Ann. N.Y. Acad. Sci.

ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
Issue: Translational Neuroscience in Psychiatry

Translational psychiatry—light at the end of the tunnel

Kenneth A. Jones,1 Frank S. Menniti,2 and Digavalli V. Sivarao3
1
Cyanaptic LLC, Glen Rock, New Jersey. 2 Mnemosyne Pharmaceuticals, Inc., Providence, Rhode Island. 3 Bristol–Myers
Squibb Co., Wallingford, Connecticut

Address for correspondence: Kenneth A. Jones, Cyanaptic LLC, 25 Warren Place, Glen Rock, NJ 07452.
kenjones120@gmail.com

Neuroscience has made tremendous progress delineating the cellular and molecular processes important for under-
standing neuronal development and behavior, but this knowledge has been slow to translate to new treatments for
psychiatric illness. To accelerate this transfer of knowledge to the human condition requires the wide-scale adoption
of biomarkers that can bridge preclinical and clinical discoveries, and serve as surrogate measures of efficacy before
commencing expensive phase III studies. Several biomarker methodologies, including imaging, electroencephalog-
raphy (EEG), and blood transcriptomics/proteomics, are now showing promise. From an industry perspective, we
highlight the utility of quantitative EEG as one example of a translatable biomarker applicable to psychiatric drug
development and discuss recent insights into glutamate system dysfunction in schizophrenia and depression gained
through translational studies of the drug ketamine.

Keywords: translational; psychiatry; biomarker; electroencephalography; glutamate; ketamine

Introduction: translational psychiatry imbalance? While we may infer answers to these

questions from animal studies, the limited abil-
Despite the tremendous growth in the field of neu-
ity to gather data directly from humans suffering
roscience over the past 30 years, the number of
from central nervous system (CNS) dysfunction
truly novel treatments for psychiatric disorders has
has been a longstanding bottleneck to treatment
been disappointing. Many reasons come to mind
development.
to explain this apparent disconnect, including an
The good news for brain research is that an
early naiveté about the complexity of the nervous
increasingly sophisticated armament of tools is
system, lack of disease models, and the inadequacy
being applied by neuroscientists to the human brain
of currently used end points for gauging the suc-
to answer these questions, offering new insights into
cess of clinical trials. However, perhaps the most
the nature of brain dysfunction that gives rise to
significant impediment has been the relative inac-
psychiatric maladies. To discuss this rapidly advanc-
cessibility of the human brain to direct measure-
ing area was the impetus for a 1-day conferencea
ments of molecular and cellular function. There
“Translational Psychiatry: Light at the End of the
is no question that the complexity of the human
Tunnel,” the spirit of which can be captured in the
brain is staggering, where numbers of neurons and
following: nothing can be done to reduce the com-
permutations of synaptic connections are immense,
plexities of the brain so they should be embraced,
and yet somehow from this complexity, sentience,
and the heretofore inadequate accessibility of the
dexterity, planning, creativity, and emotion are
brain, lack of disease models, and quantitative
born. But what happens when something goes
wrong?—when the developmental path deviates at
some point or a cluster of genes fails to main- a
Held at the New York Academy of Sciences, New York,
tain the balance of synapses, and mood plummets, NY, on April 8, 2014. Papers prepared by speakers at the
thoughts race, or hallucinations arise? Which are conference are published in Ann. N.Y. Acad. Sci. 1344:
the circuits or neurotransmitters that manifest the 1–119 (2015).

doi: 10.1111/nyas.12725
Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 
C 2015 New York Academy of Sciences. 1
Translational psychiatry
clinical end points are essentially technical issues
that ultimately will be addressed. Optimism for
this comes, in part, from sophisticated imaging and
electroencephalography (EEG) technologies that
open a rich information window into human brain
function and dysfunction. These insights, in turn,
are being translated back to the preclinical realm to
guide yet more sophisticated analyses in preclinical
species, the development of better animal disease
models, and the investigation of new drug targets.
The circle is being completed by forward translation
of this preclinical research into new biomarkers for
target engagement and efficacy that may be used in
the clinical evaluation of potential new drugs. This
paper provides the background and impetus for
the conference, an industry perspective on recent
trends in clinical development in psychiatry, and a
brief overview of some current approaches to find
suitable biomarkers for psychiatric diseases. We
focus our discussion on the emerging recognition
of the role of glutamate neurotransmission dys-
function in psychiatric illness and the use of EEG
methodology as a tool for novel discovery.
An industry perspective and the growing
need for biomarkers
Despite the compelling need for new and improved
medications to address the large unmet needs of
psychiatry patients, currently there is a near stand-
still in industry discovery.1 This is particularly true
at large pharmaceutical companies, traditionally the
most prolific stakeholders in shepherding new drugs
to clinical practice. Large pharmaceutical compa-
nies occupy a particularly important niche in the
lengthy and costly process of the late stages of drug
development: the planning and execution of phase II
and phase III efficacy trials. However, the frequently
ambiguous outcomes of phase II proof-of-concept
studies, in the face of increased costs of running large
clinical trials, have led to a recent exodus of pharma
from their traditional niche. The perception, for
better or for worse, is that the underlying science
remains immature relative to the investment risks
for success in clinical development. A major stum-
bling block often cited is the poor predictive value of
animal models of psychiatric disease. A case in point
is animal models of depression. Models such as the
forced swim test were widely adopted because they
showed responses to existing antidepressant drugs,
not because they replicated a key neurophysiological
2 Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 
Jones et al.
aspect of the human illness. As a result, new drugs
discovered using these models looked very much
like the ones used to validate the models in the first
place; the current generation of antidepressant and
antipsychotic drugs has provided limited improve-
ments in efficacy relative to drugs described 30 years
ago.
Another major reason for the exit of a significant
portion of the pharma industry from psychiatric
drug R&D has been the lack of target engagement
and efficacy biomarkers. A careful analysis2 of data
from dozens of clinical drug development studies at
Pfizer concluded that to maximize odds for success
in phase III, it was imperative to ensure that the
drug in question not only is present at the target
site but also has a demonstrable pharmacodynamic
activity commensurate with engagement.2 Not hav-
ing a clear pharmacodynamic marker often leads to
a highly unsatisfactory situation of being unable to
determine whether the original hypothesis had been
tested. While it may seem obvious that unequivo-
cal evidence for functional engagement is an essen-
tial component of a drug’s clinical development,
demonstrating such engagement has been a signif-
icant challenge for most psychiatric drug discovery
to date.3–5
The current situation has drawn the attention
of the National Institute of Mental Health (NIMH)
and other thought leaders, who have reflected on
past failures to suggest new approaches to accelerate
scientific breakthroughs.1,6 Over the past several
years, attention has shifted away from behav-
ioral animal models based on predictive validity
derived from currently used agents toward genetic
approaches to understanding brain function and
dysfunction at the molecular and circuit levels.7,8
The affordability of genomic sequencing has driven
the discovery of multiple susceptibility genes for
schizophrenia and autism,9–11 as but two examples.
Although the polygenic nature of these and other
psychiatric diseases presents a new challenge for
those building genetically based disease models,
collectively, the gene defects point to key foci of
neural function, such as synaptic transmission and
circuit development.7,9,10 These promising discov-
eries portend a more molecular and circuit-based
understanding of the processes that are compro-
mised in disease, and importantly, improved animal
models and translatable endophenotypes that will
have prognostic value in the clinic.8,12
C 2015 New York Academy of Sciences.
Jones et al.
Genetics alone, however, will not solve the cur-
rent drug discovery bottleneck. There is also new
urgency for developing truly translatable measures
of brain activity relevant to psychiatry that span
both the laboratory and the clinic. In other CNS dis-
eases such as Alzheimer’s disease, the first biomark-
ers will soon be available as surrogate end points for
proof-of-concept clinical trials.13 The importance of
these developments cannot be overstated especially
for long-duration, and therefore expensive, human
studies. Translatable biomarkers for psychiatric dis-
orders may not be far behind. To spur the develop-
ment of tools that will provide these measures, the
NIMH recently released new guidelines for requir-
ing the incorporation of biomarkers in every clinical
trial sponsored by the institute.14 Although perhaps
burdensome, this new requirement promises to pro-
vide critical data linking surrogate end points to
primary measures of clinical efficacy. It is impor-
tant to distinguish prognostic biomarkers that can
be used to predict efficacy in humans from diagnos-
tic biomarkers that can be used to correctly identify
disease subtypes. It is primarily the former that is
discussed here, particularly biomarkers with both
prognostic and translational value, even though
diagnostic biomarkers will be needed in psychiatry
to correctly identify patient segments that may bene-
fit from specific treatments. Examples of prognostic
biomarker development include more sophisticated
and widely available magnetic resonance imaging
(MRI) and functional MRI technologies used in the
study of depression that are zeroing in on areas of
the brain, such as the amygdala and medial pre-
frontal cortex, that emit different signals in nor-
mal and depressed individuals.15,16 Likewise, in the
field of schizophrenia, EEG methods are revealing
electrical signatures of cognitive deficits whose early
appearance in children predict the development of
the illness later in life.17,18 When used in concert
with event-related potentials, EEG exhibits the tem-
poral resolution necessary to detect deficits in sen-
sory processing or attention.19 Finally, blood-based
biomarkers, particularly for depression, are reveal-
ing underappreciated biochemical links between the
periphery and the brain. Interestingly, some of these
biomarkers normalize with treatment while others
do not, raising the possibility that certain blood
biomarkers could be helpful for identifying patient
subpopulations responsive to treatment.20–22 If
sufficiently developed and validated, peripheral
Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 
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Translational psychiatry
biomarkers may one day offer the practicality of
use required for inclusion in large clinical trials.
Use of quantitative EEG in drug discovery
EEG-based techniques are used to illuminate cir-
cuit dysfunction underlying psychiatric illness and
quantify circuit-relevant pharmacodynamic activ-
ity of novel drugs. Glutamatergic principal neu-
rons form the core circuitry of the forebrain,
and modulation of glutamatergic synapses is the
brain’s informational currency. Activity in forebrain
glutamatergic circuits, as modulated by the gamma-
aminobutyric acid (GABA)ergic interneuron net-
work, gives rise to the translational imaging and
electrophysiological signals currently under investi-
gation by many investigators.b Emerging from these
studies is insight into the circuit-level dysfunction
that gives rise to schizophrenia and depression.
Several EEG-based functional biomarkers, such as
mismatch negativity and 40-Hz auditory steady-
state response, lend themselves to interrogate
specific circuit-level dysfunction.23
We highlight here the characteristics of quanti-
tative EEG (qEEG) as a relatively inexpensive and
accessible functional engagement measure that can
be used to bridge preclinical and early clinical stud-
ies for glutamatergic and other targets. We then
focus on the recent explosion of cross-species stud-
ies using glutamatergic drugs, notably ketamine,
that are beginning to yield an understanding of the
molecular mechanisms underlying circuit dysfunc-
tion in depression and schizophrenia. The conver-
gence of these two themes may well represent the
beginning of a renaissance in CNS drug discovery.
On the basis of our experience from the applica-
tion of qEEG to multiple CNS discovery programs
as well as selected examples from the published
literature, we will discuss several key factors that
impact translatability. Many articles and reviews
have been published on qEEG as a potential phar-
macodynamic measure for early discovery.19,24–26
Some have focused on analytical methods for
qEEG that need to be appreciated for effective
application.27,28 We encourage the reader to consult
these monographs for an in-depth review of qEEG
as a technique, as well as the analytical approaches
used. Here, we summarize key attributes that we
b
Including some of the speakers at the conference.
3
Translational psychiatry
believe are essential for using qEEG as a transla-
tional pharmacodynamic measure and illustrate
how these have facilitated its use as a critical
biomarker for N-methyl-D-aspartate (NMDA)
channel blockers, especially in relation to treatment
options for treatment-resistant depression.
The EEG signal arises principally from summated
postsynaptic activity of large populations of neurons
within the cortical mantle. While neurons through-
out the brain contribute to fluctuations in the field
potential, the relatively large and numerous cor-
tical pyramidal neurons with their extensive den-
dritic processes and laminar arrangement are the
principal sources of fluctuating field potential reg-
istered by scalp electrodes. Quantitative EEG as a
technique refers to dividing the oscillatory EEG sig-
nal into broad frequency bands and analyzing the
signal power within these bands.29 While we do
not completely understand the individual signifi-
cance of these bands and how they may interact
with each other in support of physiological func-
tion, we do know that in many regions of the cor-
tex, higher-frequency oscillations are nested within
a slower-frequency field potential change,30,31 and
that inhibitory and excitatory neurons in the cor-
tex and thalamic nuclei interact to produce these
fluctuations.32,33 Rhythmic oscillations of a fre-
quency band are often associated with particular
physiological states. For example, delta frequency
(0.5–4 Hz) oscillations occur in deep sleep as a
result of thalamic burst firing. Sleep spindles in the
alpha frequency range (9–13 Hz) are generated
by the thalamic reticular nucleus whereas the occip-
ital alpha rhythm, characteristic of relaxed wake-
fulness, is generated in deep layers of the visual
cortex. Higher frequency beta (13–30 Hz) and
gamma (30–100 Hz) oscillations, associated with
mental alertness, appear to originate locally in the
cortex,34,35 although these too can be markedly
influenced by thalamic input.36,37 Since several
classes of drugs affect specific oscillatory bands
in an exposure- and time-dependent fashion, pre-
sumably owing to their effects on the underlying
circuits, a tactical opportunity arises to use these
changes as a pharmacodynamic biomarker as well
as to model effects over time to make predictions
regarding dose regimen and interval. It is important
to recognize that the qEEG changes may or may
not be related to efficacy of the drug, yet they can
be used as an engagement marker to demonstrate
4 Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 
Jones et al.
drug-related activity in the brain and to drive early
clinical discovery.2,3,5
In the absence of any existing clinical data that
support the use of qEEG as a pharmacodynamic
biomarker for a given target, which often is the
case for novel targets, a starting point would be
to demonstrate a robust effect in experimental ani-
mals in a dose-ranging study. Using rodents as a
starting point to investigate the potential for qEEG
as a pharmacodynamic biomarker is a viable strat-
egy, provided the cross-species target physiology is
conserved. If qEEG effects in rodents are robust and
are determined to be specific to the target, and in
the absence of clinical data, moving on to a higher
species, such as a nonhuman primate, may be con-
sidered as a bridge to clinical studies.
Preclinically, EEG is frequently recorded from
epidural electrodes that bypass the skull and sample
directly from the brain where the signal registration
is stronger and spectrally more complete. In order to
have a greater probability for success across species,
it is important to consider not only statistical sig-
nificance but also how robust the drug-mediated
effects are. Thus, an effect size analysis using an indi-
cator such as Cohen’s d (mean difference between
control and treatment in pooled standard deviation
units) is warranted. As a rule of thumb, a Cohen’s
d of 0.8 or greater could trigger further investi-
gation for translatability. A recent study used two
NMDA channel blockers, ketamine and lanicem-
ine, to show robust and dose-dependent increases
in gamma oscillations in rodents that were subse-
quently translated into healthy human volunteers.38
In addition to these two examples, there is a sig-
nificant body of literature that suggests that this
translational approach is indeed viable for certain
classes of drugs.24,39,40
Despite showing consistent and strong effects, it
is frequently not possible to explain the exact basis
for qEEG changes because they ensue following
drug exposure to very large and diverse populations
of neurons in the brain. Moreover, multiple drug
classes can in some cases produce the same qEEG
response. For example, both benzodiazepine ago-
nists and NMDA antagonists can increase cortical
high-frequency oscillations, albeit through distinct
molecular targets.41,42 However, it is possible to
determine specificity by demonstrating a causal
relationship between the target and the response.
For example, benzodiazepine agonist effects on
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Jones et al.
qEEG are blocked by selective antagonism with
flumazenil, a benzodiazepine-selective antagonist,
in rodents41 and in humans.43 On the other hand,
gamma oscillations elicited by NMDA channel
blockers are thought to result from the disinhibi-
tion of pyramidal cells owing to the NMDA block
of parvalbumin+ inhibitory interneurons.44,45
In fact, MK-801–induced gamma oscillations
have been shown to be attenuated in genetically
engineered mice that express a deficient NMDA
channel complex in parvalbumin+ interneurons.46
Additional means to ensure causality would be
to demonstrate, where available, differentiation
of response using enantiomers (e.g., R- versus
S-baclofen47 ) or by contrasting two compounds
with similar in vitro activity against the target but
different CNS penetration. The characterization of
specificity at the preclinical stage is important not
only to ensure that the EEG response is linked to
the target in question but also because, frequently,
this is the only stage where it is practical to do
so.
Although any drug that works on the nervous
system could in theory affect the qEEG response,
in practice such changes are large and consistent
enough only for certain classes of drugs. Since
synchronization within cortical columns is largely
responsible for the scalp-recorded EEG signal, it is
important for any candidate drug to target, either
directly or indirectly, cortical neurons. Immunohis-
tochemical labeling with an antibody raised against
the obligatory subunit NR1 of the NMDA channel
demonstrates a robust presence of the receptor
within the cortex, both on pyramidal cell layers
and on inhibitory neurons across multiple species,
including rodents and humans.48–50 Commensurate
with the widespread expression of its molecular
target, nonselective channel blockers, such as
ketamine, produce a strong cortical disinhibition
as evidenced by a selective reduction of fast-spiking
putative GABAergic interneurons and a widespread
increase in pyramidal cell firing in rodents.44 NMDA
channel blockers produce a robust, dose-dependent,
and long-lasting increase in high-frequency gamma
oscillations (e.g., 30–55 Hz) in mice and rats, as well
as in humans as discussed above.38,42,45,46 Perhaps
for this reason alone, many of the clinical studies in
psychiatry that employ EEG as a response measure
are evaluating drugs that target the NMDA channel.
Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 
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Translational psychiatry
An important attribute for a pharmacodynamic
biomarker is for the signal to scale in a dose- or
exposure-dependent manner. Apart from NMDA
channel blockers, several other pharmacologi-
cal classes of drugs evoke dose- or exposure-
proportional EEG responses, including opiates,
barbiturates, benzodiazepines, and inhalational and
injectable anesthetics, and lend their effects to phar-
macokinetic–pharmacodynamic correlation.24,25 A
corollary follows that the lack of a clear linearity of
dose response in qEEG measures would suggest that
this tool would be of limited utility for a phase-I
biomarker. For example, nicotinic alpha7 recep-
tor agonists frequently show an inverted U-shaped
response across multiple paradigms,51,52 perhaps
owing to rapid desensitization of the nicotinic chan-
nels at higher exposure. We have observed that EEG
changes seen at lower doses frequently disappear at
higher doses (unpublished data), making the use
of qEEG for this particular target unsuitable as a
biomarker.
In summary, a significant challenge in psychiatric
drug discovery is to have translational biomarkers
that can inform the researchers about the unequivo-
cal presence of the drug being tested in the brain and
its time course, using affordable, noninvasive, and
nondeleterious approaches. Translatability implies
that the qualitative changes noted in preclinical
species (e.g., rodents and/or primates) are essen-
tially reproducible in humans. Quantitative EEG
offers a simple and relatively inexpensive modal-
ity for translation across preclinical species and
humans. While this measure cannot always be linked
to the overall efficacy of a drug, it can offer a pharma-
codynamic sign of the drug’s presence and activity
in the brain. Such functional markers, as opposed to
physical engagement markers (e.g., receptor occu-
pancy or positron emission tomography imaging),
may be especially relevant for high-efficacy agonists
that produce pharmacological responses at very low
occupancy, an observation explained by the con-
cept of high receptor reserve.53,54 Quantitative EEG
effects in early discovery can guide dose selection
and dosing interval for subsequent phases of clini-
cal discovery. However, qEEG is not suitable for all
centrally acting targets. Its translational utility
would be target-specific and determined by such
factors as the cortical footprint of the target, effect
size, and exposure–response linearity.
5
Translational psychiatry Jones et al.

New treatments targeting glutamate psychosis in schizophrenia.60 Subsequently, it was

neurotransmission determined that these effects of PCP result from
NMDA receptor inhibition. Ketamine, a PCP ana-
A second translational approachc is the use of the
log, was then adapted as the clinical translational
drug ketamine to probe the role of glutamate in
tool to systematically probe these psychotomimetic
psychiatric illness. Ketamine is an antagonist of the
effects of NMDA receptor blockade.61,62 In fact,
NMDA receptor, one of the four classes of receptors
clinical studies by Javitt et al. established that
(AMPA, kainate, NMDA, and metabotropic) that
ketamine produces not only acute psychotic symp-
mediate glutamate neurotransmission. NMDA
toms, but also broader cognitive and negative
receptors have a critical function in regulating the
symptoms experienced by patients suffering from
excitation/inhibition balance that governs infor-
schizophrenia.62–64 Collectively, these clinical data
mation flow through glutamatergic/GABAergic
have given rise to the hypothesis that NMDA recep-
networks.55,56 These receptors also play the prin-
tor hypofunction is a key molecular defect underly-
cipal role in regulating glutamate synaptic strength
ing the expression of all of the complex symptoms
through the activation of pathways that insert or
of schizophrenia.64,65 Recent genetic evidence sup-
remove AMPA receptors from the synapse and that
ports this hypothesis.66 Indeed, the NMDA hypo-
trigger protein translational and transcriptional
function hypothesis is now driving the search for
pathways that support long-term modification
new treatments for schizophrenia.63,67
of synapses.57–59 There is a rich pharmacology
The more recent story of ketamine in depression
of NMDA receptor antagonists and these agents
arises from the drug’s use as a clinical translational
have been part of the experimental toolbox that
probe, in this case of cognitive dysfunction in
has helped gain our current understanding of
depression.68 Berman et al. gained approval in the
glutamate system physiology.56 Numerous NMDA
late 1990s to use ketamine to investigate cognition
receptor antagonists have been advanced into
in depression.68 In their study, a short intravenous
clinical trials for indications including anesthesia,
infusion of ketamine resulted in the expected acute
neuroprotection in stroke, neuropathic pain,
PCP-like psychotomimetic effects; these waned
Parkinson disease, and Alzheimer’s disease. While
rapidly after the infusion was stopped, consistent
these efforts failed to yield commercial successes
with the drug’s short half-life and indicative that
(with the exception of memantine for Alzheimer’s
these were the direct result of on-target NMDA
disease), the clinical observations proved a treasure
receptor inhibition. However, as patients waited to
trove of insight into how glutamate system dys-
be discharged, a number reported lessening of their
function may be involved in both schizophrenia
feelings of depression. Berman et al. documented
and depression. Ketamine is an approved drug,
this phenomenon to reveal a clinically significant
albeit only for limited use as a pediatric anesthetic.
antidepressant response to ketamine that developed
However, because of its availability for clinical
in the hours after the drug had been cleared from
studies, ketamine has emerged as a powerful cross-
the body.68 This finding, published in 2000, was
species translational tool in the systematic investi-
replicated in 2006 by Zarate et al.69 Since then,
gation of the previous clinical observations. This
interest in the rapid-onset antidepressant effects of
line of investigation has been, and continues to be,
ketamine gained momentum and well over a dozen
provocative of a renewed interest in the pursuit of
replications have now been published.70–72
drugs to treat psychiatric disease, as summarized
The robust clinical findings with ketamine, both
below.
as a model of schizophrenia and as an antidepres-
In the late 1950s, Luby and coworkers found that
sant, implicate glutamate system dysfunction at
in healthy volunteer studies, phencyclidine (PCP)
the core of two of the most debilitating and costly
produced a syndrome strikingly similar to acute
psychiatric illnesses. These clinical findings have
spurred back-translational studies to understand
c
Discussed by several speakers at the conference. See Ann. the molecular underpinnings that account for
N.Y. Acad. Sci. 1344: 1–119 (2015), including the papers by these findings.73–78 What are the drug-on effects
Javitt, Featherstone et al., Sivarao, Abdallah et al., Leuchter that induce schizophrenia-like symptoms, and
et al., and Lener & Iosifescu. what is the nature of the drug-off effect that

6 Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 

C 2015 New York Academy of Sciences.
Jones et al.
alleviates depression? Are these effects interrelated
and, if so, what might that imply regarding the
relatedness of these psychiatric conditions? (See
Refs. 79–84 for a discussion of these questions.)
A prevalent hypothesis stems from the putative
selectivity of ketamine for NMDA receptors on
neurons that are most active. Essentially, NMDA
receptor channel block by ketamine is activity
dependent,85 and since NMDA receptors are most
active on active neurons, such neurons are most
sensitive to ketamine. Attention has focused on
selective ketamine inhibition of cortical GABAergic
fast-spiking, parvalbumin+ interneurons, which
are believed to account for two functional effects
of the drug.44,86 Inhibition of NMDA receptors
on the parvalbumin interneurons disrupts their
ability to regulate cortical synchrony,86 reflected
in a shift of cortical gamma band frequency and
power and decreased responsiveness to external
stimuli.87 The disruption of gamma synchrony
is hypothesized to underlie the acute, drug-
on cognitive-disrupting and psychotomimetic
effects of the drug. Selective inhibition of NMDA
receptors on parvalbumin interneurons also
reduces inhibition by these neurons of gluta-
matergic principal neurons, resulting in a net
cortical hyperglutamatergic state.44,86 This drug-on
induction of gamma activity in the context of a
hyperglutamatergic state is hypothesized to engage
synaptic plasticity mechanisms that result in a long-
lasting synaptic potentiation, which may underlie
the drug-off antidepressant response. Clinical sup-
port for this hypothesis is found in the observation
of an increase in somatosensory-evoked potentials,
measured in response to tactile stimulation as an
increase in magnetoencephalographic gamma-band
power that correlates with a drug-off reduction in
depressive symptoms in patients that responded to
ketamine, but not in those that failed to respond.88
Back-translational preclinical studies have provided
biochemical73–77 evidence of such a long-lasting
synaptic potentiation after short ketamine expo-
sure. Thus, the hyperglutamatergic state hypothesis
of ketamine action provides a mechanistic link
between the drug-on and drug-off effects.
Ketamine has proven to be a powerful trans-
lational tool to probe the glutamate system in
psychiatric illness. The clinical behavioral data
strongly implicate glutamate system dysfunction in
schizophrenia and depression. These data set the
Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 
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Translational psychiatry
stage for back-translational studies in both humans
and preclinical species that have yielded an impor-
tant mechanistic framework for understanding the
nature of this dysfunction. Significantly, ketamine
as a clinical probe continues to deliver new insights,
with reports of beneficial therapeutic effects in
patients suffering from bipolar disorder,89 obses-
sive compulsive disorder,90 and posttraumatic stress
disorder.91 However, although the translational
studies with ketamine shed light, they are not the end
of the tunnel. For example, preclinical data suggest
additional complexity to the mechanistic frame-
work laid out above. There are multiple NMDA
receptor subtypes, of which NR2A and NR2B
subtypes predominate in the forebrain.58,92 Com-
pounds highly selective for inhibition of the NR2B
subtype have been developed, including Ro 25–
698193 and CP-10160694 that have been used exten-
sively in preclinical studies to investigate the role of
the NR2B subtype. Significantly, in humans, CP-
101606 causes dose-dependent psychotomimetic
effects that, at high doses, appear to be similar to
those produced by ketamine.95–98 Also similar to
ketamine, a short exposure to CP-101606 produces a
robust antidepressant response that occurs after the
drug has been cleared from the body.98 These clin-
ical data suggest that selective NR2B inhibition has
therapeutic and adverse effects similar to ketamine
in humans. Thus, back-translational studies of the
mechanistic similarities and differences between
ketamine and NR2B antagonists open a new path to
further understanding of the role of glutamate sys-
tem dysfunction in psychiatric illness. To date, pre-
clinical data indicate that both drug classes induce
similar drug-off synaptic potentiation.73,74,76,77
However, Sivarao et al. and others83,87,99 have
found that the NR2B antagonists do not dis-
rupt gamma synchrony in rodents. This lack of
effect on gamma synchrony may be accounted for
by the fact that there appears to be little NR2B
expression by fast-spiking GABAergic interneu-
rons, which predominately express NR2A.100 These
data raise questions regarding the role of gamma
disruption in relation to both psychotomimetic
and antidepressant effects of NMDA receptor inhi-
bition. Future preclinical studies should include
investigations of whether NR2B inhibition induces
a hyperglutamatergic state similar to that of
ketamine. Follow-on human translational stud-
ies might include investigations of the effects of
7
Translational psychiatry
NR2B antagonists on EEG signatures, particularly
gamma synchrony, and whether an antidepressant
response to such a drug is accompanied by a drug-
off synaptic potentiation. Fortunately, the transla-
tional approaches highlighted at the symposium are
well suited to triangulating on mechanistic effects of
these two classes of NMDA antagonists and thereby
provide further insight into the role of glutamate
system dysfunction in psychiatric illness, that is,
bringing us steps closer to the end of the tunnel.
Summary and perspective
Advances in the understanding of psychiatric ill-
nesses and the ability to improve current pharma-
cotherapy will benefit from new tools that bridge
preclinical and clinical studies. The most powerful
of these tools will provide mechanistically concor-
dant insights in both patients and laboratory test
species. We have provided some specific examples
of some promising translatable approaches, with a
focus on the use of EEG; other methods, such as
functional and structural MRI and blood biomark-
ers, are being applied as well. EEG satisfies many
criteria of a good translatable biomarker, namely
large effect size, ability to inform about disease-
relevant brain circuits, homologous measurements
in both patients and laboratory animals, and dose-
dependent effects of the drug. Historical and recent
studies point to glutamatergic mechanisms as cen-
tral to the understanding of mental disorders, and
although the role of glutamatergic signaling in dis-
ease causation is poorly understood, glutamate and
its receptors dominate synaptic signaling, especially
in cortical areas affected in psychiatric disorders.
Perturbation of cortical function by ketamine and
other NMDA antagonists is readily detected by EEG
methods that are now being used to define surro-
gate markers for both the adverse and therapeutic
effects of these novel therapies.37 It may well be that a
marriage of the renewed interest in glutamate phar-
macology with robust translatable biomarkers will
provide the impetus for an improved mechanistic
understanding of psychiatric disorders.
Acknowledgments
We wish to acknowledge the Biochemical Pharma-
cology Discussion Group at the New York Academy
of Sciences for their partnership in organizing the
conference.
8 Ann. N.Y. Acad. Sci. 1344 (2015) 1–11 
Jones et al.
Conflicts of interest
F.S.M. is currently the Chief Scientific Officer of
Mnemosyne Pharmaceuticals, Inc., which is devel-
oping glutamate receptor modulators to treat psy-
chiatric disorders.
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