Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol

Living systematic review and meta-analysis of... | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/13-452" }, "headline": "Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and...", "datePublished": "2024-05-07T11:23:17", "dateModified": "2024-07-09T10:23:59", "author": [ { "@type": "Person", "name": "Filip Milosavljević" }, { "@type": "Person", "name": "Stefan Leucht" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Introduction Carriers of variant alleles of genes that encode liver CYP450 and UGT enzymes may experience abnormal plasma levels of antipsychotics and, consequently, worse efficacy or tolerability. Although pharmacogenomics is a rapidly developing field, current guidelines often rely on limited, underpowered evidence. We have previously demonstrated that meta-analysis is a viable strategy for overcoming this problem. Here, we propose a project that will expand our previous work and create a living systematic review and meta-analysis of drug plasma level differences between carriers and non-carriers of variant genotype-predicted phenotypes for every pharmacokinetic drug-gene interaction relevant to commonly used antipsychotic drugs. Protocol First, a baseline systematic review and meta-analysis will be conducted by searching for observational pharmacogenomics-pharmacokinetic studies. Data on dose-adjusted drug plasma levels will be extracted, and participants will be grouped based on their genotype for each drug-gene pair separately. Differences in plasma drug levels between different phenotypes will be compared using a random-effect ratio-of-means meta-analysis. The risk of bias will be assessed using ROBINS-I, and the certainty of evidence will be assessed using GRADE. Following the establishment of baseline results, the literature search will be re-run at least once every six months, and the baseline data will be updated and re-evaluated as new evidence is published. A freely available website will be designated to present up-to-date results and conclusions. Discussion This systematic review will provide evidence-based results that are continuously updated with evidence as it emerges in the rapidly developing field of pharmacogenomics. These results may help psychiatrists in their decision-making, as clinicians are becoming increasingly aware of the patients’ genetic data as testing becomes more widespread and cheaper. In addition, the results may serve as a scientific basis for the development of evidence-based pharmacogenomics algorithms for personalized dosing of antipsychotics to mitigate potentially harmful drug-gene interactions. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-452/v2", "name": "Living systematic review and meta-analysis of plasma-concentrations..." } } ] } Home Browse Living systematic review and meta-analysis of plasma-concentrations... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Milosavljević F and Leucht S. Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.12688/f1000research.147794.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Revised Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] Filip Milosavljević https://orcid.org/0000-0001-6532-4661 1,2 , Stefan Leucht https://orcid.org/0000-0002-4934-4352 2 Filip Milosavljević https://orcid.org/0000-0001-6532-4661 1,2 , Stefan Leucht https://orcid.org/0000-0002-4934-4352 2 PUBLISHED 09 Jul 2024 Author details Author details 1 Department of physiology, Faculty of Pharmacy, Univerzitet u Beogradu, Belgrade, 11221, Serbia 2 Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, Bavaria, 81675, Germany Filip Milosavljević Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation Stefan Leucht Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Introduction Carriers of variant alleles of genes that encode liver CYP450 and UGT enzymes may experience abnormal plasma levels of antipsychotics and, consequently, worse efficacy or tolerability. Although pharmacogenomics is a rapidly developing field, current guidelines often rely on limited, underpowered evidence. We have previously demonstrated that meta-analysis is a viable strategy for overcoming this problem. Here, we propose a project that will expand our previous work and create a living systematic review and meta-analysis of drug plasma level differences between carriers and non-carriers of variant genotype-predicted phenotypes for every pharmacokinetic drug-gene interaction relevant to commonly used antipsychotic drugs. Protocol First, a baseline systematic review and meta-analysis will be conducted by searching for observational pharmacogenomics-pharmacokinetic studies. Data on dose-adjusted drug plasma levels will be extracted, and participants will be grouped based on their genotype for each drug-gene pair separately. Differences in plasma drug levels between different phenotypes will be compared using a random-effect ratio-of-means meta-analysis. The risk of bias will be assessed using ROBINS-I, and the certainty of evidence will be assessed using GRADE. Following the establishment of baseline results, the literature search will be re-run at least once every six months, and the baseline data will be updated and re-evaluated as new evidence is published. A freely available website will be designated to present up-to-date results and conclusions. Discussion This systematic review will provide evidence-based results that are continuously updated with evidence as it emerges in the rapidly developing field of pharmacogenomics. These results may help psychiatrists in their decision-making, as clinicians are becoming increasingly aware of the patients’ genetic data as testing becomes more widespread and cheaper. In addition, the results may serve as a scientific basis for the development of evidence-based pharmacogenomics algorithms for personalized dosing of antipsychotics to mitigate potentially harmful drug-gene interactions. READ ALL READ LESS Keywords Living systematic review, Pharmacogenomics, Antipsychotic drugs, Schizophrenia, Therapeutic drug monitoring, CYP450 Corresponding Author(s) Filip Milosavljević ( [email protected] ) Close Corresponding author: Filip Milosavljević Competing interests: In the last three years SL has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Neurotorium, Otsuka, NovoNordisk, Recordati, Rovi, Teva. FM reports no conflict of interests. Grant information: This work was supported by Alexander von Humboldt Foundation’s Postdoctoral Fellowship Stipend (awarded to FM, stipend number: 1235463-HFST-P). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Milosavljević F and Leucht S. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Milosavljević F and Leucht S. Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.12688/f1000research.147794.2 ) First published: 07 May 2024, 13 :452 ( https://doi.org/10.12688/f1000research.147794.1 ) Latest published: 09 Jul 2024, 13 :452 ( https://doi.org/10.12688/f1000research.147794.2 ) Revised Amendments from Version 1 Changes in the new version of the protocol include: 1) Updated introduction section that now comprehensively lists all major gene-candidates that could be affect antipsychotic pharmacokinetics. 2) We added the justification why we choose to focus only on CYP450 and UGT enzyme super-families and not on other gene-candidates. 3) Introduction section now explains which genes of interest have well established definitions of metabolizer status and which genes are analyzed in terms of genotypes and haplotypes. 4) Handling of antipsychotics with non-linear pharmacokinetic profiles is now added to the protocol. 5) The justification is added on why we choose to exclude data obtained by phenotyping methods with probe drugs, and why we choose to focus on genotyping data instead. 6) Two errors regarding the list of drugs of interest are corrected in the new version. Paliperidone is no longer on the list of drugs of interest as it is mainly eliminated from the body unchanged by the kidneys. Also, lurasidone is added to the list of drugs-of-interest as it is a substrate for CYP3A4/5 system. 7) Few typing errors are corrected in the extended data. 8) Criterion used to assess whether participants have reaching steady state drug blood levels is now changed in order to address the fact that poor and intermediate metabolizers (or carriers of other mutations with lowered enzyme activities) take longer time to reach steady state due to prolonged elimination half-lives in them. Changes in the new version of the protocol include: 1) Updated introduction section that now comprehensively lists all major gene-candidates that could be affect antipsychotic pharmacokinetics. 2) We added the justification why we choose to focus only on CYP450 and UGT enzyme super-families and not on other gene-candidates. 3) Introduction section now explains which genes of interest have well established definitions of metabolizer status and which genes are analyzed in terms of genotypes and haplotypes. 4) Handling of antipsychotics with non-linear pharmacokinetic profiles is now added to the protocol. 5) The justification is added on why we choose to exclude data obtained by phenotyping methods with probe drugs, and why we choose to focus on genotyping data instead. 6) Two errors regarding the list of drugs of interest are corrected in the new version. Paliperidone is no longer on the list of drugs of interest as it is mainly eliminated from the body unchanged by the kidneys. Also, lurasidone is added to the list of drugs-of-interest as it is a substrate for CYP3A4/5 system. 7) Few typing errors are corrected in the extended data. 8) Criterion used to assess whether participants have reaching steady state drug blood levels is now changed in order to address the fact that poor and intermediate metabolizers (or carriers of other mutations with lowered enzyme activities) take longer time to reach steady state due to prolonged elimination half-lives in them. See the authors' detailed response to the review by Pierre Baumann See the authors' detailed response to the review by Jhohann Richard de Lima Benzi READ REVIEWER RESPONSES 1. Introduction Pharmacotherapy for schizophrenia today is challenging because of (I) slow development of new drugs, 1 (II) treatment resistance, 2 (III) frequent need for treatment regimen adjustments 3 (IV) high relapse rates 4 and (V) risk of unpleasant adverse drug reactions. 4 In such a landscape, approaches such as pharmacogenomics hold great potential, as many enzymes and transporters involved in the pharmacokinetics of antipsychotics are coded by highly polymorphous genes. 5 In theory, mutations of these genes can cause pharmacokinetic, and consequently, pharmacodynamic variability in patients. 5 , 6 Adjusting drug choice and/or drug dose based on patient’s genomics holds promise to maximize the effectiveness of currently available antipsychotics. 5 Pharmacogenomics of pharmacokinetic processes has been researched in the context of phase 1 drug metabolism (oxidation), phase 2 drug metabolism (glucuronization) and drug transport (efflux pumps). 6 Phase 1 metabolism is the main mechanism of inactivation for the most of antipsychotics, 6 and it predominantly involves CYP450 isoenzymes, namely CYP1A2, CYP2C19, CYP2D6 and CYP3A4/5 7 ; all of which are coded by highly polymorphic genes. 8 CYP450 polymorphism is usually not analyzed in terms of specific genotypes, but rather in terms of genotype combinations called haplotypes or star alleles. The activity of enzymes translated from the specific gene variant is in most cases well characterized in in-vitro studies. 8 For CYP2C19 and CYP2D6 isoenzymes, consensus is reached on how two star alleles combine into enzyme’s genotype-predicted phenotype; i.e. enzyme’s metabolizer group. 9 Four metabolizer groups are commonly defined: Poor metabolizers (PM) – Absent or very low enzyme activity; Intermediate metabolizers (IM) – Significantly reduced enzyme activity; Normal metabolizers (NM; Previously referred to as Extensive metabolizers – EM) – Reference group; and Ultra-rapid metabolizers (UM) – Increased enzyme activity. 8 Theoretically, PMs or IMs carry risk of exhibiting too high antipsychotic plasma levels and consequent worse tolerability, 10 while UMs carry risk of too low plasma levels and the lack of efficacy. 10 Regarding CYP1A2 and CYP3A4/5 isoenzymes, definitions of metabolizer groups based on star allele combinations have been proposed, 10 but the broader consensus has not been reached yet. Instead, for CYP1A2 and CYP3A4/5, carriers of each star allele combination are analyzed as a separate group in clinical studies. Besides CYP450 superfamily, few other enzymes coded by polymorphous genes also contribute to the phase 1 metabolism of antipsychotics. For example, AOX1 (Aldehyde oxidase-1) is involved in the metabolism of ziprasidone and FMO3 (Flavin-containing monooxygenase-3) is involved in the metabolism of olanzapine. 6 Only few antipsychotics undergo phase 2 metabolism. More specifically, Asenapine, Clozapine, Haloperdiol and Olanzapine all undergo glucuronization. 6 , 11 , 12 This process involves Uridine 5’-diphospho-glucuronosyltransferase (UGT) superfamily, namely UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, UGT2B10 izoenzymes 6 , 11 , 12 ; all of which are coded by polymorphous genes. 13 Even though pharmacogenomics of UGT enzymes in psychiatry is understudied, impact of specific genotypes on glucuronization speed has been characterized for other drug classes. 13 , 14 However, this may pose some issues as there is evidence on substrate specific effect of certain genotypes. 13 In theory, genotype-induced variation in glucuronyzation rates can affect plasma concentration of biologically active, unconjugated drugs and thus affect clinical outcomes. 13 Even though the definitions of star alleles based on the genotype combination have been proposed, 14 majority of clinical trials still report data for each genotype separately, mostly in 3 groups: non-carriers, homozygous carriers and heterozygous carriers of a certain mutation. There is also no consensus on how to define metabolizer groups for UGT enzymes. Regarding drug transport, many antipsychotics are substrates for the ATP-binding cassette proteins, including multidrug resistance proteins (MDR) coded by ABCB1, ABCC1 and ABCC2 polymorphous genes, and breast cancer resistance protein coded by ABCG2 polymorphous gene. 6 , 15 Currently, the evidence on the effect of certain genotypes on efflux pump activities is inconsistent and warrants further research. 15 , 16 Efflux pumps are expressed in many different organs including gastrointestinal tract, kidneys, liver and blood-brain barrier. 16 Therefore, genotype-induced changes in efflux pump activities can theoretically impact drug absorption rate, drug elimination rate, drug distribution to the brain, or few of these processes simultaneously. 16 Finally, olanzapine and clozapine are substrates to human organic cation transporters hOCT1 and hOCT2 coded by polymorphous SLC22A1 and SLC22A2 genes, respectively. 11 , 12 These polymorphisms can in theory affect intake of these drugs into hepatocytes 11 , 12 and affect the proportion of drug available for inactivation. In order to create an evidence-based pharmacogenomics-informed dosing algorithm that can mitigate these pharmacokinetic drug-gene interactions, their precise extent must be determined first. Despite great volume of research, previous pharmacogenomics-pharmacokinetic studies were mostly inconclusive as there is a common problem of low statistical power. Meta-analysis can be an effective tool for overcoming this problem. 17 We plan to build on our previous work on precise quantification of pharmacokinetic drug-gene interactions of antipsychotics 17 by including more drug-gene interactions and by utilizing the living systematic review approach. Since pharmacogenomics is a rapidly developing field and the level of evidence in pharmacogenomics is often unsatisfactory, 18 , 19 continuously updated evidence-based data sources regarding pharmacokinetic drug-gene interactions could be very informative, as patients’ genomic data is becoming more commonly available to clinicians because commercial pharmacogenomics tools are becoming more widely adopted and cheaper over time. 1.1 Research question Our hypothesis is that polymorphisms in genes encoding CYP450 and/or UGT isoenzymes are associated with significant changes in dose-corrected plasma concentrations of antipsychotic drugs. Drug-gene pairs will be formed for every relevant polymorphic gene associated with every relevant antipsychotic drug. For every drug gene pair, our aim is to determine, as precisely as possible, the magnitude of the difference in dose-corrected plasma drug concentrations between carriers and non-carriers of variant genotype-predicted phenotypes for the given gene, and the certainty of this evidence. Table 1 presents the PICO format for research questions. Table 1. PICO format for the research question(s). Both general case and two examples of the research question are given. Risperdion-CYP2D6 and Olanzapine-UGT1A4 drug-gene pairs are used as aexamples. Criterion General formulation of the research question Example: Formulation of the research question for the Risperidone-CYP2D6 drug-gene pair Example: Formulation of the research question for the Olanzapine-UGT1A4 drug-gene pair P – Population Adults (18-65 years old) who are either healthy volunteers or psychiatric patients, treated with antipsychotic drug of interest. Adults (18-65 years old) who are either healthy volunteers of psychiatric patients treated with risperidone. Adults (18-65 years old) who are either healthy volunteers of psychiatric patients treated with Olanzapine. I – Intervention(s) Carrying of a variant genotype-determined phenotype for the gene of interest. 1) Carrying CYP2D6 poor metabolizer phenotype (PM); 2) Carrying CYP2D6 intermediate metabolizer phenotype (IM); 3) Carrying CYP2D6 ultra-rapid metabolizer phenotype (UM). 1) Carrying one UGT1A4*2 allele; 2) Carrying two UGT1A4*2 alleles; 3) Carrying one UGT1A4*3 allele; 4) Carrying two UGT1A4*3 alleles. C – Control Carrying of the reference genotype-determined phenotype for the gene of interest. Carrying CYP2D6 normal metabolizer phenotype (NM). Carrying UGT1A4*1/*1 alleles. O – Outcome Dose-adjusted plasma concentration (C/D) of antipsychotic drug of interest, either after steady state is achieved or after a single drug dose. Dose-adjusted plasma concentration of risperidone active-moiety (parent drug + active metabolite) either after steady state is achieved or after a single risperidone dose. Dose-adjusted plasma concentration of olanzapine either after steady state is achieved or after a single olanzapine dose. 2. Protocol This protocol was written in accordance with the PRISMA-P (Preferred reporting items for systematic review and meta-analysis protocols) guideline. 20 A checklist is presented in the extended data. The final report of this living systematic review will be written in accordance with MOOSE (Meta-analysis of observational studies) reporting guideline. 21 This protocol is also registered with PROSPERO (CRD42024485626). 2.1 Literature search The following databases will be searched: ClinicalTrials.gov , Cochrane Library (Cochrane Database of Systematic Reviews=CDSR and Cochrane Central Register of Controlled Trials=CENTRAL), Embase, MEDLINE, PsycINFO and WHO ICTRP. No studies that were published prior to 1.1.1995. will be searched because of the extremely limited availability of PCR genotyping technology. Both published and unpublished clinical studies will be searched, without language restrictions. The search will be re-run every time the our manuscript is submitted for peer review, as well as continuously once every 6 months during the living meta-analysis maintenance. Search strategy draft is presented in the extended data. 2.2 Drug-gene pairs of interest Even though many genes can be important for antipsychotic pharmacokinetics, first iteration of our living systematic review will focus on CYP450 and UGT isoenzymes. AOX-, FMO-, SLC22A- genes will not be considered at this moment due to the limited amount of research of their pharmacogenomics in context of antipsychotic drugs. Similarly, UGT enzymes other than UGT1A4 and UGT2B7 will not be analyzed in the first iteration of this review due to their relatively limited representation in the literature, and since UGT1A4 and UGT2B7 are among the most abundant UGT isoenzymes in the liver. 13 Efflux pump pharamcogenomics will not be considered in this review for two reasons. Firstly, previous research regarding genotype-activity relationships of efflux pumps is inconsistent. 15 Secondly, our systematic review presumes that antipsychotic plasma level is a biomarker of its biological activity, and we will assume that cerebrospinal-fluid-to-plasma ratios of antipsychotic drugs are similar between people with different CYP450/UGT genotypes. Since drugs transporters are expressed on blood-brain barrier, it has been demonstrated that changes in efflux pump activity can change cerebrospinal-fluid-to-plasma ratios of antipsychotics. 22 , 23 This could mean that two study arms with different efflux pump genotypes could have the same antipsychotic drug-plasma levels, but different antipsychotic biological activity. Therefore, we believe that analyzing drug efficacy and safety directly, or analyzing cerebrospinal fluid drug levels are more appropriate outcomes for describing efflux pump pharmacogenomics, all of which are out of the scope of this review. Based on the information from CPIC, 6 PharmVar 9 and PharmGKB 12 resources, drug-gene pairs of interest were identified and are presented in Table 2 . If new relevant data emerges during the maintenance of this living meta-analysis, this list will be updated, and a new drug-gene pair will be included. Table 2. Drug-gene pairs of interest. Drug-gene pairs that will be considered for analysis are formed by pairing most clinically relevant antipsychotic drugs and liver enzymes that are coded by polymorphic genes and are substantially involved in the metabolism of said drugs. CYP2D6 CYP3A4/5 CYP2C19 CYP1A2 UGT1A4 UGT2B7 Aripiprazole X X Asenapine X X Brexpiprazole X X Clozapine X X X X Cariprazine X X Iloperidone X X Lumateperone X X Lurasidone X Olanzapine X X X X Quetiapine X X Risperidone X X Sertindole X Zotepine X X Haloperidol X X X X Chlorpromazine X X X Perphenazine X X Zuclopentixol X X Amisulpride and paliperidone will not be analyzed, as they are mainly extracted unchanged via the kidneys. 6 , 24 , 25 Ziprasidone will not be analyzed because of its low inter-individual variability in plasma drug levels. 26 First-generation antipsychotic drugs, other than chlorpromazine, perphenazine, haloperidol, and zuclopentixol, were not included because of their limited clinical utility today. 2.3 Definition of intervention and control groups For every drug-gene pair of interest, the exposure group(s) (i.e., variant group; experimental group) and control group (i.e., wild-type group; reference group) will be defined based on the genotype-predicted phenotypes for the gene in question. Detailed definitions of the control and experimental groups based on CYP2D6, CYP3A4/5, CYP2C19, CYP1A2, UGT1A4 and UGT2B7 genotypes are adopted from consensus guidelines for every individual gene 6 , 9 , 12 and are presented in detail in the extended data. In short, for CYP2C19 and CYP2D6 genes. Normal metabolizer group will be considered as a control, and Intermediate, Poor and Ultra-rapid metabolizer groups will be considered as 3 possible exposure groups. For CYP1A2 , CYP3A4 , UGT1A4 and UGT2B7 genes, for each variant allele of interest, heterogeneous and homogeneous carriers will be considered as exposure groups while non-carriers will be considered as controls. For CYP3A5 gene, carriers of two loss-of-function alleles (for example *3/*3) will be considered as exposure group, while every other allele combination will be considered as controls. It is important to note that, besides genotyping, inter-individual variation in CYP450/UGT activity can also be determined by phenotyping techniques with one or more probe substances. 27 Still, genotyping and phenotyping have their own unique advantages and disadvantages. In short, genotyping is error-prone in the case of so-called phenoconversion or other environmental factors, while phenotyping is not. 27 , 28 Next, phenotyping requires more sophisticated methods and is more resource and time demanding compared to genotyping. 27 Finally, genotyping results are not time-dependent are one measurement can be used during entire person’s lifetime while phenotyping results vary over time and require occasional re-analysis. 28 Even though both approaches are valid, they cannot be used interchangeably due to abovementioned discrepancies. 27 Therefore, we opted to include only genotyping data since it is more compatible with psychiatric clinical practice due to its analytical convenience. 2.4 Definition of the outcome Pharmacokinetic parameters used to represent the drug plasma level will be included only if they are dose adjusted or if the entire cohort is administered the same dose. If necessary and possible, dose-adjusted pharmacokinetic parameters will be manually estimated by dividing the mean drug plasma level and mean drug dose using the Taylor expansion method. 29 The potential impact of this estimation will be explored in a sensitivity analysis, where manually estimated dose-adjusted data will be excluded. In addition, for this calculation, a correlation between drug dose and drug plasma levels of ρ=0.5 will be assumed, and two alternative values, ρ=0.2 and ρ=0.8 will be used instead in the sensitivity analysis. Drug plasma pharmacokinetic parameters are often presented as body-weight-adjusted. To increase the scope of the review, body-weight-adjusted and unadjusted data will be treated as interchangeable. If body-weight-adjusted and unadjusted data are presented simultaneously, body-weight-adjusted data will be prioritized. This decision will be tested using sensitivity analysis, in which only body-weight-adjusted data will be included. Pharmacokinetic parameters that will be used to assess drug plasma levels will be: I). Dose-adjusted steady-state drug plasma concentration (Css/D): Measured after five elimination half-lives have elapsed since drug initiation or therapy regimen change, during which patients took stable doses of the drug with good compliance. Ideally, measurements were taken in the morning, just before the new dose was taken. II). Dose-adjusted area under the steady-state plasma concentration-time curve (AUC/D): Measured after five elimination half-lives had elapsed since drug initiation or therapy regimen change, during which patients took stable doses of the drug with good compliance. Measurements were taken during the same period for all participants. III). Single-dose plasma concentration (C) or area under the plasma concentration curve (AUC): Even though drug plasma level measurements are not usually considered valid before the steady-state has been achieved owing to unpredictable variability, single-dose pharmacokinetic studies will also be included owing to their high level of confounding control and strict study design. These studies often use homogeneous study groups of healthy volunteers with controlled intake of food, water, and other substances and drugs, with standardized blood sampling times. Thus, well-controlled single-dose pharmacokinetic parameters will be used interchangeably with steady-state parameters, and this decision will be tested in a sensitivity analysis where single-dose studies are excluded. This approach is not valid in the case of drugs with non-linear pharmacokinetic profile, i.e. if drug’s pharmacokinetic parameters are dose-dependent. Even though most of the antipsychotics reviewed here follow linear pharmacokinetics, 30 Asenapine, Chlorpromazine, Lumateperone and Perphenazine have been previously detected to have non-linear pharmacokinetic profile. 31 – 34 Therefore, we will opt to exclude single-dose studies for Asenapine, Chlorpromazine, Lumateperone and Perphenazine. We expect the minor impact of this decision on the final results of our living systematic review due to scarcity of pharmacogenomic data on these specific drugs. Still, if enough single-dose studies are detected for these 4 drugs, we will post-hoc find appropriate mathematical model in the literature in order to approximate steady-state concentrations based on single-dose data. IV). Reciprocal value of the total drug clearance (1/Cl total ): For drugs with a linear pharmacokinetic profile, the reciprocal value of the total clearance is equal to the AUC/D metric. If clearance is presented as median with interquartile range and/or minimum and maximum values, these values will be transformed into their reciprocal values, which will be further transformed into mean and standard deviation. 35 This decision will be tested in the sensitivity analysis, where reciprocal value data are excluded. It is important to note that time needed to achieve steady-state may vary between patients and one of the factors influencing this variability is polymorphism in drug metabolizing enzymes. 36 Therefore, when elimination half-lives are presented as a range in the AGNP therapeutic drug monitoring guidelines, 6 highest limit of this range will be used in order to ensure that experimental groups with slower-than normal drug metabolism have achieved steady-state. If the blood sample for the Css/D measurement was not taken in the morning before the next dose, but the blood sampling time was consistent in the entire cohort, the study will be included; however, this decision will be tested in the sensitivity analysis where only studies with the ideal sampling times are included. If the drug possesses one or more active metabolites that are present in the plasma in non-negligible amounts 6 compared to the parent drugs, drug plasma levels will be expressed as “Active moiety,” i.e. the sum of the plasma parent drug levels and the plasma active metabolite levels. For risperidone, there is evidence on different blood-brain-barrier permeability of risperidone and its active metabolite 9-OH-risperidone, indicating potential difference in their biological activities of same plasma concentration of these two substances. 36 Therefore, data on risperidone/9-OH-risperdione ratio will also be included in the secondary meta-analysis in order to provide better interpretation of risperidone active moiety plasma concentration meta-analysis results. If multiple pharmacokinetic parameters are present within the same study for the same cohort, Css/D will be prioritized because it is the most common readout in our experience. 17 If the same pharmacokinetic parameter is presented for multiple time-points, the longest time point will be selected because of the lower chance that some of the included participants have not yet reached steady-state blood drug levels. 2.5 Study inclusion criteria I). For every drug-gene pair of interest, the study will be included if it reports drug plasma levels for control genotype-predicted phenotype and at least one variant genotype-predicted phenotype for the given gene. II). Studies involving participants of all ethnicities will be included. However, since the genotype frequencies vary drastically based on ethnic background, subgroup analysis will be performed to compare the results between European, East Asian, South Asian, African, and Admixed American origin cohorts. 37 III). Studies in which the participants were treated with antipsychotic drugs were included. This includes studies on patients with schizophrenia, other psychiatric illnesses, and healthy volunteers. To assess the effect of this decision, studies on healthy volunteers will be excluded as a part of the sensitivity analysis. IV). All age groups were eligible for inclusion in principle, but the main results will be presented only for adults between 18 and 65 years of age. Results on participants of all ages, results only in adolescents (12-18 years old), and the results only for the elderly (>65 years old) will be explored in the sensitivity analysis. V). Studies will be included regardless of whether the participants were on a stable dosing regimen on enrolment, started drug regimen on enrolment, or switched to a new drug on enrolment. VI). Studies on both responders and treatment resistant patients will be included. VII). Studies on participants not exposed to co-medications, foods, or smoking, in cases where these factors are known to interfere with the given antipsychotic drug, are preferred because of the lower risk of confounding. Still, studies where participants are exposed to these confounders will be eligible for inclusion only if these factors are well balanced across different phenotype groups or corrected by the authors during data analysis. In addition, studies with co-medication/food/smoking confounding factors will be excluded as a part of the sensitivity analysis. VIII). Studies on participants taking any drug formulation (immediate release tablets, extended release tablets, long-acting injections, intravenous administration, etc.) will be eligible, and the data for all formulations will be used interchangeably in the main meta-analysis. To test this decision, every formulation that is not an immediate release tablet will be excluded as a part of the sensitivity analysis. IX). Prospective studies will be preferred because of the higher reliability of the pre-planned experiments. 38 Nevertheless, retrospective studies are very common in pharmacogenomics and will be included to increase the scope of this review. To test this decision, retrospective studies will be excluded as a part of the sensitivity analysis. X). To increase the scope of this living systematic review, both published and unpublished studies will be included. 2.6 Study exclusion criteria I). Studies on pregnant women will be excluded due to unpredictable pharmacokinetics during pregnancy. II). Studies with a critical overall risk-of-bias grade based on the ROBINS-I (Risk of bias in non-randomised studies of interventions) tool 39 will be excluded (four possible risk-of-bias grades in the ROBINS-I tool are low, moderate, serious, and critical risk of bias, ranked from the best to the worst grade). III). Studies with a substantial proportion of the population consisting of non-compliers will be excluded because of the risk of erroneous drug plasma level measurements. IV). Studies on participants with severe kidney or liver impairments or other severe conditions that interfere with drug pharmacokinetics (Malabsorption, Hypoproteinemia, etc.) will be excluded because of unpredictable changes in the pharmacokinetics of these participants. V). Studies with unbalanced known confounding factors (co-medications, food, cigarette smoke) for drug plasma levels between normal and variant genotype-predicted phenotype groups will be excluded. VI). Population pharmacokinetic studies will be excluded due to incompatibility with other included studies. 2.7 Data screening and selection Both the screening and selection of the results of the systematic search will be performed independently by two researchers, and any disputes will be resolved by consensus with a third researcher. Screening will be performed based on the titles and abstracts of the search results. During the screening, search results will be labels as “not relevant,” “relevant” or “unclear relevance.” For the search results labelled as “relevant” and “unclear relevance,” full text retrieval will be attempted. If the full text could not be retrieved, the corresponding author will be contacted to provide the full text. Next, the retrieved full texts will be assessed for eligibility based on the inclusion and exclusion criteria. Process of screening and selection will be visually reported using PRISMA 2020 flowchart. 40 2.8 Data collection and missing data imputation Data will be extracted using an internally developed standardized form. Means and standard deviations of drug plasma levels, as well as the number of participants, will be extracted. Means and standard deviations will be estimated using standard procedures if the data are presented as geometric mean and 95%CI, 41 as median, interquartile range, minimum, and maximum 35 or as mean values and the p-value of the mean difference. 41 If the Plasma levels are presented graphically but not numerically, numerical data will be extracted from the digital image of the given graph. 42 If patients were not grouped into genotype-predicted phenotypes according to our desired criteria, manual regrouping will be performed when possible. For example, if plasma levels in participants carrying CYP2D6*1/*10 and *1/*5 are presented separately, but there are no data for CYP2D6 IM collectively, the mean plasma levels in *1/*10 and *1/*5 carriers will be summed manually to form the mean IM plasma levels. 41 Regarding demographics, data on ethnicity, sex, and age distribution will be collected. Regarding clinical characteristics, data on the participants’ diagnosis, drug dose, body weight, duration of treatment, blood sampling time, co-medications, and other drug-specific confounders will be collected. Finally, data on study design and the characteristics of reported pharmacokinetic parameters will be collected. If cohorts of two or more clinical studies overlap, inclusion of the studies will be performed to maximize the inclusion of as many unique participants as possible while not having any repeating participants. If the included manuscript suggests that the data of interest were measured but not presented, the corresponding author will be contacted to provide the data. If this is not possible, the study will be labelled as “Awaiting assessment”. Studies with missing data will be reported as a list and considered during the interpretation of publication bias using funnel plots. 2.9 Risk of bias analysis The ROBINS-I tool 39 will be used to assess the seven domains of bias by two researchers independently. Disputes will be resolved by consensus with a third researcher. Based on the semi-quantitative grades for all seven domains, the overall grade for each study will be assigned. Due to the nature of observational studies that will be searched, it is expected for a small number of included studies, if any, to receive the best grade: “Low” risk-of-bias. Instead, it is expected that studies with relatively better design to be graded as having “Moderate” risk-of-bias, while the studies with relatively worse design to receive “Serious” of “Critical” risk-of-bias grade. “No information” overall risk-of-bias grade will be used sparingly, i.e. everywhere where reasonable assumptions regarding the signaling question cannot be made. Studies with a risk of bias grade other than “moderate” or “low” will be excluded as a part of the sensitivity analysis. 2.10 Certainty of evidence analysis Certainty of evidence will be assessed using the GRADE tool 43 across five domains of evidence certainty; overall certainty of evidence will also be assessed for every drug-gene pair of interest. GRADE scoring will be performed independently by two researchers, and disputes will be resolved by consensus with a third researcher. 2.11 Statistical methods Quantitative data needed for the meta-analysis includes the mean plasma level, standard deviation, and number of participants in the given study group. For every drug-gene pair analyzed, all experimental groups will be compared pairwise with their corresponding control group. Drug plasma levels will be compared between the groups using the ratio-of-means (RoM) effect measure 44 and its 95% confidence interval. This will allow for an intuitive interpretation of the results, as well as the comparison of different pharmacokinetic parameters of drug plasma levels within one analysis. Our previous research showed a high probability of high heterogeneity within the included studies; therefore, a random-effect meta-analysis will be performed. Specifically, RoM=1.15 will be interpreted as 15% higher, and RoM=0.85, which will be interpreted as a 15% lower drug plasma level in the experimental group compared to the control group. RoM values for individual values will be log-transformed and pooled using the inverse-variance method to produce the grand-mean. As a secondary analysis, all meta-analysis results calculated as RoM will also be calculated as the Standardized Mean Difference (SMD, Hedges’ g). This is aimed at providing an alternative interpretation of the results, which is important considering the rare use of the RoM effect measure. Heterogeneity will be assessed using the I 2 metric, where I 2 >50% will be considered substantial heterogeneity. 41 In the case of substantial heterogeneity, the effect of outlier results on the overall results will be assessed using a sensitivity analysis. Further, heterogeneity will be explored using other sensitivity and subgroup analyses (previously described) to explore what clinical or demographic factors may be the cause of study misalignment. Potential publication bias and small-study effects will be assessed using contour-enhanced funnel plots 45 and Egger’s test. 46 If fewer than 10 studies are included for a certain drug-gene pair, publication bias will not be performed, as recommended. 45 The critical p -value for Egger’s test will be set at p<0.10, as suggested. 46 2.12 Sensitivity and sub-group analyses Sensitivity analysis will be used to test the robustness of the obtained results with regard to changes to the inclusion/exclusion criteria. The following sensitivity analyses will be performed: 1) Exclusion of the manually dose-adjustment plasma level data; 2) Usage of ρ=0.2 and ρ=0.8 as an assumed correlations levels between drug dose and drug plasma levels for manual dose-adjustment of plasma levels; 3) Exclusion of body-weight-unadjusted data; 4) Exclusion of the data estimated from reciprocal clearance values; 5) Exclusion of studies with suboptimal time of plasma sampling; 6) Inclusion of data on non-adults; 7) Exclusion of the studies with suboptimal confounding control; 8) Exclusion of “Single drug dose” studies; 9) Exclusion of the studies with “Serious” risk-of-bias overall score; 10) Exclusion of healthy volunteer data; 11) Exclusion of retrospective studies and 12) Exclusion of the data on drug formulations other than immediate release tablets. Subgroup analyses will be used to compare the meta-analysis results only between participants of different ethnic backgrounds. 2.13 Maintenance of the living systematic review and meta-analysis Following an initial literature search and data analysis, the baseline results and conclusions of the living systematic review and meta-analysis will be established. As these results are being published, designated website will be created to display these results, and thus the maintenance phase of the living systematic review will begin. In this phase, once every six months, a systematic literature search will be repeated, and two designated researchers will be tasked with screening and testing for eligibility of the new search results. Alternatively, if a sudden increase in the number of new publications is detected during the first year of maintenance, updates from that point onwards will be performed more often once every three months. The data from the eligible studies will be extracted in the same manner as during the establishment of the baseline results and will be added to the database of the baseline results. Updated results will then be published on the website, together with the change log. If a new discovery regarding pharmacogenomics of liver enzymes involved in the metabolism of antipsychotics emerges, the entire database will be updated accordingly in the shortest possible notice. This includes newly detected drug-gene pairs of interest and new consensus for genotype-determined phenotype classification. For pragmatic reasons, once all analyzed drug–gene pairs either achieve satisfactory strength of evidence or experience no new publications for an extended period of time, updates of the living systematic review will be performed less frequently, and the update frequency will depend on the probability of new evidence emerging in the future. 2.14 Dissemination As previously mentioned, the baseline results will be published in separate papers, while the up-to-date results and conclusions will be presented on a designated website. Papers published in scientific journals are planned from time to time during the living systematic review maintenance phase. 2.15 Study status At the time of writing the manuscript (29. January 2024), the literature search strategy was designed, and a systematic search was not performed for either of the drug-genes of interest. No study screening, selection, or data extraction was performed at the time of writing. 3. Discussion This project has the potential to provide much-needed clinical information to the psychiatry community. Psychiatrists are becoming increasingly aware of the CYP450 genetic status of their patients, and the implementation of evidence-based knowledge of drug-gene interactions in psychiatrists’ decision-making will improve the quality of pharmacotherapy in psychiatry. This interaction will be facilitated by up-to-date reporting of the systematic review results on a designated website, which will be freely available to any interested clinician. Furthermore, several attempts have been made to create and test clinical tools for pharmacogenomics-guided pharmacotherapy for schizophrenia. 47 – 49 Such tools aim to detect and mitigate potentially dangerous drug-gene interactions, and thus improve the efficacy and/or safety of antipsychotic drugs. One common approach is to completely avoid drugs known to interact negatively with the genetic makeup of a patient. This approach is criticized as potentially dangerous because it can overly restrict the list of effective options available to the patient. 50 Another promising approach is to use genetic information to guide the dosing regimen of antipsychotic drugs, but due to limited and often conflicting evidence, genotype-guided dose regimen adjustments are often arbitrary. The results of this systematic review may facilitate the development of new and the improvement of existing pharmacogenomic tools by providing precise estimates of expected blood drug concentration changes in carriers of different genetic variants. This may help in the transition from arbitrary to evidence-based algorithms for the mitigation of potentially harmful drug-gene interactions related to the CYP450 and UGT genotypes. 3.1 Limitations One of the most substantial limitations of this project was the expected high risk of bias in the included studies. This is because of the very common naturalistic approach with insufficient confounder control in the eligible studies observed in our previous work. 8 In addition, carriers of variant CYP450 or UGT alleles may be more likely to drop out due to their atypical drug plasma levels during observational studies, potentially biasing the results. Finally, there is a risk that some of the results of this systematic review may become outdated with the discovery of new alleles for some genes of interest. This could cause participants to become misclassified in the studies published prior to this discovery without the option to re-classify them post hoc, as this would require repeated genetic testing. Ethics and consent Ethical approval and written informed consent were not required. Data availability Underlying data No data are associated with this article. Extended data Figshare, LivingCYP - Living CYP - Extended data - F1000 7jul2024.docx, https://doi.org/10.6084/m9.figshare.25109675.v3 51 Reporting guidelines Figshare: PRISMA –P checklist for Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol, https://doi.org/10.6084/m9.figshare.25109675.v3 51 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). References 1. Miller AH, Raison CL: Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies. Mol. Psychiatry. Jan 2023; 28 (1): 68–75. PubMed Abstract | Publisher Full Text 2. Howes OD, Thase ME, Pillinger T: Treatment resistance in psychiatry: state of the art and new directions. Mol. Psychiatry. Jan 2022; 27 (1): 58–72. PubMed Abstract | Publisher Full Text | Free Full Text 3. Dold M, Leucht S: Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective. Evid. Based Ment. Health. May 2014; 17 (2): 33–37. PubMed Abstract | Publisher Full Text 4. Kaar SJ, Natesan S, McCutcheon R, et al. : Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology. Aug 1 2020; 172 : 107704. PubMed Abstract | Publisher Full Text 5. Carrascal-Laso L, Isidoro-Garcia M, Ramos-Gallego I, et al. : Review: Influence of the CYP450 Genetic Variation on the Treatment of Psychotic Disorders.J. Clin. Med.Sep 21 2021; 10 (18). PubMed Abstract | Publisher Full Text | Free Full Text 6. Hiemke C, Bergemann N, Clement HW, et al. : Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. Jan 2018; 51 (1-02): 9–62. PubMed Abstract | Publisher Full Text 7. Urichuk L, Prior TI, Dursun S, et al. : Metabolism of atypical antipsychotics: involvement of cytochrome p450 enzymes and relevance for drug-drug interactions.Curr. Drug Metab.Jun 2008; 9 (5): 410–8. PubMed Abstract | Publisher Full Text 8. Ingelman-Sundberg M, Sim SC, Gomez A, et al. : Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects.Pharmacol. Ther.Dec 2007; 116 (3): 496–526. PubMed Abstract | Publisher Full Text 9. Gaedigk A, Casey ST, Whirl-Carrillo M, et al. : Pharmacogene Variation Consortium: A Global Resource and Repository for Pharmacogene Variation. Clin. Pharmacol. Ther. Sep 2021; 110 (3): 542–545. PubMed Abstract | Publisher Full Text | Free Full Text 10. Beunk L, Nijenhuis M, Soree B, et al. : Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics.Eur. J. Hum. Genet.Mar 2024; 32 (3): 278–285. PubMed Abstract | Publisher Full Text | Free Full Text 11. Thorn CF, Muller DJ, Altman RB, et al. : PharmGKB summary: clozapine pathway, pharmacokinetics.Pharmacogenet. Genomics.Sep 2018; 28 (9): 214–222. PubMed Abstract | Publisher Full Text | Free Full Text 12. Whirl-Carrillo M, Huddart R, Gong L, et al. : An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine.Clin. Pharmacol. Ther.Sep 2021; 110 (3): 563–572. PubMed Abstract | Publisher Full Text | Free Full Text 13. Stingl JC, Bartels H, Viviani R, et al. : Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review.Pharmacol. Ther.Jan 2014; 141 (1): 92–116. PubMed Abstract | Publisher Full Text 14. UGT Alleles Nomenclature Home Page: UGT Nomenclature Commitee.June 2005. [Accessed 13. June 2024]. http://www.ugtalleles.ulaval.ca 15. Bruckmueller H, Cascorbi I: ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding?Expert Opin. Drug Met.Apr 3 2021; 17 (4): 369–396. PubMed Abstract | Publisher Full Text 16. Geers LM, Pozhidaev IV, Ivanova SA, et al. : Association between 8 P-glycoprotein (MDR1/ABCB1) gene polymorphisms and antipsychotic drug-induced hyperprolactinaemia.Br. J. Clin. Pharmacol.Sep 2020; 86 (9): 1827–1835. PubMed Abstract | Publisher Full Text | Free Full Text 17. Milosavljevic F, Bukvic N, Pavlovic Z, et al. : Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis. JAMA Psychiatry. Mar 1 2021; 78 (3): 270–280. PubMed Abstract | Publisher Full Text | Free Full Text 18. Jukic M, Milosavljevic F, Molden E, et al. : Pharmacogenomics in treatment of depression and psychosis: an update. Trends Pharmacol. Sci. Dec 2022; 43 (12): 1055–1069. PubMed Abstract | Publisher Full Text 19. Shekhani R, Steinacher L, Swen JJ, et al. : Evaluation of Current Regulation and Guidelines of Pharmacogenomic Drug Labels: Opportunities for Improvements. Clin. Pharmacol. Ther. May 2020; 107 (5): 1240–1255. PubMed Abstract | Publisher Full Text | Free Full Text 20. Shamseer L, Moher D, Clarke M, et al. : Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. Jan 2 2015; 349 : g7647. PubMed Abstract | Publisher Full Text 21. Stroup DF, Berlin JA, Morton SC, et al. : Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. Apr 19 2000; 283 (15): 2008–2012. PubMed Abstract | Publisher Full Text 22. Nikisch G, Baumann P, Oneda B, et al. : Cytochrome P450 and ABCB1 genetics: association with quetiapine and norquetiapine plasma and cerebrospinal fluid concentrations and with clinical response in patients suffering from schizophrenia. A pilot study.J .Psychopharmacol.Jul 2011; 25 (7): 896–907. PubMed Abstract | Publisher Full Text 23. Nagasaka Y, Sano T, Oda K, et al. : Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole.Xenobiotica.Oct 2014; 44 (10): 926–932. PubMed Abstract | Publisher Full Text 24. de Leon J , Wynn G, Sandson NB:The Pharmacokinetics of Paliperidone Versus Risperidone. Psychosomatics. Jan-Feb 2010; 51 (1): 80–88. PubMed Abstract | Publisher Full Text 25. Rosenzweig P, Canal M, Patat A, et al. : A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers.Hum. Psychopharmacol.Jan 2002; 17 (1): 1–13. PubMed Abstract | Publisher Full Text 26. Beedham C, Miceli JJ, Obach RS: Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J. Clin. Psychopharmacol. Jun 2003; 23 (3): 229–232. PubMed Abstract | Publisher Full Text 27. Waring RH: Cytochrome P450: genotype to phenotype.Xenobiotica.Jan 2020; 50 (1): 9–18. Publisher Full Text 28. Shah RR, Smith RL: Addressing phenoconversion: the Achilles’ heel of personalized medicine.Br. J. Clin. Pharmacol.Feb 2015; 79 (2): 222–40. PubMed Abstract | Publisher Full Text | Free Full Text 29. Stuart A, Ord JK: Kendall’s Advanced Theory of Statistics. 6th ed. vol. 1 . . Arnold; 1998. 30. Mauri MC, Paletta S, Di Pace C, et al. : Clinical Pharmacokinetics of Atypical Antipsychotics: An Update. Clin. Pharmacokinet. Dec 2018; 57 (12): 1493–1528. PubMed Abstract | Publisher Full Text 31. Blair HA: Lumateperone: First Approval.Drugs.Mar 2020; 80 (4): 417–423. PubMed Abstract | Publisher Full Text 32. Yeung PK, Hubbard JW, Korchinski ED, et al. :Pharmacokinetics of chlorpromazine and key metabolites. Eur. J. Clin. Pharmacol. 1993; 45 (6): 563–569. PubMed Abstract | Publisher Full Text 33. Hansen LB, Larsen NE:Therapeutic advantages of monitoring plasma concentrations of perphenazine in clinical practice. Psychopharmacology (Berl). 1985; 87 (1): 16–19. PubMed Abstract | Publisher Full Text 34. Saphris® (Asenapine) FDA drug label (Accessed on 17 June 2024). https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022117s014s015s016lbl.pdf 35. Wan X, Wang W, Liu J, et al. : Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. Dec 19 2014; 14 : 135. PubMed Abstract | Publisher Full Text | Free Full Text 36. de Leon J , Schoretsanitis G: CYP2D6 pharmacogenetics and risperidone: reflections after 25 years of research.Pharmacogenomics.Nov 2020; 21 (16): 1139–1144. PubMed Abstract | Publisher Full Text 37. Zhou Y, Ingelman-Sundberg M, Lauschke VM: Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin. Pharmacol. Ther. Oct 2017; 102 (4): 688–700. PubMed Abstract | Publisher Full Text | Free Full Text 38. Norvell DC: Study types and bias-Don’t judge a study by the abstract’s conclusion alone. Evid. Based Spine Care J. Aug 2010; 1 (2): 7–10. PubMed Abstract | Publisher Full Text | Free Full Text 39. Sterne JA, Hernan MA, Reeves BC, et al. : ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. Oct 12 2016; 355 : i4919. PubMed Abstract | Publisher Full Text | Free Full Text 40. Page MJ, McKenzie JE, Bossuyt PM, et al. : The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. Mar 29 2021; 372 : n71. PubMed Abstract | Publisher Full Text | Free Full Text 41. Nasser M: Cochrane Handbook for Systematic Reviews of Interventions. Am. J. Public Health. Jun 2020; 110 (6): 753–754. Publisher Full Text 42. Rohatgi A: WebPlotDigitizer 4.6. Reference Source 2022; 43. Schünemann H, Brozek J, Guyatt G, et al. : GRADE Handbook. UK: Cochrane collaboration London; 2013. 44. Friedrich JO, Adhikari NKJ, Beyene J: The ratio of means method as an alternative to mean differences for analyzing continuous outcome variables in meta-analysis: A simulation study. BMC Med. Res. Methodol. May 21 2008; 8 : 8. PubMed Abstract | Publisher Full Text | Free Full Text 45. Sterne JA, Sutton AJ, Ioannidis JP, et al. : Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. Jul 22 2011; 343 : d4002. PubMed Abstract | Publisher Full Text 46. Egger M, Davey Smith G, Schneider M, et al. : Bias in meta-analysis detected by a simple, graphical test. BMJ. Sep 13 1997; 315 (7109): 629–634. PubMed Abstract | Publisher Full Text | Free Full Text 47. Carrascal-Laso L, Franco-Martín MA, García-Berrocal MB, et al. : Application of a Pharmacogenetics-Based Precision Medicine Model (5SPM) to Psychotic Patients That Presented Poor Response to Neuroleptic Therapy. J. Pers. Med. Dec 2020; 10 (4). PubMed Abstract | Publisher Full Text | Free Full Text 48. Jurgens G, Andersen SE, Rasmussen HB, et al. : Effect of Routine Cytochrome P450 2D6 and 2C19 Genotyping on Antipsychotic Drug Persistence in Patients With Schizophrenia: A Randomized Clinical Trial. JAMA Netw. Open. Dec 1 2020; 3 (12): e2027909. PubMed Abstract | Publisher Full Text 49. Kang ZW, Qin Y, Sun YT, et al. : Multigenetic Pharmacogenomics-Guided Treatment vs Treatment As Usual Among Hospitalized Men With Schizophrenia. JAMA Netw. Open. Oct 6 2023; 6 (10): e2335518. PubMed Abstract | Publisher Full Text | Free Full Text 50. Goldberg JF, Rosenblat JD, McIntyre RS, et al. : Letter to the Editor: Clinical versus statistical significance of pharmacogenomic-guided antidepressant therapy: What’s really being measured and marketed?. J. Psychiatr. Res. Jul 2019; 114 : 208–209. PubMed Abstract | Publisher Full Text 51. Milosavljević F: Living CYP - Extended data - F1000 25mar2024.docx. figshare. 2024. Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 07 May 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of physiology, Faculty of Pharmacy, Univerzitet u Beogradu, Belgrade, 11221, Serbia 2 Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, Bavaria, 81675, Germany Filip Milosavljević Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation Stefan Leucht Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing Competing interests In the last three years SL has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Neurotorium, Otsuka, NovoNordisk, Recordati, Rovi, Teva. FM reports no conflict of interests. Grant information This work was supported by Alexander von Humboldt Foundation’s Postdoctoral Fellowship Stipend (awarded to FM, stipend number: 1235463-HFST-P). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 09 Jul 2024, 13:452 https://doi.org/10.12688/f1000research.147794.2 version 1 Published: 07 May 2024, 13:452 https://doi.org/10.12688/f1000research.147794.1 Copyright © 2024 Milosavljević F and Leucht S. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Milosavljević F and Leucht S. Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.12688/f1000research.147794.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 09 Jul 2024 Revised Views 0 Cite How to cite this report: Baumann P. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.168742.r300641 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v2#referee-response-300641 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 31 Jul 2024 Pierre Baumann , Department of Psychiatry (DP-CHUV), Universite de Lausanne, Lausanne, Vaud, Switzerland Approved VIEWS 0 https://doi.org/10.5256/f1000research.168742.r300641 The Introduction is now written more comprehensively, and it is informative. It satisfies the request of the reviewers. There are some minor spelling errors (use search function): Haloperidol (p. 3, last §) ... Continue reading READ ALL The Introduction is now written more comprehensively, and it is informative. It satisfies the request of the reviewers. There are some minor spelling errors (use search function): Haloperidol (p. 3, last §) I am surprised that drugs (Asenapine, Clozapine, … etc ) and enzymes (Uridine … etc) are (sometimes) written in capital letters (e.g. p. 3 and 7) Answer of the Authors to the comment of the reviewer (p. 18): “Even though the pharmacokinetics of inactive drug metabolites is very relevant and important topic, we find this data to be of limited usefulness for our living systematic review as we plan to focus on the clinical aspects of therapeutic drug monitoring.” This is somewhat contradictory as this protocol will mainly and almost exclusively focus on the relationship between pharmacokinetics and pharmacogenomics and not on clinical aspects. The determination of ratios parent compound/metabolite (also inactive metabolites) will allow a better understanding of the individual role of a particular enzyme in a specific metabolic pathway. This is only a comment, with no request. The reviewer thanks the Authors for their comments and corrections of their manuscript Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Baumann P. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.168742.r300641 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v2#referee-response-300641 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: de Lima Benzi JR. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.168742.r300642 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v2#referee-response-300642 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 16 Jul 2024 Jhohann Richard de Lima Benzi , University of São Paulo, São Paulo, Brazil Approved VIEWS 0 https://doi.org/10.5256/f1000research.168742.r300642 I have reviewed the revised manuscript. The authors have addressed all my comments and questions thoroughly and politely. I have no further comments or concerns. Therefore, I fully endorse this manuscript can be indexed. Thank you for the opportunity to ... Continue reading READ ALL I have reviewed the revised manuscript. The authors have addressed all my comments and questions thoroughly and politely. I have no further comments or concerns. Therefore, I fully endorse this manuscript can be indexed. Thank you for the opportunity to review this work. Best regards. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical pharmacology, pharmacokinetics, pharmacometrics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT de Lima Benzi JR. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.168742.r300642 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v2#referee-response-300642 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 07 May 2024 Views 0 Cite How to cite this report: Baumann P. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.162029.r280401 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v1#referee-response-280401 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 06 Jun 2024 Pierre Baumann , Department of Psychiatry (DP-CHUV), Universite de Lausanne, Lausanne, Vaud, Switzerland Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.162029.r280401 General comment: The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf ... Continue reading READ ALL General comment: The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf Table 1, criterion O (outcome)). It would have been of interest to include a part which concerns the clinical outcome (efficacy, effectiveness, adverse effects) of the patients, as the present protocol will not allow to clearly show the clinical relevance of pharmacokinetic-pharmacogenetic exams. However, the present project is already ambitious and the inclusion of a regularly occurring update is highly promising and novel. Other comments and questions: The issues dealing with pharmacokinetics and pharmacogenomics presented in the Introduction should be presented in more details as some references are not adequate. Indeed, some citations lack precision, e.g. ref 5 and 6, in the sentence: “It is proposed that mutations in genes that code liver CYP450 (Cytochrome p450) and UGT (UDP-glycosyltransferase) enzymes can cause either too low or too high plasma levels of antipsychotic, 5 leading to a lack of efficacy or a higher risk of adverse reactions in some patients. 6 The citation of reference 5 suggests that it presents data about the importance of UGT in the pharmacogenomics of antipsychotics. However, UGT is only mentioned as a key word (and only as UGT-2B.. but not as UGT-1A..). In ref 6, UGT is not even mentioned. Therefore, the reader with limited knowledge in this field may not get a full picture of the importance of the subject. In summary, the Introduction should be extended! Table 1 presents in “Intervention I” the different phenotypes using the example risperidone. The reader is then supposed to presume that this presentation is also valid for UGT enzymes (eg gene-drug pair: UGT-olanzapine), but this classification (poor, intermediate, extensive, ultrarapid) is seemingly not introduced for these polymorphisms. If however this is the case, this should be presented in some details and corresponding references should be presented. Indeed, the average reader will not be familiar with the genetic polymorphisms of conjugating enzymes, and in particular, with their relevance for antipsychotics. In other words: are there PM, EM, UM, IM in patients treated with e.g. asenapine or olanzapine, with regard to the metabolism by UGT-enzymes? (Admittedly, in the suppl. material is some information, but the protocol should be more precise, especially in Introduction). It is a fact that among cytochrome P-450 isozymes, only about half a dozen isozymes play a role in the metabolism of antipsychotics. In contrast, there are considerably more isozymes which contribute to the conjugation of drugs, but their individual role in the metabolism of antipsychotics is poorly characterized. The pioneering study of Haslemo et al. (CPT, 2012, 221) (besides that of Erickson et al., Pharmacogen Genom 2011, 539) shows that plasma concentrations of conjugated olanzapine (10-N-ola-glucuronide) differ in olanzapine treated patients classified according to their UGT1A genotypes, but the difference is negligible for (unconjugated) olanzapine concentrations. This rises the question whether in the present meta-analysis study both ola and conjugated ola concentrations will be considered. It could be then of interest to examine the relationships between the UGT genotypes and the ratios parent compound/metabolite (Ola/10-N-ola-glucoronide). This approach may also be valuable for all other antipsychotics, whether they are metabolized by cytochrome P-450 or by polymorphic conjugating enzymes, or by both types (e.g. risp/9-OH-risp; 9-OH-risp/conjug. 9-OH-risp; etc). Probably of little importance for the establishment of the protocol, it is to mention that in the case of risperidone, its hydroxylation to 9-OH-risperidone is stereoselective, in that CYP2D6 preferentially forms (+)-9-OH-risperidone rather than (-)-9-OH-risperidone (Yasui-Furukori et al. Drug Metab. Disp 2001, 1263). It should be considered, as rarely, stereoselective procedures were used in the published studies, the net effect of the genotype may be masked when non-stereoselective procedures are used. The authors exclude some antipsychotics, but the mentioned reasons are not always evident, and again, the citations do not always correspond to the statements. Therefore, the presentation of the reference list demands to be improved. Eg, 2.2. Drug gene pairs …: “Lurasidone will not be analyzed because of the uncertain importance of drug-blood level measurements.” Ref 6 is cited, but this ref does apparently not deal with this subject. Actually, lurasidone is mainly a substrate of CYP3A4/5. As its blood levels strongly depend on dietary conditions, this may be an important reason for recommending TDM (cf Preskorn 2013: Lurasidone should be administered with food-at least 350 kcal-to ensure maximum exposure). However, one can agree with the decision of the authors, as this drug belongs to the group of drugs mentioned in 2.5. VII (study inclusion citeria) resp. 2.6. V. 2.4. Definition of the outcome As pointed out by the authors, weight corrected drug concentrations may be advantageous, but they are often not available. Steady-state plasma concentrations: In the case of risperidone, there may be a problem in that in extensive metabolizers (CYP2D6), its T1/2 = 2 - 4h, but in poor metabolizers, considerably longer, comparable to that of its metabolite 9-OH-risperidone. This means that in EM, risp. steady-state concentrations will hardly be reached in EM but only in PM. Extended data: March : 6. UGT1A4 “At the time of writing, there is no consensus regarding the classification of different UGT1A4 diplotypes into metabolizer groups. Therefore, pragmatically, alleles known to affect CYP1A2 activity with Minor allelic frequencies >1% in the world population will be considered for this analysis.” Not clear: this suggests that there is a relationship CYP1A2 – UGT1A4 (?). Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Baumann P. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.162029.r280401 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v1#referee-response-280401 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 09 Jul 2024 Filip Milosavljević , Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany 09 Jul 2024 Author Response "The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 ... Continue reading "The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf Table 1, criterion O (outcome)). It would have been of interest to include a part which concerns the clinical outcome (efficacy, effectiveness, adverse effects) of the patients, as the present protocol will not allow to clearly show the clinical relevance of pharmacokinetic-pharmacogenetic exams. However, the present project is already ambitious and the inclusion of a regularly occurring update is highly promising and novel." We thank the reviewer for positive comment and for recognizing the scale of this project. "Other comments and questions: The issues dealing with pharmacokinetics and pharmacogenomics presented in the Introduction should be presented in more details as some references are not adequate. Indeed, some citations lack precision, e.g. ref 5 and 6, in the sentence: “It is proposed that mutations in genes that code liver CYP450 (Cytochrome p450) and UGT (UDP-glycosyltransferase) enzymes can cause either too low or too high plasma levels of antipsychotic,5 leading to a lack of efficacy or a higher risk of adverse reactions in some patients.6 The citation of reference 5 suggests that it presents data about the importance of UGT in the pharmacogenomics of antipsychotics. However, UGT is only mentioned as a key word (and only as UGT-2B.. but not as UGT-1A..). In ref 6, UGT is not even mentioned. Therefore, the reader with limited knowledge in this field may not get a full picture of the importance of the subject. In summary, the Introduction should be extended!" We sincerely apologize for inaccurate citations. In accordance with this comment and the comment from the other reviewer, introduction section is now expended to shortly summarize all gene candidates potentially important for the pharmacogenomics of antipsychotic drug pharmacokinetics. "Table 1 presents in “Intervention I” the different phenotypes using the example risperidone. The reader is then supposed to presume that this presentation is also valid for UGT enzymes (eg gene-drug pair: UGT-olanzapine), but this classification (poor, intermediate, extensive, ultrarapid) is seemingly not introduced for these polymorphisms. If however this is the case, this should be presented in some details and corresponding references should be presented." We agree, Table 1 can be misinterpreted. In the introduction section, it is now described which genes have established metabolizer status definitions and which genes are instead analyzed on the basis of genotypes and haplotypes. Also, Table 1 is now updated to include another example that involves UGT isoenzyme to further eliminate confusion. "Indeed, the average reader will not be familiar with the genetic polymorphisms of conjugating enzymes, and in particular, with their relevance for antipsychotics. In other words: are there PM, EM, UM, IM in patients treated with e.g. asenapine or olanzapine, with regard to the metabolism by UGT-enzymes? (Admittedly, in the suppl. material is some information, but the protocol should be more precise, especially in Introduction). It is a fact that among cytochrome P-450 isozymes, only about half a dozen isozymes play a role in the metabolism of antipsychotics. In contrast, there are considerably more isozymes which contribute to the conjugation of drugs, but their individual role in the metabolism of antipsychotics is poorly characterized." In line with this and previous comments, introduction section is now extended to also include this information. Also, our justification for the choice of UGT isoenzymes included in the first iteration of our living systematic review is included in the section 2.2. If the Reviewer finds that some crucial UGT or CYP450 isoenzymes are omitted, we will gladly consider them for the inclusion. "The pioneering study of Haslemo et al. (CPT, 2012, 221) (besides that of Erickson et al., Pharmacogen Genom 2011, 539) shows that plasma concentrations of conjugated olanzapine (10-N-ola-glucuronide) differ in olanzapine treated patients classified according to their UGT1A genotypes, but the difference is negligible for (unconjugated) olanzapine concentrations. This rises the question whether in the present meta-analysis study both ola and conjugated ola concentrations will be considered. It could be then of interest to examine the relationships between the UGT genotypes and the ratios parent compound/metabolite (Ola/10-N-ola-glucoronide).This approach may also be valuable for all other antipsychotics, whether they are metabolized by cytochrome P-450 or by polymorphic conjugating enzymes, or by both types (e.g. risp/9-OH-risp; 9-OH-risp/conjug. 9-OH-risp; etc)." To our knowledge, Olanzapine metabolites including 10-N-Olanzapine-Glucuronide have marginal activity and it is not recommended to measure them during therapeutic drug monitoring [PMID: 1683407]. Even though the pharmacokinetics of inactive drug metabolites is very relevant and important topic, we find this data to be of limited usefulness for our living systematic review as we plan to focus on the clinical aspects of therapeutic drug monitoring. Regarding risperidone, there is evidence that risperidone and 9-OH-risperidone have different efficacy and safety profiles due to different blood-brain-barriers permeability [PMID: 33054667]. Therefore, we agree for that analysis of riperidone/9-OH-risperidone ratio may be very useful for the interpretation of meta-analysis of risperidone active moiety (Risperidone + 9-OH-Risperidone) plasma levels. Section 2.4 is now updated to reflect this. "Probably of little importance for the establishment of the protocol, it is to mention that in the case of risperidone, its hydroxylation to 9-OH-risperidone is stereoselective, in that CYP2D6 preferentially forms (+)-9-OH-risperidone rather than (-)-9-OH-risperidone (Yasui-Furukori et al. Drug Metab. Disp 2001, 1263). It should be considered, as rarely, stereoselective procedures were used in the published studies, the net effect of the genotype may be masked when non-stereoselective procedures are used." As we mentioned previously, we would like to focus on clinical aspects of therapeutic drug monitoring, i.e. we will try to use drug blood levels as a biomarkers of drugs biological effects. Therefore, even though stereo-selective analysis highlights the influence of CYP2D6, we find very limited clinical relevance of this information for our review as two enantiomers of 9-OH-Risperidone have been previously described as equipotent (PMID: 17344104). "The authors exclude some antipsychotics, but the mentioned reasons are not always evident, and again, the citations do not always correspond to the statements. Therefore, the presentation of the reference list demands to be improved. Eg, 2.2. Drug gene pairs …: “Lurasidone will not be analyzed because of the uncertain importance of drug-blood level measurements.” Ref 6 is cited, but this ref does apparently not deal with this subject. Actually, lurasidone is mainly a substrate of CYP3A4/5. As its blood levels strongly depend on dietary conditions, this may be an important reason for recommending TDM (cf Preskorn 2013: Lurasidone should be administered with food-at least 350 kcal-to ensure maximum exposure). However, one can agree with the decision of the authors, as this drug belongs to the group of drugs mentioned in 2.5. VII (study inclusion citeria) resp. 2.6. V." We agree with the reviewer, Lurasidone is the substrate for CYP3A4/5 and should therefore be included. Also, unrelated to reviewer’s comment, we have noticed that we listed Paliperidone as CYP3A4/5 and CYP2D6 substrate even though paliperidone is minimally metabolized in the liver and is mostly eliminated by kidneys [PMID: 20118446]. We sincerely apologize for these errors; they are now corrected in the revised version of the manuscript. "2.4. Definition of the outcome As pointed out by the authors, weight corrected drug concentrations may be advantageous, but they are often not available. Steady-state plasma concentrations: In the case of risperidone, there may be a problem in that in extensive metabolizers (CYP2D6), its T1/2 = 2 - 4h, but in poor metabolizers, considerably longer, comparable to that of its metabolite 9-OH-risperidone. This means that in EM, risp. steady-state concentrations will hardly be reached in EM but only in PM." We agree, people with lower enzyme metabolism capacities might take longer time to reach steady state. Therefore, we changed the criterion for the time needed to reach steady state to be 5x the conservative t 1/2 estimate. In other words, whenever the t 1/2 is presented as the range in AGNP guidelines (PMID: 28910830) we will use the higher limit of this range (longest time). This is now reflected in section 2.4. "Extended data: March : 6. UGT1A4 “At the time of writing, there is no consensus regarding the classification of different UGT1A4 diplotypes into metabolizer groups. Therefore, pragmatically, alleles known to affect CYP1A2 activity with Minor allelic frequencies >1% in the world population will be considered for this analysis.” Not clear: this suggests that there is a relationship CYP1A2 – UGT1A4 (?)." This was a typing error, and we sincerely apologize for it. We also noticed several other typing errors in the Extended data and they are now corrected in the new version. We again thank the Reviewer for the constructive criticism. We have no further comments. "The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf Table 1, criterion O (outcome)). It would have been of interest to include a part which concerns the clinical outcome (efficacy, effectiveness, adverse effects) of the patients, as the present protocol will not allow to clearly show the clinical relevance of pharmacokinetic-pharmacogenetic exams. However, the present project is already ambitious and the inclusion of a regularly occurring update is highly promising and novel." We thank the reviewer for positive comment and for recognizing the scale of this project. "Other comments and questions: The issues dealing with pharmacokinetics and pharmacogenomics presented in the Introduction should be presented in more details as some references are not adequate. Indeed, some citations lack precision, e.g. ref 5 and 6, in the sentence: “It is proposed that mutations in genes that code liver CYP450 (Cytochrome p450) and UGT (UDP-glycosyltransferase) enzymes can cause either too low or too high plasma levels of antipsychotic,5 leading to a lack of efficacy or a higher risk of adverse reactions in some patients.6 The citation of reference 5 suggests that it presents data about the importance of UGT in the pharmacogenomics of antipsychotics. However, UGT is only mentioned as a key word (and only as UGT-2B.. but not as UGT-1A..). In ref 6, UGT is not even mentioned. Therefore, the reader with limited knowledge in this field may not get a full picture of the importance of the subject. In summary, the Introduction should be extended!" We sincerely apologize for inaccurate citations. In accordance with this comment and the comment from the other reviewer, introduction section is now expended to shortly summarize all gene candidates potentially important for the pharmacogenomics of antipsychotic drug pharmacokinetics. "Table 1 presents in “Intervention I” the different phenotypes using the example risperidone. The reader is then supposed to presume that this presentation is also valid for UGT enzymes (eg gene-drug pair: UGT-olanzapine), but this classification (poor, intermediate, extensive, ultrarapid) is seemingly not introduced for these polymorphisms. If however this is the case, this should be presented in some details and corresponding references should be presented." We agree, Table 1 can be misinterpreted. In the introduction section, it is now described which genes have established metabolizer status definitions and which genes are instead analyzed on the basis of genotypes and haplotypes. Also, Table 1 is now updated to include another example that involves UGT isoenzyme to further eliminate confusion. "Indeed, the average reader will not be familiar with the genetic polymorphisms of conjugating enzymes, and in particular, with their relevance for antipsychotics. In other words: are there PM, EM, UM, IM in patients treated with e.g. asenapine or olanzapine, with regard to the metabolism by UGT-enzymes? (Admittedly, in the suppl. material is some information, but the protocol should be more precise, especially in Introduction). It is a fact that among cytochrome P-450 isozymes, only about half a dozen isozymes play a role in the metabolism of antipsychotics. In contrast, there are considerably more isozymes which contribute to the conjugation of drugs, but their individual role in the metabolism of antipsychotics is poorly characterized." In line with this and previous comments, introduction section is now extended to also include this information. Also, our justification for the choice of UGT isoenzymes included in the first iteration of our living systematic review is included in the section 2.2. If the Reviewer finds that some crucial UGT or CYP450 isoenzymes are omitted, we will gladly consider them for the inclusion. "The pioneering study of Haslemo et al. (CPT, 2012, 221) (besides that of Erickson et al., Pharmacogen Genom 2011, 539) shows that plasma concentrations of conjugated olanzapine (10-N-ola-glucuronide) differ in olanzapine treated patients classified according to their UGT1A genotypes, but the difference is negligible for (unconjugated) olanzapine concentrations. This rises the question whether in the present meta-analysis study both ola and conjugated ola concentrations will be considered. It could be then of interest to examine the relationships between the UGT genotypes and the ratios parent compound/metabolite (Ola/10-N-ola-glucoronide).This approach may also be valuable for all other antipsychotics, whether they are metabolized by cytochrome P-450 or by polymorphic conjugating enzymes, or by both types (e.g. risp/9-OH-risp; 9-OH-risp/conjug. 9-OH-risp; etc)." To our knowledge, Olanzapine metabolites including 10-N-Olanzapine-Glucuronide have marginal activity and it is not recommended to measure them during therapeutic drug monitoring [PMID: 1683407]. Even though the pharmacokinetics of inactive drug metabolites is very relevant and important topic, we find this data to be of limited usefulness for our living systematic review as we plan to focus on the clinical aspects of therapeutic drug monitoring. Regarding risperidone, there is evidence that risperidone and 9-OH-risperidone have different efficacy and safety profiles due to different blood-brain-barriers permeability [PMID: 33054667]. Therefore, we agree for that analysis of riperidone/9-OH-risperidone ratio may be very useful for the interpretation of meta-analysis of risperidone active moiety (Risperidone + 9-OH-Risperidone) plasma levels. Section 2.4 is now updated to reflect this. "Probably of little importance for the establishment of the protocol, it is to mention that in the case of risperidone, its hydroxylation to 9-OH-risperidone is stereoselective, in that CYP2D6 preferentially forms (+)-9-OH-risperidone rather than (-)-9-OH-risperidone (Yasui-Furukori et al. Drug Metab. Disp 2001, 1263). It should be considered, as rarely, stereoselective procedures were used in the published studies, the net effect of the genotype may be masked when non-stereoselective procedures are used." As we mentioned previously, we would like to focus on clinical aspects of therapeutic drug monitoring, i.e. we will try to use drug blood levels as a biomarkers of drugs biological effects. Therefore, even though stereo-selective analysis highlights the influence of CYP2D6, we find very limited clinical relevance of this information for our review as two enantiomers of 9-OH-Risperidone have been previously described as equipotent (PMID: 17344104). "The authors exclude some antipsychotics, but the mentioned reasons are not always evident, and again, the citations do not always correspond to the statements. Therefore, the presentation of the reference list demands to be improved. Eg, 2.2. Drug gene pairs …: “Lurasidone will not be analyzed because of the uncertain importance of drug-blood level measurements.” Ref 6 is cited, but this ref does apparently not deal with this subject. Actually, lurasidone is mainly a substrate of CYP3A4/5. As its blood levels strongly depend on dietary conditions, this may be an important reason for recommending TDM (cf Preskorn 2013: Lurasidone should be administered with food-at least 350 kcal-to ensure maximum exposure). However, one can agree with the decision of the authors, as this drug belongs to the group of drugs mentioned in 2.5. VII (study inclusion citeria) resp. 2.6. V." We agree with the reviewer, Lurasidone is the substrate for CYP3A4/5 and should therefore be included. Also, unrelated to reviewer’s comment, we have noticed that we listed Paliperidone as CYP3A4/5 and CYP2D6 substrate even though paliperidone is minimally metabolized in the liver and is mostly eliminated by kidneys [PMID: 20118446]. We sincerely apologize for these errors; they are now corrected in the revised version of the manuscript. "2.4. Definition of the outcome As pointed out by the authors, weight corrected drug concentrations may be advantageous, but they are often not available. Steady-state plasma concentrations: In the case of risperidone, there may be a problem in that in extensive metabolizers (CYP2D6), its T1/2 = 2 - 4h, but in poor metabolizers, considerably longer, comparable to that of its metabolite 9-OH-risperidone. This means that in EM, risp. steady-state concentrations will hardly be reached in EM but only in PM." We agree, people with lower enzyme metabolism capacities might take longer time to reach steady state. Therefore, we changed the criterion for the time needed to reach steady state to be 5x the conservative t 1/2 estimate. In other words, whenever the t 1/2 is presented as the range in AGNP guidelines (PMID: 28910830) we will use the higher limit of this range (longest time). This is now reflected in section 2.4. "Extended data: March : 6. UGT1A4 “At the time of writing, there is no consensus regarding the classification of different UGT1A4 diplotypes into metabolizer groups. Therefore, pragmatically, alleles known to affect CYP1A2 activity with Minor allelic frequencies >1% in the world population will be considered for this analysis.” Not clear: this suggests that there is a relationship CYP1A2 – UGT1A4 (?)." This was a typing error, and we sincerely apologize for it. We also noticed several other typing errors in the Extended data and they are now corrected in the new version. We again thank the Reviewer for the constructive criticism. We have no further comments. Competing Interests: We declare no competing interest with regards to this response. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 09 Jul 2024 Filip Milosavljević , Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany 09 Jul 2024 Author Response "The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 ... Continue reading "The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf Table 1, criterion O (outcome)). It would have been of interest to include a part which concerns the clinical outcome (efficacy, effectiveness, adverse effects) of the patients, as the present protocol will not allow to clearly show the clinical relevance of pharmacokinetic-pharmacogenetic exams. However, the present project is already ambitious and the inclusion of a regularly occurring update is highly promising and novel." We thank the reviewer for positive comment and for recognizing the scale of this project. "Other comments and questions: The issues dealing with pharmacokinetics and pharmacogenomics presented in the Introduction should be presented in more details as some references are not adequate. Indeed, some citations lack precision, e.g. ref 5 and 6, in the sentence: “It is proposed that mutations in genes that code liver CYP450 (Cytochrome p450) and UGT (UDP-glycosyltransferase) enzymes can cause either too low or too high plasma levels of antipsychotic,5 leading to a lack of efficacy or a higher risk of adverse reactions in some patients.6 The citation of reference 5 suggests that it presents data about the importance of UGT in the pharmacogenomics of antipsychotics. However, UGT is only mentioned as a key word (and only as UGT-2B.. but not as UGT-1A..). In ref 6, UGT is not even mentioned. Therefore, the reader with limited knowledge in this field may not get a full picture of the importance of the subject. In summary, the Introduction should be extended!" We sincerely apologize for inaccurate citations. In accordance with this comment and the comment from the other reviewer, introduction section is now expended to shortly summarize all gene candidates potentially important for the pharmacogenomics of antipsychotic drug pharmacokinetics. "Table 1 presents in “Intervention I” the different phenotypes using the example risperidone. The reader is then supposed to presume that this presentation is also valid for UGT enzymes (eg gene-drug pair: UGT-olanzapine), but this classification (poor, intermediate, extensive, ultrarapid) is seemingly not introduced for these polymorphisms. If however this is the case, this should be presented in some details and corresponding references should be presented." We agree, Table 1 can be misinterpreted. In the introduction section, it is now described which genes have established metabolizer status definitions and which genes are instead analyzed on the basis of genotypes and haplotypes. Also, Table 1 is now updated to include another example that involves UGT isoenzyme to further eliminate confusion. "Indeed, the average reader will not be familiar with the genetic polymorphisms of conjugating enzymes, and in particular, with their relevance for antipsychotics. In other words: are there PM, EM, UM, IM in patients treated with e.g. asenapine or olanzapine, with regard to the metabolism by UGT-enzymes? (Admittedly, in the suppl. material is some information, but the protocol should be more precise, especially in Introduction). It is a fact that among cytochrome P-450 isozymes, only about half a dozen isozymes play a role in the metabolism of antipsychotics. In contrast, there are considerably more isozymes which contribute to the conjugation of drugs, but their individual role in the metabolism of antipsychotics is poorly characterized." In line with this and previous comments, introduction section is now extended to also include this information. Also, our justification for the choice of UGT isoenzymes included in the first iteration of our living systematic review is included in the section 2.2. If the Reviewer finds that some crucial UGT or CYP450 isoenzymes are omitted, we will gladly consider them for the inclusion. "The pioneering study of Haslemo et al. (CPT, 2012, 221) (besides that of Erickson et al., Pharmacogen Genom 2011, 539) shows that plasma concentrations of conjugated olanzapine (10-N-ola-glucuronide) differ in olanzapine treated patients classified according to their UGT1A genotypes, but the difference is negligible for (unconjugated) olanzapine concentrations. This rises the question whether in the present meta-analysis study both ola and conjugated ola concentrations will be considered. It could be then of interest to examine the relationships between the UGT genotypes and the ratios parent compound/metabolite (Ola/10-N-ola-glucoronide).This approach may also be valuable for all other antipsychotics, whether they are metabolized by cytochrome P-450 or by polymorphic conjugating enzymes, or by both types (e.g. risp/9-OH-risp; 9-OH-risp/conjug. 9-OH-risp; etc)." To our knowledge, Olanzapine metabolites including 10-N-Olanzapine-Glucuronide have marginal activity and it is not recommended to measure them during therapeutic drug monitoring [PMID: 1683407]. Even though the pharmacokinetics of inactive drug metabolites is very relevant and important topic, we find this data to be of limited usefulness for our living systematic review as we plan to focus on the clinical aspects of therapeutic drug monitoring. Regarding risperidone, there is evidence that risperidone and 9-OH-risperidone have different efficacy and safety profiles due to different blood-brain-barriers permeability [PMID: 33054667]. Therefore, we agree for that analysis of riperidone/9-OH-risperidone ratio may be very useful for the interpretation of meta-analysis of risperidone active moiety (Risperidone + 9-OH-Risperidone) plasma levels. Section 2.4 is now updated to reflect this. "Probably of little importance for the establishment of the protocol, it is to mention that in the case of risperidone, its hydroxylation to 9-OH-risperidone is stereoselective, in that CYP2D6 preferentially forms (+)-9-OH-risperidone rather than (-)-9-OH-risperidone (Yasui-Furukori et al. Drug Metab. Disp 2001, 1263). It should be considered, as rarely, stereoselective procedures were used in the published studies, the net effect of the genotype may be masked when non-stereoselective procedures are used." As we mentioned previously, we would like to focus on clinical aspects of therapeutic drug monitoring, i.e. we will try to use drug blood levels as a biomarkers of drugs biological effects. Therefore, even though stereo-selective analysis highlights the influence of CYP2D6, we find very limited clinical relevance of this information for our review as two enantiomers of 9-OH-Risperidone have been previously described as equipotent (PMID: 17344104). "The authors exclude some antipsychotics, but the mentioned reasons are not always evident, and again, the citations do not always correspond to the statements. Therefore, the presentation of the reference list demands to be improved. Eg, 2.2. Drug gene pairs …: “Lurasidone will not be analyzed because of the uncertain importance of drug-blood level measurements.” Ref 6 is cited, but this ref does apparently not deal with this subject. Actually, lurasidone is mainly a substrate of CYP3A4/5. As its blood levels strongly depend on dietary conditions, this may be an important reason for recommending TDM (cf Preskorn 2013: Lurasidone should be administered with food-at least 350 kcal-to ensure maximum exposure). However, one can agree with the decision of the authors, as this drug belongs to the group of drugs mentioned in 2.5. VII (study inclusion citeria) resp. 2.6. V." We agree with the reviewer, Lurasidone is the substrate for CYP3A4/5 and should therefore be included. Also, unrelated to reviewer’s comment, we have noticed that we listed Paliperidone as CYP3A4/5 and CYP2D6 substrate even though paliperidone is minimally metabolized in the liver and is mostly eliminated by kidneys [PMID: 20118446]. We sincerely apologize for these errors; they are now corrected in the revised version of the manuscript. "2.4. Definition of the outcome As pointed out by the authors, weight corrected drug concentrations may be advantageous, but they are often not available. Steady-state plasma concentrations: In the case of risperidone, there may be a problem in that in extensive metabolizers (CYP2D6), its T1/2 = 2 - 4h, but in poor metabolizers, considerably longer, comparable to that of its metabolite 9-OH-risperidone. This means that in EM, risp. steady-state concentrations will hardly be reached in EM but only in PM." We agree, people with lower enzyme metabolism capacities might take longer time to reach steady state. Therefore, we changed the criterion for the time needed to reach steady state to be 5x the conservative t 1/2 estimate. In other words, whenever the t 1/2 is presented as the range in AGNP guidelines (PMID: 28910830) we will use the higher limit of this range (longest time). This is now reflected in section 2.4. "Extended data: March : 6. UGT1A4 “At the time of writing, there is no consensus regarding the classification of different UGT1A4 diplotypes into metabolizer groups. Therefore, pragmatically, alleles known to affect CYP1A2 activity with Minor allelic frequencies >1% in the world population will be considered for this analysis.” Not clear: this suggests that there is a relationship CYP1A2 – UGT1A4 (?)." This was a typing error, and we sincerely apologize for it. We also noticed several other typing errors in the Extended data and they are now corrected in the new version. We again thank the Reviewer for the constructive criticism. We have no further comments. "The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf Table 1, criterion O (outcome)). It would have been of interest to include a part which concerns the clinical outcome (efficacy, effectiveness, adverse effects) of the patients, as the present protocol will not allow to clearly show the clinical relevance of pharmacokinetic-pharmacogenetic exams. However, the present project is already ambitious and the inclusion of a regularly occurring update is highly promising and novel." We thank the reviewer for positive comment and for recognizing the scale of this project. "Other comments and questions: The issues dealing with pharmacokinetics and pharmacogenomics presented in the Introduction should be presented in more details as some references are not adequate. Indeed, some citations lack precision, e.g. ref 5 and 6, in the sentence: “It is proposed that mutations in genes that code liver CYP450 (Cytochrome p450) and UGT (UDP-glycosyltransferase) enzymes can cause either too low or too high plasma levels of antipsychotic,5 leading to a lack of efficacy or a higher risk of adverse reactions in some patients.6 The citation of reference 5 suggests that it presents data about the importance of UGT in the pharmacogenomics of antipsychotics. However, UGT is only mentioned as a key word (and only as UGT-2B.. but not as UGT-1A..). In ref 6, UGT is not even mentioned. Therefore, the reader with limited knowledge in this field may not get a full picture of the importance of the subject. In summary, the Introduction should be extended!" We sincerely apologize for inaccurate citations. In accordance with this comment and the comment from the other reviewer, introduction section is now expended to shortly summarize all gene candidates potentially important for the pharmacogenomics of antipsychotic drug pharmacokinetics. "Table 1 presents in “Intervention I” the different phenotypes using the example risperidone. The reader is then supposed to presume that this presentation is also valid for UGT enzymes (eg gene-drug pair: UGT-olanzapine), but this classification (poor, intermediate, extensive, ultrarapid) is seemingly not introduced for these polymorphisms. If however this is the case, this should be presented in some details and corresponding references should be presented." We agree, Table 1 can be misinterpreted. In the introduction section, it is now described which genes have established metabolizer status definitions and which genes are instead analyzed on the basis of genotypes and haplotypes. Also, Table 1 is now updated to include another example that involves UGT isoenzyme to further eliminate confusion. "Indeed, the average reader will not be familiar with the genetic polymorphisms of conjugating enzymes, and in particular, with their relevance for antipsychotics. In other words: are there PM, EM, UM, IM in patients treated with e.g. asenapine or olanzapine, with regard to the metabolism by UGT-enzymes? (Admittedly, in the suppl. material is some information, but the protocol should be more precise, especially in Introduction). It is a fact that among cytochrome P-450 isozymes, only about half a dozen isozymes play a role in the metabolism of antipsychotics. In contrast, there are considerably more isozymes which contribute to the conjugation of drugs, but their individual role in the metabolism of antipsychotics is poorly characterized." In line with this and previous comments, introduction section is now extended to also include this information. Also, our justification for the choice of UGT isoenzymes included in the first iteration of our living systematic review is included in the section 2.2. If the Reviewer finds that some crucial UGT or CYP450 isoenzymes are omitted, we will gladly consider them for the inclusion. "The pioneering study of Haslemo et al. (CPT, 2012, 221) (besides that of Erickson et al., Pharmacogen Genom 2011, 539) shows that plasma concentrations of conjugated olanzapine (10-N-ola-glucuronide) differ in olanzapine treated patients classified according to their UGT1A genotypes, but the difference is negligible for (unconjugated) olanzapine concentrations. This rises the question whether in the present meta-analysis study both ola and conjugated ola concentrations will be considered. It could be then of interest to examine the relationships between the UGT genotypes and the ratios parent compound/metabolite (Ola/10-N-ola-glucoronide).This approach may also be valuable for all other antipsychotics, whether they are metabolized by cytochrome P-450 or by polymorphic conjugating enzymes, or by both types (e.g. risp/9-OH-risp; 9-OH-risp/conjug. 9-OH-risp; etc)." To our knowledge, Olanzapine metabolites including 10-N-Olanzapine-Glucuronide have marginal activity and it is not recommended to measure them during therapeutic drug monitoring [PMID: 1683407]. Even though the pharmacokinetics of inactive drug metabolites is very relevant and important topic, we find this data to be of limited usefulness for our living systematic review as we plan to focus on the clinical aspects of therapeutic drug monitoring. Regarding risperidone, there is evidence that risperidone and 9-OH-risperidone have different efficacy and safety profiles due to different blood-brain-barriers permeability [PMID: 33054667]. Therefore, we agree for that analysis of riperidone/9-OH-risperidone ratio may be very useful for the interpretation of meta-analysis of risperidone active moiety (Risperidone + 9-OH-Risperidone) plasma levels. Section 2.4 is now updated to reflect this. "Probably of little importance for the establishment of the protocol, it is to mention that in the case of risperidone, its hydroxylation to 9-OH-risperidone is stereoselective, in that CYP2D6 preferentially forms (+)-9-OH-risperidone rather than (-)-9-OH-risperidone (Yasui-Furukori et al. Drug Metab. Disp 2001, 1263). It should be considered, as rarely, stereoselective procedures were used in the published studies, the net effect of the genotype may be masked when non-stereoselective procedures are used." As we mentioned previously, we would like to focus on clinical aspects of therapeutic drug monitoring, i.e. we will try to use drug blood levels as a biomarkers of drugs biological effects. Therefore, even though stereo-selective analysis highlights the influence of CYP2D6, we find very limited clinical relevance of this information for our review as two enantiomers of 9-OH-Risperidone have been previously described as equipotent (PMID: 17344104). "The authors exclude some antipsychotics, but the mentioned reasons are not always evident, and again, the citations do not always correspond to the statements. Therefore, the presentation of the reference list demands to be improved. Eg, 2.2. Drug gene pairs …: “Lurasidone will not be analyzed because of the uncertain importance of drug-blood level measurements.” Ref 6 is cited, but this ref does apparently not deal with this subject. Actually, lurasidone is mainly a substrate of CYP3A4/5. As its blood levels strongly depend on dietary conditions, this may be an important reason for recommending TDM (cf Preskorn 2013: Lurasidone should be administered with food-at least 350 kcal-to ensure maximum exposure). However, one can agree with the decision of the authors, as this drug belongs to the group of drugs mentioned in 2.5. VII (study inclusion citeria) resp. 2.6. V." We agree with the reviewer, Lurasidone is the substrate for CYP3A4/5 and should therefore be included. Also, unrelated to reviewer’s comment, we have noticed that we listed Paliperidone as CYP3A4/5 and CYP2D6 substrate even though paliperidone is minimally metabolized in the liver and is mostly eliminated by kidneys [PMID: 20118446]. We sincerely apologize for these errors; they are now corrected in the revised version of the manuscript. "2.4. Definition of the outcome As pointed out by the authors, weight corrected drug concentrations may be advantageous, but they are often not available. Steady-state plasma concentrations: In the case of risperidone, there may be a problem in that in extensive metabolizers (CYP2D6), its T1/2 = 2 - 4h, but in poor metabolizers, considerably longer, comparable to that of its metabolite 9-OH-risperidone. This means that in EM, risp. steady-state concentrations will hardly be reached in EM but only in PM." We agree, people with lower enzyme metabolism capacities might take longer time to reach steady state. Therefore, we changed the criterion for the time needed to reach steady state to be 5x the conservative t 1/2 estimate. In other words, whenever the t 1/2 is presented as the range in AGNP guidelines (PMID: 28910830) we will use the higher limit of this range (longest time). This is now reflected in section 2.4. "Extended data: March : 6. UGT1A4 “At the time of writing, there is no consensus regarding the classification of different UGT1A4 diplotypes into metabolizer groups. Therefore, pragmatically, alleles known to affect CYP1A2 activity with Minor allelic frequencies >1% in the world population will be considered for this analysis.” Not clear: this suggests that there is a relationship CYP1A2 – UGT1A4 (?)." This was a typing error, and we sincerely apologize for it. We also noticed several other typing errors in the Extended data and they are now corrected in the new version. We again thank the Reviewer for the constructive criticism. We have no further comments. Competing Interests: We declare no competing interest with regards to this response. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: de Lima Benzi JR. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.162029.r275387 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v1#referee-response-275387 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 31 May 2024 Jhohann Richard de Lima Benzi , University of São Paulo, São Paulo, Brazil Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.162029.r275387 The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of ... Continue reading READ ALL The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of personalized medicine in psychiatric care. I commend the authors for their meticulous approach and the significance of their endeavors. However, I would like to suggest some considerations to enrich the manuscript. Firstly, the inclusion or mention of the importance of drug transporters in AP therapy warrants attention, particularly those expressed in the blood-brain barrier. Given their pivotal role in drug disposition and response, their omission from the review raises questions about their relevance in AP pharmacotherapy. Exploring the available pharmacogenetic data pertaining to these transporters could provide valuable insights into their impact on treatment outcomes. Secondly, the decision to exclude data based on probe phenotyping drug data when defining metabolizer groups requires clarification. Elaborating on the rationale behind this exclusion would enhance the transparency and reproducibility of the study, ensuring a more robust analysis of CYP pharmacogenetics in AP therapy. Thirdly, I respectfully disagree with the assertion that single-dose pharmacokinetic parameters can be used interchangeably with steady-state parameters, particularly in the context of AP drugs with non-linear pharmacokinetics. Given the complexities inherent in non-linear PK profiles, a sensitivity analysis excluding single-dose studies may not adequately capture the dynamic nature of drug metabolism. It is imperative to devise alternative strategies to handle such data, perhaps through modeling techniques or subgroup analyses, to ensure the integrity and reliability of the findings. In conclusion, while the manuscript admirably addresses the relevance of CYP pharmacogenetics in AP therapy, the incorporation of drug transporter considerations, clarification on data exclusion criteria, and careful handling of non-linear PK data are essential for a more comprehensive and nuanced analysis. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Clinical pharmacology, pharmacokinetics, pharmacometrics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT de Lima Benzi JR. Reviewer Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.162029.r275387 ) The direct URL for this report is: https://f1000research.com/articles/13-452/v1#referee-response-275387 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 09 Jul 2024 Filip Milosavljević , Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany 09 Jul 2024 Author Response "The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The ... Continue reading "The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of personalized medicine in psychiatric care. I commend the authors for their meticulous approach and the significance of their endeavors. However, I would like to suggest some considerations to enrich the manuscript." We thank the reviewer for positive feedback. "Firstly, the inclusion or mention of the importance of drug transporters in AP therapy warrants attention, particularly those expressed in the blood-brain barrier. Given their pivotal role in drug disposition and response, their omission from the review raises questions about their relevance in AP pharmacotherapy. Exploring the available pharmacogenetic data pertaining to these transporters could provide valuable insights into their impact on treatment outcomes." Indeed, drug efflux pumps are coded by highly polymorphous genes (ABCB1, ABCG2, ABCC2…) and the research of their pharmacogenomics has been very active in the recent years. We initially omitted to mention drug transporter in an effort to keep our report concise, but we agree with the reviewer that these genes have to be addressed in order to provide comprehensive overview of pharmacogenomics of antipsychotic drug pharmacokinetics, and that the omission of drug transporter genes from our analysis has to be justified in the manuscript. The main reason to exnclude pharmacogenomic studies on efflux pumps from our review is potential inappropriateness of our main outcome to capture the impact of pharmacogenomics of drug transporters on antipsychotic therapy. Our review is focused on plasma levels of antipsychotics, and in our analysis we will assume that cerebrospinal-fluid-to-plasma ratios of antipsychotic drugs are similar between people with different CYP450/UGT genotypes. Since drugs transporters are expressed on blood-brain barrier, in some antipsychotic drugs it has been demonstrated that mutations of drug transporter genes such as ABCB1 can change cerebrospinal-fluid-to-plasma ratios [PMID: 21148022, PMID: 20599439, PMID: 24666334]. This means that, for example, if two groups of patients with different ABCB1 mutations have the same antipsychotic plasma levels, they may not have the same antipsychotic cerebrospinal fluid levels, which puts into question the appropriateness of drug plasma level as a biomarker. Therefore, we believe that analyzing drug efficacy and safety directly, or analyzing cerebrospinal fluid drug levels are more appropriate outcomes for the analysis of drug transporters pharmacogenomics, all of which are out of the scope of this review. Introduction section now includes short summary of the potential significance of efflux pumps, and Section 2.2. now includes the justification of our justification not to include efflux pump pharmacogenomic data. "Secondly, the decision to exclude data based on probe phenotyping drug data when defining metabolizer groups requires clarification. Elaborating on the rationale behind this exclusion would enhance the transparency and reproducibility of the study, ensuring a more robust analysis of CYP pharmacogenetics in AP therapy." We agree with the reviewer that this decision needs more clarification. Also, upon revision of our manuscript, we noticed that our previous wording “for the purpose of this review, phenotyping will not be considered valid” can be interpreted as us questioning the validity of phenotyping method, which is not the case. Instead, section 2.3 is now updated to introduce pros and cons of both phenotyping and genotyping approaches and the justification why we opted not to use them interchangeably in this review. "Thirdly, I respectfully disagree with the assertion that single-dose pharmacokinetic parameters can be used interchangeably with steady-state parameters, particularly in the context of AP drugs with non-linear pharmacokinetics. Given the complexities inherent in non-linear PK profiles, a sensitivity analysis excluding single-dose studies may not adequately capture the dynamic nature of drug metabolism. It is imperative to devise alternative strategies to handle such data, perhaps through modeling techniques or subgroup analyses, to ensure the integrity and reliability of the findings." We thank the reviewer for raising this concern. Even though the majority of antipsychotics have linear pharmacokinetic profile, sublingual asenapine, oral lumateperone, oral chlorpromazine and oral perphenazine possess non-linear pharmacokinetic profiles (PMID: 29915922, PMID: 32060882, PMID: 8157044, PMID: 3933033). We agree with the reviewer that for the given examples, data from single dose studies and steady state studies cannot be used interchangeably and we apologize for our omission. As we are currently not aware of any model published in the literature designed to predict steady state levels of given four drugs based on single-dose data, we will, for the time being, opt to exclude single-dose studies for asenapine, lumateperone, chlorpromazine and perphenazine. We expect very small (if any) impact of this decision on the results of our meta-analyses, as we, based on our previous experience, expect to detect very few pharamcogenomic studies in the literature on these 4 drugs. If instead we happen to detect many eligible single-dose studies for these 4 drugs, we will post-hoc find appropriate model developed for other drugs that may fit the drug in question. This clarification is now reflected in the manuscript. "In conclusion, while the manuscript admirably addresses the relevance of CYP pharmacogenetics in AP therapy, the incorporation of drug transporter considerations, clarification on data exclusion criteria, and careful handling of non-linear PK data are essential for a more comprehensive and nuanced analysis." We thank the reviewer again for the constructive criticism that will improve the quality of this paper. We have no further comments. "The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of personalized medicine in psychiatric care. I commend the authors for their meticulous approach and the significance of their endeavors. However, I would like to suggest some considerations to enrich the manuscript." We thank the reviewer for positive feedback. "Firstly, the inclusion or mention of the importance of drug transporters in AP therapy warrants attention, particularly those expressed in the blood-brain barrier. Given their pivotal role in drug disposition and response, their omission from the review raises questions about their relevance in AP pharmacotherapy. Exploring the available pharmacogenetic data pertaining to these transporters could provide valuable insights into their impact on treatment outcomes." Indeed, drug efflux pumps are coded by highly polymorphous genes (ABCB1, ABCG2, ABCC2…) and the research of their pharmacogenomics has been very active in the recent years. We initially omitted to mention drug transporter in an effort to keep our report concise, but we agree with the reviewer that these genes have to be addressed in order to provide comprehensive overview of pharmacogenomics of antipsychotic drug pharmacokinetics, and that the omission of drug transporter genes from our analysis has to be justified in the manuscript. The main reason to exnclude pharmacogenomic studies on efflux pumps from our review is potential inappropriateness of our main outcome to capture the impact of pharmacogenomics of drug transporters on antipsychotic therapy. Our review is focused on plasma levels of antipsychotics, and in our analysis we will assume that cerebrospinal-fluid-to-plasma ratios of antipsychotic drugs are similar between people with different CYP450/UGT genotypes. Since drugs transporters are expressed on blood-brain barrier, in some antipsychotic drugs it has been demonstrated that mutations of drug transporter genes such as ABCB1 can change cerebrospinal-fluid-to-plasma ratios [PMID: 21148022, PMID: 20599439, PMID: 24666334]. This means that, for example, if two groups of patients with different ABCB1 mutations have the same antipsychotic plasma levels, they may not have the same antipsychotic cerebrospinal fluid levels, which puts into question the appropriateness of drug plasma level as a biomarker. Therefore, we believe that analyzing drug efficacy and safety directly, or analyzing cerebrospinal fluid drug levels are more appropriate outcomes for the analysis of drug transporters pharmacogenomics, all of which are out of the scope of this review. Introduction section now includes short summary of the potential significance of efflux pumps, and Section 2.2. now includes the justification of our justification not to include efflux pump pharmacogenomic data. "Secondly, the decision to exclude data based on probe phenotyping drug data when defining metabolizer groups requires clarification. Elaborating on the rationale behind this exclusion would enhance the transparency and reproducibility of the study, ensuring a more robust analysis of CYP pharmacogenetics in AP therapy." We agree with the reviewer that this decision needs more clarification. Also, upon revision of our manuscript, we noticed that our previous wording “for the purpose of this review, phenotyping will not be considered valid” can be interpreted as us questioning the validity of phenotyping method, which is not the case. Instead, section 2.3 is now updated to introduce pros and cons of both phenotyping and genotyping approaches and the justification why we opted not to use them interchangeably in this review. "Thirdly, I respectfully disagree with the assertion that single-dose pharmacokinetic parameters can be used interchangeably with steady-state parameters, particularly in the context of AP drugs with non-linear pharmacokinetics. Given the complexities inherent in non-linear PK profiles, a sensitivity analysis excluding single-dose studies may not adequately capture the dynamic nature of drug metabolism. It is imperative to devise alternative strategies to handle such data, perhaps through modeling techniques or subgroup analyses, to ensure the integrity and reliability of the findings." We thank the reviewer for raising this concern. Even though the majority of antipsychotics have linear pharmacokinetic profile, sublingual asenapine, oral lumateperone, oral chlorpromazine and oral perphenazine possess non-linear pharmacokinetic profiles (PMID: 29915922, PMID: 32060882, PMID: 8157044, PMID: 3933033). We agree with the reviewer that for the given examples, data from single dose studies and steady state studies cannot be used interchangeably and we apologize for our omission. As we are currently not aware of any model published in the literature designed to predict steady state levels of given four drugs based on single-dose data, we will, for the time being, opt to exclude single-dose studies for asenapine, lumateperone, chlorpromazine and perphenazine. We expect very small (if any) impact of this decision on the results of our meta-analyses, as we, based on our previous experience, expect to detect very few pharamcogenomic studies in the literature on these 4 drugs. If instead we happen to detect many eligible single-dose studies for these 4 drugs, we will post-hoc find appropriate model developed for other drugs that may fit the drug in question. This clarification is now reflected in the manuscript. "In conclusion, while the manuscript admirably addresses the relevance of CYP pharmacogenetics in AP therapy, the incorporation of drug transporter considerations, clarification on data exclusion criteria, and careful handling of non-linear PK data are essential for a more comprehensive and nuanced analysis." We thank the reviewer again for the constructive criticism that will improve the quality of this paper. We have no further comments. Competing Interests: We declare no competing interests with regards to our response. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 09 Jul 2024 Filip Milosavljević , Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany 09 Jul 2024 Author Response "The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The ... Continue reading "The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of personalized medicine in psychiatric care. I commend the authors for their meticulous approach and the significance of their endeavors. However, I would like to suggest some considerations to enrich the manuscript." We thank the reviewer for positive feedback. "Firstly, the inclusion or mention of the importance of drug transporters in AP therapy warrants attention, particularly those expressed in the blood-brain barrier. Given their pivotal role in drug disposition and response, their omission from the review raises questions about their relevance in AP pharmacotherapy. Exploring the available pharmacogenetic data pertaining to these transporters could provide valuable insights into their impact on treatment outcomes." Indeed, drug efflux pumps are coded by highly polymorphous genes (ABCB1, ABCG2, ABCC2…) and the research of their pharmacogenomics has been very active in the recent years. We initially omitted to mention drug transporter in an effort to keep our report concise, but we agree with the reviewer that these genes have to be addressed in order to provide comprehensive overview of pharmacogenomics of antipsychotic drug pharmacokinetics, and that the omission of drug transporter genes from our analysis has to be justified in the manuscript. The main reason to exnclude pharmacogenomic studies on efflux pumps from our review is potential inappropriateness of our main outcome to capture the impact of pharmacogenomics of drug transporters on antipsychotic therapy. Our review is focused on plasma levels of antipsychotics, and in our analysis we will assume that cerebrospinal-fluid-to-plasma ratios of antipsychotic drugs are similar between people with different CYP450/UGT genotypes. Since drugs transporters are expressed on blood-brain barrier, in some antipsychotic drugs it has been demonstrated that mutations of drug transporter genes such as ABCB1 can change cerebrospinal-fluid-to-plasma ratios [PMID: 21148022, PMID: 20599439, PMID: 24666334]. This means that, for example, if two groups of patients with different ABCB1 mutations have the same antipsychotic plasma levels, they may not have the same antipsychotic cerebrospinal fluid levels, which puts into question the appropriateness of drug plasma level as a biomarker. Therefore, we believe that analyzing drug efficacy and safety directly, or analyzing cerebrospinal fluid drug levels are more appropriate outcomes for the analysis of drug transporters pharmacogenomics, all of which are out of the scope of this review. Introduction section now includes short summary of the potential significance of efflux pumps, and Section 2.2. now includes the justification of our justification not to include efflux pump pharmacogenomic data. "Secondly, the decision to exclude data based on probe phenotyping drug data when defining metabolizer groups requires clarification. Elaborating on the rationale behind this exclusion would enhance the transparency and reproducibility of the study, ensuring a more robust analysis of CYP pharmacogenetics in AP therapy." We agree with the reviewer that this decision needs more clarification. Also, upon revision of our manuscript, we noticed that our previous wording “for the purpose of this review, phenotyping will not be considered valid” can be interpreted as us questioning the validity of phenotyping method, which is not the case. Instead, section 2.3 is now updated to introduce pros and cons of both phenotyping and genotyping approaches and the justification why we opted not to use them interchangeably in this review. "Thirdly, I respectfully disagree with the assertion that single-dose pharmacokinetic parameters can be used interchangeably with steady-state parameters, particularly in the context of AP drugs with non-linear pharmacokinetics. Given the complexities inherent in non-linear PK profiles, a sensitivity analysis excluding single-dose studies may not adequately capture the dynamic nature of drug metabolism. It is imperative to devise alternative strategies to handle such data, perhaps through modeling techniques or subgroup analyses, to ensure the integrity and reliability of the findings." We thank the reviewer for raising this concern. Even though the majority of antipsychotics have linear pharmacokinetic profile, sublingual asenapine, oral lumateperone, oral chlorpromazine and oral perphenazine possess non-linear pharmacokinetic profiles (PMID: 29915922, PMID: 32060882, PMID: 8157044, PMID: 3933033). We agree with the reviewer that for the given examples, data from single dose studies and steady state studies cannot be used interchangeably and we apologize for our omission. As we are currently not aware of any model published in the literature designed to predict steady state levels of given four drugs based on single-dose data, we will, for the time being, opt to exclude single-dose studies for asenapine, lumateperone, chlorpromazine and perphenazine. We expect very small (if any) impact of this decision on the results of our meta-analyses, as we, based on our previous experience, expect to detect very few pharamcogenomic studies in the literature on these 4 drugs. If instead we happen to detect many eligible single-dose studies for these 4 drugs, we will post-hoc find appropriate model developed for other drugs that may fit the drug in question. This clarification is now reflected in the manuscript. "In conclusion, while the manuscript admirably addresses the relevance of CYP pharmacogenetics in AP therapy, the incorporation of drug transporter considerations, clarification on data exclusion criteria, and careful handling of non-linear PK data are essential for a more comprehensive and nuanced analysis." We thank the reviewer again for the constructive criticism that will improve the quality of this paper. We have no further comments. "The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of personalized medicine in psychiatric care. I commend the authors for their meticulous approach and the significance of their endeavors. However, I would like to suggest some considerations to enrich the manuscript." We thank the reviewer for positive feedback. "Firstly, the inclusion or mention of the importance of drug transporters in AP therapy warrants attention, particularly those expressed in the blood-brain barrier. Given their pivotal role in drug disposition and response, their omission from the review raises questions about their relevance in AP pharmacotherapy. Exploring the available pharmacogenetic data pertaining to these transporters could provide valuable insights into their impact on treatment outcomes." Indeed, drug efflux pumps are coded by highly polymorphous genes (ABCB1, ABCG2, ABCC2…) and the research of their pharmacogenomics has been very active in the recent years. We initially omitted to mention drug transporter in an effort to keep our report concise, but we agree with the reviewer that these genes have to be addressed in order to provide comprehensive overview of pharmacogenomics of antipsychotic drug pharmacokinetics, and that the omission of drug transporter genes from our analysis has to be justified in the manuscript. The main reason to exnclude pharmacogenomic studies on efflux pumps from our review is potential inappropriateness of our main outcome to capture the impact of pharmacogenomics of drug transporters on antipsychotic therapy. Our review is focused on plasma levels of antipsychotics, and in our analysis we will assume that cerebrospinal-fluid-to-plasma ratios of antipsychotic drugs are similar between people with different CYP450/UGT genotypes. Since drugs transporters are expressed on blood-brain barrier, in some antipsychotic drugs it has been demonstrated that mutations of drug transporter genes such as ABCB1 can change cerebrospinal-fluid-to-plasma ratios [PMID: 21148022, PMID: 20599439, PMID: 24666334]. This means that, for example, if two groups of patients with different ABCB1 mutations have the same antipsychotic plasma levels, they may not have the same antipsychotic cerebrospinal fluid levels, which puts into question the appropriateness of drug plasma level as a biomarker. Therefore, we believe that analyzing drug efficacy and safety directly, or analyzing cerebrospinal fluid drug levels are more appropriate outcomes for the analysis of drug transporters pharmacogenomics, all of which are out of the scope of this review. Introduction section now includes short summary of the potential significance of efflux pumps, and Section 2.2. now includes the justification of our justification not to include efflux pump pharmacogenomic data. "Secondly, the decision to exclude data based on probe phenotyping drug data when defining metabolizer groups requires clarification. Elaborating on the rationale behind this exclusion would enhance the transparency and reproducibility of the study, ensuring a more robust analysis of CYP pharmacogenetics in AP therapy." We agree with the reviewer that this decision needs more clarification. Also, upon revision of our manuscript, we noticed that our previous wording “for the purpose of this review, phenotyping will not be considered valid” can be interpreted as us questioning the validity of phenotyping method, which is not the case. Instead, section 2.3 is now updated to introduce pros and cons of both phenotyping and genotyping approaches and the justification why we opted not to use them interchangeably in this review. "Thirdly, I respectfully disagree with the assertion that single-dose pharmacokinetic parameters can be used interchangeably with steady-state parameters, particularly in the context of AP drugs with non-linear pharmacokinetics. Given the complexities inherent in non-linear PK profiles, a sensitivity analysis excluding single-dose studies may not adequately capture the dynamic nature of drug metabolism. It is imperative to devise alternative strategies to handle such data, perhaps through modeling techniques or subgroup analyses, to ensure the integrity and reliability of the findings." We thank the reviewer for raising this concern. Even though the majority of antipsychotics have linear pharmacokinetic profile, sublingual asenapine, oral lumateperone, oral chlorpromazine and oral perphenazine possess non-linear pharmacokinetic profiles (PMID: 29915922, PMID: 32060882, PMID: 8157044, PMID: 3933033). We agree with the reviewer that for the given examples, data from single dose studies and steady state studies cannot be used interchangeably and we apologize for our omission. As we are currently not aware of any model published in the literature designed to predict steady state levels of given four drugs based on single-dose data, we will, for the time being, opt to exclude single-dose studies for asenapine, lumateperone, chlorpromazine and perphenazine. We expect very small (if any) impact of this decision on the results of our meta-analyses, as we, based on our previous experience, expect to detect very few pharamcogenomic studies in the literature on these 4 drugs. If instead we happen to detect many eligible single-dose studies for these 4 drugs, we will post-hoc find appropriate model developed for other drugs that may fit the drug in question. This clarification is now reflected in the manuscript. "In conclusion, while the manuscript admirably addresses the relevance of CYP pharmacogenetics in AP therapy, the incorporation of drug transporter considerations, clarification on data exclusion criteria, and careful handling of non-linear PK data are essential for a more comprehensive and nuanced analysis." We thank the reviewer again for the constructive criticism that will improve the quality of this paper. We have no further comments. Competing Interests: We declare no competing interests with regards to our response. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 07 May 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 09 Jul 24 read read Version 1 07 May 24 read read Jhohann Richard de Lima Benzi , University of São Paulo, São Paulo, Brazil Pierre Baumann , Universite de Lausanne, Lausanne, Switzerland Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Baumann P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 31 Jul 2024 | for Version 2 Pierre Baumann , Department of Psychiatry (DP-CHUV), Universite de Lausanne, Lausanne, Vaud, Switzerland 0 Views copyright © 2024 Baumann P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The Introduction is now written more comprehensively, and it is informative. It satisfies the request of the reviewers. There are some minor spelling errors (use search function): Haloperidol (p. 3, last §) I am surprised that drugs (Asenapine, Clozapine, … etc ) and enzymes (Uridine … etc) are (sometimes) written in capital letters (e.g. p. 3 and 7) Answer of the Authors to the comment of the reviewer (p. 18): “Even though the pharmacokinetics of inactive drug metabolites is very relevant and important topic, we find this data to be of limited usefulness for our living systematic review as we plan to focus on the clinical aspects of therapeutic drug monitoring.” This is somewhat contradictory as this protocol will mainly and almost exclusively focus on the relationship between pharmacokinetics and pharmacogenomics and not on clinical aspects. The determination of ratios parent compound/metabolite (also inactive metabolites) will allow a better understanding of the individual role of a particular enzyme in a specific metabolic pathway. This is only a comment, with no request. The reviewer thanks the Authors for their comments and corrections of their manuscript Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Baumann P. Peer Review Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.168742.r300641) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-452/v2#referee-response-300641 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 de Lima Benzi J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 16 Jul 2024 | for Version 2 Jhohann Richard de Lima Benzi , University of São Paulo, São Paulo, Brazil 0 Views copyright © 2024 de Lima Benzi J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I have reviewed the revised manuscript. The authors have addressed all my comments and questions thoroughly and politely. I have no further comments or concerns. Therefore, I fully endorse this manuscript can be indexed. Thank you for the opportunity to review this work. Best regards. Competing Interests No competing interests were disclosed. Reviewer Expertise Clinical pharmacology, pharmacokinetics, pharmacometrics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) de Lima Benzi JR. Peer Review Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.168742.r300642) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-452/v2#referee-response-300642 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Baumann P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 06 Jun 2024 | for Version 1 Pierre Baumann , Department of Psychiatry (DP-CHUV), Universite de Lausanne, Lausanne, Vaud, Switzerland 0 Views copyright © 2024 Baumann P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions General comment: The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf Table 1, criterion O (outcome)). It would have been of interest to include a part which concerns the clinical outcome (efficacy, effectiveness, adverse effects) of the patients, as the present protocol will not allow to clearly show the clinical relevance of pharmacokinetic-pharmacogenetic exams. However, the present project is already ambitious and the inclusion of a regularly occurring update is highly promising and novel. Other comments and questions: The issues dealing with pharmacokinetics and pharmacogenomics presented in the Introduction should be presented in more details as some references are not adequate. Indeed, some citations lack precision, e.g. ref 5 and 6, in the sentence: “It is proposed that mutations in genes that code liver CYP450 (Cytochrome p450) and UGT (UDP-glycosyltransferase) enzymes can cause either too low or too high plasma levels of antipsychotic, 5 leading to a lack of efficacy or a higher risk of adverse reactions in some patients. 6 The citation of reference 5 suggests that it presents data about the importance of UGT in the pharmacogenomics of antipsychotics. However, UGT is only mentioned as a key word (and only as UGT-2B.. but not as UGT-1A..). In ref 6, UGT is not even mentioned. Therefore, the reader with limited knowledge in this field may not get a full picture of the importance of the subject. In summary, the Introduction should be extended! Table 1 presents in “Intervention I” the different phenotypes using the example risperidone. The reader is then supposed to presume that this presentation is also valid for UGT enzymes (eg gene-drug pair: UGT-olanzapine), but this classification (poor, intermediate, extensive, ultrarapid) is seemingly not introduced for these polymorphisms. If however this is the case, this should be presented in some details and corresponding references should be presented. Indeed, the average reader will not be familiar with the genetic polymorphisms of conjugating enzymes, and in particular, with their relevance for antipsychotics. In other words: are there PM, EM, UM, IM in patients treated with e.g. asenapine or olanzapine, with regard to the metabolism by UGT-enzymes? (Admittedly, in the suppl. material is some information, but the protocol should be more precise, especially in Introduction). It is a fact that among cytochrome P-450 isozymes, only about half a dozen isozymes play a role in the metabolism of antipsychotics. In contrast, there are considerably more isozymes which contribute to the conjugation of drugs, but their individual role in the metabolism of antipsychotics is poorly characterized. The pioneering study of Haslemo et al. (CPT, 2012, 221) (besides that of Erickson et al., Pharmacogen Genom 2011, 539) shows that plasma concentrations of conjugated olanzapine (10-N-ola-glucuronide) differ in olanzapine treated patients classified according to their UGT1A genotypes, but the difference is negligible for (unconjugated) olanzapine concentrations. This rises the question whether in the present meta-analysis study both ola and conjugated ola concentrations will be considered. It could be then of interest to examine the relationships between the UGT genotypes and the ratios parent compound/metabolite (Ola/10-N-ola-glucoronide). This approach may also be valuable for all other antipsychotics, whether they are metabolized by cytochrome P-450 or by polymorphic conjugating enzymes, or by both types (e.g. risp/9-OH-risp; 9-OH-risp/conjug. 9-OH-risp; etc). Probably of little importance for the establishment of the protocol, it is to mention that in the case of risperidone, its hydroxylation to 9-OH-risperidone is stereoselective, in that CYP2D6 preferentially forms (+)-9-OH-risperidone rather than (-)-9-OH-risperidone (Yasui-Furukori et al. Drug Metab. Disp 2001, 1263). It should be considered, as rarely, stereoselective procedures were used in the published studies, the net effect of the genotype may be masked when non-stereoselective procedures are used. The authors exclude some antipsychotics, but the mentioned reasons are not always evident, and again, the citations do not always correspond to the statements. Therefore, the presentation of the reference list demands to be improved. Eg, 2.2. Drug gene pairs …: “Lurasidone will not be analyzed because of the uncertain importance of drug-blood level measurements.” Ref 6 is cited, but this ref does apparently not deal with this subject. Actually, lurasidone is mainly a substrate of CYP3A4/5. As its blood levels strongly depend on dietary conditions, this may be an important reason for recommending TDM (cf Preskorn 2013: Lurasidone should be administered with food-at least 350 kcal-to ensure maximum exposure). However, one can agree with the decision of the authors, as this drug belongs to the group of drugs mentioned in 2.5. VII (study inclusion citeria) resp. 2.6. V. 2.4. Definition of the outcome As pointed out by the authors, weight corrected drug concentrations may be advantageous, but they are often not available. Steady-state plasma concentrations: In the case of risperidone, there may be a problem in that in extensive metabolizers (CYP2D6), its T1/2 = 2 - 4h, but in poor metabolizers, considerably longer, comparable to that of its metabolite 9-OH-risperidone. This means that in EM, risp. steady-state concentrations will hardly be reached in EM but only in PM. Extended data: March : 6. UGT1A4 “At the time of writing, there is no consensus regarding the classification of different UGT1A4 diplotypes into metabolizer groups. Therefore, pragmatically, alleles known to affect CYP1A2 activity with Minor allelic frequencies >1% in the world population will be considered for this analysis.” Not clear: this suggests that there is a relationship CYP1A2 – UGT1A4 (?). Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 09 Jul 2024 Filip Milosavljević, Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany "The authors propose a protocol for future studies on the relationship between drug plasma concentrations in patients treated with antipsychotics and their pharmacogenetic status regarding genetic polymorphisms of cytochrome P-450 isoforms and/or UGT enzymes (cf Table 1, criterion O (outcome)). It would have been of interest to include a part which concerns the clinical outcome (efficacy, effectiveness, adverse effects) of the patients, as the present protocol will not allow to clearly show the clinical relevance of pharmacokinetic-pharmacogenetic exams. However, the present project is already ambitious and the inclusion of a regularly occurring update is highly promising and novel." We thank the reviewer for positive comment and for recognizing the scale of this project. "Other comments and questions: The issues dealing with pharmacokinetics and pharmacogenomics presented in the Introduction should be presented in more details as some references are not adequate. Indeed, some citations lack precision, e.g. ref 5 and 6, in the sentence: “It is proposed that mutations in genes that code liver CYP450 (Cytochrome p450) and UGT (UDP-glycosyltransferase) enzymes can cause either too low or too high plasma levels of antipsychotic,5 leading to a lack of efficacy or a higher risk of adverse reactions in some patients.6 The citation of reference 5 suggests that it presents data about the importance of UGT in the pharmacogenomics of antipsychotics. However, UGT is only mentioned as a key word (and only as UGT-2B.. but not as UGT-1A..). In ref 6, UGT is not even mentioned. Therefore, the reader with limited knowledge in this field may not get a full picture of the importance of the subject. In summary, the Introduction should be extended!" We sincerely apologize for inaccurate citations. In accordance with this comment and the comment from the other reviewer, introduction section is now expended to shortly summarize all gene candidates potentially important for the pharmacogenomics of antipsychotic drug pharmacokinetics. "Table 1 presents in “Intervention I” the different phenotypes using the example risperidone. The reader is then supposed to presume that this presentation is also valid for UGT enzymes (eg gene-drug pair: UGT-olanzapine), but this classification (poor, intermediate, extensive, ultrarapid) is seemingly not introduced for these polymorphisms. If however this is the case, this should be presented in some details and corresponding references should be presented." We agree, Table 1 can be misinterpreted. In the introduction section, it is now described which genes have established metabolizer status definitions and which genes are instead analyzed on the basis of genotypes and haplotypes. Also, Table 1 is now updated to include another example that involves UGT isoenzyme to further eliminate confusion. "Indeed, the average reader will not be familiar with the genetic polymorphisms of conjugating enzymes, and in particular, with their relevance for antipsychotics. In other words: are there PM, EM, UM, IM in patients treated with e.g. asenapine or olanzapine, with regard to the metabolism by UGT-enzymes? (Admittedly, in the suppl. material is some information, but the protocol should be more precise, especially in Introduction). It is a fact that among cytochrome P-450 isozymes, only about half a dozen isozymes play a role in the metabolism of antipsychotics. In contrast, there are considerably more isozymes which contribute to the conjugation of drugs, but their individual role in the metabolism of antipsychotics is poorly characterized." In line with this and previous comments, introduction section is now extended to also include this information. Also, our justification for the choice of UGT isoenzymes included in the first iteration of our living systematic review is included in the section 2.2. If the Reviewer finds that some crucial UGT or CYP450 isoenzymes are omitted, we will gladly consider them for the inclusion. "The pioneering study of Haslemo et al. (CPT, 2012, 221) (besides that of Erickson et al., Pharmacogen Genom 2011, 539) shows that plasma concentrations of conjugated olanzapine (10-N-ola-glucuronide) differ in olanzapine treated patients classified according to their UGT1A genotypes, but the difference is negligible for (unconjugated) olanzapine concentrations. This rises the question whether in the present meta-analysis study both ola and conjugated ola concentrations will be considered. It could be then of interest to examine the relationships between the UGT genotypes and the ratios parent compound/metabolite (Ola/10-N-ola-glucoronide).This approach may also be valuable for all other antipsychotics, whether they are metabolized by cytochrome P-450 or by polymorphic conjugating enzymes, or by both types (e.g. risp/9-OH-risp; 9-OH-risp/conjug. 9-OH-risp; etc)." To our knowledge, Olanzapine metabolites including 10-N-Olanzapine-Glucuronide have marginal activity and it is not recommended to measure them during therapeutic drug monitoring [PMID: 1683407]. Even though the pharmacokinetics of inactive drug metabolites is very relevant and important topic, we find this data to be of limited usefulness for our living systematic review as we plan to focus on the clinical aspects of therapeutic drug monitoring. Regarding risperidone, there is evidence that risperidone and 9-OH-risperidone have different efficacy and safety profiles due to different blood-brain-barriers permeability [PMID: 33054667]. Therefore, we agree for that analysis of riperidone/9-OH-risperidone ratio may be very useful for the interpretation of meta-analysis of risperidone active moiety (Risperidone + 9-OH-Risperidone) plasma levels. Section 2.4 is now updated to reflect this. "Probably of little importance for the establishment of the protocol, it is to mention that in the case of risperidone, its hydroxylation to 9-OH-risperidone is stereoselective, in that CYP2D6 preferentially forms (+)-9-OH-risperidone rather than (-)-9-OH-risperidone (Yasui-Furukori et al. Drug Metab. Disp 2001, 1263). It should be considered, as rarely, stereoselective procedures were used in the published studies, the net effect of the genotype may be masked when non-stereoselective procedures are used." As we mentioned previously, we would like to focus on clinical aspects of therapeutic drug monitoring, i.e. we will try to use drug blood levels as a biomarkers of drugs biological effects. Therefore, even though stereo-selective analysis highlights the influence of CYP2D6, we find very limited clinical relevance of this information for our review as two enantiomers of 9-OH-Risperidone have been previously described as equipotent (PMID: 17344104). "The authors exclude some antipsychotics, but the mentioned reasons are not always evident, and again, the citations do not always correspond to the statements. Therefore, the presentation of the reference list demands to be improved. Eg, 2.2. Drug gene pairs …: “Lurasidone will not be analyzed because of the uncertain importance of drug-blood level measurements.” Ref 6 is cited, but this ref does apparently not deal with this subject. Actually, lurasidone is mainly a substrate of CYP3A4/5. As its blood levels strongly depend on dietary conditions, this may be an important reason for recommending TDM (cf Preskorn 2013: Lurasidone should be administered with food-at least 350 kcal-to ensure maximum exposure). However, one can agree with the decision of the authors, as this drug belongs to the group of drugs mentioned in 2.5. VII (study inclusion citeria) resp. 2.6. V." We agree with the reviewer, Lurasidone is the substrate for CYP3A4/5 and should therefore be included. Also, unrelated to reviewer’s comment, we have noticed that we listed Paliperidone as CYP3A4/5 and CYP2D6 substrate even though paliperidone is minimally metabolized in the liver and is mostly eliminated by kidneys [PMID: 20118446]. We sincerely apologize for these errors; they are now corrected in the revised version of the manuscript. "2.4. Definition of the outcome As pointed out by the authors, weight corrected drug concentrations may be advantageous, but they are often not available. Steady-state plasma concentrations: In the case of risperidone, there may be a problem in that in extensive metabolizers (CYP2D6), its T1/2 = 2 - 4h, but in poor metabolizers, considerably longer, comparable to that of its metabolite 9-OH-risperidone. This means that in EM, risp. steady-state concentrations will hardly be reached in EM but only in PM." We agree, people with lower enzyme metabolism capacities might take longer time to reach steady state. Therefore, we changed the criterion for the time needed to reach steady state to be 5x the conservative t 1/2 estimate. In other words, whenever the t 1/2 is presented as the range in AGNP guidelines (PMID: 28910830) we will use the higher limit of this range (longest time). This is now reflected in section 2.4. "Extended data: March : 6. UGT1A4 “At the time of writing, there is no consensus regarding the classification of different UGT1A4 diplotypes into metabolizer groups. Therefore, pragmatically, alleles known to affect CYP1A2 activity with Minor allelic frequencies >1% in the world population will be considered for this analysis.” Not clear: this suggests that there is a relationship CYP1A2 – UGT1A4 (?)." This was a typing error, and we sincerely apologize for it. We also noticed several other typing errors in the Extended data and they are now corrected in the new version. We again thank the Reviewer for the constructive criticism. We have no further comments. View more View less Competing Interests We declare no competing interest with regards to this response. reply Respond Report a concern Baumann P. Peer Review Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.162029.r280401) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-452/v1#referee-response-280401 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 de Lima Benzi J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 31 May 2024 | for Version 1 Jhohann Richard de Lima Benzi , University of São Paulo, São Paulo, Brazil 0 Views copyright © 2024 de Lima Benzi J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of personalized medicine in psychiatric care. I commend the authors for their meticulous approach and the significance of their endeavors. However, I would like to suggest some considerations to enrich the manuscript. Firstly, the inclusion or mention of the importance of drug transporters in AP therapy warrants attention, particularly those expressed in the blood-brain barrier. Given their pivotal role in drug disposition and response, their omission from the review raises questions about their relevance in AP pharmacotherapy. Exploring the available pharmacogenetic data pertaining to these transporters could provide valuable insights into their impact on treatment outcomes. Secondly, the decision to exclude data based on probe phenotyping drug data when defining metabolizer groups requires clarification. Elaborating on the rationale behind this exclusion would enhance the transparency and reproducibility of the study, ensuring a more robust analysis of CYP pharmacogenetics in AP therapy. Thirdly, I respectfully disagree with the assertion that single-dose pharmacokinetic parameters can be used interchangeably with steady-state parameters, particularly in the context of AP drugs with non-linear pharmacokinetics. Given the complexities inherent in non-linear PK profiles, a sensitivity analysis excluding single-dose studies may not adequately capture the dynamic nature of drug metabolism. It is imperative to devise alternative strategies to handle such data, perhaps through modeling techniques or subgroup analyses, to ensure the integrity and reliability of the findings. In conclusion, while the manuscript admirably addresses the relevance of CYP pharmacogenetics in AP therapy, the incorporation of drug transporter considerations, clarification on data exclusion criteria, and careful handling of non-linear PK data are essential for a more comprehensive and nuanced analysis. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Clinical pharmacology, pharmacokinetics, pharmacometrics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 09 Jul 2024 Filip Milosavljević, Section Evidence-Based Medicine in Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany "The manuscript under review presents a comprehensive systematic review protocol into the relevance of CYP pharmacogenetics in antipsychotic (AP) therapy, offering a clear and well-written discourse on the topic. The study's goal is undeniably pertinent, addressing a critical aspect of personalized medicine in psychiatric care. I commend the authors for their meticulous approach and the significance of their endeavors. However, I would like to suggest some considerations to enrich the manuscript." We thank the reviewer for positive feedback. "Firstly, the inclusion or mention of the importance of drug transporters in AP therapy warrants attention, particularly those expressed in the blood-brain barrier. Given their pivotal role in drug disposition and response, their omission from the review raises questions about their relevance in AP pharmacotherapy. Exploring the available pharmacogenetic data pertaining to these transporters could provide valuable insights into their impact on treatment outcomes." Indeed, drug efflux pumps are coded by highly polymorphous genes (ABCB1, ABCG2, ABCC2…) and the research of their pharmacogenomics has been very active in the recent years. We initially omitted to mention drug transporter in an effort to keep our report concise, but we agree with the reviewer that these genes have to be addressed in order to provide comprehensive overview of pharmacogenomics of antipsychotic drug pharmacokinetics, and that the omission of drug transporter genes from our analysis has to be justified in the manuscript. The main reason to exnclude pharmacogenomic studies on efflux pumps from our review is potential inappropriateness of our main outcome to capture the impact of pharmacogenomics of drug transporters on antipsychotic therapy. Our review is focused on plasma levels of antipsychotics, and in our analysis we will assume that cerebrospinal-fluid-to-plasma ratios of antipsychotic drugs are similar between people with different CYP450/UGT genotypes. Since drugs transporters are expressed on blood-brain barrier, in some antipsychotic drugs it has been demonstrated that mutations of drug transporter genes such as ABCB1 can change cerebrospinal-fluid-to-plasma ratios [PMID: 21148022, PMID: 20599439, PMID: 24666334]. This means that, for example, if two groups of patients with different ABCB1 mutations have the same antipsychotic plasma levels, they may not have the same antipsychotic cerebrospinal fluid levels, which puts into question the appropriateness of drug plasma level as a biomarker. Therefore, we believe that analyzing drug efficacy and safety directly, or analyzing cerebrospinal fluid drug levels are more appropriate outcomes for the analysis of drug transporters pharmacogenomics, all of which are out of the scope of this review. Introduction section now includes short summary of the potential significance of efflux pumps, and Section 2.2. now includes the justification of our justification not to include efflux pump pharmacogenomic data. "Secondly, the decision to exclude data based on probe phenotyping drug data when defining metabolizer groups requires clarification. Elaborating on the rationale behind this exclusion would enhance the transparency and reproducibility of the study, ensuring a more robust analysis of CYP pharmacogenetics in AP therapy." We agree with the reviewer that this decision needs more clarification. Also, upon revision of our manuscript, we noticed that our previous wording “for the purpose of this review, phenotyping will not be considered valid” can be interpreted as us questioning the validity of phenotyping method, which is not the case. Instead, section 2.3 is now updated to introduce pros and cons of both phenotyping and genotyping approaches and the justification why we opted not to use them interchangeably in this review. "Thirdly, I respectfully disagree with the assertion that single-dose pharmacokinetic parameters can be used interchangeably with steady-state parameters, particularly in the context of AP drugs with non-linear pharmacokinetics. Given the complexities inherent in non-linear PK profiles, a sensitivity analysis excluding single-dose studies may not adequately capture the dynamic nature of drug metabolism. It is imperative to devise alternative strategies to handle such data, perhaps through modeling techniques or subgroup analyses, to ensure the integrity and reliability of the findings." We thank the reviewer for raising this concern. Even though the majority of antipsychotics have linear pharmacokinetic profile, sublingual asenapine, oral lumateperone, oral chlorpromazine and oral perphenazine possess non-linear pharmacokinetic profiles (PMID: 29915922, PMID: 32060882, PMID: 8157044, PMID: 3933033). We agree with the reviewer that for the given examples, data from single dose studies and steady state studies cannot be used interchangeably and we apologize for our omission. As we are currently not aware of any model published in the literature designed to predict steady state levels of given four drugs based on single-dose data, we will, for the time being, opt to exclude single-dose studies for asenapine, lumateperone, chlorpromazine and perphenazine. We expect very small (if any) impact of this decision on the results of our meta-analyses, as we, based on our previous experience, expect to detect very few pharamcogenomic studies in the literature on these 4 drugs. If instead we happen to detect many eligible single-dose studies for these 4 drugs, we will post-hoc find appropriate model developed for other drugs that may fit the drug in question. This clarification is now reflected in the manuscript. "In conclusion, while the manuscript admirably addresses the relevance of CYP pharmacogenetics in AP therapy, the incorporation of drug transporter considerations, clarification on data exclusion criteria, and careful handling of non-linear PK data are essential for a more comprehensive and nuanced analysis." We thank the reviewer again for the constructive criticism that will improve the quality of this paper. We have no further comments. View more View less Competing Interests We declare no competing interests with regards to our response. reply Respond Report a concern de Lima Benzi JR. Peer Review Report For: Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol [version 2; peer review: 2 approved] . F1000Research 2024, 13 :452 ( https://doi.org/10.5256/f1000research.162029.r275387) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-452/v1#referee-response-275387 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Living systematic review and meta-analysis...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/13-452/v2" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/13-452/v2&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/13-452/v2" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Milosavljević F and Leucht S'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/13-452/v2/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/13-452", templates : { twitter : "Living systematic review and meta-analysis of plasma-concentrations.... Milosavljević F and Leucht S, published by " + "@F1000Research" + ", https://f1000research.com/articles/13-452/v2" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/147794/168742") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("articles", "article", "168742"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "280396": 0, "280397": 0, "280398": 0, "280399": 0, "280394": 0, "280395": 0, "280400": 0, "280401": 19, "280402": 0, "280403": 0, "306532": 0, "306533": 0, "306534": 0, "306535": 0, "300641": 6, "300642": 6, "306531": 0, "302767": 0, "275380": 0, "302772": 0, "275381": 0, "302773": 0, "275382": 0, "302774": 0, "275383": 0, "302775": 0, "302768": 0, "302769": 0, "302770": 0, "302771": 0, "275388": 0, "275389": 0, "275384": 0, "302776": 0, "275385": 0, "275386": 0, "275387": 22, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "2169842b-a2fa-4d84-b242-74b0868fd231"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });