Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target

Neuropharmacology. 2013 Jan;64:337-46. doi: 10.1016/j.neuropharm.2012.08.001. Epub 2012 Aug 23.


Cognitive impairment, in particular of attention and memory, is often reported by patients suffering from major depressive disorder (MDD) and deficits in attention are part of the current diagnostic criteria of MDD. Objectively measured cognitive deficits associated with MDD have been described in many studies. They have been conceptualized as an integral facet and epiphenomenon of MDD. However, evidence accumulated in recent years has challenged this notion and demonstrated that in a subset of patients the degree of cognitive deficits cannot be accounted for by the severity of depression. In addition, in some patients cognitive deficits persist despite resolution of depressive symptomatology. It is plausible to assume that cognitive deficits contribute to functional impairment even though supportive data for such a relationship are lacking. However, the exact association between cognitive deficits and major depression and the clinical and neurobiological characteristics of patients with MDD in whom cognitive deficits seem partially or fully independent of the clinical manifestation of depressive symptoms remain poorly understood. This review focuses on objective measures of non-emotional cognitive deficits in MDD and discusses the presence of a subgroup of patients in whom these symptoms can be defined independently and in dissociation from the rest of the depressive symptomatology. The current understanding of brain circuits and molecular events implicated in cognitive impairment in MDD are discussed with an emphasis on the missing elements that could further define the specificity of cognitive impairment in MDD and lead to new therapeutics. Furthermore, this article presents in detail observations made in behavioral studies in rodents with potential novel therapeutic agents, such as negative allosteric modulators at the metabotropic glutamate receptor type 2/3 (mGlu2/3 NAM) which exhibit both cognitive enhancing and antidepressant properties. Such a compound, RO4432717, was tested in tests of short term memory (delayed match to position), cognitive flexibility (Morris water maze, reversal protocol), impulsivity and compulsivity (5-choice serial reaction time) and spontaneous object recognition in rodents, providing first evidence of a profile potentially relevant to address cognitive impairment in MDD. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Cognition Disorders / chemically induced
  • Cognition Disorders / etiology
  • Cognition Disorders / prevention & control*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Depressive Disorder, Major / physiopathology
  • Excitatory Amino Acid Agonists / adverse effects
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Agonists / therapeutic use
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Molecular Targeted Therapy*
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism
  • Nootropic Agents / pharmacology
  • Nootropic Agents / therapeutic use*
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism


  • Antidepressive Agents
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Nerve Tissue Proteins
  • Nootropic Agents
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2