洪成志 台北榮民總醫院 精神部 行為與基因實驗室 憂鬱症的分子病理 洪成志 台北榮民總醫院 精神部 行為與基因實驗室

生活壓力事件統計-量表 Brugha & Cragg:Acta Psychiatr Scand. 1990 您覺得下列之十二項生活事件，哪項與您的心情持續不好有關，請於您覺得有相關的事件的『□』內打『ˇ』，並於後方勾選發生時間 生活事件 發生時間 1.□ 經歷一場嚴重的生病、受傷或是受到重大的攻擊 □一個月前 □三個月前 □半年前 □一年前 □一年以上 2.□ 親近的親屬或很在意的人經歷一場嚴重的事故 3.□ 父母、小孩或是配偶死亡 4.□ 親近的家族朋友或其他親屬（阿姨、表兄弟姊妹、爺爺奶奶）死亡 5.□ 因為婚姻問題而需面對分離 6.□ 在一段穩定的情感上產生不好的變化 7.□ 你與親密的朋友、鄰居或親屬間有相處上的衝突 8.□ 失業或是找工作不成功一個月以上 9.□ 被解雇 10.□ 有嚴重的財務危機 11.□ 遇到官司糾紛問題 12.□ 重要物品遺失或被偷 您何時開始覺得自己的心情一直都很不好的呢？ Brugha & Cragg:Acta Psychiatr Scand. 1990

生活壓力事件統計 評分方式：全部共12個壓力事件，由病人勾選，每一個一分，但若壓力事件發生在發病之後，便不算分。 於98年2月-98年4月間，總收案數：84人 生活壓力得分 人數 百分比 51 60.7% 1 29 34.5% 2 4 4.8% 合計 84 100% 無重大壓力事件者佔較高比率 有壓力 較多個案具有之重大壓力，前三名： 1.在一段穩定的情感上產生不好的變化 2.父母、小孩或是配偶死亡 3.你與親密的朋友、鄰居或親屬間有相處上的衝突 沒壓力

Helplessness Training & Escape Test Video Video PsyLab 2002/04/04

Rats after Inescapable stress Antidepressant treatment BDNF infusion Escape tests

Rat in learned helplessness paradigm Rats after inescapable stress show longer latency in escape tests. The results are expressed as mean ± 1SD. ★ is p <0.001 (one way ANOVA and post hoc test with Scheffe’s test).

Simple T-maze

Mood與monoamines有關的證據 長期使用治療高血壓的reserpine之後會產生憂鬱的症狀 有些人則在服用治療肺結核的iproniazid後變得欣快 imipramine竟然對憂鬱症的病人有明顯的改善 A. Reserpine會掏空神經突觸的monoamine, 使突觸的monoamine減少 B. Iproniazid會抑制神經末梢的monoamine oxidase，使monoamine不容易被代謝掉, 使突觸的monoamine增加 C. Imipramine會抑制norepinephrine與serotonin的回收，使突觸的monoamine濃度上升

Milestones of Psychiatry Schizophrenia Depression 1950‘s chlorpromazine imipramine 1980‘s clozapine fluoxetine Hong CJ, Dec 1999

Antidepressant Utilization in Medicaid (USA), 1995-1998

Number of DDDs per 1000 population (aged 15+) per day in Scotland 10 DDDs/1000 population/day corresponds to a daily use of the drug by 1% of the population. Source: Information Services Division, Healthcare Information Group

What’s the mechanism of antidepressants

Axelrod's Nobel Prize (1970) Julius Axelrod investigated the presence of catecholamines in neurons and the phenomenon of release and reuptake. He discovers reuptake action in neurotransmitter norepinephrine in 1958-61. This research explained the mode of action of imipramine at a molecular level within the synaptic cleft. together with Katz and von Euler, he received the 1970 Nobel Prize for this work.

Lesch KP: Science. 1996

The effect of life events on depression was stronger among s carriers (b = 0.39, SE = 0.07, t = 5.23, P < 0.001 among s/s homozygotes, and b = 0.17, SE = 0.04, t = 4.51, P < 0.001 among s/l heterozygotes) than among l/l homozygotes (b = 0.14, SE = 0.05, t = 2.69, P < 0.01). Science 2003 July

Model of 5-HT1A Autoreceptor Effects on the Serotonergic Raphe Neuron 2010 Jan

No Change in Anxiety-like Behavior, but Altered Response in Stress/ Depression-Related Tests in 1A-Low Mice Neuron 2010 Jan

Increased Serotonin Levels in Response to Fluoxetine in 1A-Low Mice Robust Response to Fluoxetine Treatment in the NSF(Novelty Supressed Feeding) Test in 1A-Low, but Not 1A-High, Mice Neuron 2010 Jan

The molecular mechanism of long-term antidepressant treatments Duman: July 1997 Arch Gen Psychiatry

Stress Decreases and Antidepressant Treatments Increase the Expression of Brain-derived Neurotrophic Factor in the Hippocampus Stress : restrain stress (90 mins) Fluoxetine : administration 21 days BDNF mRNA were determined by in situ hybridization Duman et al.,1997

Rats after Inescapable stress Antidepressant BDNF infusion treatment Escape test J Neuroscience 2002;22:3251–61

Result DG J Neuroscience 2002;22:3251–61

Inhibition of tyrosine kinase (by K252a) or MEK (by U0126) blocks the antidepressant effect of BDNF J Neuroscience 2002;22:3251

The molecular mechanism of long-term antidepressant treatments Duman: July 1997 Arch Gen Psychiatry

Abnormal Distribution of met BDNF in Dendrites of Hippocampal Neurons in Cell Body of Hippocampal Neurons Egan: Cell 2003 26

Scince 2006

Anxiety-related behavior in BDNF Met/Met mice Chen: Science 2006

Neurogenesis-Neuroplasticity Hypothesis Monoamine Theory Neurotrophic Hypothesis Neurogenesis-Neuroplasticity Hypothesis

Chronic fluoxetine treatment increases BrdU uptake and neurogenesis in the dentate gyrus of mice Confocal micrograph of cell double-labeled for BrdU and NeuN or GFAP NeuN : neuron-specific nuclear protein GFAP : glial fibrillary acidic protein Science 2003;301:805-9 BrdU is incorporated into DNA in place of thymidine then injected into the brain (CSF). BrdU-positive indicates synthesis of DNA and a generation of new cells.

fluoxetine ? neurogenic effects ? Anti-depression effects

novelty-suppressed feeding test (NSF) H= haloperidol D= desipramine I= imipramine F= fluoxetine novelty-suppressed feeding test (NSF) Science 2003;301:805-9

SGZ= subgranular zone SVZ= subventricular zone S= sham X= X-ray V= vehicle F= fluoxetine I= imipramine

Neurogenesis-Neuroplasticity Hypothesis Stress Genetic Environmental Non-monoamine Monoamine Theory Neurotrophic Hypothesis Neurogenesis-Neuroplasticity Hypothesis

Other factors related to depression Deep brain stimulation applied to the white matter tracts surrounding Cg25 produced a sustained remission of depressive symptoms in a small cohort of treatment-resistant patients Exercise can induce neurogenesis and improve depression Electroconvulsive therapy, lithium, atypical antipsychotics are effective for depression treatment ………