老年憂鬱症與疼痛 精神科主治醫師 游佩琳

人類的心理需求 Erik Erickson將人們的心理發展隨著生命階段做以下區分 嬰兒期---信賴 vs 不信任

老年人的心理需求 中年期---生產力 vs 困頓 主要的關係建立在親子, 社會. 主要的議題是貢獻, 幫助與投入 主要的關係建立在社會, 生命與世界觀. 主要的議題是人生的意義與價值, 生命的成就

老年人容易得憂鬱症嗎? Geriatric Depression In late life First episode >= 50 y/o < 50 y/o 早發病 晚發病

憂鬱症有多恐怖? 終生盛行率： 5-11% 美國每年有一千萬到一千五百萬人 症狀可以長達數年 單次發作後 有 50 % 以上的復發率、多次發作後 復發率更高 嚴重性與心絞痛和冠狀動脈疾病相當 若未治療，則有高自殺身亡率

有多少老年人得憂鬱症? 醫院看門診民眾 20% -24% 憂鬱症狀 10%重度憂鬱 安養院 30% -75% 憂鬱症狀 20% 確診憂鬱症 社區居民 (一般民眾) 重度憂鬱: 1.8% (並不比年輕人多) 輕度憂鬱: 9.8% 憂鬱傾向: 13.5% Beekman et al, BJP 1999

憂鬱傾向(Subsyndromal Depression) Taiwan data: 輕度憂鬱 8.8%, 常見的症狀是心情低落(98.3%), 缺乏活力 (92.4%), 動作反應遲緩 (85.7%) 睡眠障礙 (81.5%). 造成明顯的社會功能喪失 合併其他憂鬱焦慮, 生理疾病, 常跑醫院 醫療人員不一定看的出來 Lebowitz et al, 1997; Judd e Akiskai 2002; Cuijpers et al 2005; Schoevers et al 2006, Cole 2008

怎麼知道得憂鬱症?

憂鬱症症狀多樣化 情緒 其他 生理症狀 自責 自殺想法 對什麼都沒興趣 悲傷 胡思亂想 煩躁 擔心身體 四處痛了了 愛哭 焦慮緊張害怕 活力差 注意力不集中 胃口不好 睡不好 反應嫚半拍 PURPOSES OF THE SLIDE To establish that depression is a complex disorder that can manifest through a variety of emotional, physical, cognitive, and other associated symptoms (e.g., anxiety, worry, and pain). Note that the complexity of symptom presentation can lead to depression being a difficult condition to diagnose. The variety of symptoms of depression suggests that many areas of the brain and neural networks may be involved in depression. KEY POINTS There is a broad range of major depressive disorder (MDD) symptoms. The mood in major depression is a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities. The mood is often described by the person as depressed, sad, hopeless, or discouraged. Some individuals emphasize somatic or physical complaints (e.g., body aches and pains) rather than reporting feelings of sadness. Many individuals report or exhibit increased irritability. Loss of interest or pleasure is nearly always present, at least to some degree. Appetite is usually reduced, yet other individuals have increased appetite. When appetite changes are severe, there may be a significant loss or gain in weight. The most common sleep disturbance associated with depression is insomnia. Less frequently, individuals present with prolonged sleep episodes at night or increased daytime sleep. Psychomotor changes include agitation (e.g., the inability to sit still, pacing, hand-wringing) or retardation (e.g., slowed speech, thinking, and body movements). Decreased energy, tiredness, and fatigue are common. The sense of worthlessness or guilt associated with depression may include unrealistic negative evaluation of one's worth, or guilty preoccupations or ruminations over minor past failings. Many individuals report an impaired ability to think, concentrate, or make decisions. They may appear easily distracted or complain of memory difficulties. Frequently, there may be thoughts of death, suicidal ideation, or suicide attempts. BACKGROUND The symptom groupings were based on the Diagnostic Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR) core criteria and text description of associated symptoms. REFERENCE American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision). Washington, DC. 2000;352–56. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision). Washington, DC. 2000;352-56. 12

為什麼會得憂鬱症?

憂鬱症的病因 真正病因：未知 生物病因 -基因遺傳 -單胺神經介質假說 -神經內分泌失調 -神經細胞發炎死亡 性格病因 社會心理壓力病因

憂鬱症是心病還是腦病? 憂鬱症代表身體沒病?

壓力引發腦神經發炎反應 PURPOSE OF THE SLIDE To discuss the underlying neurobiological changes that occur at a cellular level.   KEY POINTS This picture is a visual representation of how external stressors can provoke the activation of the inflammatory response in the brain and body. “The image shows psychosocial stressors activating the central nervous system stress circuitry, including corticotropin-releasing hormone (CRH) and the sympathetic nervous system pathways via the locus coeruleus.” “Catecholamines can increase nuclear factor-κB (NF-κB) DNA binding in immune cell types, including macrophages, resulting in the release of inflammatory mediators that promote inflammation.” “Pro-inflammatory cytokines can access the brain, induce inflammatory signaling pathways including NF-κB, and contribute to altered monoamine metabolism, increased excitotoxicity, and decreased production of relevant trophic factors.” “Cytokine-induced activation of CRH and the hypothalamic–pituitary–adrenal (HPA) axis, in turn, leads to the release of cortisol, which along with efferent parasympathetic nervous system pathways (e.g., the vagus nerve) inhibit NF-κB activation and decrease the inflammatory response.” “In the context of chronic stress and depression, and the influence of cytokines on glucocorticoid receptor function, activation of inflammatory pathways may become less sensitive to the inhibitory effects of cortisol, and the relative balance between the pro-inflammatory and anti- inflammatory actions of the sympathetic and parasympathetic nervous systems, respectively, may play an increasingly important role in the neural regulation of inflammation.” REFERENCE 1. Miller et al. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65(9):732–41. ACTH=Adrenocorticotropic hormone; CRH=Corticotropin-releasing hormone; MDD=Major depressive disorder; NF-κB=Nuclear factor κB. Miller et al. Biol Psychiatry 2009;65(9):732-41. Copyright Elsevier 2009. 16

發炎反應與精神症狀 疲倦 痠痛 疼痛 注意力不集中 內分泌失調 焦慮煩躁 睡眠 胃口 活力改變

壓力會影響全身器官 The adrenal gland releases excessive amounts of catecholamines and cortisol 3. Increase in catecholamines can lead to myocardial ischemia, diminished heart rate variability, and can contribute to ventricular arrhythmias ACTH 4. Increase in catecholamines causes platelet activation; increase in cytokines and interleukins may also contribute to atherosclerosis and eventual hypertension Hypothalamus stimulates the pituitary gland to release excessive ACTH, continuously driving the adrenal gland PURPOSE OF THE SLIDE To discuss the common mechanisms that may be associated with major depressive disorder (MDD) and other physical conditions such as diabetes or cardiovascular disease. KEY POINTS “This review of the extant literature is derived from MEDLINE searches (1966–1997) using the search terms ‘major depression,’ ‘psychiatry,’ ‘heart disease,’ and ‘pathophysiology.’” “Studies investigating pathophysiological alterations related to cardiovascular disease (CVD) in patients with depression are reviewed.” “The figure shows the hypothetical schema of pathophysiologic alterations associated with depression that likely contribute to increased vulnerability to CVD. The autonomic nervous system innervates the heart via the parasympathetic vagus (X) and sympathetic (postganglionic efferents from cervical and upper thoracic paravertebral ganglia) nerves.” BACKGROUND MDD may not only be a “psychiatric disease,” as there is evidence of widespread systemic consequences. Neuroendocrine dysregulation and an elevated sympathetic tone may result in cardiovascular morbidity and an increased risk of metabolic syndrome. The immune response may be compromised in MDD. “Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated in patients with cardiovascular disease (CVD).” “This is of particular importance because several studies have shown depression and its associated symptoms to be a major risk factor for both the development of CVD and death after an index myocardial infarction.” “Treatment of depression in patients with CVD may be able to improve their dysphoria and other signs and symptoms of depression and improve quality of life.” REFERENCE Musselman et al. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 1998;55(7):580–92. 5. Cortisol antagonizes insulin and contributes to dyslipidemia, type 2 diabetes, and obesity; increases in cortisol also suppress the immune system ACTH=Adrenocorticotropic hormone. Adapted from Musselman et al. Arch Gen Psychiatry 1998;55(7):580-92. Peeke et al. Ann NY Acad Sci 1995;771:665-76. 18

情緒與疼痛的神經傳導路徑 憂鬱症與腦中血清素與正腎上腺素失調有關 大腦會因為脊椎中血清素與正腎上腺素失調, 放大疼痛訊號 這可以說明, 為何憂鬱症病人常以疼痛等身體症狀到一般科就診

Biological similarities The emotional response to pain involves the ascending reticular activating system, which sends fibers to the dorsolateral prefrontal cortex, limbic system, hypothalamus, cerebellum, and dorsal horn of the spinal cord . 大腦處理疼痛的區域跟處理情緒的區域是重疊的 Siegal 1999, Yaksh 2001

慢性疼痛與憂鬱症 憂鬱症與慢性疼痛導致失能 慢性疼痛, 例如退化性關節炎, 下背痛, 神經痛或肌肉疼痛會導致活動力減退, 而失能狀態進一步導致憂鬱情緒 Williamson et al,1992,1995.

慢性疼痛與憂鬱症 慢性疼痛的病患常常沒有治療憂鬱症狀, 反而服用大量止痛藥與鎮靜安眠藥 慢性疼痛的病患常常沒有治療憂鬱症狀, 反而服用大量止痛藥與鎮靜安眠藥 一項針對自殺老年病患的調查發現, 他們很多人患有慢性病或疼痛, 沒有針對憂鬱症治療, 只有服用止痛藥 Mulsant et al1999; Siegal 1999

需要藥物治療嗎?

鬱卒的大腦 活動量增加: 前額葉皮質： 眼窩部外側,腹部內側；杏仁核,視 丘, 尾核 PURPOSE OF THE SLIDE To introduce some of the regional cortical activity differences observed with patients with major depressive disorder (MDD). KEY POINTS Images are from a meta-analysis of nine studies comparing patients with MDD and control subjects at rest. Total of eight areas were identified as decreased activation in patients with MDD compared with controls, including: pregenual anterior and posterior cingulate, bilateral middle frontal gyri, insula and left superior temporal gyrus. Areas identified as “overactive’’ in patients included a series of deeper brain structures (e.g., thalamus, caudate, medial and inferior frontal gyri) as well as cortical structures (including the left superior frontal and right middle frontal gyri). Depression appears to involve a considerable number of diverse cortical and subcortical brain regions and there are significant differences in the way in which differing regions are abnormally active in the disorder. REFERENCE Fitzgerald PB, et al. A meta-analytic study of changes in brain activation in depression. Human Brain Map. 2008;29:683–695. 活動量增加: 前額葉皮質： 眼窩部外側,腹部內側；杏仁核,視 丘, 尾核 活動量減低: 前額葉皮質： 背部外側；島迴,前扣帶迴, 上顳葉 迴 Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695

心情好的大腦 活動量增加: 前額葉皮質： 背部外側；前扣帶迴 活動量減低: 杏仁核，視丘 PURPOSE OF THE SLIDE To revisit the study that showed summarized differences in the regional cortical activity between patients with MDD and controls and demonstrate how treatment restored a normative pattern of activity. KEY POINTS Images are from a meta-analysis of nine studies comparing patients with major depressive disorder (MDD) from their baseline to after selective serotonin reuptake inhibitor (SSRI) treatment. Compared with baseline, increased activity was observed in the bilateral middle frontal gyri, cingulate cortex (dorsal and posterior), and putamen. Compared to baseline, decreased activity was observed in insula, parahippocampal gyrus, pre- and subgenual anterior cingulate, inferior medial prefrontal cortex, left superior frontal gyrus, and amygdala. There appears to be a network involving the dorsal/pregenual anterior cingulate, bilateral middle frontal gyrus, insula and the superior temporal gyrus where there is decreased activity at rest which is increased with SSRI treatment. In contrast, the medial and inferior frontal cortex and the basal ganglia (caudate or putamen) as well as potentially the amygdala and thalamus are overactive at rest and display a reduction in activity with SSRI treatment. REFERENCE Fitzgerald PB, et al. A meta-analytic study of changes in brain activation in depression. Human Brain Mapp. 2008;29:683–695. 活動量增加: 前額葉皮質： 背部外側；前扣帶迴 活動量減低: 杏仁核，視丘 Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.

鬱卒的大腦縮小了 * 憂鬱症病人比正常人MOFC (前額葉皮質腹部內側)少32％ 正常人 憂鬱症 *P=.02 vs comparison by ANOVA 眼窩處大腦皮質 volume (mm3) MOFC * 正常人 憂鬱症 PURPOSE OF THE SLIDE To look at some of the potential structural changes observed in patients with depression. Reduced cortical volumes have been found in subregions of the frontal cortex, including the subgenual anterior cingulate and medial orbitofrontal cortex. KEY POINTS Neuroimaging studies have begun to show how functional differences in the brain between depressed and healthy patients can be associated with structural differences—though we still do not know how this happens. The medial orbitofrontal cortex (MOFC; shaded in red on the image at left) has a role in the regulation of emotion and mood. In patients with depression (n=15), the MOFC was 32% smaller in volume than controls (n=20), as is indicated in the chart on the right. This finding was significant after statistically controlling for brain size. The authors hypothesize that decreases in volume of the MOFC in patients may be a risk factor for the development of depression. BACKGROUND The study consisted of 15 patients with a history of DSM-IV depression and currently treated with antidepressant medication (paroxetine, fluoxetine, or desipramine). Patients with a history of post-traumatic stress disorder (PTSD) or current medication use other than antidepressants were excluded. Comparison subjects (n=20) were healthy subjects selected to be similar to the patients for gender, age, years of education, and handedness. Depressed patients, on average, were in remission for 30 weeks and had an average of two prior depressive episodes. REFERENCE Bremner JD, et al. Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry. 2002;51:273–279. 憂鬱症病人比正常人MOFC (前額葉皮質腹部內側)少32％ Bremner JD, et al. Biol Psychiatry. 2002;51:273–279.

Time Since End of Treatment (Months) 吃藥不是萬能, 沒有藥卻是萬萬不能 1.0 Continued Medication Condition (n=28) 0.9 0.8 Placebo Condition (n=21) 0.7 Prior Behavioral Activation Condition (n=27) 0.6 Prior Cognitive Therapy Condition (n=30) Survival (%) 0.5 0.4 0.3 0.2 PURPOSE OF THE SLIDE To illustrate that medication is only part of the armamentarium.   KEY POINTS In this study, 188 patients were randomized to antidepressant medication (ADM) (paroxetine, a selective serotonin reuptake inhibitor [SSRI]), cognitive therapy (CT), or behavior activation (BA) at a ratio of approximately 2:1:1 for 16 weeks. They were then followed to the point of relapse or recurrence for up to 2 years following response to acute treatment. The first year of follow-up compared four groups: those who had received CT, those who had received BA, and those who received prior ADM, who were subdivided into two groups – those who continued with ADM and those given a placebo. Patients who had received prior BA or prior CT received no further treatment during follow-up. Patients treated with medication but withdrawn onto placebo had a higher rate of relapse through 1 year of follow-up compared to patients who received prior BA, prior CT, or who had continued medication. Specific comparisons indicated that patients previously exposed to CT were significantly less likely to relapse following treatment termination than patients withdrawn from medication, and patients previously exposed to BA did almost as well relative to patients withdrawn from medication, although the difference was not significantly different. REFERENCE Dobson et al. Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression. J Consult Clin Psychol. 2008;76(3):468–77. 0.1 2 4 6 8 10 12 14 16 18 20 22 24 Time Since End of Treatment (Months) Participants were initially assigned to 16 weeks of antidepressant treatment (n=100), cognitive therapy (n=45) and behavioral activation (n=43). Treatment responders on antidepressants were randomized to continue with medication or placebo. Relapse was defined as a Hamilton Depression Rating Scale score of ≥14. Dobson et al. J Consult Clin Psychol 2008;76(3):468-77. Reprinted with permission of the American Psychiatric Association. 27

吃藥有效嗎? Antidepressant and Placebo Response Rates (N=36,385; 262 drug–placebo pair-wise comparisons) 60 40 p<0.05 Response (%) 20 PURPOSE OF THE SLIDE To address the issue of the placebo effect.   KEY POINTS This graph was taken from a meta-analysis of 182 clinical trials, all of which were double-blind, randomized, placebo-controlled antidepressant trials for the treatment of major depressive disorder (MDD). All trials were a minimum of 4 weeks. The goal of the study was to ascertain whether the probability of receiving placebo influences clinical trial outcomes. Clinical response was defined as a ≥50% reduction in either the Hamilton Depression Rating Scale or Montgomery–Asberg Depression Rating Scales, or a score of <3 on the Clinical Global Impression Improvement Scale at the endpoint. A meta-regression analysis (random-effects) established that the probability of receiving placebo, year of publication, and baseline severity were independent predictors of the risk ratio of responding to antidepressants versus placebo. REFERENCE Papakostas et al. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 2009;19(1):34–40. Drug Choice Papakostas et al. Eur Neuropsychopharmacol 2009;19(1):34-40. Reprinted from European Neuropsychopharmacology. Copyright 2009, with permission of Elsevier. 28

強化腦神經連結及修復 (情緒、記憶與學習) 藥物影響一連串的神經功能 血清素再回收受體 (血清素) (正腎上腺素) (麩胺酸) (皮質素) KEY POINTS Elevation of glucocorticoids and excitatory neurotransmitters, due to chronic mood disorders, may impair neuroplasticity and cellular resilience.1 Use of antidepressants can regulate the expression of BDNF, leading to enhancement of neuroplasticity and cellular resilience.2,3 5-HT and/or NE activate intracellular cascades that can independently lead to activation of transcription factor (CREB) and eventual synthesis of BDNF. BDNF interacts with TrkB receptor to enhance neuroplasticity and neurogenesis. By facilitating synthesis of a neuroprotective factor, Bcl-2, BDNF helps improve cellular resilience. 4 REFERENCES 1. Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry. 2003;53(8):707-742. 2. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104-9110. 3. Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70-75. 4. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med. 2001;7(5): 541-547. 組織酮 乙基化 (腦神經 滋養因子) 組織酮 甲基化 強化腦神經連結及修復 (情緒、記憶與學習) Manji HK, et al. Biol Psychiatry. 2003;53(8):707-742. Tsankova NM, et al. Nat Neurosci. 2006. 29

常見的問題 服藥會不會成癮? 將來會不會變老人痴呆? 靠自己調適不行嗎? 服藥會不會昏睡/呆滯/記憶力減退? 要一輩子吃藥嗎?

飲食有差嗎?

地中海飲食 最近一項根據 10,000 西班牙裔受試者研究, 飲食中富含蔬菜, 水果, 堅果及穀物可降低憂鬱症新發生率四倍 Sanchez-Villegas, 2009, Arch Gen Pscyh

有運動的老鼠腦部較好? 腦細胞新生數目 無轉輪 有轉輪 . Rhodes, JS et al, 2005 34 34

問題與討論