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Differences in quantification of the metabotropic glutamate receptor 5 (mGluR5) across bipolar disorder and major depressive disorder

Published:November 08, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.10.018

      Abstract

      Background

      Understanding the neurobiology underlying bipolar disorder (BD) vs. major depressive disorder (MDD) is crucial for accurate diagnosis, and for driving the discovery of novel treatments. A promising target is the metabotropic glutamate receptor 5 (mGluR5), a modulator of glutamate transmission associated with synaptic plasticity. We measured mGluR5 availability in individuals with MDD and BD for the first time using positron emission tomography (PET).

      Methods

      Individuals with BD (n=17 depressed, BD-dep; n=10 euthymic, BD-euth), MDD (n=17), and 18 healthy controls (HCs) were imaged with [18F]FPEB PET to quantify mGluR5 availability in regions of the prefrontal cortex (PFC) and was compared across groups and assessed in relation to depressive symptoms and cognitive function.

      Results

      PFC mGluR5 availability was significantly different across groups (F6,116=2.18, p=0.050). Specifically, mGluR5 was lower in BD vs. MDD and HC groups, with no difference between MDD and HC groups. Further, after dividing the BD group, mGluR5 was lower in both BD-dep and BD-euth groups vs. both MDD and HC groups across ROIs. Interestingly, lower dlPFC mGluR5 was associated with worse depression in MDD (r=-0.67, p=0.005) but not in BD. Significant negative correlations were observed between mGluR5 and working memory in MDD and BD-dep groups.

      Conclusion

      This work suggests mGluR5 could be helpful in distinguishing BD and MDD, as a possible treatment target for depression symptoms in MDD and cognitive alterations for both disorders. Further work is needed to confirm differentiating roles for mGluR5 in BD and MDD and to probe modulation of mGluR5 as a preventative/treatment strategy.

      Key words

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      References

        • Judd L.L.
        • Akiskal H.S.
        • Schettler P.J.
        • Endicott J.
        • Maser J.
        • Solomon D.A.
        • et al.
        The long-term natural history of the weekly symptomatic status of bipolar I disorder.
        Archives of general psychiatry. 2002; 59: 530-537
        • Kupka R.
        • Altshuler L.
        • Nolen W.
        • Suppes T.
        • Luckenbaugh D.
        • Leverich G.
        • et al.
        Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder.
        Bipolar disorders. 2007; 9: 531-535
        • Hirschfeld R.M.
        • Cass A.R.
        • Holt D.C.
        • Carlson C.A.
        Screening for bipolar disorder in patients treated for depression in a family medicine clinic.
        The Journal of the American board of family practice. 2005; 18: 233-239
        • Schmaal L.
        • Harmelen Av
        • Chatzi V.
        • Lippard E.
        • Toenders Y.
        • Averill L.
        • et al.
        Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies.
        Molecular psychiatry. 2019; 25: 408-427
        • Pompili M.
        • Gonda X.
        • Serafini G.
        • Innamorati M.
        • Sher L.
        • Amore M.
        • et al.
        Epidemiology of suicide in bipolar disorders: a systematic review of the literature.
        Bipolar disorders. 2013; 15: 457-490
        • Goodwin Go, Psychopharmacology CGotBAf
        Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology.
        Journal of Psychopharmacology. 2009; 23: 346-388
        • Yatham L.N.
        • Kennedy S.H.
        • Parikh S.V.
        • Schaffer A.
        • Beaulieu S.
        • Alda M.
        • et al.
        Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013.
        Bipolar disorders. 2013; 15: 1-44
        • Gigante A.D.
        • Bond D.J.
        • Lafer B.
        • Lam R.W.
        • Young L.T.
        • Yatham L.N.
        Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis.
        Bipolar disorders. 2012; 14: 478-487
        • Scotti-Muzzi E.
        • Umla-Runge K.
        • Soeiro-de-Souza M.G.
        Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of (1)H-MRS studies.
        Eur Neuropsychopharmacol. 2021; 47: 62-73
        • Szulc A.
        • Wiedlocha M.
        • Waszkiewicz N.
        • Galińska-Skok B.
        • Marcinowicz P.
        • Gierus J.
        • et al.
        Proton magnetic resonance spectroscopy changes after lithium treatment. Systematic review.
        Psychiatry Res Neuroimaging. 2018; 273: 1-8
        • Yildiz-Yesiloglu A.
        • Ankerst D.P.
        Review of 1H magnetic resonance spectroscopy findings in major depressive disorder: a meta-analysis.
        Psychiatry Research: Neuroimaging. 2006; 147: 1-25
        • Luykx J.
        • Laban K.
        • Van Den Heuvel M.
        • Boks M.
        • Mandl R.
        • Kahn R.
        • et al.
        Region and state specific glutamate downregulation in major depressive disorder: a meta-analysis of 1H-MRS findings.
        Neuroscience & Biobehavioral Reviews. 2012; 36: 198-205
        • Abdallah C.G.
        • Hannestad J.
        • Mason G.F.
        • Holmes S.E.
        • DellaGioia N.
        • Sanacora G.
        • et al.
        Metabotropic glutamate receptor 5 and glutamate involvement in major depressive disorder: a multimodal imaging study.
        Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2017; 2: 449-456
        • Godfrey K.E.
        • Muthukumaraswamy S.D.
        • Stinear C.M.
        • Hoeh N.
        Effect of rTMS on GABA and glutamate levels in treatment-resistant depression: An MR spectroscopy study.
        Psychiatry Research: Neuroimaging. 2021; 317111377
        • Abdallah C.G.
        • De Feyter H.M.
        • Averill L.A.
        • Jiang L.
        • Averill C.L.
        • Chowdhury G.M.
        • et al.
        The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects.
        Neuropsychopharmacology. 2018; 43: 2154-2160
        • Sanacora G.
        • Gueorguieva R.
        • Epperson C.N.
        • Wu Y.-T.
        • Appel M.
        • Rothman D.L.
        • et al.
        Subtype-Specific Alterations of γ-Aminobutyric Acid and Glutamatein Patients With Major Depression.
        Archives of general psychiatry. 2004; 61: 705-713
        • Hashimoto K.
        • Sawa A.
        • Iyo M.
        Increased levels of glutamate in brains from patients with mood disorders.
        Biological psychiatry. 2007; 62: 1310-1316
        • Abdallah C.
        • Mason G.
        • DellaGioia N.
        • Sanacora G.
        • Jiang L.
        • Matuskey D.
        • et al.
        mGluR5 and glutamate involvement in MDD: a multimodal imaging study.
        Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2017; 2: 449-456
        • Truong V.
        • Cheng P.Z.
        • Lee H.-C.
        • Lane T.J.
        • Hsu T.-Y.
        • Duncan N.W.
        Occipital gamma-aminobutyric acid and glutamate-glutamine alterations in major depressive disorder: An mrs study and meta-analysis.
        Psychiatry Research: Neuroimaging. 2021; 308111238
        • Kempton M.J.
        • Salvador Z.
        • Munafò M.R.
        • Geddes J.R.
        • Simmons A.
        • Frangou S.
        • et al.
        Structural Neuroimaging Studies in Major Depressive Disorder: Meta-analysis and Comparison With Bipolar Disorder.
        Archives of general psychiatry. 2011; 68: 675-690
        • Syan S.K.
        • Smith M.
        • Frey B.N.
        • Remtulla R.
        • Kapczinski F.
        • Hall G.B.
        • et al.
        Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review.
        Journal of Psychiatry and Neuroscience. 2018; 43: 298-316
        • Wang Y.
        • Wang J.
        • Jia Y.
        • Zhong S.
        • Niu M.
        • Sun Y.
        • et al.
        Shared and specific intrinsic functional connectivity patterns in unmedicated bipolar disorder and major depressive disorder.
        Scientific Reports. 2017; 7: 1-11
        • Doucet G.E.
        • Bassett D.S.
        • Yao N.
        • Glahn D.C.
        • Frangou S.
        The role of intrinsic brain functional connectivity in vulnerability and resilience to bipolar disorder.
        American Journal of Psychiatry. 2017; 174: 1214-1222
        • Mulders P.C.
        • van Eijndhoven P.F.
        • Schene A.H.
        • Beckmann C.F.
        • Tendolkar I.
        Resting-state functional connectivity in major depressive disorder: a review.
        Neuroscience & Biobehavioral Reviews. 2015; 56: 330-344
        • Kaiser R.H.
        • Andrews-Hanna J.R.
        • Wager T.D.
        • Pizzagalli D.A.
        Large-Scale Network Dysfunction in Major Depressive Disorder: A Meta-analysis of Resting-State Functional Connectivity.
        JAMA Psychiatry. 2015; 72: 603-611
        • Blond B.N.
        • Fredericks C.A.
        • Blumberg H.P.
        Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala–anterior paralimbic neural system.
        Bipolar disorders. 2012; 14: 340-355
        • Blumberg H.P.
        • Leung H.-C.
        • Skudlarski P.
        • Lacadie C.M.
        • Fredericks C.A.
        • Harris B.C.
        • et al.
        A functional magnetic resonance imaging study of bipolar disorder: state-and trait-related dysfunction in ventral prefrontal cortices.
        Archives of general psychiatry. 2003; 60: 601-609
        • Tang Y.
        • Kong L.
        • Wu F.
        • Womer F.
        • Jiang W.
        • Cao Y.
        • et al.
        Decreased functional connectivity between the amygdala and the left ventral prefrontal cortex in treatment-naive patients with major depressive disorder: a resting-state functional magnetic resonance imaging study.
        Psychological medicine. 2013; 43: 1921-1927
        • Arnsten A.F.
        Stress signalling pathways that impair prefrontal cortex structure and function.
        Nat Rev Neurosci. 2009; 10: 410-422
        • Popoli M.
        • Yan Z.
        • McEwen B.S.
        • Sanacora G.
        The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission.
        Nat Rev Neurosci. 2012; 13: 22-37
        • Krystal J.H.
        • Mathew S.J.
        • D'Souza D.C.
        • Garakani A.
        • Gunduz-Bruce H.
        • Charney D.S.
        Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists.
        CNS Drugs. 2010; 24: 669-693
        • Esterlis I.
        • Holmes S.E.
        • Sharma P.
        • Krystal J.H.
        • DeLorenzo C.
        Metabotropic glutamatergic receptor 5 and stress disorders: Knowledge gained from receptor imaging studies.
        Biological psychiatry. 2018; 84: 95-105
        • Fatemi S.
        • Folsom T.
        • Rooney R.
        • Thuras P.
        mRNA and protein expression for novel GABAA receptors θ and ρ2 are altered in schizophrenia and mood disorders; relevance to FMRP-mGluR5 signaling pathway.
        Translational psychiatry. 2013; 3: 1-13
        • Fatemi S.
        • Folsom T.
        Existence of monomer and dimer forms of mGluR5, under reducing conditions in studies of postmortem brain in various psychiatric disorders.
        Schizophr Res. 2014; 158: 270-271
        • Folsom T.
        • Thuras P.
        • Fatemi S.
        Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders.
        Schizophr Res. 2015; 165: 201-211
        • DeLorenzo C.
        • Gallezot J.-D.
        • Gardus J.
        • Yang J.
        • Planeta B.
        • Nabulsi N.
        • et al.
        In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C] ABP688 and [18F] FPEB.
        Journal of Cerebral Blood Flow & Metabolism. 2017; 37: 2716-2727
        • Hefti K.
        • Holst S.C.
        • Sovago J.
        • Bachmann V.
        • Buck A.
        • Ametamey S.M.
        • et al.
        Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep.
        Biological psychiatry. 2013; 73: 161-168
        • Terbeck S.
        • Akkus F.
        • Chesterman L.P.
        • Hasler G.
        The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies.
        Frontiers in neuroscience. 2015; 9: 86
        • Cleva R.M.
        • Olive M.F.
        Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders.
        Molecules. 2011; 16: 2097-2106
        • Ménard C.
        • Quirion R.
        Successful cognitive aging in rats: a role for mGluR5 glutamate receptors, homer 1 proteins and downstream signaling pathways.
        PLoS One. 2012; 7e28666
        • Ahnaou A.
        • Langlois X.
        • Steckler T.
        • Bartolome-Nebreda J.
        • Drinkenburg W.
        Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats.
        Psychopharmacology. 2015; 232: 1107-1122
        • Milella M.S.
        • Marengo L.
        • Larcher K.
        • Fotros A.
        • Dagher A.
        • Rosa-Neto P.
        • et al.
        Limbic system mGluR5 availability in cocaine dependent subjects: A high-resolution PET [11C]ABP688 study.
        NeuroImage. 2014; 98: 195-202
        • Milella M.
        • Marengo L.
        • Larcher K.
        • Fotros A.
        • Dagher A.
        • Rosa-Neto P.
        • et al.
        Limbic system mGluR5 availability in cocaine dependent subjects: a high-resolution PET [11 C] ABP688 study.
        Neuroimage. 2014; 98: 195-202
        • Kim J.
        • Kang S.
        • Choi T.-Y.
        • Chang K.-A.
        • Koo J.W.
        Metabotropic Glutamate Receptor 5 in Amygdala Target Neurons Regulates Susceptibility to Chronic Social Stress.
        Biological Psychiatry. 2022;
        • Esterlis I.
        • DellaGioia N.
        • Pietrzak R.H.
        • Matuskey D.
        • Nabulsi N.
        • Abdallah C.G.
        • et al.
        Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C] ABP688 and PET imaging study in depression.
        Molecular psychiatry. 2018; 23: 824-832
        • Holmes S.E.
        • Girgenti M.J.
        • Davis M.T.
        • Pietrzak R.H.
        • DellaGioia N.
        • Nabulsi N.
        • et al.
        Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence.
        Proceedings of the National Academy of Sciences. 2017; 114: 8390-8395
        • Davis M.T.
        • Hillmer A.
        • Holmes S.E.
        • Pietrzak R.H.
        • DellaGioia N.
        • Nabulsi N.
        • et al.
        In vivo evidence for dysregulation of mGluR5 as a biomarker of suicidal ideation.
        Proceedings of the National Academy of Sciences. 2019; 116: 11490-11495
      1. First M, Williams J, Karg R, Spitzer R (2015): Structured clinical interview for DSM-5—Research version (SCID-5 for DSM-5, research version; SCID-5-RV). Arlington, VA: American Psychiatric Association.1-94.

        • Montgomery S.A.
        • Åsberg M.
        A new depression scale designed to be sensitive to change.
        The British journal of psychiatry. 1979; 134: 382-389
        • Pietrzak R.H.
        • Maruff P.
        • Mayes L.C.
        • Roman S.A.
        • Sosa J.A.
        • Snyder P.J.
        An examination of the construct validity and factor structure of the Groton Maze Learning Test, a new measure of spatial working memory, learning efficiency, and error monitoring.
        Archives of Clinical Neuropsychology. 2008; 23: 433-445
        • Darby D.
        • Maruff P.
        • Collie A.
        • McStephen M.
        Mild cognitive impairment can be detected by multiple assessments in a single day.
        Neurology. 2002; 59: 1042-1046
        • Park E.
        • Sullivan J.M.
        • Planeta B.
        • Gallezot J.-D.
        • Lim K.
        • Lin S.-F.
        • et al.
        Test–retest reproducibility of the metabotropic glutamate receptor 5 ligand [18F] FPEB with bolus plus constant infusion in humans.
        European journal of nuclear medicine and molecular imaging. 2015; 42: 1530-1541
        • Sullivan J.M.
        • Lim K.
        • Labaree D.
        • Lin S-f
        • McCarthy T.J.
        • Seibyl J.P.
        • et al.
        Kinetic analysis of the metabotropic glutamate subtype 5 tracer [18F] FPEB in bolus and bolus-plus-constant-infusion studies in humans.
        Journal of Cerebral Blood Flow & Metabolism. 2013; 33: 532-541
        • Elmenhorst D.
        • Mertens K.
        • Kroll T.
        • Oskamp A.
        • Ermert J.
        • Elmenhorst E.
        • et al.
        Circadian variation of metabotropic glutamate receptor 5 availability in the rat brain.
        J Sleep Res. 2016; (Epub ahead of print)
        • DeLorenzo C.
        • Gallezot J.-D.
        • Gardus J.
        • Yang J.
        • Planeta B.
        • Nabulsi N.
        • et al.
        In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C]ABP688 and [18F]FPEB.
        Journal of Cerebral Blood Flow & Metabolism. 2016; 37: 2716-2727
        • Rolls E.T.
        • Huang C.-C.
        • Lin C.-P.
        • Feng J.
        • Joliot M.
        Automated anatomical labelling atlas 3.
        Neuroimage. 2020; 206116189
        • Patel S.
        • Hamill T.G.
        • Connolly B.
        • Jagoda E.
        • Li W.
        • Gibson R.E.
        Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F] F-PEB.
        Nuclear medicine and biology. 2007; 34: 1009-1017
      2. Abdallah C (Under Review): mGluR5 and glutamate involvement in MDD: a multimodal imaging study. Biological psychiatry.

        • Elmenhorst D.
        • Mertens K.
        • Kroll T.
        • Oskamp A.
        • Ermert J.
        • Elmenhorst E.M.
        • et al.
        Circadian variation of metabotropic glutamate receptor 5 availability in the rat brain.
        J Sleep Res. 2016;
        • Lepannetier S.
        • Gualdani R.
        • Tempesta S.
        • Schakman O.
        • Seghers F.
        • Kreis A.
        • et al.
        Activation of TRPC1 channel by metabotropic glutamate receptor mGluR5 modulates synaptic plasticity and spatial working memory.
        Front Cell Neurosci. 2018; 318
        • Manahan-Vaughan D.
        • Braunewell K.-H.
        The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity.
        Cerebral cortex. 2005; 15: 1703-1713
        • Purgert C.A.
        • Izumi Y.
        • Jong Y.-J.I.
        • Kumar V.
        • Zorumski C.F.
        • O'Malley K.L.
        Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus.
        Journal of Neuroscience. 2014; 34: 4589-4598
        • Terbeck S.
        • Akkus F.
        • Chesterman L.P.
        • Hasler G.
        The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies.
        Front Neurosci. 2015; 9: 86
        • Wang J.
        • Liu P.
        • Zhang A.
        • Yang C.
        • Liu S.
        • Wang J.
        • et al.
        Specific Gray Matter Volume Changes of the Brain in Unipolar and Bipolar Depression.
        Front Hum Neurosci. 2021; 14592419
        • Jabbi M.
        • Weber W.
        • Welge J.
        • Nery F.
        • Tallman M.
        • Gable A.
        • et al.
        Frontolimbic brain volume abnormalities in bipolar disorder with suicide attempts.
        Psychiatry Res. 2020; 294113516
        • Cho I.
        • Goghari V.
        The relationship between maintenance and manipulation components of working memory and prefrontal and parietal brain regions in bipolar disorder.
        J Affect Disord. 2020; 264: 519-526
        • Abé C.
        • Liberg B.
        • Song J.
        • Petrovic B.S.
        • Ekman C.
        • Sellgren C.
        • et al.
        Longitudinal Cortical Thickness Changes in Bipolar Disorder and the Relationship to Genetic Risk, Mania, and Lithium Use.
        Biol Psychiatry. 2020; 87: 271-281
      3. Niu M, Wang Y, Jia Y, Wang J, Zhong S, Lin J, et al. Common and Specific Abnormalities in Cortical Thickness in Patients with Major Depressive and Bipolar Disorders. EBioMedicine. 16:162-171.

        • Abé C.
        • Ekman C.
        • Sellgren C.
        • Petrovic P.
        • Ingvar M.
        • Landén M.
        Cortical thickness, volume and surface area in patients with bipolar disorder types I and II.
        J Psychiatry Neurosci. 2016; 41: 240-250
      4. Oertel-Knöchel V, Reuter J, Reinke B, Marbach K, Feddern R, Alves G, et al. Association between age of disease-onset, cognitive performance and cortical thickness in bipolar disorders. J Affect Disord. 174:627-635.

        • Lan M.
        • Chhetry B.
        • Oquendo M.
        • Sublette M.
        • Sullivan G.
        • Mann J.
        • et al.
        Cortical thickness differences between bipolar depression and major depressive disorder.
        Bipolar disorders. 2014; 16: 378-388
        • Najt P.
        • Wang F.
        • Spencer L.
        • Johnston J.
        • Lippard E.C.
        • Pittman B.
        • et al.
        Anterior Cortical Development During Adolescence in Bipolar Disorder.
        Biol Psychiatry. 2016; 79: 303-310
        • Wang F.
        • Kalmar J.H.
        • Womer F.Y.
        • Edmiston E.
        • Chepenik L.
        • Chen R.
        • et al.
        Olfactocentric paralimbic cortex morphology in adolescents with bipolar disorder.
        Brain. 2011; 124: 2005-2012
        • Kalmar J.
        • Wang F.
        • Spencer L.
        • Edmiston E.
        • Lacadie C.
        • Martin A.
        • et al.
        Preliminary evidence for progressive prefrontal abnormalities in adolescents and young adults with bipolar disorder.
        J Int Neuropsychol Soc. 2009; 15: 476-481
        • Blumberg H.
        • Krystal J.
        • Bansal R.
        • Martin A.
        • Dziura J.
        • Durkin K.
        • et al.
        Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study.
        Biol Psychiatry. 2006; 59: 611-618
        • Winter N.R.
        • Leenings R.
        • Ernsting J.
        • Sarink K.
        • Fisch L.
        • Emden D.
        • et al.
        Quantifying Deviations of Brain Structure and Function in Major Depressive Disorder Across Neuroimaging Modalities.
        JAMA Psychiatry. 2022; 79: 879-888
        • Ketter T.A.
        • Wang P.W.
        The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders.
        Journal of Clinical Psychiatry. 2003; 64: 15-20
        • Popoli M.
        • Yan Z.
        • McEwen B.S.
        • Sanacora G.
        The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission.
        Nature Reviews Neuroscience. 2012; 13: 22-37
        • Duman R.S.
        • Sanacora G.
        • Krystal J.H.
        Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments.
        Neuron. 2019; 102: 75-90
        • Esterlis I.
        • DellaGioia N.
        • Pietrzak R.H.
        • Matuskey D.
        • Nabulsi N.
        • Abdallah C.G.
        • et al.
        Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11 C] ABP688 and PET imaging study in depression.
        Molecular psychiatry. 2018; 23: 824-832
        • Holmes S.E.
        • Gallezot J.-D.
        • Davis M.T.
        • DellaGioia N.
        • Matuskey D.
        • Nabulsi N.
        • et al.
        Measuring the effects of ketamine on mGluR5 using [18F]FPEB and PET.
        Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2019; (271678X19886316)
        • de Sousa R.T.
        • Loch A.A.
        • Carvalho A.F.
        • Brunoni A.R.
        • Haddad M.R.
        • Henter I.D.
        • et al.
        Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders.
        Neuropsychopharmacology. 2017; 42: 787-800
        • Normala I.
        • Abdul H.
        • Azlin B.
        • Ruzyanei N.N.
        • Hazli Z.
        • Shah S.
        Executive function and attention span in euthymic patients with bipolar 1 disorder.
        Med J Malaysia. 2010; 65: 199-203
        • Mur M.
        • Portella M.
        • Martínez-Arán A.
        • Pifarré J.
        • Vieta E.
        Long-term stability of cognitive impairment in bipolar disorder: a 2-year follow-up study of lithium-treated euthymic bipolar patients.
        J Clin Psychiatry. 2008; 69: 712-719
        • Torres I.
        • Boudreau V.
        • Yatham L.
        Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis.
        Acta Psychiatr Scand Suppl. 2007; : 17-26
        • Thompson J.
        • Gallagher P.
        • Hughes J.
        • Watson S.
        • Gray J.
        • Ferrier I.
        • et al.
        Neurocognitive impairment in euthymic patients with bipolar affective disorder.
        Br J Psychiatry. 2005; 186: 32-40
        • Frye M.
        • Gitlin M.
        • Altshuler L.
        Unmet needs in bipolar depression.
        Depress Anxiety. 2004; 19: 199-208
        • Torrisi S.
        • Moody T.
        • Vizueta N.
        • Thomason M.
        • Monti M.
        • Townsend J.
        • et al.
        Differences in resting corticolimbic functional connectivity in bipolar I euthymia.
        Bipolar disorders. 2013; 15: 156-166
        • Townsend J.
        • Altshuler L.
        Emotion processing and regulation in bipolar disorder: a review.
        Bipolar disorders. 2012; 14: 326-339
        • Kerr N.
        • Scott J.
        • Phillips M.
        Patterns of attentional deficits and emotional bias in bipolar and major depressive disorder.
        Br J Clin Psychol. 2005; 44: 343-356
        • Baune B.
        • Li X.
        • Beblo T.
        Short- and long-term relationships between neurocognitive performance and general function in bipolar disorder.
        J Clin Exp Neuropsychol. 2013; 35 (Review): 759-774
        • Daniel B.
        • Montali A.
        • Gerra M.
        • Innamorati M.
        • Girardi P.
        • Pompili M.
        • et al.
        Cognitive impairment and its associations with the path of illness in affective disorders: a comparison between patients with bipolar and unipolar depression in remission.
        J Psychiatr Pract. 2013; 19: 275-287
        • Keilp J.
        • Gorlyn M.
        • Russell M.
        • Oquendo M.
        • Burke A.
        • Harkavy-Friedman J.
        • et al.
        Neuropsychological function and suicidal behavior: attention control, memory and executive dysfunction in suicide attempt.
        Psychol Med. 2013; 43: 539-551
        • Liu Z.
        • Ma H.
        • Long S.
        • Zhang Y.
        Metabotropic Glutamate Receptor 5: A Potential Molecular Switch and Beyond.
        Biological Psychiatry. 2022; 92: 98-99