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<p class="ltrs-br-ltr-br-title"><span class="bold">Ondansetron-Induced Myoclonus With Escitalopram and Highly Active Antiretroviral Therapy: A Closer Look at 5-HT<span class="subscript">3</span> Receptors</span></p>
<p class="ltrs-br-ltr-br-body-text"><span class="semibold">To the Editor:</span> Kolli and Addula<span class="htm-cite"><a href="#ref1">1</a></span> reported an interesting case of possible serotonin syndrome as a pharmacokinetic interaction of ondansetron, escitalopram, and highly active antiretroviral therapy. </p>
<p class="ltrs-br-ltr-br-body-text">In September 2014, the US Food and Drug Administration changed the safety labeling for 5-HT<span class="subscript">3</span> receptor antagonists—ondansetron, granisetron, palonosetron, and dolasetron. The new warning suggests advising patients of the possible development of serotonin syndrome with use of the 5-HT<span class="subscript">3</span> receptor antagonists and agents used to treat depression and migraines.<span class="htm-cite"><a href="#ref2">2</a></span> It is known that 5-HT<span class="subscript">3</span> stimulation (eg, by selective serotonin reuptake inhibitors [SSRIs] increasing the availability of serotonin in the synaptic cleft to stimulate these postsynaptic receptors) accounts for the side effects of headache, nausea, and vomiting.</p>
<p class="ltrs-br-ltr-br-body-text">The recent introduction of the multimodal agent vortioxetine has provided more insight into the functions of 5-HT<span class="subscript">3</span> receptors. It has been demonstrated that when the 5-HT level increases after administration of an SSRI, activation of the ligand-gated ionic 5-HT<span class="subscript">3</span> receptors by 5-HT leads to stimulation of γ-aminobutyric acid (GABA) release. This release then inhibits cortical pyramidal neurons, and, thus, there is no amplification of 5-HT release by downstream glutamate.<span class="htm-cite"><a href="#ref3">3</a></span>  Hence, blockade of 5-HT<span class="subscript">3</span> receptors removes GABA inhibition and disinhibits pyramidal neurons, enhancing downstream release of 5-HT due to glutamatergic stimulation of serotonergic neurons in the midbrain raphe.<span class="htm-cite"><a href="#ref3">3</a></span> This pharmacologic receptor portfolio implies that agents with 5-HT<span class="subscript">3</span> antagonism (eg, ondansetron) can, in theory, contribute to the development of serotonin syndrome through pharmacodynamic mechanisms as well. Serotonin syndrome is more likely to develop if agents with 5-HT<span class="subscript">3</span> antagonism are combined with other serotonergic agents or in the setting of overdose.<span class="htm-cite"><a href="#ref4">4</a></span> Such cases are documented in the literature.<span class="htm-cite"><a href="#ref5">5</a></span> On the other hand, these 5-HT<span class="subscript">3</span>–blocking agents have been used to boost 5-HT tone in conditions such as treatment-resistant obsessive-compulsive disorder.<span class="htm-cite"><a href="#ref6">6</a></span></p>
<p class="references_references-heading"><span class="bold">References</span></p>
<p class="references-references-text-1-9"><a name="ref1"></a><span class="htm-ref"> 1. </span>Kolli V, Addula M. Ondansetron-induced myoclonus with escitalopram and HAART: role of drug interactions. <span class="italic">Prim Care Companion CNS Disord</span>. 2019;21(4):18l02364. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=31364825&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.4088/PCC.18l02364" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref2"></a><span class="htm-ref"> 2. </span>Foong A-L, Grindrod KA, Patel T, et al. Demystifying serotonin syndrome (or serotonin toxicity). <span class="italic">Can Fam Physician</span>. 2018;64(10): 720–727. <a href="https://www.ncbi.nlm.nih.gov/pubmed/30315014" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://www.cfp.ca/content/64/10/720" target="_blank"><span class="pubmed-crossref">CrossRef</span></a> </p>
<p class="references-references-text-1-9"><a name="ref3"></a><span class="htm-ref"> 3. </span>Naguy A, Alamiri B. Successful add-on vortioxetine for an adolescent with attention-deficit/hyperactivity disorder. <span class="italic">J Clin Psychopharmacol</span>. 2018;38(4):407–409. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=29912797&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1097/JCP.0000000000000912" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref4"></a><span class="htm-ref"> 4. </span>Naguy A. SSRIs-related behavioral syndromes in children and adolescents. <span class="italic">J Can Acad Child Adolesc Psychiatry</span>. 2016;25(2):69–70. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=27274740&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a></p>
<p class="references-references-text-1-9"><a name="ref5"></a><span class="htm-ref"> 5. </span>Gollapudy S, Kumar V, Dhamee MS. A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion. <span class="italic">J Clin Anesth</span>. 2012;24(3):251–252. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=22537574&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1016/j.jclinane.2011.04.017" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref6"></a><span class="htm-ref"> 6. </span>Naguy A, Alamiri B. Treatment-resistant OCD—a psychopharmacological ‘touche d’art.’ <span class="italic">Asian J Psychiatr</span>. 2018;34:98–99. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=29680776&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1016/j.ajp.2018.04.025" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Ahmed Naguy, MBBch, MSc</span><span class="superscript">a</span></p>
<p class="ltrs-br-ltr-br-author"><a href="mailto:ahmednagy@hotmail.co.uk">ahmednagy@hotmail.co.uk</a></p>
<p class="end-matter"><span class="superscript">a</span>Al-Manara CAP Centre, Kuwait Centre for Mental Health, Jamal Abdul-Nassir St, Shuwaikh, State of Kuwait</p>
<p class="end-matter"><span class="bold-italic">Published online:</span> June 18, 2020.</p>
<p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> None.</p>
<p class="end-matter"><span class="bold-italic">Funding/support:</span> None. </p>
<p class="front-matter"><span class="italic">Prim Care Companion CNS Disord 2020;22(3):19l02524</span></p>
<p class="front-matter-rule"><span class="bold-italic">To cite:</span> Naguy A. Ondansetron-induced myoclonus with escitalopram and highly active antiretroviral therapy: a closer look at 5-HT<span class="subscript">3</span> receptors. <span class="italic">Prim Care Companion CNS Disord. </span>2020;22(3):19l02524.</p>
<p class="doi-line"><span class="bold-italic">To share:</span> https://doi.org/<span class="doi">10.4088/PCC.19l02524</span></p>
<p class="front-matter"><span class="italic">© Copyright 2020 Physicians Postgraduate Press, Inc.</span></p>
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