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Glutamate and Psychiatry: Where Are We, and What Does the Future Hold?
Sanjay J. Mathew, MDProfessor of Psychiatry and Behavioral SciencesJohnson Family Chair for Research in PsychiatryMenninger Department of Psychiatry and Behavioral SciencesBaylor College of MedicineStaff Physician, Michael E. Debakey VA Medical CenterHouston, Texas
Glutamate, NMDA Receptors, and the Quest for Rapid Antidepressants
The story of ketamine
Clomipramine
(EU 1960, US 1989)
Trazodone (1981)
Evolution of Antidepressants: 1950–1980s
Imipramine (1957)
1950 1960
1970 1980
Nortriptyline (1977)
Isocarboxazid (1959) Amitriptyline (1961)
Phenelzine (1961)
Desipramine (1964)
Protriptyline (1967)
Tranylcypromine (1969)
Doxepin (1969)
Trimipramine (1979)
Bupropion (1985)
Fluoxetine (1987)
Maprotiline (1987)
Amoxapine (1989)
1955 1965
1975 1985
Antidepressants 1990s–2015
Sertraline (1991)
1990 2000
2010
Paroxetine (1992)
Venlafaxine (1993)
Mirtazapine (1996)
Milnacipran (EU – 1996)
Nefazodone (1994)
Fluvoxamine (OCD – 1994)
Citalopram (1998)
Escitalopram (2002)
Duloxetine (2004)
Desvenlafaxine
(2008)Selegiline patch (2005)Vilazodone (2011)
Levomilnacipran (2013)
Vortioxetine(2013)
Brexpiprazole (2015)
Fluoxetine /
Olanzapine (2003)
L-methylfolate (2006)
1995
Quetiapine XR
(MDD – 2009)
2000 2005
Aripiprazole(MDD – 2007)
2015
Nu
mb
er o
f M
ech
anis
tica
lly
Dis
tin
ct D
rug
s
Slow Progress in Discovering Novel Drug Targets Beyond Serotonin, Norepinephrine, and Dopamine
Insel TR, et al. Mol Psychiatry. 2006;11(1):11-17.
What are Key Unmet Needsfor Antidepressants?
• Rapid onset of activity
• Prevention of relapse
• Impacts suicide risk
• Low side effect burden
• Addresses underlying pathophysiology
Glutamate
CNS = central nervous system; TCA = tricarboxylic acid.Mason G. Presented at: 71st Annual Meeting of the Society of Biological Psychiatry; May 12-14, 2016: Atlanta, GA.
• Most common excitatory amino acid neurotransmitter in CNS
• Fundamental to brain bioenergetics and metabolism
• Derived from both neuronal/glial pathways as well as TCA cycle
• Distribution of glutamate in compartments
– Neurons: 90%–95%
– Glia: 5%–10%
– Blood: 0.02%
– Extracellular space: 0.0008% (1/100,000 of total)
Tight Physiological Control of Glutamatergic Neurotransmission and Potential Therapeutic Targets
mGluR = metabotropic glutamate receptor; NMDA = N-methyl-D-aspartate.Sanacora G, et al. Nat Rev Drug Discov. 2008;7(5):426-437. Sanacora G, et al. 2008
+TCA Cycle
Extrasynaptic Glu
Extrasynaptic NMDA
Voltage dependent
Group I mGluR
Group II
Enhancement of Cellular Plasticity May Be Final Common Pathway for Antidepressant Treatments
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.Mathew SJ, et al. Neuropsychopharmacology. 2008;33(9):2080-2092.
5-HT1A
Attenuation
NMDA Antagonists Show Antidepressant-Like Activity in Preclinical Models
AD = antidepressant; LTP = long-term potentiation.Skolnick P, et al. Trends Pharmacol Sci. 2009;30(11):563-569.
Exposure to inescapable shock disrupted hippocampal LTP, a process dependent on NMDA receptor activation
Skolnick hypothesized that pathways subserved by NMDA receptors are critical in eliciting behavioral deficits (ie, learned helplessness) induced by inescapable stressors
NMDA antagonists found to mitigate behavioral deficits similar to monoamines
Exhibit AD-like effects in chronic mild stress model Forced swim and tail suspension tests
The Washington Post
www.washingtonpost.com/national/health-science/a-one-time-party-drug-is-helping-people-with-deep-depression/2016/02/01/d3e73862-b490-11e5-a76a-0b5145e8679a_story.html. Accessed June 14, 2016.
Onetime party drug hailed as miracle for treating severe depressionBy Sara Solovitch February 1, 2016
Rave drug tested against depression: Companies and clinicians turn to ketamine to treat mental-health
disorder as pipeline of new drugs dries up
Reardon S. Nature. 2015;517:130-131.
Ketamine: History
PCP = phencyclidine.US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
• Synthesized in 1962 by Calvin Stevens, a Parke-Davis chemist seeking an alternative anesthetic to PCP
• FDA approved for use in humans in 1970 • Indications
– “…the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.”
– “…the induction of anesthesia prior to the administration of other general anesthetic agents.”
– “…to supplement low-potency agents, such as nitrous oxide.”
• Dissociative anesthetic
• Uncompetitive high-affinity NMDAR antagonist
• Binds to PCP “angel dust” site within ion channel
• Membrane depolarization relieves Mg block, and with co-agonist binding, Ca2+ and Na+ enters cell
• 4 NR2 subunits
Ketamine and NMDA Receptor
Du J, et al. Dialogues Clin Neurosci. 2004;6(2):143-155.
Extracellular Space
Cytosol
AGONIST SITE
COAGONIST SITE
CHANNEL SITE
Restin
g P
oten
tialALLOSTERIC
SITESALLOSTERIC
SITES
Ca++
GLU
GLY
NMDAReceptorResting StateActivated
State
Depolarized
Active StateCa++
Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.
Mg++
Subanesthetic Dose IV Ketamine Rapidly Efficacious in TRD
*P˂ .05; **P ˂ .01; ***P ˂ .001. HAM-D = Hamilton Rating Scale for Depression; SSRI = selective serotonin reuptake inhibitor; TRD = treatment-resistant depression.Zarate CA Jr, et al. Arch Gen Psychiatry. 2006;63(8):856-864.
Rapid Antidepressant Effects of IV Ketamine Compared to Psychoactive Control
Ketamine dose = .5 mg/kg. bReduction in MADRS score 24 hours after infusion was the primary outcome measure and was significantly greater for the ketamine group than for the midazolam group (P ≤ .002).MADRS = Montgomery-Åsberg Depression Rating Scale
Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.
Percent Improvement from Baseline in MADRS Individual Items 24 Hours after Infusion
Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.
Summary of Acute Response Rates in Ketamine Depression Studies
Murrough JW, et al. Curr Psychiatry Rep. 2012;14(6):643-649.
IV Ketamine – Efficacy in TRD
Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.
At 1 day
At 1 week
Change in Depression Severity after Intranasal Ketamine or Placebo
* *# #
*P < .001; #P < .05.Lapidus KA, et al. Biol Psychiatry. 2014;76(12):970-976.
Repeated Ketamine Infusions Eliminates Suicidal Ideation Continuously over a 2-Week Period
Price RB, et al. Biol Psychiatry. 2009;66(5):522-526.
‐3
‐2.5
‐2
‐1.5
‐1
‐0.5
0
0.5
1
Baseline 24hrs post‐infusion
Sta
nd
ard
ized
Su
icid
e C
om
po
sit
e
Ketamine
Midazolam
Reduced scores on 3 combined measures of suicidal cognition (Beck Suicide Scale, MADRS suicide item, QIDS suicide item)
53% of ketamine-treated patients score 0 on all 3 measures
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
Pat
ien
ts w
ith
All
Zer
o
Sco
res
(%)
24 hr post-infusion
Ketamine
MidazolamGroup x time: F
1,54 = 8.8, P = .01
Chi-square=4.6, p=.03
‐1
‐0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
Zero One Two Three Four
Ch
ang
e in
MA
DR
S
Su
icid
e It
em
Baseline MADRS Suicide Item
Ketamine
Midazolam
Ketamine may work best for those at highest risk:
Largest differential effects of ketamine (over midazolam) seen in patients with highest suicidality at baseline
(Group x baseline SI: β = .55, t1,70
= 2.5, P = .02)QIDS = Quick Inventory of
Depressive Symptomatology. Price RB, et al. Depress
Anxiety. 2014;31(4):335-343.
Controlled Trial of Ketamine for Suicidal Ideation
Repeated Ketamine Infusions in TRD: Pilot Experience
Murrough JW, et al. Biol Psychiatry. 2013;74(4):250-256.
Caveats
• Dissociative Side Effects
• General Side Effects
• Effects on Hemodynamics
• Abuse Liability
Effects on Positive Psychotic Symptoms
*4 key BPRS items: conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content. Scores range from 4 to 28. BPRS = Brief Psychiatric Rating Scale.Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.
Dissociative Side Effects
CADSS = Clinician Administered Dissociative States Scale.Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.
• Dissociative properties– Things in slow motion– Things seem unreal– Disconnected from body– Sense of body changed
Pooled Analysis of Behavioral and Hemodynamic Effects of IV Ketamine in TRD
Wan LB, et al. J Clin Psychiatry. 2015;76(3):247-252.
Neurocognitive Impact of Ketamine 1 Week following Treatment
Murrough JW, et al. Neuropsychopharmacology. 2015;40(5):1084-1090.
Mechanisms of Action: Beyond NMDA Receptors?
Ketamine might work in depression because of activity in non-NMDA receptors
Effects of Prolonged Stress
Duman RS, et al. Science. 2012;338(6103):68-72. mTOR = mammalian target of rapamycin. Cryan JF, et al. Science. 2010;329(5994):913-914.
Increased spine density (24 hr)
Presynaptic membrane
Ketamine or NR2B antagonist
ERK, AKT
mTOR
synapsin
Postsynaptic membrane
PSD95 GluR1
Synaptic activity inc.
4E-BP1 p70S6K
AMPA
Prefrontal cortex
A glutamate pathway to faster acting antidepressants? A single dose of ketamine induced rapid activation of
mTOR mediated signaling pathways
Duman RS, et al. Trends Neurosci. 2012;35(1):47-56.
Signaling Pathways Underlying the Rapid Antidepressant Response to Ketamine
Are the Antidepressant Actions of Ketamine Independent of NMDA Receptor Activity?
Zanos P, et al. Nature. 2016;533(7604):481-486. Malinow R. Nature. 2016;533(7604):477-478.
KYN pathway induced in suicidal patients, associated with inflammation
Mechanisms: Suicide Attempts and High Suicidal Intent Associated with Increases in
Inflammatory Marker Quinolinic Acid
KYNA = kynurenic acid; KYN = kynurenine; QUIN = quinolinic acid; TRP = tryptophan.Schwarcz R, et al. Nat Rev Neurosci. 2012;13(7):465-477. Erhardt S, et al. Neuropsychopharmacology. 2013;38(5):743-752.
“Kinder and Gentler” Glutamate-Based Approaches?
Survey of recent developments
NMDA Complex Modulators
Na Channel Riluzole
mGluR2 PAMs JNJ-40411813 ADX41149
mGluR2/3 Antagonists MGS0039 LY341495
mGluR2/3 NAMs R04491533 R04499819
mGluR5 NAMs AZD2066 STX-107 R04917523 RG7090
(Basimglurant)
GlyT-1 Inhibitors Sarcosine Bitopertin
Glycine Agonists D-serine
Glycine Partial Agonists Rapastinel NRX-1074
Glycine Antagonists D-cycloserine 4-CI-KYN (AV-101))
EAAT2 Enhancers Ceftriaxone
AMPA Potentiator ORG-26576 2S,6S-HNK; 2R,6R-
HNK
EAAT = excitatory amino acid transporter; NAMs = negative
allosteric modulators; PAMs = positive allosteric modulators.
Courtesy of Carlos A. Zarate, MD.
Candidate Glutamatergic Modulators for Depression Investigational NMDA Receptor Antagonists for Major Depressive Disorder (2016)
Compound Pharmacology Company Route Status
GLYX-13 (rapastinel)
Glycine site partial agonist
Allergan IV Phase 3
NRX-1074Glycine site partial
agonistAllergan oral Phase 2
CERC-301NR2B-selective
antagonist Cerecor Oral Phase 2
EsketamineNonselective,
noncompetitive Channel blocker
Janssen Intranasal Phase 3
AVP-786
Nonselective uncompetitive
NMDAR antagonist(deuterated
dextromethorphan + quinidine)
Avanir(Otsuka)
IV Phase 2
AV-101 (4-Chlorokynurenine)
Glycine site antagonist
VistaGen oral Phase 2
Memantine: Lack of Efficacy in Major Depressive Disorder
Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.
Early Antidepressant Effect of Memantine during Augmentation of Lamotrigine in Bipolar Depression:
A Double‐Blind, Randomized, Placebo‐Controlled Trial
P = .04.Anand A, et al. Bipolar Disord. 2012;14(1):64-70.
Inhibitsglutamate
release
IncreasesGlutamate reuptake
Riluzole Mechanism of Action
Sanacora G, et al. Nat Rev Drug Discov. 2008;7(5):426-437.
IncreasesAMPA
trafficking
RegulatesNeurotrophic
factors
Lanicemine in TRD
Sanacora G, et al. Mol Psychiatry. 2013;19(9):978-985.
Glial Cystine-Glutamate Exchanger and Regulation of Oxidative Stress
GSH = glutathione; NAC = N-acetylcysteine.Gunduz-Bruce H. Brain Res Rev. 2009;60(2):279-286. Gunduz-Bruce 2008
NAC
GSH
Glu
GlutathioneKetamine
Riluzole
Glu
D-Cycloserine: Enhancement of Extinction Learning
Repurposing an old drug used for treatment of tuberculosis
D-Cycloserine
CBT = cognitive-behavioral therapy; DCS = d-cycloserine; OCD = obsessive-compulsive disorder.Otto MW, et al. Biol Psychiatry. 2015;[Epub ahead of print].
• Partial agonist of NMDAR glycine site, with antagonist activity at higher doses
• Preclinical models have found that infusion of DCS in specific fear extinction circuits aids in the consolidation of extinction learning
• Since 2004, numerous clinical studies (anxiety disorders, OCD, addictions, schizophrenia, anorexia nervosa), with administration of DCS before exposure/CBT
• Goal: enhance the consolidation of therapeutic learning of CBT
D-Cycloserine
Otto MW, et al. Biol Psychiatry. 2015;[Epub ahead of print].
• Results in anxiety disorders – DCS works best when fear reduction achieved in-
session; it can then truly augment– Dose range 50 mg to 250 mg
• Results in substance use disorders– DCS augmentation of cue exposure less compelling,
possibly due to inadequate extinction
D-Cycloserine (1 g/day) Augmentation in TRD
Heresco-Levy U, et al. Int J Neuropsychopharmacol. 2013;16(3):501-506.
• Response over Time• Serum glycine elevations
have been associated with SSRI non-response
• Effect size largest in patients with highest serum glycine levels (≥ 300 μM)
• Favorable tolerability
• Previous trial of 250 mg/day was negative; thus, higher doses might be necessary to induce NMDAR antagonist effect
Conclusions
• Glutamate is the main excitatory amino acid neurotransmitter in the CNS
• A major function of its receptors is the modulation of synaptic plasticity, critical for memory, learning, and potentially for antidepressant response
• The initial promise of ketamine for depression has sparked interest in the role of specific glutamate receptors such as NMDA and AMPA
• Recent evidence supports the role of non-NMDA receptor activity in the cascade of events involved in rapid antidepressant activity
Practical Take-Aways
• While ketamine is increasingly administered off-label in specialized clinics, there is a lack of long-term data to guide clinicians beyond the acute phase
• Given the potential hemodynamic risks of ketamine, monitoring by an ACLS-trained clinician is prudent
• Glutamate modulators such as memantine and riluzolemay have limited or no significant benefit for depression
• D-cycloserine (high dose) has promising results for TRD, while a low dose may enhance extinction in fear-based disorders
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