Ukucindezeleka kungenye yezinkinga ezivame kakhulu zempilo yengqondo e-United States. Ucwaningo lwamanje luphakamisa ukuthi ukucindezeleka kubangelwa yinhlanganisela yezakhi zofuzo, zebhayoloji, ezemvelo, kanye nezici ezingokwengqondo. Ukucindezeleka kuyisifo sengqondo esikhulu emhlabeni wonke esinokucindezeleka okukhulu kwezomnotho nangokwengqondo emphakathini. Ngenhlanhla, ukucindezeleka, ngisho nezimo ezimbi kakhulu, kungase kwelashwe. Lapho ukwelashwa kungaqala, kuphumelela kakhulu.

Nokho, ngenxa yalokho, kunesidingo sama-biomarker aqinile azosiza ekuthuthukiseni ukuxilongwa ukuze kusheshiswe inqubo yokutholwa kwesidakamizwa kanye/noma yesiguli ngasinye esinalesi sifo. Lezi yizinkomba ze-peripheral physiological lapho ubukhona bungasetshenziswa ukubikezela amathuba okuqala noma ukuba khona kokucindezeleka, ukuhlela ngokuvumelana nobukhulu noma i-symptomatology, ukukhombisa ukubikezela nokubikezela noma ukuqapha impendulo ekungeneleleni kokwelapha. Inhloso yalesi sihloko esilandelayo ukukhombisa ukuqonda kwakamuva, izinselele zamanje namathemba esikhathi esizayo mayelana nokutholwa kwezinhlobonhlobo ze biomarkers yokucindezeleka nokuthi lokhu kungasiza kanjani ukuthuthukisa ukuxilongwa nokwelashwa.

Ama-Biomarker for Depression: Imibono Yakamuva, Izinselele Zamanje kanye Namathemba Esikhathi esizayo

abstract

Ucwaningo oluningi luye lwafaka amakhulu ezimpawu ze-biomarker zokudangala, kodwa azikakacacisi ngokugcwele izindima zazo ekuguleni okucindezelekayo noma ziveze ukuthi yini engavamile lapho iziguli kanye nolwazi lwe-biologic lungasetshenziswa kanjani ukuthuthukisa ukuxilongwa, ukwelashwa kanye nokubikezela. Lokhu kuntuleka kwenqubekelaphambili kubangelwa ingxenye yemvelo kanye nokuhlukahluka kokucindezeleka, ngokuhambisana ne-methodological heterogeneity ngaphakathi kwezincwadi zocwaningo kanye nohlu olukhulu lwama-biomarker anamandla, ukuvezwa kwakho okuvame ukuhluka kuye ngezici eziningi. Sibuyekeza izincwadi ezitholakalayo, ezibonisa ukuthi izimpawu ezihilelekile ezinqubweni zokuvuvukala, i-neurotrophic kanye ne-metabolic, kanye ne-neurotransmitter kanye ne-neuroendocrine system components, zimelela amakhandidethi athembisa kakhulu. Lokhu kungase kukalwe ngokuhlolwa kofuzo kanye ne-epigenetic, i-transcriptomic ne-proteomic, i-metabolomic kanye ne-neuroimaging. Ukusetshenziswa kwezindlela zamanoveli kanye nezinhlelo zocwaningo ezihlelekile manje kuyadingeka ukuze kunqunywe ukuthi, nokuthi yiziphi, izimpawu ze-biomarker zingasetshenziswa ukubikezela impendulo yokwelashwa, ukuhlela iziguli ekwelashweni okuqondile kanye nokuthuthukisa okuhlosiwe kokungenelela okusha. Siphetha ngokuthi kunezithembiso eziningi zokunciphisa umthwalo wokucindezeleka ngokuqhubeka nokuthuthukisa nokwandisa lezi zindlela zocwaningo.

Amagama angukhiye: ukuphazamiseka kwemizwelo, ukuphazamiseka okukhulu kokucindezeleka, ukuvuvukala, impendulo yokwelashwa, ukuhlukaniswa, imithi yomuntu siqu

Isingeniso

Izinselele Ezempilo Yengqondo kanye Nokuphazamiseka Kwemizwa

Nakuba izifo zengqondo zinomthwalo ohlobene nesifo omkhulu kunanoma yisiphi esinye isigaba sokuxilongwa kwezokwelapha, i-1 ukungalingani kokuhlonishwa kusabonakala phakathi nempilo yomzimba nengqondo ezizindeni eziningi ezihlanganisa uxhaso lwezimali locwaningo2 kanye nokushicilelwa.3 Phakathi kobunzima obubhekene nempilo yengqondo ukuntuleka kokuvumelana okuzungezile ukuhlukaniswa, ukuxilongwa kanye nokwelashwa okuvela ekuqondeni okungaphelele kwezinqubo ezibangela lezi zinkinga. Lokhu kubonakala kakhulu ekuphazamisekeni kwemizwelo, isigaba esihlanganisa umthwalo owodwa omkhulu kunayo yonke empilweni yengqondo.3 Isifo semizwa esivame kakhulu, i-depressive disorder (MDD), isifo esiyinkimbinkimbi, esiyinkimbinkimbi lapho iziguli ezingafika ku-60% zingase zibe nakho. izinga elithile lokumelana nokwelashwa okwenza kube kunde futhi kube kubi kakhulu iziqephu.4 Ngokuphazamiseka kwemizwa, nasemkhakheni obanzi wempilo yengqondo, imiphumela yokwelashwa cishe izothuthukiswa ngokutholakala kwezinhlobo ezincane eziqinile, ezilinganayo ngaphakathi (nakuwo wonke) izigaba zokuxilonga, izindlela zokwelapha kungenziwa stratified. Ngokuqaphela lokhu, imizamo yomhlaba wonke yokuchaza ama-subtypes asebenzayo manje iyaqhubeka, njengemibandela yesizinda socwaningo.5 Kuye kwabekwa ukuthi izimpawu ze-biologic ziyizikhandidethi ezibalulekile zokuphazamiseka kwengqondo.6

Ukuthuthukisa Ukusabela Ekwelapheni Ukudangala

Naphezu kohlu olubanzi lwezinketho zokwelapha zokucindezeleka okukhulu, cishe ingxenye eyodwa kwezintathu kuphela yeziguli ezine-MDD ezizuza ukukhululwa ngisho nalapho zithola ukwelashwa okwanele kwe-antidepressant ngokuvumelana neziqondiso zokuvumelana nokusebenzisa ukunakekelwa okusekelwe esilinganisweni, futhi amazinga okusabela kokwelashwa abonakala ehla ngokwelashwa okusha ngakunye. .7 Ngaphezu kwalokho, ukucindezeleka okungamelana nokwelashwa (TRD) kuhlotshaniswa nokukhubazeka kokusebenza okwandayo, ukufa, ukugula kanye neziqephu eziphindaphindiwe noma ezingapheli esikhathini eside.8,9 Ngakho, ukuthola ukuthuthukiswa ekuphenduleni ukwelashwa kunoma yisiphi isigaba somtholampilo kuzonikeza izinzuzo ezibanzi imiphumela jikelele ekucindezelekeni. Naphezu komthwalo omkhulu odalwe yi-TRD, ucwaningo kule ndawo luncane. Izincazelo ze-TRD azilinganiselwe, naphezu kwemizamo yangaphambilini: ezinye izinqubo ze-4 zidinga ukuhlolwa kokwelashwa okukodwa kuphela okuhluleka ukuzuza ukuncipha kwezimpawu ze-50% (kusukela esilinganisweni esiqinisekisiwe sobunzima bokucindezeleka), kanti ezinye zidinga ukungaphumeleli kokukhululwa okugcwele. noma ukungaphenduli okungenani kwama-antidepressants amabili ahlolwe ngokwanele amakilasi ahlukene ngaphakathi kwesiqephu okufanele sibhekwe njenge-TRD.4,10 Ngaphezu kwalokho, isiteji nokubikezela ukumelana nokwelashwa kuthuthukiswa ngokungeza izici zomtholampilo ezibalulekile zobunzima nokuhlala isikhathi eside enanini lezokwelapha ezihlulekile. .9,11 Noma kunjalo, lokhu kungqubuzana kwencazelo kwenza ukuhumusha izincwadi zocwaningo ku-TRD kube umsebenzi onzima nakakhulu.

Ukuze kuthuthukiswe impendulo ekwelashweni, kuyasiza ngokusobala ukukhomba izici ezibikezelayo zengozi yokungaphenduli. Ezinye izibikezelo ezijwayelekile ze-TRD ziye zabonakala, kuhlanganise nokuntuleka kokuxolelwa okugcwele ngemva kweziqephu zangaphambilini, ukukhathazeka kwe-comorbid, ukuzibulala kanye nokuqala kokucindezeleka, kanye nobuntu (ikakhulukazi ukukhishwa okuphansi, ukuncika komvuzo ophansi kanye neuroticism ephezulu) nezici zofuzo.12 Lokhu okutholakele kuqinisekiswa izibuyekezo ezihlanganisa ubufakazi ngokwehlukana kwe-pharmacologic13 kanye nokwelashwa kwengqondo14 yokucindezeleka. Ama-antidepressants kanye nokwelashwa kwengqondo-yokuziphatha kukhombisa ukusebenza kahle okucishe kuqhathaniswe, i-15 kodwa ngenxa yezinqubo zabo ezihlukene zokusebenza kungase kulindeleke ukuthi kube nezibikezelo ezahlukene zokuphendula. Nakuba ukuhlukunyezwa kwasekuqaleni sekuyisikhathi eside kuhlotshaniswa nemiphumela yomtholampilo empofu kanye nezimpendulo ezincishisiwe ekwelapheni, i-16 izinkomba zakuqala zibonisa ukuthi abantu abanomlando wokuhlukumezeka kwasebuntwaneni bangase baphendule kangcono ngokwengqondo kunemithi yokwelapha ye-pharmacologic.17 Naphezu kwalokhu, ukungaqiniseki kubusa kanye nokwenza komuntu siqu okuncane noma ukuhlukaniswa kokwelashwa sekufinyelele ekusebenzeni komtholampilo.18

Lokhu kubuyekezwa kugxile ebufakazini obusekela ukusetshenziswa kwama-biomarker njengamathuluzi omtholampilo angaba usizo okuthuthukisa impendulo yokwelashwa yokucindezeleka.

Ama-Biomarker: Amasistimu Nemithombo

Ama-biomarker ahlinzeka ngethagethi engaba khona yokukhomba izibikezelo zokusabela ekungeneleleni okuhlukahlukene.19 Ubufakazi kuze kube manje bubonisa ukuthi izimpawu ezibonisa umsebenzi wezinhlelo ezivuthayo, i-neurotransmitter, neurotrophic, neuroendocrine kanye ne-metabolic zingakwazi ukubikezela imiphumela yengqondo nengokwenyama kubantu abacindezelekile okwamanje. , kodwa kunokuningi ukungqubuzana phakathi kokutholakele.20 Kulesi sibuyekezo, sigxila kulezi zinhlelo ezinhlanu ze-biologic.

Ukuthola ukuqonda okugcwele kwezindlela zamangqamuzana kanye negalelo lazo ezinkingeni zengqondo, manje sekuthathwa njengebalulekile ukuhlola amazinga amaningi ezinto eziphilayo, kulokho okubizwa kakhulu ngokuthi �omics approach.21 Umfanekiso 1 unikeza ukuvezwa okuhlukile Amazinga e-biologic lapho uhlelo ngalunye kwezinhlanu lungahlolwa khona, kanye nemithombo engaba khona yamamaka lapho lokhu kuhlola kungenziwa khona. Nokho, qaphela ukuthi nakuba isistimu ngayinye ingahlolwa kuleveli ngayinye ye-omics, imithombo elungile yokulinganisa iyahluka ngokusobala kuleveli ngayinye. Isibonelo, i-neuroimaging inikeza inkundla yokuhlola okungaqondile kwesakhiwo sobuchopho noma umsebenzi, kuyilapho ukuhlolwa kwamaprotheni egazini kuhlola ngokuqondile izimpawu. I-Transcriptomics22 kanye ne-metabolomics23 iya ngokuya idume, ihlinzeka ngokuhlolwa kwezibalo ezingase zibe nkulu, futhi i-Human Microbiome Project manje izama ukuhlonza wonke ama-microorganisms kanye nokwakheka kwawo kofuzo kubantu. ; isibonelo, amahomoni afana ne-cortisol manje angahlolwa ezinweleni noma ezinzipholeni (okunikeza inkomba engapheli) noma umjuluko (okunikeza ukulinganisa okuqhubekayo),24 kanye nasegazini, uketshezi lobuchopho, umchamo namathe.

Uma kubhekwa inani lemithombo yokubeka, amazinga kanye nezinhlelo ezithintekayo ekucindezelekeni, akumangazi ukuthi isikali sama-biomarker esinamandla okuhumusha sibanzi. Ikakhulukazi, lapho ukusebenzisana phakathi komaka kucatshangelwa, cishe akunakwenzeka ukuthi ukuhlola ama-biomarker awodwa wodwa kuzoveza okutholakele okunezithelo zokuthuthukisa inkambiso yomtholampilo. U-Schmidt et al26 uhlongoze ukusetshenziswa kwamaphaneli e-biomarker futhi, ngemva kwalokho, u-Brand et al27 waveza iphaneli yokusalungiswa ngokusekelwe ebufakazini bangaphambili bomtholampilo kanye ne-preclinical ye-MDD, ehlonza okuhlosiwe kwe-biomarker engu-16 �strong�, ngayinye engavamile ukuba umaka owodwa. Zihlanganisa umthamo oncishisiwe wezinto ezimpunga (ezifundeni ze-hippocampal, i-prefrontal cortex kanye ne-basal ganglia), izinguquko zomjikelezo we-circadian, i-hypercortisolism nezinye izethulo ze-hypothalamic pituitary adrenal (HPA) hyperactivation, ukungasebenzi kahle kwegilo, i-dopamine encishisiwe, i-noradrenalinendo noma i-5-leaceaceic acid. , ukwanda kwe-glutamate, ukwanda kwe-superoxide dismutase kanye ne-lipid peroxidation, i-attenuated cyclic adenosine 3?, i-5?-i-monophosphate kanye nomsebenzi we-protein kinase we-mitogen-activated, ukwanda kwe-cytokines ye-proinflammatory, ukuguqulwa kwe-tryptophan, i-kynurenine, i-insulin kanye ne-polymorphisms ethile yofuzo. Labamaka abakavunyelwana ngokuvumelana futhi bangalinganiswa ngezindlela ezihlukahlukene; kuyacaca ukuthi umsebenzi ogxile futhi ohlelekile kufanele ubhekane nalo msebenzi omkhulukazi ukuze ufakazele izinzuzo zabo zomtholampilo.

Izinjongo zalokhu kubuyekezwa

Njengokubuyekeza okubanzi ngamabomu, le ndatshana ifuna ukunquma izidingo eziphelele zocwaningo lwe-biomarker ekucindezelekeni kanye nezinga lapho ama-biomarker anamandla angempela okuhumusha okuthuthukisa impendulo ekwelashweni. Siqala ngokuxoxa ngokutholakele okubaluleke kakhulu nokujabulisayo kulo mkhakha futhi siqondise umfundi ekubuyekezweni okuqondile okuphathelene nomaka abafanelekile nokuqhathanisa. Sibeka izinselele zamanje ezibhekene nobufakazi, ngokuhambisana nezidingo zokunciphisa umthwalo wokucindezeleka. Okokugcina, sibheke phambili ezindleleni zocwaningo ezibalulekile zokuhlangabezana nezinselele zamanje kanye nemithelela yazo ekusebenzeni komtholampilo.

Imibono Yakamuva

Ukuseshwa kwama-biomarker awusizo ezempilo kubantu abanokucindezeleka kukhiqize uphenyo olunzulu phakathi nengxenye yekhulu edlule. Izindlela zokwelapha ezisetshenziswa kakhulu zaqanjwa kumbono we-monoamine wokucindezeleka; Kamuva, imibono ye-neuroendocrine yathola ukunakwa okukhulu. Eminyakeni yamuva nje, ucwaningo olwenzeka kakhulu luye lwazungeza i-hypothesis yokuvuvukala yokucindezeleka. Kodwa-ke, inani elikhulu lama-athikili okubuyekezwa afanelekile agxile kuzo zonke izinhlelo ezinhlanu; bona Ithebula 1 nangezansi ukuze uthole iqoqo lemininingwane yakamuva kuwo wonke amasistimu e-biomarker. Nakuba kulinganiswa kumazinga amaningi, amaprotheni atholakala egazini ahlolwe kabanzi futhi ahlinzeka ngomthombo we-biomarker elula, engabizi futhi engase ibe seduze namandla okuhumusha kuneminye imithombo; ngakho-ke, imininingwane eyengeziwe inikezwa kuma-biomarker ajikeleza egazini.

Ekubuyekezweni okuhlelekile kwakamuva, u-Jani et al20 bahlole ama-biomarker asekelwe egazini e-peripheral for depression ngokuhambisana nemiphumela yokwelashwa. Ezifundweni ze-14 kuphela ezifakiwe (ziseshwe kuze kube sekuqaleni kwe-2013), ama-biomarker angu-36 afundwa lapho i-12 yayiyizibikezelo ezibalulekile zezinkomba zokuphendula kwengqondo noma ngokomzimba okungenani uphenyo olulodwa. Labo abahlonzwe njengabangase bamele izici eziyingozi zokungaphenduli bahlanganisa amaprotheni avuthayo: i-interleukin ephansi (IL) -12p70, isilinganiso se-lymphocyte nesibalo se-monocyte; izimpawu ze-neuroendocrine (i-dexamethasone engacindezeli i-cortisol, i-cortisol ejikelezayo ephezulu, i-hormone enciphisa i-thyroid-stimulating); izimpawu ze-neurotransmitter (i-serotonin ephansi ne-noradrenaline); i-metabolic (i-high-density lipoprotein cholesterol ephansi) kanye nezici ze-neurotrophic (ehlisiwe i-S100 calcium-binding protein B). Ngaphezu kwalokhu, okunye ukubuyekezwa kuye kwabika mayelana nezinhlangano phakathi kwama-biomarker engeziwe kanye nemiphumela yokwelashwa.19,28�30 Incazelo emfushane yomaka be- putative kusistimu ngayinye ichazwe ezigabeni ezilandelayo nakuThebula lesi-2.

Imiphumela Evuvukalayo Ekucindezelekeni

Kusukela iphepha likaSmith elichaza i-macrophage hypothesis, i-31 le mibhalo esunguliwe ithole amazinga anyukile ezimpawu ezihlukahlukene ze-proinflammatory ezigulini ezicindezelekile, eziye zabuyekezwa kabanzi. lawula abantu.32�37

I-IL-6 (P <0.001 kuzo zonke i-meta-analyses; izifundo ze-31 zifakiwe) kanye ne-CRP (P <0.001; izifundo ze-20) zivela njalo futhi ziphakeme ngokuthembekile ekucindezelekeni.40 I-tumor necrosis factor alpha (TNF?) ephakeme kakhulu ibonakala ezifundweni zakuqala. (P<0.001),38 kodwa i-heterogeneity enkulu yenze lokhu kungahlanganisi lapho kubalwa uphenyo lwakamuva (izifundo ezingama-31).40 IL-1? ihlobene nakakhulu nokucindezeleka, nokuhlaziywa kwe-meta okuphakamisa amazinga aphezulu ekucindezelekeni (P=0.03), amazinga aphezulu angu-41 kuphela ezifundweni zaseYurophu42 noma akukho mehluko ovela kuzilawuli.40 Naphezu kwalokhu, isihloko sakamuva siphakamise imithelela ethile yokuhumusha ye-IL- 1?,44 isekelwe umphumela obaluleke kakhulu we-IL-1 ephakeme? i-ribonucleic acid ebikezela ukusabela okungekuhle kuma-antidepressants; Okunye okutholakele okungu-45 ngenhla kuphathelene nokujikeleza kwama-cytokines atholakala egazini. I-chemokine monocyte chemoattractant protein-1 ibonise ukuphakama kwabahlanganyeli abacindezelekile ekuhlaziyeni okukodwa kwe-meta.39 I-Interleukins IL-2, IL-4, IL-8, IL-10 kanye ne-interferon gamma ayizange ihluke kakhulu phakathi kweziguli ezicindezelekile kanye nezilawuli ngesikhathi. I-meta-analytic level, kodwa noma kunjalo ikhombisile amandla mayelana nokuguqulwa ngokwelashwa: I-IL-8 kubikwe ukuthi iphakeme kulabo abanokucindezeleka okukhulu ngokuzayo nangezigaba, amaphethini angu-46 ahlukene oshintsho ku-IL-10 kanye ne-interferon gamma ngesikhathi sokwelashwa. kwenzeke phakathi kwabaphenduli bokuqala ngokumelene nabangaphenduli, i-47 kuyilapho i-IL-4 ne-IL-2 yehle ngokuhambisana nokukhululwa kwezimpawu.48 Ekuhlaziyweni kwe-meta, ukwehla okuncane okuhambisana nokwelashwa kuye kwaboniswa i-IL-6, IL-1?, IL- 10 kanye ne-CRP.43,49,50 Ukwengeza, i-TNF? ingase inciphise kuphela ngokwelashwa kwabaphendulayo, futhi inkomba yokumaka ehlanganisiwe ingase ibonise ukuvuvukala okwandayo ezigulini kamuva ezingaphenduli ekwelapheni. . Ngakho-ke, okungenani izinguquko ezithile zokuvuvukala ngesikhathi sokwelashwa cishe zibangelwa ama-antidepressants. Imiphumela eqondile yokuvuvukala yama-antidepressants ahlukene ayikasungulwa, kodwa ubufakazi obusebenzisa amazinga e-CRP buphakamisa ukuthi abantu baphendule ngendlela ehlukile ekwelapheni okuthile okusekelwe ekuvuvukeni okuyisisekelo: U-Harley et al43 ubike ukwelashwa okuphakeme kwe-CRP ebikezela impendulo embi ekwelapheni kwengqondo (ingqondo-yokuziphatha noma phakathi kwabantu. i-psychotherapy), kodwa impendulo enhle ku-nortriptyline noma i-fluoxetine; U-Uher et al51 uphindaphinde lokhu okutholakele ku-nortriptyline futhi wakhomba umphumela ophambene we-escitalopram. Ngokuphambene, u-Chang et al52 bathole i-CRP ephezulu kubaphenduli bokuqala be-fluoxetine noma i-venlafaxine kunabangaphenduli. Ngaphezu kwalokho, iziguli ezine-TRD kanye ne-CRP ephezulu ziye zasabela kangcono ku-TNF? antagonist infliximab kunalabo abanamazinga ebangeni elijwayelekile.53

Ngokubambisana, ubufakazi bubonisa ukuthi ngisho nalapho kulawulwa izici ezifana ne-body mass index (BMI) kanye neminyaka yobudala, izimpendulo ezivuthayo zibonakala ziphikisana cishe cishe ingxenye eyodwa kwezintathu yeziguli ezinokucindezeleka.55,56 Nokho, uhlelo lokuvuvukala luyinkimbinkimbi kakhulu, futhi kukhona ama-biomarker amaningi amele izici ezihlukene zalolu hlelo. Muva nje, amanoveli engeziwe ama-cytokines nama-chemokines aveze ubufakazi bokungajwayelekile kokucindezeleka. Lezi zihlanganisa: i-macrophage inhibitory protein 1a, IL-1a, IL-7, IL-12p70, IL-13, IL-15, eotaxin, granulocyte macrophage colony-stimulating factor,57 IL-5,58 IL-16,59 IL- 17,60 monocyte chemoattractant protein-4,61 thymus and activation-regulated chemokine,62 eotaxin-3, TNFb,63 interferon gamma-induced protein 10,64 serum amyloid A,65 e-soluble intracellular adhesion molecule66 kanye ne-soluble 1.67 cell adhesion vascular cell.

Imiphumela Yesici Sokukhula Ekucindezelekeni

Uma sibheka ukubaluleka okungaba khona kwezinto ezingezona ze-neurotrophic ukukhula (njengalezo ezihlobene ne-angiogenesis), sibhekisela kuma-biomarker we-neurogenic ngaphansi kwencazelo ebanzi yezinto zokukhula.

I-brain-derived neurotrophic factor (BDNF) iyona efundwa kakhulu kulezi. Ukuhlaziywa kwe-meta okuningi kubonisa ukuncishiswa kwephrotheni ye-BDNF ku-serum, ebonakala ikhula kanye nokwelashwa kwe-antidepressant.68�71 Okwakamuva kakhulu kwalokhu kuhlaziywa kubonisa ukuthi lokhu kuguqulwa kwe-BDNF kuvezwa kakhulu ezigulini ezicindezeleke kakhulu, kodwa lokho okuqeda ukucindezeleka kubonakala sengathi ukwandisa amazinga ale phrotheni ngisho nalapho kungabikho ukukhululwa komtholampilo.I-70 i-proBDNF iye yafundwa kancane kakhulu kunefomu elivuthiwe le-BDNF, kodwa lezi ezimbili zibonakala zihluke ngokusebenza (ngokwemiphumela yazo kuma-receptors e-tyrosine receptor kinase B) kanye nakamuva. ubufakazi bubonisa ukuthi nakuba i-BDNF evuthiwe ingase yehliswe ekucindezelekeni, i-proBDNF ingase ikhiqize ngokweqile.72 Isici sokukhula kwemizwa esihlolwe ngokuzungezile siye sabikwa njengesiphansi ekucindezelekeni kunokulawulwa ekuhlaziyweni kwe-meta-analysis, kodwa angeke ishintshwe ngokwelashwa kwe-antidepressant naphezu kokuba abancishwe kakhulu ezigulini ezinokucindezeleka okukhulu kakhulu.73 Ukuthola okufanayo kuye kwabikwa ekuhlaziyweni kwe-meta ye-glial cell.i-neurotrophic factor etholakala kulayini.74

I-Vascular endothelial growth factor (VEGF) inendima ekukhuthazeni i-angiogenesis ne-neurogenesis kanye namanye amalungu omndeni we-VEGF (isb, i-VEGF-C, i-VEGF-D) futhi inesithembiso sokucindezeleka.75 Naphezu kobufakazi obungaguquki, ukuhlaziya okubili kwe-meta usanda kubonisa ukuphakama kwe-VEGF egazini leziguli ezicindezelekile uma kuqhathaniswa nezilawuli (kuzo zonke izifundo ze-16; P<0.001) .76,77 Nokho, i-VEGF ephansi ikhonjwe ku-TRD78 futhi amazinga aphezulu abikezele ukungaphenduli ekwelashweni kwe-antidepressant.79 Akuqondakali. kungani amazinga ephrotheni ye-VEGF engase anyuswe, kodwa ngokwengxenye kungase kubangelwe umsebenzi wokuvuvukala kanye/noma ukwanda kwegazi�ukungena kwesithiyo sobuchopho ezifundeni ezicindezelekile ezibangela ukuncipha kokuvezwa ku-cerebrospinal fluid.80 Ubudlelwano phakathi kwe-VEGF nempendulo yokwelashwa abucaci. ; ucwaningo lwakamuva alutholanga ubuhlobo phakathi kwe-serum VEGF noma i-BDNF ngokuphendula noma ukucindezeleka okukhulu, naphezu kokunciphisa kanye nokwelashwa kwe-antidepressant. izinqubo ze-neurotrophic.81 Isici esiyisisekelo sokukhula kwe-fibroblast (noma i-FGF-1) iyilungu lomndeni we-fibroblast factor factor futhi ibonakala iphakeme kakhulu ekucindezelekeni kunamaqembu okulawula.82,83 Nokho, imibiko ayihambisani; omunye wathola ukuthi le phrotheni yayiphansi ku-MDD kunezilawuli ezinempilo, kodwa yehliswa ngokuqhubekayo kanye nokwelashwa kwe-antidepressant.2

Ezinye izici ezikhulayo ezingazange zihlolwe ngokwanele ekucindezelekeni zihlanganisa i-tyrosine kinase 2 kanye ne-soluble fms-like tyrosine kinase-1 (ebuye ibizwe nge-sVEGFR-1) esebenza ngokubambisana ne-VEGF, kanye nama-tyrosine kinase receptors (abopha i-BDNF) angase ancishiswe. ekucindezelekeni.86 I-Placent growth factor nayo iyingxenye yomndeni we-VEGF, kodwa ayizange ifundwe kumasampula acindezelekile ngokuhlelekile ngokolwazi lwethu.

Okutholakele Kwe-Metabolic Biomarker Ekucindezelekeni

Ama-biomarker ayinhloko ahlotshaniswa nokugula kwe-metabolic ahlanganisa i-leptin, i-adiponectin, i-ghrelin, i-triglycerides, i-high-density lipoprotein (i-HDL), i-glucose, i-insulin ne-albumin.87 Izinhlangano phakathi kwalezi eziningi nokucindezeleka zibuyekeziwe: i-leptin88 ne-ghrelin89 ibonakala iphansi ekucindezelekeni. kunezilawuli eziseceleni futhi ingase ikhuphuke eduze nokwelashwa kwe-antidepressant noma ukukhululwa. Ukumelana ne-insulin kungase kwandiswe ekucindezelekeni, nakuba ngamanani amancane.Amaphrofayili e-Lipid angu-90, okuhlanganisa i-HDL-cholesterol, avela eguquliwe ezigulini eziningi ezinokucindezeleka, kuhlanganise nalabo abangenazo izifo ezingokomzimba ezihlangene, nakuba lobu buhlobo bunzima futhi budinga ukucaciswa okwengeziwe.91 Ukwengeza, I-hyperglycemia92 kanye ne-hypoalbuminemia93 ekucindezelekeni kubikwe ekubuyekezweni.

Uphenyo lwezimo ze-metabolic sezijwayelekile kakhulu kusetshenziswa amaphaneli e-metabolomics ama-molecule amancane ngethemba lokuthola isiginesha eqinile ye-biochemical yezinkinga zengqondo. Ocwaningweni lwakamuva olusebenzisa i-intelligence modelling yokwenziwa, isethi yama-metabolites ebonisa ukwanda kwe-glucose-lipid signing yayibikezela kakhulu ukuxilongwa kwe-MDD, i-94 esekela izifundo zangaphambilini.95

Okutholakele Neurotransmitter Ekucindezelekeni

Nakuba ukunakwa okukhokhwe kuma-monoamines ekucindezelekeni kuye kwakhiqiza ukwelashwa okuyimpumelelo, abekho omaka be-neurotransmitter abaqinile abahlonziwe ukuze kuthuthukiswe ukwelashwa okusekelwe ekukhetheni okuhlosiwe kwe-monoamine yama-antidepressants. Umsebenzi wakamuva ukhomba ku-serotonin (i-5-hydroxytryptamine) i-1A receptor njengamandla angabaluleka kukho kokubili ukuxilongwa kanye nokubikezelwa kokucindezeleka, okulindile amasu amasha ofuzo kanye ne-imaging.96 Kukhona izindlela zokwelapha ezintsha ezingase zibe khona eziqondiswe ku-5-hydroxytryptamine; isibonelo, ukusebenzisa ukuphathwa okuhamba kancane kwe-5-hydroxytryptophan.97 Ukwenyuka kokudluliselwa kwe-dopamine kusebenzisana namanye ama-neurotransmitters ukuze kuthuthukiswe imiphumela yokucabanga njengokuthatha izinqumo nokugqugquzela.98 Ngokufanayo, i-neurotransmitters glutamate, noradrenaline, histamine ne-serotonin ingase ihlanganyele futhi isebenze. njengengxenye yempendulo yokucindezeleka ehlobene nokucindezeleka; lokhu kungehlisa ukukhiqizwa kwe-5-hydroxytryptamine �izikhukhula�. Ukubuyekezwa kwakamuva kubeka le mbono futhi kusikisela ukuthi ku-TRD, lokhu kungahlehliswa (futhi i-5-HT ibuyiselwe) ngokusebenzisa ukwelashwa kwe-multimodal okubhekiswe kuma-neurotransmitters amaningi.99 Kuyathakazelisa ukuthi ukwanda kwe-serotonin akwenzeki ngaso sonke isikhathi kanye nezinzuzo zokucindezeleka zokwelapha.100 Naphezu kwalokhu. , i-neurotransmitter metabolites efana ne-3-methoxy-4-hydroxyphenylglycol, ye-noradrenaline, noma i-homovanillic acid, ye-dopamine, ivame ukutholakala ukuthi yanda kanye nokunciphisa ukucindezeleka ngokwelashwa kwe-antidepressant101,102 noma ukuthi amazinga aphansi alawa metabolites abikezela impendulo engcono Ukwelashwa kwe-SSRI.102,103

Imiphumela Ye-Neuroendocrine Ekucindezelekeni

I-Cortisol iyi-axis biomarker ye-HPA evame kakhulu ukuthi ifundwe ekucindezelekeni. Ukubuyekezwa okuningi kugxile ekuhloleni okuhlukahlukene komsebenzi we-HPA; jikelele, lezi zisikisela ukuthi ukucindezeleka kuhlotshaniswa ne-hypercortisolemia nokuthi impendulo yokuvusa i-cortisol ivame ukuncishiswa.104,105 Lokhu kusekelwa ukubuyekezwa kwakamuva kwamazinga e-cortisol angapheli alinganiswa izinwele, okusekela i-hypothesis ye-cortisol hyperactivity ekucindezelekeni kodwa ukungasebenzi kwezinye izifo ezifana njenge-panic disorder.106 Ngaphezu kwalokho, ikakhulukazi, amazinga e-cortisol aphakeme angase abikezele impendulo empofu ekwelashweni kwengqondo107 kanye ne-antidepressant108. Ngokomlando, umaka we-neuroendocrine othembisa kakhulu wempendulo yokwelashwa okulindelwe kube ukuhlolwa kokucindezelwa kwe-dexamethasone, lapho ukungacindezeli kwe-cortisol okulandela ukuphathwa kwe-dexamethasone kuhlotshaniswa namathuba aphansi okukhululwa okulandelayo. Kodwa-ke, lesi simo asizange sithathwe njengesiqine ngokwanele ekusetshenzisweni komtholampilo. Izimpawu ezihlobene ne-corticotrophin-releasing hormone kanye ne-adrenocorticotropin hormone kanye ne-vasopressin atholakala ngokungaguquki ukuthi akhiqizwa ngokweqile ekucindezelekeni futhi i-dehydroepiandrosterone itholakala ukuthi iyancipha; isilinganiso se-cortisol kuya ku-dehydroepiandrosterone singase siphakanyiswe njengophawu oluzinzile ku-TRD, ephikelela ngemva kokuxolelwa.109 I-Neuroendocrine hormone dysfunctions sekuyisikhathi eside ihlotshaniswa nokucindezeleka, futhi i-hypothyroidism ingase ibambe iqhaza elibangela isimo sokucindezeleka.110 Ngaphezu kwalokho, izimpendulo ze-thyroid zingakwazi zijwayeze ngokwelashwa okuphumelelayo kokucindezeleka.111

Ngaphakathi kwalokhu okungenhla, kubalulekile futhi ukucabangela izindlela zokubonisa izimpawu kuzo zonke izinhlelo, njenge-glycogen synthase kinase-3, i-protein kinase e-mitogen-activated kanye ne-cyclic adenosine 3?, 5?-monophosphate, ehilelekile ku-synaptic plasticity112 futhi ishintshwe yi-antidepressants.113 Ngaphezu kwalokho. amakhandidethi angaba khona ama-biomarker asebenzisa izinhlelo ze-biologic ikakhulukazi akalwa kusetshenziswa i-neuroimaging noma i-genetics. Ukusabela ekuntulekeni komehluko oqinile futhi onengqondo we-genomic phakathi kwabantu abacindezelekile nabacindezelekile, izindlela ze-114 zenoveli zofuzo ezifana ne-polygenic scores115 noma ubude be-telomere116,117 zingase zibe usizo kakhulu. Ama-biomarker engeziwe athola ukuduma ahlola imijikelezo ye-circadian noma ama-biomarker e-chronobiologic asebenzisa imithombo ehlukene. I-Actigraphy inganikeza ukuhlolwa okuhlosiwe kokulala nokuvuka kanye nokuphumula nge-accelerometer, futhi amadivayisi we-actigraphic angakhula ngokuqhubekayo ukulinganisa izici ezengeziwe ezifana nokuchayeka kokukhanya. Lokhu kungase kube usizo kakhulu ekuhlonzweni kunemibiko evame ukusetshenziswa yeziguli futhi kungase kunikeze izibikezelo ezintsha zempendulo yokwelashwa.118 Umbuzo wokuthi yiziphi izimpawu ze-biomarker ezithembisa kakhulu ukusetshenziswa kokuhumusha inselele, onwetshwa ngezansi.

Izinselele Zamanje

Kulezi zinhlelo ezinhlanu ze-neurobiological ezibuyekeziwe, ubufakazi bulandela ukulandisa okufanayo: kunezimpawu eziningi eziphilayo ezikhona ezihlotshaniswa ngandlela thile nokudangala. Lezi zimaki zivame ukuhlotshaniswa ngendlela eyinkimbinkimbi, enzima ukwenza imodeli. Ubufakazi abuhambisani, futhi kungenzeka ukuthi ezinye ziyi-epiphenomena yezinye izici futhi ezinye zibalulekile kusethi encane yeziguli. Ama-biomarker angase abe usizo ngezindlela ezihlukahlukene (isb, lezo ezibikezela ukusabela okulandelayo ekwelapheni, lezo ezibonisa ukwelashwa okuqondile okungase kuphumelele noma lezo ezishintshayo ngokungenelela ngaphandle kokuthuthuka komtholampilo). Izindlela zamanoveli ziyadingeka ukuze kukhuliswe ukungaguquguquki kanye nokusetshenziswa komtholampilo kokuhlolwa kwe-biologic kubantu bengqondo.

Ukuhlukahluka kwe-Biomarker

Ukwehluka kwama-biomarker ngokuhamba kwesikhathi nasezimeni zonke kuthinta kakhulu ezinye izinhlobo (isb, ama-proteomics) kunezinye (i-genomics). Izinkambiso ezijwayelekile zabaningi azikho noma azikamukelwa kabanzi. Ngempela, umthelela wezici zemvelo kumakaki ngokuvamile uncike ekwakhiweni kofuzo kanye nokunye ukungezwani komzimba phakathi kwabantu okungenakubalwa konke. Lokhu kwenza ukuhlolwa komsebenzi we-biomarker, kanye nokuhlonza okungavamile kwezinto eziphilayo, kube nzima ukukuhumusha. Ngenxa yenani lama-biomarker angaba khona, amaningi awakaliwe kabanzi noma ephanelini eliphelele eduze nabanye omaka abafanelekile.

Ziningi izici ezibikwe ukuthi ziguqule amazinga amaprotheni kuzo zonke izinhlelo ze-biologic ezigulini ezinezinkinga ze-affective. Kanye nezici ezihlobene nocwaningo ezifana nobude besikhathi nezimo zokugcinwa (okungase kubangele ukuwohloka kwezinye izinhlanganisela), lezi zihlanganisa isikhathi sosuku esilinganisiwe, ubuhlanga, ukuzivocavoca, ukudla kwe-119 (isb, umsebenzi we-microbiome, ikakhulukazi uma nje izifundo eziningi ze-biomarker zegazi zenza. akudingi isampula lokuzila),120 ukubhema nokusebenzisa izidakamizwa,121 kanye nezici zempilo (njengokuvuvukala kwe-comorbid, inhliziyo nemithambo yegazi noma ezinye izifo zomzimba). Isibonelo, nakuba ukuvuvukala okuphakeme kubonakala kubantu abacindezelekile kodwa ngenye indlela enempilo uma kuqhathaniswa namaqembu angacindezelekile, abantu abacindezelekile nabo abanesimo esihlobene ne-immune ehlobene ngokuvamile banamazinga aphezulu ngisho nama-cytokines kunalabo abangenawo ukucindezeleka noma ukugula.122 Ezinye izici ezivelele ukubandakanyeka okungenzeka ebudlelwaneni phakathi kwama-biomarker, ukucindezeleka kanye nokusabela kokwelashwa kuchazwe ngezansi.

Ukucindezeleka. Kokubili izimpendulo ze-endocrine ne-immune zinezindima ezaziwayo ekuphenduleni ukucindezeleka (physiologic noma kwengqondo), futhi ukucindezeleka kwesikhashana ngesikhathi sokuqoqwa kwesampula ye-biologic akuvamile ukulinganiswa ocwaningweni locwaningo naphezu kokuhlukahluka kwalesi sici phakathi kwabantu abangase bagcizelelwe okwamanje. izimpawu zokucindezeleka. Kokubili ukucindezeleka kwengqondo okunamandla nokungapheli kusebenza njengenselele yokuzivikela komzimba, kugcizelela izimpendulo ezivuthayo esikhathini esifushane nesikhathi eside. umuntu omdala.123,124 Ngesikhathi sokuhlangenwe nakho okubuhlungu kwasebuntwaneni, ukuvuvukala okuphakeme kuye kwabikwa kuphela kulezo zingane ezazicindezelekile okwamanje.125,126 Ngokuphambene nalokho, abantu abanokucindezeleka kanye nomlando wokuhlukumezeka kwasebuntwaneni bangase babe nezimpendulo ezifiphele ze-cortisol ekucindezelekeni, uma kuqhathaniswa nalabo abanokucindezeleka nokucindezeleka. akukho ukuhlukumezeka kwangaphambi kwesikhathi.I-127 Ukuguqulwa kwe-axis ye-HPA ecindezelekile kubonakala kuhlotshaniswa nokusebenza kwengqondo, i-128 kanye ne-subtype yokucindezeleka noma ukuhluka kwezakhi zofuzo ezihlobene ne-HPA.129 Ukucindezeleka nakho kunemiphumela emfushane neyesikhathi eside yokukhubazeka ku-neurogenesis130 kanye nezinye izinzwa. izindlela.131 Akucaci kahle ukuthi ukuhlukumezeka kwasebuntwaneni kubathinta kanjani izimpawu zezinto eziphilayo kumuntu omdala ocindezelekile. s, kodwa kungenzeka ukuthi ingcindezi yempilo yangaphambi kwesikhathi ibeka abanye abantu ekubekezeleni ukusabela ekucindezelekeni lapho sebebadala okukhuliswa ngokwengqondo kanye/noma ngokwebhayoloji.

Ukusebenza kwengqondo. Ukungasebenzi kahle kwe-neurocognitive kwenzeka kaningi kubantu abanezinkinga ezithintekayo, ngisho naku-MDD engahlosiwe.133 Ukuntuleka kwengqondo kubonakala kuyanda kanye nokumelana nokwelashwa.134 I-Neurobiologically, i-HPA axis129 kanye nezinhlelo ze-neurotrophic135 cishe zizodlala indima ebalulekile kulobu buhlobo. I-neurotransmitters noradrenaline kanye ne-dopamine cishe ibalulekile ezinqubweni zokuqonda ezifana nokufunda nenkumbulo.I-136 Izimpendulo zokuvuvukala eziphakeme ziye zaxhunyaniswa nokuncipha kwengqondo, futhi cishe zithinta ukusebenza kwengqondo ezikhathini zokucindezeleka, i-137 kanye nokukhululwa, ngokusebenzisa izindlela ezihlukahlukene.138 Ngempela, U-Krogh et al139 uhlongoze ukuthi i-CRP ihlobene kakhulu nokusebenza kwengqondo kunezimpawu eziyinhloko zokucindezeleka.

Ubudala, ubulili kanye ne-BMI. Ukungabikho noma ukuba khona, kanye nesiqondiso somehluko we-biologic phakathi kwabesilisa nabesifazane kuye kwahluka ikakhulukazi ebufakazini kuze kube manje. Ukuhlukahluka kwe-hormone ye-Neuroendocrine phakathi kwamadoda nabesifazane kusebenzisana nokuthinteka kokucindezeleka.140 Ukubuyekezwa kocwaningo lokuvuvukala kubike ukuthi ukulawula iminyaka yobudala nobulili akuzange kuthinte umehluko wokulawula isiguli kuma-cytokines avuthayo (nakuba inhlangano phakathi kwe-IL-6 nokucindezeleka kuncipha njengoba iminyaka yanda, okuhambisana nezinkolelo-mbono zokuthi ukuvuvukala ngokuvamile kukhula ngeminyaka yobudala) .Ukuhluka kwe-VEGF ye-41,141 phakathi kweziguli nezilawuli kukhulu ezifundweni ezihlola amasampula amancane, kuyilapho ubulili, i-BMI kanye nezici zomtholampilo akuzange kuthinte lokhu kuqhathaniswa ezingeni le-meta-analytic.77 Nokho, ukuntuleka kokulungiswa kwe-BMI ekuhlolweni kwangaphambilini kokuvuvukala nokucindezeleka kubonakala kuphazamisa umehluko omkhulu kakhulu obikwe phakathi kwalawa maqembu.41 Izicubu ze-adipose ezikhulisiwe ziye zaboniswa ngokucacile ukuze zikhuthaze ukukhiqizwa kwe-cytokine kanye nokuxhunyaniswa eduze nezimpawu ze-metabolic.142 Ngoba imithi ye-psychotropic ingase ihlotshaniswe ne-wei ukuzuza kanye ne-BMI ephakeme, futhi lokhu kuye kwahlotshaniswa nokungazweli ekwelashweni ekucindezelekeni, lena indawo ebalulekile okufanele ihlolwe.

Imithi. Izifundo eziningi ze-biomarker ekucindezelekeni (kokubili okuphambene nezigaba kanye nobude) ziqoqe izibonelo eziyisisekelo kubahlanganyeli abangahlosiwe ukuze kuncishiswe i-heterogeneity. Kodwa-ke, okuningi kwalokhu kuhlola kuthathwa ngemva kwesikhathi sokugeza emithini, okushiya isici esingaba esididayo esingase sibe nezinguquko ezinsalela ku-physiology, okubhebhethekiswa uchungechunge olubanzi lwemithi yokwelapha etholakalayo okungenzeka ibe nemiphumela ehlukile ekuvuvukeni. Ezinye izifundo azibandakanyi i-psychotropic, kodwa hhayi okunye ukusetshenziswa kwemithi: ikakhulukazi, iphilisi lokuvimbela inzalo ngomlomo livame ukuvunyelwa kubahlanganyeli bocwaningo futhi alilawulwa ekuhlaziyweni, okusanda kuboniswa ukwandisa amazinga e-hormone kanye ne-cytokine.143,144 Ucwaningo oluningi lubonisa ukuthi i-antidepressant Imithi inemiphumela ekuphenduleni kokuvuvukala,34,43,49,145�147 HPA-axis,108 neurotransmitter,148 kanye neurotrophic149 umsebenzi. Kodwa-ke, izindlela zokwelapha eziningi ezingase zibe khona zokucindezeleka zinezakhiwo ezihlukile neziyinkimbinkimbi ze-pharmacologic, okuphakamisa ukuthi kungase kube nemiphumela ecacile ye-biologic yezinketho ezahlukene zokwelapha, ezisekelwa idatha yamanje. Kuye kwathiwa ngaphezu kwemiphumela ye-monoamine, imithi ethile eqondiswe ku-serotonin (okungukuthi, ama-SSRIs) kungenzeka iqondise amashifu e-Th2 ekuvuvukeni, kanye nama-antidepressants ama-noradrenergic (isb, ama-SNRIs) anomthelela ekushintsheni kwe-Th1 Akukakakwazi thola imiphumela yomuthi ngamunye noma wenhlanganisela kuma-biomarker. Lokhu kungenzeka kuxazululwe ezinye izici ezihlanganisa ubude bokwelashwa (izilingo ezimbalwa ezihlola ukusetshenziswa kwemithi yesikhathi eside), isampula ye-heterogeneity kanye nokungahlukanisi ababambiqhaza ngokusabela ekwelashweni.

I-Heterogeneity

Indlela yokwenza. Njengoba kushiwo ngenhla, umehluko (phakathi nangaphakathi kwezifundo) mayelana nokuthi yiziphi izindlela zokwelapha (kanye nezinhlanganisela) ababambiqhaza abazisebenzisayo futhi abazithathe ngaphambilini bazozibophezela ukwethula ukuhlukahluka kokutholwayo kocwaningo, ikakhulukazi ocwaningweni lwe-biomarker. Ngaphezu kwalokhu, ezinye izici eziningi zokuklama nesampula ziyahlukahluka kuzo zonke izifundo, ngaleyo ndlela kukhulisa ubunzima ngokuhumusha kanye nokubalula okutholakele. Lokhu kufaka phakathi amapharamitha wokulinganisa ama-biomarker (isb., amakhithi okuhlola) nezindlela zokuqoqa, ukugcina, ukucubungula nokuhlaziya omaka ekucindezelekeni. U-Hiles et al141 uhlole imithombo ethile yokungaguquki ezincwadini eziphathelene nokuvuvukala futhi wathola ukuthi ukunemba kokuxilongwa kokucindezeleka, i-BMI kanye nezifo ezithintekayo kwakubaluleke kakhulu ukulandisa ekuhloleni ukuvuvukala kwe-peripheral phakathi kwamaqembu acindezelekile nangenawo ukucindezeleka.

Umtholampilo. Ukuhlukahluka okubanzi kwabantu abacindezelekile kubhalwe kahle151 futhi kunegalelo elibalulekile ekutholeni umehluko phakathi kwezincwadi zocwaningo. Kungenzeka ukuthi nangaphakathi kokuxilongwa, amaphrofayili e-biologic angajwayelekile avalelwe kumasethi amancane abantu okungenzeka angazinzi ngokuhamba kwesikhathi. Izigaba ezincane ezihlangene zabantu abacindezelekile zingabonakala ngenhlanganisela yezinto ezingokwengqondo nezamabhayoloji. Ngezansi, siveza amandla okuhlola amaqembu amancane ukuze ahlangabezane nezinselele ezibangelwa ukuhlukahluka kwe-biomarker kanye ne-heterogeneity.

Izinhlobo ezingaphansi ngaphakathi kokucindezeleka

Kuze kube manje, awekho ama-subgroups angama-homogenous ngaphakathi kweziqephu zokucindezeleka noma ukuphazamiseka okuye kwakwazi ukwethenjwa ukuhlukanisa phakathi kweziguli ngokusekelwe ezenzweni zezimpawu noma ukuphendula kokwelashwa.152 Ukuba khona kweqembu elincane lapho ukuguqulwa kwezinto eziphilayo kuvezwa khona kakhulu kungasiza ukuchaza ukungafani phakathi kwezifundo zangaphambilini kanye kungadala indlela eya ekwelashweni kwe-stratified. U-Kunugi et al153 bahlongoze isethi yezinhlobo ezincane ezine ezingaba khona ngokusekelwe endimeni yezinhlelo ezihlukahlukene ze-neurobiological ezibonisa izinhlobo ezincane ezifanele emtholampilo ekucindezelekeni: lezo ezine-hypercortisolism ezethula ukucindezeleka kwe-melancholic, noma i-hypocortisolism ebonisa i-atypical subtype, i-subset ehlobene ne-dopamine yeziguli ezingase itholakala ngokugqamile nge-anhedonia (futhi ingaphendula kahle, isb, i-aripiprazole) kanye ne-subtype yokuvuvukala ebonakala ngokuvuvuka okuphezulu. Izihloko eziningi ezigxile ekuvuvukeni ziye zacacisa icala lokuba khona �ukuvuvukala kwe-subtype� ngaphakathi kokucindezeleka.55,56,154,155 Izixhumanisi zomtholampilo zokuvuvukala okuphakeme azikanqunywa futhi imizamo embalwa eqondile yenziwe ukuze kutholwe ukuthi yibaphi ababambiqhaza abangase bahlanganise leli qembu. Kuye kwahlongozwa ukuthi abantu abanokucindezeleka okungavamile bangase babe namazinga aphezulu okuvuvukala kune-subtype ye-melancholic, i-156 okungenzeka ukuthi ayihambisani nokutholwe mayelana ne-axis ye-HPA ku-melancholic kanye ne-atypical subtypes yokucindezeleka. I-TRD37 noma ukucindezeleka okunezimpawu ezivelele ze-somatic157 nayo ifakwe njenge-subtype engase ibe nokuvuvukala, kodwa i-neurovegetative (ukulala, isifiso sokudla, ukulahlekelwa yi-libido), isimo sengqondo (okuhlanganisa isimo sengqondo esiphansi, ukuzibulala nokucasuka) kanye nezimpawu zokuqonda (kuhlanganise nokuchema nomuzwa wecala)158 konke avele ahlobene namaphrofayili e-biologic. Abanye abangase bangenele ukhetho lwe-subtype evuthayo bahilela ulwazi lwezimpawu zokuziphatha okugula159,160 noma isifo se-metabolic.158

Ukuthambekela kwe-(hypo) mania kungase kuhlukanise ngokwebhayoloji phakathi kweziguli ezicindezelekile. Ubufakazi manje bubonisa ukuthi ukugula okuguquguqukayo kuyiqembu eliningi lezinkinga zemizwelo, nge-bipolar subsyndromal disorder etholakala kakhulu kunalokho okwakuqashelwe ngaphambili. isilinganiso sesikhathi sokulungisa ukuxilongwa ngokuvamile sidlula iminyaka eyishumi161 futhi lokhu kubambezeleka kubangela ubunzima obukhulu kanye nezindleko zokugula okuphelele.162 Njengoba iningi leziguli ezine-bipolar disorder ezethula ekuqaleni ngesiqephu sokucindezeleka esisodwa noma ngaphezulu kanye nokucindezeleka kwe-unipolar kuwukuxilonga okuvame kakhulu, ukuhlonza izici ezingase zihlukanise phakathi kokucindezeleka kwe-unipolar kanye ne-bipolar kunethonya elikhulu.163 Izinkinga ze-bipolar spectrum cishe azizange zibonwe ekuphenyweni kwangaphambili kwe-MDD biomarker, futhi ukushaywa kobufakazi kubonise ukuhlukaniswa komsebenzi we-HPA axis164 noma ukuvuvukala109 phakathi kwe-bipolar ne-unipolar depr. ession. Kodwa-ke, lezi ziqhathaniso ziyindlala, zinamasampula amasayizi amancane, imiphumela yethrendi ekhonjiwe engabalulekile noma inani labantu elibuthiwe elingazange libonakale kahle ngokuxilongwa. Lolu phenyo futhi aluyihloli indima yokusabela ekwelashweni kulobu budlelwano.

Kokubili ukuphazamiseka kwe-bipolar167 kanye nokumelana nokwelashwa168 akuzona izakhiwo ze-dichotomous futhi zilala ku-continua, okwandisa inselele yokuhlonza uhlobo oluncane. Ngaphandle kwe-subtyping, kufanele kuphawulwe ukuthi izinto eziningi ezingavamile ze-biologic ezibonwa ekucindezelekeni zitholakala ngokufanayo ezigulini ezinokunye ukuxilonga. Ngakho-ke, ukuhlolwa kwe-transdiagnostic nakho kungase kubaluleke.

Izinselelo Zokulinganisa Ze-Biomarker

Ukukhetha i-Biomarker. Inani elikhulu lama-biomarker angaba wusizo liletha inselele ku-psychobiology ekunqumeni ukuthi yibaphi omaka abathintekayo ngayiphi indlela futhi ngobani. Ukwandisa inselele, abambalwa balaba bama-biomarker baye baba ngaphansi kophenyo olwanele ekucindezelekeni, futhi kwabaningi, izindima zabo ezinembile kubantu abanempilo kanye nezokwelapha aziqondi kahle. Ngaphandle kwalokhu, kuye kwenziwa imizamo eminingi yokuphakamisa amaphaneli e-biomarker athembisayo. Ngaphezu kwamaqoqo omaka be-Brand et al angu-16 anamandla anamandla, i-27 i-Lopresti et al iveza isethi eyengeziwe ebanzi yomaka wokucindezeleka kwe-oxidative enamandla okuthuthukisa impendulo yokwelashwa. amasistimu e-biologic (i-BDNF, i-cortisol, i-TNF encibilikayo? uhlobo lwe-receptor II, i-alpha28 antitrypsin, i-apolipoprotein CIII, i-epidermal growth factor, i-myeloperoxidase, i-prolactin ne-resissin) ekuqinisekiseni nasekuphindaphindeni amasampula nge-MDD. Uma isihlanganisiwe, isilinganiso esiyinhlanganisela salawa mazinga sikwazile ukuhlukanisa phakathi kwe-MDD namaqembu okulawula anemba angu-1%�80%.90 Siphakamisa ukuthi nalawa awabafaki bonke abantu abangase bakwazi ukungena kulo mkhakha; bona Ithebula lesi-169 ukuze uthole inchazelo engaphelele yama-biomarker anamandla okuba nokucindezeleka, aqukethe kokubili lawo anesisekelo sobufakazi nomaka benoveli abathembisayo.

Ubuchwepheshe. Ngenxa yentuthuko yezobuchwepheshe, manje sekungenzeka (empeleni, kulula) ukukala uhlu olukhulu lwama-biomarker ngesikhathi esisodwa ngezindleko eziphansi futhi nokuzwela okuphezulu kunalokho obekwenzeka ngaphambilini. Njengamanje, leli khono lokulinganisa izinhlanganisela eziningi lingaphambi kwekhono lethu lokuhlaziya nokuhumusha idatha ngokuphumelelayo,170 into ezoqhubeka nokukhuphuka kwama-biomarker ahlukahlukene kanye nomaka abasha njenge-metabolomics. Lokhu kubangelwa kakhulu ukuntula ukuqonda mayelana neqhaza elinembile kanye nobudlelwano phakathi komaka, kanye nokuqonda okunganele kokuthi izimpawu ezihlobene zihlotshaniswa kanjani namaleveli e-biologic ahlukene (isb., ufuzo, ukuloba, amaprotheni) ngaphakathi naphakathi kwabantu ngabanye. Idatha enkulu esebenzisa izindlela nezindinganiso zokuhlaziya izosiza ekubhekaneni nalokhu, futhi kuhlongozwa izindlela ezintsha; isibonelo esisodwa ukuthuthukiswa kwendlela yezibalo esekelwe ekuhlaziyweni okusekelwe ekuguquguqukeni ukuze kutholwe izimpawu ezintsha ezingase zibe khona ezisekelwe ekuphenduleni kwazo phakathi kwamanethiwekhi futhi zihlanganise ukuveza izakhi zofuzo nedatha ye-metabolite.171 Amasu okufunda omshini asesetshenziswa futhi azosiza ngamamodeli asebenzisa i-biomarker. idatha yokubikezela imiphumela yokwelashwa ezifundweni ezinedatha enkulu.172

Ukuhlanganisa ama-biomarker. Ukuhlola uhlu lwama-biomarker ngesikhathi esisodwa kungenye indlela yokuhlola omaka abangabodwa abanganikeza umbono onembe kakhudlwana kuwebhu eyinkimbinkimbi yezinhlelo ze-biologic noma amanethiwekhi. kanye nokusebenzisana kuqondwa kahle), idatha ye-biomarker ingase ihlanganiswe noma ifakwe kunkomba. Enye inselele isekuboneni indlela ephelele yokwenza lokhu, futhi kungase kudinge ukuthuthukiswa kwezobuchwepheshe kanye/noma amasu okuhlaziya anoveli (bona isigaba �Idatha Enkulu�). Ngokomlando, ukulinganisa phakathi kwama-biomarker amabili ahlukene kuye kwaveza okuthakazelisayo okutholakele.26 Imizamo embalwa yenziwe yokuhlanganisa idatha ye-biomarker ngesilinganiso esikhulu, njengalabo abasebenzisa ukuhlaziya kwengxenye eyinhloko yamanethiwekhi e-proinflammatory cytokine.109,173 Ekuhlaziyweni kwe-meta, ama-cytokines a-proinflammatory abe iguqulelwe kusayizi womphumela owodwa wocwaningo ngalunye, futhi isiyonke yabonisa ukuvuvukala okuphezulu kakhulu ngaphambi kokwelashwa kwe-antidepressant, ibikezela ukungaphenduli okulandelayo ezifundweni zeziguli ezingalaliswa. Amaphaneli e-biomarker ahlanganisiwe kokubili kuyinselele kanye nethuba locwaningo lwesikhathi esizayo ukuze kutholakale imiphumela enengqondo nethembekile engasetshenziswa ukuze kuthuthukiswe imiphumela yokwelashwa.174 Ucwaningo olwenziwa nguPapakostas et al lwathatha enye indlela, ukukhetha iphaneli lama-biomarker e-serum e-heterogeneous (yokuvuvukala, I-axis ye-HPA kanye nezinhlelo ze-metabolic) eziye zaboniswa ukuthi zihluke phakathi kwabantu abacindezelekile nokulawula abantu ocwaningweni lwangaphambilini futhi zahlanganisa lezi zibe yinani lengozi elihluke kumasampula amabili azimele kanye neqembu lokulawula elinoku> 43% ukuzwela nokucacisa.80

Idatha enkulu. Ukusetshenziswa kwedatha enkulu cishe kuyadingeka ukuze kubhekwane nezinselele zamanje ezivezwe ukuhlukahluka kwe-heterogeneity, ukuhlukahluka kwe-biomarker, ukuhlonza izimpawu ezifanele nokuletha inkundla ekuhumusheni, ucwaningo olusetshenziswayo ekucindezelekeni. Nokho, njengoba kushiwo ngenhla, lokhu kuletha izinselele zobuchwepheshe nezesayensi.175 Isayensi yezempilo isanda kuqala ukusebenzisa ukuhlaziya idatha enkulu, eminyakeni eyishumi noma ngaphezulu kamuva kunomkhakha webhizinisi. Nokho, izifundo ezifana ne-iSPOT-D152 kanye ne-consortia ezifana ne-Psychiatric Genetics Consortium176 ziyaqhubeka nokuqonda kwethu izindlela ze-biologic kudokotela wengqondo. Ama-algorithms okufunda ngomshini, ezifundweni ezimbalwa kakhulu, aqale ukusetshenziswa kuma-biomarker wokucindezeleka: uphenyo lwakamuva luhlanganise idatha kusuka> kubahlanganyeli be-5,000 be-biomarker be-250; ngemva kokufakwa okuningi kwedatha, ukuhlehla okuthuthukisiwe kokufunda ngomshini kwenziwa, okubonisa ama-biomarker angaba ngu-21 angaba khona. Ngemuva kokuhlaziywa okwengeziwe kokuhlehla, ama-biomarker amathathu akhethiwe njengezihlotshaniswa kakhulu nezimpawu zokucindezeleka (usayizi wamangqamuzana abomvu egazi aguquguquka kakhulu, i-serum glucose kanye namazinga e-bilirubin). Ababhali baphetha ngokuthi idatha enkulu ingasetshenziswa ngokuphumelelayo ekukhiqizeni imibono.177 Amaphrojekthi amakhulu we-biomarker phenotyping manje ayaqhubeka futhi azosiza ukuqhubekisela phambili uhambo lwethu esikhathini esizayo se-neurobiology yokucindezeleka.

Amathemba Esizayo

I-Biomarker Panel Identification

Okutholwe emibhalweni kuze kube manje kudinga ukuphindaphinda ezifundweni ezinkulu. Lokhu kuyiqiniso ikakhulukazi kuma-biomarker anoveli, njenge-chemokine thymus kanye ne-activation-regulated chemokine kanye nesici sokukhula i-tyrosine kinase 2, ngokwazi kwethu, okungaphenywanga kumasampuli okulawula acindezelekile futhi anempilo. Ucwaningo lwedatha enkulu kufanele luhlole amaphaneli ama-biomarker abanzi futhi lusebenzise amasu okuhlaziya asezingeni eliphezulu ukuze kuqinisekiswe ngokugcwele ubudlelwano phakathi komaka nalezo zici ezibashintshayo kuzibalo zomtholampilo nezingekho emtholampilo. Ukwengeza, ukuphindaphinda kwesilinganiso esikhulu sokuhlaziywa kwengxenye eyinhloko kungase kusungule amaqembu ahlotshaniswa kakhulu ama-biomarker futhi kungase kwazise ukusetshenziswa �okuhlanganisiwe� ku-biologic psychiatry, okungase kuthuthukise ukufana kokutholwe okuzayo.

Ukutholwa kwama-Homogenous Subtypes

Mayelana nokukhethwa kwe-biomarker, kungase kudingeke amaphaneli amaningi emikhondo engase ibe khona engase isetshenziswe ucwaningo. Sekuhlanganiswe ndawonye, ​​ubufakazi bamanje bukhombisa ukuthi amaphrofayili e-biomarker aqinisekisiwe, kepha aguqulwa ngokusobala eqoqweni elincane labantu abahlushwa ukudangala. Lokhu kungase kusungulwe ngaphakathi noma kuzo zonke izigaba zokuxilonga, okungase kubangele ukungqubuzana okuthile kokutholwe okungabonwa kulezi zincwadi. Ukulinganisa i-biologic subgroup (noma ama-subgroups) kungase kwenziwe ngempumelelo kakhulu ukuhlaziywa kweqoqo elikhulu lamaphaneli enethiwekhi ye-biomarker ekucindezelekeni. Lokhu kuzobonisa ukuhlukahluka kwamanani abantu; Ukuhlaziywa kwekilasi okucashile kungabonisa izici zomtholampilo ezihlukile ezisekelwe, isibonelo, ukuvuvukala.

Imithelela Eqondile Yokwelapha Ekuvuvukeni Nokusabela

Zonke izindlela zokwelapha ezivame ukushiwo zokudangala kufanele zihlolwe kabanzi ngemiphumela yazo ethile yebhayoloji, futhi kubalwe nempumelelo yokuhlolwa kokwelashwa. Lokhu kungase kunikeze amandla ukwakhiwa okuhlobene nama-biomarker kanye nezethulo zezimpawu ukubikezela imiphumela yezinhlobonhlobo zokwelashwa okudambisa ukucindezeleka ngendlela eqondene nawe, futhi kungenzeka kumongo wokudangala kwe-unipolar kanye ne-bipolar. Lokhu kungase kube usizo ekwelashweni okungaba khona okusha kanye nokwelashwa okubonisiwe njengamanje.

Ukunqunywa Okulindelwe Kwempendulo Yokwelashwa

Ukusetshenziswa kwamasu angenhla kungenzeka kuphumele ekhonweni elithuthukisiwe lokubikezela ukumelana nokwelashwa ngokuzayo. Izinyathelo eziyiqiniso neziqhubekayo (isb, zesikhathi eside) zempendulo yokwelashwa zingaba nomthelela kulokhu. Ukuhlolwa kwezinye izilinganiso ezivumelekile zempilo yesiguli (njengekhwalithi yempilo kanye nokusebenza kwansuku zonke) kunganikeza ukuhlolwa okuphelele komphumela wokwelashwa okungase kuhlotshaniswe eduze nama-biomarker. Nakuba umsebenzi we-biologic uwodwa ungase ungakwazi ukuhlukanisa abaphenduli bezokwelapha kwabangaphenduli, ukulinganisa okufanayo kwama-biomarker aneziguquguquko zengqondo yezenhlalo noma amanani abantu kungase kuhlanganiswe nolwazi lwe-biomarker ekwakheni imodeli yokubikezela yempendulo yokwelashwa enganele. Uma imodeli ethembekile ithuthukiswa ukuze ibikezele impendulo (kungaba ngesibalo sabantu abacindezelekile noma isibalo esincane sabantu) futhi iqinisekiswa ngokubheka emuva, idizayini yokuhumusha ingasungula ukusebenza kwayo esivivinyweni esikhulu esilawulwayo.

Ibheke Ukwelashwa Kwe-Stratified

Njengamanje, iziguli ezinokucindezeleka aziqondiswa ngendlela ehlelekile ukuze zithole uhlelo lokungenelela olulungiselelwe. Uma kuqinisekiswa, idizayini yesilingo esine-stratified ingase isetshenziswe ukuze kuhlolwe imodeli ukuze kubikezelwe ukungaphenduli kanye/noma kunqunywe lapho isiguli sidinga ukucutshungulwa khona kumodeli yokunakekelwa okunyanyisiwe. Lokhu kungaba usizo kuzo zombili izilungiselelo zokwelapha ezisezingeni kanye nezemvelo, kuzo zonke izinhlobo zokungenelela. Ekugcineni, imodeli esebenza kahle emtholampilo ingase ithuthukiswe ukuze inikeze abantu ukwelashwa okufanele kakhulu, ukuqaphela labo okungenzeka babe nokucindezeleka okungavumelani futhi banikeze ukunakekelwa okuthuthukisiwe nokuqapha kulezi ziguli. Iziguli ezihlonzwe njengezisengozini yokumelana nokwelashwa zingase zinqunywe ukwelapha okuhambisanayo nengokwengqondo ne-pharmacologic noma i-pharmacotherapy eyinhlanganisela. Njengesibonelo sokuqagela, ababambiqhaza abangenakho ukuphakama kwe-cytokine ye-proinflammatory bangase baboniswe ukuthi bathole ukwelashwa kwengqondo kunokwelashwa kwe-pharmacologic, kuyilapho i-subset yeziguli ezinokuvuvukala okuphezulu ikakhulukazi ingathola i-ejenti elwa nokuvuvukala ekwandiseni ukwelashwa okujwayelekile. Ngokufana ne-stratification, amasu okukhetha ukwelashwa angenzeka esikhathini esizayo. Isibonelo, umuntu othile ocindezelekile angase abe ne-TNF ephakeme ngokuphawulekayo? amazinga, kodwa azikho ezinye izinto ezingavamile ze-biologic, futhi ezingazuza ekwelashweni kwesikhashana nge-TNF? ophikisana naye.54 Ukwelashwa komuntu siqu kungase futhi kuhilele ukuqapha inkulumo ye-biomarker ngesikhathi sokwelashwa ukuze wazise izinguquko ezingaba khona zokungenela, ubude bokwelashwa okuqhubekayo okudingekayo noma ukuthola izimpawu zokuqala zokubuyela emuva.

Okuhlosiwe Okunoveli Kokwelapha

Kunenani elikhulu lemithi yokwelapha engase isebenze kahle ekucindezelekeni, engazange ihlolwe ngokwanele, okuhlanganisa nokungenelela okunoveli noma okuphinde kwahloswe okuvela kweminye imikhakha yezokwelapha. Okunye okuhlosiwe okuthandwa kakhulu kube yimithi elwa nokuvuvukala efana ne-celecoxib (kanye nezinye i-cyclooxygenase-2 inhibitors), i-TNF? abaphikisi i-etanercept ne-infliximab, i-minocycline noma i-aspirin. Lokhu kubonakala kuthembisa.178 I-Antiglucocorticoid compounds, kuhlanganise ne-ketoconazole179 kanye ne-metyrapone, i-180 iye yaphenywa ngenxa yokucindezeleka, kodwa bobabili banezinkinga ngephrofayili yabo yomphumela futhi amandla omtholampilo we-metyrapone awaqiniseki. I-Mifepristone181 kanye ne-corticosteroids fludrocortisone ne-spironolactone, i-182 ne-dexamethasone ne-hydrocortisone183 ingase isebenze ekwelapheni ukucindezeleka esikhathini esifushane. Ukuqondisa i-glutamate i-N-methyl-d-aspartate receptor antagonists, kuhlanganise ne-ketamine, ingase imele ukwelashwa okuphumelelayo ekucindezelekeni.184 I-Omega-3 polyunsaturated fatty acids ithonya umsebenzi wokuvuvukala kanye ne-metabolic futhi ibonakala ibonisa ukusebenza kahle kokucindezeleka.185 Kungenzeka ukuthi ama-statins angase babe nemiphumela yokudambisa186 ngokusebenzisa izindlela ezifanele ze-neurobiological.187

Ngale ndlela, imiphumela ye-biochemical ye-antidepressants (bona isigaba �Imithi�) isetshenziselwe izinzuzo zomtholampilo kwezinye iziyalo: ikakhulukazi izifo ze-gastroenterological, neurologic kanye nezimpawu ezingezona eziqondile.188 Imiphumela yokulwa nokuvuvukala kwama-antidepressants ingase imele ingxenye yendlela yokwenza lezi zinzuzo. I-lithium iphinde yaphakanyiswa ukuthi yehlise ukuvuvukala, ngokujulile ngokusebenzisa izindlela ze-glycogen synthase kinase-3 Ukugxila kule miphumela kungase kubonise ulwazi ngesiginesha ye-biomarker yokucindezeleka futhi, ngokulandelayo, izimpawu ze-biomarker zingamelela izimpawu zokuthatha izidakamizwa zenoveli.

Ukuqonda kukaDkt Alex Jimenez

Ukucindezeleka wukuphazamiseka kwengqondo okubonakala izimpawu ezinzima ezithinta imizwa, okuhlanganisa ukulahlekelwa isithakazelo emisebenzini. Ucwaningo lwakamuva, nokho, zithole ukuthi kungenzeka ukuxilonga ukucindezeleka usebenzisa okungaphezu nje kwezimpawu zokuziphatha zesiguli. Ngokwabacwaningi, ukuhlonza ama-biomarker atholakala kalula angaxilonga ngokunembe kakhudlwana ukucindezeleka kubalulekile ekuthuthukiseni impilo nempilo yesiguli iyonke. Ngokwesibonelo, okutholwe emitholampilo kusikisela ukuthi abantu abanenkinga enkulu yokucindezeleka, noma i-MDD, banamazinga aphansi e-molecule i-acetyl-L-carnitine, noma i-LAC, egazini labo kunokulawula okunempilo. Ekugcineni, ukusungula ama-biomarker okucindezeleka kungasiza kangcono ukunquma ukuthi ubani osengozini yokuba nalesi sifo futhi kusize ochwepheshe bezokunakekelwa kwempilo banqume indlela yokwelapha engcono kakhulu yesiguli esinokucindezeleka.

Isiphetho

Izincwadi zibonisa ukuthi cishe izingxenye ezimbili kwezintathu zeziguli ezinokucindezeleka azikutholi ukukhululeka ekwelashweni kokuqala nokuthi amathuba okungaphenduli ayanda ngenani lokwelashwa okuhloliwe. Ukuhlinzeka ngemithi engasebenzi kunemiphumela emikhulu ezindlekweni zomuntu ngamunye nezomphakathi, okuhlanganisa ukucindezeleka okuqhubekayo kanye nokuba nempilo embi, ingozi yokuzibulala, ukulahlekelwa umkhiqizo kanye nokumoshakala kwezinsiza zokunakekelwa kwezempilo. Izincwadi eziningi zokudangala zibonisa inani elikhulu lama-biomarker anamandla okuthuthukisa ukwelashwa kwabantu abanokucindezeleka. Ngaphezu kwezimpawu ze-neurotransmitter kanye ne-neuroendocrine ebezingaphansi kocwaningo olusabalele amashumi amaningi eminyaka, imininingwane yakamuva igqamisa ukusabela okuvuvukalayo (kanye namasosha omzimba ngokuvamile kakhulu), izici ze-metabolic kanye nokukhula njengokubaluleke kakhulu ekucindezelekeni. Kodwa-ke, ubufakazi obuhluke kakhulu bubonisa ukuthi kunenqwaba yezinselelo okudingeka zixazululwe ngaphambi kokuthi kusetshenziswe ucwaningo lwe-biomarker ukuze kuthuthukiswe ukuphathwa nokunakekelwa kwabantu abanokucindezeleka. Ngenxa yobunkimbinkimbi bezinhlelo ze-biologic, ukuhlolwa ngasikhathi sinye kohlu olubanzi lomaka kumasampuli amakhulu kunenzuzo enkulu ekutholeni ukusebenzisana phakathi kwezimo ze-biologic nezengqondo kubo bonke abantu. Ukuthuthukisa ukukalwa kwayo yomibili imingcele ye-neurobiological kanye nezinyathelo zomtholampilo zokucindezeleka cishe kwenza kube lula ukuqonda. Lokhu kubuyekezwa kuphinde kuqokomise ukubaluleka kokuhlola izici ezingase ziguqule (njengokugula, ubudala, ukuqonda kanye nemithi) ekutholeni ukuqonda okuhambisanayo kwebhayoloji yokucindezeleka nezindlela zokumelana nokwelashwa. Kungenzeka ukuthi abanye omaka bazobonisa isithembiso esikhulu sokubikezela ukusabela kokwelashwa noma ukumelana nokwelashwa okuthile eqenjini elincane leziguli, futhi ukukalwa ngasikhathi sinye kwedatha yebhayoloji neyengqondo kungase kuthuthukise ikhono lokuhlonza labo abasengozini yokuthola imiphumela emibi yokwelashwa. Ukusungula iphaneli ye-biomarker kunemithelela yokuthuthukisa ukunemba kokuxilonga kanye nokubikezela, kanye nokwenza ukwelashwa komuntu ngamunye esigabeni sokuqala esingenzeka sesifo sokucindezeleka kanye nokuthuthukisa okuhlosiwe kokwelashwa okuphumelelayo. Le miphumela ingase iphelele emaqenjini amancane eziguli ezicindezelekile. Izindlela eziya kulawa mathuba zihambisana namasu okucwaninga akamuva okuxhumanisa ama-syndromes omtholampilo eduze kakhulu nama-substrates angaphansi kwe-neurobiological.6 Ngaphandle kokunciphisa ukuhlukahluka, lokhu kungase kusize ukushintshela ekulinganeni kokuhlonishwa phakathi nempilo engokomzimba neyengqondo. Kuyacaca ukuthi nakuba umsebenzi omningi udingeka, ukusungulwa kobudlelwane phakathi kwezimpawu zezinto eziphilayo ezifanele kanye neziyaluyalu zokucindezeleka kunemithelela emikhulu yokunciphisa umthwalo wokucindezeleka ezingeni lomuntu ngamunye kanye nelomphakathi.

Ukuvuma

Lo mbiko umele ucwaningo oluzimele oluxhaswe yiNational Institute for Health Research (NIHR) Biomedical Research Center eSouth London kanye neMaudsley NHS Foundation Trust kanye neKing's College London. Imibono eveziwe ingeyababhali futhi hhayi leyo ye-NHS, i-NIHR noma yoMnyango Wezempilo.

Imibhalo yaphansi

Ukudalula. U-AHY uneminyaka engu-3 edlule wathola i-honoraria ngokukhuluma kusuka ku-Astra Zeneca (AZ), uLundbeck, u-Eli Lilly, u-Sunovion; i-honaria ngokubonisana no-Allergan, uLivanova noLundbeck, uSunovion, uJanssen; kanye nokwesekwa kwesibonelelo socwaningo esivela ku-Janssen kanye nezinhlangano ezixhasa ngezimali zase-UK (NIHR, MRC, Wellcome Trust). I-AJC eminyakeni engu-3 edlule ithole ukuhlonishwa ngokukhuluma okuvela kwa-Astra Zeneca (AZ), ukuhlonishwa ngokubonisana no-Allergan, uLivanova noLundbeck, kanye nokwesekwa kwesibonelelo socwaningo esivela e-Lundbeck kanye nezinhlangano ezixhasa ngemali zase-UK (NIHR, MRC, Wellcome Trust).

Ababhali ababiki okunye ukungqubuzana kwezintshisekelo kulo msebenzi.

Ekuphetheni,�Nakuba ucwaningo oluningi seluthole amakhulukhulu ama-biomarker okucindezeleka, ababaningi abaye basungula indima yabo ekuguleni okucindezelekayo noma ukuthi ulwazi lwe-biologic lungasetshenziswa kanjani ukuthuthukisa ukuxilongwa, ukwelashwa kanye nokubikezela. Kodwa-ke, i-athikili engenhla ibuyekeza izincwadi ezitholakalayo kuma-biomarker abandakanyekayo phakathi kwezinye izinqubo futhi iqhathanisa okutholwe emitholampilo nalokho okudangele. Ngaphezu kwalokho, okutholakele okusha kuma-biomarker wokucindezeleka kungasiza ukuxilonga kangcono ukudangala ukuze kulandele ukwelashwa okungcono. Ulwazi olubhekiselwe ku-National Center for Biotechnology Information (NCBI).�Ububanzi bolwazi lwethu bukhawulelwe ku-chiropractic kanye nokulimala komgogodla nezimo. Ukuze uxoxe ngesihloko, sicela ukhululeke ukubuza uDkt. Jimenez noma usithinte kokuthi�915-850-0900 .

Ikhethwe nguDkt Alex Jimenez

Izihloko Ezengeziwe: Ubuhlungu Emuva

Ukuhlungu obusemhlane ingenye yezimbangela ezivame kakhulu zokukhubazeka nokuphuthelwa izinsuku emsebenzini emhlabeni wonke. Eqinisweni, ubuhlungu beqolo buye babhekwa njengesizathu sesibili esivame kakhulu sokuvakashelwa kwehhovisi likadokotela, okudlula kuphela izifo eziphezulu zokuphefumula. Cishe amaphesenti angu-80 abantu azothola uhlobo oluthile lobuhlungu emuva okungenani kanye kukho konke ukuphila kwabo. Umgogodla uyisakhiwo esiyinkimbinkimbi esakhiwe ngamathambo, amalunga, imigqa kanye nemisipha, phakathi kwezinye izicubu ezithambile. Ngenxa yalokhu, ukulimala kanye/noma izimo ezimbi, njengokuthi i-discni herniated, ekugcineni kungaholela ezimpawu zobuhlungu beqolo. Ukulimala kwezemidlalo noma ukulimala kwengozi yemoto ngokuvamile kuyimbangela evame kakhulu yobuhlungu beqolo, noma kunjalo, ngezinye izikhathi ukunyakaza okulula kakhulu kungaba nemiphumela ebuhlungu. Ngenhlanhla, ezinye izindlela zokwelapha, njengokunakekelwa kwe-chiropractic, zingasiza ekudambiseni izinhlungu emuva ngokusebenzisa ukulungiswa komgogodla kanye nokuphathwa ngesandla, ekugcineni kuthuthukise ukukhululeka kobuhlungu.

ISIHLOKO ESIBALULEKILE ENGEZIWE: Ukulawulwa Kobuhlungu Beqolo

IZIHLOKO EZINYE IZIHLOKO: EZENGEZIWEYO:�Ubuhlungu obungapheli kanye nokwelashwa