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さゆりすみい
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biological resear June 27, 2013 @ Tokyo Hiroshi Kunugi Department of Mental Disorder

1 Mental illness and nutrition 精神疾患と栄養 Melbourne University-NCNP joint symposium For research development in relation to Brain, Mind and Society From the viewpoint of biological resear June 27, Tokyo Hiroshi Kunugi Department of Mental Disorder Research, National Institute of neuroscience, National Center of Neurology and Psychiatry 2013/9/11 1

2 Stress Social relationship Economic crisis Family crisis etc. Diet Barrier against stress Physical activity 現代の隠れストレス Hidden stress due to modernization Excess energy intake Nutrition imbalance Inadequate physical Irregular rhythm Sleep 2013/9/11 2

3 Stress Social relationship Economic crisis Family crisis etc. Appetite dysregulation Barrier against stress うつ病 Depression Impaired physical activity Sleep disturbance 2013/9/11 3

4 Depression is associated with Obesity, diabetes, and metabolic syndrome Diet style (Mediterranean v. Western) Inadequate intake of n-3 polyunsaturated fatty acid (EPA, DHA) Reduced amino acids such as tryptophan Deficiency of vitamin Bs and vitamin D. Iron and zinc deficiency Decreased tea / coffee consumption 2013/9/11 4

5 うつ病と栄養 / 食生活肥満糖尿病メタボリック症候群地中海式食事の予防効果 (vs. 西洋式食事 ) 脂肪酸 :n-3 系脂肪酸不足アミノ酸 : トリプトファンなど必須アミノ酸不足ビタミン : ビタミンB1 B6 B12 葉酸ビタミンD 不足ミネラル : 鉄不足亜鉛不足マグネシウム不足嗜好品 : 緑茶の予防効果 2013/9/11 5

6 Arch Gen Psychiatry 2010 肥満とうつ病の双方向性の関連 N=55387 N=7196 The pooled OR for the association between obesity at baseline and depression at follow-up (8 studies) was 1.55 (95% CI: ). The pooled OR of the 9 studies examining the effect of depression on obesity over time was 1.58 (95% CI, ; P.001). 2013/9/11 6

Sofi et al (2008) Greater adherence to a Mediterranean diet is associated with a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or

7 Sofi et al (2008) Greater adherence to a Mediterranean diet is associated with a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and incidence of Parkinson s disease and Alzheimer s disease (13%). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of major chronic diseases. Mortality 死亡率欧米諸国における過去 12 研究による合計およそ 157 万人を対象とした前向き研究のメタアナリシスによれば地中海式食事に準じた食生活を送っている者は一定期間内での死亡率が低く心臓病がん神経変性疾患 ( アルツハイマー病やパーキンソン病 ) のリスクも低いことが明らかにされた 2013/9/11 7

8 Mediterranean diet Vegetables Fruits Nuts Legumes Sea food Olive oil Grains A glass of red wine 地中海式食事 2013/9/11 8

9 Western Diet Meat pie Processed meat ham sausage bacon salami Pizza Potato chip Hamburger White bread (by refined flour) Sugar Flavored milk drinks Beer 2013/9/11 9

10 Western Diet Meat pie Processed meat ham sausage bacon Standard American Diet salami Pizza Potato chip Hamburger White bread (by refined flour) Sugar Flavored milk drinks Beer SAD な ( 悲しい ) 食事? 2013/9/11 10

地中海式料理はうつ病のリスクも下げる可能性 A total of 10 094 initially healthy Spanish university students were followed up for 4.4 years. 480 new cases of depression identified.

11 地中海式料理はうつ病のリスクも下げる可能性 A total of initially healthy Spanish university students were followed up for 4.4 years. 480 new cases of depression identified. Multiple adjusted hazard ratios of depression for the 4 upper successive categories of adherence to the Mediterranean diet pattern (taking the category of lowest adherence as reference) were 0.74 ( ), 0.66 ( ), 0.49 ( ), and 0.58 ( ) (P for trend <.001). Fruit, nuts, the monounsaturated- to saturatedfatty-acids ratio, and legumes were associated with the risk. Arch Gen Psychiatry 2009 スペインの健康な大学卒業生を対象にうつ病発症の追跡調査 (4.4 年 ) 人のうち 480 人がうつ病発症地中海式食事スコアが高かった者はスコアが最も低い群と比較してうつ病発症率が低かった (HR: 0.49~0.78, p<0.001) 個別の食品との関連 ( うつ病低下 ) 果物種実豆類の摂取量が多い一価不飽和脂肪酸 / 飽和脂肪酸比が高い 2013/9/11 11

12 So we started studying diet and nutrition in psychiatric disorders. われわれの調査 2013/9/11 12

13 Methods 簡易型自記式食事歴質問票 Brief-type self-administered Diet History Questionnaire (BDHQ) Healthy controls (N=109) Major depressive disorder (N=99) Nutrient concentrations in blood (vitamins, amino acids, fatty acid, lipid, etc.) 血中栄養素測定 ( ビタミンアミノ酸脂肪酸脂質 HbA1c など ) 2013/9/11 13

14 % Depression and overweight P=0.08 Healthy controls (N=109) Major depressive disorder (N=99) BMI < > % Male Female BMI < > BMI < > 2013/9/11 14

15 Lipid abnormalities were increased in depressed patients うつ病患者群では HDL が不足している人が多く中性脂肪が高い人が多い P=0.003 P < HDL TG 42% 2% 12% 19% Healthy controls (N=109) Patients with major depressive disorder (N=99) 2013/9/11 15

Lipid abnormalities were increased in depressed patients うつ病患者群では HDL が不足している人が多く中性脂肪が高い人が多い P=0.003 P < 0.

16 Lipid abnormalities were increased in depressed patients うつ病患者群では HDL が不足している人が多く中性脂肪が高い人が多い P=0.003 P < Together, HDL our results provide support for higher TG rate of overweight or obesity and metabolic 42% abnormalities in depressed patients, which is likely 19% to result from their unhealthy diet. 2% 12% Healthy controls (N=109) Patients with major depressive disorder (N=99) 2013/9/11 16

17 Possible link between metabolic abnormalities and depression A compelling body of evidence documents that obesity is a chronic low-grade proinflammatory state. 肥満軽度の炎症 Alterations in adipokines (cytokines derived from adipocytes) such as adiponectin, leptin, and resistin as well as TNFα, IL-6, and IL-1 are commonly reported in obesity and depression. 肥満やうつ病ではアディポカイン ( サイトカイン ) が共通して異常 2013/9/11 17

18 (pg/ml) CSF IL-6 concentration *** * (pg/ml) Serum IL-6 concentration Controls Schizophrenia Depression Controls Schizophrenia Depression Sasayama et al, /9/11 18

19 セロトニン Food トリプトファンメラトニン Melatonin (Myint et al, JNT, 2012) キヌレニンキヌレニン酸 The link between neuroinflammation and depression may be mediated by altered tryptophan metabolism. キノリン酸 toxicity 炎症神経炎症セロトニン低下キヌレニン系キノリン酸興奮毒性うつ病 (Maes et al, PNP, 2011) 2013/9/11 19

うつ病患者はセロトニンの原料となるトリプトファン値が低い n Plasma Tryptophan (nmol/ml) Controls 109 58.1 ± 11.3 p=0.036 Depression 99 54.

20 うつ病患者はセロトニンの原料となるトリプトファン値が低い n Plasma Tryptophan (nmol/ml) Controls ± 11.3 p=0.036 Depression ± 11.2 p p= % 35% 基準値 37.0 ~ 74.9 Healthy controls (N=109) Major depressive disorder (N=99) 2013/9/11 20

21 うつ病患者では葉酸値 ( 基準値 > 3.1 ng/ml) が低い人 (<4 ng/ml) が多い P=0.004 Healthy controls (N=109) Major depressive disorder (N=99) 26% 11% Serum folate 2013/9/11 21

22 葉酸ビタミン B12 とメチオニンホモシステイン monoamines ( ドーパミンノルアドレナリンセロトニン ) Antidepressant effect 抗うつ効果ホモシステインメチオニン葉酸サイクル Importance of folate, vitamin B6, 12, and methionine in psychiatric disorders Prog Neuro-Psychopharmacol Biol Psychiatry (2005) 2013/9/11 22

23 Tea time Psychotropic effects of green tea 2013/9/11 23

Green tea in Japan A Note on Drinking Green Tea for Good Health written by Eisai (1193) 茶は養生の仙薬なり延齢の妙術なり山谷之を生ずれば其の地神霊なり人倫之を採れば其の人長命なり Eisai explains about the different kinds of

24 Green tea in Japan A Note on Drinking Green Tea for Good Health written by Eisai (1193) 茶は養生の仙薬なり延齢の妙術なり山谷之を生ずれば其の地神霊なり人倫之を採れば其の人長命なり Eisai explains about the different kinds of tea, methods for making powdered green tea, tea drinking for promoting health. Eisai Sen No Rikyu established Tea Ceremony in 16 th century. Sen No Rikyu /9/11 24

25 Green tea うつ病患者は緑茶やコーヒーを飲む量が少ない % Controls (N=111) Depression (N=99) (Koga et al, 2013) P< <4 cups/w Coffee >=4 cups/w Patients with major depression consume green tea and coffee less frequently than controls. 50 % <2 cups /day 2 cups or more /day Controls (N=111) Depression (N=99) P=0.029 紅茶烏龍茶は有意な関連なしコーラジュースはうつ病患者群で多かったが有意差なし 2013/9/11 25

26 Possible psychotropic effect of L-theanine (Wakabayashi et al, 2012) Theanine Glutamate Theanine is historically known as a relaxing agent. Effect of L-theanine on MK-801-induced deficits in prepulse inhibition in mice Prepulse inhibition is a measure of sensorimotor gating. Deficits in prepulse inhibition are often 2013/9/11 seen in schizophrenia patients. 26

27 Possible antidepressant-like effect of L-theanine (Wakabayashi et al, Psychopharmacology, 2012) Theanine Reduced immobility Glutamate control Theanine 2013/9/11 27

28 Possible psychotropic effect of L-theanine (Wakabayashi et al, 2012) Increased expression of BDNF in the hippocampus Intracellular Ca increase in cultured cortical neurons 2013/9/11 28

29 Prepulse inhibition (%) Effects of L-theanine on sensorimotor gating in humans 1 * * * *; p < 0.05 (corrected) 0.5 Oral administration (mg) Baseline 200 mg 400 mg 600 mg 0 60ms 86dB 60ms 90dB 120ms 86dB 120ms 90dB (Ota et al, in revision) 2013/9/11 29

30 Summary Modern diet may confer vulnerability to stress, which prompts the development of mental illness. Our data demonstrated nutritional imbalance in depressed patients. Green tea may have served as a psychotropic herb in the Japanese society. We obtained evidence for psychotropic effects of L-theanine, a unique amino acid in green tea. 2013/9/11 30

31 Towards new biomarker discovery and development of new treatment in collaboration Thank you for your attention. 2013/9/11 31

32 視床下部ー下垂体ー副腎系 (HPA axis) 海馬視床下部 CRH 分泌下垂体 ACTH 分泌 Cortisol Pre-treatment Post-treatment 副腎 DEX/CRH test in major depression (Kunugi et al, 2006) Glucocorticoid ( コルチゾール副腎皮質ステロイド ) 2013/9/11 32

33 Glucocorticoid inhibits BDNF-mediated maturation of cultured hippocampal neurons ストレスホルモン ( クルココルチコイト ) は BDNF を介した海馬の成熟を抑制する (Kumamaru et al: Mol Endocrinol, 2008) Neurite outgrowth 突起伸長 DEX: ストレスホルモンの 1 つここで動画 Synaptic formation シナフス形成 2013/9/11 33

Correlation between DEX/CRH test and Mean diffusivity in DTI (a) P < 0.

connectivity throughout the brain. ストレスホルモンの過剰は神経ネットワーク障害と関連 (b) P < 0.

34 Correlation between DEX/CRH test and Mean diffusivity in DTI (a) P < (uncorrected) Mean diffusivity Hyperactivity in the HPA axis was associated with reduced connectivity throughout the brain. ストレスホルモンの過剰は神経ネットワーク障害と関連 (b) P < (FDR) left temporal pole right anterior cingulate right occipital region rostral body of corpus callosum (Ota M, Hori H, et al: in revision) 2013/9/11 34

日本生物学的精神医学会誌 27 巻 4 号 177 特集 1 栄養学から見た精神疾患の予防治療の可能性 1. 緑茶成分テアニンの向精神作用について抄録 : L theanine N ethyl L glutamine prepulse inhibition PPI 200

日本生物学的精神医学会誌 27 巻 4 号 177 特集 1 栄養学から見た精神疾患の予防治療の可能性 1. 緑茶成分テアニンの向精神作用について抄録 : L theanine N ethyl L glutamine prepulse inhibition PPI 200 177 特集 1 栄養学から見た精神疾患の予防治療の可能性 1. 緑茶成分テアニンの向精神作用について 1 1 1 1 2 2 抄録 : L theanine N ethyl L glutamine prepulse inhibition PPI 2mg 4mg PPI 8 8 27(4):177 181, 216 Key words L theanine glutamate green tea