The Need for Novel Treatments for Bipolar Depression

Psychiatric TimesVol 39, Issue 9

In this CME article, learn more about the rationale for considering novel treatments for patients with bipolar depression.

bipolar depression



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.


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.


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.


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.


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(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 lithium and lamotrigine (Lamictal). Recently published treatment guidelines are reflective of this evidence. Pharmaceutical industry support for research on dopamine-blocking medications has contributed to their dominance in the marketplace. Older generic medications are less likely to be included in research trials and thus may not be adopted widely due to a perceived or real lack of evidence.

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 bipolar depression is another important component of a comprehensive treatment plan.

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, bupropion, and gabapentin. After the initial diagnosis of BD at age 21 years, Sam tried lamotrigine with poor results. They were started on lithium, which kept their mood stable for about a year until they began to experience a depressive episode that included hypersomnia, depressed mood, poor energy and motivation, poor appetite, and suicidal thoughts. Sam’s lithium level was 0.8 mmol/L, and they did not tolerate higher doses due to adverse effects. They tried several dopamine-blocking medications but were unable to tolerate any of them due to adverse effects, primarily sedation. Sam also tried a serotonin reuptake inhibitor in conjunction with lithium without effect on mood.

Bipolar Depression Treatment Guidelines

Standard pharmacologic treatments for bipolar depression are covered in various published treatment guidelines (Table 1). There are currently 4 guidelines that are less than 10 years old, and they include recommendations for treating acute bipolar depression.1 The organizations that have released these guidelines are the British Association for Psychopharmacology, the Canadian Network for Mood and Anxiety Treatments and the International Society for Bipolar Disorders (CANMAT/ISBD), the National Institute for Health and Care Excellence, and the Royal Australian and New Zealand College of Psychiatrists. Each of these guidelines emphasizes the importance of nonpharmacologic interventions such as psychotherapy, family engagement, and addressing substance misuse. Although these are important interventions, a detailed discussion of them is beyond the scope of this article.

TABLE 1. Available Treatment Guidelines

Table 1. Available 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, exercise is not possible due to physical limitations, patient is unable to access psychotherapy due to lack of insurance coverage, etc), the treatment plan needs to go in a different direction.

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 effect size of the drug or therapeutic intervention used.

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 Table 2. Part 2 will explore the use of these treatments, which address different targets based on a current understanding of the pathophysiology of psychiatric illness.

TABLE 2. Evidence Levels

Table 2. Evidence Levels

Inflammation and the Microbiome

A growing body of research supports the role of inflammation in the pathology of BD as well as in unipolar depression. The results of numerous studies have shown elevated proinflammatory cytokine levels in patients with BD.4,5 C-reactive protein was found to be significantly elevated in patients with BD during mania and more moderately so in depressive episodes.6 These findings can direct clinicians toward new treatment paths for patients who struggle with difficult-to-treat bipolar depression. Choosing treatments that target inflammation may improve the efficacy of current drug regimens and may also boost patients’ overall health. Many of the interventions discussed in this article are thought to target inflammation. These include probiotics, exercise, sleep, diet, and actual anti-inflammatory agents such as celecoxib.

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 trauma.17 Use of the Clinician- Administered PTSD [posttraumatic stress disorder] Scale for DSM-5 is also advised.18 All of these tools are relatively easy to use and will increase the likelihood of an accurate diagnosis.

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 bipolar depression is a sensible strategy. Patients may require a combined strategy of nonpharmacologic and pharmacologic interventions. Because many of the nonpharmacologic interventions are conducive to overall health and well-being and have minimal to no adverse effects, there is little harm in trying them alongside pharmacologic interventions.

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 type 2 diabetes and obesity, most clinicians would be less likely to select a dopamine-blocking medication with a high risk for metabolic adverse effects. Similarly, for patients who have comorbid inflammatory conditions, the use of anti-inflammatory agents may be a wise choice. Patients who have accompanying neurocognitive symptoms may benefit from a dopamine agonist medication. For patients with limited resources, light box therapy may not be attainable and would not be a reasonable recommendation. In that case, a recommendation to sit outdoors for 30 minutes every morning would be more realistic. One potential benefit of using older generic medications is that they may be more accessible than newer brand-name drugs. Tailoring treatment selections to the patient’s individual needs and preferences may increase the likelihood of success.

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.


1. Treatment guidelines: bipolar disorder. American Association of Psychiatric Pharmacists. Accessed July 19, 2022.

2. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.

3. Ghaemi SN. Levels of evidence. Psychiatric Times. 2010;27(1).

4. Rosenblat JD, Kakar R, Berk M, et al. Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 2016;18(2):89-101.

5. Ayorech Z, Tracy DK, Baumeister D, Giaroli G. Taking the fuel out of the fire: evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders. J Affect Disord. 2015;174:467-478.

6. Fernandes BS, Steiner J, Molendijk ML, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(12):1147-1156.

7. Alam R, Abdolmaleky HM, Zhou J-R. Microbiome, inflammation, epigenetic alterations, and mental diseases. Am J Med Genet Part B Neuropsychiatr Genet. 2017;174(6):651-660.

8. Zhang P, Kong L, Huang H, et al. Gut microbiota – a potential contributor in the pathogenesis of bipolar disorder. Front Neurosci. 2022;16:830748.

9. Grandjean EL, van Zonneveld SM, Sommer IEC, Haarman BCM. Anti-inflammatory dietary patterns to treat bipolar disorder? J Affect Disord. 2022;311:254-255.

10. Borkent J, Ioannou M, Laman JD, et al. Role of the gut microbiome in three major psychiatric disorders. Psychol Med. 2022;52(7):1222-1242.

11. Husain MI, Strawbridge R, Ra Stokes P, Young AH. Anti-inflammatory treatments for mood disorders: systematic review and meta-analysis. J Psychopharmacol. 2017;31(9):1137-1148.

12. Martins LB, Braga Tibães JR, Sanches M, et al. Nutrition-based interventions for mood disorders. Expert Rev Neurother. 2021;21(3):303-315.

13. Marx W, Moseley G, Berk M, Jacka F. Nutritional psychiatry: the present state of the evidence. Proc Nutr Soc. 2017;76(4):427-436.

14. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The validity of the Mini International Neuropsychiatric Interview (MINI) according to the SCID-P and its reliability. Eur Psychiatry. 1997;12(5):232-241.

15. Aiken CB, Weisler RH, Sachs GS. The Bipolarity Index: a clinician-rated measure of diagnostic confidence. J Affect Disord. 2015;177:59-64.

16. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-258.

17. McLennan JD, MacMillan HL, Afifi TO. Questioning the use of adverse childhood experiences (ACEs) questionnaires. Child Abus Negl. 2020;101:104331.

18. Weathers FW, Bovin MJ, Lee DJ, et al. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): development and initial psychometric evaluation in military veterans. Psychol Assess. 2018;30(3):383-395.

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