Download Mood Matter (Fall 2012): Tracking Synapse Lapses

MoodMatters
N E W s from T he J O H N S H O P K I N S M oo d d isor d ers center
FALL 2012
Tracking Synapse Lapses
B
ioinformatics
specialist Mehdi
Pirooznia isn’t
looking for a needle in a haystack, but he
might as well be. Studying
some 30,000 genes, Pirooznia and colleagues are on
the hunt for variations that
might predispose someone
to bipolar disorder.
It’s no fluke that their
work started with a study
of synapses—where one
nerve cell passes its signal
to another. Of course that
makes them integral to
brain function, but Pirooznia’s interest is in the sites
as a source of dysfunction
in neuropsychiatric disorders. Synapses are highly
complex, comprising up
to 2,000 protein molMehdi Perooznia combs through voluminous data in
ecules—collectively called
search of gene aberrations that raise suspicion for
the synaptome—that act
bipolar disorder.
as neurotransmitters and
their receptors, agents to regulate cell
signaling pathways, and the cytoskeleThe work is so data-heavy
ton that both supports cells from within
that it requires some 80
and permits movement of all kinds.
Pirooznia’s team created a synaptome computer network servers.
database, an online resource describing
each synaptic gene in depth, as well as
families affected by bipolar disorder to
formerly hidden stretches of DNA that
look for aberrations there.
manage gene activity.
The work is so data-heavy that it
Now, with researchers at Cold Spring requires some 80 computer network
Harbor Laboratory in New York and at
servers. Fortunately, bioinformatics is a
Iowa University, the Hopkins team is
Pirooznia specialty; his group built their
analyzing genetic material from 2,000
own computer cluster with the necessary
people—1,000 with bipolar disorder and huge storage capacity. Analyzing just
1,000 with no symptoms of psychiatric
one study subject’s DNA takes about
illness—looking for gene differences,
three to five days. n
especially in the synaptome, that may
For more information: http://psychiatry.
raise susceptibility to bipolar disorder.
igm.jhmi.edu/SynaptomeDB/index.php.
The scientists also are studying eight
Fernando Goes is seeking cell samples from former
study participants to research how genes stray off
course.
What Cells Can Teach Us
Psychiatrist Fernando Goes is turning to a familiar
source for new studies about bipolar disorder: prior patients.
With genetic information about bipolar disorder
already collected from former study participants, Goes
says he and his neurobiologist colleagues are now
looking to study how genes can go awry and lead to
disease. They have been taking small samples of skin
tissue from study participants, usually from the inside of the arm, and growing them in the lab. When
treated with certain proteins and chemicals, these cells
gradually transform to nerve cells that communicate
like brain cells.
Goes and his group also have been harvesting cells
from the inside lining of the nose, which contains
nerve cells that can be studied in the lab. Using these
cells, Goes says, “we can study disease-related genes
and their pathways, as well as look for certain responses to drugs—all in a petri dish.”
Bipolar disorder research has largely been done
using easily available samples, such as blood. However,
Johns Hopkins is one of the pioneering centers doing
work on these so-called “proxy” cells. Goes and his
colleagues hope this approach can be used not only
to study how genes go off
course but also to help disA Few
cover new medications for
Good Cells
bipolar disorder and similar
Adults with a
illnesses. To do so, says
history of bipolar
Goes, will likely require coldisorder who
lection of samples from hunare interested in
dreds of patients, beginning
donating a few cells
can contact Goes
with many of those who
at 443-287-6382 or
have previously been part of
[email protected].
prior research studies. n
To learn more about our studies, call 410-614-1017 or email [email protected].
E XP AN DE D SER V I CES
Johns Hopkins Bayview
Mood Disorder Clinic Opens
F
Branching Out
Since we distributed our last
issue of Mood Matters a year and
a half ago, there have been many
exciting developments at the
Mood Disorders Center.
One is the creation of an Outpatient Mood Disorders Clinic at
Johns Hopkins Bayview Medical
Center, where Anita Everett is
director. We are thrilled to offer
specialized treatment to mood
disorder patients, under the care
of Frank Mondimore, through
a community psychiatry clinic
where they can receive muchneeded services and be seen by
the same health care team over
time. Our hope is that through
electronic health records and a
growing research registry program, the clinic will enlighten us
more about genetic and environmental triggers.
In other exciting news, a new
National Institutes of Mental
Health grant, with principal investigators Holly Wilcox and Karen
Swartz, will permit a formal study
of our Adolescent Depression
Awareness Program’s impact.
Before the start of this program,
only half of high school health
textbooks mentioned depression,
linking its association with stress.
We are educating teens the right
way by breaking down barriers
and stigma. The program already
has reached 17 states. Now we
have the ability to put it into
high gear and move it across the
country.
I appreciate your support of
these and other endeavors. Happy
reading!
or patients with mood
problems serious enough
to need specialized
medical care, a new home
for treatment has opened in
Baltimore. The new Mood Disorders Clinic at Johns Hopkins
Bayview Medical Center offers
today’s best-practice approach.
As drug-based therapy for
depression and bipolar disorder
becomes more sophisticated,
psychiatrists will require stronger
diagnostic and pharmacology
acumen. But a boatload of studies show that patients improve
faster and stay well longer when
treatment includes psychotherapy. So, ideally, practitioners of
both forms of treatment would
work closely together.
And that’s the new clinic’s
aim.
“The collaboration allows us
to plan the most effective treatment,” says psychiatrist Francis
Mondimore, who directs the
new clinic, “and we’re able to offer longitudinal care specifically
for people with mood disorders.”
Far from being the sole mental health presence at Bayview,
the new offering draws from a
successful model of longstand-
Francis Mondimore,
left, and Daniel
Boccino outside
of the new clinic,
which brings
together all aspects
of care for mood
disorder patients.
J. Raymond DePaulo Jr., M.D.
Co-Director, The Johns Hopkins
Mood Disorders Center
Henry Phipps Professor and
Director, Department of
Psychiatry and Behavioral Sciences,
Johns Hopkins University
School of Medicine
2 • J o h n s H o p k i n s M OO D M A T T E R S • F A L L 2 0 1 2
ing specialty clinics within the
Community Psychiatry Program. The new arrangement
brings Hopkins more in sync
with the National Network of
Depression Centers that it joined
two years ago. An organization of 21 academic and clinical
medical centers, the NNDC believes that its large numbers and
expertise form a critical mass to
help transform our understanding of depressive illness.
As for the new clinic, its
team includes experienced
psychiatrists, psychotherapists
and a research coordinator.
They provide individual and
group psychotherapy, medication management and family
therapy. “It’s very convenient,
offering one-stop shopping for
patients,” says clinical chief
Daniel Buccino.
And interest is growing, says
Mondimore. Since the clinic
opened last summer, he and six
core therapists now share 90 active patients.
The clinic also has been successful in recruiting patients to
participate in two national projects for the NNDC, directed
by Hopkins researcher Peter
Zandi. One establishes a clinical care registry that NNDC
investigators can access for
research. In this first project at
Hopkins, the registry will help
determine which tests or questionnaires best track depression.
The other is a study looking
for genetic markers that predict
whether particular bipolar disorder patients will do well on the
mood-stabilizing drug lithium.
“It really helps to have our
clinician-researchers on board
with the projects,” Buccino says.
“These two cultures—the science and the clinic—have been
melded in a very successful way.”
And an added advantage
to the change: Mondimore
and colleagues have begun to
provide training for clinicians
interested in caring for mood
disorders patients. This could
lead to fellowship programs. “It’s
been a rousing success on all
levels,” Mondimore says. n
For more information, call
410-550-0104 or see http://www.
hopkinsmedicine.org/psychiatry/
specialty_areas/moods/patient_
information/bayview_mood_
clinic.html
N OV E L T H I N KIN G
A Boost for Adolescent
Depression Awareness
P
Richard Lee, Kellie Tamashiro and
Zachary Kaminsky are working to
link epigenetic markers to behaviors,
including stress, depression and suicide.
Gene Expression:
More Clues
Eye-opening research taking place at the Mood
Disorders Center of late involves epigenetics—
inheritable shifts in gene expression caused by
processes that don’t directly change the genetic
code. The lure of epigenetics is that it shows
possible links between what happens in a person’s internal or external environment and the
development of psychiatric ailments. Here we
report news from three of our labs:
Kellie Tamashiro has been studying the
long-term effects of diet and prenatal stress on
offspring, including the increased likelihood of
developing neuropsychiatric disorders, like posttraumatic stress disorder, or of medical conditions, such as diabetes.
One study involved exposing pregnant rats
to mild stress during their last week of gestation—equivalent to a human’s second trimester.
When Tamashiro and colleagues later stressed
the offspring of those pregnancies, they found
that the pups’ response was similar to those born
of mothers who hadn’t received stress. Surprisingly, the mother-stressed pups recovered faster,
suggesting that they could handle stress better
short term. That wasn’t always the case, though,
over time. They also had lower expression of
genes like BDNF (brain-derived neurotrophic
factor), associated with increased susceptibility to
stress-related disorders. And epigenetic marks on
the BDNF gene were changed, suggesting that it
might be a therapeutic target.
Richard Lee also has been investigating the
effects of stress. One gene he’s been studying,
called FKBP5, is a key regulator of stress hormone. It’s been implicated in genetic studies of
depression, suicide, PTSD and bipolar disorder.
Lee’s research has shown that mice exposed to
sychiatrist Karen Swartz has always module enabling teachers, school nurses
known that the Adolescent Depresand others to offer the program in their
sion Awareness Program (ADAP) she own settings. It also is developing supplehelped found makes an impact in
mental teaching materials targeted to spehelping high schoolers, their teachers and
cific populations, like Native Americans.
parents recognize teen depression and seek
Wilcox says the program has been
treatment. Now she has a means to prove it. effective in improving depression literacy
Colleague Holly Wilcox of Johns
in 9th and 10th graders in schools, one of
Hopkins’ Division of Child and Adolescent the best settings to reach young people,
Psychiatry, whose research interests include and is easy to implement, even in lowsuicide prevention, recently received a $1.7
resource settings. She cites letters from
million grant from the National Institute
schools “singing the praises of Karen’s
for Mental Health to study ADAP’s impact team, which counted for a lot in our grant
on treatment-seeking behavior and receipt
proposal review.”
of mental health services.
Though the formal evaluation is just
“We know anecdotally that many teens
beginning, Swartz says she’s “very optiwho have gone through the training have
mistic” that results will show that the proself-recognized depression and sought help,” gram is effective. “It’s been exciting,” she
Swartz says. “We’re making a difference, not adds, “watching some school professionals
just in education but in promoting the use
change their attitudes about depression as
of psychiatric services.”
an illness. It’s amazing how little informaADAP started in 1999 as a response to
tion they have that’s accurate.” n
several adolescent suicides in Baltimore,
Info: See http://www.hopkinsmedicine.org/
when Swartz found herself addressing
psychiatry/specialty_areas/moods/ADAP/,
students and their parents at high school
email [email protected] or call 410-502-3447
assemblies. It includes a three-hour health
education component, with videos,
group discussions, homework and
quizzes—and training for educators and parents. The take-home
message: Depression is a treatable
medical illness.
The program began with 530
students in eight schools. It has
grown exponentially each year,
Swartz says. To date, more than
26,000 high schoolers have benefited from ADAP training in more
than 100 schools in 17 states.
Among ADAP’s newer program- Holly Wilcox (left) and Karen Swartz are on a mission
to educate teens about depression in a school setting.
ming tools is a Web-based training
chronic stress had epigenetic changes in FKBP5 and
neuropsychiatric symptoms that persisted long after
stressors were removed.
“It’s definitely a candidate mechanism explaining
why we still continue to suffer after a stressful event,”
Lee says. He’s looking to see if other regions of the
brain behave similarly.
Lee also has been studying epigenetic brain differences across the sexes. Women have higher rates of
mood disorders, and recent research suggests that
female sex hormones interact with stress hormones
to cause a heightened stress response.
And Zachary Kaminsky is focused on finding
biological early warning signs (biomarkers) of devel-
oping depression, postpartum depression or suicide
attempt by looking at an epigenetic “mark” called
DNA methylation. Recently, his lab team has been
comparing brain tissue samples from deceased people who had major depression and those who did
not. Their goal: to see if there are related biomarkers that appear in the brain—or more helpful, in the
blood—that could predict a developing depression.
Kaminsky’s lab is also evaluating genetic marks
that might predict the risk of suicide attempt. Finally,
they have identified a set of biomarkers that predict
postpartum depression during pregnancy—a situation requiring careful clinical balance to minimize the
risks to both mother and child. n
J o h n s H o p k i n s M OO D M A T T E R S • F A L L 2 0 1 2 • 3
IN N O V A T I V E W O RK
Portrait of a Gene Sleuth
Genetic epidemiologist Jennifer Toolan Judy was still
a college student in 2003 when she started wondering what
she was going to do with her bachelor’s degree in psychology. A colleague from the Baltimore Rowing Club, who
worked as a data manager for the Mood Disorders Center,
suggested that Judy come in to volunteer.
Judy started as a basic research assistant, helping people
participating in studies, and quickly was hired as a project
coordinator responsible for the progress of two multisite genomics research studies. While moving up to a data manager
position, overseeing complex databases for several multisite
genomics studies, Judy continued her education, earning a
master’s degree in biotechnology from Johns Hopkins.
She took a break from full-time work while pursuing a doctorate in psychiatric epidemiology through Hopkins’ Bloomberg School of Public Health but continued her relationships
with the center staff. Judy defended her Ph.D. thesis on bipolar disorder genetics last August and was recently hired by the
Mood Disorders Center as a
full-time research associate.
Judy now conducts some
of her own research. She’s
been studying the ANK3
gene, one of the leading candidates for bipolar disorder,
and its relationships with
other proteins. She also is
looking to start a multicenter
clinical trial of the anti-epileptic drug ezogabine to see if it
will help people affected by
bipolar disorder.
“Bipolar disorder and
mood disorders are very
complex, so research is
tough,” Judy says. “You find
a lot of dead ends, but we’re
Self-described optimist
a very optimistic group. EvJennifer Toolan Judy
combs through data
eryone is here to help people
daily in search of genetic
with these disorders. In fact,
ties to bipolar disorder.
it’s such a close-knit group that
She also hopes to launch
even those who have left still
a multicenter clinical
trial in the near future.
keep in touch.”
MoodMatters
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he Johns Hopkins University and the Johns Hopkins
Health System Corporation 2012
Irving Reti sees
compelling evidence
that TMS, a coilbased, noninvasive
brain stimulation
technique, is effective.
His research to finetune TMS continues.
A Welcome Alternative to ECT
Psychiatrist Irving Reti is on a mission—to make transcranial magnetic
stimulation (TMS) as effective as the
medical standard electroconvulsive
therapy (ECT) for patients whose
depression resists treatment.
TMS is a noninvasive method of
brain stimulation. A plastic paddle
containing an insulated electric coil
is held close to a patient’s scalp and
focused on a likely mood-regulated area
of the brain. The coil generates brief
magnetic pulses, which pass easily and
painlessly through the skull and into the
brain. The procedure has been shown
to be safe and well tolerated, and can be
an effective treatment for patients who
have not benefited from antidepressant
medications (or struggle with the side
effects). A typical treatment reginen lasts
40 minutes a day for four to six weeks.
Over the past several years, as TMS
has crossed over from experimental
to clinical use, many patients with
serious disease have improved significantly. Reti, director of Hopkins’ Brain
Stimulation Program, has testified
before a government committee that
the therapy warrants Medicare/Medicaid funding.
To understand the biology of brain
stimulation, Reti has recently created
a mouse model that’s unaffected by
ECT—or likely by TMS—by shutting
down one of the animals’ first responders to the applied energy. Through the
model, which is missing a gene called
NARP, Reti says he and others are
learning more about specific brain pathways that the treatment touches.
Reti also is directing a clinical trial
with bipolar depression patients of a
new TMS coil targeting the brain’s medial prefrontal cortex, which regulates
mood in bipolar depression. The only
FDA-approved coil can’t directly reach
that area, Reti says, and preliminary
results suggest that the novel coil—designed by Israeli scientists—is effective
for unipolar depression. He hopes to
enroll about 30 patients. n
Info: See http://www.hopkinsmedicine.
org/psychiatry/specialty_areas/brain_
stimulation/tms/, call 410-614-1732 or
email [email protected].
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