AVP-923 Awaits Approval for IEED

Norman Sussman, MD, DFAPA

Editor, Primary Psychiatry and Psychiatry Weekly, Professor of Psychiatry, New York University School of Medicine

Introduction

Sometimes medical breakthroughs are the result of years of laboratory synthesis and trial and error on the part of pharmacologists. Other times they are discovered among long-used, well-characterized compounds already in clinical use. If the NDA for AVP-923 (Neurodex, Avanir) is approved by the FDA late in October, there will be a surprising new role for two agents that have been part of medical treatment for decades.

A combination containing dextromethorphan and low doses of quinidine, AVP-923 is being tested for the treatment of involuntary emotional expression disorder (IEED). The FDA is satisfied with the efficacy data for AVP-923, but feels that it needs to examine additional evidence of the drug’s QT effects. AVP-923 has received a priority review by the FDA. Currently, there is no approved product indicated for the treatment of IEED.

IEED

Involuntary episodes of emotional expression, such as crying, laughing, or related emotional displays, typically accompany various neurodegenerative diseases and CNS trauma. IEED most often occurs in patients with amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, dementias, including Alzheimer’s disease, and brain injuries, such as stroke and traumatic brain injury.

The emotional outbursts in IEED are episodic, stereotyped, and involuntary. They are beyond the ability of the patient to control in terms of timing or duration. They are mood incongruent or have an intensity that is out of proportion to the stimulus. Patients are usually anxious and embarrassed by their unpredictable involuntary emotional displays. Even though they return to normal baseline behavior between outbursts, patients with IEED often start to avoid social situations and become withdrawn and isolated.

Dextromethorphan and Quinidine

Among the pharmacologic actions ascribed to dextromethorphan are: NMDA glutamatergic receptor antagonism; dopamine reuptake inhibition; σ1 and σ2 receptor agonism; and serotonin reuptake inhibition. It has long been used as an antitussive agent and is an active ingredient in Robitussin and Romilar. Quinidine is used to treat abnormal heart rhythms and to treat malaria. Quinidine acts as an enzyme inhibitor in AVP-923, thus increasing the bioavailability of the dextromethorphan.

AVP-923

It is believed that IEED is the result of excessive signaling via glutamate (an excitatory neurotransmitter). AVP-923 may help to regulate excitatory neurotransmission through presynaptic inhibition of glutamate release via σ1 receptor agonist activity and through postsynaptic glutamate response modulation via uncompetitive, low-affinity NMDA antagonist activity.

In addition to its pharmacodynamic effects, dextromethorphan has a high potential for serious pharmacokinetic interactions. The CYP 2D6 isozyme is the primary metabolic pathway in the inactivation of dextromethorphan. Fatalities have been reported among patients and recreational drug users who are genetically poor in CYP 2D6. Many psychiatric, and other, medications are potent inhibitors of CYP 2D6, creating a potential for life-threatening drug-drug interactions involving dextromethorphan and concomitant medications.

Disclosure: Dr. Sussman reports no affiliations with or financial interests in any organization that may pose a conflict of interest.