ORIGINAL ARTICLE Dextromethorphan Plus Ultra Low-Dose Quinidine Reduces Pseudobulbar Affect Erik P. Pioro, MD, PhD, 1 Benjamin Rix Brooks, MD, 2 Jeffrey Cummings, MD, 3 Randolph Schiffer, MD, 1 Ronald A. Thisted, PhD, 4 Daniel Wynn, MD, 5 Adrian Hepner, MD, 6 and Randall Kaye, MD 6 for the Safety, Tolerability, and Efficacy Results Trial of AVP-923 in PBA Investigators Objective: To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Methods: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score 13 on the Center for Neurologic Studies–Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20). Results: In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p¼ 0.0002 and p¼ 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated. Interpretation: DMq markedly reduced PBA frequency and severity, decreasing the condition’s detrimental impact on a patient’s life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA. ANN NEUROL 2010;00:000–000 Introduction P seudobulbar affect (PBA) is a neurologic condition characterized by involuntary outbursts of laughing and/or crying incongruous or disproportionate to the patient’s emotional state. 1 The condition, hypothesized to arise from disconnection of brainstem structures from cortical inhibition, is associated with underlying central nervous system disorders, including stroke, 2 traumatic brain injury, 3 Alzheimer disease, 4 amyotrophic lateral scle- rosis (ALS), 5–7 and multiple sclerosis (MS). 8 Prevalence studies have reported that it affects 11% of patients 1 year after a stroke, 2 11% of patients during the first year after traumatic brain injury, 9 18% of patients with Alzheimer disease, 4 10% of patients with MS, 8 and 49% of patients with ALS. 10 In addition to the effects of the underlying disorder, PBA can have a severe impact on well-being and social functioning and can be highly disabling, owing in part to the stigma attached to loss of emotional control. 11 Yet even with such a significant burden of illness, PBA appears to be poorly recognized and consequently is undertreated. 11,12 In settings of ALS or MS, dextromethorphan plus quinidine (DMQ) has been found to be beneficial in reduc- ing PBA. 13,14 Dextromethorphan (DM) is known to be a low-affinity, noncompetitive antagonist of the N-methyl-d- aspartate glutamate receptor, 15 and also a sigma-receptor agonist. 16 To block its first-pass metabolism, it was originally coadministered with low-dose quinidine (Q), a potent cyto- chrome P450 2D6 inhibitor, 17 at DMQ dosage of 30/30mg in a capsule taken twice daily. Without such blockade, DM blood levels in some ALS patients have been undetectably low even following DM dosage as high as 750mg/day. 17 In Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.22093 Received Feb 24, 2010, and in revised form Apr 30, 2010. Accepted for publication May 20, 2010. Address correspondence to Dr. Pioro, Director, Section of ALS and Related Disorders, Department of Neurology, Neurological Institute, Cleveland Clinic, Desk S90, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: PIOROE@ccf.org From the 1 Cleveland Clinic, Cleveland, OH; 2 Carolinas Medical Center, Charlotte, NC; 3 David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA; 4 University of Chicago, Chicago IL; 5 Consultants in Neurology, Northbrook, IL; and 6 Avanir Pharmaceuticals, Aliso Viejo, CA. V C 2010 American Neurological Association 1