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Bipolar Disorders 2011: 13: 587–603 ª 2011 John Wiley and Sons A/S

BIPOLAR DISORDERS

Review Article

Subthreshold bipolarity: diagnostic issues and


challenges
Nusslock R, Frank E. Subthreshold bipolarity: diagnostic issues and Robin Nusslocka–c and Ellen Frankc
challenges. a
Department of Psychology, Northwestern
Bipolar Disord 2011: 13: 587–603. ª 2011 The Authors. University, Evanston, bDepartment of Psychiatry,
Journal compilation ª 2011 John Wiley & Sons A ⁄ S. Northwestern University, Chicago, IL, cDepartment
of Psychiatry, University of Pittsburgh School of
Background: Research suggests that current diagnostic criteria for Medicine, Pittsburgh, PA, USA
bipolar disorders may fail to include milder, but clinically significant,
bipolar syndromes and that a substantial percentage of these conditions
are diagnosed, by default, as unipolar major depression. Accordingly, a
number of researchers have argued for the upcoming 5th edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to
better account for subsyndromal hypomanic presentations.

Methods: The present paper is a critical review of research on


subthreshold bipolarity, and an assessment of some of the challenges that
researchers and clinicians might face if the DSM-5 were designed to
systematically document subsyndromal hypomanic presentations.

Results: Individuals with major depressive disorder (MDD) who doi: 10.1111/j.1399-5618.2011.00957.x
display subsyndromal hypomanic features, not concurrent with a major Key words: bipolar disorder – depression –
depressive episode, have a more severe course compared to individuals diagnosis – hypomania
with MDD and no hypomanic features, and more closely resemble
individuals with bipolar disorder on a number of clinical validators. Received 23 November 2010, revised and
accepted for publication 14 September 2011
Conclusion: There are clinical and scientific reasons for systematically
documenting subsyndromal hypomanic presentations in the assessment Corresponding author:
and diagnosis of mood disorders. However, these benefits are balanced Robin Nusslock, Ph.D.
with important challenges, including (i) the difficulty in reliably Departments of Psychology and Psychiatry
identifying subsyndromal hypomanic presentations, (ii) operationalizing Northwestern University
subthreshold bipolarity, (iii) differentiating subthreshold bipolarity from 2029 Sheridan Road
borderline personality disorder, (iv) the risk of over-diagnosing bipolar Evanston, IL 60208, USA
spectrum disorders, and (v) uncertainties about optimal interventions for Fax: 847-491-7859
subthreshold bipolarity. E-mail: nusslock@northwestern.edu

lar disorder also have higher rates of metabolic


Introduction
syndromes and risk factors for cardiovascular
The World Health Organization (WHO) ranks disease (e.g., obesity, hyperglycemia, hypertension,
bipolar disorder as one of the top 10 causes of and type 2 diabetes) than the general population
disability in the world (1). Bipolar disorder is (6), and have a 10-year earlier mortality rate (7).
associated with significant work impairment, high Accordingly, it is important to have precise and
rates of divorce, and substance abuse, and leads to comprehensive diagnostic criteria to reliably iden-
suicide attempts in almost one out of every five tify individuals with, and at risk for, bipolar
diagnosed individuals (2–5). Individuals with bipo- disorders.
A growing number of researchers, however, have
argued that current diagnostic criteria for bipolar
EF serves on an advisory board for Servier and receives royalties from disorders do not address milder, albeit clinically
Guilford Press. RN has no conflicts of interest to report. significant, bipolar syndromes. Moreover, a
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Nusslock and Frank

substantial percentage of these conditions, accord- have concerns with such a treatment approach
ing to some researchers, are diagnosed by default given the nature of the side effects associated with
as unipolar major depression (8–19). For the antipsychotic medications and mood stabilizers
purpose of the present review, we consider the (27–31) [It is important to note, however, that
bipolar spectrum to be the continuum from lithium is used by some to treat affective disorders
psychotic mania through other expressions of more generally, given its antisuicidal properties
bipolar I disorder, to bipolar II disorder, to soft, (32, 33)]. Moreover, there is still debate as to
subsyndromal manifestations of hypo ⁄ mania. whether antidepressants may be a risk factor for
Benazzi and Akiskal (13) and Benazzi (12) so-called ÔswitchingÕ into hypo ⁄ manic episodes
reported that approximately 50% of outpatients and ⁄ or cycle acceleration among individuals with
with major depressive disorder (MDD) were clas- bipolar I or II disorder (34–36); however, to the
sified as being in the bipolar spectrum when the best of our knowledge, this question has yet to be
strict Structured Clinical Interview for DSM-IV examined in individuals with subsyndromal hypo-
(SCID) criteria for a history of hypomania, not manic presentations. Further, how do we balance
necessarily concurrent with a major depressive the tension between reliably classifying meaningful
episode (MDE), were broadened to include those subsyndromal hypomanic presentations against the
reporting fewer than the criterion number of risk of over-diagnosing bipolar spectrum disorders
symptoms. Further reports that approximately given the severity of, and potential stigma attached
40–50% of individuals with MDD display a to, these diagnoses?
lifetime history of hypomanic features, again The purpose of the present report is threefold.
not necessarily concurrent with an MDE, come First, we review the literature on the prevalence of
from studies by Angst et al. (10), Akiskal and both bipolar spectrum disorders and subthreshold
Mallya (20), Benazzi (21), Cassano et al. (22), and hypomania. Second, we outline the clinical and
Hantouche et al. (23). Furthermore, compared to scientific utility of expanding the mood disorder
MDD with no history of hypomanic features, criteria in the DSM-5 to better account for
individuals with MDD and a history of hypomanic subsyndromal hypomanic presentations as pro-
features (not concurrent with an MDE) are posed by several researchers. Third, we directly
reported to have more general impairment (11, address a number of challenges and complexities
24, 25) and are more likely to convert to a bipolar I that researchers and clinicians face in diagnosing,
diagnosis over time (19). classifying, and treating subthreshold bipolarity.
The current focus on revising the Diagnostic and Before we proceed, it is important to briefly
Statistical Manual of Mental Disorders in prepa- address two issues. First, the present report focuses
ration for the publication of the 5th edition (DSM- only on subthreshold bipolarity in adults. The
5) in May 2013 provides an opportunity to reflect accurate and timely diagnosis of pediatric bipolar
on the optimal diagnostic criteria for the bipolar disorder is an issue of critical importance that is,
spectrum disorders. Considering the aforemen- however, beyond the scope of the present review.
tioned clinical and epidemiological data, a number Second, with respect to terminology, researchers
of researchers have argued for DSM-5 to better have examined subsyndromal hypomanic presen-
account for hypomanic features that do not satisfy tations from two different perspectives. The first
current criteria for the full syndrome (8, 9, 11, 12, focuses on a history of hypomanic presentations
14, 16, 18–20, 22, 25, 26). We agree with this that are not necessarily concurrent with an MDE;
argument, particularly in light of growing evidence that is, hypomanic presentations that occur outside
that major mood disorders form a spectrum from the context of a depressive episode. The second
MDD without bipolar features via bipolar sub- perspective examines subsyndromal hypomanic
groups to pure mania (11, 25). However, we also presentations that are concurrent with an MDE,
argue that modifying DSM-5 to more systemati- commonly referred to as mixed depressive epi-
cally document subsyndromal hypomanic states sodes. The present report focuses exclusively on
raises a number of challenges and complexities. adult individuals with a history of MDD who
For example, what are the pharmacological treat- display subsyndromal hypomanic features that are
ment implications for individuals with MDD who not concurrent with an MDE.
have a history of hypomanic symptoms that do not
meet the criteria for mania or hypomania? Should
Prevalence and the bipolar spectrum
such individuals be prescribed an antipsychotic or
mood stabilizer as opposed to an antidepressant as The DSM-IV–text revised (DSM-IV-TR) (37)
a prophylactic treatment to prevent a worsening of defines the bipolar spectrum disorders as encom-
course along the bipolar spectrum? Several groups passing three diagnoses: cyclothymia, bipolar II
588
Subthreshold bipolarity

disorder, and bipolar I disorder. All three diagno- ‘‘some people have periods lasting several days or
ses are characterized by hypomanic ⁄ manic and longer when they feel much more excited and full
depressive symptoms (except for instances of pure of energy than usual’’)1, and (ii) a failure to meet
mania), but differ in severity level, with bipolar I the full DSM-IV diagnostic criteria for hypomania.
disorder being the most severe and cyclothymia the The authors reported that nearly 40% of MDD
least severe. Cyclothymia is diagnosed as the cases experienced subsyndromal hypomania out-
presence of erratic depressive and hypomanic side the context of an MDE, noting that their
periods, in the absence of a history of a full ‘‘findings demonstrate heterogeneity of major
MDE. Bipolar II disorder is diagnosed when there depressive disorders and support the validity of a
is a history of at least one MDE and one wider spectrum of bipolar disorders’’ (11, p. 1194).
hypomanic episode, but no history of a manic Zimmerman et al. (19) used data from the pro-
episode. Bipolar I disorder is diagnosed when there spective, longitudinal Early Developmental Stages
is a history of at least one manic or mixed episode, of Psychopathology (EDSP) study to examine how
as currently defined. A diagnosis of bipolar disor- many cases previously classified as DSM-IV MDD
der not otherwise specified (NOS) is reserved for would be reclassified as being in the bipolar
individuals who display bipolar symptomatology spectrum by broadening the criteria for
that does not meet criteria for any of these three mania ⁄ hypomania. Subsyndromal hypomania
bipolar diagnoses. was defined as at least a four-day period (not
Epidemiological studies relying on DSM criteria concurrent with an MDE) with (i) elated ⁄ expan-
have consistently reported lifetime prevalence rates sive mood that created troubles or was noticed by
for bipolar I disorder between 0.0% and 1.7% (38, others as a change in functioning, but DSM-IV
39) and bipolar II disorder between 0.5% and criterion B (meeting the required minimum number
1.9% (40, 41). There is growing evidence, however, of symptoms) was not fulfilled, or with (ii) unusu-
that major mood disorders form a spectrum from ally irritable mood expressed as starting argu-
MDD to pure mania via bipolar subgroups (11, ments, or shouting at or hitting people plus the
25). This spectrum embraces mania, hypomania, presence of at least three symptoms, but criterion
recurrent brief hypomania, sporadic brief hypo- D (symptoms are observable by others) was not
mania, and cyclothymia (9). Although researchers met. In line with Angst et al. (11), the authors
have addressed this spectrum using different ter- reported that among the 488 respondents with
minology, there is growing appreciation of the MDD, 40% had subsyndromal hypomanic fea-
importance of identifying and diagnosing subsyn- tures at some point during their lifetime and 60%
dromal hypomanic presentations among individu- had no history of subsyndromal hypomanic fea-
als with MDD (8, 11, 17). It is argued that the tures. A study by Benazzi (43) interviewed 111
current diagnostic criteria for bipolar disorder fail remitted outpatients with prior depression for a
to include milder, but clinically significant, bipolar history of lifetime hypomania and hypomanic
syndromes and that a significant percentage of symptoms with the Structured Clinical Interview
these conditions are diagnosed, by default, as for DSM-IV–clinician version. All past hypomanic
unipolar major depression (9, 11, 19, 42). Accord- symptoms (especially overactivity) were assessed
ingly, researchers have begun conducting epidemi- and subsyndromal hypomania was defined as at
ological studies that give particular attention to the least a two-day period of overactivity (increased
prevalence of subsyndromal hypomania. goal-directed activity) plus at least two other
As indicated above, these studies suggest that hypomanic symptoms. He reported that a history
approximately 40–50% of individuals with MDD of subsyndromal hypomania, not concurrent with
display lifetime subsyndromal hypo ⁄ manic fea- an MDE, was present in 39% of the MDD sample.
tures when the strict DSM-IV criteria for hypo-
mania are broadened (10, 20–23). For example, a
1
recent study by Angst and colleagues (11) exam- The two screening questions used by Angst and colleagues (11) to
ined the prevalence and clinical correlates of MDD assess for subsyndromal hypomania were (i) ‘‘Some people have
with subsyndromal hypomanic features, not con- periods lasting several days or longer when they feel much more
current with an MDE, versus MDD with no excited and full of energy than usual. Their minds go fast. They talk a
history of hypomanic features in the National lot. They are very restless or unable to sit still and they sometimes do
Comorbidity Survey Replication (NCS-R), a things that are unusual for them, such as driving too fast or spending
nationally representative household survey of the too much money. Have you ever had a period like this lasting several
US population. Subsyndromal hypomania was days or longer?’’; (ii) ‘‘Have you ever had a period lasting several days
operationalized as: (i) the presence of at least one or longer when most of the time you were so irritable that you either
of two screening questions for hypomania (e.g., started arguments, shouted at people, or hit people?’’.

589
Nusslock and Frank

As reported by Angst et al. (10), a stepwise which adhered to earlier versions of the DSM
broadening of the criteria for hypomania allocated (38–41). As we examine later, this would likely
almost half of the participants with MDD to a generate challenges for both researchers and clini-
broadly defined bipolar spectrum group. cians around issues of medication management and
Researchers have argued that the substantial the stigma often associated with a bipolar spectrum
percentage of individuals with MDD who display diagnosis. However, prior to addressing these
subsyndromal hypomanic features poses a chal- challenges, we first examine the validity and clinical
lenge to the categorical perspective taken in the impact of subsyndromal hypomania, not concur-
current DSM in which unipolar depression and rent with an MDE, which are important to
bipolar disorder are viewed as separate disease consider in the cost–benefit analysis of whether
processes. It is argued that data, instead, support a to modify DSM-5 to account for subthreshold
continuum from pure MDD to bipolar I disorder bipolar features.
(9, 14, 16, 17, 43–45). This spectrum perspective
allows for a broader range of symptoms and the
Validators of subthreshold bipolarity
possibility that there is not a clear distinction
between the two mood disorder categories. In line Growing evidence indicates that individuals with
with this perspective is research indicating a strong MDD who report subsyndromal hypomania, out-
genetic relationship between unipolar depression side the context of an MDE, more closely resemble
and bipolar disorder (46) and the fact that common individuals with bipolar disorder on a number of
genetic variations increase susceptibility for the clinical validators, as compared to individuals with
entire affective spectrum (47–49). The idea, how- MDD and no history of subsyndromal hypomania
ever, that unipolar depression and bipolar disorder (see Table 1 for the cohort and definition of
are on a spectrum of severity is not a new concept. subthreshold hypomania for studies of clinical
Indeed it was first endorsed by Kraepelin (50) when validators of subthreshold bipolarity). Relative to
he created the rubric of Ômanic-depressive insanityÕ those with MDD and no history of hypomanic
that for him spanned the continuum from the symptoms, individuals with subsyndromal hypo-
mildest affective disturbance to the most extreme mania, outside the context of an MDE, have
psychosis. Goodwin and Jamison (4) also sup- increased comorbidity with impulse control and
ported a bipolar spectrum that included MDD plus substance disorders (9–11, 19, 53), and experience
what they refer to as bipolar signs (early onset, more episodes (11) (see Table 2 for an overview of
many recurrences, atypical depression, bipolar clinical validators of bipolarity for individuals with
family history, and antidepressant-associated MDD and subsyndromal hypomanic features ver-
switching) (51, 52). sus MDD and no history of subsyndromal hypo-
Researchers have also addressed how broadening manic features). The comorbidity between MDD
the spectrum of what is considered diagnosable and alcohol use disorders becomes non-significant
hypomania would affect the prevalence rates for after exclusion of individuals with subsyndromal
both MDD and bipolar disorder. Zimmerman and hypomania (19, 54). Data with respect to comor-
colleagues (19) reported that the cumulative bidity with anxiety disorders are more inconsistent,
incidence of 23.2% for DSM-IV MDD would drop however. Three studies reported that the presence
to 13.9% if cases with subsyndromal hypomanic of subsyndromal hypomania, not concurrent with
features (9.3%), not concurrent with an MDE, were an MDE, was associated with elevated rates of
deducted. Correspondingly, the rate of a lifetime comorbid anxiety (9, 11, 19), while two studies did
bipolar spectrum diagnosis would increase to not find this effect (10, 53). Lastly, a 10-year
13.7%, thus being equal to the rate of MDD with prospective longitudinal study reported that indi-
no history of subsyndromal hypomanic features. viduals with MDD who had subsyndromal hypo-
This is consistent with data from the epidemiologic mania, not concurrent with an MDE, were more
studies of Angst et al. (10) which showed a lifetime likely to convert to a DSM-IV bipolar spectrum
prevalence of 11.0% for a softly defined bipolar diagnosis as compared to individuals with pure
spectrum diagnosis versus 11.4% for MDD with no depression (19). The authors reported that, in most
history of subsyndromal hypomanic features, and cases, this conversion was to bipolar I disorder.
from clinical investigations (13). Family and genetic studies also provide support
It is apparent that modifying the DSM-5 to for the validity of subthreshold bipolarity. Cassano
systematically document subthreshold bipolarity and colleagues (22) reported that individuals with
could generate prevalence rates for bipolar spec- MDD who had hypomanic personality traits (e.g.,
trum disorders that are quite different from those uninhibited, stimulus-seeking, promiscuous, vigor-
reported in previous epidemiological research ous, full of plans, overconfident, self-assured, and
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Subthreshold bipolarity

Table 1. Cohort and definition of subthreshold hypomania for studies of clinical validators of subthreshold bipolarity

Study Cohort Definition of subthreshold hypomania ⁄ bipolar disorder

Akiskal et al., 1995 (53) National Institute of Mental Health Individuals with MDD who converted to bipolar II disorder
(NIMH) Collaborative Depression
Study (USA; N = 559)
Angst et al., 2010 (11) National Comorbidity Survey Presence of at least one of the screening questions for mania on
Replication (USA; N = 5,692) the Composite International Diagnostic Interview (CIDI) and
three or more symptoms
Angst, 1998 (9) Zurich Cohort Study (Zurich, Met DSM-IV symptomatic criteria for hypomania but only lasted
Switzerland; N = 591) 1–3 days
Angst et al., 2003 (10) Zurich Cohort Study (Zurich, ÔHypomanic symptoms onlyÕ; did not have consequences and
Switzerland; N = 591) not required to meet duration or number of symptoms criteria
Benazzi & Akiskal, 2008 (15) Outpatient psychiatry private Early onset (before age 21) MDD
practice (Italy; N = 560)
Cassano et al., 1992 (22) Collaborative initiative between MDE with pre-existing hyperthymic temperament. A hyperthymic
Institute of Clinical Psychiatry at temperament was defined as 5 of the following: (i) irritable,
the University of Pisa, Italy and cheerful, overoptimistic, or exuberant; (ii) naı̈ve, overconfident,
the Section of Affective Disorders self-assured, boastful, bombastic, or grandiose; (iii) full of
at the University of Tennessee, plans, imprudent, or carried away by restless impulses;
(USA; N = 687) (iv) over talkative; (v) warm, people-seeking, or extroverted;
(vi) over-involved and meddlesome; (vii) uninhibited, stimulus
seeking, or promiscuous
Lewinsohn et al., 2002 (24) Oregon Adolescent Depression Criterion A hypo ⁄ manic symptom plus one or more other
Project (USA; N = 1,709) hypo ⁄ manic symptoms, but never meeting criteria for the full
bipolar diagnosis
Merikangas et al., 2007 (25) National Comorbidity Survey Any of the following: (i) recurrent subthreshold hypomania
Replication (USA; N = 9,282) (‡ 2 criterion B symptoms and all other criteria for hypomania)
in the presence of intercurrent MDE; (ii) recurrent (> 2
episodes) hypomania in the absence of recurrent MDE with or
without subthreshold MDE; (iii) recurrent subthreshold
hypomania in the absence of intercurrent MDE with or without
subthreshold MDE. The number of required symptoms for a
determination of subthreshold hypomania was confined to two
criterion B symptoms
Zimmerman et al., 2009 (19) Early Development Stages of At least a 4-day period with the following: (i) noticeable elated or
Psychopathology study (Munich, expansive mood but minimum number of symptoms criterion
Germany; N = 2,210) not fulfilled, or (ii) unusually irritable mood, at least three
symptoms, but observable by others criterion not fulfilled

MDD = major depressive disorder; MDE = major depressive episode.

Table 2. Clinical validators of bipolarity for individuals with major depressive disorder (MDD) with subsyndromal hypomanic features versus MDD and no history
of subsyndromal hypomanic featuresa,b

Increased
BD Increased Increased comorbid Younger
Increased Increased family Increased conversion comorbid substance ⁄ age of
Study impairment suicidality history criminality to BD anxiety alcohol onset

Akiskal et al., 1995 (53) + ) + +


Angst et al., 2010 (11) ) ) + + + +
Angst, 1998 (9) ) + + +
Angst et al., 2003 (10) ) + ) ) + +c
Benazzi & Akiskal, 2008 (15) + +
Cassano et al., 1992 (22) ) + )
Lewinsohn et al., 2002 (24) +
Zimmerman et al., 2009 (19) ) + + + + + )

A blank cell indicates that the study did not compare groups on that particular validator. BD = bipolar disorder; + = MDD with
subsyndromal hypomanic features greater than MDD and no subsyndromal hypomanic features; ) = no difference between MDD with
subsyndromal hypomanic features and MDD with no subsyndromal hypomanic features.
a
There were notable differences in methodology, statistical analyses, and definition of subthreshold hypomanic features across the
reported studies. The present table reflects our best attempt to synthesize and summarize the literature.
b
Subsyndromal hypomanic features occur outside the context of a major depressive episode.
c
Contrast is at the trend level.

591
Nusslock and Frank

grandiose) had rates of familial bipolarity signifi- Researchers have also compared individuals
cantly higher than individuals with MDD without with MDD and subsyndromal hypomania, outside
these temperamental qualities. Zimmerman et al. the context of an MDE, to individuals with
(19) reported familial data demonstrating increased syndromal bipolar disorder (e.g., bipolar II dis-
rates of parental mania among respondents with order) on clinical validators of bipolarity (see
subthreshold bipolarity, but not among individuals Table 3). Much of this research provides support
with MDD and no history of subsyndromal for the spectrum or dimensional model of bipolar-
hypomania. Akiskal and colleagues (8) noted that ity, documenting a direct association between the
displaying subsyndromal hypomania places an severity of the bipolar diagnosis and indicators of
individual in a genetic cohort more in line with clinical validity, including number of episodes,
bipolar disorder than unipolar depression. Angst chronicity, symptom severity, and impairment (9,
et al. (9, 10) and Musetti et al. (55) provide 59). For example, Merikangas and colleagues (25)
additional evidence that family members of indi- reported that the proportion of individuals with
viduals with subthreshold bipolarity display great- work impairment increased from 19.8% for sub-
er rates of bipolar disorder. threshold bipolar disorder to 47.5% for bipolar II
Finally, research indicates that an early age at to 62.3% for bipolar I, and the estimated average
onset of first MDE (before 21 years) may be an number of lifetime episodes was 32.0 for sub-
important validator of bipolar risk status (8, 11). threshold bipolar disorder, 63.6 for bipolar II, and
Benazzi and Akiskal (15) reported that early age at 77.6 for bipolar I. Likewise, Zimmerman et al. (19)
onset was the only variable that identified a MDD noted that with increasing severity of the manic
subgroup significantly associated with all bipolar component, rates for diverse validators increased
validators. The authors noted that the odds of an (alcohol use disorders and parental mania) or
individual with MDD having bipolar disorder were decreased (harm avoidance), accordingly. Benazzi
three times higher if he or she had an early onset. and Akiskal (15) demonstrated a dose–response
Furthermore, an early age at onset of first MDE relationship between the number of bipolar vali-
has been shown to predict conversion from MDD dators and bipolar family history, suggesting that a
to syndromal bipolar disorder (bipolar I and II) clustering of bipolar markers increases the genetic
(56–58). Three additional studies reported that vulnerability to bipolarity among those with
MDD with subsyndromal hypomanic features was MDD. These data, however, need to be interpreted
associated with an earlier age of onset of a first in the context of other work indicating comparable
MDE compared to MDD and no history of profiles on clinical validators across the bipolar
subsyndromal hypomanic features (10, 11, 53). spectrum. For example, a number of studies report
These studies, however, need to be considered in equivalent rates of comorbidity for substance ⁄
light of two studies that found no differences in age alcohol abuse and anxiety disorders in individuals
of onset for MDD with and without subsyndromal with subsyndromal versus syndromal bipolar dis-
hypomanic features (19, 22). order (9, 10, 24, 25). Furthermore, in at least one

Table 3. Clinical validators of bipolarity for individuals with syndromal hypomania (e.g., bipolar II disorder) versus major depressive disorder (MDD) with
subsyndromal hypomanic featuresa,b

Increased
BD Increased comorbid Younger
Increased Increased family Increased comorbid substance ⁄ age of
Study impairment suicidality history criminality anxiety alcohol onset

Angst et al., 2010 (11) + ) ) + ) +


Angst, 1998 (9) ) + ) )
Angst et al., 2003 (10) ) ) ) ) ) )
Benazzi & Akiskal, 2008 (15) )
Cassano et al., 1992 (22) + ) +
Lewinsohn et al., 2002 (24) + + ) )
Merikangas et al., 2007 (25) + + ) +
Zimmerman et al., 2009 (19) + + + + +

A blank cell indicates that the study did not compare groups on that particular validator. BD = bipolar disorder; + = threshold hypomania
(e.g., bipolar II disorder) greater than MDD with subsyndromal hypomanic features; ) = no difference between threshold hypomania
(e.g., bipolar II disorder) and MDD with subsyndromal hypomanic features.
a
There were notable differences in methodology, statistical analyses, and definition of both threshold and subthreshold hypomanic
features across the reported studies. The present table reflects our best attempt to synthesize and summarize the literature.
b
Subsyndromal hypomanic features occur outside the context of a major depressive episode.

592
Subthreshold bipolarity

review, individuals with bipolar I or II disorder disorder are correctly diagnosed and appropriately
were found to have comparable rates of suicide treated (51, 52). Hirschfeld et al. (62) reported data
attempts (60), and individuals with bipolar II from the National Depressive and Manic Depres-
disorder, relative to those with bipolar I disorder, sive Association survey indicating that 69% of
may experience a more chronic course and a lower respondents with bipolar disorder I or II disorder
likelihood of returning to premorbid levels of were initially misdiagnosed, with the most frequent
functioning between episodes (61). Thus, although diagnosis being unipolar depression (60%). Those
bipolar disorder is organized along a spectrum of who were misdiagnosed consulted a mean of four
severity, milder or ÔsofterÕ forms of bipolar disorder physicians prior to receiving the correct diagnosis
are clearly associated with substantial impairment and over one-third waited 10 years or more before
that typically exceeds that observed in individuals receiving an accurate diagnosis. In a follow-up
with no evidence of bipolarity. study, Hirschfeld and colleagues (63) screened
adult patients diagnosed with MDD for bipolar I
or II disorder. Twenty-one percent of the patients
Clinical and scientific importance of diagnosing
with MDD screened positive for bipolar disorder,
subthreshold bipolarity
and nearly two-thirds of those who screened
Considering the epidemiological and clinical data, positive had never received a diagnosis of bipolar
a number of researchers have called on the DSM-5 disorder. Ghaemi et al. (51) reported that 40% of
to better account for subsyndromal hypomanic consecutively admitted patients with DSM-IV
presentations (8–14, 16, 18–20, 22, 25, 26). In line bipolar I disorder were previously misdiagnosed
with this perspective, we next put forth four with MDD. An average period of 7.5 ± 9.8 years
arguments supporting the need to take subthresh- elapsed in this group before the correct bipolar
old bipolarity into consideration in the diagnosis, diagnosis was made. In a follow-up study, Ghaemi
treatment, and scientific investigation of mood et al. (52) reported that bipolar disorder I, II, or
disorders. We then follow these arguments with NOS was misdiagnosed as unipolar depression in
an analysis of challenges and complexities that 37% of patients who first saw a mental health
clinicians and researchers would likely face if the professional after their initial hypo ⁄ manic episode.
DSM-5 were to be structured to account for Converging factors contribute to the frequent
subthreshold bipolarity. mis- and under-diagnosis of bipolar disorder. For
The first argument for documenting subsyndro- example, the significant impairment associated
mal hypomanic presentations is that, as discussed with bipolar depression (64) results in individuals
in the previous section, they are clinically signifi- with bipolar disorder being more likely to present
cant and associated with role impairment. Data for treatment when depressed, increasing the like-
from the NCS-R indicate that 45.9% of individuals lihood of an inaccurate diagnosis of unipolar
with subthreshold bipolar disorder reported severe depression (26). However, researchers have pro-
role impairment associated with subthreshold posed that another important factor in the frequent
hypomania, and an even higher percentage misdiagnosis of bipolar disorder may be the
(78.8%) reported severe role impairment from narrow diagnostic criteria in the current nosology,
MDEs in the context of subthreshold bipolar and the fact that clinicians and physicians do not
disorder (25). Moreover, individuals with MDD systematically assess for subthreshold bipolarity
who display subsyndromal hypomania outside the (11, 16). As proposed by Cassano et al. (16, p. 319),
context of an MDE have a more severe and ‘‘attention should be devoted to mild symptomatic
pernicious course as compared to individuals with manifestations of a manic diathesis, even if such
MDD and no hypomanic features, including manifestations may sometimes enhance quality of
greater likelihood of converting to a bipolar life’’. This attention may be critical in differentiat-
diagnosis (19), higher rates of comorbid psychiatric ing individuals with ÔpureÕ depression from those
illness (10, 11, 19, 25), and more depressive with subthreshold bipolar presentations. However,
episodes (11). it may also be important for increasing the accu-
Second, systematically assessing for subsyndro- racy with which we identify threshold bipolar
mal hypomania may help remedy an important disorder, type I or II. By assessing only the most
related concern: the fact that threshold bipolar obvious signs of type I mania (e.g., hospitalization
disorder (bipolar I or II disorder) is either fre- due to mania, and psychotic features), researchers
quently misdiagnosed, or there is a lengthy time and clinicians may fail to identify important signs
period from the point of illness onset to correct and symptoms of the larger bipolar spectrum,
diagnosis. Delays ranging from 6 to 10 years or particularly those that the patient views as ego-
longer have been reported before bipolar I or II syntonic, and increase the risk of misdiagnosing
593
Nusslock and Frank

individuals with bipolar disorder as having groups of mood disorder patients for neuroimag-
MDD. It could be argued, therefore, that system- ing and biomarker based research.
atically assessing for and documenting subsyndro-
mal hypomanic features may help remedy this
Challenges and complexities associated with
situation.
diagnosing, classifying, and managing subthreshold
It is important to mention that while there is
bipolarity
significant evidence for the under-diagnosis of
bipolar disorder, there is a parallel literature Having discussed the prevalence and validity of
documenting the fact that under certain circum- subthreshold bipolarity, we now turn our attention
stances bipolar disorder may also be overdiagosed to some of the challenges and complexities associ-
(65–70). This literature, however, is not arguing ated with the assessment, diagnosis, and manage-
that the possible overdiagnosis of bipolar disorder ment of subthreshold bipolarity and, where
is attributable to an increased awareness of the supported by research, put forth suggestions for
importance of assessing for and documenting addressing them.
subthreshold bipolarity, but rather a tendency to
attribute symptoms of other disorders such as
Reliably identifying subthreshold bipolar features
borderline personality disorder to the bipolar
spectrum. We address this issue in detail below. The first challenge is the difficulty in reliably
Third, it is argued that the assessment and assessing and identifying subsyndromal hypomania
management of subthreshold bipolar features are (16). Several factors that contribute to this diffi-
in line with a prevention-oriented treatment model culty are the fact that both syndromal and
for bipolar disorder. A goal of mental health subsyndromal hypomania: (i) are often not asso-
treatment is not only to effectively manage an ciated with stress or suffering and thus not a cause
illness once it has emerged, but ideally prevent its for pursuing treatment, (ii) are often ego-syntonic
emergence or re-emergence. Prevention strategies, and associated with heightened confidence and
however, require accurate assessment of the early productivity, (iii) may not be noticed by family
signs of an illness. Expanding the diagnostic members, and (iv) may be misinterpreted as a
criteria for mood disorders in order to systemat- personality disorder (16). Taking these factors into
ically document the presence or absence of sub- consideration, researchers and clinicians have pro-
threshold bipolar features in MDD may help posed a number of recommendations for better
facilitate cliniciansÕ identifying at-risk individuals identifying and diagnosing hypomanic features,
and ideally employing strategies in order to prevent which we review below.
the onset of threshold bipolar disorder.
Finally, documenting subthreshold bipolarity in Overactivity as a stem criterion for hypomania
individuals with MDD has important implications diagnosis. The first recommendation is to focus
for research on mood disorders. The recent the probing for history of hypomania at least as
research agenda for the DSM-5 has emphasized much on changes in goal-directed activity and
the need to apply basic and clinical neuroscience energy as on mood changes, as this has been shown
findings to develop a framework for identifying to reduce the under-diagnosis of hypomania (14).
biomarkers that reflect pathophysiological proc- Benazzi (43) reported that in a sample of remitted
esses to facilitate earlier and more accurate diag- outpatients with a history of depression, overac-
noses of psychiatric disorders (71–73). A difficulty tivity was the most common and easiest to identify
in examining biomarkers, however, is that many symptom of hypomania. Moreover, overactivity
illnesses are characterized by notable diagnostic was found to be as important as mood change for
heterogeneity (74) that introduces uncontrolled the diagnosis of hypomania on the basis of clinical,
variance into analyses. This is clearly the case in family history, and psychometric findings (10, 13).
MDD where, as documented above, upwards of Overactivity is typically better remembered than
40% of individuals with MDD display subsyndro- mood change by patients and key informants (13),
mal bipolarity. This subgroup is likely character- and is more closely linked to bipolar validators
ized by different pathophysiological processes than such as bipolar family history (10). Accordingly, a
individuals with ÔpureÕ depression, given family and number of researchers have argued that one way to
genetic studies indicating they more closely resem- address the difficulty in identifying subsyndromal
ble individuals with bipolar disorder (9, 10, 19, 22, hypomania is to balance the currently central
55). Systematically assessing for subthreshold diagnostic importance placed on the mood crite-
bipolarity in individuals with MDD may therefore rion with more emphasis on the hypomanic symp-
assist researchers in generating more homogenous toms of overactivity and excessive goal-directed
594
Subthreshold bipolarity

behavior (10, 11, 14, 16, 43). These researchers found to be a useful clinical marker of bipolar risk
propose that overactivity should be included as a status (10, 21). Perugi et al. (18) reported that 72%
stem criterion for the diagnosis of hypomania (11, of individuals whose depression was characterized
14, 43), especially given that periods of elevated by atypical features met criteria for bipolar II
activity are easier for patients to remember, and disorder or subthreshold bipolarity, and nearly
increase the sensitivity with which clinicians can 60% had cyclothymic temperaments. Benazzi (12)
identify subsyndromal hypomania (14, 43). reported that individuals with MDD who were
reclassified as having bipolar II disorder had a
Reduce duration requirement for hypomania. The depression history characterized by early onset and
minimum duration required for a diagnosis of atypical features. An earlier study by Ebert et al.
hypomania has changed significantly over the (80) showed a progression of atypical depression to
years. It was two days in the Research Diagnostic bipolar spectrum disorders: however, this progres-
Criteria (75), not specified in DSM-III or DSM- sion only reached a statistical trend in a more
III-R, and is currently four days in DSM-IV. recent study by Angst and colleagues (10). Assess-
However, the current four-day cut-off is not data- ing for atypical depressive symptoms and age of
based (76), and, according to some researchers, onset of first depressive episode may help clinicians
may unnecessarily narrow the range of bipolar and researchers more accurately identify which
spectrum disorders diagnosable in clinical and individuals with MDD are at heightened risk for
epidemiological studies (8). By contrast, a cut-off conversion to a bipolar diagnosis. We are not
of two days is supported by data (8–10, 42, 53, 56, advocating that atypical depressive symptoms or
77, 78). Angst et al. (10) reported that hypomanic an early age of depression onset be included in the
episodes of 1–3 days were of comparable clinical diagnostic criteria for the bipolar spectrum disor-
significance as episodes having a four-day mini- ders. We are suggesting, however, that they may
mum criterion. Moreover, a large clinical study on indicate a heightened risk for a bipolar spectrum
individuals with bipolar II disorder that used a diagnosis and, when present, clinicians and
definition of hypomanic duration of two days researchers may benefit from initiating a more
found that these individuals had a rate of bipolar comprehensive assessment for hypo ⁄ manic symp-
family history statistically indistinguishable from toms.
that of individuals with bipolar I disorder, both of
which were higher than that of individuals with
Operationalizing subthreshold bipolarity
MDDs. Accordingly, a number of researchers have
argued that the DSM-5 duration criteria for Recognition of the full spectrum of bipolar disor-
hypomanic episodes should be reduced to better ders is dependent on the identification of the most
reflect the data and to better capture subsyndromal appropriate definitions for these subthreshold
hypomanic features (8, 10, 14, 43). conditions. The concept of a spectrum of bipolar
disorders was stimulated by Dunner et al. (81),
Depression features may inform diagnosis of hypo- who distinguished between bipolar I and bipolar II
mania. An individualÕs depression history may disorders. Angst (82) extended this logic, drawing a
yield important information about their risk status distinction between hypomania (m), cyclothymia
for bipolar spectrum disorder and thus may serve (md), mania plus major depression (MD), and
as a cue for clinicians and researchers to probe major depression and hypomania (Dm). Akiskal
more thoroughly for a history of subthreshold and colleagues have described a ÔsoftÕ bipolar
bipolarity. As reported earlier, the odds of an spectrum and proposed broadening bipolar II
individual with MDD having bipolar disorder are criteria, as well as creating a third bipolar category,
three times higher if they had an early onset of to more fully acknowledge cyclothymic and hyper-
depression (age less than 21 years) (8, 11, 15). thymic states, family history of bipolar disorder,
Research also suggests that the depressive episodes temperament, and hypomanic episodes which
of individuals with, and at risk for, bipolar occur during pharmacotherapy (8, 77, 83). A
disorder may be more likely to be characterized consequence of these diverse definitions, however,
by atypical features. According to DSM-IV, atyp- is that many studies have operationalized sub-
ical depression is characterized by symptoms such threshold bipolarity using very different diagnostic
as mood reactivity, hypersomnia, hyperphagia, criteria. With respect to the criteria for subsyndro-
leaden paralysis, and rejection sensitivity. Atypical mal hypomania that is not concurrent with an
depression is associated with greater functional MDE, some studies have reduced the number of
impairment and more chronic dysphoria (79). symptoms required to obtain a diagnosis (11, 19,
Importantly, atypical features of MDD have been 25, 43), others the number of days or whether
595
Nusslock and Frank

change in function was obligatory (9–11, 14, 19), disorder. Using data from the Rhode Island
and others have emphasized overactivity, as Methods to Improve Diagnostic Assessment and
opposed to change in mood, as a Criterion A Services (MIDAS) project, Ruggero and colleagues
symptom (10, 43). (67) reported that nearly 40% of patients diag-
An important direction for future research is to nosed with BPD were at some point misdiagnosed
directly compare the validity and utility of different as having bipolar disorder, as compared to only
definitions of, and criteria for, subthreshold bipo- 10% of patients without BPD. Furthermore, the
larity in order to identify optimal diagnostic likelihood of being misdiagnosed with bipolar
criteria. Angst and colleagues (10, 84) have pro- disorder increased with the number of BPD criteria
posed a diagnostic system for subsyndromal hypo- a patient met. The misdiagnosis of BPD and
mania not concurrent with an MDE that is well bipolar disorder has important treatment implica-
defined, testable, and receiving preliminary empir- tions given data suggesting the medications used to
ical support across different patient samples and treat bipolar disorder may not be effective for
research groups. This proposal involves: (i) over- BPD, and vice versa (91), although Reich et al. (92)
activity plus at least two to three of the seven and Nickel et al. (93) present data suggesting that
DSM-IV hypomanic symptoms, (ii) a duration ‡ mood stabilizers may ameliorate the symptoms of
1 day, and (iii) a change in functioning that is both bipolar disorder and BPD.
noticeable to others. Benazzi (14) reported that While there are exceptions (8, 20, 43), the
when using AngstÕs proposed criteria of over- majority of research on the prevalence and valida-
activity plus 3 out of 7 symptoms, hypomania was tors of subthreshold bipolarity has not systemat-
not over-diagnosed. Comparisons between DSM- ically examined or controlled for borderline
IV hypomania and AngstÕs criteria for hypomania personality features, nor excluded individuals with
showed that there were no significant differences BPD. The importance of this fact is highlighted by
on age, gender, symptom structure of hypomania, three themes. First, research suggests that the
number of episodes, episode duration, and episode relationship and comorbidity between bipolar dis-
level of functioning. Thus, AngstÕs criteria may be order and BPD become stronger for milder forms
a useful launching pad for research on the optimal of the bipolar spectrum. In studies of individuals
diagnostic criteria for subthreshold hypomania. with bipolar II disorder, between 12% and 23%
However, as noted by Angst himself (10, p. 134), had comorbid BPD (94–96), and 22% of individ-
‘‘minimum duration, stem criteria, and the number uals with cyclothymia reported having comorbid
of signs and symptoms are three areas requiring a BPD (97). Deltito and colleagues (98) reported that
good deal more systematic investigation’’ in the depending on the level of bipolar disorder from the
study of how to optimally identify and define most severe (mania) to the most ÔsoftÕ (bipolar
hypomania. family history), between 13% and 81% of BPD
patients showed signs of bipolarity. This suggests
that the relationship between BPD and milder
Differentiating subthreshold bipolarity from
forms of the bipolar spectrum, such as cyclothymia
borderline personality disorder
and MDD with subsyndromal hypomanic features,
A challenge that both clinicians and researchers may be particularly strong, emphasizing the need
often face is determining whether the affective for sophisticated differential diagnosis. Second,
instability an individual presents is an expression researchers highlight that individuals with softer
of bipolar disorder, borderline personality disorder expressions of bipolar disorder may also be
(BPD), or both (8, 69, 85). Bipolar disorder and frequently misdiagnosed as having BPD (8, 99).
BPD share a number of phenomenological features Thus, where Ruggero and colleagues (67) argue
including affective lability, difficulty controlling that individuals with BPD are frequently misdiag-
anger and irritability, impulsivity, suicidality, and nosed as having bipolar disorder, researchers such
notable social impairment (67, 69, 85–89). Fur- as Akiskal and colleagues (8, 99) argue that that
thermore, the high frequency of inter-episode this misdiagnosis may go both ways, particularly as
residual symptoms in bipolar disorder increases it pertains to softer expressions of bipolarity such
the similarities between BPD and bipolar disorder, as bipolar II, cyclothymia, and MDD with sub-
making it difficult to distinguish the two disorders syndromal hypomanic features. Third, many of the
both cross-sectionally and longitudinally (86). clinical validators (e.g., substance use, suicidality,
Indeed, certain researchers have proposed that and early onset) that distinguish individuals with
the two disorders might share a cyclothymic MDD and subsyndromal hypomanic features from
temperament (90). These similarities frequently MDD with no history of subsyndromal hypomania
result in BPD being misdiagnosed as bipolar have also been found to distinguish between
596
Subthreshold bipolarity

depressed patients with and without BPD (88, 100– than individuals with MDD and no subsyndromal
102). The one exception is that family members of hypomanic features. However, classifying 40–50%
individuals with BPD do not show elevated rates of of individuals with MDD as having a bipolar
bipolar disorder, highlighting the fact that despite spectrum diagnosis raises some legitimate con-
their phenomenological similarities, bipolar dis- cerns. There is both a qualitative and quantitative
order and BPD appear to be genetically distinct (88). difference between bipolar I disorder, characterized
It will be important for future research on both by a history of multiple hospitalizations during
the prevalence and validators of subthreshold psychotic manic episodes, and MDD with subsyn-
bipolarity to examine and take into consideration dromal hypomania. Although revisions to diag-
co-occurring BPD and borderline features. Other nostic criteria could make it clear that
disorders that are often difficult to differentiate subsyndromal hypomania is a milder expression
from bipolar disorder and prone to misdiagnosis of the bipolar spectrum, classifying MDD with
include substance use disorders, posttraumatic subsyndromal hypomania as a bipolar spectrum
stress disorder (PTSD), and lifetime impulse con- diagnosis runs the risk of being more stigmatizing
trol disorders (70, 103). Clinically and scientifically than unipolar depression. A growing body of
validating subthreshold bipolarity will be difficult if research documents the stigma associated with a
its symptoms are frequently confused as BPD or diagnosis of bipolar disorder and the negative
other conditions such as PTSD. Moreover, diag- consequences that this diagnosis may generate
nosing bipolar disorder when it is not present and (106). Research has shown that employers, mental
thus unnecessarily starting pharmacological health workers, and prospective landlords all
treatment for bipolar disorder can have negative endorsed devaluing statements about or discrimi-
implications given medications used to treat nated against individuals with a psychiatric dis-
the illness may have negative side effects (28–31). order (107). Individuals with bipolar disorder who
The misdiagnosis of BPD as bipolar disorder, and report concerns about stigma show greater social
vice versa, may also prevent an individual impairment and social isolation (107, 108), and
from receiving treatment that targets their actual reduced self-esteem (109). Researchers have sug-
illness (67). gested that to avoid discrimination and rejection,
An important direction for future research will people with psychiatric illnesses such as bipolar
be to identify clinical characteristics and symptom disorder may limit their social interaction to
profiles that may aid the differential diagnosis of individuals who are similarly stigmatized or aware
subthreshold bipolarity from BPD and other of and accepting of the stigma (110). Social
psychiatric disorders. Preliminary research indi- isolation has also been demonstrated in caregivers
cates that bipolar disorder and BPD may be of individuals with bipolar disorder (108). How-
characterized by different profiles of elevated affect ever, two caveats are as follows. First, to the best
and elation. In contrast to bipolar disorder, BPD of our knowledge, research has not directly com-
moods rarely include elation and are more likely to pared the stigma associated with a bipolar spec-
shift from euthymia to anger (89, 104, 105). Future trum diagnosis to the stigma of unipolar
research is needed to operationalize these differ- depression, and thus it is unclear what incremental
ences and test their clinical and diagnostic utility. increase in stigma would occur if MDD with
subsyndromal hypomanic features was categorized
as a bipolar spectrum disorder. Second, research
Classifying subthreshold bipolarity
suggests that stigma is typically associated with
Identifying the optimal diagnostic criteria for behavioral factors identifying individuals as differ-
subsyndromal hypomania and differentiating it ent during symptomatic periods (108). Given that
from disorders such as BPD is an important first any impairment or change in behavior associated
step in accurately accounting for subthreshold with subsyndromal hypomania will be significantly
bipolarity. The second step is determining how less than that experienced during a manic episode,
best to classify MDD with subsyndromal hypoma- it seems probable that the stigma associated with
nia. That is, if we conceptualize a continuum from MDD and subsyndromal hypomanic features
pure unipolar to bipolar I disorder, where do we would also be significantly less than that associated
set the categorical cut point for a bipolar diagno- with a bipolar I diagnosis. That said, classifying
sis? The key message from research reviewed in the MDD with subsyndromal hypomanic features in
present report is that approximately 40–50% of the bipolar spectrum does represent an increase in
individuals with MDD display some hypomanic the severity of the diagnosis and it will be impor-
features, and these individuals have greater impair- tant for clinicians and researchers to try to mitigate
ment, and a more severe and pernicious course any increase in stigma.
597
Nusslock and Frank

A second legitimate concern in classifying indi- leaves open the possibility that symptom profiles
viduals with MDD and subsyndromal hypomania with very different degrees of severity and impair-
as having a bipolar spectrum diagnosis is that it ment are given the same diagnostic label. Accord-
could increase the risk of inappropriate treatment, ingly, we propose that if subthreshold bipolarity is
particularly with antipsychotic medications and diagnosed within the context of bipolar disorder
mood stabilizers, both of which may have notable NOS or NEC, it will be helpful to have a
side effects (28–31) and carry their own stigma mechanism within the bipolar disorder NOS or
(111). We will address this issue in detail in the next NEC classification indicating the presence versus
section on treatment recommendations. absence of MDD with subsyndromal hypomania.
A final concern in classifying MDD with sub- This will have two advantages. First, it will provide
syndromal hypomania in the bipolar spectrum is a more precise description for clinicians and
that it could increase insurance premium rates for researchers of the clinical profile of the patient
individuals with subthreshold bipolarity or elevate and make it clear that the reason behind the
the chance of individuals being denied insurance bipolar NOS or NEC diagnosis is the presence of
coverage. To date, research has not systematically MDD with subsyndromal hypomanic features.
examined the effect of having a bipolar spectrum Second, it will highlight the fact that the patient
diagnosis on insurance rates ⁄ coverage or legal with MDD and subsyndromal hypomanic features
issues. The research most directly related to this displays a mild form of bipolarity, ideally mini-
topic suggests that individuals incorrectly diag- mizing stigma-related issues.
nosed as having bipolar disorder were actually
more likely to obtain disability payments (65).
Treatment recommendations
Future research is warranted to examine the effect
of diagnostic status on insurance and legal related Regardless of where subsyndromal hypomanic
issues, not simply to document the issue, but to presentations are eventually classified in the
minimize any negative insurance and litigation- DSM-5, the act of classifying them has important
related consequences of having a bipolar spectrum clinical implications. In this next section we briefly
diagnosis. address these implications, as well as complexities,
These concerns, however, are balanced with the regarding the pharmacological management of
literature reviewed in the present paper document- patients who report subsyndromal hypomania.
ing not only the presence of subsyndromal hypo- Currently an individual with MDD and subsyn-
mania in those with MDD, but also its clinical dromal hypomania (either concurrent or not con-
importance on a number of validators. Thus, while current with an MDE) will likely have a treatment
the aforementioned concerns are of critical impor- plan that exclusively targets his or her depressive
tance, we argue that the weight of evidence symptoms (26). This is to be expected given that
highlights the importance of systematically assess- our current diagnostic criteria do not highlight the
ing for subthreshold bipolarity. A very important clinical importance of subsyndromal hypomania
challenge for the field will be to find a way to and it is likely depression for which the patient has
balance the need to diagnose and treat subsyndro- sought treatment. However, as indicated above,
mal hypomanic features in MDD with the impor- subsyndromal hypomania is of clinical importance,
tance of minimizing stigma and the risk of and likely important to address in treatment. At
providing inappropriate treatment. We also pro- the psychosocial level, we argue that individuals
pose that, within the DSM, MDD with multiple with MDD and subsyndromal hypomania may
episodes of subsyndromal hypomanic features, not benefit from psychotherapeutic interventions that
concurrent with an MDE, will likely best be involve psychoeducation about bipolar spectrum
classified within the context of what is currently disorders and that are designed to address hypo-
referred to as bipolar disorder NOS, but may mania. Currently, there are four psychosocial
eventually be called bipolar disorder not elsewhere interventions for bipolar disorder that have shown
classified (NEC) when the DSM-5 is published. promise as an adjunct to pharmacotherapy:
What is less clear is how an individual with a single Cognitive Behavioral Therapy (CBT) (112, 113)
brief episode of subsyndromal hypomania should modified for bipolar disorder, group (114) and
be classified. Future research is needed to address individual (115) psychoeducational interventions,
this issue. Family-focused Treatment (FFT) (116), and Inter-
Of note, bipolar disorder NOS, as it is currently personal Social Rhythm Therapy (IPSRT) (117).
defined in DSM-IV-TR, is quite vague, defined ‘‘as Growing evidence highlights the efficacy of these
disorders with bipolar features that do not meet interventions, as indicated in a meta-analysis (118)
criteria for any specific bipolar disorder.’’ This that reported a significant reduction in relapse
598
Subthreshold bipolarity

rates (40%) for individuals with bipolar disorder diagnosed with bipolar I or II disorder. On this
engaged in psychosocial treatment. topic, Kukopulos et al. (121) first described an
Modifying psychosocial interventions for bipo- association between antidepressant use and a new
lar disorder to be appropriate for addressing or worsening rapid-cycling course of illness in
subsyndromal hypomania may have two impor- those with bipolar disorder. In a follow-up study,
tant implications. First, it may help individuals Altshuler and colleagues (122), using retrospective
manage the greater impairment associated with data, found that 35% of patients with bipolar
these presentations. As indicated, subsyndromal disorder experienced a manic episode judged to be
hypomania in and of itself is often associated with attributable to antidepressants. Further evidence
notable impairment, and helping people identify that about one-quarter to one-third of individuals
and manage these symptoms may reduce this with bipolar I or II disorder may be susceptible to
impairment. Second, psychosocial interventions antidepressant-induced manias and cycle acceler-
for bipolar disorder could be employed as a ation come from work by Ghaemi et al. (52, 123),
prophylactic treatment to reduce the risk that an Goldberg et al. (124), and Truman et al. (125).
individual with subsyndromal hypomania will Countering these findings, however, is research by
develop a full-blown hypo ⁄ manic episode and Carlson and colleagues (34) who report that
convert to a more severe bipolar I or II diagnosis. switching from depression to mania was not
For example, patients could be educated on the early associated with antidepressant treatment in a
warning signs—or prodromes—of hypo ⁄ mania sample with severe bipolar disorder. Sachs and
and taught cognitive-behavioral strategies to coun- colleagues (35), using data from the multisite
teract such manic tendencies. Drawing from psy- Systematic Treatment Enhancement Program for
choeducational and FFT techniques (119), patients Bipolar Disorder (STEP-BD), also reported that
and their family members could be educated on the standard antidepressant medication was not asso-
types of life events shown to trigger hypo ⁄ manic ciated with increased risk of treatment-emergent
episodes and the communication patterns among affective switch. A review by Visser and col-
family systems (i.e., criticism, hostility, and ⁄ or leagues (36) summarizes additional research indi-
emotional over-involvement) that have been asso- cating no strong evidence that antidepressant use
ciated with a more severe course. Drawing from in bipolar disorder increases risk for hypo ⁄ manic
IPSRT, individuals could be taught strategies for episodes.
maintaining consistent social and circadian Second, to the best of our knowledge, research
rhythms and educated on the role that disruptions has not systematically examined whether individ-
to these rhythms can have on the course of bipolar uals with MDD and subsyndromal hypomania
disorder (120). Thus, with slight modifications, have a different or adverse response to antidepres-
existing psychosocial interventions for bipolar sant treatment as compared to individuals with
disorder could have important implications for MDD and no hypomanic features. Furthermore,
managing the course and severity of subthreshold and again to the best of our knowledge, researchers
bipolarity. have yet to examine whether mood stabilizers or
Where there appears to be a clear role for the currently popular atypical antipsychotic med-
psychosocial interventions for managing sub- ications are more or less effective in managing
threshold bipolarity, the pharmacological impli- either depression or subsyndromal hypomania
cations are more complex. One potential features in individuals with subthreshold bipolar-
argument is that individuals with MDD and ity, or whether they might serve as a prophylactic
subsyndromal hypomania should be treated with treatment against conversion to bipolar I or II
mood-stabilizing agents, as opposed to antide- disorder. Thus, at this time, and irrespective of the
pressant monotherapy. This argument is based on debate on the appropriateness of antidepressants
(i) the idea that antidepressants may be a risk for managing bipolar I or II disorders, there
factor for ÔswitchingÕ into hypo ⁄ manic episodes appears to be no clinical or scientific basis for
and ⁄ or cycle acceleration among individuals with suggesting that individuals with MDD and sub-
bipolar I or II disorder and (ii) the logic that syndromal hypomania should be treated with
mood stabilizers may serve as a prophylactic mood-stabilizing agents or antipsychotic medica-
treatment for conversion to a more severe bipolar tions. This is particularly relevant given the
diagnosis. We disagree with this argument for two heightened side effects and toxicity associated with
reasons. First, at the present time, there is still these compounds (28–31). However, we emphasize
controversy regarding the extent to which antide- ‘‘at this time,’’ as this is fundamentally an empirical
pressant treatment precipitates hypo ⁄ manic epi- question, and future research is needed to examine
sodes and ⁄ or cycle acceleration even among those this issue.
599
Nusslock and Frank

Summary used to treat syndromal level bipolar disorders.


Future research is needed to address this issue.
The research reviewed in the present report indi-
cates that approximately 40–50% of individuals
with MDD display lifetime subsyndromal hypo ⁄ Acknowledgements
manic presentations that are not necessarily con- We thank Dr. Ellen Leibenluft and Dr. Trisha Suppes for their
current with an MDE (10, 11, 19–23). Moreover, helpful comments. RN and EF were supported by grants
these individuals have a more severe and pernicious MH016804 and MH081003.
course compared to individuals with MDD and no
hypomanic features, and more closely resemble
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