Dextromethorphan/quinidine for pseudobulbar affect

A 3-arm, double-blind, 28-day, phase III multicenter trial of 140 ALS patients with PBA compared DM monotherapy, quinidine monotherapy, and DMQ 30-30.⁵ Compared with either drug alone, DMQ 30-30 showed greater reduction of CNC-LS scores, as well as improved quality of life and quality of relationships scores, with equal benefit in poor and extensive DM metabolizers. However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.

In a manufacturer-sponsored, multicenter, 12-week randomized trial, 326 patients with ALS or MS and clinically significant PBA were randomly assigned to DM, 30 mg, plus quinidine, 10 mg (DMQ 30-10), DM, 20 mg, plus quinidine, 10 mg (DMQ 20-10), or placebo, each administered twice daily.⁷ Patients with comorbid psychiatric disorders or significant depressive symptoms were excluded. Although daily PBA episodes decreased in all groups, the daily rate of PBA episodes was 47% lower for patients taking DMQ 30-10, and 49% lower with DMQ 20-10 compared with placebo (both P < .001). The mean decrease in the number of daily PBA episodes was 3.9 to 4.1 with active treatment and 3.0 with placebo. Side effects were more common with active drug than placebo and included dizziness, nausea, diarrhea, and urinary tract infection. There were no serious adverse cardiac events and no active drug recipients showed a QTc interval >480 msec or a change from baseline >60 msec.¹¹ Discontinuation rates in this study were lower than in studies of DMQ 30-30. In an open-label extension of 253 patients who completed the double-blind phase and were assigned to DMQ 30-10 for 12 weeks, the incidence of treatment-related adverse events was 28%, with a 5.5% rate of serious adverse events.¹²

Safety

Because the 10 mg dose of quinidine in the approved formulation of DMQ is 10 times lower than the antiarrhythmic dose, substantial ECG changes and adverse cardiac effects with DMQ have not been reported. The most common side effects of DM are nausea, somnolence, dizziness, and headache. Thrombocytopenia, QT prolongation, hepatotoxicity, allergic reactions, and anticholinergic side effects can occur.

In high doses and combined with other substances, DM has been used as a recreational drug. When taken in high doses, adverse effects include nausea, vomiting, malaise, dilated pupils, difficulty urinating, increased urination frequency, fever, tachycardia, loss of appetite, shakiness, seizures, and potentially coma and death. DMQ may have a greater potential for serious adverse effects than DM alone because quinidine increases DM bioavailability and blood levels. The abuse potential of DMQ is not clear.

Psychosis has been reported with higher DM doses. The psychotomimetic effects of phencyclidine (PCP) are related to binding to the PCP site on the NMDA receptor complex—to which DM also binds—with reduced glutamate signaling in information processing systems. Therefore, caution is indicated when prescribing DM to patients with psychosis.

Because DM, a CYP2D6 substrate, is combined with quinidine, a 2D6 inhibitor, administering DMQ with other 2D6 inhibitors could lead to toxicity. When DMQ is combined with SSRIs and similar agents, the serotonergic properties of DM could result in serotonin syndrome, which could be fatal if DM is combined with monoamine oxidase inhibitors.¹⁰ Combinations of DM and acetaminophen and antihistamines can be dangerous at higher doses.¹⁰ Because quinidine is metabolized by CYP3A, inhibitors of this enzyme such as ketoconazole, nefazodone, and grapefruit juice should be avoided. Similarly, inhibition of CYP2D6 by quinidine could raise levels of coadministered 2D6 substrates.

Contraindications. DMQ is contraindicated in patients with:

• heart failure
• prolonged QT interval
• congenital long QT interval
• history of torsades de pointes
• complete atrioventricular (AV) block without implanted pacemakers.¹³

DMQ also is contraindicated in patients at high risk for complete AV block.¹³

Dosing

DMQ is available as a capsule containing DM, 20 mg, and quinidine, 10 mg. The recommended starting dose is 1 capsule by mouth for 7 days, then 1 capsule every 12 hours.

Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a non-serotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated. In view of the unknown potential for abuse and toxicity as well as the cost of the proprietary drug ($3,000 to $5,000 a year), it would seem prudent to consider using an SSRI or a TCA first.⁸ These medications also act on 1-sigma receptors,^14,15 which may account in part for their reported benefit.