Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.
BACKGROUND
Patients with ALS commonly exhibit pseudobulbar affect.


METHODS
The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140).


RESULTS
AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q.


CONCLUSIONS
AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.
Brooks
B R
BR
University of Wisconsin, 600 Highland Ave., Rm. H6/563 CSC, Madison, WI 53792-5132, USA. brooks@neurology.wisc.edu
Thisted
R A
RA
Appel
S H
SH
Bradley
W G
WG
Olney
R K
RK
Berg
J E
JE
Pope
L E
LE
Smith
R A
RA
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D020828:Pseudobulbar Palsy / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D011802:Quinidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C507057:dextromethorphan - quinidine combination; D018698:Glutamic Acid; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine