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Academic Highlights

Expanded Treatment Options and Addressing Unmet Needs in the Diagnosis and Treatment of Bipolar Disorder

Joseph F. Goldberg, MDa; Melissa P. DelBello, MD, MSb; and Holly A. Swartz, MDc

Published: November 16, 2022

Abstract

Bipolar disorder presents on a spectrum, with bipolar depression on one end and bipolar I on the other and a host of other presentations in between. In addition to its many permutations and the difficulty of differentiating between diagnoses, comorbidities, incorrect treatment, and low self-report contribute to delayed diagnoses and inappropriate or delayed treatment. Once a diagnosis is reached, the latest evidence of the safety and efficacy profiles of existing and emerging treatments adds to the complexity when developing treatment strategies for patients with bipolar disorder. As guidelines are updated and new treatments become available, developing individualized treatment regimens is key and collaboration between clinician and patient and family is critical in optimizing patient outcomes. New treatment options can reduce some of the side effect burdens associated with treating bipolar disorder, and clinicians should use measurement-based care to assess whether treatment changes are necessary, which requires engaging with the patient to monitor efficacy and manage side effects. It is important to ensure that the patient and family understand the information to foster informed decision making and create a better therapeutic alliance. Involving patients in designing their own treatment strategies according to their tolerability criteria can help combat the 90% nonadherence rate, and ultimately lead to better patient care.

To cite: Goldberg JF, DelBello MP, Swartz HA. Expanded treatment options and addressing unmet needs in the diagnosis and treatment of bipolar disorder. J Clin Psychiatry. 2022;83(6):MS21058AH5.
To share: https://doi.org/10.4088/JCP.MS21058AH5
© Copyright 2022 Physicians Postgraduate Press, Inc.

aIcahn School of Medicine at Mt. Sinai, New York, New York
bUniversity of Cincinnati College of Medicine, Cincinnati, Ohio
cUniversity of Pittsburgh, Pittsburgh, Pennsylvania.

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

Bipolar I disorder has a lifetime prevalence rate of 1%, although some studies estimate a prevalence rate of 2.6%–6%.1 Bipolar disorder (BD) is often misdiagnosed, with an average delay from symptom onset to diagnosis of 10 to 15 years.1 Patients who are misdiagnosed or receive a delayed diagnosis either go untreated or receive inappropriate treatment and experience persistent or worsening symptoms and comorbidities. This report is based on a series of 6 discussions between Joseph F. Goldberg, MD; Melissa P. DelBello, MD, MS; and Holly A. Swartz, MD, and will address how to diagnose BD and select the most appropriate treatment strategy for each patient.

See all 6 bipolar disorder activities in the Bipolar Disorder Education Collection

SCREENING AND ACCURATE DIAGNOSIS OF PATIENTS WITH BD TYPE I AND TYPE II

Dr Goldberg opened the first discussion by addressing the challenge that clinicians face in differentiating between depression and the types of BD due to the spectrum-like nature of the disease. He noted that recognizing the polarity, frequency, and duration of symptoms of BD can aid in diagnosis.2 Early diagnosis of BD is key to increasing better outcomes in patients with BD. Dr Goldberg stated that the average delay from symptom onset to diagnosis is 10 years, and more than half of patients see 3 or more clinicians before receiving an accurate diagnosis.1,3,4,5 A delayed diagnosis increases the risk of inappropriate treatment and comorbidities. Existing comorbidities such as attention-deficit/hyperactivity disorder (ADHD) and substance use also present challenges in making accurate diagnoses.5 Special screenings, including the Mood Disorder Questionnaire, the Hypomania/Mania Symptom Checklist, and a number of depression rating scales and questionnaires, as well as charting and taking a comprehensive longitudinal history, are important tools in assessing BD in patients.4,5

The majority of patients with BD initially present with a depressive episode, and a diagnosis of unipolar depression would be indicated.4,5 It is not until they polarity-convert that a diagnosis of BD can be made. This initial misdiagnosis can potentially lead to inappropriate treatment strategies, particularly antidepressants.4,5,6 Dr Swartz emphasized that treating BD with antidepressants risks the occurrence of switching, or triggering mania or hypomania, as well as ineffectively treating bipolar depression.4,5

Differentiating between the types of BD requires attention to the severity and duration of symptoms. BD I is defined by manic episodes that last 1 week or require hospitalization. BD I usually includes depressive episodes that last 2 weeks or include depressive episodes with mixed features, meaning having depressive and manic symptoms at the same time.2 BD II is defined by hypomanic and depressive episodes, with hypomania described as less extreme with shorter duration and less functional impairment than mania.2 Cyclothymia includes periods of hypomanic symptoms and depressive symptoms that last at least 2 years, or 1 year for children and adolescents,2 and symptoms do not last long enough to constitute full episodes of either hypomania or major depression.

Dr DelBello offered many insights into the presentations, diagnoses, treatment, and comorbidities of BD in children and adolescents. The spectrum model of BD applies in the pediatric setting as well, and symptom presentations are many times described as unspecified, subsyndromal, or prodromal, without explicit unipolar depression or manic manifestations.7 Taking a family history, noting the presence of substance use and other comorbidities such as ADHD as well as adverse reactions to antidepressants, can provide key indicators of the risk of BD in children and adolescents.7 Misdiagnosis and inappropriate treatment, particularly with antidepressants, can risk unmasking or accelerating the onset of the disease.8 The recommended treatments for BD, mood stabilizers and second-generation antipsychotics, also increase the risk of metabolic side effects in children and adolescents.9

Patient Perspective

“When I’m manic, I tend to lose control of myself and my activities. I also experience psychosis, which is when you lose touch with reality. When I’m hypomanic, I’m very energetic. I’m impulsive. I’m risk-taking. I can be irresponsible in my decisions….You can treat mania pretty quickly when you catch it. But the depression lasts for months and for years. It’s the most debilitating part of the illness. And it’s very, very discouraging. It’s very demotivating. You can’t function during the day. You can’t pursue recovery, and recovery is what we want. But we lack the motivation to pursue these goals. And I like to say it’s the mania that gets you into to trouble, but it’s the depression that can kill you.”

Case Practice Question

Case 1. Richard is a 26-year-old patient who presents with depression. He reports having been very active in the past 4 days, completing several tasks in the same day, feeling happier than he has ever felt, and not needing as much sleep.

What steps do you take?

 a. Prescribe the patient an antidepressant.
b. Use the CAGE questionnaire.
c. Take a comprehensive history of the patient.
d. Ask the patient if he feels better and can drive himself home.

TREATMENT OPTIONS FOR BD I AND BD II

Dr Swartz helped kick off episode 2 by introducing the 3 categories of mood stabilizing medications typically used in treating BD, which include antipsychotics, anticonvulsants, and lithium (Table 1). Swartz described mood stabilizers as “managing BD 101.” “Mood stabilizers help individuals ideally maintain a constant euthymic baseline state, either addressing depression or addressing mania, or in the maintenance phase of the disorder.”

Lithium is considered the gold standard of treatment for BD, particularly in patients with a mania-predominant course of illness or who have a family history of responding to the compound.10 Second-generation antipsychotics, or atypical antipsychotics, used to treat bipolar depression include olanzapine-fluoxetine combination, quetiapine, lurasidone, cariprazine, and the newly approved lumateperone. According to Dr Swartz, these drugs have shown robust data in treating bipolar depression and have agent-specific effects regarding polarity.12

Dr Goldberg described the mechanism of action of two of the newer second-generation antipsychotics approved for BD, cariprazine and lumateperone. “If in your brain there are dopamine tracks that are overactive, let’s say your mesolimbic pathway when you’re manic, [cariprazine will] bring down dopamine,” Goldberg pointed out. “And in tracks in the brain where there’s underactivity, like the mesocortical pathway, where you can get depression or inattention, you might actually raise dopamine.”10 Lumateperone binds to the 5-HT2A and the D2 receptors and is thought to indirectly modulate glutamate transmission. It received recent approval to treat both bipolar I and II depression, an exciting prospect in that there are limited data in the treatment of BD II depression.13

The anticonvulsants divalproex, lamotrigine, and carbamazepine have demonstrated some efficacy in treating BD. Specifically, lamotrigine has an FDA indication as a maintenance treatment for BD while also showing off-label efficacy in the treatment of bipolar depression both as a monotherapy and as an adjunct therapy.10 The combination of the atypical antipsychotic olanzapine with the opioid antagonist samidorphan is indicated for the acute treatment of manic or mixed episodes as a monotherapy or an adjunct therapy with lithium or valproate in BD I as well as a maintenance monotherapy. As an opioid antagonist, samidorphan combined with olanzapine is effective in mitigating weight gain associated with olanzapine, leading to better tolerance and adherence.14

Non-racemic amisulpride (SEP-4199) is in phase 3 clinical trials for the treatment of bipolar I depression,15 and S-ketamine, which is approved to treat unipolar depression, is also being studied for bipolar depression.16 There are limited agents approved for bipolar depression in the pediatric arena, which, for the most part, only include lurasidone and the combination treatment olanzapine/fluoxetine. “We don’t use a ton of lamotrigine because of all [the] complicating factors,” Dr DelBello said. “[With] lithium there are some data, not great data, as an adjunctive treatment for bipolar depression and depressive symptoms.”

Dr Goldberg re-emphasized the risks of treating patients with antidepressants. In an analysis of treatment-emergent mania across 10,098 depressed patients with BD across 51 studies, the pooled occurrence was 18.8%.17

“I guess we can’t leave out psychotherapy,” Dr Goldberg said. Dr Swartz responded with positive data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, citing that the receipt of any psychotherapy, including cognitive behavioral therapy (CBT), family-focused therapy (FFT), interpersonal and social rhythm therapy (IPSRT), and others was associated with shorter time to recovery.18

CBT helps identify and modify maladaptive cognitions and behaviors related to mood symptoms or episodes. Psychoeducation provides information about BD and treatments, helping individuals develop mastery of their illness and promoting better treatment adherence. FFT includes family members or significant others in the interventions and aids in improving communication and improving outcomes related to mood. IPSRT is designed to help individuals entrain underlying disturbances in circadian rhythms by paying attention to daily routines, schedules, and social rhythms. Lastly, peer support pairs patients with peers to decrease stigma, create a sense of empowerment, and facilitate validation.18

ACUTE AND MAINTENANCE TREATMENT STRATEGIES FOR BIPOLAR DEPRESSION

Current guidelines for managing BD include the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the National Institute for Clinical Excellence (NICE), which recommend lithium, lamotrigine, second-generation antipsychotics, and second-generation antipsychotics combined with lithium or valproate. Guidelines advise against the use of antidepressants as a monotherapy.10,19

The two novel atypical antipsychotics cariprazine and lumateperone were both approved in 2019 for the treatment of BD depression and are showing promising drug profiles.10,13 Cariprazine treats both mania and depression in BD I  as well as mixed episodes or mixed symptoms, and its dopamine agonist effects may help to treat dysfunction in cognition and attention.10,20,21 Lumateperone was approved for the treatment of depressive episodes associated with BD I or II, both as monotherapy and as adjunctive therapy in combination with lithium and valproate.13 In a 6-week, randomized, double-blind, placebo-controlled, multicenter study in adult patients with depressive episodes associated with BD I or II, lumateperone monotherapy versus placebo showed an improvement in the least-squares mean Montgomery-Asberg Depression Rating Scale (MADRS) total score versus placebo as monotherapy –16.7 points vs –12.1 points. Improvement was statistically significant as early as week 1.22

Clinicians treating their patients with BD with atypical antipsychotics should see improvements in symptoms at 2 weeks,23 a timeframe that helps the clinician forecast for the patient. Otherwise, if they are seeing no efficacy, they may want to change course or even consider increasing the dosage. However, many times an increase in dosage will have no effect. “Sometimes there’s clearly a subtherapeutic dose,” Dr Goldberg said. “It may have more to do with reaching a threshold….There’s sometimes a reflexive perception on the part of clinicians [that we] have to titrate up. Maybe that’s just in our DNA somehow.”

Lumateperone is recommended at a fixed dose of 42 mg per day.13,22 As a monotherapy and in combination with lithium or valproate, there was no single adverse reaction leading to discontinuation that occurred at a rate of > 2% in lumateperone-treated patients. The most common adverse reactions are somnolence/sedation, dizziness, nausea, and dry mouth.13,22 Overall, 6% of the patients who received cariprazine discontinued treatment due to an adverse reaction, compared with 5% of placebo-treated patients in bipolar depression trials, with the most common adverse reactions being nausea, akathisia, restlessness, and extrapyramidal symptoms.24 Drs Goldberg, DelBello, and Swartz agree that tolerability is an important factor when considering therapeutic strategies for patients. “Having an open communication, telling patients what the side effects might be, and if they’re particularly sensitive…or types of side effects are particularly problematic…then that is definitely something to consider,” Dr DelBello said. Most atypical antipsychotics carry risks associated with metabolic profile; however, lumateperone and cariprazine have less liability to metabolic consequences.20,22 The addition of metformin to mood stabilizers in patients with insulin resistance has demonstrated not only a reversal in insulin resistance but also a reduction in depression scores versus placebo in a randomized controlled trial.25 “What is really interesting…is that targeting the insulin resistance itself might have an impact on mood,” Dr Swartz said.

Dr Goldberg closed the discussion by pointing out the opportunities these advances provide in looking panoramically and systematically at treatment strategies and offering measurement-based care to optimize patient outcomes. “That really means engaging with the patient overall,” he said (Table 2).

SHARED DECISION MAKING: COMMUNICATING WITH PATIENTS AND FAMILIES ABOUT THE TREATMENT JOURNEY OF BIPOLAR DEPRESSION

According to the CANMAT guidelines for the management of patients with BD, “A strong therapeutic alliance is central to improve treatment adherence and outcomes. Providers should encourage individuals to actively participate in treatment planning, using a shared decision-making approach.”10 For this segment in the series, Drs Goldberg, DelBello, and Swartz explored best practices in implementing these guidelines in their clinical practice.

Clear communication is step 1 in achieving optimal results regarding the therapeutic alliance and paying close attention to the patient’s priorities and desired outcomes is part and parcel to the process. “It’s incumbent upon us to listen to their concerns, their experiences, and their perspectives, and use that as the guidepost,” Dr Swartz said. “They’re the expert. [We are] in a consultative role.” The clinician must then weigh in with their own priorities as well as the family members’ and try to reach a common goal. Providing scientific evidence that supports the patient’s priorities in a way that is easily comprehensible is important so that the patient can be an informed decision-maker in their own health outcomes and communicate that information to others if needed.

It is also important to be prepared for situations in which the patient is experiencing an episode, their decisional capacity or insight is impaired, or no one can agree. Dr DelBello suggests starting with where the patient is; leveraging communication, negotiation, and compromise; and agreeing upon a similar goal as an initial step in building the alliance. However, in a situation in which the patient is at imminent risk, clinicians are morally obligated to ensure safety. Dr Swartz suggests developing a relapse prevention plan with the patient when they are well so that their actions can align with their personal values during a time of crisis.

“[I like] to say the clinician is a bit like a travel agent,” Dr Goldberg said. “Where do you want to go? What do you want to be like when you get there? How do you want to get there? What have your past experiences been when you’ve traveled places?” In essence, he said, “No decision about me without me.”

Patient Perspective

“The most important thing that physicians can do is give their patients hope. They need hope that they can live the life they want. They have to emphasize self-determination and they have to emphasize a strengths-based approach as opposed to a deficits-based approach. They have to empower their patients. They have to encourage them to participate in their care.”

Case Practice Question

Case 2. Richard is a 26-year-old man with a history of bipolar episodes. He comes to your office with his wife, and the two seem to be having a disagreement. Richard appears agitated. His wife complains that he is drinking excessively. He complains of depression. Which of the following next steps is incorrect?

 a. Use Richard’s relapse prevention plan.
b. Communicate with both parties and come to a compromise.
c. Ensure all parties are safe.
d. Discontinue Richard’s current medication.

ACUTE AND MAINTENANCE TREATMENT STRATEGIES FOR BD I: FOCUS ON MIXED AND MANIC EPISODES

When treating a patient with BD I with manic or mixed episodes, consulting an expert opinion can be especially useful. The CANMAT and NICE guidelines are two of the most relevant guidelines in treating BD. “They are a really nice synthesis of available evidence with the input of expert consensus,” Dr Swartz said. “They incorporate into the materials…prose-based discussions of what the evidence tells us…which we can use as a guidepost to treatment.” She added that “one thing we have to keep in mind about guidelines is the date they are published. Things may have changed.”

Dr Goldberg offered a scenario from previous CANMAT guidelines26 to discuss, one in which a patient presents with a first manic episode and responds well to treatment. Should the patient be prescribed a lifetime of treatment?

Dr Swartz pointed to the phenomenon of unipolar mania, which meets the criteria of BD I according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Questions arise regarding the side effect burden that accompanies a lifetime of mood stabilizers to treat one manic episode of BD I. However, taking a patient off treatment with a mood stabilizer comes with its own hefty risk. The severity of the manic episode—a patient with hospitalized psychosis vs a patient with no family history of BD who remains well for a year on medication—can inform the decision. Close observation of the latter less severe case along with patient and family education could result in discontinuing medication, but the patient can never be declared free and clear. “I’ve not been able to get patients successfully off meds, even if they started with subsyndromal manifestations,” Dr DelBello said.

Currently, the most common antimanic mood stabilizers used to treat manic or mixed episodes in patients with BD include lithium, divalproex, and carbamazepine.27 The second-generation antipsychotic olanzapine is approved to treat bipolar mania and mixed episodes as a monotherapy and as an adjunctive therapy to lithium or divalproex in maintenance therapy of BD I.28 However, its metabolic burden is well-known, and it is reserved for more severe cases. The combination drug olanzapine/samidorphan has demonstrated a decrease in the metabolic side effects associated with olanzapine due to samidorphan’s properties as an opioid antagonist, which are thought to reduce appetite.29

Two other novel agents, the approved loxapine and the anticipated dexmedetomidine, have been developed for the treatment of acute bipolar agitation. Loxapine’s formulation as an inhalant has demonstrated rapid onset, and dexmedetomidine, as a sublingual agent, has been shown to contain acute agitation without the soporific effects of its predecessors.30

Patient Perspective

“You have to have a good relationship with your psychiatrist. Your psychiatrist has to be able to explain the medications, to explain the side effects. It’s very important for a psychiatrist to take those concerns seriously and not merely suggest that the patient doesn’t want to take medication, which is what happened to me when I would express concern over my medication. So, to properly address adherence issues, you have to have good relationships between your psychiatrist and patient to talk about those side effects.”

THERAPEUTIC TOLERABILITY AND ADHERENCE IN BD

BD is associated with high morbidity and mortality rates, with the life expectancy reduced by 10 years or more in patients with BD.31 It is estimated that between 25% and 60% of patients with BD will attempt suicide at least once during the course of the illness and between 4% and 19% will die from suicide.32 Treatment adherence is key to improving these numbers, and adherence is greatly dependent on tolerability.33

In a survey conducted by the patient advocacy group Depression and Bipolar Support Alliance (DBSA), 90% of patients with BD reported that they discontinued taking their medication at some point. Almost 60% of patients cited weight gain as the most significant concern for nonadherence.33 “You have to balance what tolerability and side effects are most important to [the patient] and that are most likely to impact their adherence,” Dr DelBello said.

Dr Goldberg suggested making a “shopping list” with the patient regarding balancing efficacy with tolerability. Dr DelBello suggested being proactive in minimizing side effects, particularly in initiating a second medication to combat side effects concomitantly with the initial treatment. Medications like metformin or olanzapine/samidorphan can help combat weight gain.25,14

Patient Perspective

“We have a lot of examples in the media of people living with bipolar II, which is a bipolar type that you can function with. You don’t see a lot of the severe examples of people with bipolar I. And typically, when I see those examples, they’re often police encounters. And so, I deal with a lot of stigma. And that was one of the reasons that I refused to accept my diagnosis. People with mental illness don’t have jobs. They’re unemployed. They don’t have relationships. They’re unhappy. Who wants to live this life? I internalized that stigma. It’s only since I’ve reached recovery that I’m really proud to have a mental illness. People with mental illness are very brave and courageous. They deal with very challenging life situations.”

CLINICAL POINTS

  • The use of rating scales, a longitudinal history, charting, and checking for the presence of comorbidities can help in the diagnosis of BD.
  • Clinicians should consider patients’ concerns with medication tolerability and even initiate concomitant treatments that address side effects when developing treatment strategies to ensure adherence.
  • Most bipolar patients do not respond to antidepressants, and some may experience inductions of mania or cycle accelerations over time with antidepressants.
  • Second-generation antipsychotics olanzapine, quetiapine, lurasidone, cariprazine, and lumateperone and the anticonvulsant lamotrigine are used to treat bipolar depression.
  • Lithium; the anticonvulsants divalproex, lamotrigine, and carbamazepine; and the second-generation antipsychotic olanzapine are used to treat bipolar mania and mixed episodes.

Disclosure of off-label usage: The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the US Food and Drug Administration. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses. Please refer to the official prescribing information for each product for discussion of approved indicators, contraindications, and warnings.

REFERENCES

  1. Lublóy Á, Keresztúri JL, Németh A, et al. Exploring factors of diagnostic delay for patients with bipolar disorder: a population-based cohort study. BMC Psychiatry. 2020;20(1):75. PubMed CrossRef
  2. Bipolar Disorder. National Institute of Mental Health (NIMH). NIMH website. https://www.nimh.nih.gov/health/topics/bipolar-disorder. Accessed July 18, 2022.
  3. Dagani J, Signorini G, Nielssen O, et al. Meta-analysis of the interval between the onset and management of bipolar disorder. Can J Psychiatry. 2017;62(4):247–258. PubMed CrossRef
  4. Hirschfeld RM. Differential diagnosis of bipolar disorder and major depressive disorder. J Affect Disord. 2014;169(suppl 1):S12–S16. PubMed CrossRef
  5. Singh T, Rajput M. Misdiagnosis of bipolar disorder. Psychiatry (Edgmont). 2006;3(10):57–63. PubMed
  6. El-Mallakh RS, Karippot A. Use of antidepressants to treat depression in bipolar disorder. Psychiatr Serv. 2002;53(5):580–584. PubMed CrossRef
  7. Wozniak J, Uchida M, Faraone SV, et al. Similar familial underpinnings for full and subsyndromal pediatric bipolar disorder: a familial risk analysis. Bipolar Disord. 2017;19(3):168–175. PubMed CrossRef
  8. Goldsmith M, Singh M, Chang K. Antidepressants and psychostimulants in pediatric populations: is there an association with mania? Paediatr Drugs. 2011;13(4):225–243. PubMed CrossRef
  9. Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry. 2007;46(6):687–700. PubMed CrossRef
  10. 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. PubMed CrossRef
  11. Derry S, Moore RA. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials. BMC Psychiatry. 2007;7(1):40. PubMed CrossRef
  12. Bahji A, Ermacora D, Stephenson C, et al. Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: A systematic review and network meta-analysis. J Affect Disord. 2020;269:154–184. PubMed CrossRef
  13. Caplyta. Prescribing information. Intra-Cellular Therapies. 2021. Accessed July 21, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209500s005s006lbl.pdf
  14. Lybalvi. Prescribing information. Alkermes. 2021. Accessed July 20, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213378s000lbl.pdf
  15. Loebel A, Koblan KS, Tsai J, et al. A randomized, double-blind, placebo-controlled proof-of-concept trial to evaluate the efficacy and safety of non-racemic amisulpride (SEP-4199) for the treatment of bipolar I depression. J Affect Disord. 2022;296:549–558. PubMed CrossRef
  16. How Ketamine Drug Helps with Depression. Yale Medicine website. https://www.yalemedicine.org/news/ketamine-depression. Accessed July 20, 2022.
  17. Fornaro M, Anastasia A, Novello S, et al. Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 2018;20(3):195–227. PubMed CrossRef
  18. Novick DM, Swartz HA. Evidence-based psychotherapies for bipolar disorder. Focus Am Psychiatr Publ. 2019;17(3):238–248. PubMed CrossRef
  19. Overview | Bipolar disorder: assessment and management | Guidance | NICE. NICE website. https://www.nice.org.uk/guidance/cg185. Accessed July 21, 2022.
  20. Laszlovszky I, Barabássy Á, Németh G. Cariprazine, a broad-spectrum antipsychotic for the treatment of schizophrenia: pharmacology, efficacy, and safety. Adv Ther. 2021;38(7):3652–3673. PubMed CrossRef
  21. Stahl SM, Laredo S, Morrissette DA. Cariprazine as a treatment across the bipolar I spectrum from depression to mania: mechanism of action and review of clinical data. Ther Adv Psychopharmacol. 2020;10:2045125320905752. PubMed CrossRef
  22. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry. 2021;178(12):1098–1106. PubMed CrossRef
  23. How fast do bipolar meds work? MHA Screening. MHA website. https://screening.mhanational.org/content/how-fast-do-bipolar-meds-work/?layout=actions_neutral. Accessed July 21, 2022.
  24. Vraylar. Prescribing information. Allergan. 2019. Accessed July 25, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204370s006lbl.pdf.
  25. Calkin CV, Chengappa KNR, Cairns K, et al. Treating insulin resistance with metformin as a strategy to improve clinical outcomes in treatment-resistant bipolar depression (the TRIO-BD Study): a randomized, quadruple-masked, placebo-controlled clinical trial. J Clin Psychiatry. 2022;83(2):39459. PubMed CrossRef
  26. Yatham LN, Kennedy SH, O’Donovan C, et al; Canadian Network for Mood and Anxiety Treatments. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(suppl 3):5–69. PubMed CrossRef
  27. Gould TD, Chen G, Manji HK. Mood stabilizer psychopharmacology. Clin Neurosci Res. 2002;2(3-4):193–212. PubMed CrossRef
  28. Narasimhan M, Bruce TO, Masand P. Review of olanzapine in the management of bipolar disorders. Neuropsychiatr Dis Treat. 2007;3(5):579–587. PubMed
  29. Haddad HW, Boardman E, Williams B, et al. Combination olanzapine and samidorphan for the management of schizophrenia and bipolar 1 disorder in adults: a narrative review. Health Psychol Res. 2022;10(3):34224. PubMed CrossRef
  30. FDA Approves Dexmedetomidine Sublingual Film for Acute Agitation. Drug Topics website. Accessed July 21, 2022. https://www.drugtopics.com/view/fda-approves-dexmedetomidine-sublingual-film-for-acute-agitation.
  31. Hossain S, Mainali P, Bhimanadham NN, et al. Medical and psychiatric comorbidities in bipolar disorder: insights from national inpatient population-based study. Cureus. 2019;11(9):e5636. PubMed CrossRef
  32. Novick DM, Swartz HA, Frank E. Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar Disord. 2010;12(1):1–9. PubMed CrossRef
  33. Rosenblat JD, Simon GE, Sachs GS, et al. Treatment effectiveness and tolerability outcomes that are most important to individuals with bipolar and unipolar depression. J Affect Disord. 2019;243:116–120. PubMed CrossRef
  34. Citrome L. Food and Drug Administration-approved treatments for acute bipolar depression: what we have and what we need. J Clin Psychopharmacol. 2020;40(4):334–338. PubMed CrossRef

 

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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

Overview

Bipolar disorder presents on a spectrum, with bipolar depression on one end and bipolar I on the other and a host of other presentations in between. In addition to its many permutations and the difficulty of differentiating between diagnoses, comorbidities, incorrect treatment, and low self-report contribute to delayed diagnoses and inappropriate or delayed treatment. Once a diagnosis is reached, the latest evidence of the safety and efficacy profiles of existing and emerging treatments adds to the complexity when developing treatment strategies for patients with bipolar disorder. As guidelines are updated and new treatments become available, developing individualized treatment regimens is key and collaboration between clinician and patient and family is critical in optimizing patient outcomes. New treatment options can reduce some of the side effect burdens associated with treating bipolar disorder, and clinicians should use measurement-based care to assess whether treatment changes are necessary, which requires engaging with the patient to monitor efficacy and manage side effects. It is important to ensure that the patient and family understand the information to foster informed decision making and create a better therapeutic alliance. Involving patients in designing their own treatment strategies according to their tolerability criteria can help combat the 90% nonadherence rate, and ultimately lead to better patient care.

Learning Objectives

After studying this article, you should be able to:

  • Screen patients with major depressive episodes for bipolar I and II disorder (bipolar depression)
  • Accurately diagnose patients with bipolar I disorder with manic or mixed episodes
  • Select a treatment regimen (monotherapy or combination treatment) to alleviate bipolar depression without causing the patient an undue side effect burden
  • Use measurement-based care in long-term bipolar disorder management
  • Provide efficacious and tolerable treatment for acute episodes of bipolar I disorder
  • Evaluate evidence-based treatments available for the maintenance of bipolar I disorder, including mood stabilizers, psychotherapy, and novel therapies

Target Audience

Psychiatrists & psychiatry NPs and PAs; primary care physicians, NPs, and PAs

Support Statement

Supported by educational grants from Alkermes, Inc. and Intra-Cellular Therapies, Inc.

Learning Objective

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

  • Screen patients with major depressive episodes for bipolar I and II disorder (bipolar depression)
  • Accurately diagnose patients with bipolar I disorder with manic or mixed episodes
  • Select a treatment regimen (monotherapy or combination treatment) to alleviate bipolar depression without causing the patient an undue side effect burden
  • Use measurement-based care in long-term bipolar disorder management
  • Provide efficacious and tolerable treatment for acute episodes of bipolar I disorder
  • Evaluate evidence-based treatments available for the maintenance of bipolar I disorder, including mood stabilizers, psychotherapy, and novel therapies

Release, Review, and Expiration Dates

This CME activity was published in November 2022 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2023. The latest review of this material was October 2022.

Statement of Need and Purpose

Accurate diagnosis of bipolar I disorder is often delayed by years, while patients either go untreated or receive inappropriate treatment. Given the substantial illness burden, misdiagnosis is a critical unmet need. Additionally, treatment options for bipolar I disorder have expanded. The importance of certain side effects to patients should be discussed to improve the therapeutic alliance and their adherence.
Clinicians need education on clinical presentations, the use of screening tools, and differential diagnosis of bipolar I disorder. Education is also needed about evidence on the efficacy and tolerability of treatments for bipolar I disorder to enable clinicians to select a regimen that alleviates a patient’s symptoms without causing an undue burden of side effects.

Clinicians too often misdiagnose bipolar depression. Accurate diagnosis is often delayed by years, while patients either go untreated or receive inappropriate treatment. When bipolar disorder is treated, many clinicians fail to use measurement-based care to assess whether treatment changes are necessary. New treatments are on the horizon, and clinicians need education on:

  • Recognition of bipolar depression, e.g., risk factors, signs, assessment strategies
  • Latest evidence on safety and efficacy of existing & emerging treatments for bipolar depression
  • Selection and implementation of monotherapy versus combination therapies based on guidelines and expert recommendations
  • Ongoing measurement-based care for bipolar depression to monitor efficacy and side effects and offer individualized treatment regimens

Unlabeled and Investigational Usage

The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use.

No endorsement of unapproved products or uses is made or implied by coverage of these products or uses.

Please refer to the official prescribing information for each product for discussion of approved indicators, contraindications and warnings.

Review Process

The faculty members agreed to provide a balanced and evidence-based presentation and discussed the topics and CME objectives 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 the Chair.

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

© Copyright 2022 Physicians Postgraduate Press, Inc.

Faculty

Joseph F. Goldberg, M.D.
Clinical Professor of Psychiatry
Icahn School of Medicine at Mount Sinai
New York, NY

Holly A. Swartz, M.D.
Professor of Psychiatry
University of Pittsburgh School of Medicine
Pittsburgh, PA

Melissa P. DelBello, MD, MS
Professor of Psychiatry and Pediatrics
Dr. Stanley and Mickey Kaplan Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
University of Cincinnati College of Medicine
Cincinnati, OH

Financial Disclosure

The CME Institute adheres to the Standards for Integrity and Independence in Accredited Continuing Education of the Accreditation Council for Continuing Medical Education (ACCME). Any individuals in a position to control the content of a continuing education activity, including faculty, content developers, reviewers, staff, and others, are required to disclose to learners the presence or absence of any relevant financial relationships with an ACCME-defined ineligible company within the preceding 24 months of the activity. The ACCME defines an “ineligible company” as one whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

The CME Institute has mitigated all relevant conflicts of interest prior to the commencement of the activity. None of the individuals involved in the content have relevant financial relationships with ineligible companies except the following:

Dr Goldberg has served as a consultant for BioXcel, Intracellular Therapies, Jazz Pharmaceuticals, Lundbeck, Otsuka, Sunovion; received honoraria from Abbvie, Alkermes, Intracellular Therapies, Sunovion; has served on speaker/advisory boards for Jazz Pharmaceuticals, Lundbeck; and receives royalties from American Psychiatric Association Publishing and Cambridge University Press. Dr DelBello has served as a consultant for Medscape, CME Inc., Sage, Myriad, and Alkermes; received grant/research support from Shire, Alkermes, Acadia, Pfizer, Lundbeck, Johnson and Johnson, and Otsuka; and served on speakers/advisory boards for Myriad, Assurex, Sage, Alkermes, and Johnson and Johnson. Dr Swartz received honoraria from Medscape; has served on speaker/advisory boards for Intracellular Therapeutics; and receives royalties from Wolters Kluwer and American Psychiatric Association Publishing.

Marlene P. Freeman, MD, Editor in Chief, Boston, MA, has received research funding from JayMac and Sage; has been a member of the Independent Data Safety and Monitoring Committee for Janssen (Johnson & Johnson), Novartis, and Neurocrine; and has served on advisory boards for Eliem and Sage. As an employee of Massachusetts General Hospital (MGH), Dr Freeman works with the MGH National Pregnancy Registry, which receives funding from Alkermes, Aurobindo, AuroMedics, Johnson & Johnson/Janssen, Otsuka, Sage, Sunovion, Supernus, and Teva, and works with the MGH Clinical Trials Network and Institute, which receives research funding from multiple pharmaceutical companies and the National Institute of Mental Health. Dr Freeman has also received royalties through MGH for the Massachusetts General Hospital Female Reproductive Lifecycle and Hormones Questionnaire.

Michael R. Page, PharmD, RPh, Independent Medical Director/Medical Writer, Plainsboro, New Jersey, serves as a consultant for BioCentric, Inc., and American Medical Communications, Inc.

None of the other planners, reviewers, and CME Institute staff for this educational activity have relevant financial relationships with ineligible companies to disclose. All relevant financial relationships have been mitigated.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note: The American Nurses Credentialing Center (ANCC) and the American Academy of Physician Assistants (AAPA) accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Volume: 83

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