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

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.

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.

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

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-HT_2A 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.”

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

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

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.

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