ReviewCognitive dysfunction in depression: Neurocircuitry and new therapeutic strategies
Highlights
► Neurocognitive dysfunction in major depression involves both biases and deficits. ► Problems with cognitive control in depression may underlie these abnormalities. ► Prefrontal cortical systems may be a key substrate for deficient cognitive control. ► Subcortical emotion-processing systems may be under-regulated in depression. ► Targeting neurocognitive aspects of depression may lead to new treatments.
Introduction
Major depressive disorder (MDD) is a disabling medical condition associated with significant morbidity, mortality and public health costs (Kessler et al., 2003, World Health Organization, 2001). Mortality by suicide associated with a depressive disorder is alarmingly high and suicide has become the third leading cause of death in individuals 15–24 years of age (Insel & Charney, 2003). Despite the large public health impact, the etiology and pathophysiology of depression remain poorly understood. Current treatments for depression include pharmacotherapy targeting components of the monoamine neurotransmitter systems in the brain, as well as several psychotherapeutic approaches, including cognitive therapy. However, response rates for these treatments are only modest (Rush et al., 2006, Trivedi et al., 2006), likely reflecting an incomplete understanding of the etiological basis of depression and related psychiatric disorders (Agid et al., 2007, Manji et al., 2001, Mathew et al., 2008). Patients suffering more severe depressive symptoms or with a history of treatment-resistance are unfortunately even less likely to respond to currently available treatments (Mathew, 2008).
From a clinical perspective, MDD is a complex, heterogeneous disorder characterized by pervasive and sustained low mood and anhedonia along with disturbances in multiple domains including cognition and attention, psychomotor function, sleep, appetite and in some cases endocrine functioning (Nelson & Charney, 1981). Negative thought patterns, including pervasive and fixed negative views of the self, the world and the future are also a core feature of depression (American Psychiatric Association. Task Force on DSM-IV, 2000). Major depression may be conceptualized as a disorder of brain systems that regulate mood, motivation and related cognitive, endocrine and behavioral functions (Mayberg, 2003, Price and Drevets, 2010, Seminowicz et al., 2004).
Recent research has begun to focus specifically on cognitive aspects of depression and potential neurobiological correlates in an effort to identify new therapeutic strategies. Two basic types of cognitive dysfunction observed in MDD are: (1) cognitive biases, which include distorted information processing or attentional allocation toward negative stimuli and away from positive stimuli, and (2) cognitive deficits, which include impairments in attention, short-term memory and executive functioning. Neuroimaging research is beginning to characterize the neurocircuitry underlying these deficits and biases, which could highlight potential new therapeutic targets for interventions for this disabling disorder. In this article, we provide an overview of cognitive dysfunction in depression and related neurocircuitry and describe recent research aimed at understanding the neural basis of cognitive control and emotion regulation as it relates to depression. At the end, we highlight a few examples of potential pharmacotherapeutic and psychotherapeutic treatment interventions based on an evolving understanding of the cognitive and neural mechanisms of depression.
Section snippets
Cognitive biases in depression
Cognitive theories of depression posit that a constellation of cognitive constructs (e.g. cognitive schemas) direct attention and memory towards negative themes related to the self, the world and the future in patients suffering from depression (Beck, 2008, Beck et al., 1979). This negative bias in cognitive processing is hypothesized to give rise to symptoms of depression via a bidirectional relationship between thoughts and emotions. Cognitive therapy for depression is designed to explicitly
Overview of prefrontal-subcortical neurocircuitry in depression
Initial observations in animals suggested that specific subcortical structures were important for the expression of emotional behavior, including the hypothalamus and periaqueductal gray, anterior and medial thalamic nuclei, the amygdala, hippocampus, striatum and putamen (Alexander et al., 1986, LeDoux, 2000, Ongur and Price, 2000, Phillips et al., 2003a). More recently, studies in both animals and humans illustrate the critical role of the orbital frontal cortex (OFC), medial prefrontal
The impact of antidepressant treatment on prefrontal-subcortical neurocircuitry
All current pharmacological agents approved for the treatment of major depression act primarily on the monoaminergic system in the brain and generally lead to increased intra-synaptic availability of monoamines. Common pharmacological classes of agents include serotonin selective reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and older agents including the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Functional neuroimaging
Conclusions and future directions
Advancements in understanding the neural mechanisms of depression are expected to illuminate potential new treatment strategies that are urgently needed for patients suffering from this disabling condition. In this review we have highlighted research aimed at understanding neurocircuitry related to the cognitive biases and deficits that characterize depression and have provided examples of therapeutic strategies targeting these domains.
Although discrepancies exist, the extant literature
Conflict of interest
Dr. Charney has been named as an inventor on a use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Dr. Charney and the Mount Sinai School of Medicine could benefit financially. All other authors report no completing interests.
References (175)
The vascular depression hypothesis: 10 years later
Biological Psychiatry
(2006)- et al.
Attentional biases for negative information in induced and naturally occurring dysphoria
Behaviour Research and Therapy
(1997) - et al.
Implicit memory bias in clinical and non-clinical depression
Behaviour Research and Therapy
(1996) - et al.
Implicit and explicit memory for emotion-congruent information in clinical depression and anxiety
Behaviour Research and Therapy
(1995) - et al.
Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine
Psychiatry Research
(1999) - et al.
A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults
Journal of Affective Disorders
(2008) - et al.
Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment
Biological Psychiatry
(2007) - et al.
Neural and behavioral substrates of mood and mood regulation
Biological Psychiatry
(2002) - et al.
General and specific cognitive deficits in schizophrenia: Goliath defeats David?
Biological Psychiatry
(2008) - et al.
Rumination and attention in major depression
Behaviour Research and Therapy
(2007)
Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism
European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology
Functional imaging of ‘theory of mind’
Trends in Cognitive Sciences
Cognitive inhibition and working memory in unipolar depression
Journal of Affective Disorders
The neural bases of emotion regulation: Reappraisal and suppression of negative emotion
Biological Psychiatry
Facial emotion discrimination: II. Behavioral findings in depression
Psychiatry Research
Long-lasting cognitive impairment in unipolar major depression: A 6-month follow-up study
Psychiatry Research
Cognitive control and brain resources in major depression: An fMRI study using the n-back task
NeuroImage
Executive functions and updating of the contents of working memory in unipolar depression
Journal of Psychiatric Research
Anxiety, affect, and activity in teenagers: Monitoring daily life with electronic diaries
Journal of the American Academy of Child and Adolescent Psychiatry
Treating depression in the medically ill
The Psychiatric Clinics of North America
Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part I)
Psychiatry Research
Neurocognitive deficits and disability in major depressive disorder
Psychiatry Research
Subgenual cingulate and visual cortex responses to sad faces predict clinical outcome during antidepressant treatment for depression
Journal of Affective Disorders
Attention deficit in depressed suicide attempters
Psychiatry Research
CPT performance in major depressive disorder before and after treatment with imipramine or fluvoxamine
Journal of Psychiatric Research
The functional neuroanatomy of the human orbitofrontal cortex: Evidence from neuroimaging and neuropsychology
Progress in Neurobiology
Effects of recurrent major depressive disorder on behavior and cognitive function in female depressed patients
Psychiatry Research
Neural circuitry underlying voluntary suppression of sadness
Biological Psychiatry
How can drug discovery for psychiatric disorders be improved?
Nature Reviews Drug Discovery
Cognitive functions in depressive disorders: Evidence from a population-based study
Psychological Medicine
Parallel organization of functionally segregated circuits linking basal ganglia and cortex
Annual Review of Neuroscience
‘Vascular depression’ hypothesis
Archives of General Psychiatry
Prospective incidence of first onsets and recurrences of depression in individuals at high and low cognitive risk for depression
Journal of Abnormal Psychology
Depression and selection of positive and negative social feedback: Motivated preference or cognitive balance?
Journal of Abnormal Psychology
Attention modification program in individuals with generalized anxiety disorder
Journal of Abnormal Psychology
Cognitive deficits in depression: Possible implications for functional neuropathology
The British Journal of Psychiatry: The Journal of Mental Science
Research review: Attention bias modification (ABM): a novel treatment for anxiety disorders
Journal of Child Psychology and Psychiatry
Reduction of prefrontal cortex glucose metabolism common to three types of depression
Archives of General Psychiatry
Neural correlates of conscious self-regulation of emotion
The Journal of Neuroscience. The Official Journal of the Society for Neuroscience
Dysfunction in the neural circuitry of emotional self-regulation in major depressive disorder
NeuroReport
The evolution of the cognitive model of depression and its neurobiological correlates
The American Journal of Psychiatry
Cognitive therapy of depression
Regional cerebral blood flow in depression measured by positron emission tomography: The relationship with clinical dimensions
Psychological Medicine
Conflict monitoring and cognitive control
Psychological Review
Depressed patients’ perceptions of facial emotions in depressed and remitted states are associated with relapse: A longitudinal study
The Journal of Nervous and Mental Disease
Negative self-schemata in clinical depression
The British Journal of Clinical Psychology/The British Psychological Society
The modification of attentional bias to emotional information: A review of the techniques, mechanisms, and relevance to emotional disorders
Cognitive, Affective & Behavioral Neuroscience
The anatomical connections of the macaque monkey orbitofrontal cortex. A review
Cerebral Cortex (New York, N.Y.: 1991)
Neuropharmacological modulation of cognition
Current Opinion in Neurology
Cited by (254)
Depression as a risk factor for dementia: Pathophysiology and preclinical study models
2024, Psiquiatria BiologicaRestorative effect of NitroSynapsin on synaptic plasticity in an animal model of depression
2023, NeuropharmacologyStrain-level structure of gut microbiome showed potential association with cognitive function in major depressive disorder: A pilot study
2023, Journal of Affective DisordersMolecular changes in nucleus accumbens due to amelioration of depressive-like behavior by housing with companion
2022, Brain Research BulletinEarly indicators of vulnerability to depression: The role of rumination and heart rate variability
2022, Journal of Affective Disorders