Review
Cognitive dysfunction in depression: Neurocircuitry and new therapeutic strategies

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Abstract

Major depressive disorder (MDD) is a disabling medical condition associated with significant morbidity, mortality and public health costs. However, neurocircuitry abnormalities underlying depression remain incompletely understood and consequently current treatment options are unfortunately limited in efficacy. Recent research has begun to focus specifically on cognitive aspects of depression and potential neurobiological correlates. Two fundamental types of cognitive dysfunction observed in MDD are cognitive biases, which include distorted information processing or attentional allocation toward negative stimuli, and cognitive deficits, which include impairments in attention, short-term memory and executive functioning. In this article, we present a selective review of current research findings in these domains and examine neuroimaging research that is beginning to characterize the neurocircuitry underlying these biases and deficits. We propose that deficient cognitive functioning, attention biases and the sustained negative affect characteristic of MDD can be understood as arising in part from dysfunctional prefrontal-subcortical circuitry and related disturbances in the cognitive control of emotion. Finally, we highlight potential new pharmacological and non-pharmacological therapeutic strategies for MDD based on an evolving mechanistic understanding of the disorder.

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.

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