Introduction
Bipolar disorder is a serious psychiatric illness resulting in depression and mania that affects approximately 1.5% of the population and represents a significant source of individual morbidity and societal cost.Reference Narrow, Rae and Robins1 Patients with bipolar disorder spend considerably more time in depressive rather than manic episodes, and suffer more morbidity during depression.Reference Judd and Akiskal2 Until quite recently most treatment studies of bipolar disorder focused on the treatment of mania or less often on maintenance treatment.Reference Zornberg and Pope3–Reference Nivoli, Colom and Murru5 Yet the treatment of bipolar depression is one of the most difficult psychopharmacological challenges psychiatrists face. Fortunately, over the last decade and a half, there has been renewed interest in the treatment of the depressive phase of bipolar disorder, and a number of well designed randomized, double-blind, placebo-controlled trials in several different classes of medications have been published.Reference Van Lieshout and MacQueen4, Reference Vieta, Locklear and Gunther6 Additionally, in the last few years the number of studies has increased enough to allow the first round of meta-analyses.Reference Van Lieshout and MacQueen4, Reference Vieta, Locklear and Gunther6–Reference Bond, Lam and Yatham10 Nevertheless, the total number of well controlled studies of bipolar depression is relatively small, especially in comparison to the severity of the problem.Reference Van Lieshout and MacQueen4, Reference Vieta, Locklear and Gunther6 Only two medications are FDA approved for the treatment of bipolar depression: olanzapine/fluoxetine combination and quetiapine.Reference Fountoulakis, Grunze, Panagiotidis and Kaprinis11
The focus of this review article is the acute treatment of depressive episodes in bipolar I disorder. The literature on the treatment of bipolar type II is very sparse and will not be discussed in this article.Reference Dodd12 Studies were included in this review if they were the primary treatment for bipolar depression, were randomized and double-blind, had a placebo arm, included a clearly defined outcome measure, and were published in a peer-reviewed journal. The literature search for appropriate studies used the search engines PubMed and Scopus. Searches were performed using the keywords “bipolar,” “depression,” “treatment,” and “double-blind.” Additional manual searches were made using references of the studies identified as well as reviewing previous meta-analyses and review articles. Another initial criterion was that the study included only participants with bipolar type I disorder. However, many studies included a mix of bipolar type I and type II participants, and nearly one-third of the studies that meet the other search criteria would have had to be rejected. Therefore we removed this exclusion criterion, but whenever possible, we report the number of bipolar II participants included in each arm of the study. The initial inclusion criteria could not address one of the major controversies in the treatment of bipolar depression: the use of antidepressants. In most of the studies of antidepressants, they are used as adjunctive treatments.Reference Sidor and MacQueen13 Therefore we included a secondary set of criteria: studies of adjunctive treatment of bipolar depression were included if they were randomized and double-blind, had a placebo arm, and included a clearly defined outcome measure. Given limited data on the efficacy of primary or adjunctive treatments (ie, there are no gold standard effective treatments), direct comparisons without placebo were not included, and there are only a handful of such studies in any case.Reference Gijsman, Geddes, Rendell, Nolen and Goodwin14, Reference Spanemberg, Massuda and Lovato15
The discussion that follows organizes treatments by medication class. The evidence for the efficacy of each medication is then discussed. In addition to efficacy, it is also necessary to examine the tolerability of the medications in the specific studies of bipolar depression. Therefore we also briefly discuss tolerability if the medication was shown to be effective.
Atypical Antipsychotics
Quetiapine
Efficacy
Quetiapine is one of only two drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of bipolar depression. Five studies of quetiapine met our primary search criteria (see Table 1).Reference Calabrese, Keck and Macfadden16–Reference Young and McElroy20 The five studies involved a total of 2539 participants on quetiapine or placebo, and all five studies found that quetiapine significantly reduced the symptoms of depression as measured by the Montgomery–Åsberg Depression Rating Scale (MADRS). In three of the studies, the dose of quetiapine was separated into two arms, 300 mg and 600 mg.Reference Calabrese, Keck and Macfadden16, Reference Thase, Macfadden and Weisler17, Reference Young and McElroy20 There were no significant differences in treatment efficacy between the two doses, suggesting that relatively lower doses of quetiapine are effective and perhaps better tolerated for treating depression. One limitation of most of these studies when drawing conclusions about bipolar I was the inclusion of bipolar II participants. One-half to one-third of the participants in the Young etal. Reference Young and McElroy20 and Thase etal.Reference Thase, Macfadden and Weisler17 studies had a diagnosis of bipolar II, and it was not possible to determine the percentage of participants with bipolar II in Calabrese etal.Reference Calabrese, Keck and Macfadden16 and McElroy etal.Reference McElroy, Weisler and Chang18 (see Table 1).
Table 1 Studies of primary medications for the treatment of bipolar depression
*The number of participants with bipolar II in each group is unavailable.
MADRS: Montgomery–Åsberg Depression Rating Scale.
HAM-D: Hamilton Rating Scale for Depression.
Vieta etal.Reference Vieta, Locklear and Gunther6 performed a meta-analysis of the data from the five studies discussed above.Reference Calabrese, Keck and Macfadden16–Reference Young and McElroy20 They looked at pooled responses to both 300 mg and 600 mg doses. Both dosing groups showed significant decreases in MADRS scores and significant rates of response and remission compared to the placebo group. There was very little difference in these measures between the 300 mg and 600 mg dose groups, further supporting the notion that lower doses of quetiapine are appropriate for bipolar depression.
Tolerability
The most common side effects of quetiapine reported included sedation, somnolence, dry mouth, and dizziness.Reference Calabrese, Keck and Macfadden16–Reference Young and McElroy20 While all the studies showed higher discontinuation rates in the quetiapine group, this was not statistically significant when the data were combined by Vieta etal.Reference Vieta, Locklear and Gunther6 in their meta-analyses. Other than these nuisance side effects, the major concerns were potential weight gain and metabolic syndrome. All five studies found increased weight gain in the quetiapine group compared to the placebo group, which was further found to be dose-related in studies using multiple doses.Reference Calabrese, Keck and Macfadden16–Reference Young and McElroy20 The weight gain data from all five studies was combined in a meta-analysis by De Fruyte etal.,Reference De Fruyt, Deschepper and Audenaert8 and showed a weighted mean increase of 1.1 kg in the 300 mg dose and 1.35 kg in the 600 mg dose. All studies also found significant increases in fasting serum glucose that was dose-related in studies using multiple doses. Two of three studies that reported triglyceride levels found increases in the quetiapine group.Reference McElroy, Weisler and Chang18–Reference Young and McElroy20
Olanzapine and olanzapine/fluoxetine
Efficacy
Two studies of olanzapine or olanzapine/fluoxetine met our primary search criteria (see Table 1). Olanzapine/fluoxetine was the first medication approved for the treatment of bipolar depression in 2003.Reference Tohen, Vieta and Calabrese21 Tohen etal.Reference Tohen, Vieta and Calabrese21, Reference Tohen, McDonnell and Case22 examined olanzapine alone at doses ranging from 5 mg to 20 mg in 1261 participants. Both studies showed a significant improvement in MADRS scores compared to the placebo group. Tohen etal.Reference Tohen, Vieta and Calabrese21 examined olanzapine/fluoxetine and found that it showed significant improvement in MADRS compared to placebo and olanzapine alone.
Tolerability
Somnolence, increased appetite, headache, dry mouth, sedation, and diarrhea were common side effects in the olanzapine and olanzapine/fluoxetine groups.Reference Tohen, Vieta and Calabrese21, Reference Tohen, McDonnell and Case22 Tohen etal.Reference Tohen, Vieta and Calabrese21, Reference Tohen, McDonnell and Case22 found significantly greater weight gain (>7% of body weight) in the olanzapine and olanzapine/fluoxetine groups compared to placebo. Both studies also found increases in fasting glucose and cholesterol in the olanzapine and olanzapine/fluoxetine groups compared to placebo. There were no differences in these measures between the olanzapine and olanzapine/fluoxetine groups.Reference Tohen, Vieta and Calabrese21 One concern about using antidepressants is treatment-emergent mania, but Tohen etal.Reference Tohen, Vieta and Calabrese21 found no differences in emergent mania between the olanzapine/fluoxetine and placebo groups.
Aripiprazole
Efficacy
Two studies of aripiprazole met our primary inclusion criteria, and both studies were published in Thase etal.Reference Thase, Jonas and Khan23 (see Table 1). These studies had 374 and 375 participants, respectively. Neither study found any significant effect of aripiprazole on the primary outcome measure (decrease of MADRS scores) at 8 weeks. Aripiprazole was titrated over 6 weeks to 15 mg to 30 mg based on doses used to successfully treat mania. Because the aripiprazole group separated from the placebo group at the 5 week time point in both studies, the authors suggested that the final dosing may have been too high. Participants in the aripiprazole groups had higher levels of akathisia, extrapyramidal symptoms, insomnia, nausea, and dry mouth compared to the placebo groups. There were no differences in weight gain, fasting glucose, or lipid profile in the aripiprazole group.
Ziprasidone
Efficacy
Two studies of ziprasidone met our primary inclusion criteria, and both studies were published in Lombardo etal.Reference Lombardo, Sachs, Kolluri, Kremer and Yang24 (see Table 1). The first studied examined 165 participants on low-dose (40–80 mg) ziprasidone and 171 participants on high-dose ziprasidone (120–160 mg), and the second studied examined 185 participants on doses of 40–160 mg. Neither study found a significant effect of ziprasidone on the primary outcome measure (decrease of MADRS scores).
The only other published study that examined ziprasidone in bipolar depression was as an adjunct in patients who were already taking lamotrigine, lithium, or divalproex (see Table 2).Reference Sachs, Ice and Chappell25 In this study, Sachs etal.Reference Sachs, Ice and Chappell25 examined ziprasidone in doses of up to 160 mg in 147 participants. The treatment group failed to separate from the placebo group in the primary and secondary outcomes.
Table 2 Studies of adjunctive medications for the treatment of bipolar depression
*The number of participants with bipolar II in each group is unavailable.
MADRS: Montgomery–Åsberg Depression Rating Scale.
HAM-D: Hamilton Rating Scale for Depression.
Mood Stabilizers
Lamotrigine
Efficacy
The five studies of lamotrigine that met our primary inclusion criteria were all published in the same article by Calabrese etal.Reference Calabrese, Huffman and White26 (see Table 1), although one of the studies in that article was initially published by itself.Reference Calabrese, Bowden and Sachs27 The total number of participants in all five studies was 1072, making lamotrigine the second most studied treatment for bipolar depression behind quetiapine. In all five studies, the primary outcome measure, change in either the Hamilton Rating Scale for Depression (HAM-D) or MADRS, did not differ significantly from placebo. Shortly after the original studies were published, a meta-analysis was performed that combined data from the 5 studies.Reference Geddes, Calabrese and Goodwin7 The pooled data showed that lamotrigine participants did have increased rates of response compared to those on placebo, but the effect was relatively small. Geddes etal.Reference Geddes, Calabrese and Goodwin7 then stratified the patients by symptom severity using HAM-D scores. They found that lamotrigine had a large positive treatment effect in participants with severe depression (HAM-D ⩾ 24), but had no effect in participants with moderate depression (HAM-D < 24). However this finding may be explained by lower rates of placebo response in severe depression rather than as increased effectiveness of lamotrigine in more severe depression. A second meta-analysis of this data by Vieta etal.Reference Vieta, Locklear and Gunther6 also found a significant reduction in depressive symptoms in the lamotrigine group.
One additional study met our secondary inclusion criteria (see Table 2). Van der Loos etal.Reference van der Loos, Mulder and Hartong28 studied lamotrigine as an adjunctive treatment with lithium in 124 participants and found that it significantly decreased depressive symptoms compared to adjunctive placebo. Finally, although it did not meet our initial search criteria because of the lack of a placebo group, a double-blind direct comparison of olanzapine/fluoxetine and lamotrigine is worth mentioning.Reference Brown, McElroy and Keck29 Participants in the olanzapine/fluoxetine group showed greater improvement in the clinical global impression (CGI) scale, the primary outcome measure, compared to the lamotrigine group.
Tolerability
Overall, lamotrigine was well tolerated in all 5 studies.Reference Calabrese, Huffman and White26 Headache, nausea, nonserious rash, dry mouth, dizziness, and diarrhea were the most common side effects reported. There were no reports of any serious rash in the studies. Lamotrigine did not increase the incidence of manic episodes compared with placebo.
Divalproex
Efficacy
Three smaller studies of divalproex have been published that met our primary inclusion criteria (see Table 1).Reference Davis, Bartolucci and Petty30–Reference Muzina, Gao and Kemp32 The three studies included a total of 97 participants on divalproex or placebo. All three studies showed significant improvement in their primary outcome measures (decrease in HAM-D or MADRS) compared to placebo. Two of these studies were limited by their inclusion of participants with bipolar II: Muzina etal.Reference Muzina, Gao and Kemp32 included an unspecified number of bipolar II participants in each group, and in Ghaemi etal.,Reference Ghaemi, Gilmer and Goldberg31 participants with bipolar II made up half of each group. Bond etal.Reference Bond, Lam and Yatham10 published a meta-analysis that included data from the Davis etal.Reference Davis, Bartolucci and Petty30 and Ghaemi etal.Reference Ghaemi, Gilmer and Goldberg31 studies, along with data from 2 unpublished placebo-controlled trials of divalproex with a total a total of 97 participants in the 4 studies. They found that the rates of response and remission were significantly greater in the divalproex group.
Tolerability
Overall, divalproex was well tolerated in these studies with little difference in participant dropout compared to placebo. The most commonly seen side effects of divalproex were sedation, changes in appetite, myalgias/weakness, dizziness, fatigue, and dry mouth.Reference Davis, Bartolucci and Petty30–Reference Muzina, Gao and Kemp32
Lithium
In the late 1960s when lithium was being introduced as a treatment for mania in the U.S., there was also an interest in its effectiveness in treating depression. This resulted in almost a dozen publications in the following decade. Yetall of these studies had significant limitations, and none met our primary or secondary search criteria. Baron etal.,Reference Baron, Gershon and Rudy33 Goodwin etal.,Reference Goodwin, Murphy and Bunney34 and Noyes etal.Reference Noyes, Dempsey, Blum and Cavanaugh35 included placebo arms but were limited by the inclusion of only 6, 13, and 6 participants with bipolar disorder, respectively. The largest of these early research studies were those by Stokes etal.Reference Stokes, Stoll, Shamoian and Patton36 and Goodwin etal.,Reference Goodwin, Murphy, Dunner and Bunney37 with larger sample sizes of 38 and 40 participants with bipolar I, respectively. Goodwin etal.Reference Goodwin, Murphy, Dunner and Bunney37 found lithium to be effective in reducing depressive symptoms, while Stokes etal.Reference Stokes, Stoll, Shamoian and Patton36 found no change from placebo. Yet the interpretation of both studies was severely limited by the rapid alteration between placebo and lithium: 1 week in the Stokes etal.Reference Stokes, Stoll, Shamoian and Patton36 study and an average of 1.5 weeks in the Goodwin etal.Reference Goodwin, Murphy, Dunner and Bunney37 study. Therefore, there was only one study of lithium as monotherapy that met our primary search criteria. The Young etal.Reference Young and McElroy20 study of quetiapine mentioned previously included a lithium comparison arm (see Table 1). Lithium did not differ in reducing the symptoms of depression compared to placebo. There have been several placebo-controlled studies of adjunctive medications added to lithium that met our secondary search criteria (mostly antidepressants, see Table 2),Reference Lombardo, Sachs, Kolluri, Kremer and Yang24, Reference Sachs, Ice and Chappell25, Reference Cohn, Collins, Ashbrook and Wernicke38–Reference Calabrese, Ketter and Youakim41 2 of which were discussed above and 4 are discussed below.
Levetiracetam
Efficacy
Levetiracetam is a newer anti-epileptic medication that was studied in bipolar depression in one small study that met our secondary search criteria. Saricicek etal.Reference Saricicek, Maloney and Muralidharan42 studied levetiracetam as an adjunctive treatment in participants who were taking mood stabilizers, antidepressants, or antipsychotics (see Table 2). The treatment group failed to separate from the placebo group in the primary outcome, which was change in HAM-D scores.
Antidepressants
Efficacy
Given the controversy surrounding the use of antidepressants in bipolar disorder, it is surprising how little controlled research addresses the question. Only one study of antidepressant monotherapy met our initial search criteria. McElroy etal.,Reference McElroy, Weisler and Chang18 in the study of quetiapine mentioned previously, used paroxetine as a comparison treatment arm. Paroxetine did not differ compared to placebo in reducing the symptoms of depression. The major limitation to this study was the low dose (20 mg) of paroxetine used.
There have been four studies using antidepressants as adjuncts to mood stabilizers or antipsychotics in the acute treatment of bipolar depression that met our secondary search criteria. One study already discussed was the use of fluoxetine with olanzapine.Reference Tohen, Vieta and Calabrese21 Sachs etal.Reference Sachs, Nierenberg and Calabrese40 studied paroxetine and buproprion SR as adjunctive treatments in 366 participants taking a mood stabilizer or atypical antipsychotic. Neither medication differed from placebo in reducing symptoms of depression. Nemeroff etal.Reference Nemeroff, Evans and Gyulai39 studied paroxetine and imipramine as adjunctive treatment in 112 participants taking lithium plus either carbamazepine or divalproex. Once again, neither medication differed from placebo. However, a post-hoc analysis of the data revealed that paroxetine was effective when the lithium level was subtherapeutic (<0.8), suggesting a possible role as an adjunct if patients are unable tolerate higher lithium doses. These two studies used adequate dosing for all four antidepressants and therefore ruled out inadequate dosing as an explanation for their lack of efficacy. Last, Cohn etal.Reference Cohn, Collins, Ashbrook and Wernicke38 examined imipramine and fluoxetine in 89 participants. Concomitant medications were not clearly stated, and a significant percentage of the participants were also on lithium; hence the study met our secondary inclusion criteria. Both medications significantly reduced depressive symptoms as measured by the HAM-D compared to placebo, and fluoxetine also significantly reduced symptoms compared to imipramine.
Two important meta-analyses of antidepressant efficacy in bipolar depression have used data from the above studies along with direct comparison studies without a placebo arm.Reference Sidor and MacQueen13, Reference Gijsman, Geddes, Rendell, Nolen and Goodwin14 The initial meta-analyses found that antidepressants were moderately effective in bipolar depression.Reference Gijsman, Geddes, Rendell, Nolen and Goodwin14 However, this meta-analysis was criticized for including olanzapine monotherapy as a placebo and using a disproportionate inclusion of subjects from one study.Reference Ghaemi and Goodwin43 A latter meta-analysis by Sidor and MacQueen,Reference Sidor and MacQueen13 which included data from more recent studies, found no significant treatment effect of antidepressants. The newer antidepressants, desvenlafaxine and duloxetine, were not included in the above trials or meta-analyses, so their efficacy and potential for inducing mania are unknown.
Tolerability
One concern with using antidepressants in bipolar disorder is the risk of inducing mania, also known as switching. However, the 5 studies of antidepressants mentioned previously all found small rates of switching.Reference McElroy, Weisler and Chang18, Reference Tohen, Vieta and Calabrese21, Reference Cohn, Collins, Ashbrook and Wernicke38–Reference Sachs, Nierenberg and Calabrese40 Sidor and MacQueenReference Sidor and MacQueen13 performed a meta-analysis on clinical trials of antidepressants in bipolar disorder, and also found no evidence that antidepressants induce mania. Broader reviews outside of these controlled studies have also looked at the question and found mixed results. Goldberg and TrumanReference Goldberg and Truman44 and Tondo etal.Reference Tondo, Vazquez and Baldessarini45 found relatively high rates of switching. Patients who had tried multiple antidepressants, had a family history of bipolar disorder, and were on tricyclic antidepressants had the highest risk of switching. Licht etal.Reference Licht, Gijsman, Nolen and Angst46 found that mood stabilizers protected against the induction of mania.
Other Treatments
Modafinil/armodafinil
Efficacy
Two studies examining the stimulants modafinil and armodafinil met our secondary search criteria (see Table 2).Reference Calabrese, Ketter and Youakim41, Reference Frye, Grunze and Suppes47 Frye etal.Reference Frye, Grunze and Suppes47 found that modafinil significantly reduced depressive symptoms in 41 participants with bipolar I or II disorder compared to the placebo group. Calabrese etal.Reference Calabrese, Ketter and Youakim41 examined armodafinil in 128 participants with bipolar I disorder and also found a significant reduction in depressive symptoms compared to placebo. In these studies, modafinil was added to a mood stabilizer, while over half of the participants were also on an antidepressant.
Tolerability
Neither modafinil nor armodafinil was associated with increased incidence of mania. Nearly 70% of participants in the modafinil and armodafinil group were able to complete the study. Headache, nausea, and insomnia were the most common side effects reported in the treatment groups.
Omega-3 fatty acids
Efficacy
Two small studies of omega-3 fatty acids as adjunctive treatment for bipolar depression met our secondary search criteria (see Table 2).Reference Stoll, Severus and Freeman48, Reference Keck, Mintz and McElroy49 The findings in these studies were mixed, with Stoll etal.Reference Stoll, Severus and Freeman48 finding some benefit in depression, while Keck etal.Reference Keck, Mintz and McElroy49 found no benefit in the treatment group. The studies used relatively high doses of omega-3 fatty acids: 9.6 g per day in Stoll etal.Reference Stoll, Severus and Freeman48 and 6 g per day in Keck etal.Reference Keck, Mintz and McElroy49
Tolerability
Side effects were mild in both studies, with gastrointestinal symptoms being most common, and no differences were found in bleeding time in the Keck etal.Reference Keck, Mintz and McElroy49 study (bleeding times were not reported in the Stoll etal.Reference Stoll, Severus and Freeman48 study).
Conclusion
The medication with the most evidence for efficacy in bipolar depression is quetiapine. Quetiapine has been studied in the greatest number of participants in five studies, which all showed significantly greater efficacy compared to placebo in reducing symptoms of depression.Reference Calabrese, Keck and Macfadden16–Reference Young and McElroy20 Quetiapine had only mild nuisance side effects, but did have significant side effects of weight gain and increased fasting serum glucose levels. In contrast, lamotrigine also had five studies in bipolar depression, but all five were negative.Reference Calabrese, Huffman and White26 Pooled data from all five lamotrigine studies did show significant efficacy, especially among participants with more severe depression.Reference Vieta, Locklear and Gunther6, Reference Geddes, Calabrese and Goodwin7 Outside of quetiapine and lamotrigine, the number of studies of primary treatment of bipolar depression and number of participants in those studies diminishes greatly. Two studies of olanzapine and olanzapine/fluoxetine and three small studies of divalproex showed significant efficacy in treating bipolar depression.Reference Tohen, Vieta and Calabrese21, Reference Tohen, McDonnell and Case22, Reference Davis, Bartolucci and Petty30–Reference Muzina, Gao and Kemp32 Two studies each of aripiprazole and ziprasidone found no differences compared to placebo.Reference Thase, Jonas and Khan23–Reference Sachs, Ice and Chappell25 Early research on lithium in bipolar depression had significant methodological flaws, and only one study of lithium met our primary search criteria. That study included lithium as direct comparison of quetiapine (along with placebo) and did not find any effect.Reference Young and McElroy20 Antidepressants also had very limited data as primary treatments of bipolar depression, with only one study of paroxetine, again in a comparison arm with quetiapine, showing no efficacy.Reference McElroy, Weisler and Chang18
Given the limited data, it is difficult to directly compare the 5 medications that showed positive primary treatment effects in depression: quetiapine, lamotrigine, olanzapine, olanzapine/fluoxetine, and divalproex. Three recent meta-analyses have included data from the majority of treatment studies that were discussed in this review.Reference Van Lieshout and MacQueen4, Reference Vieta, Locklear and Gunther6, Reference De Fruyt, Deschepper and Audenaert8 Not surprisingly, the studies with the fewest number of subjects often had the greatest relative risk reduction. Given that these small studies showed the greatest variance among subjects, this observation cannot be taken as evidence that they are more effective. Instead, we are left with a qualitative assessment that quetiapine has the most evidence of efficacy in bipolar depression followed by olanzapine. Head-to-head trials, which include a placebo arm, are needed to appropriately test differences among interventions.
In terms of adjunctive treatments for bipolar depression, the main class of medications studied was antidepressants. These studies reported mixed results for a variety of antidepressants, but the majority found no differences compared to placebo. The most recent and inclusive meta-analysis of adjunctive antidepressant treatment found they have no efficacy.Reference Sidor and MacQueen13 Outside of antidepressants, there was one positive adjunctive study of lamotrigine, omega-3 fatty acids, modafinil, and armodafinil, while there was one negative trial of omega-3 fatty acids, ziprasidone, and levetiracetam.Reference Sachs, Ice and Chappell25, Reference van der Loos, Mulder and Hartong28, Reference Calabrese, Ketter and Youakim41, Reference Saricicek, Maloney and Muralidharan42, Reference Frye, Grunze and Suppes47–Reference Keck, Mintz and McElroy49
The studies discussed in this review were all short term and do not address questions about maintenance treatment of bipolar disorder. While long-term maintenance treatment of bipolar disorder is a large topic that falls outside the scope of this review, two studies that bridge the gap between acute and maintenance treatment are worth mentioning. Altshuler etal.Reference Altshuler, Post and Hellemann50 examined three different adjunctive antidepressants in bipolar depression. They then followed 83 responders for one year while continuing the double-blind treatment assignments and found that 53% of the participants maintained remission. Ghaemi etal.Reference Ghaemi, Ostacher and El-Mallakh51 followed 70 responders from the Systematic Treatment Enhancement Program for Bipolar Depression (STEP-BP) who were on mood stabilizers and adjunctive antidepressants. Subjects were openly randomized to either continue or discontinue their antidepressants for 1 to 3 years. There were no differences in remission rates in the two groups, suggesting no benefit to long-term antidepressant continuation.
Treating depression in patients with bipolar I disorder remains a clinical challenge. Unlike a decade and a half ago, there is now more quality research to guide decisions. Yet only a few medications have received adequate study as primary treatments. Larger, well-controlled studies of traditional mood stabilizers are needed: lithium, divalproex, and carbamazepine. In addition, the role, if any, of antidepressants remains controversial, and more research is needed here as well. Finally, for all treatments, many patients do not respond to monotherapy for bipolar depression, so novel approaches are sorely needed for this serious public health problem.
Disclosures
Michael Cerullo does not have anything to disclose. Stephen Strakowski has the following disclosures: University of Nebraska, consultant, consulting fees; Eli Lilly, research support; Janssen/J&J, research support; AstraZeneca, research support; Sumatomo, research support; Pfizer, research support.
