Review: Clinical Trial Outcomes DUBOVSKY Dextromethorphan/quinidine for pseudobulbar affect 4 Review: Clinical Trial Outcomes Dextromethorphan/quinidine for 2041-6806 pseudobulbar affect 2041-6792 Clinical Investigation Clin. Invest. Dextromethorphan/quinidine (DM/Q; NUEDEXTA) is approved by the US FDA for the Steven L Dubovsky treatment of pseudobulbar affect (PBA) associated with chronic neurological disorders Department of Psychiatry, University such as multiple sclerosis, stroke, traumatic brain injury and amyotrophic lateral at Buffalo, Departments of Psychiatry sclerosis. Studies of applications in other illnesses and for behavioral disinhibition are & Medicine, University of Colorado, currently underway. The primary active agent is dextromethorphan, with quinidine 462 Grider St., Room 1182, Buffalo, CLI NY 14215, USA added to inhibit its metabolism by CYP450 2D6 and increase the bioavailability of Tel.: +1 716 898 5940 dextromethorphan. Published studies suggest reduction of episodes of PBA and [email protected] Future Science LtdLondon, UK improved quality of life with reasonable tolerability. However, the combination has the potential to interact with a number of other medications used by older patients. Some antidepressants may also be helpful in low doses for PBA and are easier to use, but more controlled studies with validated outcome measures are available for DM/Q. This article reviews published studies of DM/Q and addresses its use in clinical practice. 554 Keywords: dextromethorphan • neurological disease • quinidine • pseudobulbar affect 549 Pseudobulbar affect (PBA), also known as crying [1] . Laughing and crying may accom- involuntary emotional expression disorder pany or alternate with each other because (IEED), Zwangslachen (forced laughter) and the same pontomedullary mechanisms and 10.4155/CLI.14.42 Zwangsweinen (forced crying), emotional facial, vocal and respiratory muscles are incontinence, and forced laughing and cry- involved in both forms of affective display ing, has been described in the neurological [1] . However, ‘pseudobulbar’ affect can exist literature for more than a century [1] . This without pseudobulbar palsy and vice versa. syndrome, which is always due to neuro- logical disease, is manifested by paroxysmal, Pathophysiology & differential 6 involuntary outbursts of labile, shallow affect diagnosis with unpredictable stereotyped laughing, PBA appears to be associated with bilateral crying, or mixtures of the two that are not lesions, which may involve subcortical areas appropriate to the social setting and may that interfere with corticohypothalamic and 2014 or may not be congruent with the prevail- corticobulbar inhibitory and facilitatory ing mood of the patient [1,2]. Episodes often tracts that control voluntary and involuntary appear to be provoked by minor interactions faciorespiratory mechanisms [1,4], although or events but cannot be interrupted volun- in a small number of cases an isolated brain- tarily [3]. The emotional disorder is called stem or cerebellar lesion may be present [5]. pseudobulbar because of the discrepancy The pathophysiology of pseudobulbar affect between loss of voluntary control of muscles may involve excessive release of glutamate innervated by motor nuclei of the lower pons by injured neurons, disrupting systems for and medulla (pseudobulbar palsy) resulting, motor control of emotional expression [6,7]. for example, in inability to articulate and the Disorders in which PBA is common are preservation of those muscles for involuntary listed in Box 1 [1,8,9]. The reported prevalence movement such as spasmodic laughing and of PBA is 49% in amyotrophic lateral sclero- part of 10.4155/CLI.14.42 © 2014 Future Medicine Ltd Clin. Invest. (2014) 4(6), 549–554 ISSN 2041-6792 549 Review: Clinical Trial Outcomes Dubovsky sis (ALS), 18–39% in Alzheimer’s disease, 11–34% in reuptake inhibitor (SSRI) and tricyclic (TCA) anti- stroke, and 10–11% in multiple sclerosis and traumatic depressants reduce PBA symptoms within 2–3 days, brain injury [8,9]; it has also been reported in Parkinson’s usually in doses lower than those used to treat depres- disease, brain tumors, Wilson’s disease, and syphilitic sion [1,2,11]. Although methodologies differed, only one and other encephalitides [2]. It has been estimated that small study used a validated measure of PBA [11,12]. For there are 880,000 patients with PBA in the USA [10] . example, the Pathological Laughter and Crying Scale PBA should be differentiated from other disorders demonstrated significantly more improvement with associated with inappropriate, labile affect. Primary psy- nortriptyline than placebo beginning at week 2 in a chiatric disorders in this category include bipolar disor- double-blind study of stroke and post-stroke patients der, especially with ultradian cycling, and schizophre- [13] . Similarly, in 152 post-stroke patients, self-ratings nia. In unstable bipolar disorder, very rapid mood swings of PBA-associated crying decreased by 69% with fluox- can result in abrupt shifts from hilarity to tearfulness etine versus 21% with placebo, although there were that seem unprovoked and inappropriate. In contrast to no differences in reduction of laughing [14] . While PBA, even brief emotional expression is consistent with dopaminergic agents such as l-dopa and amantadine underlying happy or sad mental content. Schizophrenia (which also has NMDA antagonist properties) have is often associated with inappropriate, shallow affect, seemed useful in open trials, controlled studies using but thinking is characterized by a consistent disorder of objective measurements have not been positive. the form of thought (e.g., dereistic thinking, loos asso- ciations) that is not present in PBA. Illicit drug intoxi- Actions of dextromethorphan/quinidine cations that can produce emotional outbursts include Because of the presumed role of excessive glutamate amphetamines and phencyclidine. Such states are less signaling in PBA, as well as the role of serotonergic sig- labile and more intense than is the affective dysregula- naling in inhibiting abnormally released behavior, the tion of PBA. The expression of major depression can be apparent benefit of dextromethorphan, a serotonergic altered by right-sided brain disease (aprosodia), resulting substance that is an agonist of sigma-1 receptors and in disturbances of recognition and expression of one’s a low-affinity, uncompetitive antagonist ofN -methyl- own emotions, so that depressed mood is manifested as d-aspartate (NMDA) glutamate receptors (through labile, shallow affect, while psychological dimensions of binding at the phencyclidine site on the NMDA com- depression are not obvious. A past and family history plex) [9,15], noted in attempts to use it to slow neuronal of depression, as well as other depressive features such apoptosis in ALS, seems logical. The sigma-1 receptor as withdrawal and appetite disturbance, can often be was once thought to be an opioid receptor subtype, but observed. Le fou rire prodromique of Féré (prodromal unlike opioid receptors it is not blocked by narcotic laughing madness) is a syndrome of abrupt uncontrol- antagonists and it does not have a known endogenous lable laughter followed by hemiplegia associated with ligand. However, the receptor does weakly modulate vascular occlusion. Protracted laughing or occasionally activity of opioid mu receptors in addition to alter- crying may also be a manifestation of partial complex ing dopamine release and possibly reducing release of seizures ( gelastic seizures) [1] . glutamate [15] . Sigma receptors are densely distributed in limbic circuits and systems involved in motor con- Previous treatment options trol of affective expression, and seem to be involved in Seven placebo-controlled trials, only two of which mood regulation, among other things [2]. Because dex- involved more than 100 patients, suggest that serotonin tromethorphan preferentially binds to brain regions Box 1. Disorders associated with pseudobulbar affect. that regulate emotional expression [16], it may have the potential to normalize glutaminergic neurotransmis- • Recurrent bilateral strokes in cerebral hemispheres or pons sion there and possibly in other relevant regions [2]. • Binswanger diffuse leukoencephalopathy However, the exact mechanism of action is unknown. • Parkinson’s disease • Alzheimer’s disease Dextromethorphan is subject to extensive first-pass • Amyotrophic lateral sclerosis with pseudobulbar palsy metabolism by CYP450 2D6 to the active metabolite • Progressive supranuclear palsy dextrorphan, which after being glucuronidated can- • Multiple sclerosis with corticobulbar demylelination not cross the blood–brain barrier. In doses 10–25- • Bilateral traumatic brain injury times lower than those used to treat cardiac arrhyth- • Wilson’s disease mias, quinidine, a type Ia sodium channel antagonist • Ischemic/hypoxic encephalopathy antiarrhythmic, inhibits 2D6 and increases dextro- • Gliomatosis cerebri methorphan bioavailability [7,16]. Blood levels of dex- • Pontine myelinosis tromethorphan increase linearly with dose following • Tertiary syphilis coadministration with quinidine but are undetectable 550 Clin. Invest. (2014) 4(6) future science group Dextromethorphan/quinidine for pseudobulbar affect Review: Clinical Trial Outcomes in most subjects given dextromethorphan alone [9,15]. apy with 30 mg each of dextromethorphan or quini- However, quinidine will not affect dextromethorphan dine, with DM/Q 30/30 [7]. The combination