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The Role Of Glutamate In Mood Disorders & Schizophrenia
James W. Murrough, MD, PhDAssociate Professor of Psychiatry and Neuroscience
Director, Depression and Anxiety Center for Discovery and TreatmentIcahn School of Medicine at Mount Sinai
Laura M. Rowland, PhDAssociate Professor of Psychiatry
Maryland Psychiatric Research CenterUniversity of Maryland School of Medicine
March 2019 MRC2.CORP.D.00405
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Today’s Speakers
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James W. Murrough, MD, PhDIcahn School of Medicine at Mount SinaiDr. Murrough is an Associate Professor of Psychiatry and Neuroscience and Director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai. He received his medical degree from Tufts University School of Medicine in Boston. Dr. Murrough completed his residency training in psychiatry at Mount Sinai and a research fellowship in experimental therapeutics and clinical neuroscience in mood disorders at Mount Sinai. He obtained a PhD in clinical research methodology and biostatistics from Mount Sinai. Dr. Murrough conducts clinical and translational research aimed at understanding the biological basis of mood and anxiety disorders.
Laura M. Rowland, PhDUniversity of Maryland School of MedicineDr. Rowland is an Associate Professor in the Maryland Psychiatric Research Center (MPRC), Department of Psychiatry at the University of Maryland, School of Medicine. She is the Director of the Chemical Imaging Core, housed within the Neuroimaging Research Program at the MPRC and the co-director of the MPRC postdoctoral training program. Dr. Rowland received her PhD in experimental psychology (behavioral neuroscience) from the University of New Mexico. Her research focuses on proton magnetic resonance spectroscopy studies of glutamatergic and GABAergic function and bioenergetic alterations in schizophrenia and related disorders.
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Provide an overview of glutamate, glutamate receptors, and the glutamatergic system
Review the potential role of glutamate in the pathophysiology of depression and schizophrenia
Discuss potential implications for glutamatergic pharmacotherapy in depression and schizophrenia
Objectives
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Introduction To Glutamate
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Glutamate
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CNS, central nervous system GABA, gamma-aminobutyric acid; Gln, glutamine.1. Stahl SM. Stahl’s Essential Psychopharmacology, 4th edition. Cambridge, UK:Cambridge University Press;2013. 2. Ramadan S et al. NMR Biomed. 2013;26(12):10.1002/nbm.3045.3. Zhou Y et al. J Neural Transm. 2014;121:799–817.
OH
O
NH2
O‾O‾
O
NH3+
O
Glutamate1
EXCITATORY
ON OFF
GABA
Gln
The most abundant excitatory neurotransmitter2
Sits at the crossroads between multiple metabolic pathways (eg, precursor to GABA)2,3
Can be harmful in both excessive or scarce amounts3
≥1 type of glutamate receptor is expressed by most, if not all, cells in the CNS3
GABA2
INHIBITORY
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Ionotropic Glutamate Receptors1,2
• Ligand-gated ion channels• Involved in excitatory neurotransmission• Usually postsynaptic• Families named for their selective agonists
Metabotropic Glutamate Receptors1
• Seven transmembrane GPCRs• 12 members encoded by 8 genes• Modulate intracellular signaling
Overview Of Glutamate Receptors
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AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Ca, calcium; Glu, glutamate; GPCR, G-protein coupled receptor; K, potassium; mGluR, metabotropic glutamatereceptors; Na, sodium; NMDA, N-methyl-D-aspartate.1. Willard SS & Koochekpour S. Int J Biol Sci. 2013;9(9):948-959.2. Stahl SM. Stahl’s Essential Psychopharmacology, 4th edition. Cambridge, UK:Cambridge University Press;2013. 3. IUPHAR. Revised recommendations for nomenclature of ligand-gated ion channels. http://www.guidetopharmacology.org/LGICNomenclature.jsp. Accessed February 6, 2019.
AMPA Kainate NMDA
GluA1-43 GluK1-53 GluN1 GluN2A-D
GluN3A & B3
Group I Group II Group III
mGluR1 & 5 mGluR2 & 3 mGluR4, 6, 7, 8
Na+, K+, Ca2+ ions1
Gq Gi Gi
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The Glutamate Synapse1,2
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AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; EAAT, excitatory amino acid transporter; mGluR, metabotropic glutamate receptor; NMDA, N-methyl-D-aspartate. 1. Murrough JW et al. Nat Rev Drug Disc. 2017;16:472-4862. Lener MS et al. Biol Psychiatry. 2017; 81(10): 886–897.
Gq
mGluR1/5receptors
Gi
mGluR2/3
Astrocyte projection
Presynaptic Neuron
Postsynaptic Neuron
AMPAreceptor
Kainatereceptor
NMDAreceptor
Downstream signaling and neurotransmission
Action potential
GlutamateGlutamineSodium ionCalcium ionGlycine
EAAT
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Measurement Of Glutamate In Vivo: Proton Magnetic Resonance Spectroscopy (1H-MRS)
• Description– Noninvasive imaging method that provides
information about cellular activity and endogenous metabolite changes1
– Used in combination with MRI, which provides spatial/anatomical information1
• Use– Has been used to demonstrate changes in
concentrations of Glu and Gln in schizophrenia and mood disorders2
– Holds promise for identifying biomarkers that can3:
• Serve as treatment targets• Predict disease onset• Predict illness exacerbation
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Gln, glutamine; Glu, glutamate; MRI, magnetic resonance imaging.1. National Cancer Institute. NCI Dictionary of Cancer Terms. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/proton-magnetic-resonance-spectroscopic-imaging.
Accessed February 15, 2019. 2. Ramadan S et al. NMR Biomed. 2013;26(12):10.1002/nbm.3045.3. Wijtenburg SA et al. Neurosci Biobehav Rev. 2015;51:276–295.
Sample 1H-MRS Spectrum
Potential Benefits2:• High signal-to-noise ratio • No exogenous material infusion required
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Glutamate In Mood Disorders
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
Prevailing Theory: The Monoaminergic Hypothesis Of Depression
• The monoaminergic hypothesis of depression posits that the pathophysiologic cause for the disease is a deficiency of monoamine* neurotransmitters1
– Monoamines were first implicated in depression when it was found that patients taking monamine-depleting antihypertensives developed depression2
– A role for monoamines in depression was further supported by the discovery of the first antidepressants, the TCAs and the MAOIs2
Pharmacotherapy for DepressionMany antidepressants act on the monoaminergic system2
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*The monoamine neurotransmitters include dopamine, norepinephrine, and serotonin. MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. 1. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. Cambridge, UK: Cambridge University Press; 2013.2. Otte C et al. Nat Rev Dis Primers. 2016;2:1-20.
Block reuptake of serotonin
SSRIs
Block reuptake of norepinephrine
and serotonin
SNRIs
Block breakdown of monoamines
MAOIs
Block reuptake of monoamines
TCAs
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The Potential Role Of Glutamate In Mood Disorders
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*Either ECT or ECT + antidepressant medication. CSF, cerebral spinal fluid; ECT, electroconvulsive therapy; MDD, major depressive disorder; NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor; PFC, prefrontal cortex. 1. Murrough JW et al. Nat Rev Drug Disc. 2017;16:472-486.2. Soares JC. Bipolar Disorders: Basic Mechanisms and Therapeutic Implications. 3rd edition. Cambridge University Press; 2016.3. Muneer A. Psychiatry Investig. 2016;13(1):18-33.4. Niciu MJ et al. J Neural Transm. 2014;121(8):907-924.
• A loss of glia in the prefrontal cortex of patients with mood disorders has been reported; glia play an important role in regulation of glutamate signaling1
• Mood stabilizers used in the treatment of bipolar disorder have been found to modulate glutamatergic neurotransmission and have been suggested to be neuroprotective against glutamate excitotoxicity2
• Comprehensive meta-analyses have identified consistent elevation of glutamate and glutamine in several brain regions in patients with bipolar disorder compared to healthy controls; these findings persisted across bipolar mood states, including euthymia3
• Glutamate levels have been shown to be elevated in the plasma, CSF, and brains of people with depression1
• MDD is associated with reduced glutamate and glutamine levels in the PFC and elevated glutamate levels in the occipital cortex1,4
• Glutamate-related gene variants have been associated with depression in a small number of studies• A series of postmortem studies has reported alterations in NMDAR subunit expression in patients with MDD or
bipolar disorder and in patients who died by suicide
Alterations in genetics/gene expression1
Alterations in glutamate levels
Indirect evidenceSeveral lines of evidence implicate the glutamate system in mood disorders:
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Glutamate In Depression Complex Mechanisms
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NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor.Murrough JW et al. Nat Rev Drug Disc. 2017;16:472-486.
NMDA receptor signaling
Cell growth & neuroprotection
Moderate levels of NMDAR activation
promote neuroprotective signaling pathways
Excitotoxicity & cell death
Misappropriated NMDAR signaling has
deleterious effects, with overactivation contributing
to excitotoxicity and synaptic loss
Promote growth & neuroplasticity Goal of NMDAR
modulators
Inhibit negative consequences of
overactivation
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Discussion
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
24 hours after treatment with an
NMDAR antagonist
24 hours after treatment with an
NMDAR antagonist
Effects Of NMDAR Antagonism On Brain Function In Depression
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1. Murrough JW et al. Transl Psychiatry. 2015; 5:e509.2. Murrough JW et al. Hum Brain Mapp. 2016;37(9):3214-3223.
3. Abdallah CG et al. Neuropsychopharmacology. 2017;42:1210-1219.
Caudate Response to Positive Emotional Stimuli1*
Healthy controls
Patients with TRD
PFC Functional Connectivity2*Healthy controls Patients with depression
Connectivity was inversely correlated with symptom severity
*Not a quantitative representation of the data. NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor; PFC, prefrontal cortex; TRD, treatment-resistant depression.
Healthy controls
Patients with TRD
Antidepressant response correlated with increases in connectivity of the caudate1
Connectivity was partially normalized 24 hours after treatment3
Healthy controls Patients with depression
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Glutamate In Schizophrenia
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
Prevailing Theory: The Dopamine Hypothesis Of Schizophrenia
Multiple lines of research support a role for dopamine dysfunction in schizophrenia:• Compounds that increase extracellular concentrations of dopamine can induce
schizophrenia-like “positive” symptoms• In the 1970s, the clinical effectiveness of antipsychotic drugs was found to be related to
their affinity for dopamine receptor binding• Elevated dopamine synthesis capacity has been consistently detected in patients who
had acute psychosis at the time of investigation
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Howes O et al. J Psychopharmacol. 2015; 29(2): 97–115.
However, dopamine dysfunction may not explain all aspects of the illness:• Dopamine-targeting antipsychotics have only modest effects on the cognitive
impairments and negative symptoms of the illness• Elevated dopamine synthesis capacity is less consistently detected in studies of patients
with chronic illness• Patients with treatment-resistant schizophrenia may have a “non-dopaminergic” subtype
of schizophrenia
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Current Pharmacotherapy For Schizophrenia
• Dopamine receptor D2 is regarded as the primary target associated with therapeutic antipsychotic effects1
• In most patients, clinical response to antipsychotics is strongly correlated with dopamine receptor D2 occupancy2
• Antipsychotics have a number of off-target effects, and emerging data indicates a potential clinical benefit for some of these actions1:
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EPS, extrapyramidal side effects; 5-HT, serotonin; NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor.1. Miyamoto S et al. Molecular Psychiatry. 2012;17:1206-1227.2. Gillespie AL et al. BMC Psychiatry. 2017;17(1):12.
Serotonin receptor modulation
NMDA receptor modulation
Other receptor modulation
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The Potential Role Of Glutamate In Schizophrenia
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NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor.Howes O et al. J Psychopharmacol. 2015; 29(2):97-115.
• Reduced NMDAR1 subunit density has been observed in the superior frontal cortex and superior temporal cortex in postmortem samples from patients with schizophrenia
• It has been proposed that the abnormality in schizophrenia may be aberrant glutamate receptor localization
Alterations in genetics/gene expression
• A large study found that patients with chronic schizophrenia had an elevated glutamine:glutamateratio (Gln/Glu) in the anterior cingulate cortex, with a correlation reported between frontal Gln/Glu and positive psychotic symptoms
Alterations in glutamate levels
• The current prevailing glutamate hypothesis is for the primary involvement of NMDA receptor dysfunction in schizophrenia
• This hypothesis initially arose from observations that non-competitive NMDA receptor antagonists led to schizophrenia-like symptoms, including both positive and negative symptom domains
Indirect evidenceSeveral lines of evidence suggest a role for the glutamate system in schizophrenia:
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Glutamate In Treatment-Resistant Schizophrenia
• ~1/3 of patients with schizophrenia are treatment resistant*
• Patients with TRS show no clinical response to antipsychotics, even when dopamine receptor D2 occupancy is above the therapeutic threshold
• A systematic review of 19 studies that compared treatment-resistant and treatment-responsive patients with schizophrenia suggested:
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*Defined by two failed antipsychotic trials. †Some conflicting reports exist in the literature.ACC, anterior cingulate cortex; TRS, treatment-resistant schizophrenia.Gillespie AL et al. BMC Psychiatry. 2017;17(1):12.
Glutamate levels in ACC† Dopamine synthesis capacity
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Explaining Schizophrenia: Potential Roles For Both Dopamine & Glutamate
• Glutamate abnormalities may be present only in a subset of patients with the illness and/or only at a particular phase of illness
• Evidence for presynaptic dopamine dysfunction is compelling and most clearly linked to psychotic symptoms in schizophrenia; evidence for involvement in negative and cognitive symptoms is less clear
• Glutamate models involving NMDA receptor blockade appear to be better able to account for the negative and cognitive symptoms of schizophrenia
• A combination of both NMDA hypofunction and presynaptic dopamine dysfunction may, therefore, provide the best explanation of all clinical aspects of schizophrenia
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NMDA, N-methyl-D-aspartate.Howes O et al. J Psychopharmacol. 2015; 29(2): 97–115.
Glutamate hypofunction
Dopamine dysfunction
Schizophrenia
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Discussion
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Questions
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Closing
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Event Speaker(s) Date Time
Benefits & Challenges of Smartphone Use in Mental Health
• Steven Stoner, PharmD, BCPP
• Britton Arey, MD, MBAMay 1, 2019 12:00 PM ET
Upcoming Webinars*
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© 2019 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
The Role Of Glutamate In Mood Disorders & Schizophrenia
James W. Murrough, MD, PhDAssociate Professor of Psychiatry and Neuroscience
Director, Depression and Anxiety Center for Discovery and TreatmentIcahn School of Medicine at Mount Sinai
Laura M. Rowland, PhDAssociate Professor of Psychiatry
Maryland Psychiatric Research CenterUniversity of Maryland School of Medicine
March 2019 MRC2.CORP.D.00405