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Pros and Cons of Approved Therapies for Bipolar Depression and Ongoing Unmet Needs

Susan L. McElroy, MD

Department of Psychiatry and Neuroscience, University of Cincinnati College of Medicine, and the Lindner Center of HOPE, Mason, Ohio

AV 1. Efficacy and Tolerability of Olanzapine-Fluoxetine Combination for Bipolar Depression (01:15)

Data from Tohen et al1
*P<.001 vs placebo
**P=.02 vs placebo

Only 3 agents have been approved by the FDA for the treatment of bipolar depression. These medications are olanzapine-fluoxetine combination, quetiapine, and lurasidone. No studies have been conducted comparing these approved treatments to each other, but the results of placebo-controlled trials of each of these agents have shown comparable efficacy rates but different side effect profiles. Thus, knowledge of the pros and cons of each treatment is important in order to select the best agent for individual patients.

Olanzapine-Fluoxetine Combination

In 2003, olanzapine-fluoxetine combination became the first agent approved by the FDA specifically for the treatment of acute bipolar depression. Tohen and colleagues1 found the combination of olanzapine and fluoxetine to be more efficacious for treating bipolar depression than placebo or olanzapine alone (AV 1). Mean reductions in MADRS total scores were significantly greater compared with placebo for both olanzapine-fluoxetine and olanzapine throughout the study (P < .001), and from weeks 4 to 8, olanzapine-fluoxetine produced significantly greater MADRS score reductions than olanzapine (P < .02). The combination did not increase the risk of developing manic symptoms over that of either olanzapine or placebo. Another study2 found olanzapine-fluoxetine to be significantly more effective than lamotrigine at reducing symptoms of bipolar depression as measured by the CGI-S (P = .002).

AV 2. Efficacy and Tolerability of Quetiapine for Bipolar Depression (01:00)

Data from Calabrese et al3
*P<.001
**P<.05

Although the olanzapine-fluoxetine combination has been found to have superior efficacy compared with olanzapine monotherapy, lamotrigine, and placebo, it has a side effect profile that limits its use in some patients. Olanzapine-fluoxetine has been found to be associated with a weight gain ≥ 7% of body weight as well as other indications of metabolic dysfunction, such as increases in triglycerides and cholesterol levels.1,2 Because of the metabolic profile of this drug combination, clinicians must assess the potential risks of this treatment for patients who are overweight or have pre-existing metabolic abnormalities.

Quetiapine

Quetiapine received FDA approval for the treatment of bipolar depression in 2006. The BOLDER I and II studies3,4 found 300 mg/d and 600 mg/d of quetiapine to be more efficacious than placebo for reducing bipolar depression, according to mean MADRS scores (P ≤ .001; AV 2). The EMBOLDEN I study5 also found that quetiapine 300 mg/d and 600 mg/d improved MADRS scores significantly more than placebo (P < .05), and quetiapine 600 mg/d improved MADRS scores significantly more than lithium (P = .013). The EMBOLDEN II study6 found both doses of quetiapine to be more efficacious than placebo according to mean MADRS score reductions (P < .001) and also found 300 mg/d and 600 mg/d doses of quetiapine to be more efficacious than paroxetine (P = .017 and P = .012, respectively).

AV 3. Adjusting Treatment for a Patient With Bipolar Depression (03:37)

 

The most frequently reported adverse events related to quetiapine treatment are dry mouth, sedation, and somnolence.3–6 Sedation and somnolence have been found to lead to treatment discontinuation,3,4 but, with bedtime dosing, these side effects may be reduced and may be useful for patients who have sleep disturbances (AV 3).3 Patients in the BOLDER studies3,4 experienced modest weight gain, but no patient discontinued treatment because of this side effect. Furthermore, no significant changes in fasting glucose were observed.

AV 4. Efficacy and Tolerability of Lurasidone for Bipolar Depression (00:54)

Data from Loebel et al8 and McElroy et al9 *P<.001

Lurasidone

Lurasidone received FDA approval for treating bipolar depression in 2013 based on the results of 2 clinical trials.7,8 Loebel et al7 found that 20 mg/d to 120 mg/d of lurasidone added to either lithium or valproate led to significantly greater reduction in MADRS scores compared with placebo (P = .005). In the lurasidone group, 57% responded to treatment and 50% achieved remission, versus 42% and 35%, respectively, with placebo. In the second study,8 lurasidone monotherapy at both 20 mg/d to 60 mg/d and 80 mg/d to 120 mg/d led to significantly greater reduction in MADRS scores compared with placebo (P < .001; AV 4).8,9

In both clinical trials,7,8 lurasidone was generally well tolerated, with nausea and akathisia being the most commonly reported adverse events. The metabolic effects of lurasidone were examined in a further study,9 which found no significant differences in weight change, cholesterol, LDL, triglycerides, glucose, insulin, or HOMA-IR between either lurasidone monotherapy or adjunctive therapy and placebo.

More

Unmet Needs

Patients with bipolar disorder spend considerably more time depressed than manic or hypomanic,10,11 and yet only 3 FDA-approved treatments are available for bipolar depression. Comparator trials among the approved treatments are needed, as well as long-term studies. Remarkably few trials have been conducted to investigate new treatments for bipolar depression, and, among the agents that have been studied, many have failed to show any benefit.12 Even the approved treatments have response rates of approximately 50% to 70%, meaning that sizeable minorities of patients may not benefit from these treatments. Furthermore, prescribing patterns for bipolar disorder indicate that, in clinical practice, patients frequently receive treatments such as antidepressants that have not been found to be effective and are not recommended by treatment guidelines.13

Conclusion

Many unmet needs still exist in the treatment of bipolar depression, but trials are continually being conducted to find new and better treatments. The approved therapies that are currently available—olanzapine-fluoxetine combination, quetiapine, and lurasidone—are effective for alleviating bipolar depression in many patients. These agents appear to have comparable efficacy but different side effect profiles. Clinicians, therefore, must balance the benefits of these treatments against any potential adverse events on a patient-by-patient basis.

Clinical Points

  • Consider the side effect profiles of available treatments when selecting agents for bipolar depression
  • Avoid olanzapine-fluoxetine combination in patients who are overweight or susceptible to metabolic disturbances
  • Consider administering quetiapine at bedtime to avoid problems with sedation or somnolence

Drug Names

lamotrigine (Lamictal and others), lurasidone (Latuda), olanzapine-fluoxetine (Symbyax), paroxetine (Paxil, Pexeva, and others), quetiapine (Seroquel and others)

Abbreviations

BOLDER = BipOlar DEpRession; CGI-S = Clinical Global Impression–Severity; EMBOLDEN = Efficacy of Monotherapy SEROQUEL in BipOLar DEpressioN; FDA = US Food and Drug Administration; HOMA-IR = homeostasis model of assessment–insulin resistance; LDL = low-density lipoprotein; MADRS = Montgomery-Asberg Depression Rating Scale

References

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  2. 2. Brown EB, McElroy SL, Keck PE Jr, et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry. 2006;67(7):1025–1033. Abstract
  3. 3. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351–1360. PubMed
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