基因突變與憂鬱症病患自殺風險上升有關


  【24drs.com】February 2, 2010 — 根據線上發表於2月1日一般精神醫學誌的研究結果,神經營養素受體解碼基因NTRK2與罹患憂鬱症病患自殺風險上升有關。
  
  自殺者的神經營養訊息傳遞是下降的,但這是第一項確認可能造成不常正常神經生長訊息傳遞基因變異的研究。
  
  資深作者,德國慕尼黑Max Planck精神學機構的Elisabeth B. Binder醫師向Medscape精神學表示,來自自殺者屍體解剖研究的發現強烈支持神經營養訊息傳遞下降。這顯示神經營養訊息傳遞,在完成訊息傳遞後不僅降低,且這個途徑的障礙可能真的使病患在憂鬱時自殺。
  
  根據Binder醫師表示,這些發現協助我們發展自殺的基因預測因子,且可以讓臨床醫師們針對有這些基因型的病患們提供更密集的治療與預防性措施。
  
  Binder醫師表示,我們對於歐洲與非洲美裔人種以及使用不同設計收納的受試者身上,相關基因變異可以預測自殺企圖感到最驚訝。對我們來說,這代表這項發現的強度。
  
  她附帶表示,其次,我們對於這個關聯在憂鬱症病患、以及與憂鬱無關的自殺企圖有特定相關感到驚訝。對我們而言,這支持了基因風險對自殺與發生憂鬱的風險是不同的說法。
  
  【降低抗壓能力】
  解剖後腦研究發現,罹患憂鬱症的自殺者前額皮質與海馬迴來自腦部的神經營養因子(BNDF)與NTRK2訊息RNA及蛋白表現降低。自殺受試者的其他神經營養因子表現同樣下降,代表不足的神經營養訊息傳遞可能已經降低自殺個體的突觸可塑性。
  
  研究者們針對394位憂鬱病患進行基因變異的研究,包括113位企圖自殺以及366位健康控制受試者。該試驗作者接著在744位罹患重鬱症的德國病患(其中152位企圖自殺)以及921位非至精神診所就診的非裔美國病患(其中119位企圖自殺)進行研究。
  
  他們檢驗兩個與神經營養系統有關基因的單一核苷酸多型性,那些基因解碼出BDNF,與其高親和力受體NTRK2。
  
  分析發現,有自殺企圖病史受試者,這5種SNP顯然更為常見。
  
  除此之外,帶有三種以上顯著標記的受試者,相較於沒有這些突變的受試者,企圖自殺的風險高了4.5倍。
  
  研究作者們寫到,我們的研究結果發現,合併NTRK2核的幾個獨立風險基因列與憂鬱症的SA(自殺企圖)有關,進一步支持了神經營養蛋白在自殺病理生理學上的角色。
  
  他們表示,基因關聯與自殺企圖之間的事實,當比較有自殺企圖與沒有自殺企圖的憂鬱病患,相較於健康控制組受試者是更強烈的,且這些SNPs並未與重鬱症有關代表這些關連性對自殺企圖是具專一性的。
  
  研究者們的結論是,這些發現支持了精神疾病、社會經濟因子、以及其他環境因子增加了對自殺行為的基因感受性。
  
  【神經保護劑可以預防自殺?】
  在評論這些研究發現時,來自賓州匹茲堡精神機構與診所的David Brent醫師,他研究自殺行為的家族遺傳,他說這項研究突顯了神經營養因子在自殺行為生成上的重要性,也確認了解剖後基因表現研究是一開始找出潛在候選基因的一個好方法。
  
  根據Brent醫師表示,給未來臨床研究重要的意義包括是否可能發展出神經保護劑來預防自殺,以及是否可能測量「神經保護」的變化、以及其與自殺風險變化的相關性。
  
  密蘇里州聖路易士華盛頓大學醫學院Anne Glowinski醫師,他研究自殺與併存疾病的基因及環境因素,他附帶提醒。
  
  Glowinski醫師表示,不論這篇文獻有多偉大,仍然有許多令人激動的偽陽性基因弱點發現。於兩個不同種族組別重複這些發現是對好的,但是這些發現仍將需要在其他樣本下重複檢驗。目前為止,當重複進行這些研究時,結果通常是令人失望的。
  
  這項研究由Max Planck學會Exzellenz-Stiftung經費贊助,以及由來自國家基因體研究網絡,德國聯邦教育與研究署的經費贊助。Binder醫師接受輝瑞藥廠的研究經費贊助。Brent醫師與Glowinski醫師表示已無相關資金上的往來。

Genetic Mutations Associated With Increased Suicide Risk in Patients With Depression

By Janis C. Kelly
Medscape Medical News

February 2, 2010 — Single mutations in the neurotrophin receptor–encoding gene NTRK2 are associated with up to a 4-fold increased risk for suicide in patients with depression, according to research published online February 1 in the Archives of General Psychiatry.

Neurotrophic signaling is downregulated in suicide victims, but this is the first study to identify genetic variants that might cause abnormal nerve growth signaling.

"This is a strong support for the findings of decreased neurotrophic signaling from postmortem studies in suicide victims. It shows that neurotrophic signaling is not only decreased after completed signaling but that disturbances in this pathway may actually predispose [patients] to attempt suicide when depressed," senior author Elisabeth B. Binder, MD, PhD, of the Max Planck Institute of Psychiatry in Munich, Germany, told Medscape Psychiatry.

According to Dr. Binder, these findings help to develop genetic predictors of suicidality and could permit clinicians to target more intense therapeutic and preventive measures in patients with these genotypes.

"We were most surprised that the associated variants did predict suicide attempt in Europeans and African Americans and in subjects recruited using a different design. For us, this is an indication of the strength of the finding," said Dr. Binder.

"Second, we were surprised that associations were specific to suicide attempt within depressed patients and were not associated with depression per se. For us, this is further support that the genetic risk for attempting suicide is different from the risk to develop depression," she added.

Reduced Ability to Cope With Stress

Postmortem brain studies have found reduced brain-derived neurotrophic factor (BDNF) and NTRK2 messenger RNA and protein expression in the prefrontal cortex and hippocampus of suicide victims with comorbid depression. Suicidal subjects also showed reduced expression of other neurotrophic factors, suggesting that insufficient neurotrophic signaling might have reduced synaptic plasticity in suicidal subjects.

The researchers investigated genetic variants among 394 depressed patients, including 113 who had attempted suicide, and 366 healthy controls. The study authors then replicated their results in 744 German patients with major depressive disorder (152 of whom had attempted suicide) and in 921 African American nonpsychiatric clinic patients (119 of whom had attempted suicide).

They examined single-nucleotide polymorphisms (SNPs) in 2 genes associated with the neurotrophic system, those coding for BDNF and for its high-affinity receptor NTRK2.

The analysis revealed 5 SNPs that were significantly more common among individuals with a history of suicide attempts.

Furthermore, subjects who carried the 3 most significant markers had a 4.5-fold higher risk of attempting suicide than those who carried none of the 3 mutations.

"Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA [suicide attempt] in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide," the study authors write.

"The fact that the genetic associations with suicide attempts were stronger when comparing depressed patients with suicide attempts vs depressed patients without suicide attempts than with healthy control subjects and that these SNPs were not associated with major depressive disorder suggest that these associations are specific to suicide attempts," they note.

The investigators conclude that these findings support the hypothesis that psychiatric disease, social risk factors, and other environmental risk factors add to genetic susceptibility to suicidal behavior.

Could Neuroprotectants Prevent Suicide?

Commenting on the findings, David Brent, MD, from the Psychiatric Institute & Clinic in Pittsburgh, Pennsylvania, who has studied familial transmission of suicidal behavior, said the study highlights the importance of neurotrophic factors in the genesis of suicidal behavior. It also confirms that postmortem gene expression studies are a good way of initially identifying potential candidate genes.

According to Dr. Brent, important implications for future clinical research include whether it might be possible to develop neuroprotective agents to prevent suicide and whether it would be possible to measure changes in "neuroprotection" and correlate that with changes in suicide risk.

Anne Glowinski, MD, Washington University School of Medicine in St. Louis, Missouri, who has studied genetic and environmental factors in suicide and comorbidities, added a note of caution.

"Regardless of how great this paper is, there have been many exciting false-positive genetic vulnerability findings. Replication of findings in 2 distinct ethnic groups is good, but the findings will still need replication in other samples. So far, results are often discouraging when that happens," Dr. Glowinski said.

The study was supported by a grant from the Exzellenz-Stiftung of the Max Planck Society and by a grant from the National Genome Research Network, German Federal Ministry of Education and Research. Dr. Binder has received grant support from Pfizer Pharmaceuticals. Dr. Brent and Dr. Glowinski have disclosed no relevant financial relationships.

Arch Gen Psychiatry. Published online February 1, 2010.

    
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