Advances in the Treatment of Bipolar Disorder

Chairperson: Terence A Ketter, MD

Therapy of Bipolar Disorders is rapidly evolving. The development of multiple new FDA-approved treatments has yielded important new management options. Mood stabilizers (lithium, divalproex, carbamazepine, and lamotrigine) and second-generation antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and asenapine) have the most evidence supporting their utility. These agents vary with respect to potential benefit profiles, as they have differential efficacy across illness phases. These medications also have differential risk profiles, as tolerability varies across medications. Clinicians and patients thus face an increasingly complex process of decision making when selecting pharmacotherapies. At the same time, there is an increasing appreciation for the need for evidence-based, personalized care. Quantitative (numerical) as opposed to qualitative (non-numerical) approaches have the potential to yield more reproducible outcomes. Number Needed to Treat (NNT) is a quantitative measure of potential benefit representing how many patients need to be treated to expect one more favorable outcome. Number Needed to Harm (NNH) is an analogously defined potential risk metric.

This symposium included presentations of NNT and NNH analyses of approved pharmacotherapies for various phases (acute mania, acute depression, and maintenance) of bipolar disorder, to facilitate assessment of risks and benefits in individual patients. In addition, this symposium included presentations regarding the treatment of bipolar disorder in children and adolescents, pregnant women, and older adults to facilitate treatment decisions in these important special populations. Taken together, the information in this symposium should facilitate clinicians’ efforts to translate the latest advances in research into evidence-based personalized state-of-the-art care for patients with bipolar disorder.

Depression is the most pervasive problem in bipolar disorder, with patients spending at least twice as much time enduring depressive symptoms compared to manic, hypomanic, or mixed symptoms. Mood stabilizers have been considered foundational agents for bipolar disorder. Historically, they are important treatment options for all phases of bipolar illness, but efficacy for acute bipolar depression may be less robust than for other aspects of the illness. Lithium and lamotrigine have limited evidence of utility for acute bipolar depression, and carbamazepine and divalproex have even more sparse evidence of efficacy. Emerging data suggest certain atypical antipsychotics provide benefit in acute bipolar depression, with the strongest evidence supporting the use of the FDA approved agents quetiapine monotherapy and the olanzapine plus fluoxetine combination, which have single-digit Numbers Needed to Treat (NNTs) for response compared to placebo. Unfortunately, these agents also have single-digit Numbers Needed to Harm (NNHs) for sedation and clinically significant (>= 7%) weight gain, respectively, indicating that the likelihood of benefit (efficacy) is comparable to that of risk (side effects). In patients with chronic (rather than acute), mild (rather than moderate to severe) bipolar depression, the poorer efficacy of an agent like lamotrigine (with a low double digit NNT for response) may be mitigated by enhanced tolerability (an even higher double-digit NNH). The utility of antidepressants in acute bipolar depression is controversial, as in some patients these agents may not relieve depression and could yield switching into mania or hypomania. Emerging data suggest that adjunctive pramipexole and adjunctive modafinil may yield benefit in acute bipolar depression. This presentation focuses on evidence-based methods using NNT and NNH to aid in selecting optimal pharmacotherapies for bipolar depression.

Advances in Maintenance Treatment of Bipolar Disorder

Terence Ketter, MD

The recurrent episodic nature of Bipolar Disorders, and the dysfunction, morbidity, illness progression, and mortality associated with acute episodes, make prevention of new episodes a crucial management goal. As of mid-2009, the FDA approved longer-term treatments for bipolar disorders included five monotherapies (lithium, lamotrigine, olanzapine, aripiprazole, and risperidone), and two adjunctive (added to lithium or valproate) therapies (quetiapine and risperidone). In addition, controlled data indicated that monotherapy with quetiapine and divalproex and adjunctive (added to lithium or valproate) therapy with ziprasidone were effective. The above-mentioned longer-term treatments, like approved treatments for other aspects of Bipolar Disorders, have single-digit Numbers Needed to Treat (NNTs) for preventing overall relapse/recurrence compared to placebo, indicating that treating less than 10 patients with an approved agent compared to placebo can be expected to yield one less relapse/recurrence. In general, mood stabilizers (lithium, lamotrigine, and divalproex) compared to second generation antipsychotics (olanzapine, aripiprazole, quetiapine and risperidone) have slightly higher NNTs, reflecting slightly less efficacy, but also have higher NNHs (Numbers Needed to Harm), indicating mitigating tolerability advantages. Medications differ not only in overall efficacy, but also in efficacy in preventing manic as compared to depressive relapse/recurrence, as well as in profiles of specific adverse effects, with there being important unmet needs for treatments that prevent depressive relapse/recurrence, and well-tolerated treatments that prevent manic/mixed episode relapse/recurrence. This presentation focuses on using NNT and NNH to aid clinicians’ in selecting pharmacotherapies with the optimal balance of benefits (efficacy) and risks (adverse effects), taking into account individual illness characteristics, vulnerability to adverse effects, and patient preferences.

Advances in Treatment of Bipolar Depression

Po Wang, MD

Depression is the most pervasive problem in bipolardisorder, with patients spending at least twice as muchtime enduring depressive symptoms compared to manic,hypomanic, or mixed symptoms. Mood stabilizers havebeen considered foundational agents for bipolar disorder.Historically, they are important treatment options for allphases of bipolar illness, but efficacy for acute bipolardepression may be less robust than for other aspects of theillness. Lithium and lamotrigine have limited evidence ofutility for acute bipolar depression, and carbamazepineand divalproex have even more sparse evidence of efficacy.Emerging data suggest certain atypical antipsychoticsprovide benefit in acute bipolar depression, with thestrongest evidence supporting the use of the FDA approvedagents quetiapine monotherapy and the olanzapine plusfluoxetine combination, which have single-digit NumbersNeeded to Treat (NNTs) for response compared to placebo.Unfortunately, these agents also have single-digit NumbersNeeded to Harm (NNHs) for sedation and clinicallysignificant (>= 7%) weight gain, respectively, indicatingthat the likelihood of benefit (efficacy) is comparableto that of risk (side effects). In patients with chronic(rather than acute), mild (rather than moderate to severe)bipolar depression, the poorer efficacy of an agent likelamotrigine (with a low double digit NNT for response)may be mitigated by enhanced tolerability (an even higherdouble-digit NNH). The utility of antidepressants in acutebipolar depression is controversial, as in some patients these agents may not relieve depression and could yieldswitching into mania or hypomania. Emerging data suggestthat adjunctive pramipexole and adjunctive modafinil mayyield benefit in acute bipolar depression. This presentationfocused on evidence-based methods using NNT and NNHto aid in selecting optimal pharmacotherapies for bipolardepression.

Treatment of Children and Adolescents with Bipolar Disorder

Kiki Chang, MD

Bipolar disorder begins before age 18 years in half to two-thirds of cases. Children and adolescents diagnosed with bipolar disorder (BD) are particularly at risk for poor psychosocial outcome, with increased risk for suicide attempts, self-injurious behaviors, recurrent syndromal or subsyndromal mood symptoms, co-occurring psychiatric disorders, psychosocial and academic problems, and substance use. The presentation and developmental course of pediatric BD vary with age and pubertal status. Due to these complexities, children and adolescents with BD require a multifaceted treatment approach including pharmacotherapy, psychotherapy, and family and educational intervention. Early identification and treatment of pediatric BD is essential to prevent the chronicity of symptoms and associated complications. By proper and timely administration of medications and therapy, children and adolescents with BD may benefit by acute improvement of mood and functioning and prophylaxis from future episodes and worsening of the disorder. Evidence-based treatments that guide clinical decision making for pediatric mood disorders are emerging. This presentation provided a summary of the clinical manifestations and controlled therapeutic trials for the treatment of bipolar disorder in children and adolescents, in order permit clinicians to make treatment decisions that provide optimal balance between benefits and risks for individuals with pediatric bipolar disorder.

Treatment of Pregnant Women with Bipolar Disorder

Mytilee Vemuri, MD, MBA

In pregnant bipolar patients, the potential for thedevelopment of fetal or neonatal adverse effects shouldbe considered when assessing the use of medications.Potential side effects include intrauterine death, perinatal toxicity, teratogenicity, growth retardation andneurobehavioral toxicity. Other considerations includespecial treatment issues associated with pregnancy (e.g.,the need for dosage adjustments) and risk of recurrenceand exacerbation of mood episodes. Substantial risk forrelapse has been found to exist during the pregnancyperiod following discontinuation of mood stabilizingmedication. However, information remains limitedregarding the risk of recurrence of bipolar disorder inpregnant women after discontinuation of lithium or othermood stabilizers. While teratogenic effects of lithium(Epstein’s anomaly in 0.1 %), valproate (neural tube defectsand other major malformations in as many as 10%), andcarbamazepine (spina bifida in 3%, craniofacial defects in11%, fingernail hypoplasia in 26 %, and developmentaldelay in 20 %) are fairly well documented, the samecannot be said for most second generation antipsychoticsand other anticonvulsants. Recent data indicate thatthe malformation risk with valproate is greater than hadpreviously been appreciated, but that with lamotriginethe malformation risk may be comparable to that withno anticonvulsant exposure and lower than that withvalproate. Although limited data suggest that lithiumdiscontinuation during pregnancy carries similar relapserates compared to other times, further studies are neededto assess discontinuation of medication and resulting acutepsychiatric illness on fetal development. This presentationprovided a summary of issues regarding the treatmentof bipolar disorder in pregnant women, in order permitclinicians to make treatment decisions that provide optimalbalance between benefits for individual patients.

Management of Bipolar Disorders in Older Adults

John Brooks, PhD, MD

Older adults are a rapidly expanding portion of the U.S. population with specific mental health and medical care needs. Bipolar disorder has a significant impact on many areas (e.g., functional decline, cognition, quality of life) in older adults, yet as of mid-2009, no large-scale, multi-center treatment study had been published. Pharmacological interventions in older adults diagnosed with bipolar disorder can be very challenging because of comorbid medical conditions, altered metabolism, and potential drug interactions. This presentation reviewed challenges in the differential diagnosis of bipolar disorder in older adults, especially in the context of complicating factors, and discussed the basic principles of pharmacotherapy of bipolar disorder in older adults. Although evidence-based guidelines are largely lacking, guidelines for initiating and titrating mood stabilizers (lithium, valproate, carbamazepine, and lamotrigine) and second-generation antipsychotics were reviewed. Finally, there was a discussion of important metabolic and treatment challenges in the context of bipolar disorder in older adults.

References

1. Ketter TA (ed): Handbook of Diagnosis and Treatment of Bipolar Disorder. Washington, DC, American Psychiatric Publishing 2010.

Adapted from materials found on the American Psychiatric Association Annual Meeting website.