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c0.3,0.3,0.3,0.5,0.2,0.9c-0.1,0.3-0.3,1-0.3,1.3c-0.1,0.4-0.4,0.6-0.8,0.4c-2.2-0.9-3.3-3.4-3.3-6.1c0-4.5,3.8-10,11.4-10 c6.1,0,10.1,4.4,10.1,9.2c0,6.3-3.5,11-8.6,11c-1.7,0-3.4-0.9-3.9-2c0,0-0.9,3.7-1.1,4.4c-0.3,1.2-1,2.5-1.6,3.4 c1.4,0.4,3,0.7,4.5,0.7c8.8,0,16-7.2,16-16C48,23.2,40.8,16,32,16z" fill="white"></path></svg></button><button aria-label="email" class="react-share__ShareButton" style="background-color:transparent;border:none;padding:0;font:inherit;color:inherit;cursor:pointer"><svg viewBox="0 0 64 64" width="32" height="32"><circle cx="32" cy="32" r="31" fill="#7f7f7f"></circle><path d="M17,22v20h30V22H17z M41.1,25L32,32.1L22.9,25H41.1z M20,39V26.6l12,9.3l12-9.3V39H20z" fill="white"></path></svg></button><a class="print-wrap flex justify-center items-center cursor-pointer"><svg id="print" xmlns="http://www.w3.org/2000/svg" width="24" height="24" fill="currentColor" class="print bi bi-printer" viewBox="0 0 16 16"> <path d="M2.5 8a.5.5 0 1 0 0-1 .5.5 0 0 0 0 1z"></path> <path d="M5 1a2 2 0 0 0-2 2v2H2a2 2 0 0 0-2 2v3a2 2 0 0 0 2 2h1v1a2 2 0 0 0 2 2h6a2 2 0 0 0 2-2v-1h1a2 2 0 0 0 2-2V7a2 2 0 0 0-2-2h-1V3a2 2 0 0 0-2-2H5zM4 3a1 1 0 0 1 1-1h6a1 1 0 0 1 1 1v2H4V3zm1 5a2 2 0 0 0-2 2v1H2a1 1 0 0 1-1-1V7a1 1 0 0 1 1-1h12a1 1 0 0 1 1 1v3a1 1 0 0 1-1 1h-1v-1a2 2 0 0 0-2-2H5zm7 2v3a1 1 0 0 1-1 1H5a1 1 0 0 1-1-1v-3a1 1 0 0 1 1-1h6a1 1 0 0 1 1 1z"></path></svg></a></div><style> .print-wrap { width: 32px; height: 32px; background: #7F7F7F; border-radius: 100%; } .print { background: #7F7F7F; color: white; padding: 2px; border-radius: 100%; } </style></div></div></div></div><div class=" lg:w-full flex flex-col lg:flex-row lg:items-center lg:justify-end"></div><p class="py-2 mb-2 text-sm italic text-gray-600">Research is underway to make psychedelics agents a treatment option for psychiatric disorders. </p><div class="py-2"><div class="blockText_blockContent__TbCXh"><p class="pb-2"><strong>PSYCH PEARLS PODCAST</strong></p><div style="min-height:250px"><noscript>Please enable Javascript</noscript></div><div class=""><div style="width:20%;float:left;max-width:525px;margin:0 1.5rem 1.5rem 0;clear:both;cursor:pointer" class=" figure"><div class="flex-none relative text-center"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27419%27%20height=%27419%27/%3e"/></span><img alt="psychedelic psychiatry" title="psychedelic psychiatry" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain"/><noscript><img alt="psychedelic psychiatry" title="psychedelic psychiatry" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F1c5144493909bb14f9bfa83ad43cea63274a0eac-419x419.png%3Ffit%3Dcrop%26auto%3Dformat&w=640&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F1c5144493909bb14f9bfa83ad43cea63274a0eac-419x419.png%3Ffit%3Dcrop%26auto%3Dformat&w=1080&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F1c5144493909bb14f9bfa83ad43cea63274a0eac-419x419.png%3Ffit%3Dcrop%26auto%3Dformat&w=1080&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%;object-fit:contain" loading="lazy"/></noscript></span></div><div id="image-caption" class="text-gray-500 italic"><div class="blockText_blockContent__TbCXh"><p class="pb-2">Amir Inamdar MBBS, DNB (Psych), MFPM</p></div></div><div class="top-[-100%] block w-[1px] transition-opacity duration-500 ease-in-out opacity-0 overflow-hidden"><img class="m-auto absolute inset-0 max-w-[0%] max-h-[0%] border-[3px] border-solid border-white shadow-[0px_0px_8px_rgba(0,0,0,0.3)] box-border transition ease-in-out duration-500" src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/1c5144493909bb14f9bfa83ad43cea63274a0eac-419x419.png?fit=crop&auto=format"/></div></div><style> #image-caption p{ font-size: 12px; max-width: 525px; margin: 0 auto; text-align: center; } </style></div><p class="pb-2">As part of a psychedelic revolution, careful research is underway to see how these compounds may benefit patients with psychiatric disorders. In this episode, Amir Inamdar MBBS, DNB (Psych), MFPM, shares insights and thoughts about the work being done and its potential to make a difference in patient care. </p><p class="pb-2"></p><p class="pb-2"></p></div></div><div class="flex items-center lg:w-3/4 mb-4 pb-12"></div><div class="jsx-19ede9f0a5a45918 py-4 relative bg-primary md:px-8 -ml-6 xs:ml-0 w-screen xs:w-auto"><div class="jsx-19ede9f0a5a45918 px-4 sm:px-0"><div class="flex justify-between items-center py-1 space-x-4 border-0 select-none sm:border-b border-secondary"><div class="text-3xl text-white text-lg sm:text-3xl">Related Videos</div></div></div><div style="scroll-snap-type:none" class="jsx-19ede9f0a5a45918 flex items-start overflow-x-auto space-x-4 py-4 relative mx-auto w-full pl-4"><a id="" class="w-[200px] h-fit space-y-3 flex-none select-none no-underline" style="scroll-snap-align:center;text-decoration:none" href="/view/psilocybin-the-complicated-conversation"><div class="w-full shadow-md shadow-gray-800 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In this episode, Amir Inamdar MBBS, DNB (Psych), MFPM, shares insights and thoughts about the work being done and its potential to make a difference in patient care. \n\n\n\n","description":"Research is underway to make psychedelics agents a treatment option for psychiatric disorders. 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He discussed the results of a study that found 60% of clinicians prescribing clozapine said that “The safe use requirements have often caused delay in my patients receiving medication.” Cotes added that missed doses due to this bureaucracy can lead to the need for re-titration, psychological distress for patients, physical discomfort/withdrawal, symptom exacerbation, and can even lead to hospitalization.","_key":"c565c799b74a0"},{"_type":"span","marks":["superscript"],"text":"2","_key":"17530ad78640"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"In addition to expert testimony, patients, caregivers, clinicians, and advocates were given an opportunity to speak before the committee voted.","_key":"6a316006ab240"}],"_type":"block","style":"normal","_key":"2a455930a838"},{"_key":"e6a2b1f72b3b","markDefs":[],"children":[{"_type":"span","marks":[],"text":"“The REMS program, while well-intentioned and -designed, does create a barrier to prescribers and patients using clozapine,” said Kathryn K. Erickson-Ridout, MD, a member of APA’s Council on Quality Care who testified on behalf of APA.3 Erickson-Ridout, who is also an inpatient psychiatrist and researcher for Kaiser Permanente, told the committee, ““I have been treating patients with treatment-resistant schizophrenia for 12 years and have seen the life-transforming benefit of this medication—controlling otherwise treatment-resistant psychotic symptoms and providing cognitive clarity.” ","_key":"51e90a4d955f0"}],"_type":"block","style":"normal"},{"children":[{"_type":"span","marks":[],"text":"She added the disruptions in care resulted from the REMS protocol can lead to “disastrous results.”","_key":"aa3cc47443430"}],"_type":"block","style":"normal","_key":"cdb1d8cd1e2d","markDefs":[]},{"_key":"27d6c40b2c46","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Similarly, epidemiologist and panelist Sascha Dublin, MD, PhD, emphasized the need for monitoring and support without “a punitive and technocratic approach.”","_key":"25820974114e0"},{"_key":"3c7ed08f4587","_type":"span","marks":["superscript"],"text":"3"}],"_type":"block","style":"normal"},{"_type":"block","style":"normal","_key":"0b6c6a7ff083","markDefs":[],"children":[{"marks":[],"text":"“I do not believe that the REMS’ approach to documenting and enforcing is serving the health of the patients or the needs of the community,” she said.","_key":"4a3dfec9d2bf0","_type":"span"}]},{"_key":"5366de8a504a","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Although the committee overwhelmingly decided the REMS was no longer appropriate, Walter Dunn, MD, PhD disagreed. Dunn, Health Sciences Assistant Clinical Professor in the department of psychiatry at UCLA David Geffen School of Medicine, director of the Mood Disorders Clinic at West Los Angeles Veterans Affairs Medical Center, preferred monitoring when the risk was the greatest—during the first 18 weeks—instead of completely getting rid of the REMS. He did, however, suggest a more streamlined program without ANC levels.","_key":"7fee48f1814e0"},{"_type":"span","marks":["superscript"],"text":"1","_key":"acfaadd1cdfd"}],"_type":"block","style":"normal"},{"markDefs":[{"href":"https://www.psychiatrictimes.com/view/clozapine-rems-regulatory-discrimination-against-psychiatrists","_key":"5a7bf474edb0","nofollow":true,"blank":true,"_type":"link"}],"children":[{"text":"In a recent article for ","_key":"80b8b91534900","_type":"span","marks":[]},{"marks":["em","5a7bf474edb0"],"text":"Psychiatric Times","_key":"80b8b91534901","_type":"span"},{"text":", Gilbert Honigfeld, PhD, detailed the onerous process and the delays in treatment that result from REMS, even referring to it as a discriminatory practice against psychiatric clinicians.","_key":"80b8b91534902","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"4","_key":"880f2a14f95c"}],"_type":"block","style":"normal","_key":"8ca00f559ec5"},{"_key":"376432600a8e","markDefs":[],"children":[{"_type":"span","marks":[],"text":"“From the point of view of professional equity alone then, clozapine REMS is clearly discriminatory and should be eliminated immediately,” he wrote.","_key":"8abb61a4f7330"},{"text":"4","_key":"c06c83f1b504","_type":"span","marks":["superscript"]},{"marks":[],"text":" “Psychiatrists are physicians first, specialists second. They are as capable of monitoring the health and well-being of their patients as physicians in all other medical specialties. No medicine is free of significant adversity, and clozapine’s low overall rate of fatal outcomes turns out to be quite comparable to other antipsychotic medicines, if not better.”","_key":"9bd3b0140e8e","_type":"span"}],"_type":"block","style":"normal"},{"_key":"35ddcc57aa61","markDefs":[],"children":[{"_type":"span","marks":[],"text":"“As well intended as it might once have seemed, the federal REMS program is now one of the primary obstacles standing in the way of patients receiving their medicine on time,” he added.","_key":"4bd19ff897f00"},{"_type":"span","marks":["superscript"],"text":"4","_key":"2cd84761ed9c"},{"_type":"span","marks":[],"text":" “It is a major factor limiting access to clozapine for individuals with serious mental illnesses whose very lives might well depend on it. Solution? Eliminate FDA’s clozapine REMS program and allow psychiatrists to practice medicine just like their peers in all other medical specialties.”","_key":"ad08774ba85f"}],"_type":"block","style":"normal"},{"_key":"aaf11f441454","markDefs":[],"children":[{"_key":"a2cacd160e480","_type":"span","marks":["em"],"text":"What do you think of this decision and how will it impact your prescribing strategy and patients? Share your thoughts with us via PTEditor@mmhgroup.com."}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"References","_key":"e5f5da6c57440"}],"_type":"block","style":"normal","_key":"208fc07548d6"},{"_type":"block","style":"normal","_key":"d6c3935bc857","markDefs":[{"_type":"link","href":"https://insights.citeline.com/pink-sheet/product-reviews/us-advisory-committees/clozapine-rems-a-barrier-to-treatment-and-unnecessary-for-safe-use-us-fda-adcomms-say-KDK6ICJKNBHPTBGVFFL3C6ME7U/","_key":"1fc3d61f6408"}],"children":[{"_type":"span","marks":[],"text":"1. Sutter S. Clozapine REMS A Barrier To Treatment And Unnecessary For Safe Use, US FDA Adcomms Say. ","_key":"f2fa6ed975360"},{"_type":"span","marks":["em"],"text":"The Pink Sheet. ","_key":"f2fa6ed975361"},{"marks":[],"text":"November 20, 2024. Accessed November 20, 2024. ","_key":"f2fa6ed975362","_type":"span"},{"text":"https://insights.citeline.com/pink-sheet/product-reviews/us-advisory-committees/clozapine-rems-a-barrier-to-treatment-and-unnecessary-for-safe-use-us-fda-adcomms-say-KDK6ICJKNBHPTBGVFFL3C6ME7U/","_key":"f2fa6ed975363","_type":"span","marks":["1fc3d61f6408"]}]},{"children":[{"_type":"span","marks":[],"text":"2. FDA Advisory Committee Meeting Clozapine Risk Evaluation and Mitigation Strategy. November 19, 2024. Accessed November 20, 2024. ","_key":"774434e85b970"},{"_type":"span","marks":["fcf608efde8c"],"text":"https://www.fda.gov/media/183655/download","_key":"774434e85b971"}],"_type":"block","style":"normal","_key":"23601345cdbd","markDefs":[{"_type":"link","href":"https://www.fda.gov/media/183655/download","_key":"fcf608efde8c"}]},{"markDefs":[{"_type":"link","href":"https://alert.psychnews.org/2024/11/fda-panel-votes-14-1-against-clozapine.html","_key":"b897a4fa8213"}],"children":[{"_key":"037ce336590f0","_type":"span","marks":[],"text":"3. "},{"_type":"span","marks":["b897a4fa8213"],"text":"FDA Panel Votes 14-1 Against Clozapine REMS","_key":"037ce336590f1"},{"marks":[],"text":". APA News Alert. November 20, 2024. Accessed November 20, 2024. https://alert.psychnews.org/","_key":"037ce336590f2","_type":"span"}],"_type":"block","style":"normal","_key":"6578599842ea"},{"children":[{"_type":"span","marks":[],"text":"4. Honigfeld G. ","_key":"4e457ef1ed930"},{"_key":"3280d930d343","_type":"span","marks":["b1e6be581e34"],"text":"Clozapine REMS: Regulatory Discrimination Against Psychiatrists? "},{"_key":"fb1bf8751661","_type":"span","marks":["em"],"text":"Psychiatric Times"},{"_type":"span","marks":[],"text":". October 3, 2024. 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PODCAST","_key":"377bc7a574bc"}],"_type":"block","style":"normal","_key":"bc74220c2a76","markDefs":[]},{"_type":"block","style":"normal","_key":"b1c156561db3","markDefs":[],"children":[{"_type":"span","marks":["em"],"text":"Transcript edited for clarity. - Ed","_key":"bb30c17257b70"}]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"71338ce3cff20"},{"_type":"span","marks":[],"text":" Lamotrigine was launched for bipolar disorder in 2003, but it was a quiet launch, and since then a few myths have gathered around it as if to fill that vacuum. Today, we will address 4 of them.","_key":"71338ce3cff21"}],"_type":"block","style":"normal","_key":"be5283bf4499"},{"style":"normal","_key":"34fc570ee2b6","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Welcome to ","_key":"e9fd90e430050"},{"text":"PsychPearls","_key":"e9fd90e430051","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":" podcast with ","_key":"e9fd90e430052"},{"_type":"span","marks":["em"],"text":"Psychiatric Times","_key":"e9fd90e430053"},{"marks":["superscript"],"text":"TM","_key":"e9fd90e430054","_type":"span"},{"text":", the voice of psychiatry. With thoughtful insights into the world of mental health, this podcast provides timely clinical commentary and practical cutting-edge pearls for you and your practice. We hope you enjoy it.","_key":"55b4e2909f49","_type":"span","marks":[]}],"_type":"block"},{"markDefs":[],"children":[{"marks":[],"text":"I am Chris Aiken, the Mood Disorders Section Editor for ","_key":"ea53b84443740","_type":"span"},{"_type":"span","marks":["em"],"text":"Psychiatric Times","_key":"ea53b84443741"},{"_type":"span","marks":["superscript"],"text":"TM","_key":"ea53b84443742"},{"_type":"span","marks":[],"text":" and the editor-in-chief of the ","_key":"2a1d567b6175"},{"_type":"span","marks":["em"],"text":"Carlat Psychiatry Report","_key":"ea53b84443743"},{"text":", and I am Kellie Newsome, a psychiatric NP and the cohost of the ","_key":"ea53b84443744","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"Carlat Psychiatry Podcast","_key":"ea53b84443745"},{"_type":"span","marks":[],"text":".","_key":"ea53b84443746"}],"_type":"block","style":"normal","_key":"308fc4380485"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"A Quiet Launch","_key":"86ea5d507ff30"}],"_type":"block","style":"normal","_key":"9e73ca7194e2"},{"children":[{"text":"KELLIE NEWSOME:","_key":"afec8962a0580","_type":"span","marks":["strong"]},{"text":" On June 20, 2003, the world had its eyes on the United States’ invasion of Iraq. Some of us were following Martha Stewart’s indictment for insider trading, and quite a few were lining up at bookstores to be the first to buy the 5th installment in the Harry Potter series. But Russell Katz, MD, was busy at his desk on this day at the US Food and Drug Administration (FDA) headquarters, writing a letter to GlaxoSmithKline announcing the approval of their anticonvulsant lamotrigine in bipolar disorder. But the approval was not a slam-dunk. GlaxoSmithKline had submitted 12 trials, and only 2 of them were positive. Lamotrigine did not work in acute mania; it did not work in acute bipolar depression; and it did not work in rapid cycling.","_key":"afec8962a0581","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"a63f35be65e5","markDefs":[]},{"style":"normal","_key":"c0eb9ce72ebb","markDefs":[],"children":[{"_type":"span","marks":[],"text":"But bipolar disorder (BD) is a chronic condition, and that is where the medication succeeded: in the maintenance phase.","_key":"9d8e4fd3af040"}],"_type":"block"},{"_type":"block","style":"normal","_key":"2b3bbb539720","markDefs":[],"children":[{"_key":"64d6e68df2480","_type":"span","marks":[],"text":"The 2 positive studies looked at lamotrigine in the long term, over 1 and a half years. There, lamotrigine helped patients stay well about twice as long as a placebo."},{"_key":"73fb7856ebbe","_type":"span","marks":["superscript"],"text":"1"},{"_type":"span","marks":[],"text":" Katz knew that long-term studies like this were expensive and hard to come by, but for patients who have to stay on a mood stabilizer year after year it is this kind of data that matters most. So he gave it an indication for delaying new episodes of depression, hypomania, and mania in BD.","_key":"5db9d5a360d0"}]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"e07cb217d3d60"},{"_type":"span","marks":[],"text":" And that is how lamotrigine was launched. But there are a lot of loose threads in that story that have tangled into myths, and today we are going to unravel 4 of them so you can use lamotrigine more effectively in practice.","_key":"e07cb217d3d61"}],"_type":"block","style":"normal","_key":"184030a32757"},{"children":[{"_type":"span","marks":["strong"],"text":"A Warning","_key":"75b3c80a10a30"}],"_type":"block","style":"normal","_key":"233f91ee925a","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"3959c05423550"},{"_key":"3959c05423551","_type":"span","marks":[],"text":" But first a warning. Lamotrigine is not a panacea. It works in BD, but it does not treat non-bipolar depression. There the studies are mixed: half positive, half negative. It has positive controlled trials in obsessive compulsive disorder, borderline personality disorder, and depersonalization disorder, but those studies are few and small."},{"_type":"span","marks":["superscript"],"text":"2","_key":"0fbe71658c79"},{"text":" So do not start prescribing lamotrigine to every moody individual you see, because this medicine has one big risk that makes those uncharted adventures unwise: the potentially fatal rash of Stevens Johnson Syndrome.","_key":"ed9d37b2069d","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"7117c4dbf031"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"That rash is part of the reason that lamotrigine had such a soft launch. Early on, the manufacturer decided not to market lamotrigine to primary care practices, and to minimize direct to consumer advertising. The decision may have hurt their quarterly profits, but it helped them stay in the market. You see, lamotrigine was nearly yanked off the market after its launch in epilepsy 10 years earlier. Back then, doctors were starting the drug at 100mg a day, which lead to an alarming rise in potentially fatal Stevens Johnson rashes. The medication only survived when the company was able to show that it could lower this risk through the slow titrations that we use today. Now that risk is around 1 in 3000.","_key":"1fb3158d8fbb0"},{"_type":"span","marks":["superscript"],"text":"3","_key":"8c34969f2243"}],"_type":"block","style":"normal","_key":"0d9d3c0fa520"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"GlaxoSmithKline was concerned that if they overhyped the drug, then clinicians with little experience in BD would prescribe it to every moody patient they saw, and if they overlooked the DSM in that way they might also overlook the titration instructions, causing a second flare of serious rashes that would cause the FDA to pull the plug again.","_key":"3a799e7b28970"}],"_type":"block","style":"normal","_key":"c81541e1df53"},{"style":"normal","_key":"fc3dcfb76df8","markDefs":[],"children":[{"text":"KELLIE NEWSOME:","_key":"6fbf95ee9eec0","_type":"span","marks":["strong"]},{"_key":"6fbf95ee9eec1","_type":"span","marks":[],"text":" And now let us get into those myths. There are 4 of them."}],"_type":"block"},{"_type":"block","style":"normal","_key":"842419cc5dfe","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Myth #1: Lamotrigine does not help mania","_key":"9731eb6e18c90"}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Myth #2: Lamotrigine does not treat acute episodes of bipolar depression","_key":"1d6c4971e1980"}],"_type":"block","style":"normal","_key":"28425af347c4"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Myth #3: Lamotrigine is a weak mood stabilizer","_key":"a2875e7deb100"}],"_type":"block","style":"normal","_key":"90e174ac7e84"},{"_key":"fa86dd8111b0","markDefs":[],"children":[{"text":"Myth #4: It is a good idea to stop lamotrigine when a patient relapses, because it is probably not working","_key":"1cc4573623ed0","_type":"span","marks":[]}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Myth #1: Lamotrigine Does not Help Mania","_key":"6e5992c2c46f0"}],"_type":"block","style":"normal","_key":"eb46f4b7a0af"},{"_type":"block","style":"normal","_key":"b38e681b0544","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"ae0762d35ea90"},{"_type":"span","marks":[],"text":" This one is kind of true. Lamotrigine failed in the acute mania trials, and nothing that we have learned about this drug in the 25 years since suggests that it has any role in acute mania. But lamotrigine does help prevent mania, although it is better at preventing bipolar depression than it is at preventing mania. What that means in practice is that you should not rely on it as the sole maintenance medication in patients with a history of severe mania, but it may be used as monotherapy in bipolar II disorder, where the depressions are more common and the manic symptoms brief and mild.","_key":"ae0762d35ea91"}]},{"_type":"block","style":"normal","_key":"3011d070f04a","markDefs":[],"children":[{"marks":[],"text":"In fact, many bipolar experts see good results in cyclothymic patients, who cycle frequently between mild depression, hypomania, and mixed states. That observation only supported by open-label studies, but hey – there are zero controlled medication trials in cyclothymic disorder so that is as good as it gets.","_key":"8aa3f8afb5920","_type":"span"},{"_type":"span","marks":["superscript"],"text":"4,5","_key":"b9fcb60198b3"}]},{"style":"normal","_key":"bc02774e1673","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Myth #2: Lamotrigine Does Treat Acute Episodes of Bipolar Depression","_key":"facc22eea3890"}],"_type":"block"},{"_type":"block","style":"normal","_key":"16a54e6b696b","markDefs":[],"children":[{"marks":["strong"],"text":"CHRIS AIKEN:","_key":"1512b45c33820","_type":"span"},{"_type":"span","marks":[],"text":" Among the 12 trials on Katz’s desk, 5 of them are good candidates for the most disappointing trials in the history of psychiatry. These were the 5 controlled trials in acute bipolar depression, all funded by the manufacturer, and all of them failed. The trials were never published, but most psychiatrists knew about them when lamotrigine was released, and it gave some of us the impression that lamotrigine was a weak mood stabilizer that barely got approved for an indication that was not at the top of the list for doctors or patients.","_key":"1512b45c33821"}]},{"_key":"5943f97d91b3","markDefs":[],"children":[{"_type":"span","marks":[],"text":"But we have since learned that lamotrigine does treat acute depression, it just takes a little longer than faster options like the atypical antipsychotics. The problem is that the early studies only lasted 7 weeks, and lamotrigine requires a slow titration that takes 4 to 6 weeks to reach a therapeutic level. Later, lamotrigine did prove efficacious for acute bipolar depression in 2 independently funded randomized placebo-controlled trials.","_key":"ad08da73d7b30"},{"_type":"span","marks":["superscript"],"text":"6,7","_key":"3f7f57eb6ddf"}],"_type":"block","style":"normal"},{"_key":"0b93e13917dc","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"1672bd87395e0"},{"_type":"span","marks":[],"text":" Wait a minute. You are saying the industry sponsored trials were all negative but the independent ones were positive? That is a first.","_key":"1672bd87395e1"}],"_type":"block","style":"normal"},{"style":"normal","_key":"80917ad9e22c","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"7bf5ca1291820"},{"_key":"7bf5ca1291821","_type":"span","marks":[],"text":" Yes, and the difference is that the independently sponsored trials gave lamotrigine a little more time. They lasted 8 to 12 weeks instead of 7 weeks. Also, lamotrigine was used as augmentation in these trials – in 1 it augmented lithium and the other quetiapine – but I think lamotrigine can work as monotherapy in acute depression and the real difference here was the timespan."}],"_type":"block"},{"markDefs":[],"children":[{"text":"KELLIE NEWSOME:","_key":"2d03b35c77350","_type":"span","marks":["strong"]},{"_type":"span","marks":[],"text":" One reason we think it works as monotherapy is that John Geddes, MD, FRCPsych, Joseph Calabrese, MD, and Guy Goodwin, DPhil, reanalyzed the original 5 negative trials in an independently funded meta-analysis.","_key":"2d03b35c77351"},{"_type":"span","marks":["superscript"],"text":"8","_key":"cb882e6e34a5"},{"_type":"span","marks":[],"text":" They found that there was a positive signal in the original studies, but they were too small to detect it. When combined together, totaling 1072 participants, lamotrigine had a small effect, bringing about a meaningful response in 1 out of 11 participants. But hey, cariprazine got FDA approval in bipolar depression with the same number needed to treat, and lamotrigine’s efficacy only starts to build at that 7-week mark. If you use lamotrigine for acute depression, you will probably need to wait about a month and a half to see an effect, and, judging from the longer trials, those benefits are likely to keep building over the next 1 to 4 months.","_key":"ccbd5a89a36a"}],"_type":"block","style":"normal","_key":"c117b51331c0"},{"style":"normal","_key":"2901ac965eb3","markDefs":[],"children":[{"_type":"span","marks":[],"text":"A common strategy then is to start lamotrigine with a faster-acting agent like an atypical antipsychotic, and then slowly taper off the antipsychotic as lamotrigine starts to kick in. This gives you the best of both worlds: lamotrigine has excellent tolerability over the long term, with a low risk of weight gain, fatigue, cognitive problems, sexual dysfunction, or any of the long-term medical problems that show up in the warnings for antipsychotics.","_key":"e869be0741ea0"}],"_type":"block"},{"style":"normal","_key":"2629a4935e8d","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"b8f816b9efef0"},{"marks":[],"text":" One risk we do not think about enough is stroke. Stroke is the #1 cause of death in bipolar disorder, and lamotrigine and lithium are the only mood stabilizers that do not increase the risk of stroke; all the others have some marks against them there.","_key":"b8f816b9efef1","_type":"span"},{"_type":"span","marks":["superscript"],"text":"9","_key":"d99521f436db"},{"_type":"span","marks":[],"text":" I am going to get on a soap box for a minute here and argue that bipolar is not a mental disorder. It’s a physical disorder, and not just because the brain is a physical organ. Heart disease starts 10 to 15 years earlier in individuals with BD, and you can even detect cardiovascular changes in teens with bipolar. Lifestyle may play a part, but I think about all that adrenaline pumping through the veins during mania and mixed states. This is a whole-body illness, and we ought to be thinking about long-term morbidity and mortality when choosing a mood stabilizer, not just relieving acute symptoms.","_key":"ba95c9c01a78"}],"_type":"block"},{"_type":"block","style":"normal","_key":"e770fed2200f","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME","_key":"602738f0ff8b0"},{"_key":"602738f0ff8b1","_type":"span","marks":[],"text":": Are you off your soap box yet?"}]},{"markDefs":[],"children":[{"text":"CHRIS AIKEN:","_key":"c1859d28767c0","_type":"span","marks":["strong"]},{"marks":[],"text":" No, I have one more thing to say. The ","_key":"c1859d28767c1","_type":"span"},{"_type":"span","marks":["em"],"text":"DSM","_key":"c1859d28767c2"},{"_type":"span","marks":[],"text":" is often criticized for promoting biological psychiatry through its black-box, symptom check-list approach. But to me, it is not biological enough. You could read the whole book and walk away with little sense that these mental illnesses are wrecking havoc on the heart, the gastrointestinal tract, the immunologic and neuroendocrine systems. You would never get that sense from reading Harrison’s textbook of internal medicine.","_key":"c1859d28767c3"}],"_type":"block","style":"normal","_key":"d5851fb382bb"},{"_key":"281873e8c0d3","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"69bc2c73c4fe0"},{"_type":"span","marks":[],"text":" OK, can we get back to lamotrigine now.","_key":"69bc2c73c4fe1"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Myth #3: Lamotrigine Is a Weak Mood Stabilizer","_key":"a045c4658a1e0"}],"_type":"block","style":"normal","_key":"1c2d625d230e"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"af6b65c916ab0"},{"marks":[],"text":" Yes, and that segues back to another myth about lamotrigine, which is that treatments that are slow to act are not strong ones. This is not how chronic diseases are approached in other medical specialties, which naturally take a long-term, disease-modifying view. You will never see a diabetes study that looks at change on a symptom check-list over 4 weeks. Or take hypertension. Clonidine lowers blood pressure right away, but most physicians prefer a thiazide for hypertension because it lowers the long-term risks of morbidity and mortality.","_key":"af6b65c916ab1","_type":"span"}],"_type":"block","style":"normal","_key":"22b7dd918fb9"},{"style":"normal","_key":"28aae8f32b92","markDefs":[],"children":[{"text":"Individuals with bipolar disorder die 10 years earlier on average, and not from suicide. Kellie, can you read the top causes of death in bipolar disorder","_key":"6dbec22f80e90","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"10","_key":"88e0210b2ee1"},{"_type":"span","marks":[],"text":":","_key":"6c7ff3169e66"}],"_type":"block"},{"_key":"5b8045ad2141","markDefs":[],"children":[{"_key":"cc0d7696d8210","_type":"span","marks":["em"],"text":"Stroke"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["em"],"text":"Heart disease","_key":"279f0a7387960"}],"_type":"block","style":"normal","_key":"a334e977573d"},{"_key":"d478f377ef13","markDefs":[],"children":[{"marks":["em"],"text":"Cancer","_key":"fc3cd57353fe0","_type":"span"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_key":"f20c00c3b8e90","_type":"span","marks":["em"],"text":"Diabetes"}],"_type":"block","style":"normal","_key":"e7d523a20836"},{"children":[{"marks":["em"],"text":"Chronic obstructive pulmonary disease (COPD)","_key":"4e21580caa460","_type":"span"}],"_type":"block","style":"normal","_key":"93584cb57e2c","markDefs":[]},{"children":[{"_key":"6f7027a8179e0","_type":"span","marks":["em"],"text":"Pneumonia and influenza"}],"_type":"block","style":"normal","_key":"37211411d6f4","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":["em"],"text":"Accidental injuries","_key":"bc3d2a45ab910"}],"_type":"block","style":"normal","_key":"31192940618e"},{"_key":"5f68a3d04a0b","markDefs":[],"children":[{"_type":"span","marks":["em"],"text":"Suicide","_key":"af30477033fe0"}],"_type":"block","style":"normal"},{"_key":"3c9ab1d299ba","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/28976944/","_key":"0fb886e1546c"},{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/26394555/","_key":"d41529e80f4d"}],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"c84f7e8587670"},{"text":" Right, so if you can find a mood stabilizer that reduces those risks, or at least does not increase them, that is golden. Lamotrigine is neutral on all of them, and ","_key":"c84f7e8587671","_type":"span","marks":[]},{"text":"lithium brings down","_key":"c84f7e8587672","_type":"span","marks":["0fb886e1546c"]},{"marks":[],"text":" most of them. Specifically, lithium lowers the risk of heart disease, ","_key":"c84f7e8587673","_type":"span"},{"_type":"span","marks":["d41529e80f4d"],"text":"stroke","_key":"c84f7e8587674"},{"marks":[],"text":", cancer, viral infections, and suicide.","_key":"c84f7e8587675","_type":"span"}],"_type":"block","style":"normal"},{"_type":"block","style":"normal","_key":"0c8384d790a6","markDefs":[],"children":[{"marks":["strong"],"text":"KELLIE NEWSOME:","_key":"49567e5202790","_type":"span"},{"_key":"49567e5202791","_type":"span","marks":[],"text":" But we are getting a bit ahead of ourselves here. I mean, long-term medical risks are important when considering a mood stabilizer, but we also want something that prevents the episodes. Here we have an interesting finding from studies that have compared lithium and lamotrigine."},{"_type":"span","marks":["superscript"],"text":"1","_key":"ec60417890f9"},{"marks":[],"text":" Lithium offers better prevention against the manic side, while lamotrigine works better against the depressive side, so combining the 2 makes sense. And one study did that – the LamLit trial – and confirmed that there are indeed additional benefits to combining the 2.","_key":"0696b2340ef6","_type":"span"},{"_type":"span","marks":["superscript"],"text":"3","_key":"e33cb03a7664"}]},{"_key":"836bb2d48eed","markDefs":[],"children":[{"text":"CHRIS AIKEN:","_key":"922aa9e34a480","_type":"span","marks":["strong"]},{"text":" And that is the long-term perspective that we need to take when choosing a mood stabilizer. This does not come naturally in psychiatry. If you work in a hospital, insurance is pressuring you to get the patient better quickly, so lamotrigine is not going to be your go-to agent. And if you work in an outpatient office, ask yourself: When was the last time a patient came in saying “I’d like a medication to prevent bipolar disorder”? In psychiatry, we treat suffering, and our patients want something that will work quickly.","_key":"922aa9e34a481","_type":"span","marks":[]}],"_type":"block","style":"normal"},{"_type":"block","style":"normal","_key":"2fecb70096c1","markDefs":[],"children":[{"marks":[],"text":"And that brings us to the fourth myth.","_key":"4208a7ebf9fb0","_type":"span"}]},{"_key":"498a1cd97284","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Myth #4: It Is a Good Idea to Stop Lamotrigine When a Patient Relapses, Because It Is Probably not Working","_key":"e18dfc91b8830"}],"_type":"block","style":"normal"},{"_key":"87a3bcf042c3","markDefs":[],"children":[{"text":"KELLIE NEWSOME:","_key":"e6e53933eaea0","_type":"span","marks":["strong"]},{"_type":"span","marks":[],"text":" In the maintenance trials, lamotrigine delayed the time to a new episode by 197 days, about half a year, vs 86 days or 3 months for placebo. So it is about twice as effective as placebo, but it does not provide 100% protection (no mood stabilizer does). In practice, here is what I tell patients when starting it:","_key":"e6e53933eaea1"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Lamotrigine’s going to have a slow build because you have to raise it slowly to prevent a serious rash. That means you’re going to feel better gradually over the next 1 to 2 months, but on the other hand you are not likely to have many side effects or medicated feelings. And that is a good thing because you are likely to need something long term to prevent mood problems, and this one does not have any major long-term risks. But keep in mind it is not going to prevent all mood episodes, but it will cut the rate of those episodes in half. So instead of having depression, say, every year, it may be every 2 years. But no medication does everything, and there is a lot you can do to raise those odds of success.","_key":"ccb544652fbd0"}],"_type":"block","style":"blockquote","_key":"0027df6157f5"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Then I talk about behavioral strategies for bipolar and depression. If you are interested in that, we have a separate podcast for patients that teaches these strategies. Search for ","_key":"2befe2137c4f0"},{"_type":"span","marks":["em"],"text":"The Pocket Psychiatrist","_key":"2befe2137c4f1"},{"text":" in your podcast store.","_key":"2befe2137c4f2","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"adc73736bb44"},{"children":[{"_key":"6413e50b25ef0","_type":"span","marks":["strong"],"text":"CHRIS AIKEN:"},{"text":" A common mistake is to stop lamotrigine when an episode returns, which is a bit like stopping blood pressure and cholesterol medications because a patient had a heart attack. Lamotrigine’s most robust effects are in prevention, and prevention is difficult to measure in psychiatry. You would need a before-and-after mood chart to confirm that the medication is lowering the frequency of episodes as it promises to do. Even then the work is difficult because so many other factors can make mood better or worse. What I look for is improvement in the first 3 to 6 months after starting lamotrigine. If a patient stops it, I watch for worsening over the next 3 to 6 months. And I also listen for something that I have heard a lot of patients say on this medication, particularly those with the frequent ups and downs of cyclothymic disorder.","_key":"6413e50b25ef1","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"0bae815f4e09","markDefs":[]},{"markDefs":[],"children":[{"text":"KELLIE NEWSOME:","_key":"b02c937742660","_type":"span","marks":["strong"]},{"_type":"span","marks":[],"text":" What is that?","_key":"b02c937742661"}],"_type":"block","style":"normal","_key":"2cc02bd19ecc"},{"_type":"block","style":"normal","_key":"29ed580449f0","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/18402630/","_key":"3c66a7c96c61"},{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/20846461/","_key":"230edd4b803d"},{"_key":"b9eb677aeb0e","blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/29944976/"}],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"db377cc4db680"},{"_type":"span","marks":[],"text":" They say they still feel the same about whatever problems they were having in life, but the feelings are less overwhelming. They see things in perspective better. And that matches up with what we see in neuroimaging studies of lamotrigine. The ","_key":"db377cc4db681"},{"_type":"span","marks":["3c66a7c96c61"],"text":"amygdala","_key":"db377cc4db682"},{"marks":[],"text":" is less reactive to emotionally disturbing images, there is a rise in brain-strengthening ","_key":"db377cc4db683","_type":"span"},{"_type":"span","marks":["230edd4b803d"],"text":"BDNF","_key":"db377cc4db684"},{"_type":"span","marks":[],"text":" in the amygdala and frontal lobes. Overall, there are volumetric changes in ","_key":"db377cc4db685"},{"_key":"db377cc4db686","_type":"span","marks":["b9eb677aeb0e"],"text":"both the amygdala"},{"_key":"db377cc4db687","_type":"span","marks":[],"text":", which react to emotional events, and the frontal lobes, which temper those emotions and help individuals see things in perspective."}]},{"style":"normal","_key":"a0300ccfb78f","markDefs":[],"children":[{"_key":"93a934eb15090","_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:"},{"_type":"span","marks":[],"text":" That sounds like something we could all use.","_key":"93a934eb15091"}],"_type":"block"},{"_key":"c2f1a26e12a2","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN: ","_key":"1642a9ca5c050"},{"_type":"span","marks":[],"text":"Hold it there! This medication is not for everyone, and those imaging studies were done in individuals with bipolar disorder.","_key":"1642a9ca5c051"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"e6fe8654b7a60"},{"_type":"span","marks":[],"text":" Always on your soapbox. 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El-Mallakh, MD","company":"South Haven Community Hospital","biography":[{"children":[{"_key":"132f46f9b7320","_type":"span","marks":["strong"],"text":"Dr El-Mallakh "},{"_type":"span","marks":["em"],"text":"is a professor in the department of psychiatry and behavioral sciences and director of the Mood Disorders Research Program at the University of Louisville School of Medicine in Louisville, Kentucky.","_key":"132f46f9b7321"}],"_type":"block","style":"normal","_key":"5dc1c31b2261","markDefs":[]},{"style":"normal","_key":"9373b1343ba6","markDefs":[],"children":[{"_type":"span","marks":["em"],"text":"Dr El-Mallakh is a speaker for Idorsia, Indivior, Intracellular Therapies, Janssen, Lundbeck, Noven, Otsuka, Sunovion, and Teva.","_key":"ed097f9f38600"}],"_type":"block"}],"_updatedAt":"2024-11-07T19:45:22Z","authorType":"author","_createdAt":"2020-02-21T11:23:21Z"},{"displayName":"Irem Hacisalihoglu Aydin, MD","_createdAt":"2024-11-07T19:45:03Z","_type":"author","biography":[{"_key":"9e5db8aee559","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Dr Aydin ","_key":"b316364e4f270"},{"marks":["em"],"text":"is a postdoctoral researcher atthe University of Louisville School of Medicine in Louisville, Kentucky.","_key":"b316364e4f271","_type":"span"}],"_type":"block","style":"normal"}],"_updatedAt":"2024-11-07T19:49:04Z","url":{"current":"irem-hacisalihoglu-aydin-md","_type":"slug"},"authorType":"author","_rev":"jzkAB1BdluwaE1Zy3g9twT","_id":"909a0325-2846-4633-aadb-0125011977b3"}],"_rev":"GksL79ka788Sw0D3X6K8kZ","_createdAt":"2024-11-07T20:19:04Z","taxonomyMapping":[{"_id":"pst_taxonomy_334_psychiatricemergencies","_updatedAt":"2024-02-21T20:31:39Z","cmeType":"per","parent":{"identifier":"topics","name":"Topics","_id":"pst_taxonomy_53202_clinical","parent":null,"isMainTopic":true,"_createdAt":"2020-03-26T06:11:21Z","_rev":"uvXJooXtzvjNOyx50HTt8m","_type":"taxonomy","_updatedAt":"2023-03-31T19:15:59Z"},"perKeywordMapping":["Psychiatry","Neurology","Emergency Medicine"],"pixelTrackingCode":null,"_rev":"IakUcQKwj7kr3xQjaaRg2s","_type":"taxonomy","ptceKeywordMapping":[""],"_createdAt":"2020-03-26T06:11:21Z","name":"Emergency Psychiatry","identifier":"topics/emergency-psychiatry"},{"_createdAt":"2020-03-26T06:11:21Z","_type":"taxonomy","_id":"pst_taxonomy_336_psychopharmacology","cmeType":"per","parent":{"isMainTopic":true,"name":"Topics","_updatedAt":"2023-03-31T19:15:59Z","identifier":"topics","_rev":"uvXJooXtzvjNOyx50HTt8m","parent":null,"_type":"taxonomy","_id":"pst_taxonomy_53202_clinical","_createdAt":"2020-03-26T06:11:21Z"},"perKeywordMapping":["Psychiatry","Neurology","New Drugs"],"identifier":"topics/psychopharmacology","pixelTrackingCode":null,"_updatedAt":"2023-03-31T19:23:25Z","_rev":"4roekEga8ZReQAdH6zkAp9","name":"Psychopharmacology"},{"identifier":"commentary","_createdAt":"2020-03-26T06:11:21Z","_rev":"CT8kz40NBv9JvHKzAk1arA","_type":"taxonomy","name":"Commentary","_id":"pst_taxonomy_54_commentary","_updatedAt":"2021-10-07T14:44:33Z","parent":null,"pixelTrackingCode":null}],"drugMentions":"{\"drug_mentions\": [\"clozapine\", \"risperidone\", \"olanzapine\", \"haloperidol\", \"asenapine\", \"loxapine\"]}","documentGroupMapping":null,"is_visible":true,"url":"time-to-think-of-aggression-as-a-treatment-target-symptom-independent-of-diagnosis","authors":[{"displayName":"Rif S. El-Mallakh, MD","url":"rif-s-el-mallakh-md"},{"displayName":"Irem Hacisalihoglu Aydin, MD","url":"irem-hacisalihoglu-aydin-md"}],"factCheckAuthors":null,"_updatedAt":"2024-11-07T20:19:10Z","_id":"3a9fff84-ae82-4ae6-b5aa-7f328bc6e781","articleType":"Commentary","summary":"This article explains the role of medications that have high affinity to block dopamine D4. ","_type":"article","title":"Time to Think of Aggression as a Treatment Target Symptom, Independent of Diagnosis ","audioUrl":"https://s3.us-east-1.amazonaws.com/ai-generated-audios/www.psychiatrictimes.com/3a9fff84-ae82-4ae6-b5aa-7f328bc6e781_1731010746370.684642c3-43b6-46b4-acb3-066d5afe590f.mp3","ExcludeFromPubMedXML":false,"body":[{"alt":"aggression","alignment":"left","disableTextWrap":false,"disableLightBox":true,"_type":"figure","widthP":50,"asset":{"_ref":"image-986628c7bb80dae06a08a56503356ed45edbefbb-4017x3734-jpg","_type":"reference"},"imgcaption":[{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Stranger Man/AdobeStock","_key":"097b9710e3660"}],"_type":"block","style":"normal","_key":"ebdae2bada1d"}],"_key":"553149736826"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"COMMENTARY","_key":"1bd9aa3e57d40"}],"_type":"block","style":"normal","_key":"2bb2fd711a7a"},{"style":"normal","_key":"359e59e78751","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Violence and aggression are not diagnostic features of any psychiatric disorder. Nonetheless, many individuals associate these symptoms with mental illness and they are often the precipitant for emergency presentations and hospitalization.","_key":"dd0ee4159d2e0"},{"_type":"span","marks":["superscript"],"text":"1","_key":"25c0df9bfdaf"},{"marks":[],"text":" Additionally, society associates severe mental illness with both aggression and violence, a belief that is reinforced by media, politicians, and others.","_key":"e1bc1b2aa3e9","_type":"span"},{"_type":"span","marks":["superscript"],"text":"2,3","_key":"577c57a62e26"},{"_type":"span","marks":[],"text":" Yet, excluding substance use, the rates of aggression and violence by patients with psychiatric disorders are similar to those occurring in the general population.","_key":"d7edc37d785f"},{"_type":"span","marks":["superscript"],"text":"4","_key":"ebf108e52610"},{"_type":"span","marks":[],"text":" Despite the fact that aggression has not been identified as a symptom of any specific psychiatric disorder, it is still seen as a consequence of associated disorders. Treatment of aggression is currently constrained within treatment of the associated disorder. However, there are sufficient data to suggest that it is reasonable to view aggression itself as a potential target for treatment.","_key":"a52a7879208b"}],"_type":"block"},{"children":[{"_key":"eb0099bdaa3c0","_type":"span","marks":[],"text":""}],"_type":"block","style":"normal","_key":"c2cdffa852f9","markDefs":[]},{"children":[{"marks":["strong"],"text":"Pathophysiology of Aggression","_key":"585c406c944f0","_type":"span"}],"_type":"block","style":"normal","_key":"036d61e37567","markDefs":[]},{"style":"normal","_key":"356f2dbed995","markDefs":[{"href":"https://www.psychiatrictimes.com/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2Faa3baeda4703fa036fd74a42fbc01ad86c954b02-940x410.png%3Ffit%3Dcrop%26auto%3Dformat\u0026w=1920\u0026q=75","_key":"72ecb582670c","nofollow":true,"blank":true,"_type":"link"}],"children":[{"_type":"span","marks":[],"text":"Several studies have attempted to discern the physiologic congenators of aggression. While there are many findings, most are probably associations rather than causative. The most reproducible and important of these studies have been associations of polymorphisms of the dopamine D4 receptor with aggression.","_key":"7009282786920"},{"_type":"span","marks":["superscript"],"text":"5","_key":"040930df2173"},{"text":" ","_key":"74d5ecd0f6db","_type":"span","marks":[]},{"marks":["em"],"text":"DRD4 ","_key":"7009282786921","_type":"span"},{"_type":"span","marks":[],"text":"is the gene that codes for the dopamine D4 receptor. It is found on the short arm of the 11th chromosome. Stimulation of D4 activates the inhibitory G protein second messenger system (Gai) and inhibits cyclic adenosine monophosphate (cAMP) formation.","_key":"7009282786922"},{"_type":"span","marks":["superscript"],"text":"6","_key":"2e2693881529"},{"_type":"span","marks":[],"text":" D4 is expressed in the frontal cortex, where it is much more common than the D2 receptor,","_key":"86a4d37560fb"},{"marks":["superscript"],"text":"7","_key":"60fe3483c239","_type":"span"},{"_type":"span","marks":[],"text":" as well as in the thalamus, hypothalamus, and olfactory bulb.","_key":"22d3658ad558"},{"_type":"span","marks":["superscript"],"text":"8 ","_key":"c0b3bfe55a52"},{"_type":"span","marks":[],"text":"The ","_key":"e53036559eef"},{"text":"DRD4","_key":"7009282786923","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":" gene has a polymorphic third exon. This part of the gene codes for the third cytoplasmic loop of the protein, which interacts with the Gai second messenger.","_key":"7009282786924"},{"marks":["superscript"],"text":"9","_key":"d84c18b89fd3","_type":"span"},{"_type":"span","marks":[],"text":" The polymorphism presents as variable number of repeats within this 48 base pair section. In the population, the number of repeats varies between 2 and 11 times. A common variant is the seven-repeat allele (7R), which is best known for its association with attention-deficit/hyperactivity disorder.","_key":"bdaf35246202"},{"_type":"span","marks":["superscript"],"text":"10-13 ","_key":"2b9a4c1c53b8"},{"_type":"span","marks":[],"text":"But it has also been associated with novelty seeking,","_key":"0bdff740d307"},{"_type":"span","marks":["superscript"],"text":"14-17","_key":"bb2f4480568d"},{"marks":[],"text":" impulsivity,","_key":"97c46314e1f9","_type":"span"},{"_type":"span","marks":["superscript"],"text":"15,18","_key":"802612b52b08"},{"_type":"span","marks":[],"text":" anger,","_key":"36f01763f485"},{"marks":["superscript"],"text":"16","_key":"ab0f4ac073c9","_type":"span"},{"_type":"span","marks":[],"text":" and aggression.","_key":"12178903b2a6"},{"_type":"span","marks":["superscript"],"text":"19","_key":"c652737ed2ff"},{"_type":"span","marks":[],"text":" This association gains importance when one becomes aware that D4 antagonists with high affinity that exceeds affinity for D2 by the same drug have significant anti-aggression properties.","_key":"479771dc29fb"},{"_type":"span","marks":["superscript"],"text":"5","_key":"c3c78359c986"},{"marks":[],"text":" The ","_key":"0cf83948b081","_type":"span"},{"_type":"span","marks":["strong","72ecb582670c"],"text":"Table","_key":"7009282786925"},{"_type":"span","marks":["strong"],"text":" ","_key":"f62db6398269"},{"marks":[],"text":"summarizes the affinities, expressed as dissociation constants (Ki), of several antipsychotics.","_key":"7009282786926","_type":"span"},{"_type":"span","marks":["superscript"],"text":"20-22","_key":"5d9ba87e2454"},{"_type":"span","marks":[],"text":" In general, while second-generation antipsychotics have been described to have greater affinity for D4 than D2, that is generally not true.","_key":"de1efa2ff898"},{"_type":"span","marks":["superscript"],"text":"23 ","_key":"ee21b11430d3"}],"_type":"block"},{"disableTextWrap":false,"disableLightBox":true,"_key":"a16d70deb086","alt":"Table. The Affinity, Expressed as the Dissociation Constant (Ki) for a Selected Group of Second-Generation Antipsychotics","asset":{"_ref":"image-aa3baeda4703fa036fd74a42fbc01ad86c954b02-940x410-png","_type":"reference"},"widthP":50,"blank":true,"_type":"figure","imgcaption":[{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Table. The Affinity, Expressed as the Dissociation Constant (Ki) for a Selected Group of Second-Generation Antipsychotics","_key":"4b30705771d60"},{"_type":"span","marks":["strong","superscript"],"text":"20-22","_key":"651e28ab15e0"}],"_type":"block","style":"normal","_key":"cf6ed237bd1e"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"587b459e53130"}],"_type":"block","style":"normal","_key":"fdb040a815aa"},{"children":[{"marks":[],"text":"The D4/D2 affinity ratio is calculated as the ratio of the inverse of the Ki.","_key":"34df90fef6fe0","_type":"span"}],"_type":"block","style":"normal","_key":"0440763a1b94","markDefs":[]},{"_key":"cfa70480d8eb","markDefs":[],"children":[{"marks":[],"text":"*Note since affinity increases as Ki decreases, the D4/D2 ratio is actually the ratio of (1/Ki/(1/Ki)","_key":"abed9c99ef190","_type":"span"}],"_type":"block","style":"normal"}],"alignment":"right"},{"children":[{"_type":"span","marks":["strong"],"text":"Anti-Aggression Agents","_key":"2551522321f20"}],"_type":"block","style":"normal","_key":"7d160da85dad","markDefs":[]},{"_key":"d87b487caeda","markDefs":[],"children":[{"_key":"4f1ea9f10ba90","_type":"span","marks":[],"text":"The most effective anti-aggression agent available is clozapine."},{"_type":"span","marks":["superscript"],"text":"24","_key":"ade4c0529363"},{"_type":"span","marks":[],"text":" This has been repeatedly demonstrated in open studies","_key":"64082846094b"},{"_type":"span","marks":["superscript"],"text":"25-28","_key":"898949e05976"},{"_type":"span","marks":[],"text":" as well as in randomized trials.","_key":"06ea4860a679"},{"_type":"span","marks":["superscript"],"text":"29-31","_key":"3a21c8a89898"},{"text":" In the blinded, randomized studies, clozapine was superior to risperidone, olanzapine, and haloperidol. Specifically, the likelihood for aggressive behaviors after study entry was significantly lower for clozapine (17.5%) vs olanzapine (23.1%), risperidone 24.4%, and haloperidol (45.9%).","_key":"df784edae84d","_type":"span","marks":[]},{"text":"29","_key":"573babd98c86","_type":"span","marks":["superscript"]},{"text":" Measured aggression was significantly less likely to happen with clozapine than haloperidol (physical aggression: odds ration [OR] = 2.04, ","_key":"d8d825f0d457","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba91"},{"_key":"4f1ea9f10ba92","_type":"span","marks":[],"text":" \u003c 0.001, aggression against property: OR = 1.85, "},{"_type":"span","marks":["em"],"text":"P ","_key":"4f1ea9f10ba93"},{"_type":"span","marks":[],"text":"\u003c 0.001, and verbal aggression: OR = 1.35, ","_key":"4f1ea9f10ba94"},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba95"},{"_type":"span","marks":[],"text":" \u003c 0.001), and olanzapine (physical aggression: OR = 1.33, ","_key":"4f1ea9f10ba96"},{"marks":["em"],"text":"P","_key":"4f1ea9f10ba97","_type":"span"},{"_type":"span","marks":[],"text":" \u003c 0.001, and verbal aggression: OR = 1.32, ","_key":"4f1ea9f10ba98"},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba99"},{"_type":"span","marks":[],"text":" \u003c 0.001, but not aggression against property: OR = 1.10, ","_key":"4f1ea9f10ba910"},{"text":"P","_key":"4f1ea9f10ba911","_type":"span","marks":["em"]},{"text":" = 0.78) (risperidone not examined in this study).","_key":"4f1ea9f10ba912","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"31","_key":"c0c11ee63496"},{"_type":"span","marks":[],"text":" In this same study, olanzapine was also superior to haloperidol (physical aggression: OR = 1.54, ","_key":"d9e725babbc5"},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba913"},{"text":" \u003c 0.001, aggression against property: OR 1.67, ","_key":"4f1ea9f10ba914","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba915"},{"text":" \u003c 0.001, but not verbal aggression: OR = 1.03, ","_key":"4f1ea9f10ba916","_type":"span","marks":[]},{"text":"P","_key":"4f1ea9f10ba917","_type":"span","marks":["em"]},{"text":" = 0.57).","_key":"4f1ea9f10ba918","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"31","_key":"afd58930ab29"},{"_type":"span","marks":[],"text":" In a comparative study that examined the hostility items of the Positive and Negative Syndrome Scale (PANNS), clozapine was the only agent that significantly reduced measured hostility vs baseline (","_key":"d9c34dad3298"},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba919"},{"text":" = 0.019) and was superior to risperidone (","_key":"4f1ea9f10ba920","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba921"},{"_key":"4f1ea9f10ba922","_type":"span","marks":[],"text":" = 0.012) and haloperidol ("},{"marks":["em"],"text":"P","_key":"4f1ea9f10ba923","_type":"span"},{"_type":"span","marks":[],"text":" = 0.021) but not olanzapine.","_key":"4f1ea9f10ba924"},{"text":"30","_key":"eb78d086bbbb","_type":"span","marks":["superscript"]},{"marks":[],"text":" More importantly, this effect occurred at therapeutic dosageand was independent of clozapine’s antipsychotic effect or the occurrence of sedation.","_key":"88b5453583d6","_type":"span"},{"_type":"span","marks":["superscript"],"text":"25,30,31","_key":"ad512761051c"},{"_type":"span","marks":[],"text":" Clozapine is also effective in a genetic animal model of a developmental disorder (immediate early gene transcription factor, ","_key":"3cbb21b2832c"},{"_key":"4f1ea9f10ba925","_type":"span","marks":["em"],"text":"Egr3"},{"_type":"span","marks":[],"text":", knockout) in which the animals become aggressive.","_key":"4f1ea9f10ba926"},{"text":"32","_key":"6be8888079fe","_type":"span","marks":["superscript"]}],"_type":"block","style":"normal"},{"_key":"00d4ce674333","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"3d3a97be187f0"}],"_type":"block","style":"normal"},{"_key":"42f4f44e7388","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Similarly, asenapine has also demonstrated anti-aggression effects in a prospective study comparing asenapine with treatment as usual (TAU) for 48 patients who were admitted with significant aggression.","_key":"ba7b7c46b2d00"},{"_type":"span","marks":["superscript"],"text":"33","_key":"3918cb318c12"},{"_type":"span","marks":[],"text":" Asenapine was superior to TAU as measured by the Modified Overt Aggression Scale [MOAS]). There was a significant reduction physical aggression (–8.0 ± 5.06 vs. –0.78 ± 2.40, ","_key":"d73f8e497c24"},{"_type":"span","marks":["em"],"text":"P","_key":"ba7b7c46b2d01"},{"_type":"span","marks":[],"text":" \u003c 0.0001), and total (–14.7 ± 11.59 vs. –5.4 ± 10.12, ","_key":"ba7b7c46b2d02"},{"_type":"span","marks":["em"],"text":"P","_key":"ba7b7c46b2d03"},{"_key":"ba7b7c46b2d04","_type":"span","marks":[],"text":" = 0.045) aggression as measured by the MOAS.33 More recently, a post hoc analysis of hostility in 442 patients with schizophrenia treated with a transdermal formulation of asenapine found that hostility item improved independent of antipsychotic effect and after correcting for covariates, indicating that the antihostility effect is independent of the antipsychotic effect."},{"_type":"span","marks":["superscript"],"text":"34","_key":"ab7135cee003"},{"marks":[],"text":" Sublingual asenapine has also demonstrated significant reductions in hostility, irritability, and disruptive behavior vs placebo in participants experiencing acute mania.","_key":"2df48b7fdf2b","_type":"span"},{"_type":"span","marks":["superscript"],"text":"35","_key":"154ff70deda8"},{"_type":"span","marks":[],"text":" Asenapine may be effective quickly and in a randomized, placebo-controlled study of agitation in a mixed diagnosis sample (schizophrenia, bipolar disorder, major depressive disorder, anxiety, and posttraumatic stress disorder) it significantly reduced the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC).","_key":"f2e7651e8fca"},{"_key":"11e45dfdba77","_type":"span","marks":["superscript"],"text":"36"},{"_key":"4bb32e731f21","_type":"span","marks":[],"text":" Adequate D4 blockade and the anti-aggression effect is likely achieved at 5 mg daily, whereas the minimum antipsychotic dose is 10 mg daily, and it is believed that aggression should improve at 5 mg."},{"marks":["superscript"],"text":"5","_key":"3ec839083c13","_type":"span"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_key":"3eea52006e950","_type":"span","marks":[],"text":""}],"_type":"block","style":"normal","_key":"08bf5f62a753"},{"style":"normal","_key":"6ba79cdf17c8","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Loxapine is a second-generation antipsychotic agent that was not identified as such prior to the introduction of clozapine.","_key":"b330f94e53490"},{"_type":"span","marks":["superscript"],"text":"37","_key":"bc4d83e703e2"},{"text":" It has a long history of treating aggression, hostility, and agitation in patients with bipolar disorder and schizophrenia experiencing acute mania and psychosis with both injectable","_key":"76a76069f4bc","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"38-40","_key":"2d0982906700"},{"_type":"span","marks":[],"text":" and inhalable formulations.","_key":"7e867f011f2e"},{"marks":["superscript"],"text":"41-43","_key":"69daa13d0c7c","_type":"span"},{"_type":"span","marks":[],"text":" Significantly, the effect on reducing aggression in agitated patients appears to occur independent of diagnosis.","_key":"3f6b315fac71"},{"_type":"span","marks":["superscript"],"text":"44","_key":"672477566378"},{"marks":[],"text":" Receptor occupancy is generally poorly studied in older medications, but the antipsychotic effect (ie, D2 receptor occupancy of 60% to 80%) probably occurs at 15 to 30 mg daily,","_key":"3051c231ba46","_type":"span"},{"_type":"span","marks":["superscript"],"text":"45","_key":"e20ed29c7dbc"},{"_key":"d989c3c10ffe","_type":"span","marks":[],"text":" and since the affinity at D4 is 3 times greater than at D2, one would expect that doses as low as 10 mg daily may be effective for aggression control."}],"_type":"block"},{"children":[{"text":"","_key":"e8d20c8ff0b60","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"f5ed401d5cda","markDefs":[]},{"style":"normal","_key":"832d49c169d7","markDefs":[{"_type":"link","href":"https://www.psychiatrictimes.com/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2Faa3baeda4703fa036fd74a42fbc01ad86c954b02-940x410.png%3Ffit%3Dcrop%26auto%3Dformat\u0026w=1920\u0026q=75","_key":"80bb7ee11446","nofollow":true,"blank":true},{"blank":true,"_type":"link","href":"https://www.psychiatrictimes.com/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2Faa3baeda4703fa036fd74a42fbc01ad86c954b02-940x410.png%3Ffit%3Dcrop%26auto%3Dformat\u0026w=1920\u0026q=75","_key":"57e734fa5f24","nofollow":true}],"children":[{"_type":"span","marks":[],"text":"Olanzapine and risperidone also have D4 affinities that exceeds D2 affinities (","_key":"b34326e935c90"},{"_key":"b34326e935c91","_type":"span","marks":["strong","57e734fa5f24"],"text":"Table"},{"_type":"span","marks":[],"text":").","_key":"b34326e935c92"},{"_type":"span","marks":["superscript"],"text":"20-22","_key":"329b377ebcc4"},{"_key":"afa2ed6dfb4f","_type":"span","marks":[],"text":" The difference is small but similar to asenapine ("},{"_key":"b34326e935c93","_type":"span","marks":["strong","80bb7ee11446"],"text":"Table"},{"_type":"span","marks":[],"text":").","_key":"b34326e935c94"},{"text":"20-22","_key":"4bdeee6e8eaa","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" For all 3 agents, it is likely that both receptors are blocked at doses that are frequently used. All these agents are frequently used in aggression because the drugs are approved for use in a wide range of psychiatric disorders. While asenapine has not been compared with clozapine, clozapine appears to be superior to both olanzapine and risperidone. Furthermore, reduction in aggression with olanzapine and risperidone appears to be related to their antipsychotic effect,","_key":"2d8e9cb2c0a2"},{"_type":"span","marks":["superscript"],"text":"29","_key":"e99a75e2e4fc"},{"_key":"4a04c7674cad","_type":"span","marks":[],"text":" which does not appear to be the case for clozapine."},{"_type":"span","marks":["superscript"],"text":"29-31","_key":"3d2987dfd041"}],"_type":"block"},{"style":"normal","_key":"7367d4649dd6","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"c8dd077e91130"}],"_type":"block"},{"_key":"c7fa69c0b548","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Some of these agents have affinity to D4 that exceeds the affinity for D2 (ie, affinity D4/affinity D2 \u003e 1).","_key":"cbd4828d00240"},{"_type":"span","marks":["superscript"],"text":"5","_key":"3e9c6be2d1be"},{"_type":"span","marks":[],"text":" Clozapine clearly has the best data and is likely superior to other agents.It is superior to risperidone, olanzapine, and haloperidol. It would appear that when a patient presents with aggression as an important symptom, targeting that symptom may have a greater impact than treating the underlying disease.","_key":"237e30e40ea7"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"fa4c62ae007a0"}],"_type":"block","style":"normal","_key":"bcbb3c6a0f0e"},{"style":"normal","_key":"6f448b703d60","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Concluding Thoughts","_key":"beaa12fcd04d0"}],"_type":"block"},{"style":"normal","_key":"5f2dc8c24cae","markDefs":[],"children":[{"_type":"span","marks":[],"text":"When aggression is the predominant clinical target symptom, agents with greater affinity to the D4 receptor vs the D2 receptor may be preferred. Clozapine, which has the greatest difference between the affinity to these 2 receptors, has been found to be superior in head-to-head studies. Furthermore, it appears that the efficacy of antipsychotic agents for aggression is related to the D4/D2 ratio, although the data are not adequate to be certain of this last point.","_key":"d75486bb76970"}],"_type":"block"},{"style":"normal","_key":"9d7f365ba966","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"85bc489e03f40"}],"_type":"block"},{"_type":"block","style":"normal","_key":"b5e231a22dbf","markDefs":[],"children":[{"marks":[],"text":"Aggression that occurs in patients with psychiatric disorders may frequently fuel psychiatric presentation to either the emergency or inpatient setting. Clinicians tend to choose treatments based on the diagnosis. However, if aggression is a major issue, it may be reasonable to choose a treatment that has demonstrated efficacy to address aggression. The availability of agents that have demonstrated efficacy in aggression should be considered when choosing treatments for patients who present with aggression as a primary symptom.","_key":"afd045c64f0c0","_type":"span"}]},{"_type":"block","style":"normal","_key":"4edb09e6a7cf","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"754427ff02c70"}]},{"_key":"6c473f05afcb","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Dr El-Mallakh ","_key":"90a97cfe5fe10"},{"marks":["em"],"text":"is a professor in the department of psychiatry and behavioral sciences and director of the Mood Disorders Research Program at the University of Louisville School of Medicine in Louisville, Kentucky. ","_key":"90a97cfe5fe11","_type":"span"},{"_type":"span","marks":["strong"],"text":"Dr Aydin ","_key":"90a97cfe5fe12"},{"text":"is a postdoctoral researcher at","_key":"90a97cfe5fe13","_type":"span","marks":["em"]},{"text":" ","_key":"90a97cfe5fe14","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"the University of Louisville School of Medicine in Louisville, Kentucky.","_key":"90a97cfe5fe15"}],"_type":"block","style":"normal"},{"style":"normal","_key":"04a830889b15","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"c87820cb47a50"}],"_type":"block"},{"style":"normal","_key":"1af9e1ae593e","markDefs":[],"children":[{"text":"References","_key":"3a0e0ca00ab70","_type":"span","marks":["strong"]}],"_type":"block"},{"markDefs":[{"_type":"link","href":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783168/","_key":"ac68ff4a2c04","blank":true}],"children":[{"_type":"span","marks":[],"text":"1. Girasek H, Nagy VA, Fekete S, et al. 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","_key":"413b6a4bf0bc0","_type":"span","marks":[]},{"_type":"span","marks":["a7b313a71e53"],"text":"Multiple dopamine D4 receptor variants in the human population.","_key":"413b6a4bf0bc1"},{"_type":"span","marks":[],"text":" ","_key":"be3c9d9738cd"},{"_type":"span","marks":["em"],"text":"Nature","_key":"413b6a4bf0bc2"},{"_type":"span","marks":[],"text":". 1992;358(6382):149-52.","_key":"413b6a4bf0bc3"}],"_type":"block"},{"children":[{"_type":"span","marks":[],"text":"10. Ding YC, Chi HC, Grady DL, et al. 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","_key":"8c637a27e8bd0","_type":"span","marks":[]},{"marks":["fb0b7a074ac0"],"text":"High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder.","_key":"8c637a27e8bd1","_type":"span"},{"_key":"23e2ec7dd732","_type":"span","marks":[],"text":" "},{"_type":"span","marks":["em"],"text":"Mol Psychiatry","_key":"8c637a27e8bd2"},{"text":". 2003;8(5):536-545.","_key":"8c637a27e8bd3","_type":"span","marks":[]}],"_type":"block"},{"markDefs":[{"blank":true,"_type":"link","href":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894686/","_key":"70b960728a02"}],"children":[{"_type":"span","marks":[],"text":"12. Nikolaidis A, Gray JR. 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Searching for an effect of allelic heterogeneity."},{"_key":"173ab7c4e6f7","_type":"span","marks":[],"text":" "},{"_type":"span","marks":["em"],"text":"Mol Psychiatry","_key":"25ec796c65372"},{"marks":[],"text":". 2012;17(5):520-526.","_key":"25ec796c65373","_type":"span"}],"_type":"block","style":"normal","_key":"331e4fd94e98","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/21403674/","_key":"e4e91d25b06d"}]},{"markDefs":[{"href":"https://pubmed.ncbi.nlm.nih.gov/15517431/","_key":"cb49150ff2e3","blank":true,"_type":"link"}],"children":[{"_type":"span","marks":[],"text":"14. Becker K, Laucht M, El-Faddagh M, Schmidt MH. ","_key":"4d73b2444f030"},{"_type":"span","marks":["cb49150ff2e3"],"text":"The dopamine D4 receptor gene exon III polymorphism is associated with novelty seeking in 15-year-old males from a high-risk community sample.","_key":"4d73b2444f031"},{"marks":[],"text":" ","_key":"4d73b2444f032","_type":"span"},{"_type":"span","marks":["em"],"text":"J Neural Transm","_key":"4d73b2444f033"},{"_type":"span","marks":[],"text":". 2005;112(6):847-858.","_key":"4d73b2444f034"}],"_type":"block","style":"normal","_key":"758584875c62"},{"children":[{"_type":"span","marks":[],"text":"15. Zalsman G, Frisch A, Lewis R, et al. ","_key":"ea2815e5139f0"},{"text":"DRD4 receptor gene exon III polymorphism in inpatient suicidal adolescents.","_key":"ea2815e5139f1","_type":"span","marks":["4b9b166f998a"]},{"_key":"09796b44997f","_type":"span","marks":[],"text":" "},{"_type":"span","marks":["em"],"text":"J Neural Transm (Vienna).","_key":"ea2815e5139f2"},{"marks":[],"text":" 2004;111(12):1593-1603.","_key":"ea2815e5139f3","_type":"span"}],"_type":"block","style":"normal","_key":"76f41e687cde","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/15565493/","_key":"4b9b166f998a"}]},{"children":[{"_type":"span","marks":[],"text":"16. Dmitrieva J, Chen C, Greenberger E, et al. ","_key":"c08b630faee20"},{"_type":"span","marks":["89ab1a87c59d"],"text":"Gender-specific expression of the DRD4 gene on adolescent delinquency, anger and thrill seeking.","_key":"c08b630faee21"},{"_key":"c08b630faee22","_type":"span","marks":[],"text":" "},{"_key":"c08b630faee23","_type":"span","marks":["em"],"text":"Soc Cognitive Affective Neurosci"},{"_type":"span","marks":[],"text":". 2011;6(1):82-89.","_key":"c08b630faee24"}],"_type":"block","style":"normal","_key":"2de4432332b9","markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/20203140/","_key":"89ab1a87c59d"}]},{"markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/21469077/","_key":"3182ed727d67"}],"children":[{"_type":"span","marks":[],"text":"17. Matthews LJ, Butler PM. ","_key":"eb968bd7a48b0"},{"text":"Novelty-seeking DRD4 polymorphisms are associated with human migration distance out-of-Africa after controlling for neutral population gene structure.","_key":"eb968bd7a48b1","_type":"span","marks":["3182ed727d67"]},{"text":" ","_key":"eb968bd7a48b2","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"Am J Phys Anthropol","_key":"eb968bd7a48b3"},{"_type":"span","marks":[],"text":". 2011;145(3):382-389.","_key":"eb968bd7a48b4"}],"_type":"block","style":"normal","_key":"17df432c9b44"},{"_type":"block","style":"normal","_key":"ff44cb4eccd8","markDefs":[{"href":"https://pubmed.ncbi.nlm.nih.gov/10402503/","_key":"7e4f5462a252","blank":true,"_type":"link"}],"children":[{"_type":"span","marks":[],"text":"18. Comings DE, Gonzalez N, Wu S, et al. 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I believe that for the most part, psychiatrists utilizing KAP come to the practice with curiosity and determination to try to help our patients who struggle chronically and who have, in most cases, tried myriad other pharmacological and sometimes interventional alternatives. I worked as a psychiatrist for over a decade before exploring this treatment modality.","_key":"008c6b6045cb0","_type":"span"}],"_type":"block","style":"normal"},{"style":"normal","_key":"81864f23321f","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"a79a204769900"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"I was trained in KAP in 2020 and entered the training (a 5-day in-person retreat with didactic and experiential components) with a healthy dose of skepticism; even after training, it took me several months to conclude that I wanted to give this a try in my own practice. Almost 4 years later, I can say I am glad I went there. 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The biggest hurdle here is affordability; like Dr Miller I sit with my patients for the 3-hour sessions and most insurance companies will only reimburse very minimally, if at all, for this non-FDA approved version of ketamine treatment.","_key":"e18ea87281482","_type":"span","marks":[]}]},{"children":[{"_type":"span","marks":[],"text":"","_key":"f47d34dd24e10"}],"_type":"block","style":"normal","_key":"ec856d2055bf","markDefs":[]},{"markDefs":[],"children":[{"text":"The views and practices expressed in these commentaries are solely those of the author and do not necessarily represent the position of Psychiatric Times or its editors.","_key":"5b0e010e1b6c0","_type":"span","marks":["em"]}],"_type":"block","style":"normal","_key":"2cad8054ab39"},{"style":"normal","_key":"2c7ad0272cfe","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"ed23301d664d0"}],"_type":"block"},{"_key":"4df0bab96fcf","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Dr Schultz 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