In Review

Bipolar II Disorder: An Overview of Recent

Developments
George Hadjipavlou, MA, MD1, Hiram Mok, MA, MB, BCh, BAO, FRCPC2,
Lakshmi N Yatham, MBBS, MRCPsych, FRCPC3

Objective: Recent research on the epidemiology, clinical course, diagnosis, and treatment of bipolar
II disorder (BD II) stands to have a considerable impact on clinical practice. This paper reviews these
developments.
Method: We conducted a Pubmed search, focusing on the period from January 1, 1994, to August 31,
2004. Articles deemed directly relevant to the epidemiology, course, diagnosis, and management of
BD II were considered.
Results: The prevalence of BD II is likely higher than previously suggested. Systematic probing for
particular clinical features and use of screening tools allow for a more timely and accurate detection
of the disorder. There is a paucity of good quality data to guide clinicians treating BD II.
Conclusion: Significant progress has been made in clarifying diagnostic and treatment issues in BD
II. Neither strong nor broad treatment recommendations can be made; a cautious interpretation of
available data suggests that lithium or lamotrigine are fairly reasonable first-line choices. More
well-designed studies with larger samples are needed to improve the evidence base for managing this
disorder.
(Can J Psychiatry 2004;49:802–812)
Information on author affiliations appears at the end of the article.

Clinical Implications

· Bipolar II disorder (BD II) may be more common than previously thought; systematic probing improves
early identification of the disorder.
· BD II patients spend considerable time experiencing syndromal or subsyndromal depressive symptoms.
· There is a dearth of high-quality evidence to guide clinicians in the management of BD II.

Limitations

· Only published data were included in the review.

· Inclusion and exclusion criteria were only applied when considering articles on treatment.
· More well-designed research is needed before strong recommendations to guide therapy can be made.

Key Words: bipolar II disorder, bipolar spectrum disorder, diagnosis, treatment, subsyndromal
symptoms

here has been a recent surge of interest in refining the def-
T inition of bipolar II disorder (BD II) (1–8). Efforts to re-
consider the conceptual contours of BD II, coupled with
emerging data on its epidemiology (9–12), natural history
(13–18), diagnosis (19–27), and management (28–38), will
likely have a considerable impact on clinical practice. We dis-
till these developments in this paper.
We begin by situating BD II within the so-called bipolar spec-
trum, summarizing various approaches to the spectrum con-
cept. Since changes in the conceptualization of the bipolar
spectrum are intimately tied to epidemiologic inquiry, we then
provide an overview of recent and converging epidemiologic
data. Issues relevant to the diagnosis of BD II, including meth-
ods for improving recognition and reliability, follow. We

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conclude by considering ongoing concerns about appropriate
treatment, summarizing the best available evidence for man-
aging BD II and bipolar spectrum disorders (BSDs).
Although the psychopathology of hypomania was described
in the 19th century, BD II was first defined by Dunner and col-
leagues in 1976 (10,39). Yet BD II did not become an offi-
cially recognized, distinct diagnostic entity until the arrival of
the DSM-IV in 1994 (40). Since its inclusion in the DSM-IV,
much attention has been paid to the idea that BD II is likely to
exist within a spectrum of closely associated conditions of
mood dysregulation (2,3,5,8,10). The term spectrum suggests
the presence of a continuum, that is, an ordered arrangement
based on a particular set of characteristics.
There is still no consensus on what this ordered arrangement
might be or what, in fact, constitutes the bipolar spectrum. A
shift toward a broader, more inclusive conceptualization of
bipolarity has been debated for over 2 decades (10). Multiple
relatively disparate diagnostic schemes have been proposed.
These various attempts to define the bipolar spectrum can be
crudely simplified into 4 conceptual approaches.
The first of these is a conservative approach that follows the
DSM-IV view of bipolar disorders (BDs) (40). Following the
DSM-IV categories, the bipolar spectrum could be described
as ranging from bipolar type I (BD I), that is, manic or mixed
episodes usually in association with depressive episodes, at
one end to cyclothymia, that is, numerous periods shifting
from hypomanic to depressive symptoms, at the other. The
DSM-IV includes only 2 other categories: BD II (recurrent
depressive episodes in association with hypomanic episodes
lasting at least 4 days) and bipolar disorder not otherwise
specified (BD NOS), which is the catch-all term for coding
disorders that have clinically significant bipolar features that
do not fit smoothly under the other 2 categories. In an effort to
safeguard the integrity of this accepted classification,
Baldessarini has argued that broadening the bipolar concept
beyond the current DSM nosology risks diluting the concept
to the point of meaninglessness, both in terms of conducting
sound research and in terms of clinical practice (41). As
Goodwin put it, “The apparent size of this so-called bipolar
spectrum invites disbelief” (42, p 95).
In the second diversifying approach, the bipolar spectrum is
parsed into multiple subtypes. Akiskal (1,10), among others
(8,43), has been most prolific in this regard, proposing the
inclusion of various subtypes. Although he has argued for at
least 6 distinct forms of BD, 2 of these are worth highlighting.
Bipolar disorder III, which is characterized by antidepressant-
induced hypomania, has recently drawn greater attention. For
example, in a review of the literature on antidepressant-
induced hypomania in major depression, Chun and Dunner
concluded that such patients are truly bipolar (44). It remains
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Bipolar II Disorder: An Overview of Recent Developments
to be seen whether such research will lend itself to the inclu-
sion of a third subtype or, more simply, to the elimination of
the current exclusion criterion in the DSM-IV (in which
antidepressant-induced hypomania is classified as a
substance-induced mood disorder). The proposed bipolar IV
category refers roughly to a hyperthymic temperament (or, in
broad strokes, the opposite of dysthymia), with the onset of
depression later in life (1). Further, some authors have used
the term soft BDs to refer to conditions involving major
depressive episodes (MDEs) in association with milder
hypomanic events, while the designation of minor BD has
been introduced to indicate the presence of milder depression
(for example, dysthymia or subthreshold MDE) associated
with a history of hypomania or hypomanic symptoms (8).
Reviewing all the ways in which the bipolar spectrum has
been subdivided goes well beyond the scope of this paper.
Whether such a diversifying approach will be borne out by
sound empirical evidence remains to be seen. As the borders
of the bipolar concept are further extended, one wonders
whether we begin to medicalize variations on normal.
The third approach blurs current diagnostic boundaries. For
instance, it has been proposed that bipolar illness can be orga-
nized into 3 overlapping clusters or subtypes, including clas-
sical BD (with typical features of BD I), psychotic spectrum
BD (which overlaps with the schizophrenia spectrum), and
characterological BD or bipolar temperament (patients with
mood lability, rapid cycling, and common comorbidities)
(45). Other boundary-blurring viewpoints might include chal-
lenges to the unipolar–bipolar dichotomy (43).
Finally, the fourth or pragmatic approach, as described by
Ghaemi and colleagues, combines all nonbipolar I or II disor-
ders with bipolar features under the category of BSD (2). One
might wonder how BSD differs from the current DSM-IV
catch-all BD NOS; in practical terms, it may not. The term
suggests a sense of discrete plurality, that there may be other
forms of the disorder that are not fully elucidated. Taking heed
of Baldessarini’s caution, but also noting that despite limited
validation, recent clinical and epidemiologic studies are
pointing toward a greater prevalence and variation of BDs
than previously thought, Ghaemi and others’ pragmatic
stance seems to offer the most clinical utility.
Epidemiology
Recent epidemiologic studies report considerable differences
in the prevalence rates of BD II, compared with older
research, raising prevalence rates from approximately less
than 1% to slightly over 5% (9,11). The US National
Epidemiologic Catchment Area (ECA) study, which included
a sample of over 18 000 adults, reported lifetime prevalence
rates of 0.8% and 0.5% for manic and hypomanic episodes,
respectively (9). Although this study helped form the
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conventional wisdom on the epidemiology of BDs, it has
drawn criticism on several fronts, the most notable being its
poor interrater agreement (2). A recent reanalysis of the ECA
data found that, when subjects experiencing subsyndromal
manic symptoms (that is, at least 2 lifetime manic or
hypomanic symptoms lasting less than the DSM-III 1-week
threshold) were included, rates for the bipolar spectrum
increased by 5.1%, for a total of 6.4% (9).
Other studies have also raised concerns about the underesti-
mation of the prevalence of BD II. The Zurich study is argu-
ably one of the most important epidemiologic studies of BD II,
comprising a sample of almost 600 patients followed prospec-
tively by means of 6 interviews from 1979 to 1999 (8,11). The
Zurich study evaluated the prevalence of mood disorders
using 3 different classifications of BD II: DSM-IV criteria,
hard BD II (in which there was no minimum duration for
hypomania, at least 3 of 7 DSM-IV symptoms were required,
overactivity was included as a possible stem criterion, and the
behavioural change was observable by others), and soft BD II
(any hypomanic symptoms). The rates of BD II using the
DSM-IV and hard and soft BD II criteria were 1.7%, 5.3%,
and 5.7%, respectively; the combined BD II prevalence was
11%. Accordingly, the prevalence of major depression
changed depending on which bipolar criteria were used;
although initially determined to be 21.3% (using the
DSM-IV), it diminished to 17.1% and 11.4% when hard and
soft criteria for BD II were used, respectively (8). The
researchers argue that because their 2 BD II subgroups did not
differ significantly from each other on diagnostic validators
except for the number of hypomanic signs and symptoms and
because they did differ significantly from those with major
depressive disorder (MDD), distinguishing between the 2 as
separate diagnostic entities may be unwarranted.
The Zurich study suggests that BD II, especially if one accepts
less stringent diagnostic criteria for hypomania, is commonly
misdiagnosed as MDD. In fact, they conclude that 1 in 4
patients diagnosed with MDD meet criteria for hard BD II and
that, overall, up to one-half of all patients diagnosed with
MDD have BD II or a milder form of it. Similarly, a French
multicentre study of 250 patients with an MDE found that
with systematic probing for hypomania (using a hypomania
checklist), the rate of BD II increased from 21.7% at the
beginning of the study to 39.8% (12).
Besides challenging traditional perspectives on the preva-
lence rates of BD II, these recent epidemiologic studies have
cast serious doubt on the duration criterion (that is, 4 days) for
hypomania (7,8,11). Patients who do not meet the diagnostic
threshold of 4 days exhibit similar symptom profiles,
responses to treatment for depression, family histories of
mood disorders, and rates of suicide attempts to patients meet-
ing DSM-IV criteria for BD II (11). Based on similar data, it
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has also been argued that overactivity should be included, in
addition to elevated, expansive, or irritable mood, as a stem
criterion for hypomania (8).
Although the converging data from these studies are compel-
ling, both in terms of the higher prevalence rates and the need
to clarify the diagnosis of BD II, it is worth highlighting that
they consist of relatively small samples. It remains to be seen
whether larger studies will continue to show that patients with
brief periods of hypomania or other subsyndromal features do
not differ on diagnostic validators.
Diagnostic Issues and Clinical Features
That BD II is underdiagnosed or misdiagnosed is a pressing
issue that has recently gained much attention (2,3,19,23,
46,47). According to the DSM-IV, diagnostic criteria for BD
II require the presence or history of one or more MDEs in
association with the presence or history of at least one
hypomanic episode (40). Making the diagnosis often hinges
on accurately eliciting a history of hypomania, which, as
much research has shown (2,3,42), is not as straightforward as
the authors of the DSM-IV might have hoped. Why is it, for
instance, that it may take up to 12 years before patients with
BD II are accurately diagnosed (2,46)? Patients’ insight into
their illness experiences; clinicians’ ineffectiveness at assess-
ing patients for bipolarity; and inherent features of the clinical
course of the illness, including high levels of comorbidity,
have all been implicated in the underdiagnosis and
misdiagnosis of BD II (2,3,5,44,48).
Recognizing Hypomania
Clinicians’ difficulty in diagnosing hypomania may be related
to one of its essential defining criteria in the DSM-IV—that
the change in mood state, unlike mania, is not severe enough
to cause marked impairment in social or occupational func-
tioning (psychotic symptoms and hospitalization must also be
absent) (2,42). Clearly, drawing diagnostic lines accordingly
may be troublingly subjective. Further, it is often noted that
hypomanic states may, in some circumstances, be productive,
enhancing rather than impairing functioning and experienced
as ego-syntonic rather than distressing (48). Recognizing
such states as part of an illness process may be less than intu-
itive for most patients.
It follows then that insight, or the lack of it, may play a role in
limiting the accurate and timely diagnosis of BDs (2,49).
Though some research has demonstrated that insight may be
as severely impaired in BD I as it is in schizophrenia and more
impaired than in psychotic depression, it is not clear whether
this is predominantly a state-dependent effect of mania
(50,51). However, given the less disruptive nature of
hypomania and its potentially more positive elements (alluded
to above) insight into hypomania as part of an illness process
W Can J Psychiatry, Vol 49, No 12, December 2004

may be even more limited than it is in mania. Consistently
involving families in the evaluation of mood disorders may
increase the recognition of behavioural symptoms of mania or
hypomania into which patients themselves have scant insight
(2,25). In fact, it has been reported that family members iden-
tify such symptoms twice as often as patients (47% vs 22%)
(2,46). According to some researchers, social consequences
observed by others, that is, notable changes from usual behav-
iour, are obligatory criteria for the accurate diagnosis of
hypomania (25).
Systematic Probing
In keeping with the epidemiologic studies discussed above,
there is evidence from clinical settings that systematically
inquiring for a history of hypomania yields considerably
increased rates of BD II (4,23). For instance, in a study of 168
outpatients presenting with an MDE, systematically probed
for past symptoms and behaviours suggestive of hypomania,
even when screening questions for past hypomanic mood
were initially negative, 61% were diagnosed with BD II (4).
Similarly, an earlier office-based study of 203 outpatients
with depression found that almost one-half (45%) met criteria
for BD II (52). However, not all studies systematically investi-
gating outpatients with depression have found such high rates.
For instance, only 19 patients in a sample of 195 outpatients
with depression (10%) followed prospectively for 3 years
were found to meet criteria for BD II (18).
The diagnosis of BD II has been shown to remain stable over
time (53), with only a small proportion of patients going on to
have a manic episode over 10 years of follow-up (53).
Contrary to concerns raised about its diagnostic reliability,
recent reports indicate that, when experienced psychiatrists
use semistructured interviews, BD II can be reliably diag-
nosed (24). Yet even without semistructured interviews or
psychiatrists with much experience in BD II, it is notable that
BD II can still be reliably identified. This is demonstrated by
studies on the self-rated Mood Disorders Questionnaire
(MDQ), which, though administered in fewer than 10 min-
utes, has a specificity of 90% and sensitivity of 73% when
compared with semistructured interviews (5,54). These find-
ing are corroborated by a recent Finnish study investigating
the MDQ’s potential role as a screening tool (27).
Despite efforts to systematically probe for bipolarity, one rea-
son BD II patents who initially present with episodes of
depression may not be diagnosed with bipolar illness is that
they have yet to experience a hypomanic episode, that is, a
switch from unipolar to bipolar illness. For instance, in an
11-year prospective study of 559 patients with (unipolar)
MDD, 48 (8.6%) converted to BD II (55). Characteristics that
differentiated those who switched to BD II included early age
of depression onset with more recurrences, higher rates of
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Bipolar II Disorder: An Overview of Recent Developments
substance abuse and minor antisocial behaviour, and a signifi-
cantly greater degree of social disruption (that is, marital,
occupational, or scholastic) (55). Habitual temperamental
instability, which remained present during depressive epi-
sodes, was especially highlighted as a specific predictor of
conversion from unipolar MDD to BD II.
Atypical and Mixed Depressive Features
The association between enduring temperamental instability
and BD II resonates with reports that depressive mixed states
(depression with concurrent hypomanic symptoms) and atyp-
ical depressive symptoms strongly suggest a diagnosis of BD
II (26,47,56). In a sample of 97 BD II patients and 64 unipolar
patients presenting with an MDE, Benazzi found that 3 or
more concurrent hypomanic symptoms and atypical features
were highly specific, but not sensitive, for detecting BD II,
with rates of 92.1% and 82.8%, respectively (47). In another
study of 140 outpatients presenting with an atypical depres-
sive episode, 64.2% were diagnosed with BD II (56).
Ghaemi and associates have pointed out that focusing on
polarity, that is, oscillations from hypomania to depression,
may obscure the close association between recurrent depres-
sion and BD, especially BD II (2). However, it has also been
suggested that clinicians screen for BD II by asking patients
about “frequent ups and downs,” a personality trait that some
authors consider a potentially clinically useful marker for
bipolarity, that is, for distinguishing between BD II and MDD
(21). Affective dysregulation or lability, coupled with mixed,
often erratic presentations during depressive episodes (for
example, hyperenergetic) may also explain why many of
these patients are diagnosed with personality disorders, par-
ticularly those under the cluster B rubric (histrionic, border-
line, and narcissistic) (55).
Comorbid Conditions
Further, distinguishing hypomanic excursions, especially
over brief time intervals, from mood swings and irritability
seen in personality disorders such as borderline or histrionic
personality disorders may be challenging (5). Some authors
suggest paying attention to the relation of such symptoms to
external circumstances; changes that occur consistently with
external stimuli suggest personality disorders, while vegeta-
tive symptoms that change independently of external events
are more in line with BD II (5). In addition, a lifelong pattern
of interpersonal turmoil may suggest a personality disorder,
though the possibility that such a pattern forms part of the
psychosocial complications of an underlying mood disorder
must also be considered (57). Despite these diagnostic con-
cerns, it has also been reported that, in an outpatient setting,
BD II can be differentiated from borderline personality disor-
der (BPD) without much difficulty by applying the Structured
Clinical Interview for DSM-IV (58). Of course, personality
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The Canadian Journal of Psychiatry—In Review
disorders and BD II can coexist; while 12% of BD II patients
met criteria for BPD (compared with 1.5% with unipolar
depression) in the above study, rates of up to 33% for a
comorbid personality disorder have been reported (5,17). The
distinction between borderline disorders and BDs is the focus
of a recent review (57).
In addition to personality disorders, it is well known that BD II
patients may carry a considerable burden of comorbidity,
including anxiety conditions such as obsessive–compulsive
disorder, panic and social anxiety disorders, alchohol and sub-
stance use disorders, eating disorders, and body dysmorphic
disorder (17,18,59). Indeed, in a recent commentary, Katzow
and colleagues suggest that, to effectively recognize BSD or
BD II, clinicians should carefully consider patients who pres-
ent with either anxiety mixed with depression or anxiety
mixed with impulsivity disorders, under which they include
BPD, attention deficit disorder, substance abuse, and bulimia
(3). Because these impulsivity disorders share some common
symptoms with BDs, impulsive behaviour itself being charac-
teristic of BD, they recommend paying close attention to
“other diagnostic validators such as family history, course,
and treatment response” (3, p 438).
Clinical Course
Family studies have demonstrated that BD II tends to run in
families (19,60,61). Benazzi has recently suggested that,
when compared with such other predictors of BD II as atypical
or recurrent depression, depressive mixed states, and early
onset, family history of BD II had the highest specificity
(82.8%), with one-half the BD II subjects having first-degree
relatives with BD II (22). Similarly, an earlier study that
included 8 BD II probands found that 40% of their 47
first-degree relatives had BD II (61).
Findings from studies investigating the natural history of BD
II challenge the notion that BD II is simply a milder form of
BD I (9,13,14,62). There is some evidence that patients suf-
fering from BD II spend a considerable proportion of their
lives ill and tend to run a more chronic course with more fre-
quent depressive episodes (14). A prospective study of 86 BD
II patients followed for over 13 years found that patients were
symptomatic for over one-half (53.9%) of all follow-up
weeks, with chronic depressive symptoms dominating their
rocky course (13,14). Patients with BD II have been shown to
spend substantial time with subsyndromal symptoms (13–15),
and there is some suggestion that BD II may be initially
expressed at a subthreshold level (48). Further, evidence sug-
gests that the rate of psychosocial impairment and the use of
mental health services are comparable between BD I and
BD II (9,62). In addition, suicide risk has also been shown to
be comparable between bipolar subtypes, with some authors
reporting a greater tendency among BD II patients (63,64). In
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a review of this topic, Rihmer and Pestality found that, when
data from studies reporting separate outcomes for BD I and
BD II patients were combined, BD II patients had signifi-
cantly higher lifetime rates of suicide attempts and ideation
(17% vs 24%, respectively), as well as more lethal means and
higher rates of completed suicides (63). When compared with
BD I, patients with BD II have also been reported to have sig-
nificantly higher rates of rapid cycling. For instance, a study
that followed 360 BD patients for over 13 years found a five-
fold increased risk of rapid cycling in BD II (30% vs 6%) (65).
Thus missed diagnoses of BD II, and by extension, missed
treatment opportunities, are not without considerable conse-
quence; they likely play an unfortunate part in the increased
suicide risk and chronic psychosocial suffering of these
patients (19,63,66). It is worth highlighting that identifying
patients with subthreshold symptoms of hypomania and BD II
is not merely academic; these patients are repeatedly shown to
experience similar adverse psychosocial events to BD II
patients (10).
Treatment
How best to treat patients with BD II remains controversial,
and this is especially true when considering depressive epi-
sodes and the role of antidepressants. Limitations in the evi-
dence base for acute and maintenance therapies for BD II
preclude broad recommendations for optimal treatment.
Despite growing recognition of the increased prevalence and
psychosocial disability of BD II, there are still no large ran-
domized, double-blind, placebo-controlled trials involving
only BD II patients. As BD II has been well established as a
distinct diagnostic entity, basing recommendations for the
treatment of BD II patients on evidence derived from studies
of BD I patients, let alone simply extending guidelines for BD
I, may prove to be hasty and premature, if not inappropriate
(42). Further, most studies investigating the pharmacotherapy
of BD II are methodologically limited, with small samples and
observational or retrospective designs.
Both the treatment of BD II and the ongoing debate regarding
antidepressants have been the subjects of several recent
reviews (49,67–69). Following the inclusion criteria and
results from a critical review of the literature on the
pharmacotherapy of BD II (29), we summarize evidence
directly relevant to BD II patients, that is, from studies that
analyzed and reported data specifically for BD II (based on
DSM-IV criteria). Here we discuss only highlights from these
studies. In addition, we have updated those results. Because of
the methodological shortcomings of most of these studies,
especially the notable absence of strategies to reduce bias such
as control groups, randomization, and blinding, their findings,
for the most part, can only be interpreted with caution.
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Lithium and Anticonvulsants
The effectiveness of lithium for both acute and maintenance
treatment of BD I is firmly established and well recognized
(70–73). Its role in BD II is still not fully clarified. Early stud-
ies done before BD II was recognized as an official diagnostic
entity in the DSM-IV, lend support for lithium in the prophy-
laxis of depression. Three small, double-blind, placebo-
controlled trials of BD I and BD II patients demonstrated that
lithium reduced the relapse rate of depressive episodes
(74–77). Further, strong support for lithium in treating
patients with BD II, based on DSM-IV criteria, comes from
long-term observational studies of 360 BD I and BD II
patients (65,78,79). Although significantly effective in both
subtypes, lithium monotherapy was shown to be more effec-
tive in the maintenance treatment of BD II patients, who had
98% fewer hospitalizations, spent 80% less time ill, and had
68% fewer illness episodes, compared with their prelithium
period (62,78). The effectiveness of lithium therapy was not
shown to diminish with long-term use of up to 30 years (78).
When lithium was compared with carbamazepine as mainte-
nance treatment in a subgroup analysis of 57 BD II and BD
NOS patients enrolled in a randomized controlled trial (RCT),
no difference was found in the efficacy of the 2 agents (80,81).
These results contrast with the overall study findings, which
demonstrated a greater benefit for lithium in BD I patients
(81).
A well-designed double-blind, randomized, placebo-
controlled trial of lamotrigine as maintenance monotherapy in
182 rapid-cycling BD I and BD II patients failed to demon-
strate significant positive results for its primary outcome mea-
sure (time to additional pharmacotherapy for emerging mood
symptoms) (32). However, when the subgroup of 52 BD II
patients was analyzed separately, lamotrigine-treated patients
differed significantly from the placebo group on some clini-
cally meaningful secondary outcome measures, such as
remaining stable without relapse at 6 months (46% vs 18%,
P = 0.04) and overall survival in the study, including any rea-
son for premature discontinuation, with median survival times
without additional pharmacotherapy of 17 and 7 weeks for the
lamotrigine and placebo groups, respectively (P = 0.015)
(32). Lamotrigine was consistently shown to be of greater
benefit in BD II than in BD I patients.
A small retrospective, open-label study of lamotrigine as
add-on therapy reported significant improvement on the Clin-
ical Global Impression (CGI) for 5 of 8 BD II patients
included in the study (82). Another double-blind, random-
ized, placebo-controlled trial investigating lamotrigine’s role
in augmentation included 23 patients with depression, 8 of
whom met criteria for BD II (33). Patients were treated with
fluoxetine, to which lamotrigine or placebo was added for 6
weeks. BD II and MDD patients receiving lamotrigine
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Bipolar II Disorder: An Overview of Recent Developments
augmentation showed significantly greater improvement on
their CGI scores, compared with placebo, but not on the Ham-
ilton Depression Rating Scale (HDRS) or the Montgomery–
Asberg Depression Rating Scale (MADRS) (33).
There is limited evidence from small, open-label observa-
tional studies suggesting a potential benefit for divalproex
sodium monotherapy in the short-term treatment of BD II
depression (34). The adjunctive use of gabapentin has also
been shown to be of some promise, but the data for this come
from a retrospective chart review that included only 19 BD II
patients (83). Preliminary reports from small (n = 19),
open-label studies with topiramate suggest that it too may
have an adjunctive role in the treatment of BD II depression
and hypomania (35).
Antipsychotics
Only one study to date has exclusively investigated the role of
novel antipsychotics in the treatment of hypomania associated
with BD II (84). This 6-month, open-label, observational
study of risperidone in 44 BD II patients reported that 60%
were rated asymptomatic, while 78% were considered to have
improved significantly. A 9-week open trial of olanzapine in
25 subjects with BDs presenting with depressed or elevated
mood reported a 60% response rate (CGI £ 2) (36). Though
results for the 10 BD II patients included in the study were not
reported separately, the authors noted that a significant differ-
ence across bipolar subtypes was not found (36). One won-
ders whether the study was adequately powered to detect such
a difference if it were in fact present.
Dopamine Agonists
A recent double-blind, randomized, placebo-controlled study
of 21 BD II patients with depression on therapeutic levels of
lithium or valproate reported that 60% of the 9 patients taking
pramipexole over 6 weeks had a reduction of more than 50%
in their MADRS scores, compared with 9% taking placebo
(37). One patient taking pramipexole and 2 assigned to pla-
cebo developed hypomania. The adjunctive role of dopamine
agonists pramipexole and ropirinole is further supported by a
retrospective study of 18 BD II patients with depression con-
currently taking mood stabilizers or mood stabilizers com-
bined with antidepressants (38). Eight of 18 patients (44%)
were considered responders according to reductions in CGI
scores (38).
Antidepressants
Given that the illness course of BD II patients is vastly spent in
the domain of depression, effective treatment for BD II
depression is of considerable importance. However, the use of
antidepressants in BD II remains a contentious issue; conflict-
ing perspectives abound (30,49,67–69, 85). Although it is
often noted that antidepressants can lead to cycle acceleration
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and switching, the likelihood of such phenomena has not been
conclusively determined. A wide range of estimates exist,
potentially reflecting methodological differences and limita-
tions across studies (for example, small samples and observa-
tional designs) and differences between antidepressant
agents, concomitant use of mood stabilizers, and the presence
of comorbidities such as substance abuse (49,67). Recent
reviewers cite contemporary estimates of antidepressant-
induced mania in BD as ranging from 20% to 40% (49,67),
though some studies have actually reported no such episodes.
In their systematic review of this topic, Ghaemi and others
“conclude that the preponderance of the evidence supports an
association between antidepressants and long-term mood
destabilization of bipolar disorder, especially cycle accelera-
tion”(49, p 426). Whether such adverse events are as promi-
nent a problem in BD II as they may be in BD I is also unclear,
though some data suggest that they are not (86). A recent pro-
spective study, published after Ghaemi and others’ review
period, of 89 BD I and BD II patients with rapid cycling drew a
contrasting conclusion: tricyclic antidepressants (TCAs) used
for depressive symptoms were not associated with precipitat-
ing or maintaining rapid cycling or with increasing the switch
from depressive to manic or hypomanic states (87). While
some studies have suggested that antidepressant-induced
cycle acceleration may be more likely in BD II patients (85),
others have not found statistically significant differences
across subtypes (86). Similarly, the data on antidepressant-
precipitated switching to hypomanic states in BD II are incon-
clusive. A study of 203 subjects with depression showed a
threefold significantly greater risk for BD II patients, com-
pared with those with unipolar depression (17.3% vs 5.8%)
(88). Two recent comprehensive reviews carefully explore
the issue of antidepressant-induced adverse events and con-
troversies surrounding the use of antidepressants in BDs
(49,67); a fuller account of these issues goes beyond the scope
of this paper. Here we summarize data from recent trials of
antidepressants in BD II patients.
Studies in the DSM-IV era specifically investigating the use
of antidepressants in BD II patients were all by Amsterdam
and his colleagues (30,31,89–91). They take issue with rec-
ommendations to limit antidepressant use and discourage
them as monotherapy, which they deem too cautious (30). As
part of a study comprising a 12-week, open-label acute treat-
ment phase; a 50-week, double-blind placebo substitution;
and a relapse-prevention phase with fluoxetine monotherapy,
89 BD II patients were retrospectively compared with 89 age-
and sex-matched and 661 unmatched patients with unipolar
depression (91). Short-term treatment was shown to be as effi-
cacious in BD II patients as in their unipolar counterparts
(61% and 51%, respectively, had > 50% reduction in HDRS
scores). Likewise, survival analyses at 26 weeks showed
808
similar relapse rates between the 2 groups, with slightly better
outcomes for the BD II patients (78% vs 67%, respectively).
Although these findings extended to 62 weeks of follow-up,
by that point only 8 BD II patients remained in the study. The
authors retrospectively ascertained symptoms suggestive of
hypomanic switch rates; 3 of 80 BD II patients (3.8%) in the
short-term period and 1 of 28 (3.6%) at 26 weeks likely had
hypomanic episodes. These findings are in line with a more
recent 8-week, open-label prospective study, in which 37 BD
II patients with either depression (n = 34) or BD NOS (n = 3)
received fluoxetine monotherapy (31). Eleven of the 23
patients (48%) who completed this 8-week trial and 14
patients overall (38%) had a reduction of over 50% on HDRS
scores. Further, the authors reported that the proportion of
patients with YMR scores ³ 8 treated with fluoxetine did not
differ from those seen during the screening and baseline peri-
ods. Three (7.8%) were considered to have hypomanic symp-
toms related to fluoxetine treatment, at least 2 of whom did not
meet DSM-IV criteria for hypomania.
There is support from small prospective studies for
venlafaxine monotherapy in the short-term treatment of BD II
depression (89). A 6-week trial of 30 unipolar and 16 BD II
patients randomly assigned to receive once or twice daily
venlafaxine monotherapy after a 1-week placebo lead-in
reported similar efficacy, based on improvements on the
HDRS, MADRS, and CGI for both groups, with a signifi-
cantly more rapid reduction in the BD II patients. A secondary
analysis of this study comparing the efficacy and safety of
venlafaxine monotherapy in 15 women with BD II and 16
women with unipolar depression found no difference between
the 2 groups in terms of their reductions in the above-
mentioned rating scales (90).
Nonpharmacologic Treatment
Given the potential for adverse events associated with the use
of antidepressants in bipolar patients and given that depres-
sion accounts for a considerable portion of illness in BD II,
studies evaluating the role of psychotherapy both in the acute
and maintenance treatment of depression in this disorder are
much needed. Despite increasing interest in the psychother-
apy of BDs (92), there are no studies that have focused on BD
II or analyzed results separately for this subtype. Whether the
efficacy of such psychotherapeutic approaches as cognitive-
behavioural therapy (CBT) or interpersonal therapy demon-
strated in the treatment of unipolar depression will extend to
the bipolar spectrum remains to be seen (71). In general, CBT
and psychoeducation have the strongest support in the mainte-
nance treatment of BDs, though, as included in the current
American Psychiatric Association (APA) practice guideline
(71), there is also some research indicating a potential role for
family and interpersonal therapies as well.
W Can J Psychiatry, Vol 49, No 12, December 2004

A recent RCT that included 20 weeks of treatment phase and 2
years of follow up investigated the efficacy of group
psychoeducation in preventing recurrences in 120 pharmaco-
logically treated BD patients, of whom 20 had BD II (93).
When compared with control subjects attending nonpsycho-
therapeutic group meetings, patients receiving group
psychoeducation demonstrated a statistically significant
reduction in the number of recurrences of mania, hypomania,
mixed episodes, or depression (38% vs 60% P < 0.05); fewer
hospitalizations over 24 months (30% vs 78%, P < 0.05); and
longer times to recurrence. Unfortunately, though the authors
conclude that psychoeducation is efficacious in preventing
recurrence in both BD I and BD II patients receiving
pharmacotherapy, results for BD II patients were not dis-
cussed separately. Interestingly, when mood episodes were
considered separately, psychoeducation was shown to reach
statistical significance in preventing hypomania, as well as
mixed and depressive episodes, but not mania, which con-
trasts with previous studies demonstrating individual psycho-
therapy’s value in reducing manic but not depressive
recurrences (93,94). This would suggest a greater benefit for
psychoeducation in BD II, but clear data on this issue are lack-
ing. Psychotherapies such as psychoeducation and CBT have
the added benefit of potentially allowing for early detection
and treatment while improving overall social function.
Conclusion and Recommendations
There are compelling data that the bipolar spectrum, including
BD II, may be more prevalent than previously thought. Given
the converging evidence from various epidemiologic sources,
the prevalence of BD II is likely to be in the order of 5%.
However, larger epidemiologic studies replicating the results
from the research reviewed above are needed to confirm this
observed trend. In addition, whether the various proposed
diagnostic schema and putative subtypes are validated by
sound empirical data remains to be seen. That there is hetero-
geneity within the bipolar rubric is difficult to contest.
Emerging epidemiologic perspectives have been intimately
tied to the growing understanding of the diagnostic challenges
inherent in making a timely and accurate diagnosis of BD II.
Several recommendations can be made in light of the research
reviewed above. Clearly, systematically probing for hypo-
mania or bipolarity may help identify patients who meet crite-
ria for BD II. Although semistructured interviews by
experienced clinicians likely yield the best results, the exigen-
cies of clinical practice would largely preclude their routine
use. Regular use of the MDQ as a screening tool is a rational
substitute that we recommend. Further, several presenting
features which may increase the likelihood of BD II should be
carefully considered. It stands to reason that the more and
these features identified, the more probable the diagnosis of
Can J Psychiatry, Vol 49, No 12, December 2004 W
Bipolar II Disorder: An Overview of Recent Developments
BD II, though there is no empirically determined threshold.
These features include family history of bipolarity, especially
BD II; increased mood instability secondary to antidepressant
use; depression with multiple recurrences or with concurrent
hypomanic or atypical symptoms; and a long-standing
hyperthymic temperament. (Ghaemi and associates have rec-
ommended a longer list of diagnostic clues, which includes
additional items such as psychotic depressive episodes and a
lack of response to multiple antidepressant trials, 2).
The traditional management of BD II is often roughly divided
into 3 parts, including the treatment of acute hypomania, the
treatment of acute depression, and the prevention of relapse of
either hypomania or depression. However, as recent natural
history data have shown, BD II patients experience
subsyndromal symptoms for a considerable portion of their
lives. Ironically, despite the fact that hypomania stands as the
hallmark of the disorder, patients spend far more time in and
experience greater distress from their depressed states.
Thus the treatment of depression is perhaps the single most
important issue in BD II. Whether antidepressants may be
used without concomitant mood stabilizers and for how long
remain unsettled questions. Every effort should be made to
avoid strategies that have the potential to cause harm, that is,
to further destabilize mood and induce hypomania or cycling.
We endorse recent recommendations that emphasize caution
in the use of antidepressants as monotherapy. However, the
authors of a current well-designed, systematic review of
RCTs of antidepressants in bipolar depression found that rates
of switching to mania with selective serotonin reuptake inhib-
itors (SSRIs) in short-term treatment were comparable to pla-
cebo (that is, 3.8% and 4.7%, respectively), suggesting that
switching may be less of a worry than commonly thought
(95). However, because the data in this review are limited to
short-term treatment (4 to 10 weeks) from relatively small
RCTs, they do not necessarily address the real-world concerns
about affective instability or the longer-term use issues raised
in other comprehensive reviews (49) and discussed above.
Nor is there firm evidence about switch rates and affective
instability specifically for BD II patients treated with antide-
pressants. We thus suggest initiating treatment with an ade-
quate trial of either lithium or lamotrigine as monotherapy,
with plans to continue with either of these medications
long-term. If this fails to achieve acceptable results, introduc-
ing an antidepressant agent in combination with the initial
mood stabilizer would be a reasonable second step. Despite
inconsistencies in the literature, there are still sufficient con-
cerns about the potential for harm to warrant avoiding the use
of TCAs in bipolar depression as often as possible. As seems
to be the case in clinical practice and in some of the studies
here reviewed, there are patients with BD II who benefit from
antidepressant monotherapy without incurring adverse out-
comes. When patients are unable to tolerate lithium or
809
The Canadian Journal of Psychiatry—In Review
anticonvulsants, a trial of antidepressants may be appropriate.
For example, according to the available data on BD II,
venlafaxine or fluoxetine are reasonable options, though other
SSRIs and buproprion (96) may work just as well. However,
some recent data suggest that the switch rate may be higher
with venlafaxine, compared with SSRIs (97). If antidepres-
sants are prescribed, patients ought to be both educated about
the risks of mood destabilization and monitored more closely.
Though some authors recommend minimizing the duration of
antidepressant exposure for BD patients, given the now
well-established chronicity of the disorder, it might be accept-
able to maintain patients long-term on antidepressants (with
concomitant mood stabilizers); clinicians should be aware
that data to support such a practice are lacking. If such an
approach is taken, clinicians must remain alert for signs of
antidepressant-induced mood instability. Although it is clear
that anticonvulsants do not exhibit a class effect (98), other
anticonvulsants for which there is some support in the treat-
ment of depression include valproate and topiramate.
Antipsychotics such as risperidone and olanzapine may be
useful in the management of hypomania, while olanzapine
may also have an adjunctive role in treating depression. A trial
of the dopamine agonist pramipexole might also prove rea-
sonable in treatment-resistant depression, though, as with data
on antipsychotics, there is only preliminary support for such a
strategy.
Large, well-designed RCTs are needed to cast more definitive
light on how best to manage patients with BD II. Given that
extrapolating from efficacy data on BD I or from unipolar
depression is problematic, specifically recruiting adequate
numbers of patients with BD II (as opposed to mixed samples)
in clinical studies is urgently needed. Currently available evi-
dence is largely preliminary and derived from studies that are
methodologically limited. Since most of the studies reviewed
comprise small samples, have only short-term follow up,
report findings for BD II in subgroup analyses, and lack strate-
gies to minimize bias such as randomization, blinding, and
control groups, the inferences drawn from their results can
only be interpreted with caution. This review has its own limi-
tations because we only included published literature. It is
with great interest that we await the results of better quality
research to help guide our therapeutic choices.
References
1. Akiskal HS, Pinto O. The evolving bipolar spectrum. Prototypes I, II, III, and IV.
Psychiatr Clin North Am 1999;22:517–34, vii.
2. Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis,
antidepressant use, and a proposed definition for bipolar spectrum disorder. Can
J Psychiatry 2002;47:125–34.
3. Katzow JJ, Hsu DJ, Nassir GS. The bipolar spectrum: a clinical perspective.
Bipolar Disord 2003;5:436 – 42.
4. Benazzi F, Akiskal HS. Refining the evaluation of bipolar II: beyond the strict
SCID-CV guidelines for hypomania. J Affect Disord 2003;73:33– 8.
5. Piver A, Yatham LN, Lam RW. Bipolar spectrum disorders. New perspectives.
Can Fam Physician 2002;48:896 –904.
810
6. Perugi G, Akiskal HS. The soft bipolar spectrum redefined: focus on the
cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge-eating connection
in bipolar II and related conditions. Psychiatr Clin North Am 2002;25:713–37.
7. Benazzi F. Is 4 days the minimum duration of hypomania in bipolar II disorder?
Eur Arch Psychiatry Clin Neurosci 2001;251:32– 4.
8. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W. Toward a
re-definition of subthreshold bipolarity: epidemiology and proposed criteria for
bipolar-II, minor bipolar disorders and hypomania. J Affect Disord
2003;73:133– 46.
9. Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum
disorders in the US population: re-analysis of the ECA database taking into
account subthreshold cases. J Affect Disord 2003;73:123–31.
10. Akiskal HS, Bourgeois ML, Angst J, Post R, Moller H, Hirschfeld R.
Re-evaluating the prevalence of and diagnostic composition within the broad
clinical spectrum of bipolar disorders. J Affect Disord 2000;59(Suppl 1):S5–S30.
11. Angst J. The emerging epidemiology of hypomania and bipolar II disorder.
J Affect Disord 1998;50:143–51.
12. Hantouche EG, Akiskal HS, Lancrenon S, Allilaire JF, Sechter D, Azorin JM,
and others. Systematic clinical methodology for validating bipolar-II disorder:
data in mid-stream from a French national multi-site study (EPIDEP). J Affect
Disord 1998;50:163–73.
13. Judd LL, Schettler PJ, Akiskal HS, Maser J, Coryell W, Solomon D, and others.
Long-term symptomatic status of bipolar I vs bipolar II disorders. Int J
Neuropsychopharmacol 2003;6:127–37.
14. Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, and others.
A prospective investigation of the natural history of the long-term weekly
symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;60:261–9.
15. Joffe RT, MacQueen GM, Marriott M, Robb J, Begin H, Young LT. A
prospective, longitudinal study of percentage of time spent ill in patients with
bipolar I or bipolar II disorders. Bipolar Disord 2004;6:62–6.
16. Benazzi F. Course and outcome of bipolar II disorder: a retrospective study.
Psychiatry Clin Neurosci 2001;55:67–70.
17. Vieta E, Colom F, Martinez-Aran A, Benabarre A, Reinares M, Gasto C. Bipolar
II disorder and comorbidity. Compr Psychiatry 2000;41:339–43.
18. Joyce PR, Luty SE, McKenzie JM, Mulder RT, McIntosh VV, Carter FA, and
others. Bipolar II disorder: personality and outcome in two clinical samples. Aust
N Z J Psychiatry 2004;38:433–8.
19. Dunner DL. Clinical consequences of under-recognized bipolar spectrum
disorder. Bipolar Disord 2003;5:456–63.
20. Benazzi F. Toward better probing for hypomania of bipolar-II disorder by using
Angst’s checklist. Int J Methods Psychiatr Res 2004;13:1–9.
21. Benazzi F. Validating Angst’s “ups & downs” personality trait as a new marker
of bipolar II disorder. Eur Arch Psychiatry Clin Neurosci 2004;254:48–54.
22. Benazzi F. Bipolar II disorder family history using the family history screen:
findings and clinical implications. Compr Psychiatry 2004;45:77–82.
23. Benazzi F. Underdiagnosis of bipolar II disorders in the community. J Clin
Psychiatry 2003;64:1130–1.
24. Simpson SG, McMahon FJ, McInnis MG, MacKinnon DF, Edwin D, Folstein
SE, and others. Diagnostic reliability of bipolar II disorder. Arch Gen Psychiatry
2002;59:736–40.
25. Angst J, Gamma A, Benazzi F, et al. Diagnostic issues in bipolar disorder. Eur
Neuropsychopharmacol 2003;13(Suppl 2):S43–S50.
26. Benazzi F. The clinical picture of bipolar II outpatient depression in private
practice. Psychopathology 2001;34:81–4.
27. Isometsa E, Suominen K, Mantere O, Valtonen H, Leppamaki S, Pippingskold
M, and others. The mood disorder questionnaire improves recognition of bipolar
disorder in psychiatric care. BMC Psychiatry 2003;3:8.
28. Suppes T, Dennehy EB. Evidence-based long-term treatment of bipolar II
disorder. J Clin Psychiatry 2002;63(Suppl 10):29–33.
29. Hadjipavlou G, Mok H, Yatham LN. Pharmacotherapy of bipolar II disorder: a
critical review of current evidence. Bipolar Disord 2004;6:14–25.
30. Amsterdam JD, Brunswick DJ. Antidepressant monotherapy for bipolar type II
major depression. Bipolar Disord 2003;5:388–95.
31. Amsterdam JD, Shults J, Brunswick DJ, Hundert M. Short-term fluoxetine
monotherapy for bipolar type II or bipolar NOS major depression - low manic
switch rate. Bipolar Disord 2004;6:75–81.
32. Calabrese JR, Suppes T, Bowden CL, Sach GS, Swann AC, McElroy SL, and
others. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in
rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry
2000;61:841–50.
33. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled
trial of augmentation with lamotrigine or placebo in patients concomitantly
treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry
2003;64:403–7.
34. Winsberg ME, DeGolia SG, Strong CM, Ketter TA. Divalproex therapy in
medication-naive and mood-stabilizer-naive bipolar II depression. J Affect
Disord 2001;67:207–12.
35. Vieta E, Sanchez-Moreno J, Goikolea JM, Torrent C, Benabarre A, Colom F,
and others. Adjunctive topiramate in bipolar II disorder. World J Biol Psychiatry
2003;4:172–6.
W Can J Psychiatry, Vol 49, No 12, December 2004

36. Janenawasin S, Wang PW, Lembke A, Schumacher M, Das B, Santosa CM, and
others. Olanzapine in diverse syndromal and subsyndromal exacerbations of
bipolar disorders. Bipolar Disord 2002;4:328–34.
37. Zarate CA, Jr., Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD,
and others. Pramipexole for bipolar II depression: a placebo-controlled proof of
concept study. Biol Psychiatry 2004;56:54–60.
38. Perugi G, Toni C, Ruffolo G, et al. Adjunctive dopamine agonists in
treatment-resistant bipolar II depression: an open case series.
Pharmacopsychiatry 2001;34:137–41.
39. Dunner DL, Gershon ES, Goodwin FK. Heritable factors in the severity of
affective illness. Biol Psychiatry 1976;11:31–42.
40. American Psychiatric Association. Diagnostic and statistical manual of mental
disorders. 4th ed. Washington (DC): American Psychiatric Association; 1994.
41. Baldessarini RJ. A plea for integrity of the bipolar disorder concept. Bipolar
Disord 2000;2:3–7.
42. Goodwin G. Hypomania: what’s in a name? Br J Psychiatry 2002;181:94–5.
43. Cassano GB, Rucci P, Frank E, Fagiolini A, Dell’Osso L, Shear MK, and others.
The mood spectrum in unipolar and bipolar disorder: arguments for a unitary
approach. Am J Psychiatry 2004;161:1264–9.
44. Chun BJ, Dunner DL. A review of antidepressant-induced hypomania in major
depression: suggestions for DSM-V. Bipolar Disord 2004;6:32–42.
45. Alda M. The phenotypic spectra of bipolar disorder. Eur Neuropsychopharmacol
2004;14(Suppl 2):S94–S99.
46. Ghaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin K. Is bipolar
disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord
1999;52:135–44.
47. Benazzi F. Sensitivity and specificity of clinical markers for the diagnosis of
bipolar II disorder. Compr Psychiatry 2001;42:461–5.
48. Cassano GB, Dell’Osso L, Frank E, Miniati M, Fagiolini A, Shear K, and others.
The bipolar spectrum: a clinical reality in search of diagnostic criteria and an
assessment methodology. J Affect Disord 1999;54:319–28.
49. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar
disorder: the case for caution. Bipolar Disord 2003;5:421–33.
50. Amador XF, Flaum M, Andreasen NC, Strauss DH, Yale SA, Clark SC, and
others. Awareness of illness in schizophrenia and schizoaffective and mood
disorders. Arch Gen Psychiatry 1994;51:826–36.
51. Pini S, Cassano GB, Dell’Osso L, Amador XF. Insight into illness in
schizophrenia, schizoaffective disorder, and mood disorders with psychotic
features. Am J Psychiatry 2001;158:122–5.
52. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case
study in private practice. J Affect Disord 1997;43:163–6.
53. Coryell W, Endicott J, Maser JD, Keller MB, Leon AC, Akiskal HS. Long-term
stability of polarity distinctions in the affective disorders. Am J Psychiatry
1995;152:385–90 (initially 40)
54. Hirschfeld RM, Williams JB, Spitzer RL, Calabrese JR, Flynn L, Keck PE, and
others. Development and validation of a screening instrument for bipolar
spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry
2000;157:1873–5.
55. Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Keller M, and others.
Switching from ‘unipolar’ to bipolar II. An 11-year prospective study of clinical
and temperamental predictors in 559 patients. Arch Gen Psychiatry
1995;52:114–23.
56. Benazzi F. Prevalence of bipolar II disorder in atypical depression. Eur Arch
Psychiatry Clin Neurosci 1999;249:62–5.
57. Magill CA. The boundary between borderline personality disorder and bipolar
disorder: current concepts and challenges. Can J Psychiatry 2004;49:551–6.
58. Benazzi F. Borderline personality disorder and bipolar II disorder in private
practice depressed outpatients. Compr Psychiatry 2000;41:106–10.
59. Perugi G, Toni C, Frare F, Travierso MC, Hantouche E, Akiskal HS.
Obsessive-compulsive-bipolar comorbidity: a systematic exploration of clinical
features and treatment outcome. J Clin Psychiatry 2002;63:1129–34.
60. Coryell W, Endicott J, Reich T, Andreason N, Keller M. A family study of
bipolar II disorder. Br J Psychiatry 1984;145:49–54.
61. Simpson SG, Folstein SE, Meyers DA, McMahon FJ, Brusco DM, DePaulo JR.
Bipolar II: the most common bipolar phenotype? Am J Psychiatry
1993;150:901–3.
62. Tondo L, Baldessarini RJ, Hennen J, Floris G. Lithium maintenance treatment of
depression and mania in bipolar I and bipolar II disorders. Am J Psychiatry
1998;155:638–45.
63. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr Clin
North Am 1999;22:667–73, ix-x.
64. Rihmer Z, Kiss K. Bipolar disorders and suicidal behaviour. Bipolar Disord
2002;4(Suppl 1):21–5.
65. Baldessarini RJ, Tondo L, Floris G, Hennen J. Effects of rapid cycling on
response to lithium maintenance treatment in 360 bipolar I and II disorder
patients. J Affect Disord 2000;61:13–22.
66. MacQueen GM, Young LT. Bipolar II disorder: symptoms, course, and response
to treatment. Psychiatr Serv 2001;52:358–61.
67. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current
controversies. Bipolar Disord 2003;5:407–20.
68. Thase ME, Sachs GS. Bipolar depression: pharmacotherapy and related
therapeutic strategies. Biol Psychiatry 2000;48:558–72.
Can J Psychiatry, Vol 49, No 12, December 2004 W
Bipolar II Disorder: An Overview of Recent Developments
69. Thase ME, Bhargava M, Sachs GS. Treatment of bipolar depression: current
status, continued challenges, and the STEP-BD approach. Psychiatr Clin North
Am 2003;26:495–518.
70. Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable
responses over three decades. Arch Gen Psychiatry 2000;57:187–90.
71. American Psychiatric Association. Practice guideline for the treatment of
patients with bipolar disorder (revision). Am J Psychiatry 2002;159:1–50.
72. Sharma V, Yatham LN, Haslam DR, Silverstone PH, Parikh SV, Matte R, and
others. Continuation and prophylactic treatment of bipolar disorder. Can J
Psychiatry 1997;42(Suppl 2):92S–100S.
73. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium
therapy for bipolar disorder: systematic review and meta-analysis of randomized
controlled trials. Am J Psychiatry 2004;161:217–22.
74. Dunner DL, Stallone F, Fieve RR. Prophylaxis with lithium carbonate: an
update. Arch Gen Psychiatry 1982;39:1344–5.
75. Fieve RR, Kumbaraci T, Dunner DL. Lithium prophylaxis of depression in
bipolar I, bipolar II, and unipolar patients. Am J Psychiatry 1976;133:925–9.
76. Kane JM, Quitkin FM, Rifkin A, Ramos-Lorenzi JR, Nayak DD, Howard A.
Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II
illness: a prospective, placebo-controlled comparison. Arch Gen Psychiatry
1982;39:1065–9.
77. Quitkin F, Rifkin A, Kane J, Ramos-Lorenzi JR, Klein DF. Prophylactic effect of
lithium and imipramine in unipolar and bipolar II patients: a preliminary report.
Am J Psychiatry 1978;135:570–2.
78. Tondo L, Baldessarini RJ, Floris G. Long-term clinical effectiveness of lithium
maintenance treatment in types I and II bipolar disorders. Br J Psychiatry Suppl
2001;41:S184–S190.
79. Tondo L, Baldessarini RJ, Floris G, Rudas N. Effectiveness of restarting lithium
treatment after its discontinuation in bipolar I and bipolar II disorders. Am J
Psychiatry 1997;154:548–50.
80. Greil W, Kleindienst N. Lithium versus carbamazepine in the maintenance
treatment of bipolar II disorder and bipolar disorder not otherwise specified. Int
Clin Psychopharmacol 1999;14:283–5.
81. Kleindienst N, Greil W. Differential efficacy of lithium and carbamazepine in
the prophylaxis of bipolar disorder: results of the MAP study.
Neuropsychobiology 2000;42(Suppl 1):2–10.
82. Suppes T, Browb ES, McElroy SL, Keck PE Jr, Nolen W, Kupka R, and others.
Lamotrigine for the treatment of bipolar disorder: a clinical case series. J Affect
Disord 1999;53 :95–8.
83. Ghaemi SN, Katzow JJ, Desai SP, Goodwin FK. Gabapentin treatment of mood
disorders: a preliminary study. J Clin Psychiatry 1998;59:426–9.
84. Vieta E, Gasto C, Colom F, Reinares M, Martinez-Aran A, Benabarre A, and
others. Role of risperidone in bipolar II: an open 6-month study. J Affect Disord
2001;67:213–9.
85. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L.
Antidepressant-induced mania and cycle acceleration: a controversy revisited.
Am J Psychiatry 1995;152:1130–8.
86. Joffe RT, MacQueen GM, Marriott M, Robb J, Begin H, Young LT. Induction of
mania and cycle acceleration in bipolar disorder: effect of different classes of
antidepressant. Acta Psychiatr Scand 2002;105:427–30.
87. Coryell W, Solomon D, Turvey C, Keller M, Leon AC, Endicott J, and others.
The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry
2003;60:914–20.
88. Benazzi F. Antidepressant-associated hypomania in outpatient depression: a
203-case study in private practice. J Affect Disord 1997;46:73–7.
89. Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II
major depressive episode. J Clin Psychopharmacol 1998;18:414–7.
90. Amsterdam JD, Garcia-Espana F. Venlafaxine monotherapy in women with
bipolar II and unipolar major depression. J Affect Disord 2000;59:225–9.
91. Amsterdam JD, Garcia-Espana F, Fawcett J, Quitkin FM, Reimherr FW,
Rosenbaum, and others. Efficacy and safety of fluoxetine in treating bipolar II
major depressive episode. J Clin Psychopharmacol 1998;18:435–40.
92. Jones S. Psychotherapy of bipolar disorder: a review. J Affect Disord
2004;80:101–14.
93. Colom F, Vieta E, Martinez-Aran A, Reinares M, Goikolea JM, Benabarre A,
and others. A randomized trial on the efficacy of group psychoeducation in the
prophylaxis of recurrences in bipolar patients whose disease is in remission.
Arch Gen Psychiatry 2003;60:402–7.
94. Colom F, Vieta E, Reinares M, Martinez-Aran A, Torrent C, Goikolea JM, and
others. Psychoeducation efficacy in bipolar disorders: beyond compliance
enhancement. J Clin Psychiatry 2003;64:1101–5.
95. Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants
for bipolar depression: a systematic review of randomized, controlled trials. Am
J Psychiatry 2004;161:1537–47.
96. Haykal RF, Akiskal HS. Bupropion as a promising approach to rapid cycling
bipolar II patients. J Clin Psychiatry 1990;51:450–5.
97. Vieta E, Martineq-Aran A, Goikolea J, Torrent C, Colom F, Benagarre A,
Reinares M, and others. A randomized train comparing paroxetine and
venlafaxine in the treatment of bipolar depressed patients taking mood
stabilizers. J Clin Psychiatry 2002;63:508–12.
98. Yatham LN. Newer anticonvulsants in the treatment of bipolar disorder. J Clin
Psychiatry 2004;65(Suppl 10):28–35.
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3
Professor of Psychiatry, Mood Disorders Centre, Department of
Psychiatry, University of British Columbia, Vancouver, British Columbia.
Address for correspondence: Dr LN Yatham, Department of Psychiatry,
Manuscript received and accepted October 2004.
1 University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC
Resident, Department of Psychiatry, University of British Columbia,
V6T 2A1
Vancouver, British Columbia.
2 e-mail: yatham@interchange.ubc.ca
Assistant Professor of Psychiatry, Mood Disorders Centre, Department of
Psychiatry, University of British Columbia, Vancouver, British Columbia.

Résumé : Le trouble bipolaire II : un aperçu des développements récents

Objectif : La recherche récente sur l’épidémiologie, l’évolution clinique, le diagnostic et le traitement
du trouble bipolaire II (TB II) pourrait avoir un effet considérable sur la pratique clinique. Cet article
examine ces développements.
Méthodes : Nous avons mené une recherche dans PubMed axée sur la période du 1 er janvier 1994 au
31 août 2004. Nous avons retenu les articles que nous jugions relever directement de l’épidémiologie,
de l’évolution, du diagnostic et du traitement du TB II.
Résultats : La prévalence du TB II est probablement plus élevée que ce qui était antérieurement
suggéré. La recherche systématique de caractéristiques cliniques particulières et l’utilisation
d’instruments de dépistage permettent une détection plus ponctuelle et exacte du trouble. Les données
de bonne qualité sont rares pour guider les cliniciens traitant le TB II.
Conclusion : Des progrès importants ont eu lieu dans la clarification des questions de diagnostic et de
traitement du TB II. Des recommandations fermes ou générales ne peuvent être faites; une
interprétation prudente des données disponibles suggère que le lithium ou la lamotrigine
sont des choix de première ligne assez responsables. Il faut plus d’études bien structurées sur des
échantillons plus importants afin d’améliorer les données probantes du traitement de ce trouble.

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