<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="x11l01140">
<div class="story">
<p class="ltrs-br-ltr-br-title">A Case of Interdose Discontinuation Symptoms With Venlafaxine Extended Release</p>
<p class="ltrs-br-ltr-br-body-text"><span class="bold">To the Editor:</span> Venlafaxine extended release (XR) is a serotonin-norepinephrine reuptake inhibitor that, like many other antidepressants, may be associated with a discontinuation syndrome. Discontinuation syndromes are, in part, related to drugs with short half-lives<span class="htm-cite"><a href="#ref1">1</a></span> (eg, for venlafaxine and its metabolite, 5 and 11 hours, respectively). Venlafaxine XR discontinuation symptoms have been clinically reported as soon as 6 hours<span class="htm-cite"><a href="#ref2">2</a></span> and as long as 9 days<span class="htm-cite"><a href="#ref3">3</a></span> after discontinuation of the drug, but typically emerge in 1–4 days.<span class="htm-cite"><a href="#ref4">4</a></span> In one study, the prevalence of typical discontinuation symptoms with venlafaxine XR (eg, dysphoria, headaches, nausea, irritability, emotional lability, sleep disturbance) was 27%.<span class="htm-cite"><a href="#ref5">5</a></span> However, discontinuation symptoms may be severe<span class="htm-cite"><a href="#ref6">6</a>,<a href="#ref7">7</a></span> in up to 5% of cases.<span class="htm-cite"><a href="#ref8">8</a></span> In addition, unexpected symptoms may emerge such as “shock-like sensations,”<span class="htm-cite"><a href="#ref9">9</a></span> gait difficulties,<span class="htm-cite"><a href="#ref10">10</a></span> palinopsia (persistent visual images),<span class="htm-cite"><a href="#ref11">11</a></span> delirium,<span class="htm-cite"><a href="#ref12">12</a></span> suicidal ideation,<span class="htm-cite"><a href="#ref13">13</a></span> and hypomania<span class="htm-cite"><a href="#ref14">14</a></span> or mania.<span class="htm-cite"><a href="#ref14">14</a>,<a href="#ref15">15</a></span> In the following case, we describe a patient who experienced routine venlafaxine XR discontinuation symptoms within hours of daily dosing.</p>
<p class="ltrs-br-ltr-br-body-text"> </p>
<p class="ltrs-br-ltr-br-body-text"><span class="bold-italic">Case report.</span> In December 2009, Ms A, a 41-year-old white woman with a history of hypertension and palpitations, was prescribed venlafaxine XR 37.5 mg/d by another primary care provider for the treatment of depression. With a change in primary care providers in January 2011, Ms A promptly discussed her concerns with venlafaxine XR. According to the patient, approximately 2 months after the onset of the venlafaxine XR trial, she began to experience a number of side effects in the absence of any other changes in medication, including nausea, irritability, emotional lability, and, most troublesome, “electrical brain shocks.” Oddly, all of these symptoms occurred on a daily basis, and they consistently emerged approximately 8–10 hours after the administration of the daily dose of venlafaxine XR. Symptoms would then promptly resolve after Ms A took the next dose of venlafaxine XR. </p>
<p class="ltrs-br-ltr-br-body-text">Because the patient seemed to be experiencing discontinuation symptoms, she was switched to regular-release venlafaxine 37.5 mg in January 2011, which was dosed twice per day. The regular-release venlafaxine was well tolerated. Within 2 weeks, the patient confirmed that most, if not all, of her symptoms had subsided.</p>
<p class="ltrs-br-ltr-br-body-text"> </p>
<p class="ltrs-br-ltr-br-body-text">Although discontinuation symptoms from venlafaxine XR have been clinically described by one author in as few as 6 hours after the last dose,<span class="htm-cite"><a href="#ref2">2</a></span> we are unaware of any actual case reports of venlafaxine XR interdose discontinuation symptoms. This phenomenon may be related to individual genetics and the cytochrome P450 isoenzyme system. Specifically, venlafaxine XR is metabolized by the 2D6 isoenzyme, which is subject to broad genetic polymorphism. In this regard, Zhou<span class="htm-cite"><a href="#ref16">16</a></span> has described 4 genetic variants: ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers, which constitute 3%–5%, 70%–80%, 10%–17%, and 5%–10% of white individuals, respectively. It is possible that our patient was an ultrarapid metabolizer and briskly eliminated venlafaxine XR through the 2D6 isoenzyme, resulting in interdose discontinuation symptoms.</p>
<p class="ltrs-br-ltr-br-body-text">As for clinical approaches to interdose discontinuation symptoms, venlafaxine XR or regular-release venlafaxine may be dosed twice per day, or a patient might be switched to an antidepressant that is less dependent on 2D6 metabolism, such as sertraline, citalopram, or mirtazapine.<span class="htm-cite"><a href="#ref17">17</a></span> To conclude, to our knowledge, this is the first case report of interdose discontinuation symptoms with venlafaxine XR.</p>
<p class="ltrs-br-ltr-br-references-head"><span class="smallcaps">References</span></p>
<p class="references-references-text-1-9"><a name="ref1"></a>1. Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. <span class="italic">J Psychopharmacol</span>. 2008;22(3):330–332. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18515448&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1177/0269881107081550">doi:10.1177/0269881107081550</a></span></p>
<p class="references-references-text-1-9"><a name="ref2"></a>2. Yanez LP, Malo P, Etxebeste M, et al. New dosage-reduction regime to avoid paroxetine discontinuation syndrome [letter]. <span class="italic">Can J Psychiatry</span>. 2003;48:129–130.</p>
<p class="references-references-text-1-9"><a name="ref3"></a>3. Jacobson N, Weiber R. Possible delayed venlafaxine withdrawal reaction: two case reports. <span class="italic">Eur Psychiatry</span>. 1997;12(7):372–373. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19698555&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1016/S0924-9338(97)80010-7">doi:10.1016/S0924-9338(97)80010-7</a></span></p>
<p class="references-references-text-1-9"><a name="ref4"></a>4. Vlaminck JJ, van Vliet IM, Zitman FG. Withdrawal symptoms of antidepressants. <span class="italic">Ned Tijdschr Geneeskd</span>. 2005;149(13):698–701. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15819135&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"><a name="ref5"></a>5. Hartford J, Kornstein S, Liebowitz M, et al. Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled trial. <span class="italic">Int Clin Psychopharmacol</span>. 2007;22(3):167–174. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17414743&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1097/YIC.0b013e32807fb1b2">doi:10.1097/YIC.0b013e32807fb1b2</a></span></p>
<p class="references-references-text-1-9"><a name="ref6"></a>6. Dallal A, Chouinard G. Withdrawal and rebound symptoms associated with abrupt discontinuation of venlafaxine. <span class="italic">J Clin Psychopharmacol</span>. 1998;18(4):343–344. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9690703&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1097/00004714-199808000-00017">doi:10.1097/00004714-199808000-00017</a></span></p>
<p class="references-references-text-1-9"><a name="ref7"></a>7. Holroyd S, Durgee J. Venlafaxine in treatment refractory geriatric depression. <span class="italic">Clin Gerontol</span>. 1998;18(3):39–50. <span class="pubmed-crossref"><a href="
http://dx.doi.org/10.1300/J018v18n03_05">doi:10.1300/J018v18n03_05</a></span></p>
<p class="references-references-text-1-9"><a name="ref8"></a>8. Campagne DM. Venlafaxine and serious withdrawal symptoms: warning to drivers. <span class="italic">Med Gen Med</span>. 2005;7(3):22. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16369248&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"><a name="ref9"></a>9. Reeves RR, Mack JE, Beddingfield JJ. Shock-like sensations during venlafaxine withdrawal. <span class="italic">Pharmacotherapy</span>. 2003;23(5):678–681. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12741444&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1592/phco.23.5.678.32198">doi:10.1592/phco.23.5.678.32198</a></span></p>
<p class="references-references-text-10-99"><a name="ref10"></a>10. Haddad PM, Devarajan S, Dursun SM. Antidepressant discontinuation (withdrawal) symptoms presenting as “stroke.” <span class="italic">J Psychopharmacol</span>. 2001;15(2):139–141. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11448088&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1177/026988110101500210">doi:10.1177/026988110101500210</a></span></p>
<p class="references-references-text-10-99"><a name="ref11"></a>11. Spindler PE. Palinopsia following discontinuation of venlafaxine. <span class="italic">Psychiatr Prax</span>. 2008;35(5):255–257. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17987543&dopt=Abstract">PubMed</a></span> <span class="pubmed-crossref"><a href="
http://dx.doi.org/10.1055/s-2007-986237">doi:10.1055/s-2007-986237</a></span></p>
<p class="references-references-text-10-99"><a name="ref12"></a>12. van Noorden MS, Vergouwen AC, Koerselman GF. Delirium during withdrawal of venlafaxine. <span class="italic">Ned Tijdschr Geneeskd</span>. 2002;146(26):1236–1237. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12132141&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-10-99"><a name="ref13"></a>13. Stone TE, Swanson C, Feldman MD. Venlafaxine discontinuation syndrome and suicidal ideation: a case series. <span class="italic">J Clin Psychopharmacol</span>. 2007;27(1):94–95. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17224725&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1097/JCP.0b013e31802e84b9">doi:10.1097/JCP.0b013e31802e84b9</a></span></p>
<p class="references-references-text-10-99"><a name="ref14"></a>14. Kora K, Kaplan P. Hypomania/mania induced by cessation of antidepressant drugs. <span class="italic">Turk Psikiyatri Derg</span>. 2008;19(3):329–333. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18791886&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-10-99"><a name="ref15"></a>15. Fava GA, Mangelli L. Mania associated with venlafaxine discontinuation. <span class="italic">Int J Neuropsychopharmacol</span>. 2003;6(1):89–90. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12899740&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.1017/S1461145703003274">doi:10.1017/S1461145703003274</a></span></p>
<p class="references-references-text-10-99"><a name="ref16"></a>16. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. <span class="italic">Clin Pharmacokinet</span>. 2009;48(11):689–723. <span class="pubmed-crossref"><a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19817501&dopt=Abstract">PubMed</a> <a href="
http://dx.doi.org/10.2165/11318030-000000000-00000">doi:10.2165/11318030-000000000-00000</a></span></p>
<p class="references-references-text-10-99"><a name="ref17"></a>17. Genelex. Antidepressants. Pharmacogenetics in the practice of medicine. <span class="hyperlink"><a href="
http://www.healthanddna.com/healthcare-professional/antidepressants-dose.html">
http://www.healthanddna.com/healthcare-professional/<br />antidepressants-dose.html</a></span>. Accessed January 11, 2011.</p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Joseph Petit, MD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Randy A. Sansone, MD</span></p>
<p class="ltrs-br-ltr-br-author"><a href="
mailto:Randy.sansone@khnetwork.org" target="_blank">
Randy.sansone@khnetwork.org</a></p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Author affiliations:</span> Departments of Internal Medicine (Dr Petit) and Psychiatry (Dr Sansone), Kettering Medical Center, Kettering; and Departments of Psychiatry and Internal Medicine, Wright State University Boonshoft School of Medicine, Dayton (Dr Sansone), Ohio.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Potential conflicts of interest: </span>None reported.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Funding/support: </span>None reported.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Published online:</span> September 1, 2011.</p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">Prim Care Companion CNS Disord 2011;13(5):</span><span class="doi">doi:10.4088/PCC.11l01140</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">© Copyright 2011 Physicians Postgraduate Press, Inc.</span></p>
</div>
</div>