reference McIntyre, Harrison, Loft, Jacobson and Olsen 67 , Reference Mahableshwarkar, Zajecka, Jacobson, Chen and Keefe 68

Psychostimulants have also been used to treat depressive symptoms in individuals with MDD; however, available evidence is mixed. Notwithstanding the inconsistent evidence, lisdexamfetamine has been shown to specifically target and improve deficits in executive function in individuals with MDD, particularly among individuals with milder cognitive symptoms comorbid with executive function deficits.Reference Madhoo, Keefe and Roth 69

Ketamine, a dissociative anesthetic that antagonizes NMDA glutamatergic receptors, has been demonstrated to have rapid-onset antidepressant effects in individuals with treatment-resistant MDD.Reference Venero 70 Available evidence indicates that baseline cognitive function may serve as a predictor of response to ketamine treatment.Reference Lee, Syeda and Maruschak 71 Moreover, it seems the antisuicidal effects of ketamine are mediated by improvements in executive function.Reference Lee, Syeda and Maruschak 71 A review written by Lee et alReference Lee, Syeda and Maruschak 71 discusses procognitive effects of ketamine treatment in greater detail.

Preliminary data suggest that incretins may also improve cognitive function. Incretins are a group of metabolic hormones involved in the regulation of blood glucose levels. Incretins are involved in gastric motility, and act as insulin secretion analogues. Exogenously administered glucagon-like peptide (GLP-1) agonists (eg, liraglutide) are FDA-approved for the treatment of adults with type II diabetes mellitus. Glucagon-like peptide is synthesized in the nucleus tractus solitarius and has receptors distributed throughout the brain, with a topographical organization of receptors in cognitive controls regions. Preliminary evidence indicates that liraglutide administered at a dose of 1.8 mg is able to improve depressive and cognitive measures in adults with a depressive mood disorder.Reference Mansur, Ahmed and Cha 72 The foregoing results validate previous findings suggesting neuroprotective and neurotrophic properties for liraglutide.

Metabolic regulators present unique opportunities as treatment targets in depressed subpopulations with elevated metabolic and inflammatory status. For example, intranasal insulin has been shown to be procognitive in individuals with MDD. In particular, the procognitive effects of intranasal insulin are stronger in individuals with a history of diabetes and insulin dysregulation comorbid with MDD. In the brain, insulin inhibits pro-apoptotic pathways and plays critical roles in neuroplasticity, neurogenesis, and neuronal growth and survival. Insulin receptors are found throughout the brain, particularly in regions involved in cognitive and emotional processing. 49 Therefore, treatment strategies targeting brain insulin may prove efficacious in treating cognitive symptoms in MDD.

Elevated levels of circulating proinflammatory cytokines have been consistently reported in individuals with MDD.Reference Raison, Rutherford and Woolwine 73 Cognitive impairment has been observed in individuals with elevated inflammation.Reference Rosenblat, Cha, Mansur and McIntyre 21 Among the most consistently identified proinflammatory cytokine disturbances in MDD is tumor necrosis factor alpha (TNF-α).Reference McIntyre, Xiao and Syeda 17 , Reference Raison and Miller 74 Treatment with TNF-α antagonists is postulated to be an efficacious adjunctive approach to target cognitive symptoms in individuals with MDD. Infliximab is a promising TNF antagonist that binds to soluble and transmembrane domains of TNF-α, thus preventing the binding of TNF-α to its receptors.Reference Raison and Miller 74 , Reference Loftus, Feagan and Colombel 75 Treatment with TNF antagonists has been associated with lower depressive symptoms subscores in subpopulations with MDD comorbid with elevated peripheral inflammationReference Raison, Rutherford and Woolwine 73 and in individuals with rheumatoid arthritis.Reference Loftus, Feagan and Colombel 75 Evidence also demonstrates efficacy of TNF antagonists in subgroups with treatment-resistant depression.Reference Persoons, Vermeire and Demyttenaere 76 , Reference Tookman, Jones, DeWitte and Lodge 77 Whether adjunctive infliximab is an efficacious approach to treating cognitive symptoms in depressive mood disorders has yet to be determined but is currently being investigated by our group in Toronto (NCT02363738).


Cognitive deficit is a core domain of depressive psychopathology and a principal mediator of psychosocial and workplace functioning. Obtaining cognitive recovery in individuals with MDD is necessary to achieve optimal functional outcomes. This objective is limited by the current clinical paradigm, which insufficiently addresses the deficits in cognitive function experienced by individuals with MDD, and the lack of mechanism-oriented drug development. However, further research is necessary to elucidate the neural substrates and metabolites involved in the development of cognitive symptoms in MDD. A domain-based approach to the assessment and treatment of psychiatric conditions, including MDD, may be more pragmatic and may lead to better therapeutic outcomes for patients. Finally, creating a standard discourse related to cognitive dysfunction in psychiatric disorders and understanding the neurobiological mechanisms underlying cognitive dysfunction will be critical steps toward optimally treating cognitive symptoms across psychiatric conditions.


Roger S. McIntyre is a consultant to speak on behalf for, and/or has received research support from, Allergan, AstraZeneca, Bristol-Myers, Janssen-Ortho, Lundbeck, Otsuka, Purdue, Pfizer, Shire, Sunovion, Neurocrine, and Takeda. Elisa Brietzke received honoraria as speaker/advisory board from Daiichi-Sankyo. Zihang Pan, Caroline Park, Hannah Zuckerman, Carola Rong, Rodrigo Mansur, Dominika Fus, Mehala Subramaniapillai, and Yena Lee have nothing to disclose.


1. Fagiolini, A, Forgione, R, Maccari, M, et al. Prevalence, chronicity, burden and borders of bipolar disorder. J Affect Disord. 2013; 148(2–3): 161169.Google Scholar
2. Marcus, M, Yasamy, MT, Ommeren, MV, Chisholm, D, Saxena, S. Depression: a global public health concern. 2012. Accessed July 22, 2014.Google Scholar
3. Collins, PY, Patel, V, Joestl, SS, et al. Grand challenges in global mental health. Nature. 2011; 475(7354): 2730.Google Scholar
4. Cha, DS, Carmona, NE, Subramaniapillai, M, et al. Cognitive impairment as measured by the THINC-integrated tool (THINC-it): association with psychosocial function in major depressive disorder. J Affect Disord. 2017; 222: 1420.Google Scholar
5. Woo, YS, Rosenblat, JD, Kakar, R, Bahk, W-M, McIntyre, RS. Cognitive deficits as a mediator of poor occupational function in remitted major depressive disorder patients. Clin Psychopharmacol Neurosci. 2016; 14(1): 116.Google Scholar
6. 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): 515527.Google Scholar
7. McIntyre, RS, Lee, Y. Cognition in major depressive disorder: a “Systemically Important Functional Index” (SIFI). Curr Opin Psychiatry. 2016; 29(1): 4855.Google Scholar
8. Rosenblat, JD, Kakar, R, McIntyre, RS. The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials. Int J Neuropsychopharmacol. 2015; 19(2): pyv082. doi: 10.1093/ijnp/pyv082Google Scholar
9. Pan, Z, Grovu, RC, Cha, DS, et al. Pharmacological treatment of cognitive symptoms in major depressive disorder. CNS Neurol Disord Drug Targets. 2017; 16(8): 891899. doi:10.2174/1871527316666170919115100Google Scholar
10. Rosenblat, JD, Brietzke, E, Mansur, RB, Maruschak, NA, Lee, Y, McIntyre, RS. Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: evidence, pathophysiology and treatment implications. J Affect Disord. 2015; 188: 149159.Google Scholar
11. Carvalho, AF, Berk, M, Hyphantis, TN, McIntyre, RS. The integrative management of treatment-resistant depression: a comprehensive review and perspectives. Psychother Psychosom 2014; 83(2): 7088.Google Scholar
12. McIntyre, RS, Cha, DS, Soczynska, JK. Cognition in Major Depressive Disorder. Oxford, UK: Oxford University Press; 2014.Google Scholar
13. Jantaratnotai, N, Mosikanon, K, Lee, Y, McIntyre, RS. The interface of depression and obesity. Obes Res Clin Pract. 2017; 11(1): 110.Google Scholar
14. Mansur, RB, Lee, Y, Zhou, AJ, et al. Determinants of cognitive function in individuals with type 2 diabetes mellitus: a meta-analysis. Ann Clin Psychiatry. 2018; 30(1): 3850.Google Scholar
15. Harrison, JE, Lam, RW, Baune, BT, McIntyre, RS. Selection of cognitive tests for trials of therapeutic agents. Lancet Psychiatry. 2016; 3(6): 499.Google Scholar
16. McIntyre, RS, Woldeyohannes, HO, Soczynska, JK, et al. Anhedonia and cognitive function in adults with MDD: results from the International Mood Disorders Collaborative Project. CNS Spectr. 2016; 21(5): 362366.Google Scholar
17. McIntyre, RS, Xiao, HX, Syeda, K, et al. The prevalence, measurement, and treatment of the cognitive dimension/domain in major depressive disorder. CNS Drugs. 2015; 29(7): 577589.Google Scholar
18. Roiser, JP, Sahakian, BJ. Hot and cold cognition in depression. CNS Spectr. 2013; 18(3): 139149.Google Scholar
19. Stahl, SM. Enhancing outcomes from major depression: using antidepressant combination therapies with multifunctional pharmacologic mechanisms from the initiation of treatment. CNS Spectr 2010; 15(2): 7994.Google Scholar
20. Bortolato, B, Carvalho, AF, Soczynska, JK, Perini, GI, McIntyre, RS. The involvement of TNF-α in cognitive dysfunction associated with major depressive disorder: an opportunity for domain specific treatments. Curr Neuropharmacol 2015; 13(5): 558576.Google Scholar
21. Rosenblat, JD, Cha, DS, Mansur, RB, McIntyre, RS. Inflamed moods: a review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 53: 2334.Google Scholar
22. Shariq, AS, Brietzke, E, Rosenblat, JD, Barendra, V, Pan, Z, McIntyre, RS. Targeting cytokines in reduction of depressive symptoms: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2018; 83: 8691.Google Scholar
23. Jiao, Q, Ding, J, Lu, G, et al. Increased activity imbalance in fronto-subcortical circuits in adolescents with major depression. PLoS One 2011; 6(9): e25159.Google Scholar
24. Pizzagalli, DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011; 36(1): 183206.Google Scholar
25. MacQueen, GM, Campbell, S, McEwen, BS, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003; 100(3): 13871392.Google Scholar
26. Stahl, SM, Zhang, L, Damatarca, C, Grady, M. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry. 2003; 64(Suppl 14): 617.Google Scholar
27. Kheirbek, MA, Hen, R. Dorsal vs ventral hippocampal neurogenesis: implications for cognition and mood. Neuropsychopharmacology 2011; 36(1): 373374.Google Scholar
28. Malykhin, NV, Carter, R, Seres, P, Coupland, NJ. Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment. J Psychiatry Neurosci. 2010; 35(5): 337343.Google Scholar
29. Gorwood, P, Corruble, E, Falissard, B, Goodwin, GM. 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): 731739.Google Scholar
30. Zeng, L-L, Shen, H, Liu, L, et al. Identifying major depression using whole-brain functional connectivity: a multivariate pattern analysis. Brain 2012; 135(Pt 5): 14981507.Google Scholar
31. Harvey, P-O, Fossati, P, Pochon, J-B, et al. Cognitive control and brain resources in major depression: an fMRI study using the n-back task. Neuroimage 2005; 26(3): 860869.Google Scholar
32. Hamilton, JP, Furman, DJ, Chang, C, Thomason, ME, Dennis, E, Gotlib, IH. Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination. Biol Psychiatry 2011; 70(4): 327333.Google Scholar
33. Cha, DS, De Michele, F, Soczynska, JK, et al. The putative impact of metabolic health on default mode network activity and functional connectivity in neuropsychiatric disorders. CNS Neurol Disord Drug Targets. 2014; 13(10): 17501758.Google Scholar
34. Li, M, Soczynska, JK, Kennedy, SH. Inflammatory biomarkers in depression: an opportunity for novel therapeutic interventions. Curr Psychiatry Rep. 2011; 13(5): 316320.Google Scholar
35. Ryan, JP, Sheu, LK, Critchley, HD, Gianaros, PJ. A neural circuitry linking insulin resistance to depressed mood. Psychosom Med 2012; 74(5): 476482.Google Scholar
36. Andreazza, AC. Combining redox-proteomics and epigenomics to explain the involvement of oxidative stress in psychiatric disorders. Mol Biosyst 2012; 8(10): 25032512.Google Scholar
37. McAfoose, J, Baune, BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev. 2009; 33(3): 355366.Google Scholar
38. McIntyre, RS, Rasgon, NL, Kemp, DE, et al. Metabolic syndrome and major depressive disorder: co-occurrence and pathophysiologic overlap. Curr Diab Rep. 2009; 9(1): 5159.Google Scholar
39. Baker, LD, Cross, DJ, Minoshima, S, Belongia, D, Watson, GS, Craft, S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 2011; 68(1): 5157.Google Scholar
40. Hidese, S, Ota, M, Matsuo, J, et al. Association of obesity with cognitive function and brain structure in patients with major depressive disorder. J Affect Disord. 2018; 225: 188194.Google Scholar
41. Buist-Bouwman, MA, Ormel, J, de Graaf, R, et al. Mediators of the association between depression and role functioning. Acta Psychiatr Scand. 2008; 118(6): 451458.Google Scholar
42. McIntyre, RS, Soczynska, 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: 279282.Google Scholar
43. McIntyre, RS, Cha, DS. Cognitive Impairment in Major Depressive Disorder: Clinical Relevance, Biological Substrates, and Treatment Opportunities. Cambridge, UK: Cambridge University Press; 2016.Google Scholar
44. Medalia, A, Revheim, N, Herlands, T. Cognitive Remediation for Psychological Disorders. Oxford, UK: Oxford University Press; 2009.Google Scholar
45. Bowie, CR, Gupta, M, Holshausen, K, Jokic, R, Best, M, Milev, R. Cognitive remediation for treatment-resistant depression: effects on cognition and functioning and the role of online homework. J Nerv Ment Dis. 2013; 201(8): 680685.Google Scholar
46. Bowie, CR, McGurk, SR, Mausbach, B, Patterson, TL, Harvey, PD. Combined cognitive remediation and functional skills training for schizophrenia: effects on cognition, functional competence, and real-world behavior. Am J Psychiatry. 2012; 169(7): 710718.Google Scholar
47. Porter, RJ, Bowie, CR, Jordan, J, Malhi, GS. Cognitive remediation as a treatment for major depression: a rationale, review of evidence and recommendations for future research. Aust N Z J Psychiatry. 2013; 47(12): 11651175.Google Scholar
48. Siegle, GJ, Thompson, W, Carter, CS, Steinhauer, SR, Thase, ME. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry 2007; 61(2): 198209.Google Scholar
49. Ragguett R-M, Cha DS, Kakar R, Rosenblat JD, Lee Y, McIntyre RS. Assessing and measuring cognitive function in major depressive disorder. Evid Based Ment Health. 2016; 19(4): 106–109.Google Scholar
50. Mohlman, J, Deckersbach, T, Weissman, A. From Symptom to Synapse: A Neurocognitive Perspective on Clinical Psychology. New York: Routledge; 2015.Google Scholar
51. Lazar, MA, Pan, Z, Ragguett, R-M, et al. Digital revolution in depression: a technologies update for clinicians. Personalized Medicine in Psychiatry. 2017; 4–6: 16.Google Scholar
52. Lam, RW, Parikh, SV, Ramasubbu, R, et al. Effects of combined pharmacotherapy and psychotherapy for improving work functioning in major depressive disorder. Br J Psychiatry. 2013; 203(5): 358365.Google Scholar
53. Parikh, SV, Quilty, LC, Ravitz, P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 2. psychological treatments. Can J Psychiatry. 2016; 61(9): 524539.Google Scholar
54. Young, S, Khondoker, M, Emilsson, B, et al. Cognitive-behavioural therapy in medication-treated adults with attention-deficit/hyperactivity disorder and co-morbid psychopathology: a randomized controlled trial using multi-level analysis. Psychol Med 2015; 45(13): 27932804.Google Scholar
55. Serafini, G, Pompili, M, Belvederi Murri, M, et al. The effects of repetitive transcranial magnetic stimulation on cognitive performance in treatment-resistant depression: a systematic review. Neuropsychobiology 2015; 71(3): 125139.Google Scholar
56. Demirtas-Tatlidede, A, Vahabzadeh-Hagh, AM, Pascual-Leone, A. Can noninvasive brain stimulation enhance cognition in neuropsychiatric disorders? Neuropharmacology 2013; 64: 566578.Google Scholar
57. Kuroda Y, Motohashi N, Ito H, Ito S, Takano A, Nishikawa T, et al. Effects of repetitive transcranial magnetic stimulation on [11C]raclopride binding and cognitive function in patients with depression. J Affect Disord. 2006; 95(1-3): 35–42.Google Scholar
58. Smith, PJ, Blumenthal, JA, Hoffman, BM, et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med 2010; 72(3): 239252.Google Scholar
59. Stanton, R, Reaburn, P. Exercise and the treatment of depression: a review of the exercise program variables. J Sci Med Sport. 2014; 17(2): 177182.Google Scholar
60. Hillman, CH, Kamijo, K, Scudder, M. A review of chronic and acute physical activity participation on neuroelectric measures of brain health and cognition during childhood. Prev Med 2011; 52(Suppl 1): S21S28.Google Scholar
61. Heyn, P, Abreu, BC, Ottenbacher, KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil. 2004; 85(10): 16941704.Google Scholar
62. Soczynska, JK, Ravindran, LN, Styra, R, et al. The effect of bupropion XL and escitalopram on memory and functional outcomes in adults with major depressive disorder: results from a randomized controlled trial. Psychiatry Res 2014; 220(1–2): 245250.Google Scholar
63. Constant, EL, Adam, S, Gillain, B, Seron, X, Bruyer, R, Seghers, A. Effects of sertraline on depressive symptoms and attentional and executive functions in major depression. Depress Anxiety 2005; 21(2): 7889.Google Scholar
64. Schrijvers, D, Maas, YJ, Pier, MP, Madani, Y, Hulstijn, W, Sabbe, BG. Psychomotor changes in major depressive disorder during sertraline treatment. Neuropsychobiology 2009; 59(1): 3442.Google Scholar
65. Raskin, J, Wiltse, CG, Siegal, A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007; 164(6): 900909.Google Scholar
66. McIntyre, RS, Lophaven, S, Olsen, CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014; 17(10): 15571567.Google Scholar
67. McIntyre, RS, Harrison, J, Loft, H, Jacobson, W, Olsen, CK. The effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials. Int J Neuropsychopharmacol. 2016; 19(10): pyw055. doi: 10.1093/ijnp/pyw055Google Scholar
68. Mahableshwarkar, AR, Zajecka, J, Jacobson, W, Chen, Y, Keefe, RSE. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology 2015; 40(8): 20252037.Google Scholar
69. Madhoo, M, Keefe, RSE, Roth, RM, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology 2014; 39(6): 13881398.Google Scholar
70. Venero, C. Pharmacological treatment of cognitive dysfunction in neuropsychiatric disorders. In: Knafo S, Venero C, eds. Cognitive Enhancement: Pharmacologic, Environmental and Genetic Factors. San Diego, CA: Academic Press; 2015: 233271.Google Scholar
71. Lee, Y, Syeda, K, Maruschak, NA, et al. A new perspective on the anti-suicide effects with ketamine treatment: a procognitive effect. J Clin Psychopharmacol. 2016; 36(1): 5056.Google Scholar
72. Mansur, RB, Ahmed, J, Cha, DS, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. J Affect Disord. 2017; 207: 114120.Google Scholar
73. Raison, CL, Rutherford, RE, Woolwine, BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013; 70(1): 3141.Google Scholar
74. Raison, CL, Miller, AH Malaise, melancholia and madness: the evolutionary legacy of an inflammatory bias. Brain Behav Immun. 2013; 31: 18.Google Scholar
75. Loftus, EV, Feagan, BG, Colombel, J-F, et al. Corrigendum: effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn’s disease: patient-reported outcomes of the CHARM Trial. Am J Gastroenterol. 2009; 104: 1894.Google Scholar
76. Persoons, P, Vermeire, S, Demyttenaere, K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol Ther. 2005; 22(2): 101110.Google Scholar
77. Tookman, AJ, Jones, CL, DeWitte, M, Lodge, PJ. Fatigue in patients with advanced cancer: a pilot study of an intervention with infliximab. Support Care Cancer. 2008; 16(10): 11311140.Google Scholar