Out of the Pipeline Dextromethorphan/quinidine for pseudobulbar affect Alfonso Tan III, MD, and Steven L. Dubovsky, MD The combination of n October 2010, the FDA approved Table dextromethorphan a combination of dextromethorphan Dextromethorphan/quinidine: and quinidine (DM) and quinidine for the treatment I Fast facts reduced the of pseudobulbar affect (PBA)—also called pathological laughing and crying, affective number of daily Brand name: Nuedexta lability, emotional dyscontrol, emotional PBA episodes in 3 Indication: Pseudobulbar affect incontinence, and involuntary emotional Approval date: October 29, 2010 randomized trials expression disorder—in patients with Availability date: First quarter of 2011 neurologic disorders and brain injuries (Ta- Manufacturer: Avanir ble). Despite receiving an approvable letter Dosage forms: Dextromethorphan, 20 mg, in 2006, the compound was not approved plus quinidine, 10 mg at that time because of concerns about the Starting dose: 1 capsule per day arrhythmogenic potential of quinidine, Target dose: 2 capsules per day which prolongs the QT interval. The man- ufacturer conducted another study using one-third of the previous quinidine dose, release of glutamate by injured neurons, which ameliorated this concern and led to disrupting systems for motor control of approval. emotional expression.4,5 PBA is most common in diseases that Clinical implications interfere bilaterally with the corticohypo- PBA is manifested by involuntary labile, thalamic and corticobulbar tracts that con- shallow affect with sudden and unpre- trol voluntary and involuntary faciorespi- dictable laughing, crying, or other emo- ratory mechanisms. However, PBA occurs tional displays that are not appropriate to in unilateral disease as well. The reported the social setting and may not be congru- prevalence of PBA is: ent with the patient’s prevailing mood.1 • 49% in amyotrophic lateral sclerosis Episodes are often paroxysmal and cannot (ALS) be interrupted voluntarily.2 PBA seems to • 18% to 39% in Alzheimer’s disease be caused by a loss of descending cor- • 11% to 34% in stroke tical control of brainstem motor nuclei • 10% to 11% in multiple sclerosis (MS) and possibly the cerebellum, disrupting and traumatic brain injury.6,7 inhibitory mechanisms and resulting in PBA also has been reported in patients inappropriate and involuntary emotional with Parkinson’s disease, brain tumors, display.3 Several studies have demonstrat- Wilson’s disease, syphilitic pseudobulbar ed involvement of subcortical areas, par- ticularly the anterior limb of the internal Dr. Tan is Assistant Professor of Psychiatry, University at Buffalo, Buffalo, NY, and Dr. Dubovsky is Professor and Chair, Department capsule and the bulbar area. The patho- Current Psychiatry of Psychiatry, University at Buffalo, Buffalo, NY, and Adjoint Profes- 60 February 2011 physiology of PBA may involve excessive sor of Psychiatry and Medicine, University of Colorado, Denver, CO. continued on page 65 Out of the Pipeline continued from page 60 palsy, and various encephalitides.1 An es- than those used to treat cardiac arrhyth- timated 880,000 U.S. patients exhibit PBA.8 mias, quinidine inhibits 2D6 and increases Previously, there was no FDA- DM bioavailability.10 DM blood levels in- approved treatment for PBA. However, crease linearly with dose following coad- small controlled trials suggest that selec- ministration with quinidine but are unde- tive serotonin reuptake inhibitors (SSRIs) tectable in most patients given DM alone.7,9 and tricyclic antidepressants (TCAs)— usually in doses lower than those used to Efficacy and tolerability treat depression—may effectively reduce A combination of DM and quinidine (DMQ) symptoms within 2 to 3 days.1 Although reduced Center for Neurologic Study-Labil- dopaminergic agents such as levodopa ity Scale (CNC-LS) scores and the number and amantadine have shown benefit in of daily PBA episodes in 3 randomized tri- open trials, results of controlled studies als.5,7,10 Visit this article at CurrentPsychiatry. using objective measurements have not com for a table summarizing these studies. been positive. An 85-day randomized, double-blind, Clinical Point placebo-controlled study of 150 patients In doses 10 to 25 How it works with PBA associated with MS found that times lower than DM is a serotonergic substance that also DM, 30 mg, plus quinidine, 30 mg, (DMQ is an agonist of 1-sigma receptors and a 30-30) was twice as effective as placebo those used to treat low-affinity, uncompetitive antagonist of within a week in reducing CNC-LS scores.10 cardiac arrhythmias, N-methyl-d-aspartate (NMDA) receptors, DMQ 30-30 patients also had approximate- quinidine inhibits which are important in glutamate signal- ly half as many episodes of inappropriate 2D6 and increases ing, through binding at the phencyclidine laughing, crying, or combined laughing site on the NMDA complex.7,9 The 1-sigma and crying and a 2-fold greater decrease DM bioavailability receptor was thought to be an opioid re- in pain intensity.10 Twenty-one percent of ceptor subtype, but unlike opioid recep- DMQ 30-30 patients experienced complete tors it is not blocked by narcotic antago- remission—no PBA episodes—compared nists and does not have an endogenous with 7% of placebo patients. There were no ligand. However, the 1-sigma receptor significant differences in QT prolongation does modulate activity of opioid mu re- between DMQ 30-30 and placebo. ceptors in addition to altering dopamine A 3-arm, double-blind, 28-day, phase III release and possibly reducing glutamate multicenter trial of 140 ALS patients with release.9 Sigma receptors are densely dis- PBA compared DM monotherapy, quini- tributed in the limbic system and in sys- dine monotherapy, and DMQ 30-30.5 Com- tems related to motor control of affective pared with either drug alone, DMQ 30- expression and seem to be involved in 30 showed greater reduction of CNC-LS learning, responses to stress, mood regula- scores, as well as improved quality of life tion, and drug dependence.1 Because DM and quality of relationships scores, with preferentially binds to brain regions that equal benefit in poor and extensive DM regulate emotional expression,10 it could metabolizers. However, the control condi- normalize glutaminergic neurotransmis- tions may not have been adequate. Quini- sion and other relevant systems in these dine alone would not be expected to have regions.1 However, DM’s exact mechanism an effect on PBA, and the DM dose, which of action is unknown. was the same in combination and mono- Quinidine is a sodium channel antago- therapy, may have been too low to be effec- nist usually used as a type Ia antiarrhyth- tive by itself. In support of this hypothesis, mic.5 DM is subject to extensive first-pass the DM plasma level was 18 times higher metabolism by cytochrome P (CYP) 450 in patients taking DMQ 30-30 than those 2D6 to dextrorphan, which after being taking DM monotherapy. glucuronidated cannot cross the blood- In a manufacturer-sponsored, multi- Current Psychiatry brain barrier. In doses 10 to 25 times lower center, 12-week randomized trial, 326 pa- Vol. 10, No. 2 65 Out of the Pipeline tients with ALS or MS and clinically signif- effects than DM alone because quinidine icant PBA were randomly assigned to DM, increases DM bioavailability and blood lev- 30 mg, plus quinidine, 10 mg (DMQ 30-10), els. The abuse potential of DMQ is not clear. DM, 20 mg, plus quinidine, 10 mg (DMQ Psychosis has been reported with high- 20-10), or placebo, each administered twice er DM doses. The psychotomimetic effects daily.7 Patients with comorbid psychiatric of phencyclidine (PCP) are related to bind- disorders or significant depressive symp- ing to the PCP site on the NMDA receptor toms were excluded. Although daily PBA complex—to which DM also binds—with episodes decreased in all groups, the daily reduced glutamate signaling in informa- rate of PBA episodes was 47% lower for tion processing systems. Therefore, cau- patients taking DMQ 30-10, and 49% lower tion is indicated when prescribing DM to with DMQ 20-10 compared with placebo patients with psychosis. (both P < .001). The mean decrease in the Because DM, a CYP2D6 substrate, is number of daily PBA episodes was 3.9 to combined with quinidine, a 2D6 inhibitor, Clinical Point 4.1 with active treatment and 3.0 with pla- administering DMQ with other 2D6 inhib- Substantial ECG cebo. Side effects were more common with itors could lead to toxicity. When DMQ is changes and adverse active drug than placebo and included diz- combined with SSRIs and similar agents, ziness, nausea, diarrhea, and urinary tract the serotonergic properties of DM could cardiac effects with infection. There were no serious adverse result in serotonin syndrome, which could DMQ have not been cardiac events and no active drug recipi- be fatal if DM is combined with mono- reported ents showed a QTc interval >480 msec or a amine oxidase inhibitors.10 Combinations change from baseline >60 msec.11 Discon- of DM and acetaminophen and antihis- tinuation rates in this study were lower tamines can be dangerous at higher dos- than in studies of DMQ 30-30. In an open- es.10 Because quinidine is metabolized by label extension of 253 patients who com- CYP3A, inhibitors of this enzyme such as pleted the double-blind phase and were ketoconazole, nefazodone, and grapefruit assigned to DMQ 30-10 for 12 weeks, the juice should be avoided. Similarly, inhibi- incidence of treatment-related adverse tion of CYP2D6 by quinidine could raise events was 28%, with a 5.5% rate of serious levels of coadministered 2D6 substrates. adverse events.12 Contraindications. DMQ is contraindi- Safety cated in patients with: Because the 10 mg dose of quinidine in the • heart failure approved formulation of DMQ is 10 times • prolonged QT interval lower than the antiarrhythmic dose, sub- • congenital long QT interval stantial ECG changes and adverse cardiac • history of torsades de pointes effects with DMQ have not been reported.