Lakshmi N Yatham, MBBS, MRCPsych, FRCPC3,
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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)
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Clinical Implications
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Bipolar II disorder (BD II) may be more common than previously thought; systematic probing improves early identification of the disorder.
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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
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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.
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Key Words: bipolar II disorder, bipolar spectrum disorder, diagnosis, treatment, subsyndromal
symptoms
Résumé : Le trouble bipolaire II : un aperçu des développements récents
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There has been a recent surge of interest in refining the definition of bipolar II disorder (BD II) (1–8). Efforts to reconsider 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 distill these developments in this paper.
We begin by situating BD II within the so-called bipolar spectrum, summarizing various approaches to the spectrum concept. 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 methods for improving recognition and reliability, follow. We conclude by considering ongoing concerns about appropriate treatment, summarizing the best available evidence for managing 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 colleagues in 1976 (10,39). Yet BD II did not become an officially 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 to be seen whether such research will lend itself to the inclusion 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 organized into 3 overlapping clusters or subtypes, including classical 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 challenges to the unipolar–bipolar dichotomy (43).
Finally, the fourth or pragmatic approach, as described by Ghaemi and colleagues, combines all nonbipolar I or II disorders 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 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 underestimation of the prevalence of BD II. The Zurich study is arguably one of the most important epidemiologic studies of BD II, comprising a sample of almost 600 patients followed prospectively 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 prevalence 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 meeting DSM-IV criteria for BD II (11). Based on similar data, it 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 compelling, 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 assessing 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 functioning (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 intuitive 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 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 identify 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 behaviour, 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 investigating 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 diagnosed (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 minutes, has a specificity of 90% and sensitivity of 73% when compared with semistructured interviews (5,54). These finding 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 reason 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 substance abuse and minor antisocial behaviour, and a significantly greater degree of social disruption (that is, marital, occupational, or scholastic) (55). Habitual temperamental instability, which remained present during depressive episodes, 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 atypical 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 depressive 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 depression 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, particularly those under the cluster B rubric (histrionic, borderline, 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 vegetative 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 concerns, it has also been reported that, in an outpatient setting, BD II can be differentiated from borderline personality disorder (BPD) without much difficulty by applying the Structured Clinical Interview for DSM-IV (58). Of course, personality 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 substance 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 present 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 characteristic 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 suffering from BD II spend a considerable proportion of their lives ill and tend to run a more chronic course with more frequent 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 suggests 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 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 significantly 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 significantly higher rates of rapid cycling. For instance, a study that followed 360 BD patients for over 13 years found a fivefold 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 consequence; 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 episodes and the role of antidepressants. Limitations in the evidence 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 randomized, 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.
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 studies done before BD II was recognized as an official diagnostic entity in the DSM-IV, lend support for lithium in the prophylaxis 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 effective 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 maintenance 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 demonstrate significant positive results for its primary outcome measure (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 clinically 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 reason 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 Clinical Global Impression (CGI) for 5 of 8 BD II patients included in the study (82). Another double-blind, randomized, 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 augmentation showed significantly greater improvement on their CGI scores, compared with placebo, but not on the Hamilton Depression Rating Scale (HDRS) or the Montgomery– Asberg Depression Rating Scale (MADRS) (33).
There is limited evidence from small, open-label observational 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 difference across bipolar subtypes was not found (36). One wonders 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 placebo 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 concurrently taking mood stabilizers or mood stabilizers combined 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; conflicting perspectives abound (30,49,67–69, 85). Although it is often noted that antidepressants can lead to cycle acceleration and switching, the likelihood of such phenomena has not been conclusively determined. A wide range of estimates exist, potentially reflecting methodological differences and limitations across studies (for example, small samples and observational 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 acceleration”(49, p 426). Whether such adverse events are as prominent 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 prospective 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 precipitating 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 inconclusive. A study of 203 subjects with depression showed a threefold significantly greater risk for BD II patients, compared 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 controversies 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 recommendations 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 treatment 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 efficacious 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 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 periods. Three (7.8%) were considered to have hypomanic symptoms 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 significantly 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 depression 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 psychotherapy 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 demonstrated 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 maintenance 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.
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 pharmacologically treated BD patients, of whom 20 had BD II (93). When compared with control subjects attending nonpsychotherapeutic 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 discussed 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 contrasts with previous studies demonstrating individual psychotherapy’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 lacking. 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 heterogeneity 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 hypomania or bipolarity may help identify patients who meet criteria for BD II. Although semistructured interviews by experienced clinicians likely yield the best results, the exigencies 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 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 recommended 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 inhibitors (SSRIs) in short-term treatment were comparable to placebo (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 antidepressants. We thus suggest initiating treatment with an adequate 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, introducing 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 concerns 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 outcomes. When patients are unable to tolerate lithium or 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 antidepressants 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 acceptable 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 treatment 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 reasonable 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 evidence 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 strategies 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 limitations 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.
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Author(s)
Manuscript received and accepted October 2004.
1. Resident, Department of Psychiatry, University of British Columbia,
Vancouver, British Columbia.
2. Assistant Professor of Psychiatry, Mood Disorders Centre, Department of
Psychiatry, University of British Columbia, Vancouver, British Columbia.
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,
University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC
V6T 2A1
e-mail: yatham@interchange.ubc.ca
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