Out Of The Pipeline

Dextromethorphan/quinidine for pseudobulbar affect

Current Psychiatry. 2011 February;10(2):60-67

The combination of dextromethorphan and quinidine reduced the number of daily PBA episodes in 3 randomized trials

References

1. Schiffer R, Pope LE. Review of pseudobulbar affect including a novel and potential therapy. J Neuropsychiatry Clin Neurosci. 2005;17:447-454.

2. Rosen HJ, Cummings J. A real reason for patients with pseudobulbar affect to smile. Ann Neurol. 2007;61:92-96.

3. Miller A. Pseudobulbar affect in multiple sclerosis: toward the development of innovative therapeutic strategies. J Neurol Sci. 2006;245:153-159.

4. Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med. 2003;3:65-94.

5. Pope LE. AVP-923 as a novel treatment for pseudobulbar affect in ALS. Progress in Neurotherapeutics and Neuropsychopharmacology. 2006;1:91-104.

6. Arciniegas DB. A clinical overview of pseudobulbar affect. Am J Geriatr Pharmacother. 2005;3(suppl A):4-8.

7. Pioro EP, Brooks BR, Cummings J, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010;68:693-702.

8. Johnston SC, Hauser SL. Marketing and drug costs: who is laughing and crying? Ann Neurol. 2007;61:11A-12A.

9. Brooks BR, Thisted RA, Appel SH, et al and. the AVP-923 ALS Study Group. Treatment of pseudobulbar affect with dextromethorphan/quinidine: a randomized trial. Neurology. 2004;63:1364-1370.

10. Panitch HS, Thisted RA, Smith RA, et al. and the Psuedobulbar Affect in Multiple Sclerosis Study Group. Randomized, controlled trial of dextromethorphan/ quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol. 2006;59:780-787.

11. Kaye R, Pratt C. Summary of cardiac safety from a randomized, placebo-controlled, trial of dextromethorphan/ quinidine (STAR) for treatment of pseudobulbar affect. Paper presented at: Annual Meeting of the American Academy of Neurology; April 15, 2010; Toronto, Ontario, Canada.

12. Pioro EP, Brooks BR, Cummings J, et al. Safety and tolerability of dextromethorphan/quinidine for pseudobulbar affect in a 12-week, open-label extension study. Paper presented at: Annual Meeting of the American Academy of Neurology; April 15, 2010; Toronto, Ontario, Canada.

13. Neudexta [package insert]. Aliso Viejo, CA: Avanir Pharmaceuticals; 2010.

14. Narita N, Hashimoto K, Tomitaka S, et al. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol. 1996;307(1):117-119.

15. Dhir A, Kulkarni SK. Involvement of sigma-1 receptor modulation in the antidepressant action of venlafaxine. Neurosci Lett. 2007;420(3):204-208.

In October 2010, the FDA approved a combination of dextromethorphan (DM) and quinidine for the treatment of pseudobulbar affect (PBA)—also called pathological laughing and crying, affective lability, emotional dyscontrol, emotional incontinence, and involuntary emotional expression disorder—in patients with neurologic disorders and brain injuries (Table). Despite receiving an approvable letter in 2006, the compound was not approved at that time because of concerns about the arrhythmogenic potential of quinidine, which prolongs the QT interval. The manufacturer conducted another study using one-third of the previous quinidine dose, which ameliorated this concern and led to approval.

Clinical implications

PBA is manifested by involuntary labile, shallow affect with sudden and unpredictable laughing, crying, or other emotional displays that are not appropriate to the social setting and may not be congruent with the patient’s prevailing mood.¹ Episodes are often paroxysmal and cannot be interrupted voluntarily.² PBA seems to be caused by a loss of descending cortical control of brainstem motor nuclei and possibly the cerebellum, disrupting inhibitory mechanisms and resulting in inappropriate and involuntary emotional display.³ Several studies have demonstrated involvement of subcortical areas, particularly the anterior limb of the internal capsule and the bulbar area. The patho-physiology of PBA may involve excessive release of glutamate by injured neurons, disrupting systems for motor control of emotional expression.^4,5

Table

Dextromethorphan/quinidine: Fast facts

Brand name: Nuedexta
Indication: Pseudobulbar affect
Approval date: October 29, 2010
Availability date: First quarter of 2011
Manufacturer: Avanir
Dosage forms: Dextromethorphan, 20 mg, plus quinidine, 10 mg
Starting dose: 1 capsule per day
Target dose: 2 capsules per day

PBA is most common in diseases that interfere bilaterally with the corticohypothalamic and corticobulbar tracts that control voluntary and involuntary faciorespiratory mechanisms. However, PBA occurs in unilateral disease as well. The reported prevalence of PBA is:

49% in amyotrophic lateral sclerosis (ALS)
18% to 39% in Alzheimer’s disease
11% to 34% in stroke
10% to 11% in multiple sclerosis (MS) and traumatic brain injury.^6,7

PBA also has been reported in patients with Parkinson’s disease, brain tumors, Wilson’s disease, syphilitic pseudobulbar palsy, and various encephalitides.¹ An estimated 880,000 U.S. patients exhibit PBA.⁸

Previously, there was no FDA-approved treatment for PBA. However, small controlled trials suggest that selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs)— usually in doses lower than those used to treat depression—may effectively reduce symptoms within 2 to 3 days.¹ Although dopaminergic agents such as levodopa and amantadine have shown benefit in open trials, results of controlled studies using objective measurements have not been positive.

How it works

DM is a serotonergic substance that also is an agonist of 1-sigma receptors and a low-affinity, uncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors, which are important in glutamate signaling, through binding at the phencyclidine site on the NMDA complex.^7,9 The 1-sigma receptor was thought to be an opioid receptor subtype, but unlike opioid receptors it is not blocked by narcotic antagonists and does not have an endogenous ligand. However, the 1-sigma receptor does modulate activity of opioid mu receptors in addition to altering dopamine release and possibly reducing glutamate release.⁹ Sigma receptors are densely distributed in the limbic system and in systems related to motor control of affective expression and seem to be involved in learning, responses to stress, mood regulation, and drug dependence.¹ Because DM preferentially binds to brain regions that regulate emotional expression,¹⁰ it could normalize glutaminergic neurotransmission and other relevant systems in these regions.¹ However, DM’s exact mechanism of action is unknown.

Clinical Point

In doses 10 to 25 times lower than those used to treat cardiac arrhythmias, quinidine inhibits 2D6 and increases DM bioavailability

Quinidine is a sodium channel antagonist usually used as a type Ia antiarrhythmic.⁵ DM is subject to extensive first-pass metabolism by cytochrome P (CYP) 450 2D6 to dextrorphan, which after being glucuronidated cannot cross the blood-brain barrier. In doses 10 to 25 times lower than those used to treat cardiac arrhythmias, quinidine inhibits 2D6 and increases DM bioavailability.¹⁰ DM blood levels increase linearly with dose following coadministration with quinidine but are undetectable in most patients given DM alone.^7,9

Efficacy and tolerability

A combination of DM and quinidine (DMQ) reduced Center for Neurologic Study-Lability Scale (CNC-LS) scores and the number of daily PBA episodes in 3 randomized trials.^5,7,10 Visit this article at CurrentPsychiatry.com for a table summarizing these studies.

An 85-day randomized, double-blind, placebo-controlled study of 150 patients with PBA associated with MS found that DM, 30 mg, plus quinidine, 30 mg, (DMQ 30-30) was twice as effective as placebo within a week in reducing CNC-LS scores.¹⁰ DMQ 30-30 patients also had approximately half as many episodes of inappropriate laughing, crying, or combined laughing and crying and a 2-fold greater decrease in pain intensity.¹⁰ Twenty-one percent of DMQ 30-30 patients experienced complete remission—no PBA episodes—compared with 7% of placebo patients. There were no significant differences in QT prolongation between DMQ 30-30 and placebo.