Eva Solé, M.D. Marina Garriga, M.D. Eduard Vieta, M.D., Ph.D. For many years, patients with bipolar II disorder (BD II) have been managed as if they had bipolar I disorder (BD I)—that is, with mood-stabilizing medications, including antipsychotic medications, as the mainstays of treatment. What is the evidence supporting this approach? What is the role of medications such as lithium, divalproex, and carbamazepine in the management of BD II? What about atypical antipsychotic medications such as quetiapine and risperidone? In this chapter we review evidence salient to these questions and provide clinical examples of how to use these medications in the management of BD II. In the absence of double-blind, placebo-controlled randomized controlled trials (RCTs) in BD II, evidence from several open-label studies supports the effectiveness of lithium, lamotrigine, and divalproex in the acute treatment of patients with BD II depression (Table 8–1). Treatment guidelines for BD II disorder patients recommend long-term use of mood stabilizer treatment to prevent future episodes. Lithium and lamotrigine continue to be recommended as first-line mood-stabilizing agents in the maintenance phase (Table 8–2) (Yatham et al. 2005, 2009, 2018). Below we review the literature supporting these recommendations. TABLE 8–1.Mood stabilizer monotherapy in bipolar II disorder Hypomania Depression Maintenance Rapid cycling Lithium +++ +/++ +++ + Divalproex +++ + ++ + Lamotrigine – ++ +++ + Carbamazepine ++ + ++ + Note.+++=strong evidence (evidence from previous studies whose designs can support causal conclusions and studies that in total include enough of the range of participants); ++=moderate evidence (evidence from previous studies whose designs can support causal conclusions but have limited generalizability [i.e., moderate external validity], or studies with high external validity but moderate internal validity); +=some evidence; –=evidence of lack of efficacy. Source.Altshuler et al. 2017; Stahl et al. 2017; Suppes et al. 2008; van der Loos et al. 2009. TABLE 8–2.Changes in guideline recommendations for mood stabilizer and atypical antipsychotics monotherapy over time in patients with bipolar II disorder (BD II) CANMAT + ISBD 2009 CANMAT + ISBD 2013 CANMAT + ISBD 2018 Acute BD II Hypomania Reference to manic bipolar treatment Consider tapering current AD therapy Reference to manic bipolar treatment LI, DIVAL, AA (RIS) Consider tapering current AD therapy LI, DIVAL, AA (QUE, RIS) Consider discontinuing AD, stimulants Acute BD II depression First-line Second-line Third-line QUE Li, LAM, DIVAL AA (ZPS) QUE Li, LAM, DIVAL – QUE Li, LAM DIVAL, AA (ZPS)a Maintenance BD II First-line Second-line Third-line Li, LAM DIVAL CRB, AA Li, LAM, QUE DIVAL CRB, AA Li, LAM, QUE – CRB, DIVAL, AA (RIS)b Note. AA=atypical antipsychotic; AD=antidepressant; CANMAT=Canadian Network for Mood and Anxiety Treatments; CRB=carbamazepine; DIVAL = divalproex; ISBD=International Society for Bipolar Disorders; LAM=lamotrigine; Li=lithium; QUE=quetiapine; RIS=risperidone; ZPS=ziprasidone. aBD II depression and mixed hypomania. bPrimarily for prevention of hypomania. Source.Adapted from CANMAT and ISBD guidelines (Yatham et al. 2009, 2013, 2018). Neither lithium nor divalproex in monotherapy is approved for use as an acute treatment for depression of any kind (unipolar, mixed, bipolar) (Stahl 2014; Vieta and Suppes 2008). Lamotrigine has been approved by the U.S. Food and Drug Administration (FDA) as a maintenance treatment in BD I (Connolly and Thase 2011; Goodwin and Consensus Group of the British Association for Psychopharmacology 2009) because studies have shown that long-term use is associated with decreased risk for new mood episodes (including depressive episodes). Many extrapolate from its use in BD I to BD II because lamotrigine is the only mood stabilizer used in treatment of bipolar disorder that appears to have its primary effects on the depressive phase of the disorder, which predominates in BD II (Goodwin and Consensus Group of the British Association for Psychopharmacology 2009; National Institute for Health and Care Excellence 2014; Vieta et al. 2018; Yatham et al. 2013). Evidence supporting the use of adjunctive lamotrigine for patients with BD II includes two retrospective naturalistic studies. In those studies, a total of 61 individuals with BD II reported clinical improvements with lamotrigine, primarily used in combination with antidepressants or lithium⁄divalproex, for an average of 20 months (Jung et al. 2008; Sharma et al. 2008). In an 8-week RCT, the acute effect of lamotrigine was greater than that of placebo as an add-on to lithium for BD I or BD II depression (n=124) (van der Loos et al. 2009). Nonresponders in this trial entered a second phase in which paroxetine was added; this addition showed benefit in nonresponders to lithium+placebo but not in nonresponders to lithium+lamotrigine (van der Loos et al. 2009). Use of lamotrigine as monotherapy has shown limited efficacy in preventing hypomanic relapses, so its utilization in combination with lithium, divalproex, or an atypical antipsychotic might be considered a good option for long-term management of individuals with BD II, in which depression predominates (Stahl et al. 2017; Yatham et al. 2013). One small study showed promise of lamotrigine monotherapy: the study, a comparative 16-week study of depressed patients with BD II, demonstrated similar efficacy between lamotrigine and lithium (Suppes et al. 2008). Given the slow titration required for lamotrigine, this treatment is recommended either as monotherapy or as an add-on therapy primarily for those with mild-to-moderate BD II depression, and in particular for those with depression recurrences, given its efficacy in preventing depressive relapses (Yatham et al. 2009, 2013, 2018). Lithium has traditionally been considered an effective augmentation strategy for management of depression. In this context, it is often prescribed at very low doses, in combination with another medication, for selected patients (Yatham et al. 2009). Lithium is well known for its antisuicide, antiaggression, anticycling, and antimanic effects; however, there are no RCT trials evaluating its efficacy for hypomania (Yatham et al. 2018). Lithium may yield less favorable effects compared with divalproex in bipolar mixed states (Solé et al. 2017; Stahl et al. 2017). Overall, lithium is recommended as a second-line agent for BD II acute depression because of controversial results from the literature (Baron et al. 1975; Donnelly et al. 1978; Goodwin et al. 1969, 1972; Judd et al. 2002; Suppes et al. 2008). A 16-week open-label randomized trial that assessed the efficacy of lithium (n=56) in comparison with lamotrigine (n=46) monotherapy in patients with acute BD II depression (Suppes et al. 2008) did not show differences in depression improvement according to mean Montgomery-Åsberg Depression Rating Scale (MADRS) scores. No differences in response between the groups with rapid cycling (72% of the sample) and without rapid cycling were found, although there was a high dropout rate in the rapid-cycling group (42% of patients). In a larger study, 142 individuals with BD II depression were randomly assigned to receive sertraline plus placebo (n=45), lithium plus placebo (n=49), or sertraline plus lithium (n=48) for 16 weeks (Altshuler et al. 2017). There were no differences in response rates across the three groups; however, the combination of sertraline and lithium was associated with a significantly higher dropout rate than was seen in either monotherapy. For nonrapid cyclers, response rates were superior in both monotherapy groups than in the combination group. Because mixed symptoms are commonly present in BD II depression and lithium has limited efficacy in mixed states, lithium has been relegated to a second-line agent for BD II acute depression (Yatham et al. 2018). The optimal serum level for treating BD II depression is unclear. However, on the basis of a placebo-controlled RCT in BD II and BD I patients (Judd et al. 2002), a serum level around 0.8 mEq/L appears to be associated with the greatest benefit. Lithium treatment requires close monitoring to prevent adverse events (Stahl 2014). Toxic levels of lithium are close to therapeutic levels (Stahl 2014). Signs of toxicity include tremor, ataxia, diarrhea, vomiting, and sedation. The most important side effect is renal failure; however, recent studies show that continuation of lithium after a diagnosis of chronic kidney disease may not necessarily result in increased risk of developing end-stage chronic kidney disease, so lithium may sometimes be considered a reasonable option, even in the setting of renal disease (Kessing et al. 2017). Divalproex is considered a first-line option for maintenance treatment in the BD I manic phase but not for the prevention or acute treatment of bipolar depression (BD I and BD II) (Yatham et al. 2013). Divalproex has been used both as monotherapy and as an augmentation strategy in a 7-week open-label trial of 28 patients with BD II depression (Ketter et al. 2007). In that study, clinical response was statistically similar when divalproex was used in monotherapy and adjunctive therapy (Ketter et al. 2007). However, a meta-analysis suggests that divalproex is only as effective as placebo for the treatment of bipolar depression (Selle et al. 2014). Safety concerns about divalproex in women of childbearing age are clinically important (see Chapter 12, “Reproductive-Age Women With Bipolar II Disorder”), and therefore its utility for treating young women is limited (Stahl et al. 2017). The extent to which these findings can be extrapolated to BD II is limited, given the paucity (i.e., absence) of studies directly evaluating divalproex in samples of individuals with BD II. Carbamazepine as monotherapy could be considered a second- or third-line option for BD II. Clinical utility of carbamazepine is constrained by its enzyme inducer role, with resultant drug interactions, dermatological and hematological side effects, and teratogenicity (Stahl 2014). In an RCT performed in BD I (n=27) and BD II (n=25), for patients who displayed residual manic or depressive symptoms on maintenance lithium treatment, the addition of 8 weeks of carbamazepine or oxcarbazepine resulted in significant depressive symptom reduction, with oxcarbazepine being more effective than carbamazepine (Juruena et al. 2009). Results were not presented separately for patients with BD II. The combination of olanzapine or risperidone with carbamazepine is not recommended because of potent pharmacokinetic induction of cytochrome P450 enzymes by carbamazepine (Nivoli et al. 2012). Atypical antipsychotics are established as the main treatment for schizophrenia, and over the past two decades they have become a primary therapeutic option for bipolar disorder, as both alternative and adjunctive treatments to traditional mood stabilizers (Vieta and Goikolea 2005). Although they have been most commonly assessed as treatments for mania (Yildiz et al. 2011), there is increasing evidence of efficacy and safety as treatments for bipolar depression and as maintenance treatments for bipolar disorder (Cruz et al. 2010; Vieta and Grunze 2011; Yatham et al. 2018). The widespread availability of atypical antipsychotics has brought important changes to the management of bipolar disorder. First, well-designed RCTs have been conducted to investigate the efficacy and safety of atypical antipsychotics as treatments for the different phases of the disorder. Second, the use of atypical antipsychotics in patients with schizophrenia has given short- and long-term results, suggesting that they constitute a safer alternative to typical antipsychotics. Third, atypical antipsychotics, via neuronal plasticity determinant molecules, may share common mechanistic pathways to generating therapeutic responses with drugs more commonly used as treatments for affective disorders (Vieta 2013). Fourth, some atypical antipsychotics may have mood-stabilizing properties (Yatham et al. 2005). Despite this compelling rationale for their use in affective disorders, the evidence base for safety and efficacy of atypical antipsychotics in BD II is scant. A majority of studies investigating the pharmacotherapy of BD II have significant methodological limitations, because they are characterized by small samples and observational or retrospective designs. There is some evidence supporting the efficacy of lurasidone, olanzapine, and cariprazine in BD I depression. Negative studies for aripiprazole and ziprasidone suggest that these medications are ineffective for BD I depression. Much less is known about the role of these medications in the management of BD II depression. With the exception of quetiapine—for which there are robust data supporting efficacy in BD II depression—the level of evidence is not high, and therapeutic decisions must be made on a case-by-case basis. The evidence for atypical antipsychotics in the management of BD II is reviewed below. Quetiapine was the first drug approved by the U.S. FDA as monotherapy treatment for bipolar depression, including BD II depression (El-Mallakh et al. 2006). Although no specific RCT addressed the efficacy and safety of quetiapine monotherapy in a sample of BD II individuals alone, pooling of data from four studies that included individuals with BD II depression permits definitive statements about its efficacy in this population. BOLDER (BipOLar DEpRession) studies I and II comprised two double-blind RCTs that investigated the efficacy and tolerability of quetiapine monotherapy for major depressive episodes in BD I and BD II patients (with a total of 351 BD II patients). Combined results focusing on BD II patients from both studies showed significantly lower scores compared with placebo in the MADRS at the first week of treatment in the quetiapine group (Suppes et al. 2006). Thus, quetiapine was considered not only effective but well tolerated as a treatment for depressive episodes in BD II. Another subanalysis of the BOLDER studies showed positive effects in rapid cycling patients (Vieta et al. 2007). The EMBOLDEN I and II studies were RCTs that examined the efficacy and safety of quetiapine (300 and 600 mg/day) compared with placebo and an active comparator: lithium in the EMBOLDEN I study (Young et al. 2010) and paroxetine in the EMBOLDEN II study (McElroy et al. 2010). In these trials quetiapine 600 mg/day was significantly more effective than lithium in improving MADRS total score after 8 weeks of treatment (P=0.013). Quetiapine-treated (both doses) patients, but not lithium-treated patients, showed significant improvements (P<0.05) in MADRS response and remission rates, Hamilton Depression Rating Scale (HDRS), Clinical Global Impressions Bipolar Severity of Illness and Change, and Hamilton Anxiety Rating Scale (HARS) scores versus placebo. Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS. The most common adverse events were somnolence, dry mouth, and dizziness with quetiapine (both doses), and nausea with lithium. The risk for recurrence of a mood event was significantly lower with quetiapine than with placebo (P<0.001). Quetiapine was associated with a lower risk for recurrence of depressive episodes (P<.001), but recurrence of manic/hypomanic episodes was not significantly reduced (P=0.263). There was a lower risk of recurrence of mood events in patients with BD I (P=0.002) and patients with BD II (P< 0.001). Rates of discontinuation due to adverse events were 4.3, 4.0, and 1.7% for quetiapine 300 mg/day, 600 mg/day, and placebo, respectively. Quetiapine has also been studied and approved by the FDA as a maintenance treatment for BD II. The results indicate that quetiapine may protect against depressive relapses over the long term in patients with bipolar depression (Young et al. 2014). Quetiapine may also be useful for bipolar disorder patients (BD I and BD II) with enduring subthreshold depressive symptoms (Garriga et al. 2017). Tolerability concerns associated with quetiapine include sedation, weight gain, and, to a lesser extent, extrapyramidal symptoms. Sedation and somnolence are also associated with quetiapine discontinuation, even in BD II patients. Patients with BD II might be more sensitive to medication side effects than those with BD I, but so far quetiapine appears to be the only compound with robust data supporting its efficacy as a treatment for BD II (Suppes et al. 2013). There is evidence for risperidone as a safe and effective treatment for mania (Khanna et al. 2005) but not for bipolar depression. Although no RCT has formally tested its efficacy in patients with BD II, risperidone appears to be well tolerated by BD II patients with hypomania and seems to be more protective against hypomanic than depressive relapses (Vieta et al. 2001). Although an observational study including BD I and BD II patients suggested that risperidone might have antidepressant properties (McIntyre et al. 2004), long-term results with the long-acting injectable formulation indicate that risperidone prevents manic but not depressive episodes (Quiroz et al. 2010; Vieta et al. 2012). Potential tolerability issues with risperidone include extrapyramidal symptoms, hyperprolactinemia-related adverse events, and weight gain. There are no published studies investigating the efficacy of olanzapine in separate samples of those with BD II, so the following data come from broader bipolar disorder samples. A mild antidepressant effect of olanzapine was observed when olanzapine was combined with fluoxetine in a sample of BD I patients (Tohen et al. 2003). This combination might also be recommended in depression with mixed features (Stahl et al. 2017). The combination of olanzapine and fluoxetine has been approved by the FDA for the treatment of BD I depression, but there is no current evidence for its efficacy as a treatment for mania, and there are no trials so far for the treatment of BD II. There are no trials of olanzapine in hypomania, but there is one study in mild mania (which can be considered a proxy for hypomania) in which olanzapine was superior to placebo but not to divalproex (Tohen et al. 2008). The principal tolerability concerns related to olanzapine treatment are weight gain and increased potential to develop metabolic syndrome. Lurasidone has been approved by the FDA and by some European regulatory agencies for the treatment of BD I depression, but there is no current evidence for its efficacy as a treatment for mania, and there have been no trials so far for the treatment of BD II. However, because of the dearth of evidence-based treatments for bipolar depression and lower risk of weight gain and metabolic problems with lurasidone compared with other antipsychotics, lurasidone may be a very reasonable option for BD II depression. Additional testing is needed, however, before definitive statements about efficacy can be made. Antipsychotics are often used as adjunctive treatment to other medications for the management of BD II, but there is little or no evidence derived from RCTs to directly support this approach. Aripiprazole has been approved in the United States for the treatment of mania and prevention of manic relapse. However, there are no specific studies of aripiprazole in BD II, and trials of the compound for treatment of BD I depression as monotherapy did not demonstrate efficacy (Thase et al. 2008). Despite absence of studies supporting this approach, adjunctive treatment with aripiprazole has been successful for some cases of BD II (Dunn et al. 2008; McElroy et al. 2007). A similar situation applies to asenapine (Berk et al. 2015), ziprasidone (Sachs et al. 2011), and cariprazine (Durgam et al. 2016), which have had positive results as adjunctive or monotherapies for BD I depression—although no evidence supports their use for BD II depression. None of the other commonly prescribed atypical antipsychotics (clozapine, amisulpride, and paliperidone) have been assessed in BD II. Mood episodes with mixed symptoms are very common in BD II. The following case vignette provides an example of a depressive episode with mixed symptoms (Part 1) and a hypomanic episode with mixed symptoms (Part 2). Treatment approaches to these cases are discussed. In Part 1, the mixed symptoms are precipitated by the addition of an antidepressant to lithium and resolve with antidepressant discontinuation and initiation of lamotrigine. In Part 2, the mixed symptoms emerged in the context of medication discontinuation and an acute stressor (miscarriage). Addition of quetiapine to lithium and lamotrigine was used to manage hypomania with mixed symptoms. Part 1: Depression With Mixed Symptoms Maria is 35-year-old woman who works as a school teacher. Her first depressive episode occurred at age 20 and was treated with fluoxetine 20 mg/day, resulting in a full recovery after 6 months of treatment. She was maintained on fluoxetine because of a strong family history of depression. At age 25, while still taking fluoxetine, Maria experienced an episode of hypomania consisting of a 2-week period of expansive mood, increased shopping, decreased need for sleep, and hypersexuality. She was given a diagnosis of BD II, and the fluoxetine was discontinued. She improved after the fluoxetine was stopped, and she remained off all medications for 10 years. Maria presents to the clinic with a major depressive episode that makes it difficult for her to concentrate in the classroom and keep up a “cheerful face” with her students. She reports low mood, low interest, social isolation, poor concentration, hypersomnia, and daytime sleepiness. Because of Maria’s prior history and diagnosis of BD II, the clinician initiates treatment with lithium, which is titrated up to a therapeutic plasma level (0.8 mmol/L). Despite therapeutic levels of lithium, the depressive episode worsens. She is no longer able to get out of bed in the mornings and decides to take a leave of absence from her teaching job. Her psychiatrist adds fluoxetine, up to 40 mg/day. Over the ensuing 2 months, little improvement is observed, so Maria’s medication is changed from fluoxetine to vortioxetine, starting with 10 mg/day. Maria continues to report low mood and starts to experience suicidal ideation. Her treatment team notices pressured speech and psychomotor restlessness. Maria is relieved that she is no longer tired all the time, but she begins awakening at 5 A.M. with a subjective sense of increased energy. Maria is diagnosed as experiencing a depressive episode with mixed symptoms. Vortioxetine is discontinued, and lamotrigine is added to the lithium. The dosage of lamotrigine is gradually titrated to 100 mg/day. After 3 weeks, Maria experiences an improvement in hypomanic symptoms but continues to report moderately low mood, decreased interest, and low energy. Her suicidal ideation resolves. Her psychiatrist further increases the dosage of lamotrigine up to 200 mg/day. After 1 month taking a combination of therapeutic doses of lithium and lamotrigine, Maria experiences a resolution of her symptoms. Within 6 months, she has returned to full-time work without evidence of recurrence. Part 2: Hypomania With Mixed Symptoms One year later, Maria learns she is 8 weeks pregnant and decides to stop both the lithium and the lamotrigine. Two weeks later she has a spontaneous miscarriage. Without consulting her psychiatrist, she restarts both her lithium and lamotrigine at the previous doses. She returns to the psychiatry clinic 1 month later, experiencing distress about having lost the pregnancy and complaining of poor sleep in spite of having resumed treatment with lithium and lamotrigine. Maria reports that she has only been sleeping 4–5 hours per night and has been fighting a lot with her boyfriend about the miscarriage. She is observed to be irritable, labile, and experiencing moderate levels of anxiety. On further inquiry, she endorses racing thoughts, excessive spending (“to make myself feel better”), and guilty rumination about the miscarriage (“My boyfriend says that if I hadn’t taken medication in the first weeks of my pregnancy, maybe I wouldn’t have miscarried. Maybe he’s right.”). Maria’s presentation meets criteria for a hypomanic episode with mixed symptoms. Quetiapine is added to her regimen, with the dosage increased to 300 mg/night over 2 weeks. Maria experiences a rapid improvement in sleep, cessation of overspending, and a decrease in irritability. After 1 month, Maria returns to the clinic and has a normal mood. All hypomanic and depressive symptoms have resolved. She reports good sleep and an improved relationship with her boyfriend. After 6 months, Maria continues to have a stable mood with stable sleep, but she has gained 10 pounds, which is thought to be secondary to the quetiapine. Because of weight gain, quetiapine is gradually discontinued with close monitoring. Maria continues to take the lithium and lamotrigine and does well over the follow-up period.
8
Mood Stabilizers and Antipsychotic Medications in Bipolar II Disorder
Role of Mood Stabilizers in Bipolar II Disorder
Lamotrigine
Lithium
Divalproex
Carbamazepine
Role of Atypical Antipsychotics in Bipolar II Disorder
Quetiapine
Risperidone
Olanzapine
Lurasidone
Other Atypical Antipsychotics
Case Vignette
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