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Vol 17, No 6
Table of Contents

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<p class="frontmatter-fieldnotes disclaimernew" style="margin-bottom:15px;">This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s <a href="/pages/termsofuse.aspx" target="_blank">Terms & Conditions</a>.</p> <div id="_idContainer000">
  <p class="ltrs-br-ltr-br-title"><span class="bold">Dextromethorphan/Quinidine For Neuropsychiatric Manifestations of Wilson’s Disease</span></p>
  <p class="ltrs-br-ltr-br-body-text"><span class="semibold">To the Editor:</span> Wilson’s disease is an autosomal recessive disorder in which copper accumulates in the brain and liver of affected individuals, resulting in a wide range of symptoms. Most individuals with Wilson’s disease have neurologic sequelae such as dystonia, parkinsonism, and extrapyramidal symptoms. Patients also experience psychiatric manifestations, such as irritability, impulsivity, personality changes, and depression. Neurologic damage that occurs prior to treatment is often permanent.<span class="htm-cite"><a href="#ref1">1</a></span> We describe a case in which dextromethorphan/quinidine was utilized to treat mood lability in an individual with Wilson’s disease intolerant of other agents.</p>
  <p class="ltrs-br-ltr-br-body-text">&nbsp;</p>
  <p class="ltrs-br-ltr-br-body-text"><span class="semibold-ital">Case report.</span> Ms A, a 34-year-old woman with a 14-year history of Wilson’s disease, was treated for neuropsychiatric manifestations of the disorder in a clinic for individuals with neurologic deficits or traumatic brain injuries. Her symptoms consisted of mood lability, depression, impulsivity, dystonia, and parkinsonian features such as hypophonia, hypomimia, bradykinesia, impaired fine motor coordination, and an ataxic gait. She had no family history of Wilson’s disease, but there was a family history of Parkinson’s disease. She was first diagnosed with Wilson’s disease at age 20, and her initial chelation therapy resulted in a paradoxical worsening of her neurologic symptoms, most likely resulting in further neurologic damage. Since being stabilized, Ms A has been maintained on zinc acetate to prevent further copper accumulation. Prior treatments included lithium, haloperidol, chlorpromazine, and olanzapine. No therapeutic effect was observed with these treatments but rather a worsening of extrapyramidal symptoms and no change in mood lability and impulsivity. Notably, use of first-generation neuroleptics has been cautioned against in Wilson’s disease.<span class="htm-cite"><a href="#ref2">2</a></span> Ms A had also been started on quetiapine, which has been shown to have a lower risk of causing Parkinsonian symptoms. However, despite a sustained treatment dose of 400 mg for 4 months, quetiapine was discontinued due to lack of efficacy and the emergence of akathisia.</p>
  <p class="ltrs-br-ltr-br-body-text">Dextromethorphan/quinidine was started and titrated to 20/10 mg twice a day. There was a marked improvement clinically in mood lability and impulsivity, with a Clinical Global Impressions—Improvement scale (CGI-I) score of 2 indicating response and no worsening of her extrapyramidal symptoms. </p>
  <p class="ltrs-br-ltr-br-body-text">Dextromethorphan/quinidine is approved by the US Food and Drug Administration for the treatment of pseudobulbar affect, a condition consisting of uncontrolled laughing or crying and mood lability. Dextromethorphan/quinidine was initially studied in hopes of slowing <span class="hyperlink">a</span><span class="Emphasis">myotrophic lateral sclerosis</span> progression. While ineffective in this regard, dextromethorphan/quinidine was found to reduce episodes of emotional lability, resulting in approval for pseudobulbar affect.<span class="htm-cite"><a href="#ref3">3</a></span></p>
  <p class="ltrs-br-ltr-br-body-text">Dextromethorphan is a sigma-1 receptor agonist and noncompetitive <span class="italic">N</span>-methyl-<span class="smallcaps">d</span>-aspartate<span class="apple-converted-space">&#160;</span> receptor antagonist. Sigma-1 receptors are distributed throughout the brain with a dense localization in the limbic system, suggesting a role in stress and mood regulation.<span class="htm-cite"><a href="#ref3">3</a></span> Additionally, agonism of these receptors inhibits glutamate neurotransmission in the cerebellum and brainstem.<span class="htm-cite"><a href="#ref4">4</a></span> If abused, dextromethorphan, the chief ingredient in over-the-counter medications such as Coricidin and Robitussin DM, can induce stimulation, euphoria, and dissociative states. However, the threshold for euphoria and stimulation is 100–200 mg and for dissociative states is 200–400 mg, making it unlikely that dextromethorphan/quinidine would be abused.<span class="htm-cite"><a href="#ref5">5</a></span> Quinidine functions to increase plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which metabolizes dextromethorphan. Dextromethorphan/quinidine is, in this sense, analogous to carbidopa/levodopa, a treatment for Parkinson’s disease, in that quinidine serves to prevent the breakdown of dextromethorphan like carbidopa serves to prevent the peripheral conversion of levodopa into dopamine.</p>
  <p class="ltrs-br-ltr-br-body-text">Excess glutamate can result in neuron excitotoxicity and cell death and may be a factor in traumatic brain injuries and chronic neurologic disorders.<span class="htm-cite"><a href="#ref6">6</a></span> Dextromethorphan/quinidine may lower available glutamate and so reduce emotional lability and impulsivity. A previous case report<span class="htm-cite"><a href="#ref4">4</a></span> demonstrated that dextromethorphan/quinidine was effective in treating aggression and agitation associated with a cerebellar injury. The positive response in our case with abolition of mood lability suggests that this compound may have some mood stabilization properties. This case report appears to be the first to show benefit with dextromethorphan/quinidine in treating mood lability and stabilizing mood in Wilson’s disease.</p>
  <p class="references_references-heading">REFERENCES</p>
  <p class="references-references-text-1-9"><a name="ref1"></a><span class="htm-ref"> 1.&#9;</span>Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. <span class="italic">Lancet Neurol</span>. 2015;14(1):103–113. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=25496901&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1016/S1474-4422(14)70190-5"><span class="pubmed-crossref">doi:10.1016/S1474-4422(14)70190-5</span></a></p>
  <p class="references-references-text-1-9"><a name="ref2"></a><span class="htm-ref"> 2.&#9;</span>Carta MG, Mura G, Sorbello O, et al. Quality of life and psychiatric symptoms in Wilson’s disease: the relevance of bipolar disorders. <span class="italic">Clin Pract Epidemol Ment Health</span>. 2012;8:102–109. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=23049615&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.2174/1745017901208010102"><span class="pubmed-crossref">doi:10.2174/1745017901208010102</span></a></p>
  <p class="references-references-text-1-9"><a name="ref3"></a><span class="htm-ref"> 3.&#9;</span>Rosen H. Dextromethorphan/quinidine sulfate for pseudobulbar affect. <span class="italic">Drugs Today (Barc).</span> 2008;44(9):661–668. <a href="doi:10.1358/dot.2008.44.9.1258664"><span class="pubmed-crossref">doi:10.1358/dot.2008.44.9.1258664</span></a><span class="pubmed-crossref"> </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/19137121"><span class="pubmed-crossref">PubMed</span></a></p>
  <p class="references-references-text-1-9"><a name="ref4"></a><span class="htm-ref"> 4.&#9;</span>Daly JP, Caplan JP. A naturalistic on-off-on trial of dextromethorphan/quinidine for agitation associated with cerebellar injury. <span class="italic">Psychosomatics</span>. 2012;53(5):470–473. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=22458990&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1016/j.psym.2011.11.001"><span class="pubmed-crossref">doi:10.1016/j.psym.2011.11.001</span></a></p>
  <p class="references-references-text-1-9"><a name="ref5"></a><span class="htm-ref"> 5.&#9;</span>Burns JM, Boyer EW. Antitussives and substance abuse. <span class="italic">Subst Abuse Rehabil</span>. 2013;4:75–82. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=24648790&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a></p>
  <p class="references-references-text-1-9"><a name="ref6"></a><span class="htm-ref"> 6.&#9;</span>Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. <span class="italic">Neuromolecular Med</span>. 2003;3(2):65–94. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=12728191&amp;dopt=Abstract"><span class="pubmed-crossref">PubMed</span></a> <a href="http://dx.doi.org/10.1385/NMM:3:2:65"><span class="pubmed-crossref">doi:10.1385/NMM:3:2:65</span></a></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">Justin Faden, DO</span></p>
  <p class="ltrs-br-ltr-br-author"><a href="mailto:Fadenju@rowan.edu">Fadenju@rowan.edu</a></p>
  <p class="ltrs-br-ltr-br-author"><span class="bold">John P. O’Reardon, MD</span></p>
  <p class="end-matter"><span class="bold-italic">Author affiliations:</span> Department of Psychiatry, Rowan University School of Osteopathic Medicine, Cherry Hill, New Jersey.</p>
  <p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> <span class="semibold">Dr O’Reardon</span> has received research support from Stanley Medical Research Institute and Neosync. <span class="semibold">Dr Faden</span> reports no conflicts of interest related to the subject of this letter.</p>
  <p class="end-matter"><span class="bold-italic">Funding/support:</span> None reported.</p>
  <p class="end-matter"><span class="bold-italic">Published online:</span> November 19, 2015.</p>
  <p class="end-matter"><span class="italic">Prim Care Companion CNS Disord 2015;17(6):</span><span class="doi italic">doi:10.4088/PCC.15l01820</span></p>
  <p class="end-matter"><span class="italic">© Copyright 2015 Physicians <a id="_idTextAnchor000"></a>Postgraduate Press, Inc.</span></p>
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