iences 259 (2007) 67–73www.elsevier.com/locate/jns

Journal of the Neurological Sc

Therapeutic use of dextromethorphan: Key learnings fromtreatment of pseudobulbar affect

Ariel Miller a,⁎, Hillel Panitch b

a Center for Multiple Sclerosis, Carmel Medical Center, Rappaport Faculty of Medicine and Research Institute,Technion-Israel Institute of Technology, Haifa, Israel

b Multiple Sclerosis Center, Department of Neurology, University of Vermont College of Medicine, 1 South Prospect Street,Burlington, VT 05401, USA

Received 20 February 2006; received in revised form 2 June 2006; accepted 12 June 2006Available online 16 April 2007

Abstract

Avariety of neurological conditions and disease states are accompanied by pseudobulbar affect (PBA), an emotional disorder characterizedby uncontrollable outbursts of laughing and crying. The causes of PBA are unclear but may involve lesions in neural circuits regulating themotor output of emotional expression. Several agents used in treating other psychiatric disorders have been applied in the treatment of PBAwithsome success but data are limited and these agents are associated with unpleasant side effects due to nonspecific activity in diffuse neuralnetworks. Dextromethorphan (DM), a widely used cough suppressant, acts at receptors in the brainstem and cerebellum, brain regionsimplicated in the regulation of emotional output. The combination of DM and quinidine (Q), an enzyme inhibitor that blocks DM metabolism,has recently been tested in phase III clinical trials in patients with multiple sclerosis and amyotrophic lateral sclerosis and was both safe andeffective in palliating PBA symptoms. In addition, clinical studies pertaining to the safety and efficacy of DM/Q in a variety of neurologicaldisease states are ongoing.© 2007 Elsevier B.V. All rights reserved.

Keywords: Pseudobulbar effect; Emotion; Laughing; Crying; Explosive; Multiple sclerosis; Amyotrophic lateral sclerosis; Neuroprotection

1. Introduction

Patients with neurologic disease or injury face manystruggles and challenges. Among these, involuntary emo-tional expression disorder (IEED) presents a significant im-pact on patient quality of life. IEED consists of numerousinvoluntary displays of emotion, including episodic anger,agitation, and frustration, as well as episodes of pathologiccrying and laughing. Such episodes of uncontrollable cryingand laughing are referred to as pseudobulbar affect (PBA).PBA is a common consequence of a number of neurologicalconditions including, but not limited to, multiple sclerosis(MS), amyotrophic lateral sclerosis (ALS), traumatic brain

⁎ Corresponding author. Tel.: +972 4 8250 851; fax: +972 4 8250 909.E-mail addresses: millera@tx.technion.ac.il, milleras@netvision.net.il

(A. Miller).

0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2006.06.030

injury (TBI), ischemic stroke, and Alzheimer's disease (AD)[1]. Patients with PBA experience uncontrollable, sociallyinappropriate bouts of crying, laughing, or both. The lack ofan FDA approved treatment for PBA has lead to an explo-ration of candidate agents that are both safe and efficacious.This article will provide a general overview of PBAsymptomatology and pathophysiology. Included will be areview of recent clinical trials and planned future studies witha novel therapeutic agent and potential therapeutic and neu-roprotective mechanisms of action of this agent.

2. Pseudobulbar affect

2.1. Background

In PBA, pathological emotional outbursts are generallyunrelated to the patient's underlying mood [2,3]. In some

68 A. Miller, H. Panitch / Journal of the Neurological Sciences 259 (2007) 67–73

instances, the outbursts are entirely incongruent to thepatient's mood, while in others they are mood-congruentbut out of proportion with the patient's subjective experience[4,5]. Crying and/or laughing episodes in PBA patients areoften stereotyped, with each episode being, often times, re-markably similar to previous episodes, despite being pro-voked by different, nonspecific stimuli [1,2]. The uncontrol-lable and inappropriate nature of these episodes can result inembarrassment and social isolation of patients and distress toboth patients and caregivers [4].

Reports of emotionally inappropriate outbursts in patientswith neurological disorders can be traced back to as early as1872 [7]. Differences of opinion pertaining to the nature andseverity of symptoms [1,2,5,8,9] and the definitions of psy-chological constructs like mood, affect, and emotion, how-ever, have led to the use of many different terms to describethe clinical syndromes related to PBA. These include patho-logical laughing and crying (weeping), emotional lability,affective lability, emotionalism, emotional incontinence,pathologic emotionality or affect, and emotional dyscontrol[3,9]. PBA is a relatively older term which has reemerged[10] as the ideal descriptor of these episodes that may or maynot be congruent with mood [11]. A singular classification ofthis emotional disorder, coupled with an accepted definitionof symptoms, is likely lead to a more accurate diagnosis andtreatment of PBA.

2.2. Assessment

Clinicians recognize PBA as a distinct disorder; however,its symptoms may either mimic those of other disorders [12–15] or coexist with them [8,16,17]. For these reasons and forthe purpose of evaluating PBA's severity and the efficacy oftreatment, several assessment tools specific to PBA havebeen developed.

A self-reported measure of changeable affect, the AffectiveLability Scales (ALS) was used prior to the development ofPBA-specific diagnostic tools. TheALS is a collection of itemsused to measure self-reported lability in a range of affectivestates including euthymia, depression, anxiety, anger, andhypomania [18]. The more specific Pathological Laughter andCrying Scale (PLACS) developed byRobinson and colleagues[17] is a battery of 16 items administered to patients by aninterviewer. Eight of the items concern crying, and theremaining 8 pertain to laughing. The items serve as a toolto quantify aspects of laughter and/or crying episodes with anemphasis on the degree of voluntary control per episode,duration of episodes, inappropriateness of episodes in termsof mood congruity, degree of stress resulting from episodes,and the relationship between episodes and external events.The interviewer rates the response of the patient on a scale of0 to 3 points and computes the total points for all items. Ifthis value is equal to or greater than 13 points, a diagnosis ofPBA is likely correct. The utility of the PLACS as a diag-nostic tool for PBA has been validated in stroke patients [17],Alzheimer's patients [19], and patients with TBI [20].

A battery of modifications to the PLACS resulted in theEmotional Lability Questionnaire (ELQ) [21]. This diag-nostic tool includes an assessment of abnormal smiling inaddition to laughing and crying, and is administered as astructured interview to both the patient (self-rated), and acaregiver (independent-rated).

The Center for Neurologic Study-Lability Scale (CNS-LS) is an additional diagnostic tool specifically developed toassess PBA symptoms [22]. The CNS-LS is a short, easilyadministered self-report used to quantify perceived aspects ofPBA such as frequency, intensity, lability, degree of voluntarycontrol and inappropriateness of context. Patients respond to4 items pertaining to laughter and 3 items to assess tearfulnesson a scale of 1 (applies never) to 5 (applies most of the time).Like the PLACS, a point total from all items equal to orgreater than 13 points is predictive of a correct diagnosis ofPBA. The CNS-LS has been validated in both patients withALS [22] and patients with MS [23].

2.3. Pathophysiology

Although the precise neuroanatomical basis of PBA isstill in question, the pathophysiology underlying the uncon-trollable and emotionally inappropriate outbursts character-istic of PBA is thought to involve disruption of inhibitorysignals descending from the cerebral cortex to motor regionsof the brainstem implicated in the regulation of emotionaloutput [24]. The emotional dysregulation observed in PBAmay result from impairments to any of a number of neuralstructures or connections in a complex cortico-limbic-sub-cortico-thalamo-ponto-cerebellar network [10].

PBA is most commonly associated with neural damage(bilateral or unilateral) to the inhibitory prefrontal corticalcircuitry descending to diencephalic and brainstem structuresthat regulate both involuntary and voluntary faciorespiratorymechanisms: the corticohypothalamic and corticobulbartracts [9,25–29]. Although PBA has been associated withboth bilateral and unilateral lesions, the expression of PBAsymptoms may be differentially influenced by laterality [30–34]. The co-occurrence of PBA with a variety of otherwiseunrelated neurological conditions involving either bilateralor unilateral neural damage is intimately linked to the wide-spread nature of the circuitry in this network and suggeststhat the location of the lesion is more significant than themechanism of damage.

An alternative explanation for PBA symptoms suggests adisconnect between the neural networks underlying experi-enced emotion and displayed emotion [35]. In this model,circuits originating in any of several cortical regions thatterminate in the cerebellum (cortico-ponto-cerebellar path-ways) may be disrupted resulting in faulty coordination ofenvironmental cues and emotional output. The cerebellarpeduncles are a component of this circuit, and have beenpreviously implicated as one of the neuroanatomical loci inPBA pathophysiology [35]. In a recent MRI study of apatient with MS, a scan taken before the onset of PBA

69A. Miller, H. Panitch / Journal of the Neurological Sciences 259 (2007) 67–73

symptoms (pathological laughter) demonstrated a lesion inthe left cerebellar peduncle, and a post-PBA symptom onsetscan revealed an increase in the size of this lesion as well as anew lesion in the contralateral peduncle [36]. These datasuggest that the severity of cerebellar disconnection may bedirectly related to PBA onset. Together, these data suggestthat the disruption of neural circuitry in PBA may be a directconsequence of a variety of lesion types to a variety of neuralregions. It is also likely, however, that PBA is due at least inpart to secondary neurochemical dysregulation of serotoner-gic [1], dopaminergic [37] and/or glutamatergic [38] neuro-transmission [10]. Useful treatments for PBA are likely tomodulate this altered state of neurotransmission.

3. Therapeutic options

Although there are no currently available FDA approveddrugs for the treatment of PBA, several classes of agentsincluding the tricyclic antidepressants, selective serotoninreuptake inhibitors, and dopaminergic agents have beenstudied in PBA [16,17,39–42]. Despite reports of efficacy,the use of these agents in the treatment of PBA has not beensupported in large well-controlled trials and studies con-ducted to date have used variable endpoints, differing de-finitions of PBA, and different inclusion/exclusion criteria[43]. The use of these agents is associated with a suite ofunpleasant side effects that may be particularly problematicin elderly patients or in those with brain injury [44,45]. Theconcern over side effects provoked by nonspecific activity inthe diffuse neural networks targeted by these agents may beovercome by the use of drugs that target receptors in theneural networks implicated in PBA.

3.1. Dextromethorphan/Quinidine

Dextromethorphan (DM) is the active ingredient in manyover-the-counter cough suppressant (antitussive) medica-tions. An increasing body of evidence suggests that DM alsohas therapeutic potential for treating neuronal disorders [46–48] since it can cross the blood–brain barrier [50] and bind tospecific high and low affinity binding sites [51] concentratedin the brainstem and cerebellum [52,53]. In the centralnervous system, DM can act as both a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist [51,54–57], and as a potent sigma1 receptor agonist [55,58]. Both invitro and in vivo animal studies have demonstrated that DMhas anticonvulsant and neuroprotective properties [51] andthe use of DM as a neuroprotective agent in humans has beentested in limited clinical trials in patients with ALS [59,60],Huntington's disease [61], Parkinson's disease [62], andvarious types of neuropathic pain [63–69]. The results ofthese trials hinted at clinical efficacy, but have yet to result inoverwhelming therapeutic efficacy [70].

Of particular importance was the discovery that, despitethe administration of 8 times the maximum antitussive dose,plasma levels of DM were undetectable in some patients in

one of the Huntington's disease trials [61]. It was theorizedthat these results may have been attributable to the rapid andextensive first-pass hepatic metabolism of DM to its primarymetabolite dextrorphan (DX), catalyzed by the cytochromeP450 2D6 (CYP2D6) enzyme [71]. By co-administering DMwith quinidine (Q), a specific inhibitor of CYP2D6 activity[72–77], Zhang and colleagues [46] demonstrated a way toincrease systemically available levels of DM. In a subse-quent study, 25–30 mg of Q, an amount 10–20 times lowerthan that used to treat cardiac arrhythmias [46,78], wasdetermined to be sufficient to provide maximal suppressionof DMmetabolism [70]. The combination of DM and Q is anattractive candidate for use in the treatment of PBA based onthe purported neuroprotective effects of DM, the bioavail-ability and safety of the DM/Q combination, and the locationof DM binding sites in brain regions implicated in emotionalexpression.

4. Results of phase III clinical trial in MS

PBA has been reported to affect anywhere from 7 to 95%of patients with MS [11,43] although a more recentassessment using the PLACS and a rigorous definition ofPBA placed the prevalence of PBA in MS at 10% [3]. Toexplore the safety and efficacy of DM/Q as a treatment forPBA in MS, we conducted a phase III clinical trial in 150 MSpatients at 22 sites in the United States and Israel [79].

In a randomized, double-blind, placebo-controlled study,a fixed combination of DM and Q (30 mg DM and 30 mg Q)or placebo was administered twice daily for 12 weeks.Included patients demonstrated a clinical diagnosis of PBAwithout a prior history of major psychiatric disturbance orcoexistent major systemic disease and a score of 13 or morepoints on the CNS-LS. To assess efficacy, patients weregiven a CNS-LS throughout the study. Additionally, qualityof life (QoL) and quality of relationships (QoR) were as-sessed by use of visual analogue scales (VAS). Pain expe-rienced during the previous 24 h was assessed by use of a 5-point pain intensity rating scale.

All efficacy endpoints were statistically significant infavor of the DM/Q group compared to the placebo group.The primary efficacy variable, change in CNS-LS score,showed a statistically greater reduction in patients receivingDM/Q (P<0.0001). The number of episodes per week, oneof the secondary efficacy variables, also showed a statis-tically greater reduction in patients receiving DM/Q for allthree types of episodes (crying: P<0.0001; laughing:P=0.0077; crying and laughing: P=0.0002). The otherthree secondary efficacy variables–change in overall QoLVAS score, change in overall QoRVAS score, and change inpain intensity rating scale score–were likewise statisticallysignificant in favor of DM/Q treatment (P<0.0001, P=0.0001, and P=0.0271, respectively). Additionally, thepercentage of patients experiencing complete remission ofcrying and/or laughing episodes was significantly greater inDM/Q treated patients by the end of the first week of the

70 A. Miller, H. Panitch / Journal of the Neurological Sciences 259 (2007) 67–73

study (P=0.036) and in all subsequent periods examined[79].

In addition to these robust efficacy results, the safetyprofile of DM/Q was favorable. Of the AEs reported by 5%or more of patients, headache occurred more often in patientsreceiving placebo, and only dizziness was statistically morefrequent in DM/Q treated patients as compared to controls(P=0.01). There were no other safety results of concern fromphysical examinations, vital signs ECG values, or laboratorymeasurements. The results of this phase III clinical trialconfirmed the efficacy and safety of DM/Q in palliating thesymptoms of PBA in patients with MS (Table 1).

5. Results of phase III clinical trial in ALS

The efficacy of DM/Q in alleviating PBA in patients withMS had been previously demonstrated in patient with ALS, adisease in which the prevalence of PBA is extremely common[43]. Brooks and colleagues [38] conducted a phase IIIclinical trial in 140 ALS patients at 17 sites in the UnitedStates. In a randomized, double-blind, controlled study, either30 mg of DM, 30 mg of Q, or a fixed combination of DM/Q(30 mg DM and 30 mg Q) was administered twice daily for28 days. The primary and secondary efficacy variables, safetyassessment variables, and inclusion criteria were similar tothose used by Panitch and colleagues [79]. A pain ratingvariable was not assessed in this study, however, and theHamilton Scale for Depression was utilized to excludepatients with underlying moderate or severe depression.

All efficacy measures significantly differed in favor ofpatients treated with DM/Q. Compared to either DM or Qalone, patients treated with DM/Q experienced significantlygreater improvement in CNS-LS scores (P=0.001, P<0.001,respectively), decreased overall rate of crying episodes andcombined crying and laughing episodes (all P<0.001) and adecreased rate of laughing episodes (P=0.05 vs. DM or Q).Treatment with DM/Q also resulted in significant improve-ment in QoL (P=0.002 vs. DM, P=0.001 vs. Q) and QoR(P<0.001 vs. DM or Q), as measured by VAS scores.Dizziness, nausea, and somnolence were reported at a higherfrequency in the DM/Q treated patients as compared to eitherDM or Q alone [38]. The similar efficacy of DM/Q in bothMS and ALS patients suggests that this agent will be useful in

Table 1Comparison of the recent two phase III clinical trials of DM/Q

Study Disease state Length ofstudy

Includedgroups

Brooks et al. [38] Amyotrophiclateral sclerosis

30 days DM/Q (n=70)DM alone (n=33)Q alone (n=37)

Panitch et al. [79] Multiple sclerosis 3 months DM/Q (n=76)Placebo (n=74)

the treatment for PBA regardless of the underlying neuro-logical condition.

6. Future studies

To examine the safety and tolerability of DM/Q during alonger term of administration (6 months to 1 year) an open-label trial has been initiated. This trial is not limited topatients with MS or ALS, but includes PBA patients withany neurological condition, including but not limited to MS,ALS, AD, stroke, TBI, and Parkinson's disease. The dosageand safety endpoints are similar to those used in the phase IIIclinical trials in MS [79] and ALS [38].

The combination of DM/Q is being studied as a potentialtherapeutic agent in other conditions as well. It is likely thatDM/Q will be efficacious in the treatment of the othercomponents of IEED, including episodic anger. Furthermore,analgesic properties have been attributed to DM [80], andtreatment with DM/Q appeared to be well tolerated andpossibly efficacious in reducing diabetic neuropathic pain inan open-label multicenter study of 36 diabetic patients withpainful distal symmetrical neuropathy (Avanir Study Report01-AVR-105). To continue to explore the safety, efficacy, andtolerability of DM/Q treatment in the reduction of diabeticneuropathic pain, a randomized, multicenter, double-blind,placebo-controlled phase III clinical trial has been initiated(Avanir Study Report 04-AVR-109).

The mechanism of action by which DM exerts therapeuticrelief of IEED and PBA symptoms or diabetic neuropathicpain remains unknown. Several possibilities have beensuggested [10], including modulation of excitatory neuro-transmission. As mentioned, DM acts as an agonist at sigma1receptors [55,58] and as a noncompetitive NMDA receptorantagonist [51,54–57]. Acting at either receptor, DM maydecrease excitatory glutamatergic signaling [81–83]. It is notknown whether or to what extent excessive excitatoryglutamatergic neurotransmission provokes episodes of IEEDor diabetic neuropathic pain, however. Also unknown is therelative involvement of these two types of receptors in thetherapeutic response to DM, and whether DM acts in apresynaptic, postsynaptic, or mixed pre- and postsynapticfashion to exert its effects. More basic research is required tounderstand the underlying causes of these diseases and the

BaselineCNS-LS

Efficacy of treatment Adverse events(P<0.05)

20.0 DM/Q resulted in significantly greater(P<0.05) improvement on CNS-LS,QoL, and QoR scores

Nausea21.4 Dizziness22.2 Somnolence20.3 DM/Q resulted in significantly greater

(P<0.05) improvement on CNS-LS,QoL, and QoR scores

Dizziness21.4

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role of DM at the cellular and molecular level in palliatingtheir symptoms.

7. Neuroprotection

Glutamate-induced neuronal toxicity (excitotoxicity) is amajor cause of neuronal cell death in response to certainneurological disease states and TBI [84–87]. Elevated con-centrations of extracellular glutamate provoked by ischemia,seizures, or TBI stimulate the entry of toxic levels of calciuminto neuronal cytoplasm which eventually causes the deathof the neuron [88]. The excitotoxicity attributed to glutamateis mediated through the NMDA receptor, antagonists ofwhich are highly neuroprotective in vitro [84,87,89]. Sigma1receptor ligands can indirectly modulate the NMDA receptor[83] and are also effective in vitro neuroprotective agents[90]. Because DM is a noncompetitive NMDA receptorantagonist [51,54–57], and a sigma1 receptor agonist[55,58], it has the unique potential to mediate neuropro-tection via multiple mechanisms. DM has been shown tohave neuroprotective properties in several different invitro models [81,90–93], as well as in animal models offocal and global cerebral ischemia [52,53,94–96] and TBI[97]. As it is well tolerated in humans [38,46,70,79] DM/Q is an excellent candidate for therapeutic use in neuro-logical disorders characterized by excitotoxic neuronal celldeath.

8. Conclusions

PBA affects a substantial number of patients with MS,ALS, TBI, ischemic stroke, AD, and other neurologicaldisorders. The observed pathophysiology of PBA suggestslesion and/or neurotransmitter abnormalities in neural cir-cuits regulating the expression of emotion. Current treat-ments, while somewhat effective, are not specific in natureand provoke side effects that may outweigh therapeuticbenefits. DM binds with specificity to receptors in brainregions implicated in the regulation of emotion output, andhas demonstrated neuroprotective properties both in vitroand in vivo. By increasing bioavailability with Q, DM is apromising therapeutic option in the treatment of PBA, asdemonstrated in both MS and ALS patients. As Q is aspecific inhibitor of cytochrome P450 2D6 enzyme, the bio-availability of other drugs metabolized by this enzyme couldbe significantly modified when taken concomitantly. It isalso important to note that a number of agents also act toinhibit this enzymatic pathway, including fluoxetine andparoxetine, and care should be taken when prescribing anyagent that inhibits this system. The ability of DM/Q topalliate PBA symptoms in more than one neurologicalcondition suggests that it may be effective in treating thissyndrome in a variety of disorders. DM also shows promisefor the treatment of other forms of IEED, as well as diabeticneuropathic pain, and may be useful in treating a variety ofconditions associated with excitotoxic glutamate release.

Acknowledgements

Supported through an unrestricted educational grant byAvanir Pharmaceuticals.

References

[1] Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect: anapproach to evaluation and treatment. Semin Clin Neuropsychiatry2000;5:290–306.

[2] Poeck K. Pathological laughing and weeping in patients with prog-ressive bulbar palsy. Ger Med Mon 1969;14:394–7.

[3] Feinstein A, Feinstein K, Gray T, O'Connor P. Prevalence and neuro-behavioral correlates of pathological laughing and crying in multiplesclerosis. Arch Neurol 1997;54:1116–21.

[4] Lieberman A, Benson DF. Control of emotional expression inpseudobulbar palsy. A personal experience. Arch Neurol 1977;34:717–9.

[5] House A, Dennis M, Molyneux A, Warlow C, Hawton K.Emotionalism after stroke. BMJ 1989;298:991–4.

[7] Darwin C. The expression of the emotions in man and animals. NewYork: D Appleton and Company; 1872.

[8] Morris PL, Robinson RG, Raphael B. Emotional lability after stroke.Aust N Z J Psychiatry 1993;27:601–5.

[9] Dark FL, McGrath JJ, Ron MA. Pathological laughing and crying.Aust N Z J Psychiatry 1996;30:472–9.

[10] Arciniegas DB, Lauterbach EC, Anderson KE, Chow TW, FlashmanLA, Hurley RA, et al. The differential diagnosis of pseudobulbar affect(PBA): distinguishing PBA among disorders of mood and affect. CNSSpectr 2005;10:1–14.

[11] Miller A. Pseudobulbar affect in multiple sclerosis: toward the develop-ment of innovative therapeutic strategies. J Neurol Sci 2006;245(1–2):153–9.

[12] Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventoryfor measuring depression. Arch Gen Psychiatry 1961;4:561–71.

[13] Black KJ. Pathological laughing and crying. Am J Psychiatry 1994;151:456.

[14] Sato T, Bottlender R, Kleindienst N, Moller HJ. Syndromes andphenomenological subtypes underlying acute mania: a factor analyticstudy of 576 manic patients. Am J Psychiatry 2002;159:968–74.

[15] Robertson GM. Does mania include two distinct varieties of Insanity,and should it be sub-divided? J Ment Sci 1890;36:338–47.

[16] Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologiclaughing and weeping with amitriptyline. N Engl J Med 1985;312:1480–2.

[17] Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR.Pathological laughing and crying following stroke: validation of ameasurement scale and a double-blind treatment study. Am J Psychiatry1993;150:286–93.

[18] Harvey PD, Greenberg BR, Serper MR. The affective lability scales:development, reliability, and validity. J Clin Psychol 1989;45:786–93.

[19] Starkstein SE, Migliorelli R, Teson A, Petracca G, ChemerinskyE, Manes F. Prevalence and clinical correlates of pathologicalaffective display in Alzheimer's disease. J Neurol Neurosurg Psychiatry1995;59:55–60.

[20] Tateno A, Jorge RE, Robinson RG. Pathological laughing and cryingfollowing traumatic brain injury. J Neuropsychiatry Clin Neurosci2004;16:426–34.

[21] Newsom-Davis IC, Abrahams S, Goldstein LH, Leigh PN. Theemotional lability questionnaire: a newmeasure of emotional lability inamyotrophic lateral sclerosis. J Neurol Sci 1999;169:22–5.

[22] Moore SR, Gresham LS, Bromberg MB, Kasarkis EJ, Smith RA. Aself report measure of affective lability. J Neurol Neurosurg Psychiatry1997;63:89–93.

[23] Smith RA, Berg JE, Pope LE, Callahan JD, Wynn D, Thisted RA.Validation off cns emotional liability scale for pseudobulbar affect

72 A. Miller, H. Panitch / Journal of the Neurological Sciences 259 (2007) 67–73

(pathological laughing and crying) in multiple sclerosis patients. MultScler 2004;10:679–85.

[24] Wilson SAK. Some problems in neurology. II: Pathological laughingand crying. J Neurol Psychopathol 1924;IV:299–333.

[25] Ironside R. Disorders of laughter due to brain lesions. Brain1956;79:589–609.

[26] Poeck K. Pathophysiology of emotional disorders associated withbrain damage. In: Vinken PJ, Bruyn GW, editors. Handbook of clinicalneurology. New York: American Elsevier Publishing Company, Inc.;1969. p. 343–67.

[27] Ceccaldi M, Poncet M, Milandre L, Rouyer C. Temporary forcedlaughter after unilateral strokes. Eur Neurol 1994;34:36–9.

[28] Kim JS. Pathological laughter and crying in unilateral stroke. Stroke1997;28:2321.

[29] Kim JS, Choi-Kwon S. Poststroke depression and emotional incon-tinence: correlation with lesion location. Neurology 2000;54:1805–10.

[30] Sackeim HA, Greenberg MS, Weiman AL, Gur RC, Hungerbuhler JP,Geschwind N. Hemispheric asymmetry in the expression of positiveand negative emotions. Neurologic evidence. Arch Neurol1982;39:210–8.

[31] Robinson RG, Kubos KL, Starr LB, Rao K, Price TR. Mood changesin stroke patients: relationship to lesion location. Compr Psychiatry1983;24:555–66.

[32] Robinson RG, Kubos KL, Starr LB, Rao K, Price TR. Mooddisorders in stroke patients. Importance of location of lesion. Brain1984;107(Pt 1):81–93.

[33] Starkstein SE, Robinson RG, Price TR. Comparison of patients withand without poststroke major depression matched for size and locationof lesion. Arch Gen Psychiatry 1988;45:247–52.

[34] Starkstein SE, Robinson RG. Affective disorders and cerebral vasculardisease. Br J Psychiatry 1989;154:170–82.

[35] Parvizi J, Anderson SW, Martin CO, Damasio H, Damasio AR. Patho-logical laughter and crying: a link to the cerebellum. Brain 2001;124:1708–1719.

[36] Okuda DT, Chyung AS, Chin CT, Waubant E. Acute pathologicallaughter. Mov Disord 2005;20:1389–90.

[37] Lauterbach EC, Schweri MM. Amelioration of pseudobulbar affect byfluoxetine: possible alteration of dopamine-related pathophysiology bya selective serotonin reuptake inhibitor. J Clin Psychopharmacol 1991;11:392–3.

[38] Brooks BR, Thisted RA, Appel SH, Bradley WG, Olney RK, Berg JE.Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 2004;63:1364–70.

[39] Udaka F, Yamao S, Nagata H, Nakamura S, Kameyama M. Pathologiclaughing and crying treated with levodopa. Arch Neurol 1984;41:1095–6.

[40] Andersen G, Vestergaard K, Riis JO. Citalopram for post-strokepathological crying. Lancet 1993;342:837–9.

[41] Burns A, Russell E, Stratton-Powell H, Tyrell P, O'Neill P, Baldwin R.Sertraline in stroke-associated lability of mood. Int J Geriatr Psychiatry1999;14:681–5.

[42] Muller U, Murai T, Bauer-Wittmund T, von Cramon DY. Paroxetineversus citalopram treatment of pathological crying after brain injury.Brain Inj 1999;13:805–11.

[43] Schiffer R, Pope LE. Review of pseudobulbar affect including a noveland new potential therapy; 2005.

[44] PollockBG,Mulsant BH,Nebes R,KirshnerMA,BegleyAE,MazumdarS. Serum anticholinergicity in elderly depressed patients treated withparoxetine or nortriptyline. Am J Psychiatry 1998;155:1110–2.

[45] Baldessarini RJ. Drugs and the treatment of psychiatric disorders:depression and anxiety disorders. In: Hardman JG, Limbird LE,Gilman AG, editors. Goodman and Gilman's the pharmacologicalbasis of therapeutics. New York: The McGraw-Hill Companies, Inc.;2001. p. 447–83.

[46] Zhang Y, Britto MR, Valderhaug KL, Wedlund PJ, Smith RA.Dextromethorphan: enhancing its systemic availability by way of low-

dose quinidine-mediated inhibition of cytochrome P4502D6. ClinPharmacol Ther 1992;51:647–55.

[47] Palmer GC. Neuroprotection by NMDA receptor antagonists in avariety of neuropathologies. Curr Drug Targets 2001;2:241–71.

[48] Liu Y, Qin L, Li G, Zhang W, An L, Liu B. Dextromethorphan protectsdopaminergic neurons against inflammation-mediated degenerationthrough inhibition of microglial activation. J Pharmacol Exp Ther2003;305:212–8.

[50] Wills RJ, Martin KS. Dextromethorphan/dextrorphan disposition in ratplasma and brain. Pharm Res 1988;5:193S.

[51] Tortella FC, Martin DA, Allot CP, Steel JA, Blackburn TP, LovedayBE. Dextromethorphan attenuates post-ischemic hypoperfusion fol-lowing incomplete global ischemia in the anesthetized rat. Brain Res1989;482:179–83.

[52] Tortella FC, Davey R, Pellicano M, Bowery NG. Autoradiographiclocalization of 3H-dextromethorphan binding sites differs fromNMDA. NIDA Res Monogr 1989;95:548–9.

[53] Tortella FC, Pellicano M, Bowery NG. Dextromethorphan and neuro-modulation: old drug coughs up new activities. Trends Pharmacol Sci1989;10:501–7.

[54] Klein M, Musacchio JM. High affinity dextromethorphan bindingsites in guinea pig brain. Effect of sigma ligands and other agents.J Pharmacol Exp Ther 1989;251:207–15.

[55] Maurice T, Lockhart BP. Neuroprotective and anti-amnesic potentialsof sigma (sigma) receptor ligands. Prog Neuropsychopharmacol BiolPsychiatry 1997;21:69–102.

[56] Ebert B, Thorkildsen C, Andersen S, Christrup LL, Hjeds H. Opioidanalgesics as noncompetitive N-methyl-D-aspartate (NMDA) antago-nists. Biochem Pharmacol 1998;56:553–9.

[57] Maurice T, Urani A, Phan VL, Romieu P. The interaction betweenneuroactive steroids and the sigma1 receptor function: behavioralconsequences and therapeutic opportunities. Brain Res Brain Res Rev2001;37:116–32.

[58] Musacchio JM, Klein M, Canoll PD. Dextromethorphan and sigmaligands: common sites but diverse effects. Life Sci 1989;45:1721–32.

[59] Blin O, Azulay JP, Desnuelle C, Bille-Turc F, Braguer D, Besse D. Acontrolled one-year trial of dextromethorphan in amyotrophic lateralsclerosis. Clin Neuropharmacol 1996;19:189–92.

[60] Gredal O, Werdelin L, Bak S, Christensen PB, Boysen G, KristensenMO. A clinical trial of dextromethorphan in amyotrophic lateralsclerosis. Acta Neurol Scand 1997;96:8–13.

[61] Walker FO, Hunt VP. An open label trial of dextromethorphan inHuntington's disease. Clin Neuropharmacol 1989;12:322–30.

[62] Chase TN, Oh JD, Konitsiotis S. Antiparkinsonian and antidyskineticactivity of drugs targeting central glutamatergic mechanisms. J Neurol2000;247(Suppl 2):II36–42.

[63] McQuay HJ, Carroll D, Jadad AR, Glynn CJ, Jack T, Moore RA.Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design.Pain 1994;59:127–33.

[64] Vinik AI. Diabetic neuropathy: pathogenesis and therapy. Am J Med1999;107:17S–26S.

[65] Sang CN. NMDA-receptor antagonists in neuropathic pain: experimentalmethods to clinical trials. J Pain Symptom Manage 2000;19:S21–5.

[66] Weinbroum AA, Rudick V, Paret G, Ben Abraham R. The role ofdextromethorphan in pain control. Can J Anaesth 2000;47:585–96.

[67] Ben Abraham R, Marouani N, Kollender Y, Meller I, Weinbroum AA.Dextromethorphan for phantom pain attenuation in cancer amputees: adouble-blind crossover trial involving three patients. Clin J Pain2002;18:282–5.

[68] Heiskanen T, Hartel B, Dahl ML, Seppala T, Kalso E. Analgesic effectsof dextromethorphan and morphine in patients with chronic pain. Pain2002;96:261–7.

[69] Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphanand memantine in painful diabetic neuropathy and postherpetic neu-ralgia: efficacy and dose–response trials. Anesthesiology 2002;96:1053–61.

73A. Miller, H. Panitch / Journal of the Neurological Sciences 259 (2007) 67–73

[70] Pope LE, Khalil MH, Berg JE, Stiles M, Yakatan GJ, Sellers EM.Pharmacokinetics of dextromethorphan after single or multiple dosingin combination with quinidine in extensive and poor metabolizers. JClin Pharmacol 2004;44:1132–42.

[71] Vetticaden SJ, Cabana BE, Prasad VK, Purich ED, Jonkman JH, deZeeuw R. Phenotypic differences in dextromethorphan metabolism.Pharm Res 1989;6:13–9.

[72] Brinn R, Brosen K, Gram LF, Haghfelt T, Otton SV. Sparteineoxidation is practically abolished in quinidine-treated patients. Br JClin Pharmacol 1986;22:194–7.

[73] Inaba T, Tyndale RE, Mahon WA. Quinidine: potent inhibition ofsparteine and debrisoquine oxidation in vivo. Br J Clin Pharmacol1986;22:199–200.

[74] Leemann T, Dayer P, Meyer UA. Single-dose quinidine treatmentinhibits metoprolol oxidation in extensive metabolizers. Eur J ClinPharmacol 1986;29:739–41.

[75] Mikus G, Ha HR, Vozeh S, Zekorn C, Follath F, Eichelbaum M.Pharmacokinetics and metabolism of quinidine in extensive and poormetabolisers of sparteine. Eur J Clin Pharmacol 1986;31:69–72.

[76] Brosen K, Gram LF, Haghfelt T, Bertilsson L. Extensive metabolizersof debrisoquine become poor metabolizers during quinidine treatment.Pharmacol Toxicol 1987;60:312–4.

[77] Broly F, Libersa C, Lhermitte M, Bechtel P, Dupuis B. Effect ofquinidine on the dextromethorphan O-demethylase activity of micro-somal fractions from human liver. Br J Clin Pharmacol 1989;28:29–36.

[78] Roden DM. Antiarrhythmic drugs. In: Hardman JG, Limbird LE,Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman and Gil-man's the pharmacological basis of therapeutics. New York: McGraw-Hill; 1996. p. 839–74.

[79] Panitch HS, Thisted RA, Wynn DR, Wymer JP, Achiron A, Miller A.Dextromethorphan/quinidine for pseudobulbar affect in multiplesclerosis. Ann Neurol 2006;59(5):780–7.

[80] Desmeules JA, Oestreicher MK, Piguet V, Allaz AF, Dayer P.Contribution of cytochrome P-4502D6 phenotype to the neuromodu-latory effects of dextromethorphan. J Pharmacol Exp Ther 1999;288:607–12.

[81] Choi DW, Peters S, Viseskul V. Dextrorphan and levorphanolselectively block N-methyl-D-aspartate receptor-mediated neurotoxi-city on cortical neurons. J Pharmacol Exp Ther 1987;242: 713–20.

[82] Chapman AG, Meldrum BS. Non-competitive N-methyl-D-aspartateantagonists protect against sound-induced seizures in DBA/2 mice. EurJ Pharmacol 1989;166:201–11.

[83] Yamamoto H, Yamamoto T, Sagi N, Klenerova V, Goji K, Kawai N.

Sigma ligands indirectly modulate the NMDA receptor-ion channelcomplex on intact neuronal cells via sigma 1 site. J Neurosci1995;15:731–6.

[84] Lipton SA. Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. TrendsNeurosci 1993;16:527–32.

[85] Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S,Lipton SA. Glutamate-induced neuronal death: a succession ofnecrosis or apoptosis depending on mitochondrial function. Neuron1995;15:961–73.

[86] Bittigau P, Ikonomidou C. Glutamate in neurologic diseases. J ChildNeurol 1997;12:471–85.

[87] Parsons CG, Danysz W, Quack G. Glutamate in CNS disorders as atarget for drug development: an update. Drug News Perspect 1998;11:523–69.

[88] Olney JW, de Gubareff T. Glutamate neurotoxicity and Huntington'schorea. Nature 1978;271:557–9.

[89] Seif EN, Peruche B, Rossberg C, Mennel HD, Krieglstein J.Neuroprotective effect of memantine demonstrated in vivo and invitro. Eur J Pharmacol 1990;185:19–24.

[90] DeCoster MA, Klette KL, Knight ES, Tortella FC. Sigma receptor-mediated neuroprotection against glutamate toxicity in primary ratneuronal cultures. Brain Res 1995;671:45–53.

[91] Monyer H, Choi DW. Morphinans attenuate cortical neuronal injuryinduced by glucose deprivation in vitro. Brain Res 1988;446:144–8.

[92] Radek RJ, Giardina WJ. The neuroprotective effects of dextromethor-phan on guinea pig-derived hippocampal slices during hypoxia.Neurosci Lett 1992;139:191–3.

[93] Luhmann HJ, Scheid M. Dextromethorphan attenuates hypoxia-induced neuronal dysfunction in rat neocortical slices. Neurosci Lett1994;178:171–4.

[94] Steinberg GK, George CP, DeLaPaz R, Shibata DK, Gross T.Dextromethorphan protects against cerebral injury following transientfocal ischemia in rabbits. Stroke 1988;19:1112–8.

[95] Prince DA, Feeser HR. Dextromethorphan protects against cerebralinfarction in a rat model of hypoxia–ischemia. Neurosci Lett 1988;85:291–6.

[96] Bokesch PM, Marchand JE, Connelly CS, Wurm WH, Kream RM.Dextromethorphan inhibits ischemia-induced c-fos expression anddelayed neuronal death in hippocampal neurons. Anesthesiology1994;81:470–7.

[97] Golding EM, Vink R. Efficacy of competitive vs noncompetitiveblockade of the NMDA channel following traumatic brain injury. MolChem Neuropathol 1995;24:137–50.