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

Neuropharmacology 64 (2013) 337e346

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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm

Invited review

Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target Celia Goeldner, Theresa M. Ballard, Frederic Knoflach, Juergen Wichmann, Silvia Gatti, Daniel Umbricht* Building 74, Room 3W.209 F. Hoffmann-La Roche AG, DTA CNS, Pharma Research & Early Development, Grenzacherstrasse 124, CH4070 Basel, Switzerland

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 July 2012 Accepted 3 August 2012

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’. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Major depression Cognitive flexibility Hippocampus Neuronal plasticity mGlu2

1. Introduction Subjectively perceived impairment in cognitive function has always been recognized as a symptom in patients with Major Depressive Disorder (MDD) (Rohling et al., 2002; Naismith et al.,

Abbreviations: MDD, Major depressive disorder; mGluR, metabotropic glutamate receptor; 5-CSRT, 5-choice- serial reaction time; TRD, treatment resistant depression; BDD, bipolar depressive disorder; DL, dorso-lateral; VM, ventro-medial; PFC, Prefrontal cortex; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; CMS, Chronic mild unpredictable stress. * Corresponding author. Tel.: þ41 6168830. E-mail address: [email protected] (D. Umbricht). 0028-3908/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropharm.2012.08.001

2007; Mowla et al., 2008). Consequently the diagnostic criteria of both DSM-IV and ICD-10 include items of ‘Diminished ability to think or concentrate” and “reduced concentration and attention”, respectively. However, subjective complaints of cognitive impairment do not correlate with objectively measured cognitive deficits (Rohling et al., 2002; Naismith et al., 2007; Mowla et al., 2008). Research over the last two decades has convincingly demonstrated the presence of objectively measurable deficits in key cognitive functions in a large proportion of patients in the midst of a major depressive episode (for reviews and meta-analysis studies see: Austin et al., 2001; Biringer, 2007; Castaneda et al., 2008; Clark et al., 2009; McDermott and Ebmeier, 2009; McClintock et al., 2010; Hasselbalch et al., 2011; Lee et al., 2012; Wagner et al.,

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2012). The cognitive functions most impaired in MDD included attention, working and episodic memory and executive functions (Clark et al., 2009; McClintock et al., 2010). To a large extent cognitive deficits1 have been conceptualized as clinical phenomena that are driven by depressive symptomatology e or the pathophysiology driving depressive symptoms e and hence their resolution has been expected as a function of amelioration of the depressive symptomatology. However, there is emerging evidence that in some patients the cognitive deficits go beyond a degree that can be accounted for by the severity of depressive symptoms (Harvey et al., 2004; Airaksinen et al., 2007; McDermott and Ebmeier, 2009; Reppermund et al., 2009; McClintock et al., 2010; Douglas et al., 2011; Lee et al., 2012). In addition, persistence of cognitive impairment in patients with partial or full resolution of depressive symptoms has been demonstrated (Weiland-Fiedler et al., 2004; Airaksinen et al., 2007; Reppermund et al., 2009; Behnken et al., 2010). Thus, evidence is accumulating that supports the view that in subgroups of patients cognitive deficits constitute a dimension of MDD that is independent of and dissociable from depressive symptomatology (Naismith et al., 2003; Iverson et al., 2011). Many questions remain to be answered as to the characteristics of these patients and their deficits (Dunkin et al., 2000; GudayolFerre et al., 2010), the exact relationship between subjective complaints of impaired cognitive processes and objective measures of cognitive deficits in this subgroup, and finally how the well demonstrated negative ‘cognitive’ bias relates to cognitive impairment (Barry and Livingstone, 2006; Everaert et al., 2012). The most important point to clarify is the role that cognitive dysfunctions play in the relationship between functional outcome and remission of depression (Baune et al., 2010). Current antidepressant therapies have limited capacity to alleviate the cognitive deficits in MDD (Biringer, 2005; Herrera-Guzman et al., 2009; Behnken et al., 2010; Spronk et al., 2011). There is some evidence that cognitive deficits in MDD patients are predictive of a failure to respond to SSRI/SNRI, suggesting that some cognitive aspects of MDD may define a subtype of patients who require additional therapeutic interventions (Dunkin et al., 2000; Gorlyn et al., 2008; Herrera-Guzman et al., 2008). Novel antidepressants that also enhance cognition, independently of their antidepressant activity, might offer a clear therapeutic advantage in these patients (Clark et al., 2009). 2. Definition of cognitive impairment in MDD versus hot cognition, negative cognitive set It is important to note that cognitive impairment in patients with MDD are defined as deficits in cognitive functions that are objectively measurable by validated neuropsychological tests. Often these impairments are confused with subjective complaints of patients about their inability to think and concentrate and their memory problems. Although such complaints do not directly correlate with cognitive deficits (Rohling et al., 2002; Naismith et al., 2007; Mowla et al., 2008) and represent another aspect of MDD they may still be related in some fashion to specific characteristics of cognitive impairment. However, such relations have not been characterized in larger studies. Likewise, care must be taken to differentiate cognitive impairment from the well demonstrated bias in processing of emotional stimuli in favor of negatively valenced information and the resulting negative ‘cognitive’ set or bias often referred to as cognitive dysfunction (Clark et al., 2009; Roiser et al., 2011). This negative cognitive bias is more aptly

1 We use the terms ‘cognitive deficit’ and ‘cognitive impairment’ interchangeably in this article.

defined as an abnormal over-efficiency in processing negative emotional information at the cost of positive emotional information rather than as a general deficit and has been referred to as abnormalities in ‘hot cognition’. (Roiser et al., 2009a,b) Deficits in cognition that are associated with depression have typically been studied separately from this negative cognitive bias with no unifying hypothesis linking the two aspects, except the “resource allocation” theory which proposes that reduced psychomotor function and preferential negative processing and rumination limits available resources for cognitive processing. The current review focuses only on impairments in objectively assessed cognitive domains in MDD and the specific domains affected are discussed below. 2.1. Cross-sectional findings Recent comprehensive reviews have tried to define the extent and characteristics of cognitive impairment in MDD (McDermott and Ebmeier, 2009; McClintock et al., 2010). There is good evidence that many patients with MDD demonstrate clinically significant deficits particularly in executive, attention and memory functions when assessed during a depressive episode although there are also studies that did not find such deficits suggesting that cognitive impairment may only affect a subset of patients (Iverson et al., 2011). Likewise, the relationship of cognitive impairment to the severity of the current depressive episode and to the number of previous episodes is inconsistent, suggesting that at least in some patients, cognitive impairments are not related to severity of current depression. In some patients, the number and severity of previous episodes may contribute to the development of cognitive impairment in the sense of increasing ‘scarring’ of key brain circuits (McClintock et al., 2010). McDermott and Ebmeier (2009) conducted a systematic review and meta-analysis in order to quantify the association of severity of depression with the level of impairment across cognitive domains. Out of 69 studies that met the initial inclusion criteria of their literature search only 14 studies were included in the final meta-analysis highlighting the diverse nature of studies on cognition and major depression. The number of patients in the studies that provided the basis for the meta-analysis ranged from 41 up to 1150 again highlighting the challenge when trying to uniformly assess the relationship of depression to cognitive impairment. The authors found significant correlations between impairment in episodic memory, executive function and processing speed with severity of depression. The mean correlation ranged from 0.16 for processing speed to, 0.31 for episodic memory and 0.32 for executive function. No significant correlations were evident for semantic and visuo-spatial memory. Importantly, the relationship to severity of depression was observed both for tests in which an element of speed was important and those where speed did not count. This indicates that the association of specific function with severity of depression cannot be explained by increased psychomotor retardation in more severely depressed patients. However, as the authors point out, even in the case of significant correlations the variance explained by severity of depression is small and does not exceed 10%. It may be conceded that the most widely used tools to assess the severity of depression (HAMD and MADRS scales) may not be optimal to measure the “true” severity of depression in a linear fashion similar to cognitive tests that measure the severity of cognitive deficits objectively. Thus, a relatively small correlation between a pseudo-linear, monotonic measure and a truly linear assessment may to some extent be due to this problem. Nonetheless, it does seem to be a fair conclusion that a large proportion of cognitive deficits observed during a depressive episode cannot be solely accounted for as a pure epiphenomenon of the

C. Goeldner et al. / Neuropharmacology 64 (2013) 337e346

depressive state. In conclusion, cross-sectional studies of major depression and cognitive deficits confirm the presence of clinically significant cognitive impairment during depressive episodes but also provide evidence that at least in some patients cognitive deficits can be independent of or only partially be accounted for by the severity of the current depression. 2.2. Cognitive impairment in patients in remission and in patients followed longitudinally A methodologically sounder approach to assess the question to which extent cognitive impairment is independent from severity of depression in patients with MDD is given by studies in patients who have achieved remission and in patients who are followed prospectively. Marcos et al. (Marcos et al., 1994) found significant impairment in measures of memory and learning in 28 euthymic patients with a history of recurrent melancholic depression. The effect sizes of the observed significant differences ranged from 0.6 to 1. Similarly, Paradiso et al. (1997) reported deficits in executive function, immediate memory and attention in 22 currently asymptomatic patients with a history of recurrent unipolar depression. When compared to the control group in this study effect sizes hovered around 1. Tham et al. (1997) reported that among a small group of euthymic patients (N ¼ 10) with a history of hospitalization for major depression half of the patients were impaired on tests of reasoning and non-verbal memory. WeilandFiedler et al. (2004) used the CANTAB battery and found pronounced deficits in sustained attention and more subtle impairment on mnemonic and strategic aspects of working memory in 28 euthymic patients with a history of recurrent MDD. On measures of executive function no deficits were observed. The observed effect size for the deficit in sustained attention was 0.86. However, Clark et al (Clark et al., 2005) could not replicate this finding of deficient sustained attention in a small sample (N ¼ 15) of euthymic MDD patients. Smith et al (Smith et al., 2006) found evidence of deficits in verbal learning and attention/executive function in 42 euthymic patients with recurrent MDD with effect sizes ranging from 0.67 in verbal learning to 1 in attention/executive functions. Gualtieri et al. (2006) compared depressed patients off medication and successfully treated MDD patients with healthy controls. While depressed patients differed on measures in the domains of cognitive flexibility, complex attention and vigilance and a general Neurocognition Index, no specific differences were found between treated MDD patients and controls. However, the overall pattern of performance across all tests suggested subtle but persistent neurocognitive impairment in treated MDD patients. In summary, cross-sectional studies find evidence of cognitive impairment in patients who have recovered from a major depressive episode. However, this evidence is based on small studies and thus specific impairments differ somewhat between studies although they most often involve attentional, executive and memory functions. Evidence from longitudinal studies supports the persistence of cognitive impairment in some patients with response/remission of depressive symptomatology. Kuny and Stassen (1995) were among the first to report the persistence of substantial cognitive deficits in up to 50% of patients hospitalized for MDD upon discharge when the majority of patients showed an improvement of their depressive symptoms. Hammar et al. (2003) also observed persistent deficits in effortful tasks in a small cohort of patients with MDD six months after an index episode. Similarly, Neu et al. (2005) reported persistence of deficits in verbal memory and verbal fluency in 27 patients with MDD followed up for six months. More recently, Reppermund et al. (2009) investigated cognitive functioning in 53 inpatients shortly after admission and at discharge (mean interval

339

9 weeks [SD 4.8 Weeks]). In a subset of 20 patients cognitive functioning was assessed 6 months after discharge. Defining impaired cognition as a performance level of 2 standard deviations below the normal mean the authors report that on average approximately a third of patients were impaired upon admission across the various tests. On some tests of executive function and attention the percentage of patients fulfilling the above definition of impairment reached 60% and 51%, respectively. At discharge, when 43 patients met the remission criterion of a HAMD of 9 or less, the average percentage of patients with impairment had fallen to about 22%. However, on selected measures of attention and executive function it was as high as 47% and 57%, respectively. In those 20 subjects who were tested 6 months later about 15e20% of patients still showed significant impairment (6 patients had sustained a relapse). Cognitive impairment at baseline did not predict outcome or response nor was there any difference between patients with first episode and recurrent depression. Although other studies have also observed normalization of cognitive deficits upon remission of MDD (Williams et al., 2000; Biringer et al., 2005; Biringer, 2007), the available evidence clearly demonstrates the presence of cognitive deficits during and, in some patients, after the occurrence of a major depressive episode that are independent of the depressive symptomatology, and thus do not just represent an epiphenomenon of MDD. However, it is poorly understood how cognitive deficits are intertwined with MDD, the patients who do show cognitive deficits are not well characterized nor is the prevalence of cognitive deficits that are independent of MDD symptomatology known. For instance, it is not clear if in some patients cognitive deficits represent trait or vulnerability markers for MDD that precede the occurrence of MDD although a recent meta-analysis of studies of patients in their first episode of MDD clearly demonstrated the presence of trait-like cognitive deficits (Lee et al., 2012). It can be speculated that cognitive deficits may reduce the person’s ability to cope with and adapt successfully to stressful life situations and thus be associated with a higher risk for developing MDD and relapse. However, it remains an open question if persistence of cognitive deficits is indeed associated with a higher relapse risk. 3. Neurocircuitry relevant for cognitive impairment in MDD from imaging and morphological evidence As previously discussed the cognitive domains predominantly impaired in MDD include working memory, executive function, cognitive flexibility and episodic memory. From a neurobiological perspective, the altered cognitive and affective processing of patients suffering from depression has been associated with changes in fronto-cingulate activity (Clark et al., 2009; Pizzagalli, 2011), more generally to aberrant function of prefrontal, orbitofrontal, and ventromedial prefrontal cortices without further possible discrimination (Diener et al., 2012). Frontal and cingulate changes involve multiple sites: the dorso- and ventro-lateral (dlPFC and vlPFC, respectively), dorso- and ventro-medial prefrontal cortex (dmPFC and vmPFC) and dorsal, rostral, and subgenual cingulate cortices (Seminowicz et al., 2004). Healthy subjects normally activate dorso-lateral prefrontal cortex when recruiting executive control functions, such as working memory, forward planning and cognitive flexibility (Clark et al., 2009). In MDD, dlPFC and vlPFC hypoactivity has been reported in depressed patients with impaired performance (Elliott, 1998; Okada et al., 2003), whereas aberrant hyperactivity in dlPFC and anterior cingulate is present in depressed patients with maintained cognitive performance (Harvey et al., 2004; Rose and Ebmeier, 2006; Matsuo et al., 2007; Walsh et al., 2007; Fitzgerald et al., 2008; Schoning et al., 2009). Cingulate hyperactivation during working memory tasks also persisted in

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remitted patients (Schoning et al., 2009) suggesting that dysfunctional cortical processing could persist independently of the manifestation of depressive symptoms. In most cases, hyperactivation has been interpreted as a compensatory mechanism against impaired cortical function, in order to achieve normal task performance (Fitzgerald et al., 2008; Thomas and Elliott, 2009). These results highlight abnormal dlPFC function in depressed patients during cognitive processing. However, the variability in the degree and the direction of the alterations in frontal activity suggests that broader cortico-cortical and cortico-limbic dysfunction also described in MDD likely contributes to impaired cognition. Through disrupted connectivity between the frontal and parietal cortices and the hippocampal formation in MDD (Seminowicz et al., 2004; Cao et al., 2012), altered hippocampal activity likely contributes to poor cognition in MDD patients. Surprisingly only a few dedicated studies have evaluated the role of the hippocampus in learning and memory deficits in MDD (see also the work of Gould et al., 2007; Gorwood et al., 2008; Cornwell et al., 2010; Correa et al., 2012). A strong relationship between hippocampal activation and encoding success is expected in healthy subjects. In MDD patients, failure of hippocampal activation occurs during the encoding phase in non-emotional memory task (Bremner et al., 2004) and during impaired recollection performance in subjects with repeated episodes of MDD (Milne et al., 2012), but not in firstepisode MDD patients (van Eijndhoven et al., 2012). A single dedicated study in MDD patients designed to test memory deficits driven by hippocampal dysfunction found changes in activity specific to the hippocampus, which did not result from overall network deficits or motivational disparities between MDD and control populations (Fairhall et al., 2010). As for the PFC, these studies suggest a link between hippocampal activity and cognitive performance rather than a correlation to general depressive symptomatology. A more comprehensive list of clinical studies reporting cognitive impairment in MDD patients is provided as Supplementary material. 4. Structural and functional synaptic changes, preclinical models and cognitive dysfunction in MDD Anatomo-pathological convergence across morphological and structural deficits in post-mortem studies in MDD show reduced gray matter or volume in dl- and vl-PFC, anterior cingulate (Abe

et al., 2010; Li et al., 2010; Salvadore et al., 2011) and hippocampus (Drevets et al., 2008; Abe et al., 2010) accompanied by cellular abnormalities (Cotter et al., 2002) such as reductions in glial density, neuron size and synaptic numbers (Ongur et al., 1998; Rajkowska et al., 2007; Banasr et al., 2011). The exact contribution of these morphological, cellular and synaptic changes to the functionality of these brain regions is difficult to infer. Functionally, impaired structural and functional synaptic plasticity, a fundamental mechanism underlying neuronal adaptation has been associated with mood disorders (Duman, 2002; Barry and Livingstone, 2006; Schloesser et al., 2008). The overlap between mechanisms of synaptic plasticity at the functional (synaptic strength LTP, LTD) and structural level (synaptic remodeling and connectivity) and those targeted by antidepressants (Bessa et al., 2009a; Vidal et al., 2011) also provide evidence for a mechanistic convergence between plasticity and depression. Indeed, the slow onset of classical antidepressant treatment targeting the monoaminergic system (tricyclics, MAOI and atypical) has been attributed to the necessity of long-term neuroplastic effects (Manji and Duman, 2001; Manji et al., 2003) to exert their therapeutic effects. Although hippocampal synaptic plasticity, modeled by LTP, is widely accepted as mechanistic basis of hippocampal-dependent memory, a direct causal link between reduced plasticity and synaptic abnormalities, and the presence and/or persistence of cognitive deficits remain yet to be studied in MDD patients. The mechanisms underlying impaired cognitive processes in MDD and their dependence on mood pathology can more readily be investigated in preclinical models of depression. In rodents, the repeated social defeat, chronic unpredictable mild stress (CMS) and chronic corticosterone models of depression have been extensively validated for the study of anhedonic and learned helplessness behaviors, modeling the negative mood symptomatology of MDD. Interestingly, these models also recapitulate the deficits in cognitive domains observed in MDD. Indeed, these models induce impairments in working memory evaluated in spontaneous or delayed alternation tasks (Mizoguchi et al., 2000; Song et al., 2006; Henningsen et al., 2009; Palumbo et al., 2010; Andreasen et al., 2011; Yu et al., 2011), cognitive flexibility assessed in attentional set shifting (Lapiz et al., 2007; Bondi et al., 2008, 2010), spatial reversal learning without affecting acquisition (Cerqueira et al., 2005; Hill et al., 2005; Bessa et al., 2009b; Bisaz et al., 2011) and fear extinction (Garcia et al., 2008; Gourley et al., 2009), without

Table 1 Animals models of cognitive impairment in depression. List of studies which have evaluated the co-occurrence and relationship between depressive-like and cognitive symptoms in animal models of depression. CMS: chronic mild stress; CORT: corticosterone; FST: forced swim test, MWM: Morris water maze; Y decrease; [ increase, 4 no change. U and #: Reversal by antidepressant treatment, specified in the table.

Bessa et al. (2009a,b)

Rats CMS

Depressive-like phenotype

Cognitive impairment

Anhedonia

Despair-like

Working memory Learning and memory

Behavioral flexibility

Sucrose

FST

Y-maze or T-maze Spatial in MWM Object and place discrimination Contextual fear learning

Reversal learning in MWM Fear extinction

Y preference U [ immobility U #

Henningsen et al. (2009) Rats CMS Orsetti et al. (2007) Rats CMS

Y preference Y preference U

Li et al. (2008)

Mice CMS

Y intake

Elizalde et al. (2008) Andreasen et al. (2011)

Mice CMS Rats CMS

Y intake U Y intake U #

Gourley et al. (2009)

Rats Chronic Y preference CORT Mice Social Y preference defeat

Yu et al. (2011)

4 spatial learning Y alternation

[ immobility U

[ Y Y Y Y Y

Y reversal learning U # Fluoxetine U Imipramine #

context freezing object discrimination U place discrimination object discrimination place discrimination object discrimination U

Amitriptyline U

Paroxetine U SertalineU Nicotine #

Y alternation # Y fear extinction Y alternation

4 spatial learning [ context freezing

4 reversal learning

C. Goeldner et al. / Neuropharmacology 64 (2013) 337e346

5. Glutamatergic alterations and cognitive impairment in MDD The fronto-limbic circuits described above are locally regulated by GABAergic interneurons, and are interconnected via corticocortical glutamatergic projections. A decrease in GABAergic function (Rajkowska et al., 2007; Karolewicz et al., 2010; Maciag et al., 2010) and imbalanced cortical glutamatergic transmission have been implicated in the pathophysiology of MDD by several groups (Sanacora et al., 2008; Duman and Voleti, 2012) and associated with alterations in glial glutamine/glutamate turnover which are most prominent in cortical regions (e.g. subgenual) but present also in subcortical nuclei. Also fast acting antidepressants like ketamine (Autry et al., 2011; Chowdhury et al., 2012; Duman and Voleti, 2012) are directly targeting pre- and post-synaptic control on glutamate release and effects. Specific alterations in the density of glutamatergic receptors have also been reported in cortical regions of depressed people: in particular AMPA ionotropic receptor and metabotropic glutamate receptor 2 (mGlu2) have been shown to be significantly increased in cortical regions in post-mortem tissue from patients suffering from major depressive disorder (Feyissa et al., 2010; Gibbons et al., 2012) suggesting a composite pattern of

reactive alterations affecting directly glutamate receptor density, and possibly function, in these regions. Particularly relevant for this review is the observation that ketamine and other NMDA receptor antagonists produce fast-acting behavioral antidepressant-like effects in mouse models because they deactivate eukaryotic elongation factor 2 (eEF2) kinase resulting in de-suppression of translation of brain-derived neurotrophic factor. This enzyme directly controls dendritic spine stability and synaptic structure by modulating activity-dependent dendritic BDNF synthesis and therefore plays a key role in the network of molecular events controlled by glutamatergic receptor activation in cognitive processes. Altered glutamatergic function could also be relevant in the context of hippocampal/neurogenesis-related cognitive impairment. Hippocampal deficit in MDD is reported by many authors, but because of its sensitivity to multiple factors like age, co-morbidities (e.g. anxiety), chronic cortisol levels, genetic risk factors e.g. related to BDNF alleles (Gatt et al., 2007; Haeffel et al., 2012) and SSRI treatment, it may not be per se sufficient to describe the specificity of the cognitive impairment observed in MDD. Connectivity reduction in mediotemporal lobe regions in MDD and general damage of fasciculi of fibers connecting the prefrontal cortex with subcortical areas were also reported in MDD, but more research is required to define the direct or indirect role played by the hippocampal network in the cognitive deficits observed in MDD. 6. Metabotropic glutamate receptor 2/3 antagonists have cognitive enhancing properties in rodent behavioral models relevant for cognitive deficits in MDD Morphological, electrophysiological and behavioral studies carried out by our group have associated mGlu2/3 receptors with cognitive processes involving mainly cortico-cortical connections within medial-temporal lobe structures e.g. the perforant path inputs to the dentate gyrus (Higgins et al., 2004; Spinelli et al., 2005). mGlu2 positive glutamatergic connections (perforant path and temporo-ammonic path) seem to be responsible for the

mGlu2/3 NAM increases LTP following theta burst stimulation in dentate gyrus control

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% pretetanic EPSP slope

affecting fear learning processes (or facilitating them e see Sandi et al., 2001; Henningsen et al., 2009; Yu et al., 2011). Learning and memory deficits in spatial learning and object recognition also develop (Orsetti et al., 2007; Elizalde et al., 2008; Li et al., 2008). Morphologically, neuronal loss, dendritic and spine atrophy (Cerqueira et al., 2007b; Dias-Ferreira et al., 2009; Holmes and Wellman, 2009) as well as glial cell pathology (Banasr and Duman, 2008) can be recapitulated. Interestingly, CMS-induced cognitive deficits are associated with impaired neuroplasticity in the PFC and hippocampus, with a decrease in LTP between the hippocampus and mPFC at the functional level (Garcia et al., 2008) and structural changes in dendritic remodeling and synaptic contacts (Cerqueira et al., 2007a). Very few preclinical studies have taken advantage of these models to study co-occurrence of cognitive deficits and depressivelike symptoms and their relationship (Table 1). This is likely due to the difficulty of validating such models, taking in account our incomplete understanding of the etiology of cognitive deficits in depression and of the pathophysiological mechanisms underlying their dependence, as well as the obvious absence of clinical reference compounds for cognitive enhancement in depression. Recent attempts have used this approach to correlate the different dysfunctional behavioral dimensions triggered by CMS procedures. Bessa et al. (2009b) found deficits in cognitive flexibility e but not spatial learning e which significantly correlated with anhedonia and measures of despair, whereas Henningsen et al. (2009) found impairments in working memory which were independent of anhedonia measures. Furthermore, such models appear valuable to study the persistence of cognitive deficits, and their sensitivity to classical antidepressant treatment. Indeed, certain cognitive deficits such as object recognition seem to be ameliorated (Orsetti et al., 2007; Elizalde et al., 2008), whereas others, such as working memory or spatial learning deficits, remain generally insensitive to classical antidepressant treatment (Bessa et al., 2009b; Andreasen et al., 2011). Altogether, this set of data suggests that a potential dissociation between mood-dependent and independent cognitive impairments, as described in patients with MDD, can be recapitulated in the CMS model. Further development and validation will enable the possibility to discover and differentiate novel antidepressant therapies with cognitive enhancing properties (see the effects of nicotine versus sertaline in Andreasen et al., 2011).

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+ RO0711371 300nM

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Picrotoxin 100 µM

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-40

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Tetanus: 8 trains (200 Hz; 40 ms; 200 µs); 0.3 sec train interval

Fig. 1. LTP: mGlu2 negative allosteric modulators are able to increase LTP in rat dentate gyrus. Long-term potentiation studies were carried out in rat hippocampal sections with a stimulating electrode placed in the subiculum and a recording electrode in dentate gyrus. The mGlu2 NAM RO0711371, a compound of the same chemical series as RO4432717 but more soluble in assay buffer, was tested at 300 nM final concentration. The protocol of LTP used in this study has been validated using mGlu2 KO mice (data not shown).

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synchronization of activation across the whole hippocampus and also affect the GABAergic interneurons in CA1 with a powerful feed forward stimulation. The work of Daumas et al. (2009) has dissected the role of mGlu2 receptor activation and reduced glutamate release in CA1/CA3 and DG hippocampal regions, confirming the prominent impact of the projecting perforant path on contextual memory formation. mGlu2 receptors are also densely expressed in prefrontal cortex and other cortical regions (Frank et al., 2011; Kawasaki et al., 2011) where their function is most likely mainly presynaptic. The pharmacological blockade of mGlu2 with an antagonist, either competitively or non-competitively i.e. by a negative allosteric modulator (NAM), has been characterized as reversal of the reduction in glutamate release induced by mGlu2/3 agonists like LY354740, but an effect in synaptic function can be also studied using LTP protocols as shown in Fig. 1 where an mGlu2/ 3 NAM mediated an increase in LTP in dentate gyrus in

A Working memory ###

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**

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% correct

B Response inhibition & cognitive flexibility 35

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hippocampal slices (see Supplementary material for methods). Consistent with these findings selective mGlu2/3 NAM are effective in cognitive studies using the operant conditioning delayed match to position (DMTP) task (Woltering et al., 2010). Preclinical evidence suggests that mGlu2/3 receptor antagonists induce neurochemical changes indicative of antidepressant activity like increase in firing rate of raphe neurons, increased neurogenesis in hippocampus and increased serotonin release in prefrontal cortex (Pilc et al., 2008; Chaki et al., 2012). Potent mGlu2/3 antagonists which have been evaluated in rodent tests that are indicative of antidepressant activities, include MSG0039 (Chaki et al., 2004), LY341495 (Kingston et al., 1998), as well as RO4491533 (Woltering et al., 2010; Campo et al., 2011). RO4491533 is a negative allosteric modulator at mGlu2/3 receptors structurally and pharmacologically similar to RO4432717 which is described in the present study (see also Supplementary text for materials and methods). Several groups

***

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#

15 10 5

Perseverative responses

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+V

C Reversal learning

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V 1 3 10 Dose (mg/kg p.o.)

V 1 3 10 Dose (mg/kg p.o.)

Fig. 2. Assessment of RO4432717 on working memory (A), response inhibition and cognitive flexibility (B), reversal learning (C) and long-term recognition memory (D). (A). RO4432717 at 10 mg/kg p.o., 24 h prior to testing ( ), significantly reversed LY354740 ( ; 6 mg/kg i.p.) induced working memory deficit in the DMTP task indicating a long duration of activity. Data are expressed as mean  SEM percent correct responses at each delay interval: n ¼ 12 male Lister hooded rats pre-trained to the task. Statistics: **p < 0.01, ***p < 0.001 vs vehicle-treated group (B); ##p < 0.01, ###p < 0.001 vs LY354740-treated group ( ). (B). RO4432717 (1, 3 and 10 mg/kg p.o. 3 h prior to testing) significantly reversed LY354740 (6 mg/kg i.p.) induced increase in the number of premature and perseverative responses, without affecting percent correct responses (Table 2 supplementary information) in the 5-CSRT task. Data are expressed as mean  SEM: n ¼ 15 male Lister hooded rats pre-trained to the task. Statistics: **p < 0.01 vs. vehicle-treated group; #p < 0.05 vs. LY354740-treated group. (C). RO4432717 (3 and 10 mg/kg p.o. 3 h prior to testing) significantly reversed LY354740 (6 mg/kg i.p.) induced reversal learning impairment in the water maze. Data are presented as mean  SEM: n ¼ 10 male Lister hooded rats per dose group. Percent time spent in left (,), platform ( ), right ( ) and opposite ( ) quadrants during the probe trial. Statistics: **p < 0.01 vs. vehicle-treated group; ##p < 0.01 vs. LY354740-treated group. (D). RO4432717 at 10 mg/kg p.o. 3 h prior to trial 1 tended to reverse the delay-induced memory impairment in the object recognition test as shown by significantly increased time to explore the novel (,) compared to the familiar ( ) object during trial 2. However the discrimination index ((time exploring novel e familiar object)/(total time exploring novel þ familiar objects)) vs. vehicle-treated group did not reach significance (p ¼ 0.07). Data are expressed as mean  SEM: n ¼ 14e15 male SpragueeDawley rats per dose group. Statistics: ***p < 0.001 vs. vehicle.

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have shown that these compounds are active in rat and mouse forced swim and mouse tail suspension tests (Chaki et al., 2004; Bespalov et al., 2008; Campo et al., 2011) as well as in the marble burying test in mice (Shimazaki et al., 2004; Bespalov et al., 2008). MGS0039 antidepressant properties have also been assessed in other models of depression, such as the olfactory bulbectomy and isolation rearing models (Palucha-Poniewiera et al., 2010; Kawasaki et al., 2011). The antidepressant activity of MGS0039 was shown to be dependent on AMPA receptor activation (Palucha-Poniewiera et al., 2010). Furthermore, both MGS0039 and LY341495 showed sustained effects on mouse tail suspension test when administered 24 h prior to testing and this was blocked by pretreatment with rapamycin, an mTOR inhibitor, indicating that the antidepressantlike activity of mGlu2/3 antagonists involve activation of mTORmediated signaling pathways (Koike et al., 2011). Interestingly, it has also been shown that MGS0039 enhanced social recognition memory in rats, which was dependent on AMPA receptor activation (Shimazaki et al., 2007) and attenuated the learning deficit in a passive avoidance test induced in rats by olfactory bulbectomy (Palucha-Poniewiera et al., 2010). It has also been shown that LY341495 exhibits mild arousal enhancing effects in rats (Feinberg et al., 2005). Subsequently, it has been proposed that mGlu2/3 receptor antagonists may have an antidepressant profile with wakepromoting and cognition enhancing effects (Witkin and Eiler, 2006). Therefore it is particularly interesting to explore the effects of RO4432717 within cognitive domains which are impaired in MDD, such as working memory, executive function/cognitive flexibility and episodic-like memory (reviewed above). RO4432717 completely blocks the delay-dependent working memory deficit induced by LY354740 in the DMTP task with a long duration of activity, as shown by the significant full reversal following an oral dose of 10 mg/kg administered 24 h prior to testing (Fig. 2A). The in vivo activity is closely associated with plasma exposure at these time points. The compound administered alone did not affect working memory in well-trained animals in this task (Supplementary information: Table 1). Moreover, there was no effect of RO4432717 on measures of motivation and/or motor performance in the DMTP task (Supplementary information: Table 1). When tested in the 5-CSRT task, RO4432717 significantly improved the ability of rats to reduce both impulsive and perseverative responses induced by an mGlu2/3 agonist (Fig. 2B), indicating effects on response inhibition and cognitive flexibility. In a reversal learning paradigm in the water maze, RO4432717 significantly reversed an mGlu2/3 agonist-induced deficit (Fig. 2C). Finally, RO4432717 showed an effect on long-term recognition memory in an object recognition test following a long inter-trial interval (Fig. 2D). Altogether the current dataset provides evidence that treatment with an mGlu2/3 NAM improves cognitive processes dependent upon the effective functioning of cortico-cortical and/or hippocampal regions. As discussed earlier, these are brain regions which are thought to be relevant for cognitive impairment in MDD based on imaging and morphological studies. These findings extend the previous dataset on cognition with mGlu2/3 NAM, and suggest that mGlu2/3 NAM provide a novel mechanism of action with both pro-cognitive and antidepressant properties. Furthermore, the effect of this mechanism in preclinical models assessing impairment in cognitive domains relevant to depression should be evaluated. These models are currently at an early stage of pharmacological validation (see Table 1) and so further work is required to develop these models prior to testing potential drug therapies. 7. Concluding remarks In this review we have summarized the evidence demonstrating objectively measurable cognitive deficits, involving attention,

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working memory, executive function, cognitive flexibility and episodic memory in MDD patients. The available studies strongly suggest that in some patients with MDD cognitive deficits are independent and dissociable from depressive symptomatology and may require additional therapeutic interventions. The glutamatergic hypothesis of MDD provides a potential framework for the introduction of promising new therapeutic targets possibly relevant for this type of intervention. It should be able to provide a real alternative to the current monoaminergic standard of care, which has limited impact on the cognitive deficits of MDD. This review of novel glutamatergic targets has focused on mGlu2/3 negative allosteric modulators. They exert both antidepressant and cognitive enhancing properties in different behavioral paradigms that depend on cortico-cortical as well as hippocampal activity, regions shown to be affected in imaging studies of cognitively impaired MDD patients. Preclinical animal models like chronic mild stress seem to be extremely relevant for the evaluation of the cognitive enhancing abilities of new antidepressants targeting the glutamatergic system in cortical regions and will be further explored for mGlu2/3 negative allosteric modulators. Finally, the assessment of this mechanism of action in a subset of cognitively impaired MDD patients would be extremely important to understand whether the glutamatergic hypothesis of MDD can also be extended to the treatment of cognitive dysfunction in this disorder. The ongoing clinical trial testing the antidepressant properties of a mGlu2 NAM in patients with MDD (NCT01457677) is including cognition measures relevant to provide a better definition of non-emotional cognitive deficits in MDD and to answer the question whether? this mechanism of action indeed improves cognitive impairment associated with this disorder. Acknowledgments The authors would like to thank Marie Haman, Roger Wyler and Marie Claire Pflimlin for the technical support, Linda Hedley for the novel object recognition work, Dr. Thomas Woltering, Nicole Grossmann, and Philippe Oberli for the synthesis of the compounds, and J. Huwyler and Monique Schmitt for the pharmacokinetic measurements of RO4432717 in rats in vivo. The authors are also grateful to Will Spooren for reviewing the manuscript and for helpful discussions of earlier versions of the manuscript. Appendix A. Supplementary material Supplementary material related to this article can be found at http://dx.doi.org/10.1016/j.neuropharm.2012.08.001. References Abe, O., Yamasue, H., Kasai, K., Yamada, H., Aoki, S., Inoue, H., Takei, K., Suga, M., Matsuo, K., Kato, T., Masutani, Y., Ohtomo, K., 2010. Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression. Psychiatry Res. 181, 64e70. Airaksinen, E., Wahlin, A., Forsell, Y., Larsson, M., 2007. Low episodic memory performance as a premorbid marker of depression: evidence from a 3-year follow-up. Acta Psychiatr. Scand. 115, 458e465. Andreasen, J.T., Henningsen, K., Bate, S., Christiansen, S., Wiborg, O., 2011. Nicotine reverses anhedonic-like response and cognitive impairment in the rat chronic mild stress model of depression: comparison with sertraline. J. Psychopharmacol. 25, 1134e1141. Austin, M.P., Mitchell, P., Goodwin, G.M., 2001. Cognitive deficits in depression: possible implications for functional neuropathology. Br. J. Psychiatry 178, 200e206. Autry, A.E., Adachi, M., Nosyreva, E., Na, E.S., Los, M.F., Cheng, P.F., Kavalali, E.T., Monteggia, L.M., 2011. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91e95. Banasr, M., Duman, R.S., 2008. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol. Psychiatry 64, 863e870.

344

C. Goeldner et al. / Neuropharmacology 64 (2013) 337e346

Banasr, M., Dwyer, J.M., Duman, R.S., 2011. Cell atrophy and loss in depression: reversal by antidepressant treatment. Curr. Opin. Cell. Biol. 23, 730e737. Barry, D., Livingstone, V., 2006. The investigation and correction of recall bias for an ordinal response in a case-control study. Stat. Med. 25, 965e975. Baune, B.T., Miller, R., McAfoose, J., Johnson, M., Quirk, F., Mitchell, D., 2010. The role of cognitive impairment in general functioning in major depression. Psychiatry Res. 176, 183e189. Behnken, A., Schoning, S., Gerss, J., Konrad, C., de Jong-Meyer, R., Zwanzger, P., Arolt, V., 2010. Persistent non-verbal memory impairment in remitted major depression e caused by encoding deficits? J. Affect. Disord. 122, 144e148. Bespalov, A.Y., van Gaalen, M.M., Sukhotina, I.A., Wicke, K., Mezler, M., Schoemaker, H., Gross, G., 2008. Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression. Eur. J. Pharmacol. 592, 96e102. Bessa, J.M., Ferreira, D., Melo, I., Marques, F., Cerqueira, J.J., Palha, J.A., Almeida, O.F.X., Sousa, N., 2009a. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol. Psychiatry 14, 764e773. Bessa, J.M., Mesquita, A.R., Oliveira, M., Pego, J.M., Cerqueira, J.J., Palha, J.A., Almeida, O.F.X., Sousa, N., 2009b. A trans-dimensional approach to the behavioral aspects of depression. Front. Behav. Neurosci. 3 Biringer, E., 2005. Functional impairment recovers after episodes of major depression. Evid. Based Ment. Health 8, 65. Biringer, E., 2007. Neurocognitive function in depression, during remission and beyond. In: Briscoe, W.P. (Ed.), Focus on Cognitive Disorder Research. Nova Science Publishers, Inc., New York, pp. 117e153. Biringer, E., Lundervold, A., Stordal, K., Mykletun, A., Egeland, J., Bottlender, R., Lund, A., 2005. Executive function improvement upon remission of recurrent unipolar depression. Eur. Arch. Psychiatry Clin. Neurosci. 255, 373e380. Bisaz, R., Schachner, M., Sandi, C., 2011. Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress-induced cognitive impairments. Hippocampus 21, 56e71. Bondi, C.O., Jett, J.D., Morilak, D.A., 2010. Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1adrenergic receptors in medial prefrontal cortex. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 913e923. Bondi, C.O., Rodriguez, G., Gould, G.G., Frazer, A., Morilak, D.A., 2008. Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology 33, 320e331. Bremner, J.D., Vythilingam, M., Vermetten, E., Vaccarino, V., Charney, D.S., 2004. Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression. Am. J. Psychiatry 161, 637e645. Campo, B., Kalinichev, M., Lambeng, N., El Yacoubi, M., Royer-Urios, I., Schneider, M., Legrand, C., Parron, D., Girard, F., Bessif, A., Poli, S., Vaugeois, J.M., Le Poul, E., Celanire, S., 2011. Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J. Neurogenet. 25, 152e166. Cao, X., Liu, Z., Xu, C., Li, J., Gao, Q., Sun, N., Xu, Y., Ren, Y., Yang, C., Zhang, K., 2012. Disrupted resting-state functional connectivity of the hippocampus in medication-naive patients with major depressive disorder. J. Affect. Disord. Castaneda, A.E., Tuulio-Henriksson, A., Marttunen, M., Suvisaari, J., Lonnqvist, J., 2008. A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. J. Affect. Disord. 106, 1e27. Cerqueira, J.J., Mailliet, F., Almeida, O.F., Jay, T.M., Sousa, N., 2007a. The prefrontal cortex as a key target of the maladaptive response to stress. J. Neurosci. 27, 2781e2787. Cerqueira, J.J., Pego, J.M., Taipa, R., Bessa, J.M., Almeida, O.F.X., Sousa, N., 2005. Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J. Neurosci. 25, 7792e7800. Cerqueira, J.J., Taipa, R., Uylings, H.B.M., Almeida, O.F.X., Sousa, N., 2007b. Specific configuration of dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by differing corticosteroid regimens. Cereb. Cortex 17, 1998e2006. Chaki, S., Ago, Y., Palucha-Paniewiera, A., Matrisciano, F., Pilc, A., 2012. mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology. Chaki, S., Yoshikawa, R., Hirota, S., Shimazaki, T., Maeda, M., Kawashima, N., Yoshimizu, T., Yasuhara, A., Sakagami, K., Okuyama, S., Nakanishi, S., Nakazato, A., 2004. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology 46, 457e467. Chowdhury, G.M.I., Behar, K.L., Cho, W., Thomas, M.A., Rothman, D.L., Sanacora, G., 2012. H-1-[C-13]-Nuclear magnetic resonance spectroscopy measures of Ketamine’s effect on amino acid neurotransmitter metabolism. Biol. Psychiatry 71, 1022e1025. Clark, L., Chamberlain, S.R., Sahakian, B.J., 2009. Neurocognitive mechanisms in depression: implications for treatment. Annu. Rev. Neurosci. 32, 57e74. Clark, L., Kempton, M.J., Scarna, A., Grasby, P.M., Goodwin, G.M., 2005. Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression. Biol. Psychiatry 57, 183e187. Cornwell, B.R., Salvadore, G., Colon-Rosario, V., Latov, D.R., Holroyd, T., Carver, F.W., Coppola, R., Manji, H.K., Zarate Jr., C.A., Grillon, C., 2010. Abnormal hippocampal functioning and impaired spatial navigation in depressed individuals: evidence from whole-head magnetoencephalography. Am. J. Psychiatry 167, 836e844.

Correa, M.S., Balardin, J.B., Caldieraro, M.A., Fleck, M.P., Argimon, I., Luz, C., Bromberg, E., 2012. Contextual recognition memory deficits in major depression are suppressed by cognitive support at encoding. Biol. Psychol. 89, 293e299. Cotter, D.R., Mackay, D., Beasley, C.L., Everall, I.P., Landau, S., 2002. The density, size and spatial pattern distribution of neurons and glia in area 9 prefrontal cortex in schizophrenia, bipolar disorder and major depression. Schizophr. Res. 53, 107e108. Daumas, S., Ceccom, J., Halley, H., Frances, B., Lassalle, J.M., 2009. Activation of metabotropic glutamate receptor type 2/3 supports the involvement of the hippocampal mossy fiber pathway on contextual fear memory consolidation. Learn. Mem. 16, 504e507. Dias-Ferreira, E., Sousa, J.C., Melo, I., Morgado, P., Mesquita, A.R., Cerqueira, J.J., Costa, R.M., Sousa, N., 2009. Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325, 621e625. Diener, C., Kuehner, C., Brusniak, W., Ubl, B., Wessa, M., Flor, H., 2012. A metaanalysis of neurofunctional imaging studies of emotion and cognition in major depression. Neuroimage 61, 677e685. Douglas, K.M., Porter, R.J., Knight, R.G., Maruff, P., 2011. Neuropsychological changes and treatment response in severe depression. Br. J. Psychiatry 198, 115e122. Drevets, W.C., Price, J.L., Furey, M.L., 2008. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct. Funct. 213, 93e118. Duman, R.S., 2002. Pathophysiology of depression: the concept of synaptic plasticity. Eur. Psychiatry 17 (Suppl. 3), 306e310. Duman, R.S., Voleti, B., 2012. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 35, 47e56. Dunkin, J.J., Leuchter, A.F., Cook, I.A., Kasl-Godley, J.E., Abrams, M., RosenbergThompson, S., 2000. Executive dysfunction predicts nonresponse to fluoxetine in major depression. J. Affect. Disord. 60, 13e23. Elizalde, N., Gil-Bea, F.J., Ramirez, M.J., Aisa, B., Lasheras, B., Del Rio, J., Tordera, R.M., 2008. Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment. Psychopharmacology (Berl.) 199, 1e14. Elliott, R., 1998. The neuropsychological profile in unipolar depression. Trends Cogn. Sci. 2, 447e454. Everaert, J., Koster, E.H., Derakshan, N., 2012. The combined cognitive bias hypothesis in depression. Clin. Psychol. Rev. 32, 413e424. Fairhall, S.L., Sharma, S., Magnusson, J., Murphy, B., 2010. Memory related dysregulation of hippocampal function in major depressive disorder. Biol. Psychol. 85, 499e503. Feinberg, I., Schoepp, D.D., Hsieh, K.C., Darchia, N., Campbell, I.G., 2005. The metabotropic glutamate (mGLU)2/3 receptor antagonist LY341495 [2S-2amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid] stimulates waking and fast electroencephalogram power and blocks the effects of the mGLU2/3 receptor agonist ly379268 [(-)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylate] in rats. J. Pharmacol. Exp. Ther. 312, 826e833. Feyissa, A.M., Woolverton, W.L., Miguel-Hidalgo, J.J., Wang, Z.X., Kyle, P.B., Hasler, G., Stockmeier, C.A., Iyo, A.H., Karolewicz, B., 2010. Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 34, 279e283. Fitzgerald, P.B., Laird, A.R., Maller, J., Daskalakis, Z.J., 2008. A meta-analytic study of changes in brain activation in depression. Hum. Brain Mapp. 29, 683e695. Frank, E., Newell, K.A., Huang, X.F., 2011. Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age. Schizophr. Res. 128, 56e60. Garcia, R., Spennato, G., Nilsson-Todd, L., Moreau, J.L., Deschaux, O., 2008. Hippocampal low-frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats. Neurobiol. Learn. Mem. 89, 560e566. Gatt, J.M., Clark, C.R., Kemp, A.H., Liddell, B.J., Dobson-Stone, C., Kuan, S.A., Schofield, P.R., Williams, L.M., 2007. A genotypeeendophenotypeephenotype path model of depressed mood: integrating cognitive and emotional markers. J. Integr. Neurosci. 6, 75e104. Gibbons, A.S., Brooks, L., Scarr, E., Dean, B., 2012. AMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder. J. Affect. Disord. 136, 1232e1237. Gorlyn, M., Keilp, J.G., Grunebaum, M.F., Taylor, B.P., Oquendo, M.A., Bruder, G.E., Stewart, J.W., Zalsman, G., Mann, J.J., 2008. Neuropsychological characteristics as predictors of SSRI treatment response in depressed subjects. J. Neural Transm. 115, 1213e1219. Gorwood, P., Corruble, E., Falissard, B., Goodwin, G.M., 2008. 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 165, 731e739. Gould, N.F., Holmes, M.K., Fantie, B.D., Luckenbaugh, D.A., Pine, D.S., Gould, T.D., Burgess, N., Manji, H.K., Zarate Jr., C.A., 2007. Performance on a virtual reality spatial memory navigation task in depressed patients. Am. J. Psychiatry 164, 516e519. Gourley, S.L., Kedves, A.T., Olausson, P., Taylor, J.R., 2009. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology 34, 707e716. Gualtieri, C.T., Johnson, L.G., Benedict, K.B., 2006. Neurocognition in depression: patients on and off medication versus healthy comparison subjects. J. Neuropsychiatry Clin. Neurosci. 18, 217e225.

C. Goeldner et al. / Neuropharmacology 64 (2013) 337e346 Gudayol-Ferre, E., Herrera-Guzman, I., Camarena, B., Cortes-Penagos, C., HerreraAbarca, J.E., Martinez-Medina, P., Cruz, D., Hernandez, S., Genis, A., CarrilloGuerrero, M.Y., Aviles Reyes, R., Guardia-Olmos, J., 2010. The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder. J. Affect. Disord. 127, 343e351. Haeffel, G.J., Eastman, M., Grigorenko, E.L., 2012. Using a cognitive endophenotype to identify risk genes for depression. Neurosci. Lett. 510, 10e13. Hammar, s, Lund, A., Hugdahl, K., 2003. Long-lasting cognitive impairment in unipolar major depression: a 6-month follow-up study. Psychiatry Res. 118, 189e196. Harvey, P.O., Le Bastard, G., Pochon, J.B., Levy, R., Allilaire, J.F., Dubois, B., Fossati, P., 2004. Executive functions and updating of the contents of working memory in unipolar depression. J. Psychiatr. Res. 38, 567e576. Hasselbalch, B.J., Knorr, U., Kessing, L.V., 2011. Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J. Affect. Disord. 134, 20e31. Henningsen, K., Andreasen, J.T., Bouzinova, E.V., Jayatissa, M.N., Jensen, M.S., Redrobe, J.P., Wiborg, O., 2009. Cognitive deficits in the rat chronic mild stress model for depression: relation to anhedonic-like responses. Behav. Brain Res. 198, 136e141. Herrera-Guzman, I., Gudayol-Ferre, E., Herrera-Guzman, D., Guardia-Olmos, J., Hinojosa-Calvo, E., Herrera-Abarca, J.E., 2009. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J. Psychiatr. Res. 43, 855e863. Herrera-Guzman, I., Gudayol-Ferre, E., Lira-Mandujano, J., Herrera-Abarca, J., Herrera-Guzman, D., Montoya-Perez, K., Guardia-Olmos, J., 2008. Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res. 160, 72e82. Higgins, G.A., Ballard, T.M., Kew, J.N.C., Richards, J.G., Kemp, J.A., Adam, G., Woltering, T., Nakanishi, S., Mutel, V., 2004. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology 46, 907e917. Hill, M.N., Patel, S., Carrier, E.J., Rademacher, D.J., Ormerod, B.K., Hillard, C.J., Gorzalka, B.B., 2005. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology 30, 508e515. Holmes, A., Wellman, C.L., 2009. Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci. Biobehavioral Rev. 33, 773e783. Iverson, G.L., Brooks, B.L., Langenecker, S.A., Young, A.H., 2011. Identifying a cognitive impairment subgroup in adults with mood disorders. J. Affect. Disord. 132, 360e367. Karolewicz, B., Maciag, D., O’Dwyer, G., Stockmeier, C.A., Feyissa, A.M., Rajkowska, G., 2010. Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int. J. Neuropsychopharmacol. 13, 411e420. Kawasaki, T., Ago, Y., Yano, K., Araki, R., Washida, Y., Onoe, H., Chaki, S., Nakazato, A., Hashimoto, H., Baba, A., Takuma, K., Matsuda, T., 2011. Increased binding of cortical and hippocampal group II metabotropic glutamate receptors in isolation-reared mice. Neuropharmacology 60, 397e404. Kingston, A.E., Ornstein, P.L., Wright, R.A., Johnson, B.G., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., Schoepp, D.D., 1998. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37, 1e12. Koike, H., Iijima, M., Chaki, S., 2011. Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists. Neuropharmacology 61, 1419e1423. Kuny, S., Stassen, H.H., 1995. Cognitive performance in patients recovering from depression. Psychopathology 28, 190e207. Lapiz, M.D.S., Bondi, C.O., Morilak, D.A., 2007. Chronic treatment with desipramine improves cognitive performance of rats in an attentional set-shifting test. Neuropsychopharmacology 32, 1000e1010. Lee, R.S., Hermens, D.F., Porter, M.A., Redoblado-Hodge, M.A., 2012. A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder. J. Affect. Disord. 140, 113e124. Li, C.T., Lin, C.P., Chou, K.H., Chen, I.Y., Hsieh, J.C., Wu, C.L., Lin, W.C., Su, T.P., 2010. Structural and cognitive deficits in remitting and non-remitting recurrent depression: a voxel-based morphometric study. Neuroimage 50, 347e356. Li, S., Wang, C., Wang, W., Dong, H., Hou, P., Tang, Y., 2008. Chronic mild stress impairs cognition in mice: from brain homeostasis to behavior. Life Sci. 82, 934e942. Maciag, D., Hughes, J., O’Dwyer, G., Pride, Y., Stockmeier, C.A., Sanacora, G., Rajkowska, G., 2010. Reduced density of Calbindin immunoreactive GABAergic neurons in the Occipital cortex in major depression: relevance to neuroimaging studies. Biol. Psychiatry 67, 465e470. Manji, H.K., Duman, R.S., 2001. Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol. Bull. 35, 5e49. Manji, H.K., Quiroz, J.A., Sporn, J., Payne, J.L., Denicoff, K., Gray, N.A., Zarate, C.A., Charney, D.S., 2003. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol. Psychiatry 53, 707e742.

345

Marcos, T., Salamero, M., Gutierrez, F., Catalan, R., Gasto, C., Lazaro, L., 1994. Cognitive dysfunctions in recovered melancholic patients. J. Affect. Disord. 32, 133e137. Matsuo, K., Glahn, D.C., Peluso, M.A., Hatch, J.P., Monkul, E.S., Najt, P., Sanches, M., Zamarripa, F., Li, J., Lancaster, J.L., Fox, P.T., Gao, J.H., Soares, J.C., 2007. Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder. Mol. Psychiatry 12, 158e166. McClintock, S.M., Husain, M.M., Greer, T.L., Cullum, C.M., 2010. Association between depression severity and neurocognitive function in major depressive disorder: a review and synthesis. Neuropsychology 24, 9e34. McDermott, L.M., Ebmeier, K.P., 2009. A meta-analysis of depression severity and cognitive function. J. Affect. Disord. 119, 1e8. Milne, A.M.B., MacQueen, G.M., Hall, G.B.C., 2012. Abnormal hippocampal activation in patients with extensive history of major depression: an fMRI study. J. Psychiatry Neurosci. 37, 28e36. Mizoguchi, K., Yuzurihara, M., Ishige, A., Sasaki, H., Chui, D.H., Tabira, T., 2000. Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J. Neurosci. 20, 1568e1574. Mowla, A., Ashkani, H., Ghanizadeh, A., Dehbozorgi, G.R., Sabayan, B., Chohedri, A.H., 2008. Do memory complaints represent impaired memory performance in patients with major depressive disorder? Depress. Anxiety 25, E92eE96. Naismith, S.L., Hickie, I.B., Turner, K., Little, C.L., Winter, V., Ward, P.B., Wilhelm, K., Mitchell, P., Parker, G., 2003. Neuropsychological performance in patients with depression is associated with clinical, etiological and genetic risk factors. J. Clin. Exp. Neuropsychol. 25, 866e877. Naismith, S.L., Longley, W.A., Scott, E.M., Hickie, I.B., 2007. Disability in major depression related to self-rated and objectively-measured cognitive deficits: a preliminary study. BMC Psychiatry 7, 32. Neu, P., Bajbouj, M., Schilling, A., Godemann, F., Berman, R.M., Schlattmann, P., 2005. Cognitive function over the treatment course of depression in middle-aged patients: correlation with brain MRI signal hyperintensities. J. Psychiatr. Res. 39, 129e135. Okada, G., Okamoto, Y., Morinobu, S., Yamawaki, S., Yokota, N., 2003. Attenuated left prefrontal activation during a verbal fluency task in patients with depression. Neuropsychobiology 47, 21e26. Ongur, D., Drevets, W.C., Price, J.L., 1998. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl. Acad. Sci. U. S. A. 95, 13290e13295. Orsetti, M., Colella, L., Dellarole, A., Canonico, P.L., Ghi, P., 2007. Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats. Int. J. Neuropsychopharmacol. 10, 345e357. Palucha-Poniewiera, A., Wieronska, J.M., Branski, P., Stachowicz, K., Chaki, S., Pilc, A., 2010. On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039. Psychopharmacology 212, 523e535. Palumbo, M.L., Canzobre, M.C., Pascuan, C.G., Rios, H., Wald, M., Genaro, A.M., 2010. Stress induced cognitive deficit is differentially modulated in BALB/c and C57Bl/6 mice Correlation with Th1/Th2 balance after stress exposure. J. Neuroimmunol. 218, 12e20. Paradiso, S., Lamberty, G.J., Garvey, M.J., Robinson, R.G., 1997. Cognitive impairment in the euthymic phase of chronic unipolar depression. J. Nerv. Ment. Dis. 185, 748e754. Pilc, A., Chaki, S., Nowak, G., Witkin, J.M., 2008. Mood disorders: regulation by metabotropic glutamate receptors. Biochem. Pharmacol. 75, 997e1006. Pizzagalli, D.A., 2011. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 36, 183e206. Rajkowska, G., O’Dwyer, G., Teleki, Z., Stockmeier, C.A., Miguel-Hidalgo, J.J., 2007. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 32, 471e482. Reppermund, S., Ising, M., Lucae, S., Zihl, J., 2009. Cognitive impairment in unipolar depression is persistent and non-specific: further evidence for the final common pathway disorder hypothesis. Psychol. Med. 39, 603e614. Rohling, M.L., Green, P., Allen 3rd, L.M., Iverson, G.L., 2002. Depressive symptoms and neurocognitive test scores in patients passing symptom validity tests. Arch. Clin. Neuropsychol. 17, 205e222. Roiser, J.P., Rubinsztein, J.S., Sahakian, B.J., 2009a. Neuropsychology of affective disorders. Psychiatry 8, 91e96. Roiser, J.P., Cannon, D.M., Gandhi, S.K., Taylor Tavares, J., Erickson, K., Wood, S., Klaver, J.M., Clark, L., Zarate Jr, C.A., Sahakian, B.J., Drevets, W.C., 2009b. Hot and cold cognition in unmedicated depressed subjects with bipolar disorder. Bipolar Disord. 11, 178e189. Roiser, J.P., Elliott, R., Sahakian, B.J., 2011. Cognitive mechanisms of treatment in depression. Neuropsychopharmacology Rev. 37, 117e136. Rose, E.J., Ebmeier, K.P., 2006. Pattern of impaired working memory during major depression. J. Affect. Disord. 90, 149e161. Salvadore, G., Nugent, A.C., Lemaitre, H., Luckenbaugh, D.A., Tinsley, R., Cannon, D.M., Neumeister, A., Zarate, C.A., Drevets, W.C., 2011. Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder. Neuroimage 54, 2643e2651. Sanacora, G., Zarate, C.A., Krystal, J.H., Manji, H.K., 2008. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 7, 426e437. Sandi, C., Merino, J.J., Cordero, M.I., Touyarot, K., Venero, C., 2001. Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the

346

C. Goeldner et al. / Neuropharmacology 64 (2013) 337e346

neural cell adhesion molecule, its polysialylation, and L1. Neuroscience 102, 329e339. Schloesser, R.J., Huang, J., Klein, P.S., Manji, H.K., 2008. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33, 110e133. Schoning, S., Zwitserlood, P., Engelien, A., Behnken, A., Kugel, H., Schiffbauer, H., Lipina, K., Pachur, C., Kersting, A., Dannlowski, U., Baune, B.T., Zwanzger, P., Reker, T., Heindel, W., Arolt, V., Konrad, C., 2009. Working-memory fMRI reveals cingulate hyperactivation in euthymic major depression. Hum. Brain Mapp. 30, 2746e2756. Seminowicz, D.A., Mayberg, H.S., McIntosh, A.R., Goldapple, K., Kennedy, S., Segal, Z., Rafi-Tari, S., 2004. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 22, 409e418. Shimazaki, T., Hirota-Okuno, S., Iijima, M., Yoshimizu, T., Chaki, S., 2004. Antidepressant and anti-OCD-like activity of MGS0039, a potent and selective group II metabotropic glutamate receptor antagonist. Behav. Pharmacol. 15, A26. Shimazaki, T., Kaku, A., Chaki, S., 2007. Blockade of the metabotropic glutamate 2/3 receptors enhances social memory via the AMPA receptor in rats. Eur. J. Pharmacol. 575, 94e97. Smith, D.J., Muir, W.J., Blackwood, D.H., 2006. Neurocognitive impairment in euthymic young adults with bipolar spectrum disorder and recurrent major depressive disorder. Bipolar Disord. 8, 40e46. Song, L., Che, W., Min-Wei, W., Murakami, Y., Matsumoto, K., 2006. Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacol. Biochem. Behav. 83, 186e193. Spinelli, S., Ballard, T., Gatti-McArthur, S., Richards, G.J., Kapps, M., Woltering, T., Wichmann, J., Stadler, H., Feldon, J., Pryce, C.R., 2005. Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys. Psychopharmacology 179, 292e302. Spronk, D., Arns, M., Barnett, K.J., Cooper, N.J., Gordon, E., 2011. An investigation of EEG, genetic and cognitive markers of treatment response to antidepressant medication in patients with major depressive disorder: a pilot study. J. Affect. Disord. 128, 41e48. Tham, A., Engelbrektson, K., Mathe, A.A., Johnson, L., Olsson, E., Aberg-Wistedt, A., 1997. Impaired neuropsychological performance in euthymic patients with recurring mood disorders. J. Clinical Psychiatry 58, 26e29.

Thomas, E.J., Elliott, R., 2009. Brain imaging correlates of cognitive impairment in depression. Front. Hum. Neurosci. 3, 30. van Eijndhoven, P., van Wingen, G., Fernandez, G., Rijpkema, M., PopPurceleanu, M., Verkes, R.J., Buitelaar, J., Tendolkar, I., 2012. Neural basis of recollection in first-episode major depression. Hum. Brain Mapp. Vidal, R., Pilar-Cuellar, F., dos Anjos, S., Linge, R., Treceno, B., Vargas, V.I., RodriguezGaztelumendi, A., Mostany, R., Castro, E., Diaz, A., Valdizan, E.M., Pazos, A., 2011. New strategies in the development of antidepressants: towards the modulation of neuroplasticity pathways. Curr. Pharm. Des. 17, 521e533. Wagner, S., Doering, B., Helmreich, I., Lieb, K., Tadic, A., 2012. A meta-analysis of executive dysfunctions in unipolar major depressive disorder without psychotic symptoms and their changes during antidepressant treatment. Acta Psychiatr. Scand. 125, 281e292. Walsh, N.D., Williams, S.C.R., Brammer, M.J., Bullmore, E.T., Kim, J., Suckling, J., Mitterschiffthaler, M.T., Cleare, A.J., Pich, E.M., Mehta, M.A., Fu, C.H.Y., 2007. A longitudinal functional magnetic resonance imaging study of verbal working memory in depression after antidepressant therapy. Biol. Psychiatry 62, 1236e1243. Weiland-Fiedler, P., Erickson, K., Waldeck, T., Luckenbaugh, D.A., Pike, D., Bonne, O., Charney, D.S., Neumeister, A., 2004. Evidence for continuing neuropsychological impairments in depression. J. Affect. Disord. 82, 253e258. Williams, R.A., Hagerty, B.M., Cimprich, B., Therrien, B., Bay, E., Oe, H., 2000. Changes in directed attention and short-term memory in depression. J. Psychiatr. Res. 34, 227e238. Witkin, J.M., Eiler, W.J.A., 2006. Antagonism of metabotropic glutamate group II receptors in the potential treatment of neurological and neuropsychiatric disorders. Drug Dev. Res. 67, 757e769. Woltering, T.J., Wichmann, J., Goetschi, E., Knoflach, F., Ballard, T.M., Huwyler, J., Gatti, S., 2010. Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective noncompetitive metabotropic glutamate receptor 2/3 antagonists. Bioorg. Med. Chem. Lett. 20, 6969e6974. Yu, T., Guo, M., Garza, J., Rendon, S., Sun, X.L., Zhang, W., Lu, X.Y., 2011. Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction. Int. J. Neuropsychopharmacol. 14, 303e317.