Bipolar Disorder: Particle or Wave? DSM Categories or Spectrum Dimensions?

Bipolar Disorder: Particle or Wave? DSM Categories or Spectrum Dimensions?

Psychiatric diagnosis is currently
based on a system of categories,
much like the Linnaean classification
in biology. However, a seemingly
opposite diagnostic system is emerging,
usually dubbed the “dimensional view,”
in which related psychiatric conditions
such as major depressive disorder (MDD)
and bipolar disorder (BD) are seen as
end points of a spectrum.

With this expansion of the concept
of BD to include intermediate forms (ie,
manifestations between clearly unipolar
and clearly bipolar cases), concerns
have arisen about the potential for overdiagnosis
of BD1 and the blurring of our
understanding.2 However, diagnostic
error thus far has been skewed in the
direction of underdiagnosis.3

The concept of overdiagnosis or underdiagnosis
presumes some “natural
types” that we diagnosticians are
correctly or incorrectly classifying. Indeed,
the term “classify” implies that we
are looking at native classes. This is,
for example, the process used by an
ornithologist to identify a particular
bird: scientists use visible traits such as
size, color, beak shape, wing bars, eye
rings, and other field signs. They may
also observe preferences such as habitat
(ground or high trees), interactions
(flocking or pairing), diet (seeds, worms,
or fish), and even behavior over time
(eg, migration or wintering-over).

The DSM system is like that of the
ornithologist. The purpose of the diagnostic
interview is to gather observations,
for which the DSM serves as a
“field guide,” organizing the observed
findings by category of illness. But just
as in ornithology, over time an experienced
clinician relies less and less on
the specific DSM rules and progressively
more on pattern recognition. A
good bird watcher distinguishes a
woodpecker from a hawk not so much
by specific field signs but from an overall
gestalt--rapid synthesis of a whole
complex of findings (eg, location in the
tree, position on the branch, size, shape, color, behavior, call). Likewise, an experienced
clinician might strongly
suspect that a patient has BD based on
observations on an inpatient unit, even
before an interview.

Unlike birding, however, experience
gives clinicians the ability to recognize
intermediate cases that blur the boundaries
of the classification system.
Indeed, this lack of discrete boundaries
has been studied quantitatively in at
least 2 research settings, both of which
showed a continuum of symptoms in
patients with DSM-diagnosed MDD
and BD. Some patients with MDD
have no symptoms suggestive of BD,
others have a few such symptoms, and
still others have many with no gaps in
this progression that might serve as a
natural point of cleavage between the

The same result was obtained by
Benazzi5 in a study designed specifically
to look for such gaps. Similarly,
Mackinnon and Pies6 recently presented
an elegant model for rapid-cycling and
mixed-state BD, demonstrating that
mood, energy, and creativity/speed-ofthought
symptoms fluctuating asynchronously
can create a continuum of
forms of the illness. Although this
model has not yet been subjected to
rigorous study, it accords well with clinical
impressions, just as Jamison7
summarized over a decade ago: “The
clinical reality of manic-depressive
illness is far more lethal and infinitely
more complex than the current psychiatric
nomenclature . . . would suggest.”


Is the DSM system incorrect, then? Is
BD really just one end of a mood spectrum
continuum? The key word here is
really: notice that again we are presuming
to model reality. We are assuming
there is a correct way of explaining,
such that there could be overrecognition
and underrecognition of bipolarity.
Yet we still lack biologic underpinnings
for these models. A truly valid
nosologic system will ultimately be
anchored by understanding etiology--from genetic susceptibilities through
molecular differences to anatomic
and/or physiologic changes. We are
witnessing exciting progress in this
regard. For example, recent work by
Tsankova and colleagues8 on regulation
of brain-derived neurotrophic factor
transcription by histone methylation
and acetylation in response to social
defeat stress further calcifies neuroplasticity,
an important bone in the
skeleton of mood disorder pathology.

Must we wait for the rest of the skeleton
to form to see how bipolar and unipolar
mood disorders really are related?
(Is there truly a joint in there somewhere?)
One hopes not--critical clinical
decisions rest on these distinctions.
Many patients do not respond, or do not
sustain their response, to antidepressant
treatment. What percentage of them
have an underlying bipolar component
as the basis for that failed treatment?
Who is at risk for a dangerous reaction
to antidepressants? How can we recognize
subthreshold bipolarity if, as shown
in the most recent iteration of the United
States National Comorbidity Survey, it
can cause as much disability as diabetes
or asthma?9

Many have suggested that the DSM
should include a broader range of bipolarity,
including Klerman's 10 categories
I through VI; Akiskal and Pinto's11 I
through IV, including 1½, 2½, 3½; and
the recent bipolar spectrum disorder
proposed by Ghaemi and colleagues.12
A review for the International Society
for Bipolar Disorders' position paper
series on bipolar diagnosis13 concludes
that 3 groups of patients should be
considered for such an extension of the
categoric system, including:

  • Subthreshold cases, as suggested by
    the National Comorbidity Survey
    Replication Study (NCS-R)9 and the
    Zurich cohort.14
  • Patients with multiple soft signs
    of bipolarity, as defined by Ghaemi
    and colleagues,12 even if they lack
    detectable hypomania.
  • Patients with antidepressant-induced
    hypomania or mania.

Or, might it be better to view bipolarity
as an illness dimension, one that
can be present to varying degrees? This
approach has been adopted, at least as
a working approach awaiting further
study, by the bipolar clinic at Harvard's
teaching hospital, where instead of
asking, “Does this patient have bipolar
disorder or not?” clinicians are
taught to ask “How much bipolarity might this patient have?”15 Among
other diagnostic tools (available at, the clinic
uses the Bipolarity Index, a 100-point
scale with 20 points for hypomania or
mania, but an additional 80 points for
other features (eg, family history, age
at onset, course of illness, response to

What problem do we need to
solve right now? When should
antidepressants be used?

As we consider revisions to the current
diagnostic system, we should remember
the problem we are trying to solve.
At present, the DSM system works
well at the extremes of diagnosis:
mania identifies BD well when recognized
as such. (Numerous factors can
impede this recognition, such as lack
of insight on the part of the patient or lack of sufficient search on the part
of the clinician; neither is the fault
of the DSM system.) Conversely, an
adult with a single episode of major
depression following severe psychosocial
stress with no family history of
BD will be widely recognized as having
MDD. These fully expressed, recognizable
cases--shown in the Figure (See Psychiatric Times, July 2006, p. 76) as
points E and A--will be treated with
mood stabilizers and antidepressants,

Point D in the Figure (See Psychiatric Times, July 2006, p. 76) represents
identifiable BD II, with fully expressed
hypomania. The DSM system of diagnosis
works reasonably well for such a
patient. Our problem comes with intermediate
forms. Point C represents subthreshold
cases per the NCS-R. Some
psychiatrists would call this BD not
otherwise specified (BD NOS; ie, bipolar
but not meeting BD II criteria).
However, others would regard this as a
form of depression, perhaps atypical but
not bipolar because DSM criteria for
hypomania are not met.

The same disagreement arises--and
perhaps with more strength--at point
B, where only a few bipolar-minded clinicians
might persist in calling this BD
NOS, and most psychiatrists would call
it MDD. Obviously, from a spectrum
viewpoint there are almost an infinite variety of other intermediate cases (but
let us not digress into Zeno's paradox!).

Some clinicians are already using a
spectrum view of diagnosis, but many
are not. The resulting division of opinion
was demonstrated dramatically in
a 2005 Webcast presented by Harvard
faculty, with an audience of hundreds
of psychiatrists.17 The program focused
on a patient with clear symptoms of depression,
as well as anger, anxiety, sleep
problems, and alcohol use. His case was
clearly selected to present features of
MDD yet suggests possible BD II. His
symptoms were presented in considerable
detail to focus on this differential.
After the Harvard experts concluded in
favor of a unipolar diagnosis, the audience
was asked to voice their opinion--
bipolar or unipolar? Two thirds chose
bipolar. Not only did they disagree with
the experts, they were substantially divided
among themselves. What an embarrassment
for our field.

Notice that on this disagreement
hinges a critical, relatively immediate
decision. Suppose a patient presents
with depression. Suppose the important
elements in a standard differential diagnosis
have been excluded: substance use
or hypothyroidism and other suborganic
causes such as Parkinson disease or B12
deficiency (some would include personality
disorders, but that is a complex
issue18). Suppose the patient strongly
prefers a medication approach to
psychotherapy and is unlikely to adopt
an exercise program as the primary intervention.
If the patient is electing a
pharmacologic approach for managing depression, should the clinician begin
with an antidepressant or consider a mood
stabilizer with antidepressant clout?

We can debate whether the line
between unipolar and bipolar should be
drawn farther to the left on the continuum.
We can debate whether there really
is a continuum. These debates have persisted
for years. (The term “soft bipolar
spectrum” was first used in 1987.19) Perhaps
in a few years the DSM-V will include
one more intermediate form (eg,
BD III). Yet here we sit in the field of
psychiatry with a system of diagnosis
that forces us to disagree with one
another in public. This system may
even be doing harm by forcing misclassification
of patients as unipolar, leading
to dangerous adverse effects from
antidepressants. All of this, because we
persist in clinging to a categoric system
for a continuum of symptoms.

To address this dilemma now, instead
of waiting for the DSM-V, we could
reframe our current division of opinion
in new, more manageable terms. Thus,
when considering a medication approach
to depression, which findings
warrant changing our current default
assumption from antidepressants to
mood stabilizers? This reframing alone
will not solve our problem; some psychiatrists
would require clear-cut mania or
hypomania, setting the bar for this shift
in strategy between points C and D in
the Figure (See Psychiatric Times, July 2006, p. 76). Others would extend use of
mood stabilizers as far as C and others
even to B. Several well-known researchers
have even suggested that some
patients at Point A (ie, no observable
signs or history of hypomania) might
warrant consideration for mood stabilizers.
The bipolar spectrum disorder
proposed by Ghaemi and colleagues12
suggests that even patients who have
never had hypomania, only multiple soft
signs--such as a first degree relative
with BD, depression onset between
ages 15 and 19, and subsequent repeated
brief episodes--may still have enough
bipolarity to present some risk if treated
with antidepressants alone.

By comparison, another research
group has shown up to 6 months of
improvement treating BD II with antidepressant
monotherapy, which would
appear to contradict the concerns about
this practice. However, Amsterdam and
Shults20 did indeed see an increase in
mania scores (Young Mania Rating
Scale [YMRS]) in patients treated with
fluoxetine. Although they dismiss it as
“not clinically meaningful,” the YMRS
is not very sensitive to subtle hypomania;
thus finding any increase with this
instrument may warrant concern.

In general practice, however, most
physicians are “lumpers”--when using
a medication approach, they treat
depression with antidepressants. Indeed,
physicians verge on lumping even bipolar depression into the same approach:
as of 2003, as many as 80% of community
psychiatrists' patients with BD
were taking antidepressants.21 So
perhaps a more operational reframing
of the diagnostic dilemma might be
summarized by a single question:
presuming, as discussed above, that a
proper differential diagnosis of depression
has been conducted and a medication
approach is now to be initiated, how
many antidepressants should be tried
in a patient lacking DSM indications of
BD (and, therefore, “unipolar”), before
trying a mood stabilizer?

In current practice, we routinely try
multiple antidepressants, do we not?
But for a patient with a family history
of BD, perhaps the transition in strategy
should come earlier. And for a
patient with many soft signs of bipolarity,
perhaps the transition should
come after a single antidepressant trial--
or even before. This is the principle value
of the spectrum concept: it makes you
think. It adds bipolarity to the differential
of apparently unipolar depression,
even when a thorough search for hypomania
has yielded little. (Credit for this
concept goes to Jack Katzow, MD, my
colleague on the International Society
for Bipolar Disorders' spectrum

Should we simply expand the range
of patients for whom one can rationally
consider mood stabilizers? All of the
atypical antipsychotics have been used
with some evidence of efficacy,22 but
few formal randomized trials have been
conducted. Interestingly, 2 important
randomized trials were not published.
Data from these studies show that lamotrigine
failed to improve the course of
treatment-resistant patients with unipolar
disorder,23 even though one would
think such a group would represent an
enriched sample of soft bipolarity. These
data obviously give us pause in considering
the breadth of applicability of lamotrigine.
Furthermore, olanzapine in this
population caused the same weight gain
problems we know all too well.24

Clinicians also consider medication
risks when choosing among options. In
my opinion, we may be underestimating
the risk of antidepressants relative
to those of mood stabilizers (a very broad
and complex group, none of which meet
the most rigorous definition of this
term25). When, for a given patient, antidepressants
lack efficacy as evidenced
by a series of failed but presumably wellconducted
treatments, what should we
do next (besides reconsidering the
differential yet again)? In my opinion,
clinicians--and patients--may be slow
to consider mood stabilizers because of
the greater perceived risks of such
medications. This deserves study,
certainly. In the meantime, let's exam-ine what we know so far about these
relative risks.


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