{"id":29104,"date":"2021-01-05T00:00:50","date_gmt":"2021-01-05T08:00:50","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=29104"},"modified":"2024-01-30T14:38:14","modified_gmt":"2024-01-30T22:38:14","slug":"new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/de\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/","title":{"rendered":"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients"},"content":{"rendered":"

LA JOLLA\u2014Lithium is considered the gold standard for treating bipolar disorder (BD), but nearly 70 percent of people with BD don\u2019t respond to it. This leaves them at risk for debilitating, potentially life-threatening mood swings. Researchers at the Salk Institute have found that the culprit may lie in gene activity\u2014or lack of it.<\/p>\n

A new study led by Salk Professor and President Rusty Gage<\/a>, which published in the journal Molecular Psychiatry<\/em><\/a> on January 4, 2021, shows that decreased activation of a gene called LEF1 disrupts ordinary neuronal function and promotes hyperexcitability in brain cells\u2014a hallmark of BD. The work could result in a new drug target for BD as well as a biomarker for lithium nonresponsiveness.<\/p>\n

\"From
From left: iPSC-derived dentate gyrus (DG)-like neurons (green) from control subject; bipolar lithium responder; and bipolar lithium nonresponder. While the percentage of DG-like neurons is the same for control and bipolar, the gene activation profiles are different and the nonresponder has low levels of Lef1.<\/p>\n

Klicken Sie hier<\/a> f\u00fcr ein hochaufl\u00f6sendes Bild.<\/p>\n

Kredit: Salk Institut<\/figcaption><\/figure>\n

\u201cOnly one-third of patients respond to lithium with disappearance of the symptoms,\u201d says Renata Santos, co-first author on the study and a Salk research collaborator.\u00a0 \u201cWe were interested in the molecular mechanisms behind lithium resistance, what was blocking lithium treatment in nonresponders. We found that LEF1 was deficient in neurons derived from nonresponders. We were excited to see that it was possible to increase LEF1 and its dependent genes, making it a new target for therapeutic intervention in BD.\u201d<\/p>\n

The study builds on the team\u2019s earlier findings<\/a>, which reported that the neurons of people with BD who don\u2019t respond to lithium are larger, fire differently (are more easily stimulated, or hyperexcitable), and have increased potassium flow.<\/p>\n

Subjects in the team\u2019s current study included lithium responders, nonresponders and people without BD (controls). Using stem-cell methods, the researchers grew neurons from the subjects\u2019 blood cells and compared the genetic disposition and behavior of the neurons for the three groups.<\/p>\n

They looked at many genes across the board, but LEF1 stood out as one of the most different in nonresponders. Normally, LEF1 plays a decisive role in neuronal function by pairing with another protein called beta-catenin. The pairing typically activates other genes that regulate the level of activity in the neuron. In control or responding neurons, lithium enables beta-catenin to pair with LEF1. But in nonresponders, lithium is ineffective because LEF1 levels are too low for the pairing to occur, so there\u2019s no regulation of cell activity.\u00a0 <\/strong><\/p>\n

When the team administered valproic acid, a treatment often used for nonresponders, measurements showed increased levels of LEF1 and activation of the other relevant genes. And when the team silenced the LEF1 gene in control neurons, they found that the related genes were not activated. Together, these results indicate the critical role LEF1 plays in controlling neuronal hyperexcitability.<\/p>\n

\u201cWhen we silenced the LEF1 gene, the neurons became hyperexcitable,\u201d says Shani Stern, co-first author on the study and a Salk visiting scientist.\u00a0 \u201cAnd when we used valproic acid, expression of LEF1 increased, and we lowered the hyperexcitability. That shows there is a causative relationship, and that’s why we think LEF1 may be a possible target for drug therapy.\u201d<\/p>\n

LEF1 may also help researchers develop a screening test for responsiveness. Currently, clinicians can only determine whether a patient is responsive to lithium by administering a complete course of treatment, which could take a year. Now, subdued activity of LEF1 may be an indicator that a patient won\u2019t respond to lithium, enabling a faster and more efficient way to approach therapy.<\/p>\n

Team members already contemplating next steps. These include looking at other cell types, such as astrocytes and GABAergic neurons, to understand the bipolar neural network as a whole; identifying other genes that could be beneficial for nonresponders; and finding other drugs that can activate LEF1.<\/p>\n

\u201cLEF1 works in various ways in different parts of the body, so you can\u2019t just turn it on everywhere,\u201d says Carol Marchetto, co-corresponding author and Salk research collaborator. \u201cYou want to be more specific, either activating LEF1 on a targeted basis or activating downstream genes that are relevant for lithium nonresponsiveness.\u201d<\/p>\n

Other authors on the study were Sara B. Linker, Ana P. D. Mendes, Lynne Randolph-Moore, Vipula Racha, Yeni Kim, Maxim N. Shokhirev, and Galina Erikson of Salk; John R. Kelsoe of the University of California San Diego; Anne G. Bang of the Sanford Burnham Prebys Medical Discovery Institute; and M. Alda of Dalhousie University.<\/p>\n

The work was funded by the National Institutes of Health, the Chapman Foundation and the Helmsley Charitable Trust, the National Cancer Institute, the National Cooperative Reprogrammed Cell Research Groups, the JPB Foundation, Annette C. Merle-Smith, the Robert and Mary Jane Engman Foundation, and the Zuckerman STEM leadership program funding.<\/p>","protected":false},"featured_media":29120,"template":"","faculty":[76],"disease-research":[333,124],"class_list":["post-29104","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-rusty-gage","disease-research-genetics","disease-research-neuroscience-and-neurological-disorders"],"acf":[],"yoast_head":"\nNew clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/de\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/\" \/>\n<meta property=\"og:locale\" content=\"de_DE\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Lithium is considered the gold standard for treating bipolar disorder (BD), but nearly 70 percent of people with BD don\u2019t respond to it. This leaves them at risk for debilitating, potentially life-threatening mood swings. Researchers at the Salk Institute have found that the culprit may lie in gene activity\u2014or lack of it.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.salk.edu\/de\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/\" \/>\n<meta property=\"og:site_name\" content=\"Salk Institute for Biological Studies\" \/>\n<meta property=\"article:modified_time\" content=\"2024-01-30T22:38:14+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2021\/01\/BD-Prox1-Neurons-cover-767.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"767\" \/>\n\t<meta property=\"og:image:height\" content=\"767\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"4 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/\",\"name\":\"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients - Salk Institute for Biological Studies\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/#primaryimage\"},\"image\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2021\\\/01\\\/BD-Prox1-Neurons-cover-767.jpg\",\"datePublished\":\"2021-01-05T08:00:50+00:00\",\"dateModified\":\"2024-01-30T22:38:14+00:00\",\"breadcrumb\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/#breadcrumb\"},\"inLanguage\":\"de-DE\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"de-DE\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/#primaryimage\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2021\\\/01\\\/BD-Prox1-Neurons-cover-767.jpg\",\"contentUrl\":\"https:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2021\\\/01\\\/BD-Prox1-Neurons-cover-767.jpg\",\"width\":767,\"height\":767},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\\\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\\\/\\\/www.salk.edu\\\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#website\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/\",\"name\":\"Salk Institute for Biological Studies\",\"description\":\"The Power of Science\",\"publisher\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#organization\"},\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\\\/\\\/www.salk.edu\\\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"de-DE\"},{\"@type\":\"Organization\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#organization\",\"name\":\"Salk Institute for Biological Studies\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/\",\"logo\":{\"@type\":\"ImageObject\",\"inLanguage\":\"de-DE\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#\\\/schema\\\/logo\\\/image\\\/\",\"url\":\"http:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2023\\\/03\\\/salk_logo_696.jpg\",\"contentUrl\":\"http:\\\/\\\/www.salk.edu\\\/wp-content\\\/uploads\\\/2023\\\/03\\\/salk_logo_696.jpg\",\"width\":696,\"height\":696,\"caption\":\"Salk Institute for Biological Studies\"},\"image\":{\"@id\":\"https:\\\/\\\/www.salk.edu\\\/#\\\/schema\\\/logo\\\/image\\\/\"}}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients - Salk Institute for Biological Studies","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/www.salk.edu\/de\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/","og_locale":"de_DE","og_type":"article","og_title":"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients - Salk Institute for Biological Studies","og_description":"LA JOLLA\u2014Lithium is considered the gold standard for treating bipolar disorder (BD), but nearly 70 percent of people with BD don\u2019t respond to it. This leaves them at risk for debilitating, potentially life-threatening mood swings. Researchers at the Salk Institute have found that the culprit may lie in gene activity\u2014or lack of it.","og_url":"https:\/\/www.salk.edu\/de\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/","og_site_name":"Salk Institute for Biological Studies","article_modified_time":"2024-01-30T22:38:14+00:00","og_image":[{"width":767,"height":767,"url":"https:\/\/www.salk.edu\/wp-content\/uploads\/2021\/01\/BD-Prox1-Neurons-cover-767.jpg","type":"image\/jpeg"}],"twitter_card":"summary_large_image","twitter_misc":{"Est. reading time":"4 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"WebPage","@id":"https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/","url":"https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/","name":"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients - Salk Institute for Biological Studies","isPartOf":{"@id":"https:\/\/www.salk.edu\/#website"},"primaryImageOfPage":{"@id":"https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/#primaryimage"},"image":{"@id":"https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/#primaryimage"},"thumbnailUrl":"https:\/\/www.salk.edu\/wp-content\/uploads\/2021\/01\/BD-Prox1-Neurons-cover-767.jpg","datePublished":"2021-01-05T08:00:50+00:00","dateModified":"2024-01-30T22:38:14+00:00","breadcrumb":{"@id":"https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/#breadcrumb"},"inLanguage":"de-DE","potentialAction":[{"@type":"ReadAction","target":["https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/"]}]},{"@type":"ImageObject","inLanguage":"de-DE","@id":"https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/#primaryimage","url":"https:\/\/www.salk.edu\/wp-content\/uploads\/2021\/01\/BD-Prox1-Neurons-cover-767.jpg","contentUrl":"https:\/\/www.salk.edu\/wp-content\/uploads\/2021\/01\/BD-Prox1-Neurons-cover-767.jpg","width":767,"height":767},{"@type":"BreadcrumbList","@id":"https:\/\/www.salk.edu\/news-release\/new-clues-why-gold-standard-treatment-for-bipolar-disorder-doesnt-work-for-majority-of-patients\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/www.salk.edu\/"},{"@type":"ListItem","position":2,"name":"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients"}]},{"@type":"WebSite","@id":"https:\/\/www.salk.edu\/#website","url":"https:\/\/www.salk.edu\/","name":"Salk-Institut f\u00fcr biologische Studien","description":"Die Macht der Wissenschaft","publisher":{"@id":"https:\/\/www.salk.edu\/#organization"},"potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.salk.edu\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"de-DE"},{"@type":"Organization","@id":"https:\/\/www.salk.edu\/#organization","name":"Salk-Institut f\u00fcr biologische Studien","url":"https:\/\/www.salk.edu\/","logo":{"@type":"ImageObject","inLanguage":"de-DE","@id":"https:\/\/www.salk.edu\/#\/schema\/logo\/image\/","url":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/03\/salk_logo_696.jpg","contentUrl":"http:\/\/www.salk.edu\/wp-content\/uploads\/2023\/03\/salk_logo_696.jpg","width":696,"height":696,"caption":"Salk Institute for Biological Studies"},"image":{"@id":"https:\/\/www.salk.edu\/#\/schema\/logo\/image\/"}}]}},"ACF":{"hero":"https:\/\/www.salk.edu\/wp-content\/uploads\/2021\/01\/BD-Prox1-Neurons-cover-header.jpg","line_1":"New clues why gold standard treatment for bipolar disorder doesn\u2019t work for majority of patients ","line_2":"Salk researchers find decreased activation of gene called LEF1 is more common in neurons of people with bipolar disorder who do not respond to lithium, pointing way to potential new treatment","poster_quote":"","paper_url":"https:\/\/www.nature.com\/articles\/s41380-020-00981-3","journal_title":"Molecular Psychiatry","paper_author_list":"Renata Santos, Sara B. Linker, Shani Stern, Ana P. D. Mendes, Maxim N. Shokhirev, Galina Erikson, Lynne Randolph-Moore, Vipula Racha, Yeni Kim, John R. Kelsoe, Anne G. Bang, M. Alda, Maria C. Marchetto, Fred H. Gage","doi":"10.1038\/s41380-020-00981-3","paper_title":"Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients","subhead":"Salk researchers find decreased activation of gene called LEF1 is more common in neurons of people with bipolar disorder who do not respond to lithium, pointing way to potential new treatment","home_photo":"","listing_photo":"","legacy_boilerplate":[],"hide_boilerplate":[],"disable_date":false,"listing_excerpt":"","descriptive_blurb":"","has_journal_cover":false,"og_image_override":false,"gallery":false},"_links":{"self":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure\/29104","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure"}],"about":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/types\/disclosure"}],"version-history":[{"count":5,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure\/29104\/revisions"}],"predecessor-version":[{"id":29131,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disclosure\/29104\/revisions\/29131"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/media\/29120"}],"wp:attachment":[{"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/media?parent=29104"}],"wp:term":[{"taxonomy":"faculty","embeddable":true,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/faculty?post=29104"},{"taxonomy":"disease-research","embeddable":true,"href":"https:\/\/www.salk.edu\/de\/wp-json\/wp\/v2\/disease-research?post=29104"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}