Underfunded and Underdiagnosed: What’s Next for BD

Bipolar disorder (BD) is common, affecting some 6 million Americans and 3% of individuals worldwide. Despite its high prevalence, experts say the disorder is poorly understood, underdiagnosed, and underfunded.

It’s been more than 50 years since the US Food and Drug Administration (FDA) approved lithium, the best treatment and gold standard for BD. But lithium — and the dozen or so anticonvulsants and atypical antipsychotics approved for BD since 1970 — weren’t developed to treat the condition. They were essentially repurposed therapeutics. The same is true for antidepressants, which may be used off-label for BD.

Research into novel pharmacologic therapies for BD has been hampered in part by a lack of understanding of the disorder’s etiology and pathophysiology — and a lack of funding. Between 2010-2019, the National Institute of Mental Health spent $1.4 billion on BD research, significantly less than the agency allocated to the study of other psychiatric illnesses.

“There aren’t a lot of companies that really focus on bipolar disorder. It’s like an orphan disease,” Andrew A. Nierenberg, MD, director of the Dauten Family Center for Bipolar Treatment Innovation at Massachusetts General Hospital, Boston, told Medscape Medical News.

But that could be changing, thanks in part to efforts to create better diagnostics, a number of novel therapeutics currently in clinical trials, and the launch of two new national collaboratives — the Bipolar Action Network (BAN) and BD2: Breakthrough Discoveries for thriving with Bipolar Disorder — which focus on clinical practice and research on the diagnosis, treatment, and management of BD. Both collaboratives aim to shine a light on what they believe is a neglected corner of psychiatric research.

More Cases or Better Diagnosis?

It’s not clear whether BD incidence is on the rise, experts said. An analysis published in 2024 in General Psychiatry concluded that the incidence among adolescents and young adults increased from 79.21 per 100,000 in 1990 to 84.97 per 100,000 in 2019.

But Steve Strakowski, MD, professor of psychiatry at Indiana University Indianapolis, is not convinced. BD is a genetic condition, and “it’s hard to imagine that gene prevalence has actually gone up since this has been present the entire course of human history,” he said.

Instead, it’s more likely that clinicians’ ability to identify BD has improved — but only slightly. Diagnosis still lags symptom onset by about 7-10 years, Strakowski said.

“The illness is so dynamic that it can present in a variety of different states and sets of symptoms,” he noted.

There are three bipolar subtypes — I, II, and cyclothymia — which are described in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders. In bipolar I, manic episodes last a week or more, alternating with depression. Those with bipolar II experience hypomania, which is a less elevated mood state than mania, alternating with depression. Cyclothymia includes mood swings but not extreme mania or depression.

Busy clinicians — especially in primary care — often don’t have the time to take a deep history or may not see the expression of the illness as it progresses, said Strakowski. In addition, misdiagnosis is common, especially among people of color and those with lower socioeconomic status.

Nierenberg agreed. For example, an individual who presents with an episode of major depression might not be asked about any history of mania or hypomania and may only be treated for depression. People with irritable depression or anxious rumination, or other issues such as personality disorders with mood instability, may be misdiagnosed with BD, Nierenberg said.

Currently, diagnosis is somewhat of an “ad hoc process,” said Nierenberg. It often includes gathering a narrative from the patient and then determining whether what is described meets the criteria for a diagnosis.

The Mood Disorder Questionnaire (MDQ), developed in 2000, can be used by primary care and other clinicians to assess for BD. The updated self-administered questionnaire asks patients about manic and hypomanic symptoms, and whether any blood relatives had “manic-depressive illness” or “bipolar disorder.”

However, BD screening tools including the MDQ, “have poor sensitivity and specificity but, nevertheless, can help flag those individuals for whom a more detailed assessment is needed,” wrote the authors of the joint Canadian Network for Mood and Anxiety Treatments (CANMAT)/International Society for Bipolar Disorders (ISBD) most-recent guidelines on BD.

The six-question Rapid Mood Screener may also help tease out whether patients with depressive symptoms might need further evaluation for BD, but these types of tools are often underutilized, Roger S. McIntyre, MD, screen developer and professor of psychiatry and pharmacology at the University of Toronto, Toronto, Ontario, Canada, told Medscape Medical News on a podcast series.

What Causes BD?

The exact cause of BD is unknown, but it is thought that both genetic and environmental factors are involved. About 80%-90% of people with BD have a relative with the condition.

Many mechanisms have been postulated, but “I don’t think we at this point in time really have a refined, discerned understanding of what the mechanism is,” said McIntyre.

Compared with depression or schizophrenia, little is known about BD’s underlying genetics. Although genome-wide association studies have identified approximately 30 common genetic variants that are significantly associated with BD, researchers have yet to identify any genetic biomarkers for the condition.

But a $150 million philanthropic venture launched in 2022 could help advance the study of the biology underlying BD. Breakthrough Discoveries for thriving with Bipolar Disorder, or BD2, was started by Google co-founder Sergey Brin, Roblox founder David Baszucki, and Keystone Capital Chair Kent Dauten.

The collaborative includes a network of six academic research centers and hundreds of clinicians, researchers, and patients and families. Among the projects BD2 will fund is the collection and genetic sequencing of more than 30,000 samples from people with BD from Africa, Central America, South America, and Asia, and from individuals who are participating in studies across the six institutions in its network, which may help identify risk factors.

Gene panels could be used as diagnostic tools, as could imaging of brain networks, said Strakowski. But so far, none is ready for clinical use.

“Eventually something will be isolated that really does predict something, but we’re just not there yet,” he said.

Blood-based biomarkers have also been piloted. A 2023 study, was successful as a “proof of concept,” in separating those with BD who had been misdiagnosed with major depressive disorder, the authors reported in JAMA Psychiatry.

Biomarkers are “still a holy grail, and no one has actually found anything to date that is clinically useful,” said Nierenberg.

Best Practice Model?

There are a number of evidence-based recommendations to help inform best practice in the treatment of BD, including the joint CANMAT/ISBD guideline, which was last updated in 2023. The US Department of Veterans Affairs also offers treatment guidelines, with the most recent edition released in 2023, which Nierenberg said are up-to-date.

The American Psychiatric Association, which has not updated its BD guidelines since 2002, is now working on a new iteration, a spokesperson told Medscape Medical News. However, no publication date has been set.

In late 2023, Canadian researchers noted that, “Although pragmatic treatment guidelines for BD exist, clinicians have scant data on direct comparisons of medications to guide treatment selection for patients with acute bipolar depression.”

“This can lead to an ad hoc approach to sequential pharmacotherapy, resulting in the use of untested polypharmacy, which could in part explain high rates of treatment-resistant bipolar depression,” they added.

While guidelines exist, the question is “how do people actually use them,” said Nierenberg. He speculated that a survey of clinicians would likely reveal that “

Ensuring there is less variability in treatment is one of the goals of the BAN, a collective of healthcare systems, academic centers, clinicians, patients, and caregivers. Nierenberg and Strakowski are founding members of the project.

The collective aims to form Learning Health Networks at 10-20 pilot sites across the country, following a quality improvement format based on a similar effort at the Cincinnati Children’s James M. Anderson Center for Health Systems Excellence. The network will share data, collaborate on research, and develop diagnostic tools, training programs, and consensus statements on the care of patients with BD.

Among the network’s first projects is an effort to gather data on effectiveness of various medications so that clinicians have a better sense of what works and what doesn’t in BD.

“We can help each of the healthcare systems who are part of the network understand and know the proportion of treatments that they’re giving people with bipolar disorder that are consistent with guidelines,” said Nierenberg.

Partners in BAN will share data, “with the ultimate purpose of learning from each other and getting better outcomes,” said Nierenberg.

The shared large databases essentially allow for so-called pragmatic clinical trials. Artificial intelligence can assess the data to determine if a treatment might work better for a person of a certain age, sex, or risk profile. The goal is “to personalize care, improve access and to share best practices, and to get them distributed as quickly as possible,” he said.

The network is finalizing collaboration agreements, said Nierenberg. The group has established a website and is looking at specific outcome measures that could be applied across all of the sites that agree to participate, said Strakowski.

Pharmacological Treatments

Only five drugs — cariprazine, lumateperone, lurasidone, olanzapine-fluoxetine combination, and quetiapine —have been approved to treat acute BD. The use of antipsychotics and anticonvulsants — both of which help stabilize mood — are increasing, but lithium remains a first-line choice for the condition, despite its age and a lack of understanding of how it works, said Strakowski.

Even so, lithium use has declined over the last two decades. A Danish researcher reported even lower usage, noting that only about 7.5% of initial prescriptions for BD in the United Staes are for lithium. And regardless of which medication patients use, drug adherence is a problem. Only about 15% of those with BD take their medication as prescribed, said Nierenberg.

There appears to be a fundamental tension between what the science shows — that lithium is effective — and with perceptions among patients and prescribers, who believe it is a “bad” medication because of side effects, or that newer antipsychotics are better, wrote Lars Vedel Kessing in the International Journal of Bipolar Disorders.

Lithium is known to have neuroprotective, anti-inflammatory, and anti-oxidative effects, Keiichiro Nishida and colleagues, from Osaka Medical and Pharmaceutical University, Takatsuki, Japan, wrote in a survey of what’s in development for BD in the Journal of Psychiatric Research. “No candidate drugs with clear neuroprotective effects akin to lithium have been identified,” they noted.

Despite the historical lack of new treatments, Nishida noted seven agents that are in clinical trials for BD, including such novel drugs as NRX-101, which has been granted breakthrough therapy designation by the FDA. The experimental therapeutic is a fixed-dose combination of d-cycloserine and lurasidone for suicidal ideation in BD.

Another new drug under study is JNJ 55308942, a P2X7 antagonist that may have anti-inflammatory effects. Janssen Pharmaceuticals has completed a phase 2, placebo-controlled trial but has not reported results.

An open-label trial by the University of Gothenburg, Gothenburg, Sweden is investigating the efficacy of OSU6162, a dopamine stabilizer. And SEP-4199, a fixed-dose, nonracemic amisulpride, is being evaluated for major depressive episodes in bipolar I. It did not meet the primary endpoint in a randomized, controlled trial but is being studied in phase 3.

Clinical trials are also underway for a number of drugs previously approved for other conditions. Brexpiprazole (Otsuka Pharmaceutical) is a dopamine partial agonist approved for schizophrenia, which failed to meet the primary endpoint for manic episodes associated with bipolar I. The company is conducting an ongoing open label trial for bipolar I depression.

Dexmedetomidine, approved in 1999 for sedation, is under study in an in-home phase 3 trial as a sublingual film (BXCL501) for acute agitation. In addition, cannabidiol, approved as Epidiolex for seizures, is under investigation in Canada in individuals with acute BD who have not responded to lithium, lamotrigine, or other standard therapies.

Other prospective treatments include psilocybin, which was shown in a small open-label study reported in 2023 in JAMA Psychiatry to be associated with remission in patients with bipolar II in combination with psychotherapy. Ketamine, an anesthetic agent used as an antidepressant, is also considered safe and effective for treatment-resistant BD.

Nierenberg and his team have received a grant from the Patient-Centered Outcomes Research Institute to compare safety and effectiveness of cariprazine, lurasidone, quetiapine and the combination of aripiprazole and escitalopram.

Nierenberg’s team is also investigating whether bezafibrate, a medication for hypercholesterolemia, might be effective as a mood-stabilizer. BD seems to cause energy dysregulation at the molecular level and bezafibrate regulates genes related to energy homeostasis.

Nonpharmacologic Therapies

Many psychotherapies, including cognitive behavioral therapy, interpersonal therapy, and family focused therapy, are helpful in BD. But historically, researchers have not evaluated the therapies specifically for the disorder, said Strakowski.

“There are opportunities to add therapies that are more effective than what we have currently,” he said.

Lifestyle interventions can be helpful, Nierenberg added. Among these: Getting enough sleep, exercising, eating healthfully, good dental hygiene, not smoking, steering clear of illicit drugs, managing stress, cultivating good relationships, and having a purpose.

Both Nierenberg and Strakowski said that neuromodulation, including transcranial magnetic stimulation (TMS), is promising. The technology, which is FDA-approved for depression, delivers magnetic pulses to the brain through an insulated coil placed over the scalp. Neuroimaging can direct the pulses, said Strakowski. TMS has not yet proven effective in BD, but that may be because “we aren’t doing it right yet,” said Strakowski, who counts the therapy as one of the most promising advances for BD.

Studies of TMS for BD are under way in the United States at Stanford University, Harvard, the University of Pittsburgh, and the University of Iowa. Neuromodulation is also being studied in Canada, China, Egypt, Poland, and Taiwan, according to Clinicaltrials.gov.

Faster Fixes With Collaboration?

Strakowski and Nierenberg are hopeful that efforts like BAN and BD2 can move the field forward in a way that has not happened before.

“The trick is not to overpromise,” cautioned Strakowski. “It’s going to take several years to get these things up and running,” including having the data that identifies the best ways to diagnose the disorder, and the evidence-based interventions that work, he said.

Many patients he sees are “failing because their care has been not based on evidence,” said Strakowski. The care they’ve received “feels haphazard, almost,” he said.

Clinicians may be overwhelmed. “There’s nobody who’s going to know everything,” said Nierenberg. The BAN hopefully will find ways to synthesize the evidence in a usable way, he said.

There’s no magic bullet, Nierenberg said, adding that “it’s just going to take effort, time, and money.”

Strakowski reported that his institution received funding for clinical trials from Janssen. Nierenberg disclosed receiving consulting fees or honoraria from Alkermes, Clexio, Ginger/Headspace Health, Janssen, Merck, Neuronetics, NeuroRX, Otsuka, Protagenics, SAGE, Sunovion, Unravel Biosciences, and Belvoir. McIntyre had received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, and Neurocrine and received research grants from CIHR/GACDN/National Natural Science Foundation of China and Milken Institute.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in many health and science publications, including Smithsonian.com. You can find her on X @aliciaault and on Bluesky @aliciaault.bsky.social.