sign in sign up
<<
Home , Psychotomimetic, Serotonin syndrome

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 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 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 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 tical control of brainstem motor nuclei • 10% to 11% in (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 , 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 reuptake inhibitors (SSRIs) tectable in most patients given DM alone.7,9 and tricyclic (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 substance that also DM, 30 mg, plus quinidine, 30 mg, (DMQ is an 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 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 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 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 , 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 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 . When DMQ is changes and adverse active drug than placebo and included diz- combined with SSRIs and similar agents, ziness, , , 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, , 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. • complete atrioventricular (AV) block The most common side effects of DM are without implanted pacemakers.13 nausea, somnolence, dizziness, and head- DMQ also is contraindicated in patients ache. Thrombocytopenia, QT prolonga- at high risk for complete AV block.13 tion, hepatotoxicity, allergic reactions, and ONLINE side effects can occur. Dosing ONLY In high doses and combined with other DMQ is available as a capsule containing Visit this article at substances, DM has been used as a recre- DM, 20 mg, and quinidine, 10 mg. The recom- CurrentPsychiatry.com ational drug. When taken in high doses, mended starting dose is 1 capsule by mouth for a table summarizing adverse effects include nausea, vomiting, for 7 days, then 1 capsule every 12 hours. evidence of efficacy of DMQ malaise, dilated pupils, difficulty urinating, Although DMQ is convenient, its ad- for pseudobulbar affect increased urination frequency, , tachy- vantage over starting with DM alone and cardia, loss of appetite, shakiness, , adding a small dose of a non-serotonergic and potentially and death. DMQ may 2D6 inhibitor if DM is not effective re- Current Psychiatry 66 February 2011 have a greater potential for serious adverse mains to be demonstrated. In view of the Out of the Pipeline

unknown potential for abuse and toxicity as well as the cost of the proprietary drug Related Resource ($3,000 to $5,000 a year), it would seem • Neudexta [package insert]. Aliso Viejo, CA: Avanir Pharmaceuticals; 2010. prudent to consider using an SSRI or a Drug Brand Names TCA first.8 These also act on Amantadine • Symmetrel Levodopa • Sinemet 14,15 1-sigma receptors, which may account Dextromethorphan/quinidine Nefazodone • Serzone in part for their reported benefit. • Neudexta Quinidine • Quinidex Ketoconazole • Nizoral

References Disclosures 1. Schiffer R, Pope LE. Review of pseudobulbar affect Dr. Dubovsky receives research support from Biogen Idec, Bristol- including a novel and potential therapy. J Neuropsychiatry Clin Neurosci. 2005;17:447-454. Myers Squibb, Dainippon Sumitomo Pharma, Otsuka, the Peter and Elizabeth C. Tower Foundation, and Pfizer, Inc. 2. Rosen HJ, Cummings J. A real reason for patients with pseudobulbar affect to smile. Ann Neurol. 2007;61:92-96. Dr. Tan reports no financial relationship with any company whose 3. Miller A. Pseudobulbar affect in multiple sclerosis: toward products are mentioned in this article or with manufacturers of the development of innovative therapeutic strategies. J competing products. Neurol Sci. 2006;245:153-159. 4. Mattson MP. Excitotoxic and excitoprotective mechanisms: Clinical Point abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med. 2003;3:65-94. 11. Kaye R, Pratt C. Summary of cardiac safety from a When DMQ is 5. Pope LE. AVP-923 as a novel treatment for pseudobulbar randomized, placebo-controlled, trial of dextromethorphan/ affect in ALS. Progress in Neurotherapeutics and quinidine (STAR) for treatment of pseudobulbar affect. combined with SSRIs Neuropsychopharmacology. 2006;1:91-104. Paper presented at: Annual Meeting of the American Academy of Neurology; April 15, 2010; Toronto, Ontario, and similar agents, 6. Arciniegas DB. A clinical overview of pseudobulbar affect. Canada. Am J Geriatr Pharmacother. 2005;3(suppl A):4-8. 12. Pioro EP, Brooks BR, Cummings J, et al. Safety and tolerability the serotonergic 7. Pioro EP, Brooks BR, Cummings J, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. of dextromethorphan/quinidine for pseudobulbar affect in properties of DM Ann Neurol. 2010;68:693-702. a 12-week, open-label extension study. Paper presented at: Annual Meeting of the American Academy of Neurology; 8. Johnston SC, Hauser SL. Marketing and drug costs: who is April 15, 2010; Toronto, Ontario, Canada. could result in laughing and crying? Ann Neurol. 2007;61:11A-12A. 13. Neudexta [package insert]. Aliso Viejo, CA: Avanir serotonin syndrome 9. Brooks BR, Thisted RA, Appel SH, et al, and the AVP- Pharmaceuticals; 2010. 923 ALS Study Group. Treatment of pseudobulbar affect with dextromethorphan/quinidine: a randomized trial. 14. Narita N, Hashimoto K, Tomitaka S, et al. Interactions Neurology. 2004;63:1364-1370. of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol. 1996; 10. Panitch HS, Thisted RA, Smith RA, et al, and the 307(1):117-119. Psuedobulbar Affect in Multiple Sclerosis Study Group. Randomized, controlled trial of dextromethorphan/ 15. Dhir A, Kulkarni SK. Involvement of sigma-1 receptor quinidine for pseudobulbar affect in multiple sclerosis. Ann modulation in the action of . Neurol. 2006;59:780-787. Neurosci Lett. 2007;420(3):204-208.

Bottom Line As a result of NMDA antagonism, 1-sigma agonism, and serotonergic effects, dextromethorphan/quinidine ameliorates pseudobulbar affect in patients with chronic neurologic disease. Addition of quinidine enhances dextromethorphan Current Psychiatry levels, with the potential for both greater therapeutic and toxic effects. Vol. 10, No. 2 67 Out of the Pipeline

Table 2 Dextromethorphan/quinidine for PBA: Evidence shows efficacy

Study Patients Dosages Results Panitch et al, 200610; 150 MS patients DMQ 30-30 or DMQ 30-30 was associated with 85-day, randomized, with PBA placebo, given greater reductions in CNC-LS double-blind, placebo- twice a day scores, fewer PBA episodes, controlled improvement in QOL and QOR, and decrease in pain intensity Pope, 20065; 3-arm, 140 ALS patients DMQ 30-30, DM, DMQ 30-30 was associated with double-blind, 28-day with PBA 30 mg, or quinidine, greater decreases in CNC-LS phase III multicenter 30 mg, given twice scores and number of laughing trial daily and crying episodes and improvements in QOL and QOR compared with DM or quinidine alone Pioro et al, 20107; 326 ALS and DMQ 30-10, DMQ CNC-LS scores decreased in 12-week, randomized, MS patients 20-10, or placebo, all groups but the daily rate of double-blind, placebo- with clinically given twice daily PBA episodes was 47% lower controlled trial significant PBA for DMQ 30-10 and 49% lower for DMQ 20-10 compared with placebo ALS: amyotrophic lateral sclerosis; CNC-LS: Center for Neurologic Study-Lability Scale; DM: dextromethorphan; DMQ 20-10: dextromethorphan, 20 mg, plus quinidine, 10 mg; DMQ 30-10: dextromethorphan, 30 mg, plus quinidine, 10 mg; DMQ 30-30: dextromethorphan, 30 mg, plus quinidine, 30 mg; MS: multiple sclerosis; PBA: pseudobulbar affect; QOL: quality of life; QOR: quality of relationships

Current Psychiatry Vol. 10, No. 2 A