Strategies for Shifting From Acute to Maintenance Treatment for Bipolar I Disorder

Abstract

Supported by an educational grant from Otsuka America Pharmaceutical, Inc., and Lundbeck.

Learning Objective

After completing this educational activity, you should be able to:

• Work with patients to successfully transition from acute to maintenance treatment for bipolar I disorder.

Release, Review, and Expiration Dates

This brief report activity was published in December 2019 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2021. The latest review of this material was November 2019.

Statement of Need and Purpose

Too many patients receive incorrect treatment for bipolar disorder; prescribing seems to differ more by clinician than by patient characteristics. Third-generation antipsychotics target the symptoms of bipolar disorder in a novel way and may help patients avoid side effects associated with other antipsychotics. However, many clinicians lack familiarity with these medications’ pharmacologic attributes. Therefore, clinicians need education on how to manage bipolar I disorder symptoms with evidence-based treatment options. In addition, as new treatment targets are identified, clinicians need education on psychopharmacologic and pharmacokinetic advances.

The treatment of bipolar disorder requires that both manic and depressive symptoms be controlled, and the therapeutic effect must be maintained after an acute mood episode has resolved. Although numerous treatments are available, many patients are unable to maintain recovery. Consequently, clinicians need updated information on best practices for addressing not only acute treatment of bipolar disorder but also maintenance treatment, including weighing the evidence about the utility of oral versus long-acting injectable agents, measurement-based care, and strategies for promoting adherence and functional improvement.

This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on bipolar I disorder.

Disclosure of Off-Label Usage

Dr Suppes has determined that, to the best of her knowledge, aripiprazole and paliperidone are not approved by the US Food and Drug Administration for the treatment of bipolar disorder. For drugs mentioned in this activity, consult product labeling for indications for acute manic, mixed, and depressive episodes and maintenance treatment.

Review Process

The faculty member agreed to provide a balanced and evidence-based presentation and discussed the topic and CME objective during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by a peer reviewer who is without conflict of interest.

Acknowledgment

This Brief Report is derived from the planning teleconference series “Strategies for Acute and Maintenance Treatment of Bipolar I Disorder,” which was held in July and August 2019 and supported by an educational grant from Otsuka America Pharmaceutical, Inc., and Lundbeck. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.

Faculty Affiliation

Trisha Suppes, MD, PhD
Stanford University School of Medicine and the US Department of Veterans Affairs Palo Alto Health Care System, California

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The Accreditation Council for Continuing Medical Education (ACCME) defines a commercial interest as any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. The ACCME defines relevant financial relationships as financial relationships in any amount occurring within the past 12 months that create a conflict of interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr. Suppes is a consultant for Allergan, Impel NeuroPharma, and Sunovion; has received grant/research support from Merck, National Institutes of Health, National Institute on Drug Abuse, Palo Alto Health Sciences, Stanley Medical Research Institute, the US Department of Veterans Affairs (VA) Cooperative Studies Program, and the VA Office of Research & Development PRIME Care Study; and has received other financial or material support from Jones and Bartlett, Wolters Kluwer Health (UpToDate), and Hogrefe Publishing.

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Find more articles on this and other psychiatry and CNS topics:
The Journal of Clinical Psychiatry
The Primary Care Companion for CNS Disorders

Recurrence rates for bipolar disorder are high. Vázquez et al¹ compared data from 10 naturalistic studies and 15 randomized controlled trials and found respective recurrence rates of 26% and 22% each year in treated patients over 2 years. With no treatment (ie, placebo), the recurrence rate in the controlled trials was 31% each year. Recurrence is associated with physical changes in brain matter, decreased cognitive function, increased functional impairment, more relapses and increased severity of relapse, and poorer treatment response compared with individuals achieving sustained remission.² Early initiation of effective maintenance therapy may lessen cognitive impairment for patients able to sustain remission³ and may minimize neurodegeneration in the brain,⁴ potentially interrupting bipolar progression and improving the disorder’s long-term prognosis.⁵

The 2018 treatment guidelines from the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD)⁶ lay out a comprehensive strategy for the maintenance phase of bipolar I disorder, including a multi-level, evidence-based algorithm for pharmacologic and psychosocial interventions. (See 2 patient cases illustrating maintenance treatment strategies.)

Pharmacotherapy for Bipolar I Maintenance

The CANMAT treatment algorithm includes first- through third-line pharmacotherapeutic treatment options ranked by level of evidence and safety/tolerability. However, clinicians initiating maintenance therapy should not immediately utilize a top-down approach to treatment selection when using the algorithm; patient characteristics including previous history of medication response and tolerance and the predominant illness polarity should be considered. Usually, the medication that was effective in the acute phase should be continued in the maintenance phase regardless of its position in the algorithm’s hierarchy.⁶ However, in cases where a patient’s acute symptoms required rapid stabilization, the acute medication may not be appropriate for long-term use. In some cases, if the acute agent is likely to produce tolerability issues during maintenance, a lower dose might maintain efficacy while reducing adverse events.⁶ Antidepressant therapy is not recommended as maintenance therapy, but for patients who achieved remission using polytherapy including an antidepressant, antidepressant cessation may contribute to recurrence.⁷

For patients entering the maintenance phase, the acute treatment should be optimized or gradually replaced with a first-line maintenance treatment if not appropriate for long-term use. If dosages are already optimal and the response is inadequate or the treatment is not well tolerated, clinicians should either switch among first-line options or add an additional first-line medication. The CANMAT guidelines recommend multiple trials of first-line agents alone or in combination before second-line options are considered, and it is critical that adherence be assessed at each stage before changes are made.⁶  However, immediate clinical necessity and judgement may lead the physician and patient to move more quickly through different stages of treatment.

Patient Perspectives

One individual described the need for managing both depression and mania when living with bipolar disorder: “If you want to manage bipolar disorder and lead a stable life where you’re able to work and have long-lasting and loving relationships, both sides of the coin have to be managed. It took me years to face this reality.… I want to travel the world. I want a fun and loving romantic relationship. I want to write books and help others find happiness in life. To do this, I simply have to be stable. Otherwise, I’m on the constant up and down of being ok for a while, then getting SUPER OK, eventually morphing into a high-energy nastiness and finally crashing and burning to the point that I can hardly get out of bed. This was my life for a long time… This constant crash and burn takes up so much energy. There are too many apologies and worries in this chasing-mania life. I decided a long time ago that stability was the goal. The answer was managing both sides of the coin equally. It meant spending as much time managing and preventing mania as I did preventing and managing the depression.”8

The following clinical features should guide treatment selection:

Bipolar polarity. The predominant polarity of the disorder, if known, or the most recent episode is a primary determining factor in treatment selection (Table 1).⁶ Among first-line options, lithium, quetiapine, lamotrigine, or quetiapine plus lithium or divalproex have the most robust evidence for efficacy in the prevention of depressive episodes. Newer evidence also supports asenapine monotherapy as a first-line option for prevention of depressive relapse. Divalproex is recommended as a first-line treatment option, with evidence suggesting efficacy for the prevention of any mood episode. For preventing manic relapse, lithium, quetiapine, or quetiapine plus lithium or divalproex have the highest level of evidence for efficacy. Asenapine monotherapy is again included as a first-line option, as are aripiprazole monotherapy (oral or once-monthly) and aripiprazole plus lithium or divalproex due to evidence suggesting efficacy in the prevention of any mood episode.⁶

Table 1. First- and Second-Line Recommendations for Pharmacologic Maintenance Therapy in Bipolar Disorder^a

^aBased on Yatham et al.^6
bLevel 1 = meta-analysis with narrow confidence interval or replicated double-blind, randomized controlled trial that includes a placebo or active control comparison; Level 2 = meta-analysis with wide confidence interval or one double-blind, randomized controlled trial with placebo or active control comparison condition; Level 3 = at least one double-blind, randomized controlled trial with placebo or active control comparison condition; Level 4 = uncontrolled trial, anecdotal reports, or expert opinion.
^cDid not separate from placebo in those with index mania; no studies available evaluating for index depression.
^dTrend for superiority on the primary efficacy measure, hence the lower rating.
^eEffective in those with an index episode of depression. Abbreviations: LAI = long-acting injectable, n.d. = no data

Suicidality. Among individuals with bipolar disorder, approximately 43% of patients report suicidal ideation and 16% report at least one suicide attempt during their life.⁹ Approximately 26% of individuals with bipolar disorder who commit suicide do so within 6 weeks of discharge from the inpatient setting,¹⁰ indicating the importance of assessing suicide risk during initiation of maintenance therapy. However, due to the prevalence of suicidality in the bipolar population, suicide risk should be comprehensively assessed at all clinical interactions.⁶

Patient Perspectives
An individual described suicidal feelings associated with bipolar depression: “My depression reached such an unbearably low point all I wanted was to die. I felt like there was nothing more I could be and no one would care if I left. I was prepared to let it all go and leave my friends and family behind.”11

Among pharmacologic treatment options, lithium appears to have the most evidence for suicide prevention.¹² Shaffer et al¹⁰ reviewed literature evaluating anticonvulsants for suicide reduction in bipolar disorder and found some evidence of efficacy, but more research is needed. Some data indicate a possible preventive effect of antipsychotic and antidepressant medications,¹⁰ but this possibility should be weighed against the potential toxicity and lethality of some agents if used in suicide attempts via overdose.¹³

Comorbidity. Although lithium remains the gold standard for bipolar maintenance therapy, responders generally have lower rates of comorbidity compared with those with a poorer response.¹⁴ For example, comorbid anxiety and substance use disorders stand out as potential indicators of poor lithium response.^15,16

Mixed features. Evidence suggests that quetiapine plus lithium or divalproex may be effective maintenance therapy for patients with mixed features. One study¹⁷ found that the combination therapy was associated with a longer time to recurrence compared with placebo plus lithium or divalproex for participants with a history of mixed symptoms.

Rapid cycling. When a history of rapid cycling is present, the clinician should discontinue antidepressants and stimulants and assess the patient for potential contributing factors such as hypothyroidism, other medical causes, and substance use.⁶ A combination of mood stabilizers may be the best pharmacotherapeutic strategy, as mood stabilizer monotherapy is generally not effective for patients with rapid cycling.⁶

Treatment refractoriness. Patients appearing resistant to pharmacotherapy may also simply be nonadherent, require medication optimization and consideration of side effects, or have unaddressed comorbidities that complicate treatment response.⁶ Clinicians should ensure that multiple first- and second-line treatment options are employed and adhered to at optimized doses for adequate time periods before considering a patient truly resistant to medication. For patients not responding to multiple high-dose options from all levels of current treatment algorithms, clinicians should consider genotyping for cytochrome P450 enzymes to determine if treatment refractoriness could be related to ultra-rapid metabolic status.⁶

Managing Nonadherence

Studies^18–20 report prescription nonadherence rates as high as 46%–60% in bipolar populations. Nonadherence can be mistaken for non-response or poor response and may lead to the modification or abandonment of a treatment that may have worked if adhered to properly.⁶ Treatment nonadherence or discontinuation is associated with increased risks of recurrence, hospitalization, and suicidality.²¹ A variety of sociodemographic and medical factors are associated with poor adherence to bipolar pharmacotherapy (AV 1).⁶ Factors associated with higher rates of adherence include:

• Healthy working alliance between the patient and clinician^26,27,28
• Patient’s knowledge of bipolar disorder²⁴
• Positive patient attitude toward treatment²⁴
• Patient insight into  their symptoms²⁴
• Social/family support for the patient^27,28

AV 1. Factors Associated With Poor Bipolar Medication Adherence^a (00:46)

^aBased on Yatham et al.⁶ and Leclerc et al.²²

Patient Perspectives

An individual living with bipolar disorder describes the result of a break in medication during remission: “I have been taking prophylactic medication for over 20 years. I’ve had episodes during this time. I had my doubts about the efficacy of the medication, but I kept taking it. Recently, when I changed my medical insurance, there was a period when I could not obtain the medication. I doubt it was just a coincidence that my first episode in eight years occurred while I was not taking the tablets. I should have paid for the medication myself and claimed it back on the insurance later.”25

Because prescription adherence is positively correlated with factors related to patient engagement in the treatment process and knowledge or insight of bipolar disorder,²¹ clinicians should employ adherence-focused psychoeducation for patients and their families.^26,27 Such interventions may improve patient acceptance of bipolar pharmacotherapy²² and increase adherence rates.^27–31

Velligan and colleagues³¹ described experts’ strategies for addressing adherence problems. Psychosocial interventions—which should be tailored to patients’ specific problems that lead to nonadherence—include ongoing monitoring and treatment adjustment for symptoms and side effects; services that target logistical problems; environmental supports for lack of routine or cognitive deficits. Other interventions include patient psychoeducation, more frequent and/or longer visits if possible, cognitive-behavioral therapy (CBT), and family-focused therapy. For pharmacologic interventions, the experts recommended (1) switching to a long-acting antipsychotic when lack of insight, substance use, persistent symptoms, logistical problems, lack of routine, or lack of social support interfere with adherence and (2) simplifying the treatment regimen when logistical problems, lack of routine, cognitive deficits, or lack of social support interfere with adherence.³¹ A multifaceted approach may be required because multiple issues may be involved.

Psychosocial Therapy for Bipolar I Maintenance

Pharmacotherapy alone may not prevent recurrence for patients. Psychosocial therapy adjunctive to pharmacotherapy improves adherence rates by approximately 15% on average and should be the standard approach for patients with bipolar disorder.⁶ Evidence suggests that treatment combining psychotherapy with pharmacotherapeutic best practices provides improved outcomes compared with pharmacotherapy alone.^32,33

The CANMAT guidelines recommend psychoeducation as the only first-line psychosocial intervention for bipolar maintenance and suggests that it be offered to all patients.⁶ Psychoeducation modalities aim to teach patients strategies for relapse prevention through skills such as prodrome detection, stress management, medication adherence, and healthy lifestyle choices.⁶ Specific examples of evidence-backed psychoeducational interventions cited in the CANMAT guidelines include the Barcelona BDs Program,³⁴ the Life Goals Program,³⁵ or an individualized approach based on either program. Analysis of evidence supporting the efficacy of various psychoeducational models^36–38 found that provision of at least 5 sessions of any of the included psychosocial interventions meets the evidentiary threshold for a first-line recommendation.⁶ One study found that 6 sessions of the Life Goals Program demonstrated similar efficacy in relapse prevention to that of 20 sessions of CBT while being far more affordable.³⁹

The CANMAT psychosocial treatment algorithm (Table 2)⁶ includes several second- and third-line options that may be useful depending on patient characteristics.

Table 2. Recommendations for Adjunctive Psychosocial Therapy in Maintenance Therapy for Bipolar Disorder^a

^aBased on Yatham et al.⁶

Conclusion

For bipolar maintenance therapy, clinicians should optimize the acute phase treatment unless it is not appropriate for long-term use, in which case the safest first-line treatment with demonstrated efficacy in treating the patient’s presenting illness features should be selected. Pharmacotherapy should be combined with psychotherapy to improve patient insight and help establish the necessity of full pharmacotherapeutic adherence.

Clinical Points

• Optimize the acute pharmacotherapy for maintenance treatment unless tolerability is an issue with long-term use.
• Offer psychosocial therapy to all patients with bipolar disorder.
• Assess for and promote prescription adherence.
• Assess suicidality at all clinical encounters.

Abbreviations

CBT = cognitive-behavioral therapy
LAI = long-acting injectable
n.d. = no data

© Copyright 2019 Physicians Postgraduate Press, Inc.

REFERENCES