Journal of Affective Disorders 169 S1 (2014) S34–S44

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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Review

Managing the side effects associated with commonly used treatments for bipolar depression David E. Kempa,* a

Department of Psychiatry, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA

article

info

Article history: Received 15 May 2014 Received in revised form 8 August 2014 Accepted 3 September 2014 Keywords: Bipolar disorder Depression Pharmacotherapy Side effects

abstract

Background: The most commonly used pharmacologic therapies for bipolar depression are mood stabilizers, atypical antipsychotics, and antidepressants. This paper reviews common side effects associated with these medications and provides recommendations for managing adverse medication effects in clinical practice. Methods: Narrative review based on literature searches of Medline and evidence-based treatment guidelines for agents that have been approved by the US Food and Drug Administration and/or are commonly used to treat bipolar depression. Results: Side effects of bipolar depression pharmacotherapies are common and vary by medication, with weight gain, metabolic dysregulation, sedation/somnolence, and akathisia among those observed most frequently. These adverse events (weight gain and sedation/somnolence, in particular) negatively affect treatment adherence in patients with bipolar disorder. Furthermore, endocrine and metabolic comorbidities, weight gain, and obesity may reduce the likelihood of positive clinical responses to pharmacologic therapies. Clinicians may consider switching patients to bipolar depression medication(s) with a lower propensity for sedation or adverse metabolic effects. Lifestyle modification (e.g., dietary changes, exercise) is an important component in the treatment of weight gain/obesity, dyslipidemia, hypertension, and hyperglycemia; in addition, a wide range of medications are available as therapeutic options for patients in whom non-pharmacologic management strategies are insufficient. The use of adjunctive medication may also reduce treatment-related sedation and somnolence. Limitations: The selection of relevant studies from the literature search relied primarily on the author’s expertise in the area of bipolar depression and knowledge of the issues addressed. Conclusions: Successful treatment of bipolar depression extends beyond managing mood symptoms to also monitoring adverse medication events and managing associated medical disorders. © 2014 Elsevier B.V. All rights reserved.

Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S35 2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S35 3. Atypical antipsychotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S35 3.1 Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S35 3.2 Olanzapine-fluoxetine combination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36 3.3 Lurasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36 4. Mood stabilizers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36 5. Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37 5.1 Selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37 5.2 Other antidepressants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37 6. Managing adverse effects of pharmacotherapy for bipolar depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37 6.1 Weight and metabolic issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38 6.2 Sedation/somnolence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39 6.3 Cardiovascular issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39 6.4 Other adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S40 7. Limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S40 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S40

* Corresponding author at: Case Western Reserve University, 10524 Euclid Avenue, 12th Floor, Cleveland, OH 44106, USA. Tel.: +1 216 844 2865; fax: +1 216 844 2875. E-mail address: [email protected] (D.E. Kemp). 0165-0327/© 2014 Elsevier B.V. All rights reserved.



D.E. Kemp / Journal of Affective Disorders 169 S1 (2014) S34–S44

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Disclosures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41 Funding/support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41 Contributor’s statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41

1. Introduction

2. Methods

As reviewed by Shefali Miller, MD, and colleagues in this supplement, there is substantial evidence demonstrating that bipolar disorder, particularly during the more pervasive depressive phase, is associated with significant disability (Kupka et al., 2007; Sanchez-Moreno et al., 2009). This functional impairment is further compounded by the substantial number of medical comorbidities that are seen in bipolar disorder patients (Kemp et al., 2013). In particular, it has been well documented that there is a relationship between bipolar disorder and certain metabolic abnormalities, including obesity, dyslipidemia, and insulin resistance (Kemp and Fan, 2012). These interrelated symptoms — abdominal obesity, elevated triglyceride levels, decreased high-density lipoprotein cholesterol levels, hypertension, and hyperglycemia — are collectively known as metabolic syndrome and are associated with increased risk for the development of cardiovascular disease and type 2 diabetes (Grundy et al., 2004). The increased prevalence of metabolic syndrome and obesity in patients with bipolar disorder, as high as twice the rate observed in the general population, has been theorized to involve lifestyle factors (e.g., poor diet, lack of exercise, smoking), lack of proper healthcare resources, common underlying neurobiological processes, and adverse effects of commonly used treatments (Calkin et al., 2013; Correll et al., 2010; Ford et al., 2002; McIntyre et al., 2012; Salvi et al., 2008; Sicras et al., 2008; Vancampfort et al., 2013; Vuksan-Cusa et al., 2010). Two of the three treatments that are currently approved for treating bipolar depression (olanzapine [in combination with fluoxetine, OFC] and quetiapine) are among the atypical anti­ psychotics known to cause significant weight gain and metabolic dysregulation, as well as other tolerability issues, such as sedation/ somnolence (Frye, 2011). Lurasidone, the most recent (third) atypical antipsychotic approved to treat bipolar depression, appears to have a lower propensity for weight gain and metabolic adverse effects than the two older agents; however, akathisia has been commonly reported (Latuda® [lurasidone hydrochloride] tablets, for oral use, 2013; Kane et al., 2009). Potentially serious safety concerns are also associated with traditional mood stabilizers, including lithium-related toxicity, valproate-associated reproductive abnormalities, and rare but serious lamotrigineinduced rash (Frye, 2011). The limited number of approved treatments, the safety and tolerability profiles of the available medications, and the medical comorbidities and profile of risk factors unique to each individual patient all make the management of bipolar depression a challenging task. The objective of this article is to provide an overview of the tolerability and safety issues associated with bipolar depression medications and to discuss strategies for effectively managing them. By increasing their familiarity with the tolerability and safety profiles of these drugs, clinicians may be able to more efficiently identify the most appropriate treatment regimens for individual patients, provide proactive management strategies to help improve adherence and treatment outcomes, and reduce the potential for serious long-term medical complications and comorbidities.

Evidence-based treatment guidelines for bipolar disorder were reviewed to identify agents that have been approved by the US Food and Drug Administration (FDA) and/or are commonly used for bipolar depression. Searches of the PubMed database were then conducted for clinical trials and other articles on the use of these agents to treat patients with bipolar depression. In addition, prescribing information for these medications was consulted, and ongoing trials of products in development were identified using ClinicalTrials.gov. 3. Atypical antipsychotics Antipsychotic agents were developed for the treatment of schizophrenia and now are also widely used for mood disorders, including bipolar disorder and treatment-resistant depression. Most of the 10 atypical antipsychotics originally indicated for the treatment of schizophrenia have demonstrated efficacy in manic or mixed episodes associated with bipolar disorder, and 3 (quetiapine monotherapy, OFC, and lurasidone monotherapy or adjunctive to mood stabilizers) are approved to treat depressive episodes associated with bipolar disorder (Latuda® [lurasidone hydrochloride] tablets, for oral use, 2013; Seroquel® [quetiapine fumarate] tablets, 2013; Symbyax® [olanzapine and fluoxetine hydrochloride] capsule for oral use, 2012; Yatham et al., 2013). Common areas of concern across atypical antipsychotics include the potential for treatmentemergent weight gain and metabolic dysregulation, sedation, and extrapyramidal symptoms (Henderson, 2007; Henderson et al., 2006; McIntyre and Konarski, 2005; Newcomer, 2007). 3.1 Quetiapine Quetiapine at a daily dose of 300 mg or 600 mg has consistently demonstrated efficacy for treating acute episodes of bipolar depression (Calabrese et al., 2005; McElroy et al., 2010; Suppes et al., 2010; Thase et al., 2006; Young et al., 2010). Sedation/ somnolence has been shown to develop in approximately half of patients enrolled in short-term studies of bipolar depression (Calabrese et al., 2005; McElroy et al., 2010; Suppes et al., 2010; Thase et al., 2006; Young et al., 2010) and is the adverse event that most often led to premature treatment discontinuation (Calabrese et al., 2005; Suppes et al., 2010; Thase et al., 2006). Quetiapine is also associated with weight gain (albeit to a lesser extent than OFC) in patients with bipolar depression. Mean weight change was 1–2 kg during short-term treatment and 0–1 kg during long-term treatment (Calabrese et al., 2005; McElroy et al., 2010; Suppes et al., 2010; Thase et al., 2006; Young et al., 2010; Young et al., 2012). Clinically significant weight gain (≥7% of baseline weight) occurred in 4–11% of bipolar depression patients treated with quetiapine, compared with 1–4% of patients who received placebo (Table 1) (Calabrese et al., 2005; McElroy et al., 2010; Suppes et al., 2010; Thase et al., 2006; Young et al., 2010; Young et al., 2012). However, mean changes in lipid and glucose levels during treatment with quetiapine were generally small and similar

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D.E. Kemp / Journal of Affective Disorders 169 S1 (2014) S34–S44

Table 1 Proportion of patients* with clinically relevant changes† during short-term (8-12 weeks) and long-term (48-52 weeks) treatment with quetiapine and olanzapine-fluoxetine combination (OFC) for bipolar depression.

Weight Gain ≥7% Short- term

Long- term

Glucose (Fasting) ≥126 mg/dL

Glucose (Fasting) ≥200 mg/dL

Short- term

Long- term

Short- term

Long- term

Triglycerides ≥200 mg/dL Short- term

Long- term

Triglycerides >500 mg/dL Short- term

Long- term

Total Cholesterol ≥240 mg/dL Short- term

Longterm

Quetiapine 300 mg/d

3.9–9.0%

6.4%

2.6–5.6%

10.5%

NA

NA

9.9–14.2%

5.6%

NA

NA

4.1–8.1%

14.1%

Quetiapine 600 mg/d

8.3–11.3%

9.4%

3.0–4.3%

7.3%

NA

NA

14.7–14.8%

14.7%

NA

NA

8.2–8.9%

12.7%

Placebo

0.8–4.1%

4.0%

1.4–4.3%

5.9%

NA

NA

9.1–13.0%

6.9%

NA

NA

3.6–10.1%

6.5%

22.0%

66.0%

NA

NA

4.4%

5.4%

NA

NA

9.8%

NA

20.9%

NA

1.8%

NA

NA

NA

0.5%

NA

NA

NA

NA

NA

4.9%

NA

OFC Placebo

Patients receiving OFC had a diagnosis of bipolar depression or treatment-refractory depression. As measured at the final assessment in short-term studies of quetiapine (Calabrese et al., 2005; McElroy et al., 2010; Suppes et al., 2010; Thase et al., 2006; Young et al., 2010) or any study visit in the long-term study of quetiapine (Young et al., 2012) and based on random glucose levels and nonfasting lipid levels for OFC. NA = not available. Data from Calabrese, J.R., et al., 2005, Am. J. Psychiatry 162 (7), 1351-1360; McElroy, S.L., et al., 2010, J. Clin. Psychiatry 71 (2), 163-174; Suppes, T., et al., 2010, J. Affect. Disord 121 (1-2). 106-115; Symbyax® (olanzapine and fluoxetine hydrochloride) capsule for oral use [package insert], Indianapolis, IN: Eli Lilly and Company, 2012; Thase, M.E., et al., 2006, J. Clin. Psychopharmacol 26 (6), 600-609; Young, A.H., et al., 2010, J. Clin. Psychiatry 71 (2) 150-162; Young, A.H., et al., 2014, World J. Biol. Psychiatry 15 (2), 96–112.

*

†

to those in the placebo group (Calabrese et al., 2005; McElroy et al., 2010; Suppes et al., 2010; Thase et al., 2006; Young et al., 2010; Young et al., 2012). In short-term studies, the proportion of patients with clinically relevant changes in metabolic parameters was generally similar for quetiapine and placebo; during longerterm treatment, clinically relevant shifts occurred more often with quetiapine (particularly 600 mg/d) (Table 1). 3.2 Olanzapine-fluoxetine combination OFC has demonstrated efficacy in short-term and long-term studies of bipolar depression, but is associated with significant weight gain and metabolic dysregulation (Table 1) (Brown et al., 2009; Brown et al., 2006; Corya et al., 2006; Tohen et al., 2003b). The proportion of patients with potentially clinically significant weight gain (≥7%) during short-term (6–8 weeks) treatment of acute bipolar depression with OFC was 19–23%, compared with 0.3% with placebo and 0% with lamotrigine (Brown et al., 2006; Tohen et al., 2003b). During a 6-month extension study, rates of clinically significant weight gain were 33.8% with OFC and 2.1% with lamotrigine (p