
- Vol 39, Issue 9
The Need for Novel Treatments for Bipolar Depression
In this CME article, learn more about the rationale for considering novel treatments for patients with bipolar depression.
CATEGORY 1 CME
Premiere Date: September 20, 2022
Expiration Date: March 20, 2024
This activity offers CE credits for:
1. Physicians (CME)
2. Other
All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.
ACTIVITY GOAL
The goal of this activity is to help readers conceptualize the difference between the use of standard and novel treatment approaches when treating patients with bipolar depression.
LEARNING OBJECTIVES
1. Understand the rationale for considering novel treatments for patients with bipolar depression.
2. Articulate a decision-making process for implementing novel treatments for patients with bipolar depression.
TARGET AUDIENCE
This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.
ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC, and Psychiatric Times™. Physicians’ Education Resource®, LLC, is accredited by the ACCME to provide continuing medical education for physicians.
Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.
OFF-LABEL DISCLOSURE/DISCLAIMER
This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.
FACULTY, STAFF, AND PLANNERS’ DISCLOSURES AND CONFLICT OF INTEREST (COI) MITIGATION
The staff members of Physicians’ Education Resource®, LLC, and Psychiatric Times™, and the authors, have no relevant financial relationships with commercial interests.
None of the staff of Physicians’ Education Resource®, LLC, or Psychiatric Times™, or the planners of this educational activity, have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.
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HOW TO CLAIM CREDIT
Once you have read the article, please use the following URL to evaluate and request credit:
(This is the first part of a 2-part article discussing novel treatments for bipolar depression. Part 2 will appear in subsequent issue and will discuss specific options and treatment strategies. –Ed.)
Bipolar depression is a condition that proves difficult to treat for many patients. When patients with bipolar disorder (BD) go through a depressive episode, medication adjustment is often the first intervention that clinicians consider. Evidence for standard pharmacologic treatments for bipolar depression shows the strongest support for several dopamine-blocking agents, as well as for
A number of novel pharmacologic treatments have been studied for bipolar depression, and clinicians will be well served by becoming familiar with them. When standard treatments fail or cause intolerable adverse effects, having another set of options in your arsenal can be invaluable. In addition, utilizing nonpharmacologic treatments that have been shown to be effective for managing
Case Study “Sam” is a nonbinary person assigned female at birth, aged 22 years, who is diagnosed with BD II. They have a personal history of depressive episodes, anxiety symptoms, and hypomanic symptoms, as well as a strong family history of BD. They were originally diagnosed with major depressive disorder and generalized anxiety disorder in high school and, at that time, tried escitalopram,
Bipolar Depression Treatment Guidelines
Standard pharmacologic treatments for bipolar depression are covered in various published treatment guidelines (
The guidelines also include recommendations for pharmacologic treatments for acute bipolar depression. The CANMAT/ISBD guidelines include many of the novel treatments (which will be discussed here and in Part 2) as third-line recommendations.2 Guidelines also promote the engagement of the patient/service user in the treatment-planning process, and they highlight the importance of selecting interventions that are agreeable and likely to be followed. Clinicians may have the best of intentions in selecting treatments that are reflected in treatment guidelines, but if the patient is not on board due to concerns about adverse effects or difficulty achieving the recommendation (eg,
Using Novel Treatment Protocols
If first-line, FDA-approved treatments have been trialed without success, it becomes necessary to use treatments that lack official FDA approval. Whatever is chosen, treatment options should be evidence based. All of the medications and interventions discussed have varying degrees of evidence. Clinicians should understand what the levels of evidence signify and should have reasonable expectations for the
Nassir Ghaemi, MD, MPH, an expert in this field, provides a concise and useful overview of evidence levels; he ranks them as levels 1 through 5, with the strongest evidence at level 1 and the weakest at level 5.3 Level 1 includes blinded randomized controlled trials (RCTs); level 2, open-label RCTs; level 3, large observational studies; level 4, small observational studies; and level 5, expert opinions and case studies. However, as Ghaemi has noted, level 4 or 5 evidence—although weaker—is not necessarily without value. Rather, the designation simply means that the evidence is not as strong. In a perfect world, treatment choices would be guided by evidence at levels 1 and 2. In the real world, however, conducting blinded RCTs on every treatment option is not always feasible or possible.
When patients struggle for relief from debilitating symptoms, it is often necessary to push forward with options that have a weaker evidence base. As clinicians progress down the levels of evidence, they should have realistic expectations of outcomes. When using third- and fourth-line treatments, the expected result may only be some degree of symptom relief and not complete remission. Fortunately, when patients present with severe symptoms, even a slight degree of improvement is usually welcome and acceptable to the patient. Additionally, patients may be interested in trying nonpharmacologic approaches as well as different pharmacologic options. The treatments to be discussed in this article have been listed according to their levels of evidence in
Inflammation and the Microbiome
A growing body of research supports the role of
Within the context of the inflammatory hypothesis are the roles of the microbiome and the gut-brain axis, which comprises several somatic components, including the gut microbiome, enteric nervous system, vagus nerve, neuroendocrine system, and central nervous system.7,8 The relationship between inflammation and the microbiome is currently not well understood, but it is known that the gut microbiome impacts immune system functioning through its relationship with cytokine modulation.7,9 In addition, gut microbiota modulate the production of neurotransmitters, and have been shown to be altered in individuals with BD, although findings have been mixed.10 External factors that may influence the biodiversity of the gut microbiome include diet, alcohol and other substances, medication, environment, genetics, and mode of birth (vaginal versus Cesarean).10 Evidence points toward a possible causal relationship between gut-brain axis alterations and the development of BD and other psychiatric disorders, mediated by epigenetic changes.7,8 Current knowledge of the relationship among the gut-brain axis, immune system activity, inflammation, and psychiatric symptoms has not yet yielded strong evidence for specific treatment interventions, but emerging evidence provides some support for the use of modalities such as anti-inflammatory diets and medications.5,9,11-13
Clinical Decision-Making With Novel Approaches
When standard treatments have not worked, an important first step is to rework the diagnosis using evidence-based assessment tools. Some indispensable tools include the Mini International Neuropsychiatric Interview (MINI) and the Harvard Bipolarity Index (HBI). The MINI has been validated and is often more accurate than clinician opinion alone.14 The HBI is also key in helping clinicians to refine a diagnosis and to distinguish between BD and other psychiatric conditions.15
The HBI considers 5 clinical domains: signs and symptoms, age of onset, course of illness, response to treatment, and family history. A score of 50 or more highly suggests a BD diagnosis. Additionally, screening for the presence of trauma may be helpful, as a comorbid trauma diagnosis makes treating most psychiatric conditions more difficult. A tool such as the Adverse Childhood Experiences Questionnaire can also be useful,16 although some critics say that this tool may not be substantive enough to fully assess the impacts of childhood
After confirming or altering the diagnosis, clinicians can then move on to selecting appropriate treatment options. If a diagnosis of bipolar depression is confirmed, and standard treatments have been unsuccessful, clinicians can begin to explore the treatments that will be discussed further in Part 2. Although using treatments that are not FDA approved may be a new experience for some clinicians, the evidence hierarchy can guide clinical decision-making. There is no evidence that trying more and more medications with the same mechanism of action is likely to be effective. Indeed, selecting pharmacologic interventions with different mechanisms of action that have evidence of efficacy in the treatment of
Evaluating patient-specific factors is also important when selecting treatments. Clinicians should already be familiar with this process when using standard FDA-approved medications. For example, if a patient has
Case Study, Continued After considering Sam’s treatment history, presenting symptoms, and treatment preferences, the treating clinician decided to start pramipexole along with lithium. Pramipexole was titrated over 3 weeks to 1 mg daily with PRN ondansetron for nausea. The clinician also recommended that Sam increase their physical exercise and morning sunlight exposure.
About 3 weeks later, Sam began to notice improvement in motivation and energy, appetite, sleep patterns, and suicidal thoughts. Their depressed mood persisted, however, and Sam’s therapist noted it was likely related to situational factors and past trauma. Sam experiences a great deal of family stress associated with their mother and grief related to their father’s death a few years prior. Sam and their therapist continued to work through these issues, and Sam’s mood slowly improved over the next several months.
NP Hardy is a psychiatric mental health nurse practitioner and clinical assistant professor at the Virginia Commonwealth University School of Nursing in Richmond, VA. Mr McCarthy is a psychiatric mental health nurse practitioner at the Mood Treatment Center in Winston-Salem, NC.
References
1. Treatment guidelines: bipolar disorder. American Association of Psychiatric Pharmacists. Accessed July 19, 2022.
2. Yatham LN, Kennedy SH, Parikh SV, et al.
3. Ghaemi SN. Levels of evidence. Psychiatric Times. 2010;27(1).
4. Rosenblat JD, Kakar R, Berk M, et al.
5. Ayorech Z, Tracy DK, Baumeister D, Giaroli G.
6. Fernandes BS, Steiner J, Molendijk ML, et al.
7. Alam R, Abdolmaleky HM, Zhou J-R.
8. Zhang P, Kong L, Huang H, et al.
9. Grandjean EL, van Zonneveld SM, Sommer IEC, Haarman BCM.
10. Borkent J, Ioannou M, Laman JD, et al.
11. Husain MI, Strawbridge R, Ra Stokes P, Young AH.
12. Martins LB, Braga Tibães JR, Sanches M, et al.
13. Marx W, Moseley G, Berk M, Jacka F.
14. Sheehan DV, Lecrubier Y, Sheehan KH, et al.
15. Aiken CB, Weisler RH, Sachs GS.
16. Felitti VJ, Anda RF, Nordenberg D, et al.
17. McLennan JD, MacMillan HL, Afifi TO.
18. Weathers FW, Bovin MJ, Lee DJ, et al.
Articles in this issue
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Burnout and Its Remediesabout 3 years ago
8 Tips for Psychiatrists to Prevent Burnoutabout 3 years ago
The Alluring Mistress: Reflections From My Affair With Medicineabout 3 years ago
Planning for Your 2022 Taxesabout 3 years ago
School Is in Sessionabout 3 years ago
"Grappelli’s Smile"about 3 years ago
Headaches: The Common, Challenging Comorbidityabout 3 years ago
Using Cognitive Behavioral Therapy to Enhance Well-BeingNewsletter
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