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self-start">Author(s):</p><div class="flex flex-col xs:flex-row mb-3 md:mb-0"><div class="flex flex-wrap"><span class="text-md mr-2"><a class="text-author text-gray-500 hover:text-primary underline hover:no-underline decoration-gray-400" href="/authors/vania-modesto-lowe-md-mph">Vania Modesto-Lowe, MD, MPH</a><span class="mx-1">,</span></span><span class="text-md mr-2"><a class="text-author text-gray-500 hover:text-primary underline hover:no-underline decoration-gray-400" href="/authors/roberto-leon-barriera-md">Roberto León-Barriera, MD</a></span></div><button class="text-xs text-gray-500 flex items-center mt-2 xs:mt-0 xs:ml-2">+1 More<span class="ml-1"><svg stroke="currentColor" fill="currentColor" stroke-width="0" viewBox="0 0 512 512" height="1em" width="1em" xmlns="http://www.w3.org/2000/svg"><path d="M256 294.1L383 167c9.4-9.4 24.6-9.4 33.9 0s9.3 24.6 0 34L273 345c-9.1 9.1-23.7 9.3-33.1.7L95 201.1c-4.7-4.7-7-10.9-7-17s2.3-12.3 7-17c9.4-9.4 24.6-9.4 33.9 0l127.1 127z"></path></svg></span></button></div></div><div class="max-w-full"><div class="flex flex-wrap sm:flex-nowrap items-center w-fit "></div><div class="w-full flex flex-col sm:flex-row justify-between mt-2"><div class="block md:hidden "><div class="mt-2 flex items-center max-w-fit"><button title="“Happy Accidents”: Repurposing Metformin" aria-label="facebook" 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="#3b5998"></circle><path d="M34.1,47V33.3h4.6l0.7-5.3h-5.3v-3.4c0-1.5,0.4-2.6,2.6-2.6l2.8,0v-4.8c-0.5-0.1-2.2-0.2-4.1-0.2 c-4.1,0-6.9,2.5-6.9,7V28H24v5.3h4.6V47H34.1z" fill="white"></path></svg></button><button aria-label="twitter" class="react-share__ShareButton" style="background-color:transparent;border:none;padding:0;font:inherit;color:inherit;cursor:pointer"><svg fill="#DC7633" xmlns="http://www.w3.org/2000/svg" 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!important; box-shadow: 0px 0px 2px 2px rgba(0,0,0,0.1); } .rhap_progress-section { width: 150px; margin-left: 35px; } .rhap_controls-section { position: relative; bottom: .75rem; } .rhap_time { font-size: 12px; color: rgb(0,55,103); } .rhap_progress-bar { color: rgb(0,55,103) !important; } .rhap_progress-filled { background-color: rgb(0,55,103) !important; } .rhap_progress-indicator { height: 15px; width: 5px; top: -5px; margin-left: 1px; background-color: rgb(0,55,103) !important; } .rhap_repeat-button { display: none; } .rhap_volume-bar, rhap_volume-button, .rhap_volume-indicator { background: rgb(0,55,103) !important; } .rhap_volume-bar { height: 2px; width: 35px; position: relative; left: 22px; bottom: 21px; } .rhap_volume-button { // width: 5px; // height: 5px; flex: 0 0 26px; position: relative; left: 22px; bottom: 21px; } .rhap_volume-button svg { height: 18px; width: 18px; } .rhap_volume-indicator { height: 8px; width: 8px; top: -2.75px } .rhap_button-clear { color: rgb(0,55,103) !important; } .rhap_play-pause-button { color: rgb(0,55,103) !important; font-size: 30px !important; width: 30px !important; height: 30px !important; position: relative; right: 90px; bottom: 22px; } .rhap_main-controls button { color: rgb(0,55,103) !important; } audio::-webkit-media-controls-play-button, video::-webkit-media-controls-play-button { -webkit-appearance: media-play-button; color: #b8dcf6; } audio::-webkit-media-controls-panel { background-color: white !important; color: #000; } audio::-webkit-media-controls-current-time-display, audio::-webkit-media-controls-time-remaining-display { font-size: 12px; } </style></div></div></div><div class=" lg:w-full flex flex-col lg:flex-row lg:items-center lg:justify-end"></div><div class="w-full flex flex-col px-4 py-4 border-t border-b border-solid border-gray-400 my-4 "><h3 class="text-primary text-xl font-semibold">Key Takeaways</h3><ul class="list-disc px-8"><li class="py-2 "> Metformin is being investigated for anti-aging benefits, potentially reducing age-related diseases by influencing cellular mechanisms like inflammation and oxidative stress. </li><li class="py-2 "> It may improve gut microbiota composition, enhancing glucose homeostasis and reducing inflammation, contributing to its potential geroprotective effects. </li><li class="py-2 hidden"> Despite promising preclinical and observational data, metformin's anti-aging effects remain investigational, with ongoing studies like the TAME trial seeking to clarify its impact.</li></ul><span class="text-xs font-bold text-primary underline cursor-pointer mt-2 ml-4">SHOW MORE</span></div><p class="py-2 mb-2 text-sm italic text-gray-600">There is an accumulating body of evidence that metformin may have benefits in aging beyond its effect on glycemic control.</p><div class="py-2"><div class="blockText_blockContent__TbCXh"><div class=""><div style="width:50%;float:left;max-width:525px;margin:0 1.5rem 1.5rem 0;clear:both;cursor:" 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=%272048%27%20height=%272048%27/%3e"/></span><img alt="metformin" title="metformin" 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="metformin" title="metformin" srcSet="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2Fe043699441b7cb5a79c8ffaaeb75a30836c12c9d-2048x2048.jpg%3Ffit%3Dcrop%26auto%3Dformat&w=2048&q=75 1x, /_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2Fe043699441b7cb5a79c8ffaaeb75a30836c12c9d-2048x2048.jpg%3Ffit%3Dcrop%26auto%3Dformat&w=3840&q=75 2x" src="/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2Fe043699441b7cb5a79c8ffaaeb75a30836c12c9d-2048x2048.jpg%3Ffit%3Dcrop%26auto%3Dformat&w=3840&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 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/e043699441b7cb5a79c8ffaaeb75a30836c12c9d-2048x2048.jpg?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">A recent article on the multiple uses of metformin brings up the important topic of repurposing medications.<sup class="text-inherit">1</sup> Repurposing has been around since the advent of modern medicine. One prominent example is the use of chlorpromazine (CPZ) as an antipsychotic.<sup class="text-inherit">2</sup> Chlorpromazine was first synthesized in 1951 as a potentiator of general anesthesia.<sup class="text-inherit">2</sup> The psychiatric benefits were found later by Henri Laborit, a surgeon in the French army, who was doing research with artificial hibernation in the prevention of surgical shock. Laborit employed CPZ as an adjunct to anesthetics. He observed that CPZ at doses of 50 mg to 100 mg produced a lowering of body temperature, sedation, and disinterest without loss of consciousness. He was able to persuade his colleagues in the military hospital in Paris, France, to try CPZ in the treatment of a patient who was experiencing psychotic agitation. The mechanism of action was not fully known, and it was thought that it worked in controlling agitation because of its cooling effect and induction of artificial hibernation in patients.<sup class="text-inherit">2</sup> The pharmacological mechanism was not fully understood until many years later, and the way it has impacted the practice of psychiatry needs no introduction.</p><p class="pb-2">These happy accidents in medicine have played a vital role in getting where we are right now in patient care compared with just 50 years ago. This begs the question, are we onto another happy accident with metformin? There is an accumulating body of evidence that metformin may have benefits in aging beyond its effect on glycemic control.<sup class="text-inherit">3</sup></p><p class="pb-2"><strong>Repurposing Metformin</strong></p><p class="pb-2">Metformin is endorsed by the American Diabetes Association and the European Association for the Study of Diabetes as initial therapy for patients with type 2 diabetes (T2D), and it is one of the most prescribed antidiabetic medications worldwide.<sup class="text-inherit">4</sup> It is widely recognized that metformin improves hyperglycemia and insulin sensitivity.<sup class="text-inherit">4</sup> Recently, the observation that metformin decreased the development of certain age-associated pathology in individuals with and without diabetes has garnered attention.<sup class="text-inherit">3</sup> Aging refers to the time-dependent physiological loss of cellular integrity<sup class="text-inherit">5</sup> and is associated with T2D, dementia, cancer, and cardiovascular disease.<sup class="text-inherit">6</sup> The United Kingdom Prospective Diabetes Study has shown that metformin is associated with a lower all-cause mortality rate in patients with diabetes.<sup class="text-inherit">7</sup> This study was a 20-year randomized multicenter longitudinal study, and researchers found cardiovascular benefits of metformin in patients with diabetes.<sup class="text-inherit">7</sup> Similarly, a systematic review of 53 studies showed that metformin use resulted in a decrease in all-cause mortality linked with aging-related diseases such as cancer and cardiovascular disease.<sup class="text-inherit">8</sup> As the aging population grows and life expectancy increases, we are searching for ways to maintain quality of life for as long as possible.</p><p class="pb-2">In the US, advances in health care and public health have afforded increases in life expectancy.<sup class="text-inherit">5</sup> Unfortunately, this longevity has been accompanied by an increase in the incidence of age-related diseases, which leads to a decreased quality of life.<sup class="text-inherit">5</sup> Health span refers to the life period in which one is healthy and free from chronic illness and aging-related dysfunction; it serves as a proxy for quality of life during the older years.<sup class="text-inherit">6</sup> There is a pressing need for interventions that can delay age-associated diseases and improve health span. Preclinical data indicate that metformin may influence cellular mechanisms associated with aging, including inflammation, oxidative stress, cell senescence, and autophagy.<sup class="text-inherit">3,5</sup> Of note, metformin mimics the metabolic actions of caloric restriction, which is a recognized strategy to prolong health and life span in mammals.<sup class="text-inherit">9</sup> Metformin may also mimic the geroprotective effects of exercise.<sup class="text-inherit">5</sup> Since metformin is inexpensive and offers a good tolerability and safety profile, it is attractive as a focus of antiaging research.<sup class="text-inherit">3</sup></p><p class="pb-2"><strong>Reducing Inflammation</strong></p><p class="pb-2">As early as 1907, Élie Metchnikoff theorized that cell senescence resulted from chronic systemic inflammation due to increased permeability in the colon, and the escape of bacteria and their toxic metabolites into the systemic circulation.10 Accordingly, these toxic bacterial products activated phagocytes and an inflammatory response that led to death of adjacent tissues.<sup class="text-inherit">11</sup> Interestingly, more than a century later, aging is thought to be associated with a persistent low-grade inflammation, referred to as <em>inflammaging</em>, that originates in the gut.<sup class="text-inherit">11</sup> We now know that the intestinal mucosal layer is a key modulator of inflammatory responses, protecting against invasion of dietary and microbial antigens and lumen contents. With aging there is a reduction in thickness of this mucus layer, resulting in weakened intestinal barrier function. The term <em>leaky gut</em> refers to excessive bacterial translocation from the intestinal lumen into the systemic circulation, which triggers inflammatory cascades and low-grade chronic inflammation. Results of recent research in mice lend support to the hypothesis that metformin may decrease inflammation by maintaining the integrity of the intestinal barrier.<sup class="text-inherit">12</sup></p><p class="pb-2">In one study, metformin significantly decreased bacterial translocation in older mice and the expression of inflammatory markers such as interleukins (ILs) and tumor necrosis factor α.<sup class="text-inherit">12</sup> In addition to low-grade inflammation, contemporary views of aging suggest a decline in several mediators of cell maintenance.<sup class="text-inherit">5</sup> For example, autophagy (a cellular recycling program that removes dysfunctional organelles from the cytoplasm) deteriorates with aging.<sup class="text-inherit">5</sup> Of interest, metformin has been implicated in improving autophagy and slowing several cellular mechanisms of aging.<sup class="text-inherit">5</sup> It has been posited that metformin’s anti-inflammatory effects modulate cellular integrity by maintenance of cell-to-cell communication, leading to a reduction in proinflammatory cytokines.<sup class="text-inherit">3</sup></p><p class="pb-2">In addition to chronic inflammation and dysregulation of cell-cell connectivity, other hallmarks of aging include mitochondrial dysfunction, genomic instability, and oxidative stress.<sup class="text-inherit">3</sup> Although knowledge of metformin’s effects on these aging processes remains elusive, there is increasing interest in this field. One example is the Metformin in Longevity Study (MILES; NCT02432287), a double-blind, placebo-controlled clinical study that included 14 patients. Researchers sought to establish associations between 6-week metformin intake and youthful gene expression in older persons with impaired glucose tolerance.<sup class="text-inherit">13</sup> Preliminary results indicate that in older individuals, metformin is implicated in metabolic changes, including DNA repair in the muscle tissue and mitochondrial fatty acid oxidation in the adipose tissue.<sup class="text-inherit">6,13</sup></p><p class="pb-2">Early on, the antidiabetic benefits of metformin were deemed to occur via decreased lipogenesis and gluconeogenesis in the liver because of its impact on molecular signaling and mitochondrial function.<sup class="text-inherit">3</sup> The end result was a decrease in plasma glucose and decreased insulin resistance.<sup class="text-inherit">3</sup> Metformin also exerts action in extrahepatic sites such as the gut. After oral administration, metformin concentrations in the intestinal lumen are significantly higher than in the systemic circulation.<sup class="text-inherit">14</sup> Metformin exerts many actions within the gut, such as an increase in lactate production and intestinal glucose uptake, an increase in glucagon-like peptide-1 (GLP-1), and advantageous changes in the gut microbiota.<sup class="text-inherit">14</sup> The gut microbiota is an ecosystem that interacts in a symbiotic fashion with the host to promote health.<sup class="text-inherit">15</sup> The microbiota impacts vitamin and short-chain fatty acid production, digestion, immunity, and the permeability of the intestinal barrier.<sup class="text-inherit">15</sup> With aging, there are changes in the gut microbiome leading to increased inflammation, gut permeability, and release of proinflammatory cytokines.<sup class="text-inherit">11</sup> Metformin may improve the gut microbe composition by increasing the ratio of bacteria that produce anti-inflammatory short chain fatty acids (SFCAs).<sup class="text-inherit">16</sup> These bacteria ferment dietary carbohydrates that humans cannot digest.<sup class="text-inherit">16</sup> SCFAs are widely known for enhancing glucose homeostasis in adipose tissue, liver, and muscles.<sup class="text-inherit">16</sup> Metformin also reduces the abundance of proinflammatory bacterial species supporting the integrity of the intestinal barrier.<sup class="text-inherit">12</sup> In animal studies, metformin expanded the gut population of <em>Akkermansia</em> spp, a producer of short-chain fatty acids that is correlated with a decrease in adipose tissue inflammation.16 Although human studies are yet to uncover a metformin signature on the gut microbiome, this is an area that merits further examination.<sup class="text-inherit">16</sup></p><p class="pb-2"><strong>Anticancer Effects</strong></p><p class="pb-2">In terms of aging-related diseases, there has been interest in exploring the putative anticancer actions of metformin. Preclinical evidence has shown that metformin inhibits tumor growth and metastasis in mouse models for head and neck squamous cell carcinoma, hepatocellular carcinoma, and breast cancer.<sup class="text-inherit">9</sup> Observational studies have also revealed that metformin exerts beneficial effects on individuals with diabetes who also have comorbid cancer.<sup class="text-inherit">9</sup> Recent attempts to explore whether metformin decreases the incidence of age-related disease in humans have yielded variable results. Notably, the largest randomized trial of metformin as adjuvant treatment for breast cancer (N = 3649 women, 5-year follow-up) found no advantage of metformin in measures of disease-free survival or overall survival.<sup class="text-inherit">9</sup> Whether metformin can delay the onset of other age-associated cancer and pathology remains unclear.</p><p class="pb-2"><strong>Neuroprotective Effects</strong></p><p class="pb-2">Finally, a neuroprotective effect of metformin has also been proposed. Aging and neurodegenerative disease share similar cellular dysfunction patterns, including inflammation, oxidative stress, and mitochondrial dysfunction. It is possible that regulation of glucose metabolism and insulin sensitivity may counter some of these cellular processes. In 5528 patients with diabetes with a median follow-up of 5.2 years, prolonged metformin use (> 2 years) significantly decreased the risk of developing neurodegenerative disorders.<sup class="text-inherit">17</sup> However, in a subsequent meta-analysis, metformin did not decrease the risk of developing Alzheimer disease.17 Doubts about the neurocognitive effects of metformin persist. Does long-term metformin treatment alter the risk of cognitive decline?</p><p class="pb-2">Major efforts to clarify these putative effects include the Targeting Aging With Metformin (TAME) trial, which is a large double-blind, placebo-controlled study that seeks to establish antiaging properties of metformin.<sup class="text-inherit">18</sup> Specifically, the TAME trial aims to examine whether giving metformin to healthy individuals delays the onset of aging-associated diseases.18 It will include 3000 participants aged 65 to 79 years, and it is the first large trial for geroprotective medications.<sup class="text-inherit">18</sup></p><p class="pb-2"><strong>Concluding Thoughts</strong></p><p class="pb-2">In sum, the repurposing of metformin has been of research and clinical interest worldwide. Interest in metformin’s potential benefits in aging-related diseases has been renewed given the increase in human life span and the need to extend quality of life in geriatric populations. Despite promising data from preclinical and observational studies, the use of metformin for antiaging continues to be investigational. Whether geroprotection will become another avatar of metformin remains to be seen.</p><p class="pb-2"><strong>Dr Modesto-Lowe</strong> <em>is medical director at Hartford Behavioral Health and community faculty at the University of Connecticut. </em><strong>Dr León-Barriera</strong> <em>is an assistant professor of psychiatry at the University of Pittsburgh School of Medicine in Pennsylvania.</em> <strong>Dr Kaur</strong><em> is a principal psychiatrist at the Connecticut Valley Hospital in Middletown.</em></p><p class="pb-2"><strong>References</strong></p><p class="pb-2">1. Mandell BF. <a rel="nofollow noreferrer noopener" target="_blank" href="https://www.ccjm.org/content/90/9/523">Born again: the many lives of metformin.</a> <em>Cleve Clin J Med</em>. 2023;90(9):523-524.</p><p class="pb-2">2. Ban TA. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2655089/">Fifty years chlorpromazine: a historical perspective.</a> <em>Neuropsychiatr Dis Treat</em>. 2007;3(4):495-500.</p><p class="pb-2">3. Kulkarni AS, Gubbi S, Barzilai N. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/32333835/">Benefits of metformin in attenuating the hallmarks of aging. </a><em>Cell Metab</em>. 2020;32(1):15-30.</p><p class="pb-2">4. Lee CB, Chae SU, Jo SJ, et al. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/33808194/">The relationship between the gut microbiome and metformin as a key for treating type 2 diabetes mellitus.</a> <em>Int J Mol Sci.</em> 2021;22(7):3566.</p><p class="pb-2">5. De Sousa Lages A, Lopes V, Horta J, et al. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/36077358/">Therapeutics that can potentially replicate or augment the anti-aging effects of physical exercise.</a> <em>Int J Mol Sci</em>. 2022;23(17):9957.</p><p class="pb-2">6. Zajda A, Huttunen KM, Sikora J, et al. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/32905803/">Is metformin a geroprotector? A peek into the current clinical and experimental data.</a> <em>Mech Ageing Dev</em>. 2020;191:111350.</p><p class="pb-2">7. UK Prospective Diabetes Study (UKPDS) Group. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/9742977/">Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).</a> <em>Lancet</em>. 1998;352(9351):854-865.</p><p class="pb-2">8. Campbell JM, Bellman SM, Stephenson MD, Lisy K. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/28802803/">Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.</a> <em>Ageing Res Rev</em>. 2017;40:31-44.</p><p class="pb-2">9. Hua Y, Zheng Y, Yao Y, et al. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/37344841/">Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing.</a> <em>J Transl Med</em>. 2023;21(1):403.</p><p class="pb-2">10. Metchnikoff E. <em>The Prolongation of Life: Optimistic Studies.</em> 1907; reissued, University Press of the Pacific; 2003.</p><p class="pb-2">11. Thevaranjan N, Puchta A, Schulz C, et al. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/28407483/">Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction.</a> <em>Cell Host Microbe.</em> 2017;21(4):455-466.e4.</p><p class="pb-2">12. Ahmadi S, Razazan A, Nagpal R, et al. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/32129462/">Metformin reduces aging-related leaky gut and improves cognitive function by beneficially modulating gut microbiome/goblet cell/mucin axis.</a> <em>J Gerontol A Biol Sci Med Sci.</em> 2020;75(7):e9-e21.</p><p class="pb-2">13. Mohammed I, Hollenberg MD, Ding H, Triggle CR. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/34421827/">A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan.</a> <em>Front Endocrinol (Lausanne).</em> 2021;12:718942.</p><p class="pb-2">14. McCreight LJ, Bailey CJ, Pearson ER. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/26780750/">Metformin and the gastrointestinal tract. </a><em>Diabetologia.</em> 2016;59(3):426-435.</p><p class="pb-2">15. Modesto Lowe V, Chaplin M, Sgambato D. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC9943825/">Major depressive disorder and the gut microbiome: what is the link?</a> <em>Gen Psychiatry.</em> 2023;36(1):e100973.</p><p class="pb-2">16. Rena G, Hardie DG, Pearson ER. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/28776086/">The mechanisms of action of metformin.</a> <em>Diabetologia.</em> 2017;60(9):1577-1585.</p><p class="pb-2">17. Nowell J, Blunt E, Gupta D, Edison P. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/37328112/">Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease.</a> <em>Ageing Res Rev.</em> 2023;89:101979.</p><p class="pb-2">18. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. <a rel="nofollow noreferrer noopener" target="_blank" href="https://pubmed.ncbi.nlm.nih.gov/27304507/">Metformin as a tool to target aging. </a><em>Cell Metab.</em> 2016;23(6):1060-1065.</p></div></div><div class="flex items-center lg:w-3/4 mb-4 pb-12"><div class="flex sm:inline"><a target="_blank" class="mr-[5px] md:mr-2 p-[.56rem] border rounded-md bg-primary text-white" href="https://cdn.sanity.io/files/0vv8moc6/psychtimes/e10ffe3e89a70766afa190f65812cbcf1744c8eb.pdf/PSY1124_eZine.pdf">Download Issue PDF</a></div></div><div class="mb-6"><div class="jsx-19ede9f0a5a45918 py-4 relative bg-primary md:px-8 pl-2 -ml-6 xs:ml-0 w-screen xs:w-full mb-4 "><div class="jsx-19ede9f0a5a45918 px-4 sm:px-0"><div class="jsx-19ede9f0a5a45918 text-white text-2xl md:text-3xl pb-2 md:pb-1">Articles in this issue</div><hr class="jsx-19ede9f0a5a45918 -mr-2"/></div><div style="scroll-snap-type:none" class="jsx-19ede9f0a5a45918 flex items-start 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text-gray-500 mt-[1rem] sm:mt-0">August 3rd 2021</span><p class="jsx-ad50481d5ee26850 article-title font-bold text-[1rem]"><a class="jsx-ad50481d5ee26850" href="/view/four-myths-lamotrigine?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent">Four Myths About Lamotrigine</a></p><div class="jsx-ad50481d5ee26850 authors flex-row wrap gap-[0.2rem]"><a class="jsx-ad50481d5ee26850 text-[#00ADEF] underline text-sm italic" href="/authors/chris-aiken-md">Chris Aiken, MD</a><span class="jsx-ad50481d5ee26850 mr-1 ml-[1px]"> </span><a class="jsx-ad50481d5ee26850 text-[#00ADEF] underline text-sm italic" href="/authors/kellie-newsome-pmh-np">Kellie Newsome, PMH-NP</a></div><div class="jsx-ad50481d5ee26850 article-summary"><a class="jsx-ad50481d5ee26850" href="/view/four-myths-lamotrigine?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent"></a></div></div></div><div style="border-bottom:1px solid #CCCCCC" class="jsx-ad50481d5ee26850"></div></div><div class="jsx-ad50481d5ee26850 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href="/view/time-to-think-of-aggression-as-a-treatment-target-symptom-independent-of-diagnosis?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent">Time to Think of Aggression as a Treatment Target Symptom, Independent of Diagnosis </a></p><div class="jsx-ad50481d5ee26850 authors flex-row wrap gap-[0.2rem]"><a class="jsx-ad50481d5ee26850 text-[#00ADEF] underline text-sm italic" href="/authors/rif-s-el-mallakh-md">Rif S. El-Mallakh, MD</a><span class="jsx-ad50481d5ee26850 mr-1 ml-[1px]"> </span><a class="jsx-ad50481d5ee26850 text-[#00ADEF] underline text-sm italic" href="/authors/irem-hacisalihoglu-aydin-md">Irem Hacisalihoglu Aydin, MD</a></div><div class="jsx-ad50481d5ee26850 article-summary"><a class="jsx-ad50481d5ee26850" href="/view/time-to-think-of-aggression-as-a-treatment-target-symptom-independent-of-diagnosis?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent"></a></div></div></div><div style="border-bottom:1px solid #CCCCCC" class="jsx-ad50481d5ee26850"></div></div><div class="jsx-ad50481d5ee26850 w-full h-full"><div class="jsx-ad50481d5ee26850 flex flex-col sm:flex-row justify-between my-4 gap-x-4"><a class="jsx-ad50481d5ee26850" href="/view/schizophrenia-pharmacology-version-2-0?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent"><img src="https://cdn.sanity.io/images/0vv8moc6/psychtimes/35d1f00931670ff03617de6b210f8376e4210447-4581x2618.jpg?fit=crop&auto=format" alt="pharmacology" width="288" class="jsx-ad50481d5ee26850 lg:w-[110px] lg:h-[100px] xl:w-[135px] xl:h-[125px] xs:w-[288px] "/></a><div class="jsx-ad50481d5ee26850 article-detail flex flex-col gap-[0.2rem] w-full xl:w-[70%]"><span class="jsx-ad50481d5ee26850 article-publish-date block italic text-sm text-gray-500 mt-[1rem] sm:mt-0">November 7th 2024</span><p class="jsx-ad50481d5ee26850 article-title font-bold text-[1rem]"><a class="jsx-ad50481d5ee26850" href="/view/schizophrenia-pharmacology-version-2-0?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent">Schizophrenia Pharmacology: Version 2.0</a></p><div class="jsx-ad50481d5ee26850 authors flex-row wrap gap-[0.2rem]"><a class="jsx-ad50481d5ee26850 text-[#00ADEF] underline text-sm italic" href="/authors/john-j-miller-md">John J. Miller, MD</a></div><div class="jsx-ad50481d5ee26850 article-summary"><a class="jsx-ad50481d5ee26850" href="/view/schizophrenia-pharmacology-version-2-0?utm_source=www.psychiatrictimes.com&utm_medium=relatedContent"></a></div></div></div><div style="border-bottom:1px solid #CCCCCC" class="jsx-ad50481d5ee26850"></div></div></div></div></div><div class="pb-24"></div></div><script type="application/ld+json">{"@context":"https://schema.org","@type":"NewsArticle","headline":"“Happy Accidents”: Repurposing Metformin","datePublished":"2024-11-11T18:00:18.436Z","dateModified":"2024-11-11T17:55:35Z","inLanguage":"en-US","image":"https://cdn.sanity.io/images/0vv8moc6/psychtimes/e043699441b7cb5a79c8ffaaeb75a30836c12c9d-2048x2048.jpg?fit=crop&auto=format","mainEntityOfPage":{"@type":"WebPage","@id":"https://www.psychiatrictimes.com/view/happy-accidents-repurposing-metformin"},"publisher":{"@type":"Organization","name":"Psychiatric Times","logo":{"@type":"ImageObject","url":"https://www.psychiatrictimes.com/PsychiatricTimesLogo.png"}},"articleBody":"\n\nA recent article on the multiple uses of metformin brings up the important topic of repurposing medications.1 Repurposing has been around since the advent of modern medicine. One prominent example is the use of chlorpromazine (CPZ) as an antipsychotic.2 Chlorpromazine was first synthesized in 1951 as a potentiator of general anesthesia.2 The psychiatric benefits were found later by Henri Laborit, a surgeon in the French army, who was doing research with artificial hibernation in the prevention of surgical shock. Laborit employed CPZ as an adjunct to anesthetics. He observed that CPZ at doses of 50 mg to 100 mg produced a lowering of body temperature, sedation, and disinterest without loss of consciousness. He was able to persuade his colleagues in the military hospital in Paris, France, to try CPZ in the treatment of a patient who was experiencing psychotic agitation. The mechanism of action was not fully known, and it was thought that it worked in controlling agitation because of its cooling effect and induction of artificial hibernation in patients.2 The pharmacological mechanism was not fully understood until many years later, and the way it has impacted the practice of psychiatry needs no introduction.\n\nThese happy accidents in medicine have played a vital role in getting where we are right now in patient care compared with just 50 years ago. This begs the question, are we onto another happy accident with metformin? There is an accumulating body of evidence that metformin may have benefits in aging beyond its effect on glycemic control.3\n\nRepurposing Metformin\n\nMetformin is endorsed by the American Diabetes Association and the European Association for the Study of Diabetes as initial therapy for patients with type 2 diabetes (T2D), and it is one of the most prescribed antidiabetic medications worldwide.4 It is widely recognized that metformin improves hyperglycemia and insulin sensitivity.4 Recently, the observation that metformin decreased the development of certain age-associated pathology in individuals with and without diabetes has garnered attention.3 Aging refers to the time-dependent physiological loss of cellular integrity5 and is associated with T2D, dementia, cancer, and cardiovascular disease.6 The United Kingdom Prospective Diabetes Study has shown that metformin is associated with a lower all-cause mortality rate in patients with diabetes.7 This study was a 20-year randomized multicenter longitudinal study, and researchers found cardiovascular benefits of metformin in patients with diabetes.7 Similarly, a systematic review of 53 studies showed that metformin use resulted in a decrease in all-cause mortality linked with aging-related diseases such as cancer and cardiovascular disease.8 As the aging population grows and life expectancy increases, we are searching for ways to maintain quality of life for as long as possible.\n\nIn the US, advances in health care and public health have afforded increases in life expectancy.5 Unfortunately, this longevity has been accompanied by an increase in the incidence of age-related diseases, which leads to a decreased quality of life.5 Health span refers to the life period in which one is healthy and free from chronic illness and aging-related dysfunction; it serves as a proxy for quality of life during the older years.6 There is a pressing need for interventions that can delay age-associated diseases and improve health span. Preclinical data indicate that metformin may influence cellular mechanisms associated with aging, including inflammation, oxidative stress, cell senescence, and autophagy.3,5 Of note, metformin mimics the metabolic actions of caloric restriction, which is a recognized strategy to prolong health and life span in mammals.9 Metformin may also mimic the geroprotective effects of exercise.5 Since metformin is inexpensive and offers a good tolerability and safety profile, it is attractive as a focus of antiaging research.3\n\nReducing Inflammation\n\nAs early as 1907, Élie Metchnikoff theorized that cell senescence resulted from chronic systemic inflammation due to increased permeability in the colon, and the escape of bacteria and their toxic metabolites into the systemic circulation.10 Accordingly, these toxic bacterial products activated phagocytes and an inflammatory response that led to death of adjacent tissues.11 Interestingly, more than a century later, aging is thought to be associated with a persistent low-grade inflammation, referred to as inflammaging, that originates in the gut.11 We now know that the intestinal mucosal layer is a key modulator of inflammatory responses, protecting against invasion of dietary and microbial antigens and lumen contents. With aging there is a reduction in thickness of this mucus layer, resulting in weakened intestinal barrier function. The term leaky gut refers to excessive bacterial translocation from the intestinal lumen into the systemic circulation, which triggers inflammatory cascades and low-grade chronic inflammation. Results of recent research in mice lend support to the hypothesis that metformin may decrease inflammation by maintaining the integrity of the intestinal barrier.12\n\nIn one study, metformin significantly decreased bacterial translocation in older mice and the expression of inflammatory markers such as interleukins (ILs) and tumor necrosis factor α.12 In addition to low-grade inflammation, contemporary views of aging suggest a decline in several mediators of cell maintenance.5 For example, autophagy (a cellular recycling program that removes dysfunctional organelles from the cytoplasm) deteriorates with aging.5 Of interest, metformin has been implicated in improving autophagy and slowing several cellular mechanisms of aging.5 It has been posited that metformin’s anti-inflammatory effects modulate cellular integrity by maintenance of cell-to-cell communication, leading to a reduction in proinflammatory cytokines.3\n\nIn addition to chronic inflammation and dysregulation of cell-cell connectivity, other hallmarks of aging include mitochondrial dysfunction, genomic instability, and oxidative stress.3 Although knowledge of metformin’s effects on these aging processes remains elusive, there is increasing interest in this field. One example is the Metformin in Longevity Study (MILES; NCT02432287), a double-blind, placebo-controlled clinical study that included 14 patients. Researchers sought to establish associations between 6-week metformin intake and youthful gene expression in older persons with impaired glucose tolerance.13 Preliminary results indicate that in older individuals, metformin is implicated in metabolic changes, including DNA repair in the muscle tissue and mitochondrial fatty acid oxidation in the adipose tissue.6,13\n\nEarly on, the antidiabetic benefits of metformin were deemed to occur via decreased lipogenesis and gluconeogenesis in the liver because of its impact on molecular signaling and mitochondrial function.3 The end result was a decrease in plasma glucose and decreased insulin resistance.3 Metformin also exerts action in extrahepatic sites such as the gut. After oral administration, metformin concentrations in the intestinal lumen are significantly higher than in the systemic circulation.14 Metformin exerts many actions within the gut, such as an increase in lactate production and intestinal glucose uptake, an increase in glucagon-like peptide-1 (GLP-1), and advantageous changes in the gut microbiota.14 The gut microbiota is an ecosystem that interacts in a symbiotic fashion with the host to promote health.15 The microbiota impacts vitamin and short-chain fatty acid production, digestion, immunity, and the permeability of the intestinal barrier.15 With aging, there are changes in the gut microbiome leading to increased inflammation, gut permeability, and release of proinflammatory cytokines.11 Metformin may improve the gut microbe composition by increasing the ratio of bacteria that produce anti-inflammatory short chain fatty acids (SFCAs).16 These bacteria ferment dietary carbohydrates that humans cannot digest.16 SCFAs are widely known for enhancing glucose homeostasis in adipose tissue, liver, and muscles.16 Metformin also reduces the abundance of proinflammatory bacterial species supporting the integrity of the intestinal barrier.12 In animal studies, metformin expanded the gut population of Akkermansia spp, a producer of short-chain fatty acids that is correlated with a decrease in adipose tissue inflammation.16 Although human studies are yet to uncover a metformin signature on the gut microbiome, this is an area that merits further examination.16\n\nAnticancer Effects\n\nIn terms of aging-related diseases, there has been interest in exploring the putative anticancer actions of metformin. Preclinical evidence has shown that metformin inhibits tumor growth and metastasis in mouse models for head and neck squamous cell carcinoma, hepatocellular carcinoma, and breast cancer.9 Observational studies have also revealed that metformin exerts beneficial effects on individuals with diabetes who also have comorbid cancer.9 Recent attempts to explore whether metformin decreases the incidence of age-related disease in humans have yielded variable results. Notably, the largest randomized trial of metformin as adjuvant treatment for breast cancer (N = 3649 women, 5-year follow-up) found no advantage of metformin in measures of disease-free survival or overall survival.9 Whether metformin can delay the onset of other age-associated cancer and pathology remains unclear.\n\nNeuroprotective Effects\n\nFinally, a neuroprotective effect of metformin has also been proposed. Aging and neurodegenerative disease share similar cellular dysfunction patterns, including inflammation, oxidative stress, and mitochondrial dysfunction. It is possible that regulation of glucose metabolism and insulin sensitivity may counter some of these cellular processes. In 5528 patients with diabetes with a median follow-up of 5.2 years, prolonged metformin use (> 2 years) significantly decreased the risk of developing neurodegenerative disorders.17 However, in a subsequent meta-analysis, metformin did not decrease the risk of developing Alzheimer disease.17 Doubts about the neurocognitive effects of metformin persist. Does long-term metformin treatment alter the risk of cognitive decline?\n\nMajor efforts to clarify these putative effects include the Targeting Aging With Metformin (TAME) trial, which is a large double-blind, placebo-controlled study that seeks to establish antiaging properties of metformin.18 Specifically, the TAME trial aims to examine whether giving metformin to healthy individuals delays the onset of aging-associated diseases.18 It will include 3000 participants aged 65 to 79 years, and it is the first large trial for geroprotective medications.18\n\nConcluding Thoughts\n\nIn sum, the repurposing of metformin has been of research and clinical interest worldwide. Interest in metformin’s potential benefits in aging-related diseases has been renewed given the increase in human life span and the need to extend quality of life in geriatric populations. Despite promising data from preclinical and observational studies, the use of metformin for antiaging continues to be investigational. Whether geroprotection will become another avatar of metformin remains to be seen.\n\nDr Modesto-Lowe is medical director at Hartford Behavioral Health and community faculty at the University of Connecticut. Dr León-Barriera is an assistant professor of psychiatry at the University of Pittsburgh School of Medicine in Pennsylvania. Dr Kaur is a principal psychiatrist at the Connecticut Valley Hospital in Middletown.\n\nReferences\n\n1. Mandell BF. Born again: the many lives of metformin. Cleve Clin J Med. 2023;90(9):523-524.\n\n2. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500.\n\n3. Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32(1):15-30.\n\n4. Lee CB, Chae SU, Jo SJ, et al. The relationship between the gut microbiome and metformin as a key for treating type 2 diabetes mellitus. Int J Mol Sci. 2021;22(7):3566.\n\n5. De Sousa Lages A, Lopes V, Horta J, et al. Therapeutics that can potentially replicate or augment the anti-aging effects of physical exercise. Int J Mol Sci. 2022;23(17):9957.\n\n6. Zajda A, Huttunen KM, Sikora J, et al. Is metformin a geroprotector? A peek into the current clinical and experimental data. Mech Ageing Dev. 2020;191:111350.\n\n7. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9351):854-865.\n\n8. Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev. 2017;40:31-44.\n\n9. Hua Y, Zheng Y, Yao Y, et al. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J Transl Med. 2023;21(1):403.\n\n10. Metchnikoff E. The Prolongation of Life: Optimistic Studies. 1907; reissued, University Press of the Pacific; 2003.\n\n11. Thevaranjan N, Puchta A, Schulz C, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4):455-466.e4.\n\n12. Ahmadi S, Razazan A, Nagpal R, et al. Metformin reduces aging-related leaky gut and improves cognitive function by beneficially modulating gut microbiome/goblet cell/mucin axis. J Gerontol A Biol Sci Med Sci. 2020;75(7):e9-e21.\n\n13. Mohammed I, Hollenberg MD, Ding H, Triggle CR. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol (Lausanne). 2021;12:718942.\n\n14. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426-435.\n\n15. Modesto Lowe V, Chaplin M, Sgambato D. Major depressive disorder and the gut microbiome: what is the link? Gen Psychiatry. 2023;36(1):e100973.\n\n16. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-1585.\n\n17. Nowell J, Blunt E, Gupta D, Edison P. Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease. Ageing Res Rev. 2023;89:101979.\n\n18. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23(6):1060-1065.","description":"There is an accumulating body of evidence that metformin may have benefits in aging beyond its effect on glycemic control.","author":[{"@type":"Person","name":"Vania Modesto-Lowe, MD, MPH"},{"@type":"Person","name":"Roberto León-Barriera, MD"},{"@type":"Person","name":"Jasleen Kaur, MD"}]}</script></div></div><div class="flex-none w-[300px] z-[9999] relative hidden md:block"><div style="top:5rem" class="sticky custom-spacing"><div class="collapse-container " style="overflow:hidden;max-height:900px;transition:max-height .4s ease-in-out"></div></div></div></div><div id="div-gpt-ad-pixel" style="width:1px;height:1px" class=""></div><noscript><iframe src="https://www.googletagmanager.com/ns.html?id=GTM-5V9L5PL" height="0" width="0" style="display:none;visibility:hidden"></iframe></noscript><div id="footerOuterWrap" class="w-full bg-primary flex flex-col items-center justify-center"><div class="container w-[1340px]"><div id="footerInnerWrap" 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Evidence suggests metformin may reduce age-related diseases, such as cancer and cardiovascular conditions, by influencing cellular mechanisms like inflammation and oxidative stress. It may also improve gut microbiota composition, enhancing glucose homeostasis and reducing inflammation. Despite promising preclinical and observational data, metformin's anti-aging effects remain investigational. Ongoing studies, including the TAME trial, aim to clarify its potential geroprotective properties and impact on health span and life span.","contentCategory":{"_id":"8bdaa7fc-960a-4b57-b076-75fdce3741bb","name":"Articles"},"articleType":"Publication","_type":"article","_updatedAt":"2024-11-11T17:55:35Z","documentGroupMapping":null,"factCheckAuthorMapping":null,"issueSection":null,"pdfUrl":null,"published":"2024-11-11T18:00:18.436Z","ExcludeFromPubMedXML":false,"body":[{"upload_doc":null,"medias":null,"alt":"metformin","_key":"8ebcfb14ed94","widthP":50,"disableTextWrap":false,"disableLightBox":true,"uploadAudio":null,"_type":"figure","alignment":"left","asset":{"_ref":"image-e043699441b7cb5a79c8ffaaeb75a30836c12c9d-2048x2048-jpg","_type":"reference"}},{"_key":"84c0e2ff246f","markDefs":[],"upload_doc":null,"uploadAudio":null,"medias":null,"children":[{"text":"A recent article on the multiple uses of metformin brings up the important topic of repurposing medications.","_key":"bdf42da2b97f0","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"1","_key":"5491a79ae1b3"},{"text":" Repurposing has been around since the advent of modern medicine. One prominent example is the use of chlorpromazine (CPZ) as an antipsychotic.","_key":"57788e4101da","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"2","_key":"63808ee8df77"},{"_type":"span","marks":[],"text":" Chlorpromazine was first synthesized in 1951 as a potentiator of general anesthesia.","_key":"6d01330aaf36"},{"_type":"span","marks":["superscript"],"text":"2","_key":"4e630420cd93"},{"_type":"span","marks":[],"text":" The psychiatric benefits were found later by Henri Laborit, a surgeon in the French army, who was doing research with artificial hibernation in the prevention of surgical shock. Laborit employed CPZ as an adjunct to anesthetics. He observed that CPZ at doses of 50 mg to 100 mg produced a lowering of body temperature, sedation, and disinterest without loss of consciousness. He was able to persuade his colleagues in the military hospital in Paris, France, to try CPZ in the treatment of a patient who was experiencing psychotic agitation. The mechanism of action was not fully known, and it was thought that it worked in controlling agitation because of its cooling effect and induction of artificial hibernation in patients.","_key":"0248a8cec900"},{"_type":"span","marks":["superscript"],"text":"2","_key":"bf265fface94"},{"_type":"span","marks":[],"text":" The pharmacological mechanism was not fully understood until many years later, and the way it has impacted the practice of psychiatry needs no introduction.","_key":"fddf3b368355"}],"_type":"block","style":"normal"},{"medias":null,"_type":"block","style":"normal","_key":"7fac76e86563","markDefs":[],"children":[{"text":"These happy accidents in medicine have played a vital role in getting where we are right now in patient care compared with just 50 years ago. This begs the question, are we onto another happy accident with metformin? There is an accumulating body of evidence that metformin may have benefits in aging beyond its effect on glycemic control.","_key":"b0c3fe283bd90","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"3","_key":"30ea0ef1ce7f"}],"upload_doc":null,"uploadAudio":null},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Repurposing Metformin","_key":"aa9a379177900"}],"_type":"block","style":"normal","_key":"14e6ebfe8a30","upload_doc":null,"uploadAudio":null,"medias":null},{"medias":null,"_key":"dda1f07781a7","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Metformin is endorsed by the American Diabetes Association and the European Association for the Study of Diabetes as initial therapy for patients with type 2 diabetes (T2D), and it is one of the most prescribed antidiabetic medications worldwide.","_key":"06d6fee7cace0"},{"_type":"span","marks":["superscript"],"text":"4","_key":"f1cb215206b1"},{"_key":"f1e0932e8960","_type":"span","marks":[],"text":" It is widely recognized that metformin improves hyperglycemia and insulin sensitivity."},{"_type":"span","marks":["superscript"],"text":"4","_key":"975b9db5a95e"},{"_type":"span","marks":[],"text":" Recently, the observation that metformin decreased the development of certain age-associated pathology in individuals with and without diabetes has garnered attention.","_key":"709fcd30bf33"},{"_type":"span","marks":["superscript"],"text":"3","_key":"033e25ef7b30"},{"_type":"span","marks":[],"text":" Aging refers to the time-dependent physiological loss of cellular integrity","_key":"0742cbf9a273"},{"marks":["superscript"],"text":"5","_key":"4e32b9347666","_type":"span"},{"_key":"3737df516fee","_type":"span","marks":[],"text":" and is associated with T2D, dementia, cancer, and cardiovascular disease."},{"_type":"span","marks":["superscript"],"text":"6","_key":"7b5b5e24bc18"},{"text":" The United Kingdom Prospective Diabetes Study has shown that metformin is associated with a lower all-cause mortality rate in patients with diabetes.","_key":"c6aecba4cff4","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"7","_key":"ed81224bc2e0"},{"text":" This study was a 20-year randomized multicenter longitudinal study, and researchers found cardiovascular benefits of metformin in patients with diabetes.","_key":"ce30c364f03e","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"7","_key":"f1ddc8dd0418"},{"_type":"span","marks":[],"text":" Similarly, a systematic review of 53 studies showed that metformin use resulted in a decrease in all-cause mortality linked with aging-related diseases such as cancer and cardiovascular disease.","_key":"96a5bcd7b950"},{"text":"8","_key":"f1173eed37a8","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" As the aging population grows and life expectancy increases, we are searching for ways to maintain quality of life for as long as possible.","_key":"851909c44ac8"}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null},{"style":"normal","_key":"898f9e41d9ea","markDefs":[],"children":[{"text":"In the US, advances in health care and public health have afforded increases in life expectancy.","_key":"b21e3742dcb40","_type":"span","marks":[]},{"_key":"0f9339c87b3d","_type":"span","marks":["superscript"],"text":"5"},{"_type":"span","marks":[],"text":" Unfortunately, this longevity has been accompanied by an increase in the incidence of age-related diseases, which leads to a decreased quality of life.","_key":"c56da861efe7"},{"_type":"span","marks":["superscript"],"text":"5","_key":"eac32f92cac5"},{"text":" Health span refers to the life period in which one is healthy and free from chronic illness and aging-related dysfunction; it serves as a proxy for quality of life during the older years.","_key":"1c980fc82b14","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"6","_key":"d7266bcbe7d9"},{"_key":"0e666333917a","_type":"span","marks":[],"text":" There is a pressing need for interventions that can delay age-associated diseases and improve health span. Preclinical data indicate that metformin may influence cellular mechanisms associated with aging, including inflammation, oxidative stress, cell senescence, and autophagy."},{"text":"3,5","_key":"536d6ccc4c78","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Of note, metformin mimics the metabolic actions of caloric restriction, which is a recognized strategy to prolong health and life span in mammals.","_key":"d6745c91351a"},{"marks":["superscript"],"text":"9","_key":"05f3f1c21f0d","_type":"span"},{"_key":"acda869d7c33","_type":"span","marks":[],"text":" Metformin may also mimic the geroprotective effects of exercise."},{"_key":"75b714e72f29","_type":"span","marks":["superscript"],"text":"5"},{"_type":"span","marks":[],"text":" Since metformin is inexpensive and offers a good tolerability and safety profile, it is attractive as a focus of antiaging research.","_key":"9c3ef26dd42f"},{"_type":"span","marks":["superscript"],"text":"3","_key":"0c81f29f4808"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block"},{"children":[{"_key":"ba9f35da59e00","_type":"span","marks":["strong"],"text":"Reducing Inflammation"}],"_type":"block","style":"normal","_key":"6f4731648f18","markDefs":[],"upload_doc":null,"uploadAudio":null,"medias":null},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"As early as 1907, Élie Metchnikoff theorized that cell senescence resulted from chronic systemic inflammation due to increased permeability in the colon, and the escape of bacteria and their toxic metabolites into the systemic circulation.10 Accordingly, these toxic bacterial products activated phagocytes and an inflammatory response that led to death of adjacent tissues.","_key":"67ffac31606c0"},{"_key":"9a83f83e277c","_type":"span","marks":["superscript"],"text":"11"},{"_type":"span","marks":[],"text":" Interestingly, more than a century later, aging is thought to be associated with a persistent low-grade inflammation, referred to as ","_key":"4eda992e53e0"},{"_type":"span","marks":["em"],"text":"inflammaging","_key":"a4950ba0a33f"},{"_type":"span","marks":[],"text":", that originates in the gut.","_key":"adcc3daab207"},{"_type":"span","marks":["superscript"],"text":"11","_key":"a4b5af286d03"},{"_type":"span","marks":[],"text":" We now know that the intestinal mucosal layer is a key modulator of inflammatory responses, protecting against invasion of dietary and microbial antigens and lumen contents. With aging there is a reduction in thickness of this mucus layer, resulting in weakened intestinal barrier function. The term ","_key":"ce8227013417"},{"_type":"span","marks":["em"],"text":"leaky gut","_key":"971f33dbd4a2"},{"_type":"span","marks":[],"text":" refers to excessive bacterial translocation from the intestinal lumen into the systemic circulation, which triggers inflammatory cascades and low-grade chronic inflammation. Results of recent research in mice lend support to the hypothesis that metformin may decrease inflammation by maintaining the integrity of the intestinal barrier.","_key":"ed74a6dadd30"},{"marks":["superscript"],"text":"12","_key":"a3a5b907b15c","_type":"span"}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null,"_key":"f55f70c04179"},{"_key":"295d9b8efc6a","markDefs":[],"children":[{"_type":"span","marks":[],"text":"In one study, metformin significantly decreased bacterial translocation in older mice and the expression of inflammatory markers such as interleukins (ILs) and tumor necrosis factor α.","_key":"800a366150060"},{"_type":"span","marks":["superscript"],"text":"12","_key":"0cfb1a6c1850"},{"_type":"span","marks":[],"text":" In addition to low-grade inflammation, contemporary views of aging suggest a decline in several mediators of cell maintenance.","_key":"5d9ed0e1bf39"},{"marks":["superscript"],"text":"5","_key":"67df2baf9e08","_type":"span"},{"_type":"span","marks":[],"text":" For example, autophagy (a cellular recycling program that removes dysfunctional organelles from the cytoplasm) deteriorates with aging.","_key":"848a603bb9aa"},{"_type":"span","marks":["superscript"],"text":"5","_key":"707bd5e0da72"},{"_type":"span","marks":[],"text":" Of interest, metformin has been implicated in improving autophagy and slowing several cellular mechanisms of aging.","_key":"258d1f409e75"},{"_type":"span","marks":["superscript"],"text":"5","_key":"4c3a8e06e572"},{"_type":"span","marks":[],"text":" It has been posited that metformin’s anti-inflammatory effects modulate cellular integrity by maintenance of cell-to-cell communication, leading to a reduction in proinflammatory cytokines.","_key":"87babbf490d0"},{"_type":"span","marks":["superscript"],"text":"3","_key":"13fcb52d2b7a"}],"_type":"block","style":"normal","upload_doc":null,"uploadAudio":null,"medias":null},{"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal","_key":"4cf19120eca8","markDefs":[],"children":[{"_type":"span","marks":[],"text":"In addition to chronic inflammation and dysregulation of cell-cell connectivity, other hallmarks of aging include mitochondrial dysfunction, genomic instability, and oxidative stress.","_key":"607b146a243e0"},{"_type":"span","marks":["superscript"],"text":"3","_key":"f54b4bf052cb"},{"marks":[],"text":" Although knowledge of metformin’s effects on these aging processes remains elusive, there is increasing interest in this field. One example is the Metformin in Longevity Study (MILES; NCT02432287), a double-blind, placebo-controlled clinical study that included 14 patients. Researchers sought to establish associations between 6-week metformin intake and youthful gene expression in older persons with impaired glucose tolerance.","_key":"e3a2759a9a60","_type":"span"},{"text":"13","_key":"b0f481c886b3","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" Preliminary results indicate that in older individuals, metformin is implicated in metabolic changes, including DNA repair in the muscle tissue and mitochondrial fatty acid oxidation in the adipose tissue.","_key":"913aa07e6624"},{"_type":"span","marks":["superscript"],"text":"6,13","_key":"cd57411e06fd"}]},{"upload_doc":null,"uploadAudio":null,"medias":null,"_key":"73a7f73e6d72","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Early on, the antidiabetic benefits of metformin were deemed to occur via decreased lipogenesis and gluconeogenesis in the liver because of its impact on molecular signaling and mitochondrial function.","_key":"92696997ef930"},{"_type":"span","marks":["superscript"],"text":"3","_key":"46ca5b922f64"},{"_type":"span","marks":[],"text":" The end result was a decrease in plasma glucose and decreased insulin resistance.","_key":"62ede7391789"},{"_type":"span","marks":["superscript"],"text":"3","_key":"1cf738f968c6"},{"text":" Metformin also exerts action in extrahepatic sites such as the gut. After oral administration, metformin concentrations in the intestinal lumen are significantly higher than in the systemic circulation.","_key":"183201f2ed1c","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"14","_key":"eab906a2b0f1"},{"text":" Metformin exerts many actions within the gut, such as an increase in lactate production and intestinal glucose uptake, an increase in glucagon-like peptide-1 (GLP-1), and advantageous changes in the gut microbiota.","_key":"7fc4591f9d96","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"14","_key":"7197224f33b9"},{"_type":"span","marks":[],"text":" The gut microbiota is an ecosystem that interacts in a symbiotic fashion with the host to promote health.","_key":"f761270411f9"},{"_type":"span","marks":["superscript"],"text":"15","_key":"a98ecdd92b2a"},{"_type":"span","marks":[],"text":" The microbiota impacts vitamin and short-chain fatty acid production, digestion, immunity, and the permeability of the intestinal barrier.","_key":"ea580290ac99"},{"_type":"span","marks":["superscript"],"text":"15","_key":"6d1fcfac8007"},{"_type":"span","marks":[],"text":" With aging, there are changes in the gut microbiome leading to increased inflammation, gut permeability, and release of proinflammatory cytokines.","_key":"318f63ce3ab3"},{"_type":"span","marks":["superscript"],"text":"11","_key":"3079a4a577f2"},{"_type":"span","marks":[],"text":" Metformin may improve the gut microbe composition by increasing the ratio of bacteria that produce anti-inflammatory short chain fatty acids (SFCAs).","_key":"23e7c8cef248"},{"_type":"span","marks":["superscript"],"text":"16","_key":"35627fe68f52"},{"_type":"span","marks":[],"text":" These bacteria ferment dietary carbohydrates that humans cannot digest.","_key":"057002cfde4b"},{"marks":["superscript"],"text":"16","_key":"14fc4a784ada","_type":"span"},{"text":" SCFAs are widely known for enhancing glucose homeostasis in adipose tissue, liver, and muscles.","_key":"f988f93121f3","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"16","_key":"8fb2600e6096"},{"_type":"span","marks":[],"text":" Metformin also reduces the abundance of proinflammatory bacterial species supporting the integrity of the intestinal barrier.","_key":"81a0e45c8014"},{"text":"12","_key":"eb4abd61b50c","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" In animal studies, metformin expanded the gut population of ","_key":"cc75fa8c9558"},{"_type":"span","marks":["em"],"text":"Akkermansia","_key":"a6167e8d3934"},{"_type":"span","marks":[],"text":" spp, a producer of short-chain fatty acids that is correlated with a decrease in adipose tissue inflammation.16 Although human studies are yet to uncover a metformin signature on the gut microbiome, this is an area that merits further examination.","_key":"d3e58e05610c"},{"_type":"span","marks":["superscript"],"text":"16","_key":"63840f62a8d4"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Anticancer Effects","_key":"5f2cc84aaeb60"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal","_key":"4fb1300d4915"},{"medias":null,"markDefs":[],"children":[{"text":"In terms of aging-related diseases, there has been interest in exploring the putative anticancer actions of metformin. Preclinical evidence has shown that metformin inhibits tumor growth and metastasis in mouse models for head and neck squamous cell carcinoma, hepatocellular carcinoma, and breast cancer.","_key":"879cfb84df880","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"9","_key":"e04a5705068e"},{"text":" Observational studies have also revealed that metformin exerts beneficial effects on individuals with diabetes who also have comorbid cancer.","_key":"752241ccbd85","_type":"span","marks":[]},{"_key":"65488d3d600d","_type":"span","marks":["superscript"],"text":"9"},{"_key":"6207d380f7fc","_type":"span","marks":[],"text":" Recent attempts to explore whether metformin decreases the incidence of age-related disease in humans have yielded variable results. Notably, the largest randomized trial of metformin as adjuvant treatment for breast cancer (N = 3649 women, 5-year follow-up) found no advantage of metformin in measures of disease-free survival or overall survival."},{"_key":"c20ba9c15a85","_type":"span","marks":["superscript"],"text":"9"},{"text":" Whether metformin can delay the onset of other age-associated cancer and pathology remains unclear.","_key":"a0bf1b68d57b","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"fa3b304ce712","upload_doc":null,"uploadAudio":null},{"_key":"6b26c11ddbc0","markDefs":[],"children":[{"text":"Neuroprotective Effects","_key":"f20573a7f2b40","_type":"span","marks":["strong"]}],"_type":"block","upload_doc":null,"uploadAudio":null,"medias":null,"style":"normal"},{"upload_doc":null,"uploadAudio":null,"medias":null,"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Finally, a neuroprotective effect of metformin has also been proposed. Aging and neurodegenerative disease share similar cellular dysfunction patterns, including inflammation, oxidative stress, and mitochondrial dysfunction. It is possible that regulation of glucose metabolism and insulin sensitivity may counter some of these cellular processes. In 5528 patients with diabetes with a median follow-up of 5.2 years, prolonged metformin use (\u003e 2 years) significantly decreased the risk of developing neurodegenerative disorders.","_key":"05ae61429d830"},{"_key":"7af7604a4b66","_type":"span","marks":["superscript"],"text":"17"},{"_type":"span","marks":[],"text":" However, in a subsequent meta-analysis, metformin did not decrease the risk of developing Alzheimer disease.17 Doubts about the neurocognitive effects of metformin persist. Does long-term metformin treatment alter the risk of cognitive decline?","_key":"f6141d94acda"}],"_type":"block","style":"normal","_key":"dedc390636a7"},{"style":"normal","_key":"0a36ebb4e75f","markDefs":[],"children":[{"text":"Major efforts to clarify these putative effects include the Targeting Aging With Metformin (TAME) trial, which is a large double-blind, placebo-controlled study that seeks to establish antiaging properties of metformin.","_key":"e55ef0fa77640","_type":"span","marks":[]},{"_key":"18c23f4046a3","_type":"span","marks":["superscript"],"text":"18"},{"_key":"63279bb71faf","_type":"span","marks":[],"text":" Specifically, the TAME trial aims to examine whether giving metformin to healthy individuals delays the onset of aging-associated diseases.18 It will include 3000 participants aged 65 to 79 years, and it is the first large trial for geroprotective medications."},{"_type":"span","marks":["superscript"],"text":"18","_key":"b13dfd23b892"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Concluding Thoughts","_key":"cbfdef33f8d50"}],"upload_doc":null,"uploadAudio":null,"medias":null,"_type":"block","style":"normal","_key":"e7a3e448ff05"},{"uploadAudio":null,"medias":null,"_key":"652263f9a7cc","markDefs":[],"children":[{"marks":[],"text":"In sum, the repurposing of metformin has been of research and clinical interest worldwide. Interest in metformin’s potential benefits in aging-related diseases has been renewed given the increase in human life span and the need to extend quality of life in geriatric populations. Despite promising data from preclinical and observational studies, the use of metformin for antiaging continues to be investigational. Whether geroprotection will become another avatar of metformin remains to be seen.","_key":"b05a01dd20e40","_type":"span"}],"_type":"block","style":"normal","upload_doc":null},{"children":[{"_type":"span","marks":["strong"],"text":"Dr Modesto-Lowe","_key":"d37e11def5620"},{"text":" ","_key":"a89fe7ef3c7f","_type":"span","marks":[]},{"text":"is medical director at Hartford Behavioral Health and community faculty at the University of Connecticut. ","_key":"575ab1288c9f","_type":"span","marks":["em"]},{"_type":"span","marks":["strong"],"text":"Dr León-Barriera","_key":"63ce04ebfa4b"},{"marks":[],"text":" ","_key":"460b92c492a0","_type":"span"},{"_type":"span","marks":["em"],"text":"is an assistant professor of psychiatry at the University of Pittsburgh School of Medicine in Pennsylvania.","_key":"732108c5419c"},{"text":" ","_key":"52c34c5d664f","_type":"span","marks":[]},{"_type":"span","marks":["strong"],"text":"Dr Kaur","_key":"f5d1e876305d"},{"marks":["em"],"text":" is a principal psychiatrist at the Connecticut Valley Hospital in Middletown.","_key":"887cde5be847","_type":"span"}],"_type":"block","upload_doc":null,"uploadAudio":null,"medias":null,"style":"normal","_key":"8694ff4d405a","markDefs":[]},{"medias":null,"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"References","_key":"c8b6cfb164660"}],"_type":"block","style":"normal","_key":"f18ede3b023b","upload_doc":null,"uploadAudio":null},{"_key":"eff0856c7f5a","markDefs":[{"_key":"651e51b33902","nofollow":true,"blank":true,"_type":"link","href":"https://www.ccjm.org/content/90/9/523"}],"children":[{"_key":"24080cdd9f440","_type":"span","marks":[],"text":"1. Mandell BF. "},{"_type":"span","marks":["651e51b33902"],"text":"Born again: the many lives of metformin.","_key":"0bfa7b823b48"},{"marks":[],"text":" ","_key":"9f97cce5394c","_type":"span"},{"_type":"span","marks":["em"],"text":"Cleve Clin J Med","_key":"13f930faa29f"},{"_key":"99f7d2afe041","_type":"span","marks":[],"text":". 2023;90(9):523-524."}],"_type":"block","upload_doc":null,"uploadAudio":null,"medias":null,"style":"normal"},{"markDefs":[{"_type":"link","href":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2655089/","_key":"de3e02566b86","nofollow":true,"blank":true}],"children":[{"marks":[],"text":"2. Ban TA. ","_key":"f66d710dc8e60","_type":"span"},{"text":"Fifty years chlorpromazine: a historical perspective.","_key":"b0d063451902","_type":"span","marks":["de3e02566b86"]},{"_type":"span","marks":[],"text":" ","_key":"fba200964924"},{"text":"Neuropsychiatr Dis Treat","_key":"24fbf556c0f4","_type":"span","marks":["em"]},{"marks":[],"text":". 2007;3(4):495-500.","_key":"0b9c4f7596a1","_type":"span"}],"_type":"block","upload_doc":null,"uploadAudio":null,"medias":null,"style":"normal","_key":"3e6424f9561d"},{"markDefs":[{"_key":"94b0da9b30f5","nofollow":true,"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/32333835/"}],"children":[{"_type":"span","marks":[],"text":"3. Kulkarni AS, Gubbi S, Barzilai N. ","_key":"942a95d426320"},{"text":"Benefits of metformin in attenuating the hallmarks of aging. 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","_key":"746695cd52170","_type":"span"},{"_type":"span","marks":["518132438d38"],"text":"The relationship between the gut microbiome and metformin as a key for treating type 2 diabetes mellitus.","_key":"2c39d81038db"},{"_type":"span","marks":[],"text":" ","_key":"e31c8442a750"},{"_type":"span","marks":["em"],"text":"Int J Mol Sci.","_key":"3f8fde30690e"},{"_key":"25c09e9f896f","_type":"span","marks":[],"text":" 2021;22(7):3566."}],"_type":"block"},{"uploadAudio":null,"medias":null,"markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/36077358/","_key":"98f2286b98bf"}],"children":[{"_type":"span","marks":[],"text":"5. De Sousa Lages A, Lopes V, Horta J, et al. 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","drugMentions":"{\"drug_mentions\": [\"clozapine\"]}","factCheckAuthors":null,"contentCategory":{"_createdAt":"2020-02-06T09:15:47Z","_rev":"snQqhhB4O8T5bi1viURsgs","_type":"contentCategory","name":"Articles","_id":"8bdaa7fc-960a-4b57-b076-75fdce3741bb","_updatedAt":"2020-02-25T09:35:56Z"},"gptSummary":"The FDA's advisory committees have voted overwhelmingly to dismiss the clozapine REMS protocol, citing it as an unnecessary barrier to treatment. Experts, including Dr. John Kane and Dr. Robert O. Cotes, highlighted clozapine's benefits for treatment-resistant schizophrenia and the challenges posed by REMS, such as delays and disruptions in care. 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Kane and Cotes discussed the clinical context and implications of clozapine for patient populations.","_key":"58adf704430f0","_type":"span","marks":[]},{"marks":["superscript"],"text":"2","_key":"bbfdb38e51b7","_type":"span"}],"_type":"block","style":"normal","_key":"433d0c10b4ee","markDefs":[]},{"_type":"block","style":"normal","_key":"6bd7ddc663c8","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Kane noted that “Clozapine is a cornerstone in the treatment of schizophrenia,” detailing its impact on treatment resistant schizophrenia in general as well as its ability to improve functioning, reduce mortality, reduce risk of relapse, among other clinical features.","_key":"84deadf9c8cc0"},{"_type":"span","marks":["superscript"],"text":"2","_key":"12827f71f7b7"},{"_type":"span","marks":[],"text":" Kane also described the delays in obtaining clozapine, adding that the US lags behind in its use as compared to other countries.","_key":"be42b1dfc088"}]},{"children":[{"_type":"span","marks":[],"text":"Kane specifically addressed the risk of clozapine-induced neutropenia, which has been the foundation for the REMS protocol. He explained that the most serious cases occur within the first 18 weeks and that the risk decreases over time, becoming almost negligible after 2 years. “Long-term risk excess is small compared with advantages of clozapine in outcomes, including life expectancy,” he reported. ”Relaxing long-term monitoring could favor the advantages of clozapine use, without incurring risk of neutropenia.”","_key":"18e22a4b3fd30"},{"marks":["superscript"],"text":"2","_key":"7b77547d7ad1","_type":"span"}],"_type":"block","style":"normal","_key":"aeafb3a8adcf","markDefs":[]},{"_key":"2d2f1b8ac65e","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Meanwhile, Cotes addressed prescriber, patient, and caregiver concerns, including challenges working with some pharmacies in submitting information. 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"},{"_type":"block","style":"normal","_key":"2a455930a838","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":"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"}]},{"markDefs":[],"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":[],"children":[{"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","_type":"span"},{"_type":"span","marks":["superscript"],"text":"3","_key":"3c7ed08f4587"}],"_type":"block","style":"normal","_key":"27d6c40b2c46"},{"children":[{"_type":"span","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":"block","style":"normal","_key":"0b6c6a7ff083","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"},{"marks":["superscript"],"text":"1","_key":"acfaadd1cdfd","_type":"span"}],"_type":"block","style":"normal","_key":"5366de8a504a","markDefs":[]},{"style":"normal","_key":"8ca00f559ec5","markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://www.psychiatrictimes.com/view/clozapine-rems-regulatory-discrimination-against-psychiatrists","_key":"5a7bf474edb0"}],"children":[{"_key":"80b8b91534900","_type":"span","marks":[],"text":"In a recent article for "},{"marks":["em","5a7bf474edb0"],"text":"Psychiatric Times","_key":"80b8b91534901","_type":"span"},{"_type":"span","marks":[],"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":["superscript"],"text":"4","_key":"880f2a14f95c"}],"_type":"block"},{"children":[{"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","_type":"span","marks":[]},{"_key":"c06c83f1b504","_type":"span","marks":["superscript"],"text":"4"},{"_key":"9bd3b0140e8e","_type":"span","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.”"}],"_type":"block","style":"normal","_key":"376432600a8e","markDefs":[]},{"_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"},{"_key":"2cd84761ed9c","_type":"span","marks":["superscript"],"text":"4"},{"_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? 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","_rev":"wAtYdBFli02EyTgIVN4VaN","gptSummary":"Adial Pharmaceuticals has completed a pharmacokinetics study of AD04, a serotonin-3 receptor antagonist for treating alcohol use disorder (AUD). This study informs the design of a phase 3 clinical trial, focusing on optimal dosing for efficacy and safety. Conducted with 30 healthy volunteers, the study assessed the bioavailability and dose proportionality of AD04 compared to a marketed ondansetron tablet. Results indicated lower ondansetron exposure with AD04 and confirmed its administration in fed or fasted states. 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This data will help guide the study design for the upcoming phase 3 clinical trial of AD04.","_key":"855a9e56c29b0","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"1","_key":"f80db535ff0a"}],"_type":"block","style":"normal","_key":"e5a8812eb80c"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"119abd3fbcf00"}],"_type":"block","style":"normal","_key":"2027b333be0c"},{"style":"normal","_key":"85a27dc567c0","markDefs":[],"children":[{"_type":"span","marks":[],"text":"“Completion of this study achieves our goal to obtain the data we needed to design a more precise and informed phase 3 trial protocol, including evaluating the optimal dosing regimen to maximize the efficacy and safety of AD04 in patients with AUD. Its completion is in accord with previous guidance provided by the FDA and is intended to enhance the likelihood of success in our upcoming phase 3 trial,” said Cary Claiborne, president and chief executive officer of Adial.","_key":"f0a34af42e660"}],"_type":"block"},{"_type":"block","style":"normal","_key":"5cf090b1cc33","markDefs":[],"children":[{"_key":"d6c14c6e19220","_type":"span","marks":[],"text":""}]},{"_key":"a0cabcadd906","markDefs":[],"children":[{"_key":"fc22775a398b0","_type":"span","marks":[],"text":"In this single-center, relative bioavailability, open label study, investigators enrolled a total of 30 healthy adult volunteers in 2 cohorts. Heavy drinking was defined as less than 10 drinks/drinking day. Cohort 1 (n=6) was a randomized, open-label, 2-sequence, 2-period crossover study to evaluate the PK variability of ondansetron from AD04 0.33 and 0.99 mg. Cohort 2 (n=24) was a randomized, open-label, 6-sequence, 4-period crossover study to evaluate the relative bioavailability of the AD04 0.33 mg tablet to a marketed ondansetron 4 mg tablet, dose proportionality of ondansetron PK between AD04 0.33 and 0.99 mg, and the effect of food on the bioavailability of ondansetron administered as the AD04 0.33 mg tablet. Results showed that, because of the lower dose, AD04 0.33 mg delivered lower ondansetron PK exposure than the marketed reference standard ondansetron 4 mg tablet. Furthermore, ondansetron PK exposure increased in proportion to dose across a 3-fold AD04 dose range. Lastly, AD04 can be taken in fed or fasted states."}],"_type":"block","style":"normal"},{"_key":"5be8faa3324c","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"9e908a030f680"}],"_type":"block","style":"normal"},{"children":[{"marks":[],"text":"“This relatively short and low-cost study was a key element of our strategy to advance ongoing partnership discussions. Additionally, the study will provide data necessary to support an application for approval of AD04 under a 505(b)(2) regulatory pathway with the FDA. We plan to engage with the FDA during Q4 2024 with the results of this pharmacokinetics study and obtain feedback which will assist with the AD04 phase 3 study program. 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Adial Pharmaceuticals announces positive topline results from the AD04-103 pharmacokinetics study of AD04 for the treatment of alcohol use disorder. News release. November 14, 2024. ","_key":"27ef8dfe90b70","_type":"span","marks":[]},{"_type":"span","marks":["09f7d27bf55e"],"text":"https://www.adial.com/adial-pharmaceuticals-announces-positive-topline-results-from-the-ad04-103-pharmacokinetics-study-of-ad04-for-the-treatment-of-alcohol-use-disorder/","_key":"27ef8dfe90b71"}],"_type":"block","style":"normal"},{"markDefs":[{"href":"https://www.who.int/news-room/fact-sheets/detail/alcohol","_key":"0dc23cea65c3","blank":true,"_type":"link"}],"children":[{"_type":"span","marks":[],"text":"2. Alcohol. World Health Organization. May 9, 2022. Accessed November 14, 2024. 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Today, we will address 4 of them.","_key":"71338ce3cff21"}]},{"style":"normal","_key":"34fc570ee2b6","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Welcome to ","_key":"e9fd90e430050"},{"_type":"span","marks":["em"],"text":"PsychPearls","_key":"e9fd90e430051"},{"_key":"e9fd90e430052","_type":"span","marks":[],"text":" podcast with "},{"text":"Psychiatric Times","_key":"e9fd90e430053","_type":"span","marks":["em"]},{"_type":"span","marks":["superscript"],"text":"TM","_key":"e9fd90e430054"},{"_type":"span","marks":[],"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":"block"},{"markDefs":[],"children":[{"_key":"ea53b84443740","_type":"span","marks":[],"text":"I am Chris Aiken, the Mood Disorders Section Editor for "},{"_type":"span","marks":["em"],"text":"Psychiatric Times","_key":"ea53b84443741"},{"_type":"span","marks":["superscript"],"text":"TM","_key":"ea53b84443742"},{"marks":[],"text":" and the editor-in-chief of the ","_key":"2a1d567b6175","_type":"span"},{"_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"},{"_key":"9e73ca7194e2","markDefs":[],"children":[{"text":"A Quiet Launch","_key":"86ea5d507ff30","_type":"span","marks":["strong"]}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"afec8962a0580"},{"_type":"span","marks":[],"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":"block","style":"normal","_key":"a63f35be65e5"},{"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"},{"markDefs":[],"children":[{"_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":"64d6e68df2480"},{"_type":"span","marks":["superscript"],"text":"1","_key":"73fb7856ebbe"},{"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","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"2b3bbb539720"},{"style":"normal","_key":"184030a32757","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"},{"_key":"233f91ee925a","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"A Warning","_key":"75b3c80a10a30"}],"_type":"block","style":"normal"},{"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"3959c05423550"},{"_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.","_key":"3959c05423551"},{"_key":"0fbe71658c79","_type":"span","marks":["superscript"],"text":"2"},{"_key":"ed9d37b2069d","_type":"span","marks":[],"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."}],"_type":"block","style":"normal","_key":"7117c4dbf031","markDefs":[]},{"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"},{"style":"normal","_key":"c81541e1df53","markDefs":[],"children":[{"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":"span"}],"_type":"block"},{"children":[{"_key":"6fbf95ee9eec0","_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:"},{"_type":"span","marks":[],"text":" And now let us get into those myths. There are 4 of them.","_key":"6fbf95ee9eec1"}],"_type":"block","style":"normal","_key":"fc3dcfb76df8","markDefs":[]},{"_key":"842419cc5dfe","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Myth #1: Lamotrigine does not help mania","_key":"9731eb6e18c90"}],"_type":"block","style":"normal"},{"style":"normal","_key":"28425af347c4","markDefs":[],"children":[{"marks":[],"text":"Myth #2: Lamotrigine does not treat acute episodes of bipolar depression","_key":"1d6c4971e1980","_type":"span"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Myth #3: Lamotrigine is a weak mood stabilizer","_key":"a2875e7deb100"}],"_type":"block","style":"normal","_key":"90e174ac7e84"},{"_type":"block","style":"normal","_key":"fa86dd8111b0","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Myth #4: It is a good idea to stop lamotrigine when a patient relapses, because it is probably not working","_key":"1cc4573623ed0"}]},{"style":"normal","_key":"eb46f4b7a0af","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Myth #1: Lamotrigine Does not Help Mania","_key":"6e5992c2c46f0"}],"_type":"block"},{"_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"},{"style":"normal","_key":"3011d070f04a","markDefs":[],"children":[{"_key":"8aa3f8afb5920","_type":"span","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."},{"_type":"span","marks":["superscript"],"text":"4,5","_key":"b9fcb60198b3"}],"_type":"block"},{"children":[{"_type":"span","marks":["strong"],"text":"Myth #2: Lamotrigine Does Treat Acute Episodes of Bipolar Depression","_key":"facc22eea3890"}],"_type":"block","style":"normal","_key":"bc02774e1673","markDefs":[]},{"_type":"block","style":"normal","_key":"16a54e6b696b","markDefs":[],"children":[{"_key":"1512b45c33820","_type":"span","marks":["strong"],"text":"CHRIS AIKEN:"},{"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","_type":"span","marks":[]}]},{"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":"5943f97d91b3"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"1672bd87395e0"},{"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":"span","marks":[]}],"_type":"block","style":"normal","_key":"0b93e13917dc"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"7bf5ca1291820"},{"_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.","_key":"7bf5ca1291821"}],"_type":"block","style":"normal","_key":"80917ad9e22c"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"2d03b35c77350"},{"_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"},{"markDefs":[],"children":[{"_key":"e869be0741ea0","_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."}],"_type":"block","style":"normal","_key":"2901ac965eb3"},{"children":[{"marks":["strong"],"text":"CHRIS AIKEN:","_key":"b8f816b9efef0","_type":"span"},{"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","marks":[]},{"_type":"span","marks":["superscript"],"text":"9","_key":"d99521f436db"},{"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":"span","marks":[]}],"_type":"block","style":"normal","_key":"2629a4935e8d","markDefs":[]},{"_key":"e770fed2200f","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME","_key":"602738f0ff8b0"},{"_type":"span","marks":[],"text":": Are you off your soap box yet?","_key":"602738f0ff8b1"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"c1859d28767c0"},{"_key":"c1859d28767c1","_type":"span","marks":[],"text":" No, I have one more thing to say. The "},{"_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"},{"children":[{"_key":"69bc2c73c4fe0","_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:"},{"_type":"span","marks":[],"text":" OK, can we get back to lamotrigine now.","_key":"69bc2c73c4fe1"}],"_type":"block","style":"normal","_key":"281873e8c0d3","markDefs":[]},{"children":[{"_key":"a045c4658a1e0","_type":"span","marks":["strong"],"text":"Myth #3: Lamotrigine Is a Weak Mood Stabilizer"}],"_type":"block","style":"normal","_key":"1c2d625d230e","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"af6b65c916ab0"},{"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","marks":[]}],"_type":"block","style":"normal","_key":"22b7dd918fb9"},{"_key":"28aae8f32b92","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Individuals with bipolar disorder die 10 years earlier on average, and not from suicide. 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Lamotrigine is neutral on all of them, and "},{"_type":"span","marks":["0fb886e1546c"],"text":"lithium brings down","_key":"c84f7e8587672"},{"_type":"span","marks":[],"text":" most of them. Specifically, lithium lowers the risk of heart disease, ","_key":"c84f7e8587673"},{"_type":"span","marks":["d41529e80f4d"],"text":"stroke","_key":"c84f7e8587674"},{"text":", cancer, viral infections, and suicide.","_key":"c84f7e8587675","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"3c9ab1d299ba"},{"markDefs":[],"children":[{"text":"KELLIE NEWSOME:","_key":"49567e5202790","_type":"span","marks":["strong"]},{"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.","_key":"49567e5202791","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"1","_key":"ec60417890f9"},{"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","marks":[]},{"_type":"span","marks":["superscript"],"text":"3","_key":"e33cb03a7664"}],"_type":"block","style":"normal","_key":"0c8384d790a6"},{"style":"normal","_key":"836bb2d48eed","markDefs":[],"children":[{"text":"CHRIS AIKEN:","_key":"922aa9e34a480","_type":"span","marks":["strong"]},{"_type":"span","marks":[],"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":"block"},{"style":"normal","_key":"2fecb70096c1","markDefs":[],"children":[{"_type":"span","marks":[],"text":"And that brings us to the fourth myth.","_key":"4208a7ebf9fb0"}],"_type":"block"},{"_type":"block","style":"normal","_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":[{"_type":"span","marks":["strong"],"text":"KELLIE NEWSOME:","_key":"e6e53933eaea0"},{"_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":"blockquote","_key":"0027df6157f5","markDefs":[],"children":[{"_key":"ccb544652fbd0","_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."}]},{"children":[{"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"},{"_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","markDefs":[]},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"CHRIS AIKEN:","_key":"6413e50b25ef0"},{"_type":"span","marks":[],"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":"block","style":"normal","_key":"0bae815f4e09"},{"children":[{"text":"KELLIE NEWSOME:","_key":"b02c937742660","_type":"span","marks":["strong"]},{"text":" What is that?","_key":"b02c937742661","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"2cc02bd19ecc","markDefs":[]},{"markDefs":[{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/18402630/","_key":"3c66a7c96c61"},{"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/20846461/","_key":"230edd4b803d","blank":true},{"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/29944976/","_key":"b9eb677aeb0e"}],"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. 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","_key":"0086abeb16ef3"},{"_type":"span","marks":[],"text":"2004;65(3):432-441.","_key":"0086abeb16ef4"}],"_type":"block"},{"style":"normal","_key":"65bca383bfcd","markDefs":[{"href":"https://www.ncbi.nlm.nih.gov/pubmed/23945444","_key":"cb083527de84","blank":true,"_type":"link"}],"children":[{"_type":"span","marks":[],"text":"2. Reid JG, Gitlin MJ, Altshuler LL. ","_key":"cb46d4e52c3d0"},{"text":"Lamotrigine in psychiatric disorders.","_key":"cb46d4e52c3d1","_type":"span","marks":["cb083527de84"]},{"text":" ","_key":"d028c0590145","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"J Clin Psychiatry. ","_key":"cb46d4e52c3d2"},{"_type":"span","marks":[],"text":"2013;74:675-684.","_key":"cb46d4e52c3d3"}],"_type":"block"},{"markDefs":[{"href":"https://www.ncbi.nlm.nih.gov/pubmed/20532155","_key":"3676c2e5698d","blank":true,"_type":"link"}],"children":[{"_type":"span","marks":[],"text":"3. Aiken CB, Orr C. ","_key":"66b2ea74dbaa0"},{"_type":"span","marks":["3676c2e5698d"],"text":"Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature.","_key":"66b2ea74dbaa1"},{"_type":"span","marks":[],"text":" ","_key":"d8517851c886"},{"marks":["em"],"text":"Psychiatry (Edgmont).","_key":"66b2ea74dbaa2","_type":"span"},{"_type":"span","marks":[],"text":" 2010;7:27-32.","_key":"66b2ea74dbaa3"}],"_type":"block","style":"normal","_key":"2f89a580de66"},{"_key":"a15b3b40d8a6","markDefs":[{"blank":true,"_type":"link","href":"https://www.ncbi.nlm.nih.gov/pubmed/15708424","_key":"96923a3ac473"}],"children":[{"_type":"span","marks":[],"text":"4. Manning JS, Haykal RF, Connor PD, et al. ","_key":"c24cc23d45300"},{"_type":"span","marks":["96923a3ac473"],"text":"Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament.","_key":"c24cc23d45301"},{"_type":"span","marks":[],"text":" ","_key":"bfeb38779038"},{"_type":"span","marks":["em"],"text":"J Affect Disord","_key":"c24cc23d45302"},{"text":". 2005;84:259-266.","_key":"c24cc23d45303","_type":"span","marks":[]}],"_type":"block","style":"normal"},{"_key":"3ee2ca0f1314","markDefs":[{"blank":true,"_type":"link","href":"https://www.ncbi.nlm.nih.gov/pubmed/17543894","_key":"187a40acf134"}],"children":[{"_type":"span","marks":[],"text":"5. Goldberg JF, Bowden CL, Calabrese JR. 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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"},{"_type":"span","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","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","style":"normal","_key":"359e59e78751","markDefs":[]},{"markDefs":[],"children":[{"marks":[],"text":"","_key":"eb0099bdaa3c0","_type":"span"}],"_type":"block","style":"normal","_key":"c2cdffa852f9"},{"markDefs":[],"children":[{"_key":"585c406c944f0","_type":"span","marks":["strong"],"text":"Pathophysiology of Aggression"}],"_type":"block","style":"normal","_key":"036d61e37567"},{"_key":"356f2dbed995","markDefs":[{"nofollow":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":"72ecb582670c"}],"children":[{"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"},{"_type":"span","marks":["superscript"],"text":"5","_key":"040930df2173"},{"_type":"span","marks":[],"text":" ","_key":"74d5ecd0f6db"},{"_type":"span","marks":["em"],"text":"DRD4 ","_key":"7009282786921"},{"_key":"7009282786922","_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."},{"_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"},{"_type":"span","marks":["superscript"],"text":"7","_key":"60fe3483c239"},{"_key":"22d3658ad558","_type":"span","marks":[],"text":" as well as in the thalamus, hypothalamus, and olfactory bulb."},{"_type":"span","marks":["superscript"],"text":"8 ","_key":"c0b3bfe55a52"},{"_key":"e53036559eef","_type":"span","marks":[],"text":"The "},{"marks":["em"],"text":"DRD4","_key":"7009282786923","_type":"span"},{"_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"},{"_type":"span","marks":["superscript"],"text":"9","_key":"d84c18b89fd3"},{"_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"},{"text":"But it has also been associated with novelty seeking,","_key":"0bdff740d307","_type":"span","marks":[]},{"_type":"span","marks":["superscript"],"text":"14-17","_key":"bb2f4480568d"},{"_key":"97c46314e1f9","_type":"span","marks":[],"text":" impulsivity,"},{"marks":["superscript"],"text":"15,18","_key":"802612b52b08","_type":"span"},{"marks":[],"text":" anger,","_key":"36f01763f485","_type":"span"},{"_key":"ab0f4ac073c9","_type":"span","marks":["superscript"],"text":"16"},{"_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"},{"_type":"span","marks":[],"text":" The ","_key":"0cf83948b081"},{"_type":"span","marks":["strong","72ecb582670c"],"text":"Table","_key":"7009282786925"},{"_type":"span","marks":["strong"],"text":" ","_key":"f62db6398269"},{"_type":"span","marks":[],"text":"summarizes the affinities, expressed as dissociation constants (Ki), of several antipsychotics.","_key":"7009282786926"},{"_type":"span","marks":["superscript"],"text":"20-22","_key":"5d9ba87e2454"},{"_key":"de1efa2ff898","_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."},{"marks":["superscript"],"text":"23 ","_key":"ee21b11430d3","_type":"span"}],"_type":"block","style":"normal"},{"imgcaption":[{"_key":"cf6ed237bd1e","markDefs":[],"children":[{"_key":"4b30705771d60","_type":"span","marks":["strong"],"text":"Table. The Affinity, Expressed as the Dissociation Constant (Ki) for a Selected Group of Second-Generation Antipsychotics"},{"marks":["strong","superscript"],"text":"20-22","_key":"651e28ab15e0","_type":"span"}],"_type":"block","style":"normal"},{"_key":"fdb040a815aa","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"587b459e53130"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"text":"The D4/D2 affinity ratio is calculated as the ratio of the inverse of the Ki.","_key":"34df90fef6fe0","_type":"span","marks":[]}],"_type":"block","style":"normal","_key":"0440763a1b94"},{"style":"normal","_key":"cfa70480d8eb","markDefs":[],"children":[{"_type":"span","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":"block"}],"_key":"a16d70deb086","asset":{"_ref":"image-aa3baeda4703fa036fd74a42fbc01ad86c954b02-940x410-png","_type":"reference"},"blank":true,"disableTextWrap":false,"alt":"Table. The Affinity, Expressed as the Dissociation Constant (Ki) for a Selected Group of Second-Generation Antipsychotics","_type":"figure","alignment":"right","widthP":50,"disableLightBox":true},{"_type":"block","style":"normal","_key":"7d160da85dad","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Anti-Aggression Agents","_key":"2551522321f20"}]},{"_key":"d87b487caeda","markDefs":[],"children":[{"_type":"span","marks":[],"text":"The most effective anti-aggression agent available is clozapine.","_key":"4f1ea9f10ba90"},{"text":"24","_key":"ade4c0529363","_type":"span","marks":["superscript"]},{"text":" This has been repeatedly demonstrated in open studies","_key":"64082846094b","_type":"span","marks":[]},{"_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"},{"_type":"span","marks":[],"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"},{"marks":["superscript"],"text":"29","_key":"573babd98c86","_type":"span"},{"_type":"span","marks":[],"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":["em"],"text":"P","_key":"4f1ea9f10ba91"},{"_type":"span","marks":[],"text":" \u003c 0.001, aggression against property: OR = 1.85, ","_key":"4f1ea9f10ba92"},{"text":"P ","_key":"4f1ea9f10ba93","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":"\u003c 0.001, and verbal aggression: OR = 1.35, ","_key":"4f1ea9f10ba94"},{"_key":"4f1ea9f10ba95","_type":"span","marks":["em"],"text":"P"},{"text":" \u003c 0.001), and olanzapine (physical aggression: OR = 1.33, ","_key":"4f1ea9f10ba96","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba97"},{"text":" \u003c 0.001, and verbal aggression: OR = 1.32, ","_key":"4f1ea9f10ba98","_type":"span","marks":[]},{"_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"},{"_key":"4f1ea9f10ba911","_type":"span","marks":["em"],"text":"P"},{"_type":"span","marks":[],"text":" = 0.78) (risperidone not examined in this study).","_key":"4f1ea9f10ba912"},{"_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"},{"_type":"span","marks":[],"text":" \u003c 0.001, aggression against property: OR 1.67, ","_key":"4f1ea9f10ba914"},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba915"},{"text":" \u003c 0.001, but not verbal aggression: OR = 1.03, ","_key":"4f1ea9f10ba916","_type":"span","marks":[]},{"marks":["em"],"text":"P","_key":"4f1ea9f10ba917","_type":"span"},{"_type":"span","marks":[],"text":" = 0.57).","_key":"4f1ea9f10ba918"},{"_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"},{"marks":[],"text":" = 0.019) and was superior to risperidone (","_key":"4f1ea9f10ba920","_type":"span"},{"marks":["em"],"text":"P","_key":"4f1ea9f10ba921","_type":"span"},{"marks":[],"text":" = 0.012) and haloperidol (","_key":"4f1ea9f10ba922","_type":"span"},{"_type":"span","marks":["em"],"text":"P","_key":"4f1ea9f10ba923"},{"_type":"span","marks":[],"text":" = 0.021) but not olanzapine.","_key":"4f1ea9f10ba924"},{"text":"30","_key":"eb78d086bbbb","_type":"span","marks":["superscript"]},{"_type":"span","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","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"},{"text":"Egr3","_key":"4f1ea9f10ba925","_type":"span","marks":["em"]},{"_type":"span","marks":[],"text":", knockout) in which the animals become aggressive.","_key":"4f1ea9f10ba926"},{"_type":"span","marks":["superscript"],"text":"32","_key":"6be8888079fe"}],"_type":"block","style":"normal"},{"_key":"00d4ce674333","markDefs":[],"children":[{"_key":"3d3a97be187f0","_type":"span","marks":[],"text":""}],"_type":"block","style":"normal"},{"_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"},{"marks":["superscript"],"text":"33","_key":"3918cb318c12","_type":"span"},{"_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"},{"text":" \u003c 0.0001), and total (–14.7 ± 11.59 vs. –5.4 ± 10.12, ","_key":"ba7b7c46b2d02","_type":"span","marks":[]},{"_type":"span","marks":["em"],"text":"P","_key":"ba7b7c46b2d03"},{"_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.","_key":"ba7b7c46b2d04"},{"text":"34","_key":"ab7135cee003","_type":"span","marks":["superscript"]},{"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"},{"_key":"f2e7651e8fca","_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)."},{"marks":["superscript"],"text":"36","_key":"11e45dfdba77","_type":"span"},{"_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.","_key":"4bb32e731f21"},{"_type":"span","marks":["superscript"],"text":"5","_key":"3ec839083c13"}]},{"children":[{"_type":"span","marks":[],"text":"","_key":"3eea52006e950"}],"_type":"block","style":"normal","_key":"08bf5f62a753","markDefs":[]},{"_type":"block","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"},{"_type":"span","marks":[],"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":["superscript"],"text":"38-40","_key":"2d0982906700"},{"_type":"span","marks":[],"text":" and inhalable formulations.","_key":"7e867f011f2e"},{"_type":"span","marks":["superscript"],"text":"41-43","_key":"69daa13d0c7c"},{"_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"},{"_type":"span","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","marks":["superscript"],"text":"45","_key":"e20ed29c7dbc"},{"_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.","_key":"d989c3c10ffe"}]},{"markDefs":[],"children":[{"marks":[],"text":"","_key":"e8d20c8ff0b60","_type":"span"}],"_type":"block","style":"normal","_key":"f5ed401d5cda"},{"_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},{"_key":"57e734fa5f24","nofollow":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"}],"children":[{"_type":"span","marks":[],"text":"Olanzapine and risperidone also have D4 affinities that exceeds D2 affinities (","_key":"b34326e935c90"},{"_type":"span","marks":["strong","57e734fa5f24"],"text":"Table","_key":"b34326e935c91"},{"_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 ("},{"_type":"span","marks":["strong","80bb7ee11446"],"text":"Table","_key":"b34326e935c93"},{"_key":"b34326e935c94","_type":"span","marks":[],"text":")."},{"_type":"span","marks":["superscript"],"text":"20-22","_key":"4bdeee6e8eaa"},{"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"},{"_type":"span","marks":["superscript"],"text":"29","_key":"e99a75e2e4fc"},{"_type":"span","marks":[],"text":" which does not appear to be the case for clozapine.","_key":"4a04c7674cad"},{"_key":"3d2987dfd041","_type":"span","marks":["superscript"],"text":"29-31"}],"_type":"block","style":"normal"},{"style":"normal","_key":"7367d4649dd6","markDefs":[],"children":[{"marks":[],"text":"","_key":"c8dd077e91130","_type":"span"}],"_type":"block"},{"_type":"block","style":"normal","_key":"c7fa69c0b548","markDefs":[],"children":[{"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"},{"_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","_key":"bcbb3c6a0f0e","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"fa4c62ae007a0"}]},{"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":[{"_key":"85bc489e03f40","_type":"span","marks":[],"text":""}],"_type":"block"},{"_type":"block","style":"normal","_key":"b5e231a22dbf","markDefs":[],"children":[{"_type":"span","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"}]},{"children":[{"_type":"span","marks":[],"text":"","_key":"754427ff02c70"}],"_type":"block","style":"normal","_key":"4edb09e6a7cf","markDefs":[]},{"children":[{"_type":"span","marks":["strong"],"text":"Dr El-Mallakh ","_key":"90a97cfe5fe10"},{"_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":"90a97cfe5fe11"},{"_type":"span","marks":["strong"],"text":"Dr Aydin ","_key":"90a97cfe5fe12"},{"_type":"span","marks":["em"],"text":"is a postdoctoral researcher at","_key":"90a97cfe5fe13"},{"_type":"span","marks":[],"text":" ","_key":"90a97cfe5fe14"},{"_type":"span","marks":["em"],"text":"the University of Louisville School of Medicine in Louisville, Kentucky.","_key":"90a97cfe5fe15"}],"_type":"block","style":"normal","_key":"6c473f05afcb","markDefs":[]},{"style":"normal","_key":"04a830889b15","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"c87820cb47a50"}],"_type":"block"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"References","_key":"3a0e0ca00ab70"}],"_type":"block","style":"normal","_key":"1af9e1ae593e"},{"style":"normal","_key":"e72697b86550","markDefs":[{"blank":true,"_type":"link","href":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783168/","_key":"ac68ff4a2c04"}],"children":[{"_key":"0f184534c3ba0","_type":"span","marks":[],"text":"1. Girasek H, Nagy VA, Fekete S, et al. "},{"_type":"span","marks":["ac68ff4a2c04"],"text":"Prevalence and correlates of aggressive behavior in psychiatric inpatient populations.","_key":"0f184534c3ba1"},{"_key":"5a4f8003cff4","_type":"span","marks":[],"text":" "},{"_type":"span","marks":["em"],"text":"World J Psychiatry","_key":"0f184534c3ba2"},{"text":". 2022;12(1):1-23.","_key":"0f184534c3ba3","_type":"span","marks":[]}],"_type":"block"},{"markDefs":[{"blank":true,"_type":"link","href":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508769/","_key":"0a44e22c5ea6"}],"children":[{"_key":"955010daff290","_type":"span","marks":[],"text":"2. Pescosolido BA, Monahan J, Link BG, et al. 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Miller, MD"}],"is_visible":true,"_createdAt":"2024-11-07T15:32:17Z","published":"2024-11-07T16:00:53.264Z","ExcludeFromPubMedXML":false,"authors":[{"displayName":"John J. Miller, MD","url":"john-j-miller-md"}],"issueGroup":{"_ref":"7d283d85-869a-4578-b7e0-00266f149eb6","_type":"reference"},"_type":"article","gptTakeaways":"• KarXT (Cobenfy) introduces a novel nondopaminergic mechanism for schizophrenia treatment, combining xanomeline and trospium to target muscarinic cholinergic receptors.\n\n• Clinical trials demonstrated KarXT's efficacy and safety, showing significant improvement in PANSS scores without traditional antipsychotic adverse effects.\n\n• Cobenfy is not classified as an antipsychotic, lacking dopamine-2 receptor antagonism, and may offer benefits for cognitive and negative symptoms.\n\n• Prescribers must familiarize themselves with Cobenfy's unique properties, as it represents a shift in schizophrenia treatment towards muscarinic cholinergic pathways.","url":"schizophrenia-pharmacology-version-2-0","factCheckAuthors":null,"audioUrl":"https://s3.us-east-1.amazonaws.com/ai-generated-audios/www.psychiatrictimes.com/7790f21f-cb1b-48b0-baed-1a572750c605_1730993555775.37be70b1-cf54-43e8-a7c9-e6c7d7cbd585.mp3","_id":"7790f21f-cb1b-48b0-baed-1a572750c605","documentGroupMapping":null,"_rev":"GksL79ka788Sw0D3X5MKiL","gptSummary":"The FDA's approval of KarXT (Cobenfy) marks a significant advancement in schizophrenia treatment, introducing a novel nondopaminergic mechanism. Developed by Karuna Therapeutics, KarXT combines xanomeline and trospium to target muscarinic cholinergic receptors, potentially improving symptoms without the adverse effects associated with traditional antipsychotics. Clinical trials demonstrated its efficacy and safety, distinguishing it from dopamine-2 receptor antagonists. Cobenfy's approval signifies a shift in schizophrenia treatment, focusing on muscarinic cholinergic pathways. Prescribers must understand its unique properties and potential benefits for cognitive and negative symptoms.","summary":"The medication treatment of schizophrenia has finally diversified to a novel neurotransmitter system: the muscarinic cholinergic system.","documentGroup":null,"articleType":"Publication","body":[{"asset":{"_ref":"image-35d1f00931670ff03617de6b210f8376e4210447-4581x2618-jpg","_type":"reference"},"imgcaption":[{"_type":"block","style":"normal","_key":"21307c7766de","markDefs":[],"children":[{"_key":"af0f9da9475a0","_type":"span","marks":[],"text":"ipopba/AdobeStock"}]}],"disableTextWrap":false,"_type":"figure","_key":"e14664737add","alignment":"left","disableLightBox":true,"alt":"pharmacology","widthP":50},{"style":"normal","_key":"48544abe5f72","markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://www.psychiatrictimes.com/topics/schizophrenia","_key":"d81b4629fb70"}],"children":[{"_type":"span","marks":[],"text":"September 26, 2024, turned out to be a paradigm-changing day for the treatment of individuals with ","_key":"efb75d31820c0"},{"_type":"span","marks":["d81b4629fb70"],"text":"schizophrenia","_key":"5ea1c038fe79"},{"marks":[],"text":". KarXT (Cobenfy) was approved by the US Food and Drug Administration (FDA) after a 15-year journey that started with a young scientist’s remarkable vision for developing a medication with the first new mechanism of action since 1954 to treat individuals with schizophrenia. The name KarXT defines the story: a small start-up company named Karuna Therapeutics, Inc, hypothesized that by combining 2 well-established molecules—xanomeline and trospium—brain circuits associated with schizophrenia could be modulated by a novel nondopaminergic mechanism to improve symptoms and have an entirely different pharmacology than all the other medications currently approved to treat schizophrenia that were developed over the past 70 years.","_key":"2324ff57db30","_type":"span"}],"_type":"block"},{"_type":"block","style":"normal","_key":"ebc371cb72fd","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"The Visionary","_key":"1570d908a5750"}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"At age 27, Andrew Miller, who had just completed his chemical engineering doctorate, began to explore possible innovations for unmet needs in medicine. With no background in pharmacology or medicine, after much effort and investigation, Dr Miller became passionate about developing a new treatment for schizophrenia. Researching the existing literature on possible novel mechanisms of action, he identified an established model of treating cognitive and psychotic symptoms by agonizing 2 specific muscarinic cholinergic receptors (mAChRs) in the brain: M1 and M4. Back in the 1990s, Eli Lilly and Company studied xanomeline, a molecule that binds tightly to all 5 of the mAChRs and has significant agonism activity at the M1 and M4 receptors, as a possible treatment for cognitive function in Alzheimer disease. Significantly, xanomeline demonstrated improvement compared with placebo in cognitive function, and in an astounding and serendipitous finding, it also demonstrated improvements in psychotic symptoms in patients with Alzheimer disease. Subsequently, data from a study demonstrated improvement in psychosis and cognition in patients with schizophrenia. However, further development of xanomeline was abandoned due to the poor tolerability that is expected from a medication that agonizes the mAChRs in the peripheral nervous system, specifically nausea, vomiting, diarrhea, sweating, and salivation.","_key":"0d95956b7ca60"}],"_type":"block","style":"normal","_key":"56eb1cc39b5c"},{"style":"normal","_key":"c9e779451b41","markDefs":[],"children":[{"text":"Thinking outside the metaphorical box, Dr Miller asked himself if adding an anticholinergic medication that could not cross the blood-brain barrier might just allow for the central M1 and M4 agonism while mitigating the peripheral mAChR adverse effects. Dr Miller and colleagues created a list of all existing candidate medication combinations, which numbered 7410. The first combination on that list was xanomeline and trospium—an anticholinergic medication the FDA approved in 2004 for overactive bladder. Dr Miller hypothesized that finding an optimal dosing combination of xanomeline and trospium could provide the central benefits for psychosis and cognition while minimizing the peripheral adverse events. The final obstacle in testing this hypothesis was a lack of financial resources, with only $4000 left in the bank account. At this point in the journey, Dr Miller was the only employee of Karuna, which was founded around the development of KarXT. He applied for funding from the Wellcome Trust, a philanthropic organization based in the United Kingdom, which awarded Karuna funding for the initial clinical trial with KarXT. With $5.5 million in hand, Dr Miller could assemble a team to investigate whether or not the xanomeline/trospium combination had a future in the treatment of individuals with schizophrenia.","_key":"ed5a6a468e560","_type":"span","marks":[]}],"_type":"block"},{"_key":"4d7974fdaa73","markDefs":[],"children":[{"marks":["strong"],"text":"KarXT Clinical Development","_key":"320c2f9baf250","_type":"span"}],"_type":"block","style":"normal"},{"style":"normal","_key":"b01d0137fbcc","markDefs":[],"children":[{"_key":"c65ebfc1d0d90","_type":"span","marks":[],"text":"The phase 2 clinical trial, named EMERGENT-1, was a 5-week double-blind placebo-controlled trial of KarXT in individuals with schizophrenia experiencing a significant relapse of symptoms, with an average Positive and Negative Syndrome Scale (PANSS) total score of 97, which places these patients in the “markedly ill” category. At the end of 5 weeks, the least square mean (LSM) improvement in total PANSS score, the primary outcome, in the KarXT group was 11.6 points greater than in the placebo group, with an effect size of 0.81."},{"_type":"span","marks":["superscript"],"text":"1 ","_key":"9d7bca75dd6b"},{"_type":"span","marks":[],"text":"This robust outcome paved the way for 2 more identically designed phase 3 trials (EMERGENT-2 and -3), the findings of which demonstrated a similar improvement in the total PANSS score compared with placebo, as well as strong effect sizes (LSM improvements, 9.6 points and 8.4 points; effect sizes, 0.61 and 0.60, respectively).","_key":"bce7ed37ab6d"},{"_type":"span","marks":["superscript"],"text":"2,3","_key":"a74c806f7f08"},{"_type":"span","marks":[],"text":" Finally, 2 open-label, 52-week phase 3 studies designed to further assess the long-term safety, tolerability, and efficacy of KarXT in adult patients with schizophrenia were completed. Data from those studies, EMERGENT-4 and -5, supported the findings of the 5-week studies.","_key":"497e4976e003"},{"_type":"span","marks":["superscript"],"text":"4,5","_key":"2d1c1312d2a4"}],"_type":"block"},{"_type":"block","style":"normal","_key":"2dd49e8b1fc0","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Not an Antipsychotic","_key":"abc7560b1b350"}]},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"Significantly, in the FDA product insert (PI), Cobenfy is defined as being “indicated for the treatment of schizophrenia in adults.”","_key":"f1e51ebf4f090"},{"_type":"span","marks":["superscript"],"text":"6","_key":"bcb7559f53dd"},{"_type":"span","marks":[],"text":" Throughout the PI, it is never referred to as an antipsychotic medication. This is notable, as the FDA has described all other medications currently approved to treat schizophrenia, from chlorpromazine (Thorazine) in 1954 to lumateperone (Caplyta) in 2019, as antipsychotics. A common property of all these antipsychotic medications is antagonism or antagonism/partial agonism of the dopamine-2 receptor (D2R), which has been hypothesized to be the mechanism that decreases the positive symptoms of schizophrenia, such as auditory hallucinations and delusions.","_key":"9c26f867690b"}],"_type":"block","style":"normal","_key":"2970e2991a81"},{"markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://www.psychiatrictimes.com/view/medication-pipeline-schizophrenia-and-ptsd","_key":"5f62ae5fa389"}],"children":[{"marks":[],"text":"Schizophrenia has been well established as a syndrome with 3 primary symptom clusters—positive, negative, and cognitive symptoms. However, from 1954, when chlorpromazine became available in the United States, the treatment focus turned almost entirely to treatment of the positive symptoms because these responded to D2R blockade. Unfortunately, the antagonism of D2Rs in other parts of the brain comes at quite a cost, worsening the cognitive and negative symptoms (called secondary),","_key":"9557d6ae08350","_type":"span"},{"text":"7","_key":"ff18a76de960","_type":"span","marks":["superscript"]},{"_type":"span","marks":[],"text":" muscle dystonia, akathisia, drug- induced parkinsonism, tardive dyskinesia, weight gain, sedation, prolactin elevation, neuroleptic malignant syndrome, and others. Cobenfy has not demonstrated any of these adverse events. It remains to be seen if Cobenfy improves cognitive and/or negative symptoms in schizophrenia. Additionally, Cobenfy has no boxed warnings from the FDA, and its adverse events, contraindications, warnings, and precautions documented in its PI are quite different from the antipsychotic medications we have been prescribing for the past 70 years. As a result, the prescriber has much to learn about this novel treatment option for individuals with schizophrenia. The interested reader can learn more about the putative mechanism of action of Cobenfy in ","_key":"7b2cb6614b94"},{"_type":"span","marks":["5f62ae5fa389"],"text":"reference 8","_key":"3ab02daadccb"},{"_type":"span","marks":[],"text":".","_key":"f660df0dff5d"},{"text":"8","_key":"97a1f9417b89","_type":"span","marks":["superscript"]}],"_type":"block","style":"normal","_key":"1923035f4778"},{"_key":"16e913c4cc67","markDefs":[],"children":[{"_key":"a8241f80c94c0","_type":"span","marks":["strong"],"text":"Adverse Events, Warnings"}],"_type":"block","style":"normal"},{"_type":"block","style":"normal","_key":"5488a7bba695","markDefs":[{"blank":true,"_type":"link","href":"https://www.psychiatrictimes.com/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2Fbfd7da2da86e0aee0aff179174f205eb06bdeaf8-250x638.png%3Ffit%3Dcrop%26auto%3Dformat\u0026w=640\u0026q=75","_key":"aa45d3edf823","nofollow":true}],"children":[{"_key":"cdbe1d4741530","_type":"span","marks":[],"text":"Both xanomeline and trospium target the muscarinic cholinergic system, albeit oppositional to each other. Xanomeline has a strong affinity to all 5 mAChRs but significantly agonizes only 2: the M1 and the M4. Its action at these 2 mAChRs in the brain is hypothesized to decrease presynaptic dopamine release in the circuits relevant to schizophrenia while not affecting the circuits involved in motor function or hormones. In the peripheral nervous system, xanomeline demonstrates the expected adverse effects of nausea, vomiting, diarrhea, hypersalivation, and sweating. Trospium, which poorly crosses the blood-brain barrier, has minimal effects on the central nervous system but mitigates the procholinergic adverse effects of xanomeline in the peripheral nervous system through its anticholinergic activity. Not surprisingly, the common adverse events result from either procholinergic or anticholinergic activity, demonstrating the delicate balance that results from optimally dosing these 2 opposing mechanisms. "},{"_type":"span","marks":["strong","aa45d3edf823"],"text":"Table 1","_key":"9d0b15f5042c"},{"_type":"span","marks":[],"text":" lists the common adverse events of Cobenfy.","_key":"e1f0ce9aeeab"}]},{"alt":"TABLE 1. Common Adverse Reactions to Cobenfy","disableLightBox":true,"imgcaption":[{"markDefs":[],"children":[{"marks":["strong"],"text":"Table 1. ","_key":"7d1c8d8a9d480","_type":"span"},{"_type":"span","marks":[],"text":"Common Adverse Reactions to Cobenfy","_key":"f29624ae05cb"},{"_type":"span","marks":["superscript"],"text":"6","_key":"8cb7e5d62b41"}],"_type":"block","style":"normal","_key":"497ba5e70359"}],"_key":"1a580b34b226","alignment":"right","asset":{"_ref":"image-bfd7da2da86e0aee0aff179174f205eb06bdeaf8-250x638-png","_type":"reference"},"blank":true,"_type":"figure","disableTextWrap":false,"widthP":49},{"style":"normal","_key":"b389462117da","markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://www.psychiatrictimes.com/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fpsychtimes%2F57be0ef1d9c109ce14292559ec271dbb4bbcc809-254x488.png%3Ffit%3Dcrop%26auto%3Dformat\u0026w=640\u0026q=75","_key":"e6399295b187"}],"children":[{"text":"Xanomeline is extensively metabolized by the liver, and as a result, Cobenfy is contraindicated in the presence of moderate to severe hepatic impairment. CYP2D6 also metabolizes it, and the dose may need to be decreased in the presence of potent CYP2D6 inhibitors. Trospium, on the other hand, is minimally metabolized in the body, and approximately 90% of it is excreted unchanged in the urine. Hence Cobenfy is contraindicated in patients with urinary retention and is not recommended in patients with moderate to severe renal impairment. In these conditions, trospium serum levels are likely to increase, increasing the anticholinergic load. ","_key":"f699bdcd564e0","_type":"span","marks":[]},{"_type":"span","marks":["strong","e6399295b187"],"text":"Table 2","_key":"7c7baf47c0d2"},{"_type":"span","marks":[],"text":" lists the contraindications for Cobenfy.","_key":"574d85a14dc7"}],"_type":"block"},{"_type":"figure","alignment":"right","widthP":50,"disableTextWrap":false,"disableLightBox":true,"imgcaption":[{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Table 2. ","_key":"8341e997dc010"},{"_key":"b6619df40431","_type":"span","marks":[],"text":"Contraindications of Cobenfy"},{"marks":["superscript"],"text":"6","_key":"e647008ac7f0","_type":"span"}],"_type":"block","style":"normal","_key":"1a1bc4a68257"}],"blank":true,"alt":"TABLE 2. Contraindications of Cobenfy","_key":"1f55d4144761","asset":{"_type":"reference","_ref":"image-57be0ef1d9c109ce14292559ec271dbb4bbcc809-254x488-png"}},{"_key":"2352a5054c22","markDefs":[],"children":[{"_type":"span","marks":[],"text":"It is important to know about the presence of any other medication, prescribed or over the counter, that has anticholinergic activity. Benztropine, diphenhydramine, tricyclic antidepressants, clozapine, olanzapine, quetiapine, and chlorpromazine are some of the common medications our patients may be taking that have significant anticholinergic effects. Patients should be warned about the signs and symptoms of increased anticholinergic load.","_key":"c886ce98e9cf0"}],"_type":"block","style":"normal"},{"_type":"block","style":"normal","_key":"96218392221f","markDefs":[],"children":[{"_key":"160f03a931000","_type":"span","marks":[],"text":"It is crucial to instruct the patient to take Cobenfy on an empty stomach, either 1 hour before or 2 hours after a meal. Food will decrease the absorption of trospium and can lead to increased procholinergic adverse events from xanomeline. With half-lives of 5 hours for xanomeline and 6 hours for trospium, Cobenfy is prescribed twice a day, commonly upon awakening and at bedtime, to maximize adherence."}]},{"_key":"f9e24cf9577d","markDefs":[],"children":[{"marks":[],"text":"Before starting Cobenfy, liver function tests and a bilirubin level should be checked, as well as baseline heart rate. These should be monitored during treatment as clinically indicated. Prior to prescribing Cobenfy, the entire PI should be read and understood.","_key":"516e3b764e700","_type":"span"}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"The Pipeline","_key":"e5421f17a0a30"}],"_type":"block","style":"normal","_key":"3b3a2d629788"},{"_type":"block","style":"normal","_key":"01f78e392d51","markDefs":[],"children":[{"_type":"span","marks":[],"text":"Cobenfy is the first in a novel class of medications that provide a muscarinic cholinergic mechanism of action for the treatment of individuals with schizophrenia. Two other drug candidates with similar mechanisms have recently completed phase 2 clinical trials. Emraclidine, an M4-selective positive allosteric modulator, is being evaluated in 2 placebo-controlled phase 2 trials in schizophrenia, EMPOWER-1 and EMPOWER-2, as well as in a 52-week open-label safety extension study, EMPOWER-3; trial results are expected to be released in late 2024. NBI-1117568 is a highly selective M4 agonist for the potential treatment of adults with schizophrenia and was evaluated in a recently completed phase 2 study. If FDA approved, these 2 molecules will help us understand the role of M1 agonism in the treatment of adults with schizophrenia, as this property is unique to Cobenfy.","_key":"ac088838001e0"}]},{"markDefs":[],"children":[{"text":"Concluding Thoughts","_key":"e353958bbec20","_type":"span","marks":["strong"]}],"_type":"block","style":"normal","_key":"a8922d68bb7f"},{"markDefs":[],"children":[{"_type":"span","marks":[],"text":"The medication treatment of schizophrenia has finally diversified to a novel neurotransmitter system, the muscarinic cholinergic system, with the FDA approval of Cobenfy on September 26, 2024. Our clinical experience with Cobenfy over the next several years will educate us on how this mechanism compares with the traditional blockade of D2Rs. Prescribers should familiarize themselves with all aspects of Cobenfy before using it, as it is a novel mechanism with important properties that are very different from the D2R antagonists. It is exciting and refreshing that after 70 years of domination by D2R antagonists, we have a novel neurotransmitter target for the treatment of individuals with schizophrenia.\n","_key":"eb6894edbc2e0"}],"_type":"block","style":"normal","_key":"9b1631d64744"},{"style":"normal","_key":"9ac20fc8d553","markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"Dr Miller ","_key":"762a2d16d5a90"},{"marks":["em"],"text":"is medical director of Brain Health in Exeter, New Hampshire; editor in chief of ","_key":"3ac807c2b296","_type":"span"},{"_key":"be226e34ff65","_type":"span","marks":[],"text":"Psychiatric Times"},{"marks":["em"],"text":"; staff psychiatrist at Seacoast Mental Health Center, Exeter; and consulting psychiatrist at the Insight Meditation Society in Barre, Massachusetts.","_key":"fe9ba826b285","_type":"span"}],"_type":"block"},{"_key":"bc0305290b53","markDefs":[],"children":[{"_type":"span","marks":[],"text":"","_key":"68af3e6211bf"}],"_type":"block","style":"normal"},{"_key":"a0aab41aac36","markDefs":[],"children":[{"_key":"ede6feb807640","_type":"span","marks":["em"],"text":"Dr Miller would like to disclose that he was on the Advisory Board for Karuna and is part of the Speakers’ Bureau for Bristol Myers Squibb."}],"_type":"block","style":"normal"},{"markDefs":[],"children":[{"_type":"span","marks":["strong"],"text":"References","_key":"9a96b23c47ab0"}],"_type":"block","style":"normal","_key":"4f2ad877f278"},{"markDefs":[{"blank":true,"_type":"link","href":"https://www.nejm.org/doi/full/10.1056/NEJMoa2017015","_key":"fb9aa80d05ea","nofollow":true}],"children":[{"marks":[],"text":"1. Brannan SK, Sawchak S, Miller AC, et al. ","_key":"aa22ed54e2220","_type":"span"},{"_type":"span","marks":["fb9aa80d05ea"],"text":"Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia.","_key":"d2ee2968cf7e"},{"_type":"span","marks":[],"text":" ","_key":"121ba6ed9a3b"},{"_type":"span","marks":["em"],"text":"N Engl J Med","_key":"253f7d3fb816"},{"_type":"span","marks":[],"text":". 2021;25;384(8):717-726.","_key":"61bc02b81318"}],"_type":"block","style":"normal","_key":"339db4658d28"},{"markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/38104575/","_key":"19549e777d7a"}],"children":[{"marks":[],"text":"2. Kaul I, Sawchak S, Correll CU, et al. ","_key":"ad234e9daa7a0","_type":"span"},{"_type":"span","marks":["19549e777d7a"],"text":"Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial.","_key":"22a9fd90bca3"},{"_type":"span","marks":[],"text":" ","_key":"c8f04e7ffb2f"},{"_type":"span","marks":["em"],"text":"Lancet","_key":"d44199f7ca06"},{"_type":"span","marks":[],"text":". 2024;13;403(10422):160-170.","_key":"f533e653f148"}],"_type":"block","style":"normal","_key":"72db80a47fd4"},{"children":[{"_type":"span","marks":[],"text":"3. Kaul I, Sawchak S, Walling DP, et al. ","_key":"ac8c6a55d0600"},{"_type":"span","marks":["6edc20ef2234"],"text":"Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial.","_key":"26629ebeaf76"},{"_type":"span","marks":[],"text":" ","_key":"83eeeb2d699c"},{"marks":["em"],"text":"JAMA Psychiatry.","_key":"1dae1e743e05","_type":"span"},{"_type":"span","marks":[],"text":" 2024;81(8):749-756.","_key":"621402d1abdc"}],"_type":"block","style":"normal","_key":"661483d2b055","markDefs":[{"_type":"link","href":"https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2818047","_key":"6edc20ef2234","nofollow":true,"blank":true}]},{"children":[{"_type":"span","marks":[],"text":"4. An extension study to assess long-term safety, tolerability, and efficacy of KarXT in adult patients with schizophrenia (EMERGENT-4). ClinicalTrials.gov. Updated November 29, 2023. Accessed October 14, 2024. ","_key":"672b009c6b850"},{"_type":"span","marks":["314cb01a35c8"],"text":"https://clinicaltrials.gov/study/NCT04659174","_key":"941ef4de5eb7"}],"_type":"block","style":"normal","_key":"da3fba47c5d4","markDefs":[{"blank":true,"_type":"link","href":"https://clinicaltrials.gov/study/NCT04659174","_key":"314cb01a35c8","nofollow":true}]},{"markDefs":[{"href":"https://clinicaltrials.gov/study/NCT04820309","_key":"352b3bf17511","nofollow":true,"blank":true,"_type":"link"}],"children":[{"marks":[],"text":"5. An open-label study to assess the long-term safety, tolerability, and efficacy of KarXT in adult patients with schizophrenia (EMERGENT-5). ClinicalTrials.gov. Updated August 20, 2024. Accessed October 14, 2024. ","_key":"5497ef887b410","_type":"span"},{"_key":"d5efc9a781d6","_type":"span","marks":["352b3bf17511"],"text":"https://clinicaltrials.gov/study/NCT04820309"}],"_type":"block","style":"normal","_key":"44c0656dbf79"},{"style":"normal","_key":"41efb1dfa894","markDefs":[{"nofollow":true,"blank":true,"_type":"link","href":"https://packageinserts.bms.com/pi/pi_cobenfy.pdf","_key":"08c66599101d"}],"children":[{"text":"6. Cobenfy. Prescribing information. Bristol Myers Squibb; 2024. Accessed October 14, 2024. ","_key":"1a93fdc85fdf0","_type":"span","marks":[]},{"text":"https://packageinserts.bms.com/pi/pi_cobenfy.pdf","_key":"4d3b9b17277e","_type":"span","marks":["08c66599101d"]}],"_type":"block"},{"style":"normal","_key":"9b922ee04d85","markDefs":[{"_key":"021e89de8863","nofollow":true,"blank":true,"_type":"link","href":"https://pubmed.ncbi.nlm.nih.gov/35046851/"}],"children":[{"_key":"2bbdfa3dc9bb0","_type":"span","marks":[],"text":"7. Mosolov SN, Yaltonskaya PA. 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