July 24, 2014

No Laughing Matter: Defining the Role of a New Agent for Pseudobulbar Affect

Exploring new uses of first approved therapy for PBA

690×380-Pioro-Pseudobulbar

By Erik P. Pioro, MD, PhD

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Imagine experiencing sudden, brief and uncontrollable episodes of laughing or crying, sometimes at inappropriate moments, up to 30 or more times a day. That’s reality for the estimated 2 million U.S. patients with various brain disorders who suffer from pseudobulbar affect (PBA), also known as emotional lability or pathologic laughing and crying.

Our team at Cleveland Clinic co-led the pivotal multicenter study that formed the basis for the recent FDA approval of the first medication indicated for treatment of PBA, dextromethorphan/quinidine (Nuedexta®). This article reviews the essentials of PBA and the role of this agent in treating PBA in patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and other neurologic conditions — as well as potential additional benefits of the drug in these diseases.

PBA: Unclear pathophysiology, stark manifestations

PBA has an unclear pathophysiology but seems to arise from disinhibition of brainstem motor expression due to lesions along the cortico-ponto-cerebellar pathway (Figure 1). It has a high prevalence among patients with a number of neurologic disorders, particularly ALS:

  • Up to 50 percent in ALS
  • Up to 30 percent in MS, dementia and stroke
  • Up to 20 percent in Parkinson disease and traumatic brain injury

When crying is the primary manifestation of PBA, it can often be confused with depression, resulting in misdiagnosis, mismanagement and inappropriate treatments. A major distinguishing feature from depression is that emotional expressions of PBA are usually incongruent or exaggerated relative to the individual’s underlying mood. A person with PBA will laugh when not necessarily feeling happy or cry when not feeling sad. Episodes tend to be paroxysmal, brief (lasting seconds to minutes), frequent, and stereotypical in frequency, duration and intensity.

Episodes of PBA frequently cause distress to patients and caregivers, impaired social and occupational function, embarrassment, social phobia, withdrawal and isolation, and feelings of frustration and humiliation.

First approved PBA therapy emerges

Until recently, antidepressants, including tricyclic agents and selective serotonin reuptake inhibitors (SSRIs), were used off label as the first-choice treatment for symptoms of PBA, but a recent review shows that data from well-controlled trials to support their efficacy are sparse. Moreover, tricyclic antidepressants and SSRIs have substantial side effects, especially in the elderly, which can limit their utility for PBA.

In October 2010, the FDA approved dextromethorphan/quinidine for the treatment of PBA, regardless of the condition underlying it, making the agent the first approved therapy for this disorder. The European Medicines Agency (EMA) approved it for similar use in June 2013.

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Dextromethorphan (DM) is the active ingredient, whereas quinidine (Q) inhibits the liver enzymes that metabolize DM, which allows therapeutic concentrations of DM sufficient to cross the blood-brain barrier and interact at sigma-1 and glutamate receptors in the brain. Although DM’s exact mechanism of action is uncertain, it is believed to influence glutamate signaling through presynaptic inhibition of glutamate release and postsynaptic glutamate response modulation (Figure 2).

Profile of the pivotal trial

The STAR trial (Safety, Tolerability and Efficacy Results of AVP-923 in PBA) demonstrated the efficacy of DM/Q for reducing the rate of PBA episodes in patients with ALS (n = 197) or MS (n = 129). The study enrolled patients from 64 sites, with Cleveland Clinic enrolling the largest number of ALS patients.

Patients were randomized to 12 weeks of double-blind treatment with DM/Q at one of two dosages (30/10 mg or 20/10 mg twice daily) or placebo, followed by a 12-week open-label phase with DM/Q 30/10mg twice daily. At 12 weeks, both DM/Q dosages produced clinically and statistically significant improvements relative to placebo in:

  • Frequency of PBA episodes as assessed by mean change in the daily PBA episode rate (primary endpoint) and appropriate statistical models
  • Severity of PBA as measured by the validated Center for Neurologic Study–Lability Scale (CNS-LS)
  • Likelihood of PBA remission during the study’s final 14 days, with half of all DM/Q-treated patients achieving remission

The higher dosage of DM/Q was also associated with statistically significant improvements vs. placebo on measures of social function and mental health. Reductions in manifestations of PBA began during week 1 of therapy and were sustained thereafter. Both DM/Q dosages were safe and well-tolerated. Although the FDA approved only the lower dosage for treating PBA, the EMA approved both dosages.

Beyond PBA: Additional studies in ALS, MS, Alzheimer disease

The mechanism of action of DM/Q may also be important in controlling pain, aggression and agitation in dementia, and even disease progression in ALS as related to bulbar function.

To test these hypotheses, other centers in Cleveland Clinic’s Neurological Institute are involved in ongoing clinical trials to assess DM/Q for relief of central pain in MS and reduction of aggressive outbursts in Alzheimer disease. Our group is testing DM/Q’s potential to improve speech, swallowing and saliva control in patients with ALS. We look forward to sharing results as they emerge.

Dr. Pioro is the Barry Winovich Endowed Chair in ALS Research and Director of the Section of ALS and Related Disorders in the Neuromuscular Center.

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590x-Inset-Pioro

Figure 1 (on the left). Pseudobulbar affect is believed to arise from disinhibition of brainstem motor expression resulting from lesions along the cortico-ponto-cerebellar pathway.

Figure 2 (on the right). Dextromethorphan/quinidine is thought to control pseudobulbar affect by regulating glutamate signaling through presynaptic inhibition of glutamate release and postsynaptic glutamate response modulation.

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