Current and Emerging Therapies for Bipolar Disorder

US Pharm. 2024;49(5):22-34.

ABSTRACT: Bipolar disorder (BD) is a complex and lifelong mental health disorder characterized by episodes of mania, hypomania, and/or depression. Affected individuals are often diagnosed with comorbidities including metabolic syndrome and substance use disorder, and life expectancy is partly reduced by suicidal ideation. Current pharmacotherapies, many of which were serendipitously discovered, sufficiently target aberrant neurotransmission but yield inadequate outcomes and cause burdensome side effects. Alternative treatments with fewer adverse effects are in development. Some alternative pharmacotherapies entail reappropriation of classic drugs, such as ketamine and scopolamine. Nonpharmacologic treatments help individuals develop coping mechanisms, improve medication adherence, and establish mood-stabilizing social rhythms.

Bipolar disorder (BD) is a severe and chronic mental health disorder characterized by intense mood swings that are often irrespective of external circumstances.¹ Mood ranges from euphoria (highs) to depression (lows).¹ Despite its classification as a “mood disorder,” BD also negatively impacts cognition and behavior.² Individuals with BD can experience feelings of guilt and worthlessness, engage in substance abuse, and consider suicide, with 25% to 60% of affected individuals attempting suicide and 5% to 20% following through with it.^2-6 Suicidal behavior is more strongly associated with mixed states (i.e., simultaneous symptoms of mania and depression) than with pure mania or hypomania, largely attributable to increased time spent in a depressive state.^2,7,8 Psychotic events, including delusions and hallucinations (more associated with bipolar mania), are possible.⁹ Individuals with BD commonly exhibit comorbidities, including cardiovascular and metabolic diseases (e.g., hypertension, dyslipidemia, hypertriglyceridemia, insulin resistance, abdominal obesity), which can further impair executive function.^10-12 Life expectancy is generally reduced by at least a decade.¹³ According to the Depression and Bipolar Support Alliance, a nonprofit organization providing support for people with BD and depression, approximately 5.7 million Americans aged ≥18 years (~2.6% of the population) have been diagnosed with BD.¹⁴ The current National Institute of Mental Health estimate is slightly higher at 2.8%.¹⁵ Epidemiologic data indicate that BD is equally distributed across sex, ethnicity, and geographic area (urban vs. rural).^16,17 

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5) delineates BD subtypes, including bipolar I (BD I), bipolar II (BD II), and cyclothymia (see TABLE 1).¹⁸ A manic episode, or mania, is described as a distinct period of abnormally and persistently elevated mood that lasts for at least 1 week (or shorter if hospitalization is required) and is associated with significant impairment, psychosis, and/or need for hospitalization.^5,19 Manic symptoms include abnormally elevated mood (i.e., euphoria, irritability, hyperactivity).^2,18 A hypomanic mood episode resembles mania; however, it has a shorter duration, lasting only 4 days.^2,5,18 Hypomania is not severe enough to cause marked impairment or require hospitalization.² Depressive symptomology includes depressed mood and an emotional state manifesting as anhedonia, apathy, sadness, hopelessness, and pessimism.⁵ Thus, a distinguishing feature between BD I and BD II is the presence of either a manic or hypomanic state, respectively.²⁰ Multiple grading scales are used to categorize mood disorders and select appropriate treatment regimens, including the Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS).²¹ The YMRS quantitatively assesses manic symptom severity, whereas the MADRS monitors changes in depressive symptom severity in response to antidepressant therapy.^22,23 The U.S. aggregate lifetime (and 12-month) prevalence estimates are 1.0% (0.6%) for BD I and 1.1% (0.8%) for BD II.²⁴

Etiology and Pathophysiology

The etiopathophysiology of BD remains largely unknown. It likely involves a complex interplay of genetic, epigenetic, neurochemical, and environmental factors.²⁵ Imbalances in key intracellular signaling systems that regulate mood and behavior are implicated. Upward of 30 dysregulated genes are linked to an increased risk of developing BD.^25,26 These genes encode for various neurotransmitter receptors (e.g., dopamine, serotonin) as well as regulatory enzymes involved in neurotransmitter production, breakdown, and cellular detoxification (e.g., aldehyde dehydrogenase, alcohol dehydrogenase, monoamine oxidase, tryptophan hydroxylase).^19,25 Normal levels of neurotrophins, such as brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, and neurotrophin-4, are important for mediating neuroplasticity (i.e., the ability of neural networks in the brain to adapt, grow, and reorganize via structural and functional changes).^27,28 A reduced BDNF serum level, a protein that plays key roles in neuronal survival and growth, neurotransmitter modulation, and neuronal plasticity critical for learning and memory, is implicated in the development of BD.^29-33 Regarding genetic susceptibility, children of one parent or both parents with a history of BD have a 15% to 30% and 50% to 75% risk of developing the disorder themselves, respectively.¹⁴ Other culprits include mitochondrial dysfunction, oxidative stress, immune-inflammatory imbalance, and a compromised hypothalamic-pituitary-adrenal axis.²⁵ Childhood mistreatment (emotional abuse, neglect, trauma) is also linked to an increased risk of developing BD.²⁵ Nearly 60% of adults report a stressful trigger before a manic or depressive episode.^17,25 Additional risk factors include prenatal and perinatal factors (i.e., perinatal infections, obstetric complications), psychological stressors (i.e., life events), substance misuse (e.g., cannabis, opioids, tranquilizers, stimulants, sedatives, cocaine), and medical comorbidities (e.g., irritable bowel syndrome, asthma, obesity, migraines, multiple sclerosis).¹⁷

Diagnosis

BD I: An individual must experience at least one manic episode that is unattributable to schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or any other psychotic disorder.^18,34 When selecting a diagnostic code, the following items should be listed sequentially: BD I, type of episode experienced including severity (mild, moderate, or severe); psychotic features; and remission status.^18,34 The diagnostic code should be followed by as many uncoded specifiers as apply to the current or most recent episode.^18,34

BD II: An individual must experience a current hypomanic episode or have experienced one previously.^18,34 At least one major depressive episode that is not attributable to any other mood disorder must also be experienced.^18,34 BD II patients experience anguish and limitations to functional ability (e.g., social, occupational) due to the depression experienced.^18,34 Although the type of current or most recent episode as well as severity/psychotic/remission specifiers are not accounted for in a BD II diagnostic code, these characteristics should still be specified in writing following one specific diagnostic code (ICD-10 F31.81).^18,34

Current Pharmacotherapies

Mainstay BD medications are mood stabilizers, atypical antipsychotics, and antidepressants (TABLE 2). Although their mechanisms of action are generally unclear, they restore normal adrenergic, catecholaminergic, dopaminergic, gamma-aminobutyric acid-ergic (GABAergic), glutamatergic, histaminergic, ionic, and serotonergic signaling. Safety and efficacy require agent- and BD subtype–specific dosing regimens. Despite often being serendipitously discovered and sometimes achieving suboptimal outcomes, they display varying degrees of superiority over placebo and/or alternative BD medications as monotherapy or adjunctive therapy in terms of alleviating symptom severity (as assessed by BD grading scales) and prolonging time to escalated intervention (e.g., hospitalization).^35-49 Alarmingly, long-term use of lithium, the first-line and cornerstone maintenance therapy for bipolar mania, is linked to decreased kidney concentrating ability, hypothyroidism, hypercalcemia, and hyperparathyroidism.⁵⁰ Lamotrigine (Lamictal) is a BD I maintenance treatment that is administered in combination with lithium in adults experiencing acute BD mood episodes because it delays time to occurrence.^47,51,52 Lumateperone (Caplyta), a more recently FDA-approved medication for BD I and BD II depression, differs from other agents by its high affinity and association for the 5-HT2A receptor, with less D2 and alpha-1 adrenergic receptor affinity.^53,54 This feature results in fewer side effects (little to no weight gain, fewer extrapyramidal symptoms [EPS]). Lumateperone has no known contraindications other than hypersensitivity to drug ingredients; however, patients should avoid concomitant use with cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and if they have moderate-to-severe hepatic impairment.⁵⁵

Emerging Treatments

Despite their benefits, currently used medications can elicit bothersome and potentially serious side effects that might hinder patient compliance and cause significant harm. Pharmacologic treatments as well as nonpharmacologic therapies with fewer adverse effects and more tolerability are in development. They generally work to ameliorate disease-causing neurotransmitter dysfunction, perturbed cerebral glucose metabolism, and oxidative stress.

Ketamine: This anesthetic, antidepressant, and psychotomimetic agent is an N-methyl-D-aspartate (NMDA) receptor antagonist.⁵⁶ Utilized for treatment-resistant, unipolar major depression and suicide ideation, low-dose IV ketamine infusion as standalone treatment at subpsychedelic dosages is also generally safe and effective for treatment-resistant BD.^57-64 Antidepressant actions target lack of interest and enjoyment.⁶⁵ Adverse effects include dissociation, elevated pulse and/or blood pressure, headache, nausea, anxiety, changes in vision, and muscle tension; however, these effects are generally well tolerated and usually abate within 2 hours of administration.^59,66 Typically dosed at 0.5 mg/kg, IV ketamine has a rapid onset (~30 seconds) and short elimination half-life (~2-4 hours), but its antidepressant effect lasts for 1 week following a single infusion.⁶³ The treatment holds superiority over placebo for up to 12 days, with 1-week-long superiority consistently observed in BD patients.⁵⁷ BD patients display alterations in glutamatergic dysfunction and cerebral glucose metabolism in brain regions involved in emotion and cognition, including the amygdala-sensorimotor pathway, hippocampus, and prefrontal cortex.^67,68 In preclinical mouse studies, ketamine improved depressive-like behavior by increasing cerebral glucose uptake; in humans, it facilitates prefrontal cortex glutamatergic neurotransmission and restores normal glucose metabolism.^69-71 Although several current clinical trials report promising results with acute use, more are needed to further ascertain the tolerability, safety, and efficacy of long-term use. Further studies are also required to address potential withdrawal effects since ketamine acts at the mu-opioid receptor.⁷² Frequent IV infusions of racemic ketamine may be intolerable, so ongoing studies are evaluating the efficacy of esketamine, the L-isomer of ketamine, nasal spray (Spravato).⁷³

Scopolamine: This agent is utilized to manage postoperative nausea, motion sickness, and hypersalivation.⁷⁴ Due to its antidepressant properties, it is being investigated as a rapid treatment option to reduce depressive symptoms in moderate-to-severe BD.⁷⁵ The antidepressant actions of scopolamine were gleaned from observations that physostigmine, a cholinesterase inhibitor, exacerbated depressive symptoms and promoted emotional instability in individuals with BD.⁷⁶ Scopolamine exerts opposite effects to those of physostigmine by inhibiting postganglionic cholinergic receptors. As a pan-muscarinic antagonist, scopolamine reduces the hypersensitivity associated with depressive episodes.⁷⁷ Findings from studies examining the utility of IV scopolamine in individuals with schizophrenia are promising and indicate potential for overlapping use in BD with no serious adverse effects.⁷⁸ A phase IIb clinical trial investigating the use of IV scopolamine to treat BD is currently under way.⁷⁹ Successful outcomes with IV scopolamine could pave the way for at-home administration as a dermal patch.⁸⁰

Dexmedetomidine: This agent (Igalmi) is a selective alpha-2 adrenergic receptor agonist with a quick onset of action and short half-life.⁸¹ Its hypnotic action has been leveraged to successfully treat mild-to-moderate agitation associated with BD and schizophrenia.^81-83 The noninvasive sublingual formulation (120-mg and 180-mg doses) exhibits no dopaminergic activity, which prevents EPS, such as akathisia and dystonia; these adverse effects are commonly seen with other treatments for acute agitation (e.g., intramuscular benzodiazepines).^81,84 Patients aged ≥65 years or with any degree of hepatic impairment should be dose-adjusted accordingly and may require subsequent dosing after initial administration.⁸⁵ Concomitant use with opioids, hypnotics, sedatives, anesthetics, and medications that may cause QT prolongation should be avoided, as dexmedetomidine is metabolized by cytochrome P450 2A6 (CYP2A6).⁸⁵

Risperidone: FDA-approved in 2023 and branded as Rykindo, this serotonin and norepinephrine reuptake inhibitor is a once-biweekly IM gluteal injection used to treat schizophrenia in adult patients.⁸⁶ It is currently being investigated as a potential BD treatment. Injection applies microsphere technology to deliver a long-acting, extended-release formulation of risperidone as an adjunctive therapy to lithium or divalproex, which could improve adherence and disorder management.^87,88 Individuals must establish oral tolerability to risperidone, as the injection must be initially administered with 7 days of oral risperidone. The recommended IM dosage is 25 mg every 2 weeks, with titration up to 37.5 mg or 50 mg at intervals of at least 4 weeks.⁸⁹ There are many warnings for risperidone, the most concerning being that it can cause death in elderly patients with dementia-related psychosis due to increased risk for adverse cardiovascular events, such as transient ischemic attacks and stroke.⁸⁹ Additional side effects include significant weight gain, tremor, and Parkinsonism.^89,90 Patients should be titrated appropriately if they have renal or hepatic impairment and should avoid use with strong CYP2D6 inhibitors and strong CYP3A4 inducers.⁸⁷

Cognitive Behavioral Therapy (CBT): CBT operates on the premise that thoughts, mood, and behavior influence each other and guides individuals to acknowledge their diagnosis, overcome depressive episodes, reconstruct negative thoughts, and recognize prodromal symptoms to prevent relapse.^34,101 In BD I patients, addition of CBT to mood-stabilizer pharmacotherapy results in higher social functioning, fewer mood symptoms, better coping mechanisms, and reduced fluctuations in manic symptoms compared with patients who are treated with mood-stabilizing agents only.¹⁰² Regular engagement in therapy sessions may help BD patients develop a form of cognitive control over their condition and prevent relapse.

Interpersonal and Social Rhythm Therapy (IPSRT): IPSRT focuses on averting disease flares and/or prolonging the intervals between occurrences.¹⁰³ IPSRT achieves this in BD patients by improving medication adherence, resolving stressful interpersonal situations, and reducing disruptions in social rhythms (e.g., patterns of daily routines and interactions).¹⁰³ Patients diagnosed with BD I who receive IPSRT live longer without a relapse and display more consistent social rhythms.¹⁰⁴

Transcranial Magnetic Stimulation (TMS): TMS is a noninvasive, brain-stimulating therapy for treatment-resistant depression approved by the FDA in 2008.¹⁰⁵ TMS administers a swift current pulse through a coil positioned over the scalp to stimulate cortical activity and evoke neuronal action potentials.¹⁰⁶ TMS may be effective for treatment-resistant BD depressive episodes, as ~50% of treatment-resistant BD participants respond favorably to TMS treatment, with an additional ~25% partially responding.¹⁰⁵

Investigational Approach

Calcium-Calmodulin–Dependent Protein Kinase Kinase-2 Activators (CaMKK2): The neuronal enzyme CaMKK2 regulates bioenergetic, metabolic, and neuronal processes governing higher order cognitive and behavioral functions, including mood, long-term memory, and other affective functions.⁹¹ CaMKK2 loss-of-function genetic polymorphisms and missense mutations are linked to disease etiopathophysiology.⁹¹ In preclinical mouse studies, genetic deletion of CaMKK2 results in bipolar-like behaviors that are ameliorated by lithium, which increases CaMKK2 activity.⁹² Oxidative stress, a hallmark of BD, increases with disorder severity.⁹³ Reactive oxygen species partly derived from increased lipid peroxidation rise with CaMKK2 deficiency and are elevated in serum from BD patients.^94-98 CaMKK2 suppresses lipid peroxidation by increasing the activity of a transcription factor that promotes the expression of antioxidant and detoxification enzymes, as well as that of the glutathione and thioredoxin antioxidant systems.^99,100 Activating CaMKK2-mediated signaling, therefore, shows potential as a viable pharmacotherapeutic strategy.

Challenges With Emerging Therapies

Novel therapies do have drawbacks. Drowsiness is possible with ketamine, so individuals should refrain from possibly unsafe activities within 24 hours of undergoing treatment.¹⁰⁷ Scopolamine use carries seizure potential.¹⁰⁸ With dexmedetomidine, patients should report any experiences of weakness, confusion, or excessive sweating within 48 hours of treatment.¹⁰⁹ Risperidone should be cautiously used during pregnancy and avoided with breastfeeding over concerns about it affecting newborns postnatally and passing into breastmilk.¹¹⁰ CBT can make individuals emotionally uncomfortable because it involves exploring potentially painful feelings and experiences.¹¹¹ Side effects of TMS include scalp discomfort and pain, headache, lightheadedness, and tingling, spasms, or twitching of facial muscles; however, these symptoms are typically mild to moderate, improve shortly after a session, and diminish with repeat sessions.¹¹² Taken together, individual-specific tolerability should be prioritized.

The Pharmacist’s Role

According to the 2012 National Alliance on Mental Illness national survey, only 53% of individuals who are prescribed mental health medications reported a strong relationship with their pharmacist, with 43% reporting no relationship.¹¹³ Disappointingly, 75% of respondents reported not receiving effective pharmacist-led assistance, including safety monitoring.¹¹³ Medication nonadherence is a major treatment barrier, with ~50% of BD patients nonadherent or partially adherent.¹¹⁴ Common adverse effects of mainstay pharmacotherapies are weight gain, metabolic dysregulation, sedation/somnolence, and cardiovascular issues (e.g., hypertension, myocardial infarction, stroke).¹¹⁵ Other contributing factors are complex dosing regimens, skepticism about poorly understood medications, rapid cycling BD, substance use, and weak therapeutic alliance.¹¹⁶ Pharmacists should regularly discuss therapeutic versus adverse medication effects to promote adherence.¹¹⁷ Counseling points include nonpharmacologic strategies to mitigate weight gain, such as lifestyle modification (i.e., exercise, dietary changes, cognitive interventions), as well as pharmacologic treatments to combat overweight/obesity, Parkinsonism, insulin resistance, hyperglycemia, sedation, gastroesophageal reflux disease, and seizure activity.¹¹⁷

Conclusion

Individuals with BD face significant disease burdens, and conventional treatments do not always achieve optimal outcomes. Emerging pharmacologic and nonpharmacologic treatment approaches that are more targeted show promise in terms of improved efficacy and tolerability and appear to be generally safe.

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