【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。
  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。
  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。
  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。
  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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