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REVIEW ARTICLE
Year : 2008  |  Volume : 30  |  Issue : 1  |  Page : 14-23 Table of Contents   

Pharmacologic management of bipolar-II disorder


1 Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
2 Department of Psychiatry, University of British Columbia, Vancouver, Canada

Correspondence Address:
Lakshmi N Yatham
Associate Head for Research and International Affairs, The University of British Columbia, 2255, Wesbrook Mall, Vancouver, BC, V6T 2A1
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7176.43130

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How to cite this article:
Bond DJ, Yatham LN. Pharmacologic management of bipolar-II disorder. Indian J Psychol Med 2008;30:14-23

How to cite this URL:
Bond DJ, Yatham LN. Pharmacologic management of bipolar-II disorder. Indian J Psychol Med [serial online] 2008 [cited 2019 Oct 20];30:14-23. Available from: http://www.ijpm.info/text.asp?2008/30/1/14/43130

According to the Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition, Text Revision (DSM-IV-TR) [1], bipolar II disorder (BDII) consists of recurrent episodes of depression and hypomania. Although the lifetime prevalence of BDII remains a matter of debate, with some studies reporting rates as high as 5% [2], most epidemiological surveys suggest a prevalence of 1%-2% [3],[4] . This makes BDII at least as common as bipolar I disorder (BDI), which has a lifetime prevalence of 1% [4] . BDII is sometimes viewed as a "mild" form of bipolar illness, but this is a misconception, as it is associated with rates of disability that are comparable to BDI [5] . As well, BDII may have the highest frequency of suicidal behaviour of any mood disorder [6] .

Although BDII is defined by the occurrence of hypomania, for many patients it appears to be a predominantly depressive illness. Studies in treated samples demonstrate that BDII patients spend approximately half of their lives with depressive symptoms [7],[8] , In fact, BDII is likely the most common cause of depression after major depressive disorder, with studies suggesting that 18.5% of family practice patients with depression and 40% of depressed patients in psychiatric specialty settings suffer from BDII [9],[10] . This is indicative of both the frequency of depressive symptoms, and the possibility that depressions do not respond as well to treatment as hypomanias. Hypomanias, in contrast to depressions, are often brief and are not uncommonly associated with minimal to mild disability [2],[5] .

The frequency and severity of depression in BDII, coupled with the difficulties inherent in retrospectively ascertaining a history of hypomania, commonly lead to the misdiagnosis of BDII as major depressive disorder (MDD). To avoid this pitfall, clinicians should be finely attuned to the possibility of BDII as a cause of depression, and must be rigorous in screening all depressed patients for a history of hypomania. Furthermore, it is important to be aware of a number of barriers to the diagnosis of hypomania. First, patients and their families often do not recognize hypomania as a pathological state, and they frequently do not volunteer a history of hypomanic symptoms. Second, although the DSM-IV-TR requires a 4-day duration of symptoms to diagnose hypomania, hypomania is frequently briefer, with some studies suggesting a median duration of 1-3 days [2] . Thus, in addition to thoroughly screening patients for hypomanic symptoms, we have found a number of clinical tools useful in making the diagnosis. These include obtaining collateral history from family members; having patients keep daily mood diaries; and also having them complete the Mood Disorders Questionnaire (MDQ), a 13-item self reported questionnaire with queries about common hypomanic symptoms [11] . Although the MDQ has not been as rigorously studied as a screening instrument in BDII as it has in BDI, our clinical experience suggests that it can be a helpful diagnostic aid. Finally, the value of long-term follow-up cannot be overstated, as hypomanic symptoms often become obvious during long-term follow-up.

Partly as a result of difficulties in making the correct diagnosis, the prevalence of hypomania has until recently been underestimated, and its treatment consequently understudied. Lacking an adequate evidence base, physicians are sometimes left with no alternative but to make treatment decisions for BDII patients based on the results of BDI studies. However, genetic [12] , family history [13] , and long-term follow-up studies [14] clearly indicate that BDI and BDII are distinct illnesses. More importantly, a number of clinical trials suggest that BDII patients may respond quite differently to mood stabilizing medications [15],[16],[17] and antidepressants [18] compared to patients with BDI.

The primary challenges for clinicians managing patients with BDII are 1) to treat acute episodes of depression without causing switches into hypomania and 2) to prevent depressions and hypomanias during long-term follow-up. The last several years have witnessed a surge in the awareness of BDII as a cause of depression, and a number of acute and maintenance treatment studies have recently been published. The purpose of this review, then, is to summarize for the clinician the available evidence regarding the efficacy of mood stabilizing medications, antidepressants, and other medications in the treatment and prevention of depression and hypomania in BDII. We will focus on data from randomized controlled trials, but we will also highlight results from important single blinded and open label studies where appropriate. Trials which enrolled both BDI and BDII patients will be included as long as they presented results separately for BDII patients.


   Acute Phase Studies Top


Clinical trials have been carried out to assess the efficacy of mood stabilizers, antidepressants, second generation antipsychotics, and other medications in the acute treatment of BDII. In keeping with the high frequency of depressive episodes in BDII, almost all acute phase studies have focused on the treatment of depression, with only one also enrolling hypomanic patients [19] . These studies are reviewed below.

Mood Stabilizers

Lithium.
Lithium has been used in the treatment of bipolar disorder for well over 50 years, and it is still widely considered to be the "gold-standard" mood stabilizing medication. Thus, it is remarkable that no published placebo controlled trials have assessed the acute phase efficacy of lithium in BDII depression. However, preliminary results from an 8 week placebo controlled trial comparing lithium 600-1800 mg/d (serum level 0.6-1.2 mEq/l), quetiapine and placebo have recently been presented [20] . The data indicate that lithium (N=49) did not separate from placebo (N=51) on the primary outcome measure, change from baseline to endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) score. Response and remission rates were not reported.

In addition, 2 lithium studies with non-RCT designs have been published. A 16-week randomized single blinded comparison of lithium (serum level 0.8-1.2 mEq/L) and lamotrigine 200-400 mg/d in 98 depressed BDII patients did not detect a difference in efficacy between the 2 treatments, with response rates of 68% for lamotrigine and 55% for lithium [21] . As lamotrigine was not found to be superior to placebo in a separate RCT (see below), these data do not support the efficacy of lithium. The final study, a randomized open-label trial comparing lithium (serum level 0.5­1.5 mEq/L) and the antidepressant venlaflaxine 37.5­375 mg/d in 83 depressed BDII patients [22] suggested a benefit for venlaflaxine over lithium, with response rates of 58% vs 20% (p < 0.0005). One venlafaxine treated patient (2%), compared to no lithium treated patients, experienced hypomanic episodes. This study, however, was limited by the fact that the lower end of the permitted range of lithium levels was likely subtherapeutic for the treatment of depression. Nonetheless, when these studies are taken together, there is currently little evidence for the efficacy of lithium in the treatment of acute BDII depression.

Divalproex. Two open label studies have assessed the efficacy of divalproex in BDII depression. In the first study, the response rate in 19 patients treated with divalproex for 12 weeks was 63% [23] . Interestingly, medication-naive patients had a greater response rate than those who had previously been treated with antidepressants or stimulants (82% vs 38%, p < 0.08). The second study enrolled 28 patients who received divalproex extended release as monotherapy (N=21, mean dose = 1288 mg/d) or in combination with antidepressants, lamotrigine, or benzodiazepines (N=7, mean dose = 1546 mg/d), and reported an overall response rate of 52% [24] . Rates of response were 45% for monotherapy and 71% for combination therapy (p = NS). These data, though suggestive, require confirmation from well-designed RCTs.

Lamotrigine. One randomized placebo controlled trial, as yet unpublished, has examined the acute phase efficacy of lamotrigine in BDII depression. Two hundred-twenty one patients were randomized to receive lamotrigine 200 mg/d (N=111) or placebo (N=110) over 8 weeks. No significant difference was detected in the primary outcome, change from baseline to endpoint in Montgomery-Asberg Depression Rating Scale score (13 points for lamotrigine vs 12 points for placebo, p = 0.328). Rates of response (52% vs 46%) and remission (41% vs 34%) were also similar between treatments.

Topiramate. Only one small open-label study (N=19) has assessed the efficacy of topiramate (mean dose = 177 mg/d) as monotherapy (N=5) or in combination with mood stabilizing medications (N=14) in the treatment of hypomania (N=15) or depression (N=4) in BDII [19] . Fifty-three percent of hypomanic patients and 50% of depressed patients met criteria for treatment response by study endpoint. Given the small sample size, mixed population, and open-label design of this study, it is difficult to assess the true efficacy of topiramate from these data.

Quetiapine. Two large, identically-designed 8-week randomized controlled trials (RCTs) comparing quetiapine 300 mg/d and 600 mg/d to placebo in acute BDII depression have been published [16],[25] , and preliminary results from 2 further trials with the same design have also recently been presented [20],[26] . Only 1 of the 2 published trials demonstrated superiority for quetiapine over placebo on the primary outcome, change form baseline to endpoint in MADRS scores [25]. However, when the results from both trials were combined, [27] , quetiapine was superior to placebo on improvement in MADRS scores beginning at week 1 and at all subsequent timepoints, with endpoint changes in MADRS scores of 17.1 for quetiapine 300 mg/d (p < 0.005), and 17.9 for quetiapine 600 mg/d (p < 0.001), and 13.3 for placebo. Interestingly, a post­hoc analysis indicated that while quetiapine was associated with significant improvement in rapid cycling patients, it did not separate from placebo in those with a non-rapid cycling course. Rates of response (quetiapine 300 mg/d = 54%, quetiapine 600 mg/d = 52%, and placebo = 44%) and remission (50%, 47%, and 35%, respectively) were also significantly greater in both quetiapine arms. Rates of treatment associated mania were low and did not differ between groups (placebo = 3%, 300 mg/d = 1.7%, 600 mg/d = 3%). Preliminary results from the 2 unpublished studies were very similar to the published data, with quetiapine separating from placebo in 1 of the 2 studies on change at endpoint in MADRS scores. Response and remission rates were not reported. The data from these 4 placebo-controlled trials, in aggregate, suggests that quetiapine is efficacious in the short term treatment of acute BDII depression.

Antidepressants

Antidepressants are among the most frequently prescribed medications for BDII [28] . Notwithstanding their widespread use, questions have been raised about their safety, specifically the possibility that they may induce manic and hypomanic episodes [29] . However, this concern is based primarily on studies in BDI, and it has been unclear whether the same caution is warranted in BDII. A recent meta-analysis addressed this question by summarizing data from studies comparing rates of antidepressant associated mood elevations (AAME) in BDI and BDII [18] . It reported that AAME was more frequent and more severe in BDI during acute phase treatment (< 16 weeks), occurring in 14% of BDI patients and 7% of BDII patients, with a relative risk of 1.94 (p=0.06). Furthermore, mood elevations occurred almost exclusively into hypomania in BDII, while mania and hypomania occurred with approximately equal frequency in BDI. Unfortunately, the available data did not permit an assessment of whether antidepressants were associated with a greater frequency of mood elevations in BDII compared to placebo, or whether mood stabilizing medications protected against mood elevations during antidepressant treatment.

With respect to efficacy, only 2 placebo-controlled trials have assessed antidepressants in BDII depression. Preliminary results from an 8-week RCT that compared monotherapy with paroxetine 20 mg/d to placebo and 2 doses of quetiapine have recently been presented [26] . Paroxetine did not separate from placebo on the primary outcome, change from baseline to endpoint in MADRS scores. Response and remission rates were not presented. One limitatonof this study is that the paroxetine dose was fixed at 20 mg/day, and hence it is unknown if the higher dose might have been effective. The second study randomized 240 depressed BDI patients and 114 BDII patients to receive an antidepressant (paroxetine 10-40 mg/d or bupropion 150-375 mg/d) or placebo for up to 6 months as adjunctive treatment to one or more mood stabilizing medications [30] . Combined analysis of BDI and BDII patients revealed that antidepressant treatment did not separate from placebo on the primary outcome, the percentage of patients who achieved 8 consecutive weeks of euthymia (24% vs 27%, p = 0.40). Only 20% of BDII patients treated with antidepressants responded. Unfortunately, data for placebo treated patients were not presented separately for BDI and BDII. Mood elevations occurred in 10% of antidepressant treated patient and 11% of placebo treated patients. In assessing this trial, certain limitations must be noted. Its primary outcome measure has not been used in other trials, and so it is difficult to gauge whether it is an appropriate measure of short term treatment efficacy. As well, it's length, 6 months, is intermediate between most acute and maintenance studies. Furthermore, patients were permitted to receive treatment with numerous psychotropic medications besides antidepressants, including combinations of mood stabilizers or mood stabilizers plus second generation antipsychotics, and psychotherapy was also permitted, introducing numerous confounding variables.

Two additional RCTs have compared monoamine oxidase inhibitors to imipramine in the treatment of BDII depression. While these medications are not commonly used in the treatment of BDII depression in clinical practice, we will review them briefly. The first was a report of a post-hoc analysis of BDII data from a 6 week RCT which compared phenelzine 15­90 mg/d, imipramine 50-300 mg/d, and placebo in the treatment of depression in patients with BDII and MDD [31] . Response rates were 52% for phenelzine, 57% for imipramine, and 23% for placebo. A statistical analysis of these results was not performed, and rates of AAME were not measured during the trial. The second trial compared tranylcypromine 20-60 mg/d and imipramine 50-300 mg/d in a mixed sample of BDI and BDII patients over 6 weeks [32] . When BDI and BDII patients were combined, tranylcypromine was associated with a significantly higher response rate among patients who completed at least 4 weeks of treatment (81% vs 48%, p=0.02). A graphical representation of the results indicated that BDI and BDII patients responded similarly to each antidepressant, though exact response rates, rates of AAME, and statistical analyses were not provided separately for BDII patients. In the absence of placebo controls, the efficacy of these antidepressants relative to no treatment cannot be assessed.

Finally, several open-label studies of fluoxetine and venlaflaxine in the treatment of BDII depression have been reported. Two of these studies reported response rates of 48% over 8 weeks for fluoxetine [33] and 58% over 12 weeks for venlaflaxine [22]. Two additional open label trials did not specify response rates, but reported reductions in Hamilton Depression Rating Scale scores of approximately 17 points over 12 weeks for fluoxetine [34] and 12 points over 6 weeks for venlaflaxine [35]. Open label studies, of course are limited by the possibility of bias on the part of both patients and investigators, and must be interpreted with caution.

Thus, the evidence from the above antidepressant studies, is mixed, with the highest quality evidence from 2 placebo controlled trials indicating a lack of efficacy although the dose of paroxetine used in one of the studies may have been an issue. However, several open label trials, as well as clinical experience, suggest that these medications alleviate symptoms of depression, at least in a subset of patients. We will discuss this further in the section on clinical recommendations (below).

Other medications

Pramipexole.
Pramipexole is a dopamine D 2 /D 3 receptor agonist used in the treatment of Parkinson's disease. One small 6 week RCT compared pramipexole 1-3 mg/d (N=10) versus placebo (N=11) as adjunctive treatment to lithium or divalproex in acute BDII depression [36] . By endpoint, pramipexole treated patients experienced a significantly greater improvement in MADRS score compared to those receiving placebo (17 points vs 4 points , p = 0.01). Response rates were also greater for pramipexole (60% vs 9%, p = 0.02). Remission rates, were numerically greater for pramipexole, but did not reach statistical significance (40% vs 9%, p = 0.15). Ten percent (1/10) of pramipexole treated patients and 18% (2/11) of placebo treated patients experienced hypomanic episodes. A large placebo-controlled RCT is cuurently underway to confirm these findings.


   Maintenance Studies Top


Mood Stabilizers

Lithium :
Four RCTs have assessed the efficacy of lithium in the maintenance treatment of BDII. Three of them were conducted by the same research group and followed cohorts of BDII patients for varying periods. The first study assigned 18 euthymic BDII patients to lithium (serum level 0.7-1.3 mEq/L, N=7) or placebo (N=11) and followed them for an average of 25 months [37] . Lithium treated patients experienced almost 50% fewer depressive episodes compared to placebo treated patients (0.212/year vs 0.367/year), and depressions that did occur were substantially shorter (mean of 57 days vs 194 days). Forty-three percent of lithium treated patients versus 27% of placebo treated patients remained free of depression and hypomania during the follow-up period. Due to the small sample size, however, statistical analyses were not carried out. The second study included 40 BDII patients randomized to lithium (N=16) or placebo (N=24), with an average follow-up period of 15 months [38] . Although lithium treated patients experienced significantly fewer hypomanic episodes (0.09/year vs 0.27/year, p < 0.001), depressive episodes actually occurred nonsignificantly more frequently in lithium treated patients (0.85/year vs 0.72/ year). Based on the results of these 2 studies, the authors hypothesized that the prophylactic benefit of lithium might only be apparent during long follow-up periods. Accordingly, the last trial included 38 patients (lithium: N= XXX; placebo: N=XXX) who were followed for an average of XXX months [39] . In keeping with the authors' hypothesis, lithium treated patients experienced significantly fewer depressive episodes per year (0.19 vs 0.45) over this follow-up period. Hypomanic episodes were also nonsignificantly less frequent in the lithium treated group.

The fourth RCT compared 10 lithium treated patients (serum level 0.8-1.2 mEq/L; 6 also received imipramine) and 7 placebo treated patients for an average of 10 months [40] . Lithium was superior to placebo in preventing relapse into any mood episode. Relapse into depression occurred in 20% of lithium treated patients vs 57% of those who received placebo, and hypomanic relapse in 0% of lithium treated patients and 14% of placebo treated patients. Lithium plus imipramine offered no additional benefit compared to lithium alone. Imipramine monotherapy was no better than placebo.

A large open label study also supports the long-term effectiveness of lithium in BDII patients. Tondo et al [41] prospectively followed 129 lithium treated patients (mean serum level 0.55 mEq/L) for 8 years, and compared their course of illness during this time with retrospectively ascertained data from the 6 years preceding lithium treatment. Lithium was associated with marked improvements in all phases of illness, with total time ill reduced by 80%, time with hypomanic symptoms reduced by 79%, and time depressed reduced by 64%. Time to recurrence in 50% of patients was increased from 8 months before lithium treatment to 100 months. When BDII patients were compared to the 188 BDI patients who were also enrolled in this study, BDII patients had a 5.9-fold longer interval between mood episodes, and BDI patients were almost twice as likely to require additional pharmacotherapy for new mood episodes.

Carbamazepine : A single randomized but unblinded study compared the efficacy of carbamazepine (N=29, mean dose 630 mg/d) and lithium (N=28, mean serum level 0.65) in the maintenance treatment of BDII [17] . No significant differences were detected between the two medications in rates of recurrence (28% vs 38%), recurrence or subclinical recurrence (55% vs 71%), or hospitalization for a mood episode (17% vs 33%). Mean survivial time in the study was numerically but nonsignificantly greater for carbamazepine treated patients. Interestingly, these results are discordant from those obtained in a similar study of BDI patients, for whom lithium was superior to carbamazepine in preventing recurrence or subclinical recurrence (71% vs 48%), and superior at a trend level in preventing recurrence (59% vs 40%) and hospitalization (55% vs 37%). Well-designed placebo-controlled RCTs are required to confirm this finding.

Lamotrigine : Fifty-two BDII patients were included in a 6-month study of lamotrigine in the maintenance treatment of rapid cycling BD, along with 128 patients with BDI [15] . Patients who responded to lamotrigine in addition to other mood stabilizing medications during open-label treatment were randomized to receive lamotrigine 100-500 mg/d or placebo, and were followed for up to 6 months. When BDI and BDII patients were combined, lamotrigine did not separate from placebo on the primary outcome measure, survival time in the study until additional medication was required for emerging symptoms of depression or mania. However, a post-hoc analysis of data from the BDII sample suggested a trend toward a greater survival time for lamotrigine (median = 17 weeks vs 7 weeks for placebo, p = 0.073), and a statistically significant difference in favour of lamotrigine on a secondary outcome, survival time in the study until discontinuation for any reason (p = 0.015). Furthermore, significantly more BDII patients receiving lamotrigine remained stable without relapse during 6 months of treatment (46% vs 18% for placebo, p = 0.04). Thus, lamotrigine appears to be efficacious in the maintenance therapy of rapid cycling BDII.

Risperidone : A 6-month open label study of risperidone which enrolled 44 hypomanic BDII patients has been reported. However, it is worth noting that the average Young Mania Rating Scale score at baseline was 22, with a score of 20 generally considered to indicate full mania, and that approximately 20% of patients were judged to be severely ill, also out of keeping with the diagnosis of hypomania. Thus, this study appears to actually include a mixed sample of BDI and BDII patients. In any case, risperidone was prescribed either as monotherapy (N=14, mean dose = 3.1 mg/d) or in combination with other mood stabilizers (N=30, mean = 2.6 mg/d). Over the 6-month follow-up period, 73% of patients responded to treatment, but 27% experienced relapses, with depressions outnumbering mood elevations (25% vs 4%). Given the open-lebel design and mixed population of sthis study, it is difficult to draw firm conclusions from these data.

Antidepressants

A meta-analysis comparing rates of AAME in BDI and BDII has reported that, similarly to acute treatment, maintenance treatment with antidepressants leads to higher rates of mood elevations in patients with BDI (23% vs 14%), with a relative risk of 1.82 (p = 0.006). Almost all mod elevations in BDII were into hypomania, while mania and hypomania were both relatively common in BDI.

With respect to efficacy, 2 placebo-controlled RCTs have examined the antidepressants imipramine and fluoxetine in the maintenance treatment of BDII. The first, which compared imipramine 100-150 mg/d (N=11, 6 of whom also received lithium), lithium monotherapy (N=4) and placebo (N=7) in euthymic patients over an average of 10 months reported no benefit for imipramine over placebo, nor did the combination of imipramine and lithium offer any additional benefit over lithium alone [40] . Depressive relapses occurred in 40% (3/5) of imipramine treated patients, 57% of placebo treated patients, 25% (1/4) of lithium treated patients, and 17% (1/6) treated with lithium and imipramine. Mania occurred in 1 imipramine treated patient, and hypomania in 1 patient treated with placebo. In contrast, lithium was superior to placebo in preventing mood episodes in this study. In the second RCT, 12 patients whose depression remitted with open label fluoxetine were randomized to continue fluoxetine 20 mg/d (N=8) or switch to placebo (N=4) for up to 6 months [42] . During the follow-up period, depressive relapse was documented in 43% of fluoxetine treated patients and 100% of those who received placebo (p = 0.08). No hypomanic episodes were observed. Both of these studies are limited by their small sample sizes. In assessing the results, it is also worth noting that in the second study only 32% (12/37) patients in the open label treatment phase recovered and elected to take part in the double­blinded trial.

Finally, a placebo-controlled cross over study reported that 10 patients who took escitalopram 10 mg/d for 3 months experienced fewer days depressed or hypomanic, reduced severity of depression, and reduced impairment compared to an equivalent period of placebo treatment [43] .

Thus, the available evidence suggests that fluoxetine, and possibly escitalopram, are effective in the maintenance treatment of BDII depression, while the TCA imipramine is not. However, each of these studies has significant limitations, and large well-designed maintenance trials assessing the efficacy and safety of second-generation antidepressants in BDII are clearly needed.


   Summary of Efficacy and Clinical Recommendations Top


In reviewing the available evidence, it is clear that despite the recent and laudable increase in awareness of BDII, as evidenced by the number of clinical trials published over the past 5 years, significant gaps in our knowledge remain with respect to both acute and maintenance therapy. For example, in acute therapy, only 1 placebo-controlled RCT has been conducted to assess the efficacy of lithium, and only preliminary results from that trial are currently available. Among the other "traditional" mood stabilizers, there is very limited evidence for divalproex, and no trials have been carried out with carbamazepine. Lamotrigine and the second generation antipsychotic quetiapine are the only medications to have been studied in well designed placebo controlled RCTs, and only quetiapine has evidence from replicated RCTs. The evidence base for maintenance therapy is of somewhat better quality, though still limited compared to BDI or MDD. Although a number of placebo-controlled RCTs of lithium have been conducted, they are limited by small sample sizes, making it difficult to draw definitive conclusions about the efficacy of this medication. No clinical trials have been carried out with divalproex, and only one single-blinded trial exists for carbamazepine. The only data for lamotrigine is derived from a post-hoc analysis of an RCT that included both BDI and BDII patients, and no well designed trials have assessed the efficacy of any of the second generation antipsychotics. Evidence for the efficacy of antidepressants in both acute and clinical trials is contradictory,

Treatment of Acute BDII Depression

What conclusions can be drawn, then, regarding the best treatment practices for BDII? Given the limitations of the evidence base, the recommendations we will offer are based both on the clinical trials we have reviewed above, and our clinical experience from treating BDII patients in a busy mood disorders clinical and research program. The objective of treatment must be to treat depression without an increased risk of switching patients into hypomania.

Based on data from the clinical trials we have reviewed above, the best evidence currently available for the acute treatment of BDII is for quetiapine, and the results of 4 placebo-controlled RCTs suggest that quetiapine can be recommended as a treatment for acute BDII depression. However, we must qualify even this recommendation by pointing out that quetiapine separated from placebo in only 2 of the 4 RCTs, and that its effect may be not as pronounced as it is in BDI, for which quetiapine separated from placebo in all 4 studies. As well, in a small RCT pramipexole was superior to placebo in BDII depression, and can be given a qualified recommendation in combination with mood stabilizers on this basis. A large replication trial is currently underway to confirm its efficacy. Two open label trials for divalproex suggest possible efficacy in BDII depression, but further well designed RCTs are needed before it can be recommended with any degree of confidence as a monotherapy. Both lithium and lamotrigine currently have only negative evidence. Lamotrigine failed to separate from placebo in a well designed RCT, and 3 studies suggest a lack of effect for lithium: it did not separate from placebo in 1 RCT, was inferior to venlaflaxine in an open-label study, and was equivalent to lamotrigine in a slingle blinded trial. The evidence for antidepressants is mixed, but it is worth highlighting that the best designed trials, 2 placebo controlled RCTs, did not demonstrate superiority of antidepressants over placebo.

In general, our clinical experience is in keeping with the data derived from these clinical trials. The main exceptions are with respect to lamotrigine monotherapy, which is effective in BDII depression in at least some patients, and particularly second generation antidepressants such as SSRIs and bupropion, which are also efficacious in at least a subset of patients with BDII. This stands to reason, as dozens of trials have proven that antidepressants are efficacious in MDD, and BDII is known to be intermediate between BDII and MDD in several respects, particularly in its high frequency of depressive symptoms. We also wish to point out that combining a mood stabilizing medication with an antidepressant can be helpful for some patients and that this appears to be particularly true for the combination of lamotrigine plus antidepressant. We are currently conducting a proof-of-concept study to assess the efficacy of this combination therapy in the treatment of acute BDII depression. As well, given the long term efficacy of lithium for maintenance treatment of bipolar II disorder, it may also be appropriate to combine an antidepressant with lithium.

Thus, in summary, the following treatments can be considered reasonable options for the treatment of acute BDII depression: quetiapine monotherapy, lamotrigine monotherapy, antidepressant monotherapy for those with a history of very infrequent hypomanias and chronic severe depressions, the combination of a mood stabilizing medication (particularly lamotrigine or lithium) and an antidepressant, and the combination of a mood stabilizing medication and pramipexole.

Maintenance Treatment of BDII

It is easier to make recommendations regarding maintenance therapy for BDII based on the results of the studies we reviewed above. The evidence for lithium from RCTs is mixed, though the fullest interpretation suggests that benefits from lithium accrue over time, and that it may be most efficacious during very long follow-up periods. As well, based on the results of one single- blinded trial, carbamazepine may also be effective in maintenance treatment, and possibly even marginally superior to lithium, though this requires confirmation from further studies. As it induces the metabolism of numerous medications, and is associated with the possibility of serious side effects such as blood dyscrasias and hepatitis, it is generally not considered a first line treatment option for BD.A similarly qualified recommendation may be made for lamotrigine, as the evidence for its efficacy comes primarily from a post­hoc analysis of a single placebo-controlled RCT in rapid cycling BDII patients. Our clinical experience also supports the proposition that lamotrigine monotherapy is an effective treatment for some patients, and that it may be more effective still when given in combination with second generation antidepressants. While no studies have assessed the efficacy of divalproex, our clinical experience suggests that it is effective in some patients. Based purely on clinical trial data, there is no evidence at the current time to support the efficacy of any of the second generation antipsychotics in maintenance treatment of BDII. To date, only risperidone has been studied, and this trial was limited by its open label design, inclusion of a mixed sample of BDI and BDII patients, and a relatively high rate of depressive relapse over the 6 month follow-up period. Maintenance studies for quetiapine have been carried out, but the results are not yet available. Our clinical experience suggests that quetiapine is an effective maintenance treatment for some patients. Finally, regarding antidepressants, monotherapy with fluoxetine appeared to have some benefit over placebo in a small RCT. This is in keeping with our experience with second generation antidepressants, though we note that it is not uncommon for patients to have a partial response to long-term antidepressant treatment, with ongoing subsyndromal symptoms or recurrences despite adequate treatment. As with acute therapy, we suggest adding a mood stabilizing medication, particularly lamotrigine, to antidepressants in patients with partial response may provide better symptom control.

In summary, we recommend the following treatment options for the maintenance treatment of BDII: lithium monotherapy, lamotrigine monotherapy, antidepre­ssant monotherapy, and the combination of a mood stabilizing medication (particularly lamotrigine) and an antidepressant. Monotherapy with quetiapine, carbamazepine, or divalproex, or the combination of these medications and a second generation antidepre­ssant can also be considered based primarily on clinical experience.

 
   References Top

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