Opinion
VIEWPOINT
Preventing the Malignant Transformation
of Bipolar Disorder
Robert M. Post, MD Stigma is one of the factors contributing to inad-
George Washington equate recognition and treatment of recurrent mood
University School of disorders, including unipolar depression and bipolar dis-
Medicine, Bethesda,
order. In addition, the potential seriousness of these ill-
Maryland; and Bipolar
Collaborative Network, nesses is often underestimated. This Viewpoint de-
Bethesda, Maryland. scribes an analogy to the development and spread of
a malignancy as a way of trying to emphasize the perni-
cious course of bipolar disorder in particular, but many of
the comments are also relevant to recurrent depression.
Why an analogy to cancer? Similar to mood disor-
ders, cancer often progresses through a series of stages
to become an overt malignancy. First there is cytologi-
cal evidence of dysplasia, then increasing cellular disor-
ganization eventually leading to a localized lesion that
can then increase in size and invasiveness, and ulti-
mately may metastasize. This sequential process
involves increasing numbers of somatic mutations,
including both the loss of tumor suppressor factors and
the gain of function with cellular proliferative factors.1
The therapeutic focus of a cancer is early detection
and treatment. In contrast, a first episode of mania is
often treated less intensively. A short hospitalization
is typically followed by a referral to a psychiatrist or
Some might think that the analogy
to cancer is exaggerated because
malignancies are life-threatening
illnesses and potentially fatal.
However, so are mood disorders.
primary care physician in the community who may,
at the patient’s urging, agree that it is reasonable for
the patient to stop the medications once a stable mood
has been achieved.
This all-too-common occurrence, as well as nonad-
herence to medications in approximately 50% of
patients,2 likely contributes to a poor long-term course
of illness and outcome. Episodes of illness, stressors,
and bouts of substance abuse (which are particularly
common among patients with bipolar disorder) each
tend to recur and accumulate, and each is associated
with a process of sensitization or increased reactivity to
Corresponding the next recurrence.3
Author: Robert M. In the analogy to cancer progression associated
Post, MD, George with an increasing accumulation of somatic mutations,
Washington University
School of Medicine,
each type of sensitization occurring with mood disor-
Bipolar Collaborative ders is associated with a progressive accumulation of
Network, 5415 W epigenetic changes.3 Epigenetic alterations are induced
Cedar Ln, Ste 201-B,
by events in the environment that lead to chemical
Bethesda, MD 20814
(robert.post groups being added to or subtracted from DNA and his-
@speakeasy.net). tones or microRNA is altered, thus changing the ease
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with which DNA is activated and transcribed. These
epigenetic marks can have long-term, if not lifelong,
adverse effects on neurochemistry and behavior.
Whether this phenomenon occurs in bipolar disorder is
unknown, but plausible.
Sensitization appears to have an epigenetic basis.3
This is demonstrated by the observation that an inhibi-
tor of DNA methylation, zebularine, prevents increases
in behavioral reactivity to repeated exposure to cocaine
or stressors. In an animal model of depression involving
repeated defeat stress, the resulting depressive-like
behaviors also have an epigenetic basis.4 This model is
likely relevant to humans because adults with either a
diagnosis of depression or who experienced abuse dur-
ing childhood, or both, have greater numbers of epi-
genetic marks (DNA methylation or histone alterations)
in their white blood cells and brains at autopsy than
those without these experiences.5
Data from 3 studies suggest that intensive treat-
ment should be started after a first manic episode.
Kessing et al6 conducted a randomized clinical trial of
158 patients having a first hospitalization for mania.
Compared with patients receiving treatment as usual,
those randomized to 2 years of expert
treatment in a specialty clinic showed
a longer time to rehospitalization, and
the between-group differences per-
sisted and increased during the next
6 years (shown in the Kaplan-Meier
curves) with fewer patients (36.1%)
readmitted compared with patients
who received treatment as usual
(54.7%) and the duration of readmissions was shorter.
Kozicky et al7 reported that after a first hospitalization
for mania, cognition on a comprehensive battery of
tests improved more (returned toward normal) in the
27 patients who experienced no further manic epi-
sodes during the next year compared with the 26 who
experienced recurrences.
In another trial, Berk et al8 randomized 61 patients
who had a first hospitalization for mania to 1 year of
treatment with either lithium or the atypical antipsy-
chotic quetiapine (ⱕ800 mg/d). In mixed-model
repeated-measures analyses, lithium was more effec-
tive than quetiapine on every outcome measure,
including mood, functioning, cognition, and brain
imaging alterations with large differences emerging
during the second half of the year.
The recommendation for vigorous treatment after
a first manic episode is reinforced by the extensive lit-
erature that early initiation of lithium and most other
treatments is more effective than beginning treatment
later after many episodes have occurred.3 Similarly,
(Reprinted) JAMA March 27, 2018 Volume 319, Number 12 1197
 Opinion Viewpoint

treatment of a primary malignancy is typically more effective than
after the cancer has metastasized.
What are the consequences of treating a first manic episode
without the care, caution, and follow-up that would be used for treat-
ing cancer? With inadequate long-term treatment and follow-up of
patients with a manic episode, the recurrence of greater numbers
of episodes is associated with increasing dysfunction, disability, cog-
nitive dysfunction, treatment resistance, telomere shortening, medi-
cal comorbidity, prefrontal cortex deficits, and the risk of receiving
a diagnosis of dementia during old age.3 The accumulation of so many
illness-related liabilities would appear to merit the term malignant
transformation of bipolar disorder.
Some might think that the analogy to cancer is exaggerated be-
cause malignancies are life-threatening illnesses and potentially fa-
tal. However, so are mood disorders. Suicide is one of the leading
causes of mortality among 13- to 18-year-olds and suicide rates are
high among those with a diagnosis of depression or bipolar disor-
der. Moreover, there is a loss in life expectancy of 1 decade or lon-
ger that is predominantly attributable to the increases in cardiovas-
cular disorders associated with mood disorders.9
Further complicating the problem is a relative lack of random-
ized clinical trials among highly recurrent patients with bipolar dis-
order. In contrast, very complex combinations of treatment are
both available and well-studied among patients with metastatic
malignancies. As a consequence, during the late stages of bipolar
disorder, the patient and physician are essentially left to their own
clinical experiences without high-quality evidence to guide decision
making. This too would appear to have much to do with stigma.
Some may view these illnesses as not serious enough to deserve
the necessary funding even for what could be relatively inexpen-
sive clinical trials that compare 2 active randomized treatments.
The situation and need for treatment guidance is espe-
cially critical in the United States compared with many European
countries.10 Compared with European patients, US patients with
bipolar disorder have a more adverse course of illness, including
more treatment refractoriness to prospective naturalistic treat-
ment (administered according to the best judgment of physi-
cians), more anxiety and substance abuse comorbidities, and
more episodes and faster cycling between mania and depression.
Two-thirds of US patients with bipolar disorder have childhood
and adolescent onsets, and these are associated with a greater
delay to first treatment compared with in Europe where only one-
third of patients have childhood onset of bipolar disorder. Both
early onset illness and treatment delay are independent risk fac-
tors for a poor outcome during adulthood. The excess of early
onset and the associated adverse course of illness have been asso-
ciated with both more genetic and familial vulnerability and more
psychosocial adversity during childhood in the United States com-
pared with the Netherlands and Germany.10
Perhaps emphasizing to physicians, patients, and funders of
research that the first episode of mania has to be handled with
the same care as an initial malignant lesion to prevent illness pro-
gression and transformation to a more treatment refractory ill-
ness will better highlight and help reverse the potentially cata-
strophic consequences of inadequate treatment of patients with
bipolar disorder.

ARTICLE INFORMATION
Published Online: March 5, 2018.
doi:10.1001/jama.2018.0322
Conflict of Interest Disclosures: The author has
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr Post
reported receiving speaking fees from AstraZeneca,
Sunovion, Takeda-Lundbeck, Validus,
and Pam Labs.
Additional Contributions: I acknowledge the
editorial assistance of Jessica Pollack, BS
(Bipolar Collaborative Network). Ms Pollack
was not compensated.
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