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THE NEWSLETTER
O F T H E J O H N S H O P K I N S D E PA RT M E N T O F P S Y C H I AT RY A N D B E H AV I O R A L S C I E N C E S
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Koko Ishizuka, right, together
with research program manager
Yukiko Lema, center, and research
assistant Cecilia Higgs, is tapping
the unique characteristics of
olfactory neurons to study
dynamic changes in patients with
neuropsychiatric disorders.
A Whiff of Psychiatric Disorder
M
uch like other stealth diseases—think pancreatic
and liver cancers, for example—schizophrenia
is notorious for seeming to arrive only in fullblown severity.
And just as oncology researchers have been seeking
biomarkers that signal the presence of neoplasms at a
stage when they’re most easily halted, Johns Hopkins
psychiatrist Koko Ishizuka and colleagues are on the trail
of clues to the earliest workings of the pathology of major
mental disorders—long before patients become captives
of their symptoms.
The challenge has been to find a true window into the
brain in action. Although several lines of evidence indicate
that disturbances during neurodevelopment play a role
in the etiology of schizophrenia and other major mental
disorders, it hasn’t been possible to “see” brain-associated
molecular activity as it’s occurring. Just as a publicity
photo for a film can’t capture the experience of viewing
the actual movie, neither blood cells, induced pluripotent
stem cells nor autopsied brains provide a useful way to
correlate neuronal changes with dynamic changes in
patients’ mood, drive and cognition. What does offer that
capability, says Ishizuka, is the nose.
The olfactory epithelium, she explains, is not only a
unique part of the central nervous system that regenerates
continuously throughout life, it’s a source of easily
accessible neurons that originate from the two olfactory
bulbs just above the nasal septum.
Using cultured olfactory cells, her research group
is able to measure molecular changes that may reflect
those in the brain. “We are looking in these neuronal
cells,” says Ishizuka, “for molecular markers of
phosphorylation of a protein called DISC1.” Her team
originally reported that the phosphorylation is a key
switch for neuronal maturation and have since found
that the phosphorylation level was altered in cells from
patients with schizophrenia and some mood disorders.
Furthermore, the phosphorylation level was correlated
with brain structure and cognitive function, indicating
that the phosphorylation may be used as a predictive
marker for such clinical phenotypes, after its validation
with a larger cohort.
Ishizuka’s team is also looking for potential biomarkers
to detect the effects of drug treatment in patients with
bipolar disorder. Combining the nasal biopsy with a
sophisticated microscopy technique called laser-capture
microdissection, which they used to extract olfactory
neurons from a larger biopsy sample, they are comparing
results from a nasal biopsy before and six weeks after
lithium treatment in patients, and results from nasal
biopsies between similar time points in control subjects
who received no lithium. “In the control subjects, the
biomarker should be virtually unchanged from the first to
the second biopsy,” says Ishizuka. “However, in lithiumtreated patients, the changes in biomarker expression
should differ markedly, a likely indication of drug
efficacy.”
Results of these studies, says Akira Sawa, director
of the Johns Hopkins Schizophrenia Center, could be
applied clinically in as little as five years for making timely
diagnoses of major mental disorders and for studying
treatment responses with existing therapies—drug and
behavioral—and perhaps even for testing new ones.
“We believe that by combining a biomarker with
imaging studies and clinical evaluation,” says Ishizuka,
“we’ll have a powerful set of tools for making an
accurate, early diagnosis of schizophrenia and other mood
disorders.” n
Sachiko Kuno
and Ryuji
Ueno
Innovation
Professorship
Psychiatrist Akira Sawa has been
awarded the Sachiko Kuno and Ryuji
Ueno Innovation Professorship, an
honor that is intended to cultivate
the leadership necessary to reduce
the social stigma and to improve the
care of schizophrenia globally. The
professorship is endowed by the S&R
Foundation, begun by Sachiko Kuno
and Ryuji Ueno to support individuals
who are interested in furthering
international collaboration in the arts,
sciences or social entrepreneurship.
As director of the Johns Hopkins
Schizophrenia Center, Sawa oversees
a number of programs structured to
provide the most comprehensive,
coordinated care for patients.
Research, education and outreach are
integral components of the programs.
With this professorship, Sawa
likens his role to that of an orchestra
conductor, who does not directly
make music, but by coaching and
coordinating the musicians contributes
to the orchestra’s beautiful sounds.
“I am proud and feel lucky that I
am surrounded by many great team
members,” says Sawa. “My job for
them is neither as a clinician nor a
researcher, but a supporter who helps
them toward one common goal—
improved outcomes for patients with
schizophrenia.”
ideas at work
Johns Hopkins Psychiatry Goes
POC-IT Size
I
n a patient with diabetes whose glycemic control is not improving despite
intensification of glucose-lowering therapy, should the clinician suspect a
depressive disorder?
Is it OK to prescribe clonazepam for panic attacks in a patient with a history
of substance abuse?
Answers to questions such as these—and hundreds of others—are now
available at the tap of a finger, thanks to the resourcefulness of four Johns
Hopkins psychiatry residents and the many colleagues they corralled to create
an evidence-based clinical decision support tool that brings vital information
to clinicians at the point of care. Called the Johns Hopkins POC-IT Guide
for Psychiatry, it’s available on the Web and mobile devices, and contains over
160 interconnected sections about psychiatric illness, psychiatric medications,
psychiatric emergency care, appropriate referrals and much more.
The brainchild of Paul Kim, Paul Nestadt, Matthew Peters and Traci Speed,
the guide was conceived originally as a resource for primary care physicians and
mental health professionals such as psychologists and social workers. Primary
care physicians prescribe three-quarters of the antidepressant medications in the
U.S. and many antianxiety medications.
The idea of the guide quickly won the support of Department Director
J. Raymond DePaulo and Joe Bienvenu, who heads both the Johns Hopkins
Anxiety Disorders Clinic and the Psychiatry Residents’ Outpatient Continuity
Clinic. Serving as the guide’s co-editors-in-chief, DePaulo and Bienvenu
helped the residents and nearly 150 department collaborators get the product
written, edited and produced in a
matter of two short years. Equally
important to launching the guide
was the technical know-how of the
Johns Hopkins POC-IT Center,
which also offers similar guides on
antibiotics, HIV and diabetes.
In October 2014, the guide was
launched at the annual meeting
of the American Association of
Family Physicians, where it was
well received.
Paul Kim, Paul Nestadt, Traci Speed and Matthew Peters envisioned the POC-IT Guide
over coffee. All are planning academic careers in their respective specialty areas: Kim in
neuroscience research, Nestadt in anxiety disorders, Speed in mood disorders and Peters in
neurocognitive disorders.
“We learned a lot from the doctors there about what they wanted to know
about most,” says Bienvenu. The guide, which incorporates their feedback,
debuted to psychiatric colleagues in May 2015 at the American Psychiatric
Association Annual meeting. “It is an added benefit that psychiatry residents
and medical students also find the guide useful,” says Speed.
Far from being a one-and-done project, the guide will be completely updated
biannually and also if a hot topic emerges. “We will follow the model of our
Division of Infectious Diseases,” Bienvenu says, “which quickly updates the
ABX POC-IT Guide when there’s a new outbreak, like Ebola. We want the
psychiatry guide to supplement the knowledge of both new and experienced
physicians in all patient settings.” n
The Johns Hopkins POC-IT Guide for Psychiatry is available on all
major Web browsers and for many smartphones and tablets. To
learn more, scan the code or visit bit.ly/HopkinsPsychiatryPOCIT.
“It takes a village to do this kind of work,” says Joe Bienvenu, co-editor-in-chief of
the Johns Hopkins POC-IT Guide for Psychiatry. The electronically available guide
is equivalent to about 400 pages of the type of hard-copy pocket guide Bienvenu
remembers lugging around during his medical training.
image gallery
Effects of Serotonin Degeneration on Emotion and Memory Networks
Frederick Barrett, Haris Sair, Gwenn
Smith and colleagues are using multimodal
brain imaging to study how degeneration of
the serotonin system affects brain function in
patients with mild cognitive impairment (MCI).
To do so, they measured serotonin system
degeneration by imaging serotonin transporter
binding with positron emission tomography
(PET), and cortical and limbic brain circuits with
functional magnetic resonance (fMR) imaging.
In the images at left, the grey spheres are
superimposed on the brain images in the fusiform
gyrus (FG) of the temporo-parietal cortex that is
affected in MCI. Serotonin transporter loss in the
cell bodies of origin of the serotonin projections
(dorsal raphe nucleus) leads to decreased
communication between the FG and cortical
regions including superior frontal gyrus (SFG),
supramarginal gyrus (SMG) and premotor cortex
(blue spheres), and a compensatory increase in
communication between the fusiform gyrus and
limbic regions including entorhinal cortex (ERC),
subgenual anterior cingulate cortex (sgACC) and
laterobasal amygdala (red spheres).
These data, say the researchers, suggest that
in MCI, serotonin degeneration is associated with
alterations of the intrinsic organization of cortical
and limbic structures involved in memory and
emotional processing.
The project is a collaboration between
Johns Hopkins’ Division of Geriatric Psychiatry
and Neuropsychiatry, the Biological Psychiatry
Research Unit, and the Department of Radiology
and Radiological Science. n
traumatic brain injury
This PET scan shows increased binding of a protein (represented in yellow), known to indicate brain injury, in the brain of a former NFL football player compared to a healthy male of similar
age. The player sustained sports-related traumatic brain injury and belatedly reports impaired brain function. Johns Hopkins researchers introduced this neuroimaging approach for showing
changes in the brain that could be related to sports-related brain trauma.
Can a Protein Indicate Brain
Injury in Older NFL Players?
M
ost of us who play or watch football have seen
players get hurt. Some injuries are mild. Some
can be career ending. But what about those
that aren’t immediately visible? Today, researchers
and the sports industry are looking at whether
sports-related traumatic brain injury can launch
progressive brain pathologies whose symptoms may
go undetected for years.
To help shed light on that question and open doors
to treatments, cures and new ways of protecting the
brain from the initial traumatic injury, researchers
from the Johns Hopkins Department of Psychiatry and
Behavioral Sciences and the Department of Radiology
and Radiological Sciences are testing a new imaging
approach for spotting signs of sports-related traumatic
brain injury in former NFL football players.
In their study published in the February 2015 issue
of the journal Neurobiology of Disease, psychiatrist
Jennifer Coughlin and colleagues enrolled retired
NFL players, ages 57 to 74, who were recruited to the
study by the NFL Players Association and by word of
mouth. In both the players and normal aged-matched
controls, the researchers used positron emission
tomography (PET) to detect binding of a radiolabel
to a known indicator of brain injury and repair called
translocator protein.
Results showed that radiolabel binding was higher
in players than in controls. Of the 12 brain regions
studied, three—the right and left supramarginal cortex
and the right side amygdala—
showed significantly elevated
radiolabel binding in the
football players compared to the
controls.
Coughlin emphasizes that
this was a pilot study to test
whether their approach is valid
for studying brain injury. “Only
nine players were studied,” she
says, “which means that the number
is too small to rule out other factors
that might cause similar symptoms,” such
as smoking, drug and alcohol use, and family
history of dementia.
“We hope to recruit more participants and partner
with our colleagues around the country who will join
us in using this and related PET scan techniques to
look for brain events in football players,” Coughlin
adds. “That may be the best way to provide enough
data to reach more solid conclusions so we can
eventually better guide players who suffer concussions.”
The research was supported by several funders
including the National Institutes of Health, the NFL
Charities and the GE/NFL Head Health Challenge.
All want to know whether (and if so, how) repetitive
hits to the head can trigger a biological pathway
in the brain and cognitive, mood and behavioral
impairments. n
We hope to be
able to draw
a correlation
between biological
markers of brain
injury and the
latent memory
deficits that some
retired players
experience, and to
lay out a timeline that
could help explain the
pathobiology of the injury.
—Jennifer Coughlin
paper trail
save the date
A smattering of
the psychiatry
and behavioral
sciences
research
and thinking
underway at
Johns Hopkins
Structural imaging in late-life depression:
association with mood and cognitive
responses to antidepressant treatment.
Christopher Marano, Clifford Workman,
Christopher Lyman, Cynthia Munro,
Michael Kraut, Gwenn Smith: Am J Geriatr
Psychiatry 2015;23:4-12
Assessment and management of
behavioral and psychological symptoms of
dementia.
Helen Kales, Laura Gitlin, Constantine
Lyketsos: BMJ 2015;350:h369
Cocaine dependent individuals discount
future rewards more than future losses
for both cocaine and monetary outcomes.
Johnson MW, Bruner NR, Johnson PS: Addict
Behav 2015;40:132-136
Delirium diagnosis methodology used in
research: a survey-based study.
Fourth Annual
Schizophrenia Symposium
Fall 2015
A day to hear about the latest in
schizophrenia research and clinical care
Johns Hopkins School of Medicine
Baltimore, MD
Karin Neufeld, Archana Nelliot, Sharon K.
Inouye, E. Wesley Ely, O. Joseph Bienvenu,
Hochang Lee, Dale Needham: Am J Geriatr
Psychiatry 2014;22(12):1513-1521
Watch for details here:
bit.ly/JHSchizophrenia2015
Neuropsychiatric disturbances associated
with traumatic brain injury: a practical
approach to evaluation and management.
Vani Rao, Vassilis Koliatsos, Faizi Ahmed,
Constantine Lyketsos, Kathleen Kortte:
Semin Neurol 2015;35:64-82
Hopkins
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T H E NE W S L ET T ER
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O F T H E J O H N S H O P K I N S D E PA R T M E N T O F P S Y C H I AT RY A N D B E H AV I O R A L S C I E N C E S
A Whiff of
Pyschiatric
Disorder
PAGE 1
Johns
Hopkins
Psychiatry
Goes POC-IT
Size
PAGE 2
Can a
Protein
Indicate
Brain
Injury in
Older NFL
Players?
PAGE 3