PsychUpdate
Psychiatry and Psychology News From Mayo Clinic Vol. 8, No. 3, 2016
INSIDE THIS ISSUE Misconceptions Hinder Good
Psychiatric Management of BPD
2 Biobank Research
Identifies Bipolar-
Obesity Link
Borderline personality disorder (BPD) is a
severe psychiatric illness affecting 2 to 3
percent of the population. It is marked by
Epigenetic Gene pervasive instability in interpersonal rela-
3 Regulation
May Play Role
tionships, moods, behavior and self-image,
and although it commonly co-occurs with
major depressive disorder, it is often more
in Psychiatric subjectively severe, with distinct symptoms
Disorders and treatment responses.
Dialectical-behavioral therapy, developed
in the late 1980s as a therapy for patients who
are chronically suicidal, is the most widely
practiced of the empirically validated treat-
ments for BPD, and in multiple controlled
trials, it proved superior to treatment as usual
for BPD across most domains. But a pivotal
study, published in The American Journal
of Psychiatry in 2009, found that general
psychiatric management — a combination
of psychodynamically informed therapy and
symptom-targeted medication management —
was as effective at reducing suicidal and self-
injurious episodes and other BPD symptoms
as dialectical-behavioral therapy was.
Brian A. Palmer, M.D., M.P.H., a psychia-
trist specializing in borderline personality
disorder and psychiatric education at Mayo
Clinic’s campus in Rochester, Minnesota,
says general psychiatric management, when
delivered by psychiatrists experienced in BPD
using specific techniques and approaches, can
provide care on a par with more-expensive
and intensive dialectical-behavioral therapy.
“The reality is that good treatment can and
usually does result in significant improvement
Brian A. Palmer, M.D., M.P.H. in patients with this misunderstood disorder,
whereas poor treatment is unhelpful and can
make patients worse,” he explains.
Dr. Palmer, who trains psychiatrists in the
general psychiatric management of BPD based
on the pioneering work of John G. Gunderson,
M.D., describes three common mistakes clini-
cians make: treatment of mood symptoms
only, lack of treatment goals, and failure to
anticipate and understand BPD challenges.
Treatment of mood symptoms only
“At its core, BPD is an interpersonal disor-
der,” he says. “A common mistake is focusing
on the mood symptoms without appreciat-
ing the interpersonal context in which they
occur. Depression is unlikely to improve until
BPD improves, and BPD is the single largest
cause of persistent depression.” Dr. Palmer
and co-author Kei Yoshimatsu described the
unique features and clinical trajectory of BPD
depression in an article published in Harvard
Review of Psychiatry in 2014.
Lack of treatment goals
Good psychiatric management teaches that
continued therapy is contingent on progress
during treatment. But Dr. Palmer says the
dictate is often ignored because clinicians
fear it will trigger the fear of abandonment
common in patients with BPD. “Anchoring
the treatment in goals outside the therapeutic
relationship helps guard against complicity
with the patient’s avoidance of work or school
and helps ensure that treatment is account-
able for progress,” he explains.
Another obstacle is the common misper-
ception that patients with BPD rarely get
better — often driven by a sampling error in
 Relevant sive responsibility and ongoing litigation risks.
Target Area Changes Time Although BPD is characterized by recurrent
Interventions
suicidal gestures or threats and self-mutilating
1. Subjective Support, situational behavior, Dr. Palmer points out that success-
Anxiety and
distress and 1-6 weeks changes, ful litigation is rare and usually seen in poorly
depression
dysphoria self awareness
conducted treatments, including those with
2. Behavior Awareness of self and boundary crossing. “Successful clinicians
Self-harm,
rages and 2-6 months
interpersonal triggers anticipate and manage BPD symptoms effec-
promiscuity problem-solving tively,” he says. “Case management, including
strategies a focus on functional involvement, solving
3. Interpersonal Devaluation, real-life problems, and the appropriate level of
Mentalization,
assertiveness 6-12 months stability of care and support, particularly during transi-
plus dependency attachment tions, may be the most important aspect of
treatment. The second most important aspect
4. Social School/work/ Fear, failure and is therapy that helps patients make narrative
function domestic 6-18 months abandonment,
sense of their inner experience — moving from
responsibilities coaching
‘I feel like cutting,’ to ‘I feel alone and afraid; I
Figure. Sequence of expectable changes in patients with borderline personality see a pattern and here’s what I can do.’ That is a
disorder. Based on Gunderson JG, et al. Borderline Personality Disorder: A Clinical well-managed case.”
Guide. 2nd ed. Washington, D.C.: American Psychiatric Publishing Inc.; 2008. Dr. Palmer is also involved in orienting
inpatient care to effectively address BPD and
residency training, where patients who have teaching other specialists, including internists,
not yet improved may be seen frequently in the gastroenterologists, neurologists and pedia-
emergency department or inpatient unit. But tricians, effective principles for managing
Dr. Palmer notes that long-term outcome stud- patients with BPD.
ies have shown the vast majority of patients with
BPD achieve remission. About 10 percent remit For more information
within six months, 25 percent within a year, 45 McMain SF, et al. A randomized trial of dialec-
percent within two years and close to 80 percent tical behavior therapy versus general psychi-
by 10 years, even without extended or stable atric management for borderline personality
treatment. “Change is an expected and natural disorder. The American Journal of Psychiatry.
course of treatment, and patients are expected 2009;166:1365.
to be active within treatment in controlling their
lives,” Dr. Palmer says (Figure). Yoshimatsu K, et al. Depression in patients
with borderline personality disorder. Harvard
Failure to anticipate and Review of Psychiatry. 2014;22:266.
understand BPD challenges
Another misperception is that the recurrent
risk of suicide burdens clinicians with exces-

Biobank Research Identifies Bipolar-Obesity Link

Joanna M. Biernacka, Ph.D.
The heritability of bipolar disorder — a severe
mood disorder characterized by recurrent epi-
sodes of mania or hypomania and depression
— has been estimated at around 85 percent.
In the last decade, replicated genome-wide
association studies have identified several risk
loci, most notably ANK3, NCAN, CACNA1C
and ODZ4. Genes associated with circadian
rhythm patterns, including circadian locomotor
output cycles kaput (CLOCK) genes, have also
been linked to bipolar disorder.
Although these studies have provided valu-
able information about the molecular mecha-
nisms of bipolar disorder, they don’t fully explain
its heritability, which is likely the result of a large
number of risk genes, each conferring a small
degree of disease susceptibility. Thus, more
research is needed, ideally using large patient
populations with precisely defined phenotypes.
To further this aim, Mayo Clinic in Roches-
ter, Minnesota, established a bipolar biobank in
collaboration with the Lindner Center of HOPE
and the University of Minnesota in 2009. The goal
was to create a resource for clinical and biomarker
studies of disease risk and treatment response.
To date, nearly 2,000 patients have contrib-
uted medical information and blood samples to
the biobank. Most participants are white and

2 MAYO CLINIC | PsychUpdate

female, with diagnosed bipolar I disorder. Clin-
ical phenotypes include a history of psychosis,
attempted suicide, nicotine or alcohol addiction,
and antidepressant-induced mania. Nearly 43
percent of biobank patients met the criteria for
obesity (body mass index of 30 or higher).
Genetic variation regulated by BMI
The obesity phenotype has proved a fruitful area
of research, according to biobank co-principal
investigator and lead statistical geneticist,
Joanna M. Biernacka, Ph.D., who directs the
Psychiatric Genomics and Pharmacogenomics
Program at Mayo Clinic’s campus in Minnesota.
“The way in which some genetic variations
associated with bipolar disorder impact disease
presentation appears to be regulated by factors
related to BMI,” she explains. “Our research
group found that rs12772424 — a variant of the
gene-encoding TCFL2 — may help mediate the
onset of bipolar disorder. The effect of the gene
increases with body mass index (BMI), which
may reflect the role of psychiatric comorbidities
such as binge-eating disorder.”
The group’s initial finding was published in
Molecular Psychiatry in 2014; the replication was
published in Bipolar Disorders in 2016. A related
2016 study published in the Journal of Affective
Disorders found an increased prevalence of
obesity and binge-eating disorder in patients
with bipolar disorder.
Still, the precise relationship between
obesity and bipolar disorder remains unclear,
says Mark A. Frye, M.D., the biobank’s other
principal investigator and a psychiatrist
specializing in bipolar disorder at Mayo Clinic’s
Epigenetic Gene Regulation
May Play Role in Psychiatric Disorders
Schizophrenia, bipolar disorder and other
psychiatric disorders are complex illnesses in
which neural circuit structure and function are
altered. Although inheritance plays an impor-
tant role in the etiology of these conditions,
the 50 to 70 percent concordance rates among
identical twins indicate that environmental
factors are also involved. Evidence increasingly
suggests that these changes are maintained
by epigenetic modifications, especially DNA
methylation, according to Marin Veldic, M.D., a
psychiatrist and epigenetics researcher at Mayo
Clinic’s campus in Rochester, Minnesota.
DNA methylation — the addition of a methyl
group on the cytosine of CpG dinucleotides —
may alter gene expression by restricting access
campus in Minnesota. “Was there an elevated
BMI from the beginning? Did the BMI increase
over time? We want to better understand the
genetic risk and interaction with obesity, yet it’s
very challenging due to the complexity of this
disease,” he says.
Nevertheless, Dr. Frye says the detailed phe-
notype obtained for biobank participants is an
important research tool. He points out that com-
posite measures of mood instability, comorbid
anxiety and multiple drug addiction, beyond the Mark A. Frye, M.D.
confirmed bipolar disorder subtype, are novel
quantifications that may provide more-detailed
clinical disease characteristics that can be used
in future biomarker genomic studies.
“Future studies that focus not on a DSM-5
bipolar disorder diagnosis but on a more-
detailed phenotype such as bipolar disorder
with obesity may uncover risk genes not previ-
ously identified,” he explains.
For more information
Winham SJ, et al. Genome-wide association
study of bipolar disorder accounting for effect
of body mass index identifies a new risk allele
in TCF7L2. Molecular Psychiatry. 2014;19:1010.
Cuellar-Barboza AB, et al. Accumulating evi-
dence for a role of TCF7L2 variants in bipolar
disorder with elevated body mass index. Bipolar
Disorders. 2016;18:124.
McElroy SL, et al. Clinical features of bipolar
spectrum with binge eating behaviour. Journal
of Affective Disorders. 2016;201:95.
of transcription factors to promoter regions or
changing mRNA processing. Although these
alterations don’t change the genetic code, they
are long lasting and may be heritable.
Methylation studies
Most of what is known about the role of DNA
methylation in schizophrenia and other psychi-
atric disorders is based on studies of postmortem
brain tissue, peripheral blood or both. Dr. Veldic
co-authored a study published in Schizophrenia Marin Veldic, M.D.
Research in 2009 that found overexpression of
both DNA-methyltransferase-1 (DNMT-1) and
DNMT3a mRNA — but not DNMT3b — in
cortical GABAergic neurons in patients with
schizophrenia, leading to promoter hypermeth-
MAYO CLINIC | PsychUpdate 3
Mayo Clinic
Psych Update
ylation. A twofold increase of DNMT-1
Medical Editors: and DNMT3a mRNA was also observed in
Matthew M. Clark, Ph.D., L.P. peripheral blood lymphocytes.
Mark A. Frye, M.D. Conversely, a 2013 study published in
Simon Kung, M.D. Alcoholism: Clinical and Experimental Research
Bruce Sutor, M.D. found that the increase in DNMT-1 was
reversed in patients with schizophrenia
Mayo Clinic Psych Update is written for physicians
or bipolar disorder who had a history of
and should be relied upon for medical education
purposes only. It does not provide a complete excessive alcohol use. Dr. Veldic suggests
overview of the topics covered and should not that alcohol addiction may represent a form
replace the independent judgment of a physician
of acquired comorbidity for some patients.
about the appropriateness or risks of a procedure
for a given patient. More recently, large methylome- and
epigenome-wide association studies have
used next-generation sequencing to identify
schizophrenia methylation biomarkers in
blood. A study published in JAMA Psychiatry
Contact Us in 2014 reported alterations in methylation of
genes related to hypoxia and infection, two
help confirm that environmental factors can
affect methylation in many areas, not just
brain tissue.
“The whole field is growing enormously,”
Dr. Veldic says. “When I was starting out
more than 15 years ago, there were just a few
papers — now there are hundreds, and this
research will have a significant clinical and
translational impact.”
For more information
Zhubi A, et al. An upregulation of DNA-
methyltransferase 1 and 3a expressed
in telencephalic GABAergic neurons of
schizophrenia patients is also detected in
peripheral blood lymphocytes. Schizophrenia
Research. 2009;111:115.

Mayo Clinic welcomes inquiries and referrals,
and a request to a specific physician is not
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Phoenix/
Scottsdale, Arizona
866-629-6362 (toll-free)
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risk factors in early life associated with later
schizophrenia. And a 2016 epigenome-wide
association study, also in JAMA Psychiatry,
identified 172 replicated sites of altered meth-
ylation in patients with schizophrenia.
Dr. Veldic says the growing number
of high-quality methylation studies can
advance mental health research in several
important ways. For example, it may be
possible to identify disease subtypes using
easily obtained blood biomarkers that
would allow for earlier or more precise
diagnosis. Methylation studies can also
generate hypotheses about disease mecha-
nisms. And methylation sites in the brain
that are reflected in peripheral blood may
Guidotti A, et al. DNA methylation/
demethylation network expression in
psychotic patients with a history of alcohol
abuse. Alcoholism: Clinical and Experimental
Research. 2013; 37:417.
Aberg KA, et al. Methylome-wide associa-
tion study of schizophrenia: Identifying
blood biomarker signatures of environmen-
tal insults. JAMA Psychiatry. 2014;71:255.
Montano C, et al. Association of DNA
methylation differences with schizophrenia
in an epigenome-wide association study.
JAMA Psychiatry. 2016;73:506.

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