Relief From Pseudobulbar Affect Remains Elusive for Some

Nancy A. Melville

November 20, 2012

SAN DIEGO, California — The US Food and Drug Administration's (FDA's) approval of dextromethorphan and quinidine (Nuedexta, Avanir), the first drug in the United States to have an indication for pseudobulbar affect disorder (PBA), has provided a much needed, safe treatment option for the condition. However, contraindications prevent some, particularly those takin certain Parkinson's disease (PD) medications, from benefiting from the therapy

Characterized by episodes of uncontrollable and inappropriate laughing and crying, PBA is associated with neurological conditions that include traumatic brain injury (TBI), multiple sclerosis (MS), stroke, and amyotrophic lateral sclerosis (ALS), in addition to PD and other movement disorders.

Estimated prevalence rates of PBA in the disorders vary considerably, with one review showing rates ranging from 2% to 49% in ALS and from 7% to as high as 95% in MS (J Neuropsychiatry Clin Neurosci 2005;17:447-54).

Results of studies of prevalence across all of the disorders sponsored by Nuedexta maker Avanir even vary, ranging from 10% in a 2011 study to 36.6% in the interim results of a newer disease registry the company presented here at Psych Congress 2012: US Psychiatric and Mental Health Congress.

"It is estimated that 15% of residents in the long-term-care setting have some degree of PBA," said lead author David Crumpacker, MD, assistant chief of the Department of Psychiatry at Baylor University Medical Center at Dallas, Texas.

"Perhaps up to 50% of patients with Parkinson's, stroke, and MS will elaborate symptoms of PBA," Dr. Crumpacker told Medscape Medical News.

A much lower PBA rate of 7.1% was reported among patients with PD and movement disorders by researchers at Wake Forest University School of Medicine (J Neurol 2010;257:1382-7), but even 7% in a population as large as that of patients with PD is a concern, said neurologist Mustafa Saad Siddiqui, MD, a coauthor on the Wake Forest studies.

"Parkinson's is far more common than MS or ALS, so overall, a much larger population is affected with PBA," said Dr. Siddiqui, associate professor of neurology and director of the Movement Disorders Program at Wake Forest Baptist Health in Winston-Salem, North Carolina.

"Furthermore, there is the contraindication of dextromethorphan with monoamine oxidase-B inhibitors [MAO-Bi], so for patients taking those medications, the treatments for PBA are limited."

He noted that about one quarter of his PD patients take the MAO-Bi drugs selegiline and rasagiline, and he instead typically resorts to selective serotonin reuptake inhibitors (SSRIs) for PBA in PD patients.

SSRIs Less than Optimal

"SSRIs are the common medication for PBA in these patients, but the response is mixed, and I can't say I'm very happy with the results I see with SSRIs," Dr. Siddiqui said.

As demonstrated in the Wake Forest research, PBA can take a heavy toll on patients' quality of life — those with the condition had higher depression scores and lower emotional well-being scores (both P < .0001) compared with those without PBA.

Dr. Siddiqui described one patient's painful experience, which he said reflected the social embarrassment common with PBA.

"One of my [PD] patients, a biologist, said he was giving an address before a group of scientists and during his speech he became emotional for no particular reason — he said it was as if he couldn't hold it back, became quite tearful, and it was extremely embarrassing."

"Another typical experience is patients will report watching a movie that would never have otherwise made them emotional, and some trivial event in the story will make them inappropriately cry," he added. "Again, if they are in public, it can be very embarrassing."

Intriguing Finding

The severity of the underlying condition may not always play a role in PBA, Dr. Siddiqui noted.

"Sometimes, simply a strategically placed lesion on a particular area of the brain such as the cerebellum can trigger a PBA affect more distinctively than the presence of many more lesions," he said.

"It's hard to say if there is a correlation with severity of disease, however, and I would say the more severe the disease, the greater likelihood there is of PBA."

In another intriguing finding, Dr. Siddiqui noted that in the course of treating movement disorder patients with deep brain stimulation, the researchers noted that some patients experienced an upswing in PBA.

"Deep brain stimulation patients actually showed a higher incidence of PBA after the procedure, but it did resolve very quickly in the majority of cases."

One key reason for the widely varying prevalence estimates is vague differences in definitions of the disorder and the common presentation of symptoms that may or may not suggest PBA in patients with neurological disorders, particularly those with TBI.

Easy to Spot

But trained neurologists can typically identify the symptoms quickly, according to Gregory A. Jicha, MD, PhD, an associate professor of neurology at the University of Kentucky Alzheimer's Disease Center, in Lexington.

"Frequently, traumatic brain injury patients will have behavioral symptoms, but PBA is unique," said Dr. Jicha, who holds the Robert T. and Nyles Y. McCowan Endowed Chair in Alzheimer's Disease.

"TBI patients may be prone to mood lability, certainly, but PBA in the classic sense involves a disassociation between emotions that neurologists can spot right off the bat because it's very striking."

"The definition of PBA includes not just noncongruent affective symptoms — laughing when you should be crying and vice versa, but extremes — weeping incessantly for 10 or 20 minutes, and only in a minority of cases does it also involve excessive elation," he said.

In some cases, the patient may not even be aware that the response is inappropriate, making the condition particularly difficult for caregivers, Dr. Jicha said.

"In my clinical experience, PBA is often more distressing to the caregivers than the patients themselves," he said.

"Caregivers can often manage cognitive difficulties and the aspects of physical disability, but they may feel very helpless with the behavioral and psychiatric symptoms of the disease. These types of behavioral symptoms are some of the most distressing for patients and caregivers alike."

Novel Treatment

Among patients who can be treated with dextromethorphan without contraindications, the drug is a useful, novel treatment for PBA, he noted.

"Many patients with PBA have cognitive difficulties behind their symptoms, but with the FDA black box warning on antipsychotics for dementia, our options are limited," he said.

"We're left with sedatives to knock people out, antidepressants to stabilize depressive symptoms, or mood stabilizers to treat mood lability, but at least this drug offers an option that won't leave you mired in black box concerns."

Dr. Crumpacker is a speaker for Avanir Pharmaceuticals Inc and has served on the company's scientific advisory board. Dr. Jicha and Dr. Siddiqui have disclosed no relevant financial relationships.

Psych Congress 2012: US Psychiatric and Mental Health Congress. Abstract 101. Presented November 9, 2012.

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