Synaptic Potentiation Is Critical for Rapid Antidepressant Response to Ketamine in Treatment-Resistant Major Depression

doi:10.1016/j.biopsych.2012.03.029

Biological Psychiatry

Volume 72, Issue 7, 1 October 2012, Pages 555-561

https://doi.org/10.1016/j.biopsych.2012.03.029 Get rights and content

Background

Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine.

Methods

Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores.

Results

Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders.

Conclusions

These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.

Section snippets

Patients

All patients were studied at the National Institute of Mental Health in Bethesda, Maryland, between January 2007 and December 2009. Twenty right-handed patients (5 women, 46 ± 14 years of age) with a DSM-IV diagnosis of MDD (30) without psychotic features met the following inclusion criteria: current major depressive episode of at least 4-week duration, current or past history of lack of response to two adequate antidepressant trials (19 of 20 patients met this criterion for the current

Symptomatic Change

Paired t tests (Bonferroni-corrected) were conducted to assess symptom change at each time point after ketamine, relative to baseline scores taken 60 min before the infusion. One patient was missing a MADRS score at 40 min, a BPRS-pos score at 40 min and 80 min, and a CADSS score at 80 min. A second patient was missing a CADSS score at 40 min. The MADRS scores were significantly reduced at all time points (all t values > 4.7, p values < .001) (Figure 2A). Nine patients reached a response

Discussion

Here we investigated cortical changes associated with ketamine administration in the context of treatment response in treatment-resistant MDD patients. Stimulus-evoked responses and spontaneous SS ctx activity were measured with MEG before and after a single infusion of ketamine to extend our previous work that focused exclusively on pretreatment brain-based predictors of treatment response (43, 49, 50). For those patients exhibiting a rapid and robust reduction in depressive symptoms

References (57)

C. Yüksel et al.
Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders
Biol Psychiatry
(2010)
S. Maeng et al.
Cellular mechanisms underlying the antidepressant effects of ketamine: Role of αa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
Biol Psychiatry
(2008)
H. Koike et al.
Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression
Behav Brain Res
(2011)
R.S. Duman et al.
Signaling pathways underlying the pathophysiology and treatment of depression: Novel mechanisms for rapid-acting agents
Trends Neurosci
(2012)
I. Song et al.
Regulation of AMPA receptors during synaptic plasticity
Trends Neurosci
(2002)
A. Maksimow et al.
Increase in high frequency EEG activity explains the poor performance of EEG spectral entropy monitor during S-ketamine anesthesia
Clin Neurophysiol
(2006)
D. Pinault
N-methyl D-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant γ oscillations in the rat neocortex
Biol Psychiatry
(2008)
J. Vrba et al.
Signal processing in magnetoencephalography
Methods
(2001)
B.R. Cornwell et al.
Evoked amygdala responses to negative faces revealed by adaptive MEG beamformers
Brain Res
(2008)
G. Salvadore et al.
Increased anterior cingulate cortical activity in response to fearful faces: A neurophysiological biomarker that predicts rapid antidepressant response to ketamine
Biol Psychiatry
(2009)

R.W. Cox

AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages

Comput Biomed Res

(1996)

G. Salvadore et al.

Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine

Neuropsychopharmacol

(2010)

J.W. Newcomer et al.

Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis

Neuropsychopharmacol

(1999)

G.W. Valentine et al.

The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [¹H]-MRS

Psychiatry Res: Neuroimage

(2011)

E.C. Fuchs et al.

Recruitment of parvalbumin-positive interneurons determines hippocampal function and associative behavior

Neuron

(2007)

G. Sanacora et al.

Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

Nat Rev Drug Discov

(2008)

R. Bernard et al.

Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression

Mol Psychiatry

(2011)

P.V. Choudary et al.

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Proc Natl Acad Sci U S A

(2005)

C.A. Zarate et al.

A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression

Arch Gen Psychiatry

(2006)

N. DiazGranados et al.

A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression

Arch Gen Psychiatry

(2010)

C.A. Zarate et al.

Replication of ketamine's antidepressant efficacy in bipolar depression: A randomized controlled add-on trial

Biol Psychiatry

(2012)

A.E. Autry et al.

NMDA receptor blockage at rest triggers rapid behavioural antidepressant response

Nature

(2011)

N. Li et al.

mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists

Science

(2010)

J. Du et al.

The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: Relationship to clinical effects in mood disorders

Neuropsychopharmacol

(2007)

R.-J. Liu et al.

Brain-derived neurotropic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex

Biol Psychiatry

(2011)

R. Machado-Viera et al.

Brain-derived neurotrophic factor and initial antidepressant response to an N-Methyl-D-Aspartate antagonist

J Clin Psychiatry

(2009)

H. Homayoun et al.

NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons

J Neurosci

(2007)

B. Moghaddam et al.

Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade

J Neurosci

(1997)

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Archival ReportSynaptic Potentiation Is Critical for Rapid Antidepressant Response to Ketamine in Treatment-Resistant Major Depression

Background

Methods

Results

Conclusions

Section snippets

Patients

Symptomatic Change

Discussion

Biol Psychiatry

Biol Psychiatry

Behav Brain Res

Trends Neurosci

Trends Neurosci

Clin Neurophysiol

Biol Psychiatry

Methods

Brain Res

Biol Psychiatry

Comput Biomed Res

Neuropsychopharmacol

Neuropsychopharmacol

Psychiatry Res: Neuroimage

Neuron

Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

Nat Rev Drug Discov

Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression

Mol Psychiatry

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Proc Natl Acad Sci U S A

A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression

Arch Gen Psychiatry

A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression

Arch Gen Psychiatry

Replication of ketamine's antidepressant efficacy in bipolar depression: A randomized controlled add-on trial

Biol Psychiatry

NMDA receptor blockage at rest triggers rapid behavioural antidepressant response

Nature

mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists

Science

The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: Relationship to clinical effects in mood disorders

Neuropsychopharmacol

Brain-derived neurotropic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex

Biol Psychiatry

Brain-derived neurotrophic factor and initial antidepressant response to an N-Methyl-D-Aspartate antagonist

J Clin Psychiatry

NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons

J Neurosci

Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade

J Neurosci

Archival Report
Synaptic Potentiation Is Critical for Rapid Antidepressant Response to Ketamine in Treatment-Resistant Major Depression