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<p class="ltrs-br-ltr-br-title"><span class="bold">A Case of Amelioration of Venlafaxine-Discontinuation “Brain Shivers” With Atomoxetine</span></p>
<p class="ltrs-br-ltr-br-body-text"><span class="semibold">To the Editor:</span> Antidepressant discontinuation syndrome is a common syndrome seen following abrupt termination of treatment with a serotonin reuptake inhibitor.<span class="htm-cite"><a href="#ref1">1</a></span> It occurs at rates ranging from 17.2% to as high as 78% with venlafaxine.<span class="htm-cite"><a href="#ref2">2</a>,<a href="#ref3">3</a></span> There is, however, little literature on “brain shivers,”<span class="htm-cite"><a href="#ref4">4</a>,<a href="#ref5">5</a></span> a common antidepressant-discontinuation symptom described by patients taking venlafaxine, duloxetine, citalopram, and paroxetine. Much of the information comes from Internet blogs and Web sites.<span class="htm-cite"><a href="#ref6">6–8</a></span> The symptom is described variously as “an electrical shock–like sensation in the brain,” “the sensation of the brain shivering,” “brain zaps,” “brain shocks,” “brain shivers,” “head shocks,” or “cranial zings.” The etiology of the symptom is not known, and there is no known treatment for this distressing symptom.</p>
<p class="ltrs-br-ltr-br-body-text">We describe a case in which “brain shivers” occurred as part of venlafaxine discontinuation syndrome and abated with atomoxetine treatment.</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> Mr A, a 34-year-old man, presented with <span class="italic">DSM-IV</span> major depressive disorder (MDD) that responded well to venlafaxine (300 mg/d). He achieved remission except for seasonal exacerbations during autumn during the next 4 years. In view of a family history of bipolar disorder, it was decided to add lamotrigine and taper venlafaxine. Mr A maintained remission on venlafaxine (37.5 mg/d) and lamotrigine (200 mg/d) without seasonal exacerbations. Mr A abruptly discontinued venlafaxine 37.5 mg/d. On the second day following discontinuation, he reported feeling an unpleasant sensation of “electricity in the head” that “felt like the brain was shaking inside the skull.” Mr A was also noticed to demonstrate emotional incontinence and complained of anhedonia, anxiety, tinnitus, headache, nausea, and increased sensitivity to noise. Since the “brain shivers” were the most distressing symptom, a trial of atomoxetine 40 mg/d was attempted based on the hypothesis that the symptom was a result of noradrenergic imbalance.<span class="htm-cite"><a href="#ref9">9</a></span> An immediate improvement in “brain shivers” was reported within 2 or 3 hours of taking the first dose. Over the next 3 days, Mr A reported further improvement in “brain shivers” and anhedonia although emotional incontinence and increased sensitivity to noise persisted. Given the severity of other withdrawal symptoms, venlafaxine (37.5 mg/d) was reinstated and atomoxetine was stopped. All withdrawal symptoms disappeared during the next day.</p>
<p class="ltrs-br-ltr-br-body-text">&nbsp;</p>
<p class="ltrs-br-ltr-br-body-text">The case adds to the interesting speculation about the noradrenergic imbalance as the basis of “brain shivers.”<span class="htm-cite"><a href="#ref9">9</a></span> “Brain shivers,” conceptually related to Lhermitte’s phenomenon,<span class="htm-cite"><a href="#ref10">10</a></span> have also been reported with the noradrenergic drug 3,4-methylenedioxy-<span class="italic">N</span>-methylamphetamine (MDMA). The psychotropic effects of MDMA are mediated via norepinephrine transporter<span class="htm-cite"><a href="#ref11">11</a></span> and results in an increase in synaptic norepinephrine levels. Venlafaxine’s affinity for norepinephrine transporter (K[i]<span class="thinspace"> </span>=<span class="thinspace"> </span>2,984 nM<span class="htm-cite">)12</span> is 10<span class="superscript">3</span>-fold lower than that of atomoxetine (K[i]<span class="thinspace"> </span>=<span class="thinspace"> </span>5 nM),<span class="htm-cite"><a href="#ref13">13</a></span> yet venlafaxine causes an increase (242%)<span class="htm-cite"><a href="#ref14">14</a></span> in synaptic norepinephrine levels comparable to that by atomoxetine (290%<span class="thinspace"> </span>±<span class="thinspace"> </span>33%).<span class="htm-cite"><a href="#ref13">13</a></span> Curiously, chronic treatment with venlafaxine does not reduce norepinephrine transporter binding sites.<span class="htm-cite"><a href="#ref15">15</a></span> These facts point to the possibility that increases in synaptic norepinephrine are due to norepinephrine transporter reversal, akin to dopamine transporter reversal associated with amphetamine.<span class="htm-cite"><a href="#ref16">16</a></span> Abrupt withdrawal of venlafaxine would hence result in paradoxical increase in synaptic norepinephrine via efflux through norepinephrine transporter channels, which is normalized by atomoxetine’s norepinephrine transporter blockade. This speculation of the noradrenergic basis of “brain shivers” warrants further study.</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. Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. <span class="italic">J&nbsp;Clin Psychiatry</span>. 2006;67(suppl 4):27–30. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16683860&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"><a name="ref2"></a>2. Coupland NJ, Bell CJ, Potokar JP. Serotonin reuptake inhibitor withdrawal. <span class="italic">J&nbsp;Clin Psychopharmacol</span>. 1996;16(5):356–362. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8889907&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1097/00004714-199610000-00003">doi:10.1097/00004714-199610000-00003</a></span></p>
<p class="references-references-text-1-9"><a name="ref3"></a>3. Fava M, Mulroy R, Alpert J, et al. Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. <span class="italic">Am J Psychiatry</span>. 1997;154(12):1760–1762. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9396960&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"><a name="ref4"></a>4. Christmas DMB. ‘Brain shivers’: from chat room to clinic. <span class="italic">Psychiatric Bulletin</span>. 2005;29:219–221.</p>
<p class="references-references-text-1-9"><a name="ref5"></a>5. 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-1-9"><a name="ref6"></a>6. Schimelpfening N. “Brain Shivers” as an Effexor withdrawal symptom. <span class="hyperlink"><a href="http://depression.about.com/cs/venlafaxine/a/brainshivers.htm">http://depression.about.com/cs/venlafaxine/a/brainshivers.htm</a></span>. Accessed July 16, 2012.</p>
<p class="references-references-text-1-9"><a name="ref7"></a>7. Understanding brain shivers—prescription drug withdrawal symptoms. <span class="hyperlink"><a href="http://www.howtodothings.com/health-and-fitness/a4391-how-to-understand-brain-shivers.html">http://www.howtodothings.com/health-and-fitness/a4391-how-to-understand-brain-shivers.html</a></span>. Accessed July 16, 2012.</p>
<p class="references-references-text-1-9"><a name="ref8"></a>8. Brain shivers… brain zaps… brain shocks….<span class="hyperlink"><a href="http://theblondepharmacist.com/2007/11/17/brain-shivers-brain-zaps-brain-shocks/">http://theblondepharmacist.com/2007/11/17/brain-shivers-brain-zaps-brain-shocks/</a></span>. Updated November 17, 2007. Accessed July 16, 2012.</p>
<p class="references-references-text-1-9"><a name="ref9"></a>9. Campagne DM. Venlafaxine and serious withdrawal symptoms: warning to drivers. <span class="italic">MedGenMed</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-10-99"><a name="ref10"></a>10. Boland B, Mitcheson L, Wolff K. Lhermitte’s sign, electric shock sensations and high dose ecstasy consumption: preliminary findings. <span class="italic">J&nbsp;Psychopharmacol</span>. 2010;24(2):213–220. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19240087&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1177/0269881108100528">doi:10.1177/0269881108100528</a></span></p>
<p class="references-references-text-10-99"><a name="ref11"></a>11. Hysek CM, Simmler LD, Ineichen M, et al. The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA (“ecstasy”) in humans. <span class="italic">Clin Pharmacol Ther</span>. 2011;90(2):246–255. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21677639&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1038/clpt.2011.78">doi:10.1038/clpt.2011.78</a></span></p>
<p class="references-references-text-10-99"><a name="ref12"></a>12. Lengyel K, Pieschl R, Strong T, et al. Ex vivo assessment of binding site occupancy of monoamine reuptake inhibitors: methodology and biological significance. <span class="italic">Neuropharmacology</span>. 2008;55(1):63–70. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18538356&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1016/j.neuropharm.2008.04.014">doi:10.1016/j.neuropharm.2008.04.014</a></span></p>
<p class="references-references-text-10-99"><a name="ref13"></a>13. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. <span class="italic">Neuropsychopharmacology</span>. 2002;27(5):699–711. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12431845&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1016/S0893-133X(02)00346-9">doi:10.1016/S0893-133X(02)00346-9</a></span></p>
<p class="references-references-text-10-99"><a name="ref14"></a>14. Piacentini MF, Clinckers R, Meeusen R, et al. Effects of venlafaxine on extracellular 5-HT, dopamine and noradrenaline in the hippocampus and on peripheral hormone concentrations in the rat in vivo. <span class="italic">Life Sci</span>. 2003;73(19):2433–2442. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12954452&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1016/S0024-3205(03)00658-1">doi:10.1016/S0024-3205(03)00658-1</a></span></p>
<p class="references-references-text-10-99"><a name="ref15"></a>15. Gould GG, Altamirano AV, Javors MA, et al. A comparison of the chronic treatment effects of venlafaxine and other antidepressants on serotonin and norepinephrine transporters. <span class="italic">Biol Psychiatry</span>. 2006;59(5):408–414. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16140280&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1016/j.biopsych.2005.07.011">doi:10.1016/j.biopsych.2005.07.011</a></span></p>
<p class="references-references-text-10-99"><a name="ref16"></a>16. Kahlig KM, Binda F, Khoshbouei H, et al. Amphetamine induces dopamine efflux through a dopamine transporter channel. <span class="italic">Proc Natl Acad Sci U S A</span>. 2005;102(9):3495–3500. <span class="pubmed-crossref"><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15728379&dopt=Abstract">PubMed</a> <a href="http://dx.doi.org/10.1073/pnas.0407737102">doi:10.1073/pnas.0407737102</a></span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Jose A. Cortes, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Rajiv Radhakrishnan, MD</span></p>
<p class="ltrs-br-ltr-br-author"><a href="mailto:rajivr79@yahoo.com">rajivr79@yahoo.com</a></p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Author affiliations:</span> Psychiatry Service, VA Connecticut Healthcare System, and Department of Psychiatry, Yale University School of Medicine, New Haven.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Potential conflicts of interest:</span> None reported.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Funding/support:</span> None reported.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Published online:</span> March 21, 2013.</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">Prim Care Companion CNS Disord 2013;15(2):</span><span class="doi">doi:10.4088/PCC.12l01427</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">© Copyright 2013 Physicians Postgraduate Press, Inc. </span></p>
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