初老期不安障害における不眠に対する

塩酸トラゾドンの有用性

福 山 裕 夫

Effects of Trazodone on the sleep disturbance of

Anxiety patients in elderly

Hiroo FUKUYAMA

【要約】初老期の抑うつ，不安障害は，身体的不定愁訴や老化そのものによる生体リズムの変化に

伴う不眠，さらには耐糖能異常や高血圧，高コレステロール血症などの脳血管性の病理学的変化に

よる中枢神経への影響など，様々な要因が因子として病態を形成する疾患である．今回，初老期の

不安障害において，非定型抗うつ薬の一つである塩酸トラゾドンを使用し，その効果と MRI 所見

について検討を行った．対象は，精神科外来を受診し「不安障害」F41.1 と診断された患者 12名

（女性：8 名，男性；4名）である．就眠前に塩酸トラゾドン 50mg を投与し，1週間後に評価を行っ

た．初診時における血液検査のデータでは，患者 12人中 4人で血中コレステロール値の異常，う

ち 1名で中性脂肪の異常が確認された．MRI においては，12人中 10名で白質の無症候性脳梗塞

の存在を認めた．さらに，無症候性脳梗塞の存在する 10名中，4名で脳室周囲の虚血系変化であ

る PLMの存在を確認した．塩酸トラゾドン投与 7 日後における，ハミルトン不安尺度の総得点は

有意に低下し，不眠，抑うつ，不安，認知傾向の項目で有意な低下がみられた．塩酸トラゾドンの

短回投与は，初老期における不安障害における不眠に対して有用であり，これらの効果は老化によ

る睡眠構造の変化に対するセロトニン 2ｃアンタゴニスト作用による改善であることが考えられ

る．また，MRI 所見からこれらの病態に対して，老化に伴う虚血性病変の関連が考えられた．

【キーワード】Trazodone, Anxiety, Vascular depression

Ⅰ はじめに

近年，うつ病をはじめとする感情障害は，

REM潜時の短縮や体温，ホルモンリズムの

振幅，位相の変化などのリズム障害という観

点から様々なな検討がなされている．また，

臨床的には不安障害の重要な一因子となるス

トレスが，不眠や気分障害の時間制生物学的

な変化に影響を与えているという報告も多

い．動物実験による基礎医学的な報告によれ

ば，強制歩行や断眠による睡眠構造の変化は，

深睡眠の低下，睡眠構造の断片化など，うつ

病モデルと類似した睡眠覚醒リズムの変化を

惹起することが報告されている．さらに，近

年の分子生物学的な研究の成果により，Per

遺伝子由来の蛋白質のリズムが，うつ病や不

安障害の患者においてもそのサーカディアン

リズムの異常が指摘されている．時間（睡眠）

遺伝子である CLOCK の KO マウスにおい

てはうつ病類似の行動，内分泌学的異常が報

告されており，同じく生体リズムに関与する

BMAIL遺伝子においては，その日内変動が

末梢機関である肝臓の代謝リズムに駆動して

いることなどが報告されており，うつ病や不

安障害と関連のある睡眠や精神活動に限ら

ず，睡眠をはじめとした時間生物学的要素が

糖や脂質の代謝といった生活習慣病に関与し

久留米大学文学部社会福祉学科

久 留 米 大 学 文 学 部 紀 要

社会福祉学科編第10号・第11号合併号 (2011)

ており，その生理学的機序と臨床応用の研究

報告が多くなされている1-6)．

また，認知症，うつ病，不安障害などの老

年期における精神疾患は，その病態形成の複

雑さから，レビー小体やアミロイドなどの加

齢による生成物の量的質的検討や，認知機能

などの老化による精神生理学的変化，内分泌

学的変化，さらには心理学的変化といった

様々な分野からのアプローチがなされてい

る．老年期の精神科疾患における不眠，不安，

抑うつ，認知機能の低下といった精神症状は，

日常診療においてもっともよく診られるもの

であり，成人期におけるこれらの症状とはそ

の病態を老年期特有として研究報告，診療が

なされている．老化による睡眠覚醒リズムの

変化は，その周期の短縮や振幅の低下など気

分障害やアルコールによる変化と類似してお

り，これらの加齢による変化に対して時間生

物学的変化の期待できる抗うつ薬などの使用

が試みられている7-9)．

さらに MRI をはじめとする中枢神経の画

像診断の進歩により，1990 年代から「脳血管

性うつ病」（vascularDepression）の概念が提

唱され，認知症などのなどの老年期における

中枢神経疾患において，初老期からの微小な

血管性病変がこれらの病態の形成に従来より

影響が大きい可能性が指摘されている．

Vascular Depression については，ミルタザ

ピンやミアンセリン，SSRIsなどの抗うつ薬

や循環器用剤，抗凝固製剤などの有用性が指

摘されている10,11)．

塩酸トラゾドンは欧米における一般医の処

方では不眠に対して日常的に使用されてお

り，我が国においても非定型抗うつ薬として

使用されている．今回，精神科外来において

不安障害（F41.1）と診断された不眠を呈す

る患者に対して，塩酸トラゾドンを夜間に短

回投与しその不眠を主とした不安障害に対す

る効果について検討し，これらの患者のMRI

検査における加齢性の変化について検討し

た．

方法

対象は，精神科を標榜する総合病院の精神

科外来において，初診において全般性不安障

害（F41.1 ICD-10）と診断された患者 12名

（女性：8 名，男性；4名）である．初診時お

いて，基本的な血液検査（CBC，GOT（AST），

GPT（ALT），TP（総蛋白），ChoE，総ビリ

ルビン値，BUN，クレアチニン，総コレステ

ロール，中性脂肪）と除外診断のための甲状

腺ホルモン（T4，TSH）が行われた．さらに，

脳の器質性病変を除外するための頭部 MRI

検査（TOSHIBAもしくは Philips1.5テスラ）

を 7日以内に施行した．神経精神医学的診察

において，頭部外傷，アルコール，薬物依存，

内分泌疾患の既往があるものは除外された．

十分な説明と同意の後，治療のために塩酸ト

ラゾドン 50mg，不眠時のためロラメタゼパ

ム 0.125mg の投与が行われた．不安障害の

評価には，ハミルトン不安評価尺度（14項目）

を使用し，塩酸トラゾドン投与前と投与 7 日

後の，午前 9-12時の間（昼食前）に評価を行っ

た．統計学的解析には，Wilcoxon's 検定

（SPSS Ver.11）を用いた．

結果

塩酸トラゾドン投与前と投与 7 日後のハミ

ルトン不安評価尺度の総得点は，投与前が

24.5点（SD；2.5），投与 7 日後が 18 点（SD；

3.7）であり，投与前に比較して投与 7 日後に

は有意にハミルトン不安評価尺度の総得点の

低下が示された．（Wilcoxon's 検定 p＜0.05

see；Fig.1）

ハミルトン不安評価尺度の各項目ごとにお

ける投与前と投与 7 日後の値は，投与前にお

いて，不安気分；2.5，精神的緊張；2，恐怖

感；1.5，認知傾向；1.5，不眠；3.1，抑うつ

気分；2.1，身体症状（筋骨格系）；2.3，身体

症状（感覚知覚系）；1.8，循環器系；2.3，呼

久留米大学文学部紀要社会福祉学科編第 10 号・第 11 号合併号42

吸器系；1.3，消化器系；0.8，泌尿器系；0.8，

自律神経系；0.9，臨床場面での異常 1.6，投

与 7 日後で不安気分；1.8，精神的緊張；1.7，

恐怖感；0.9，認知傾向；0.7，不眠；1.6，抑

うつ気分；1.5，身体症状（筋骨格系）；1.6，

身体症状（感覚知覚系）；2.1，循環器系；1.7，

呼吸器系；1.3，消化器系；0.7，泌尿器系；

0.8，自律神経系；0.8，臨床場面での異常で

あった．不眠，抑うつ，不安，認知傾向の項

目で有意な低下がみられた．（Wilcoxon's検

定 p＜0.05 see；Fig.2）

MRI による，脳血管性病変の検索では 12

人中 10名で白質の無症候性脳梗塞の存在を

認めた．さらに，無症候性脳梗塞の存在する

10名中，4名で脳室周囲の虚血系変化である

PVH（脳室周囲高信号）の存在を確認した．

（Table.1，Fig.3）

考察

感情障害や適応障害，不安障害において，

不眠はその中核をなす症状ののうちの一つで

ある．感情障害においては，様々な報告があ

るものの特に内因性の単極性障害において，

深睡眠（睡眠段階 3＆ 4）の減少，REM潜時

の短縮，中途覚醒の増加などの指標が報告さ

れている．一方，不安障害の基礎的なモデル

であるストレスによる睡眠構造の変化につい

ては，様々な報告がなされているが深睡眠（睡

眠段階 3＆ 4）の減少と中途覚醒の増加の報

告が多い．また，生死にかかわるトラウマを

福山：初老期不安障害における不眠に対する塩酸トラゾドンの有用性 43

0

5

10

15

20

25

30

治療前 治療後

不安障害患者に塩酸トラゾドン 100 g を就眠前投与を行った。投

与 7 日後において，ハミルトン不安評価尺度の総得点において，

有意な改善が認められた。(Wicoxon's検定 p＜0.05)

Fig.1 塩酸トラゾドン投与におけるハミルトン

不安評価尺度総得点の変化

0

0.5

1

1.5

2

2.5

3

3.5

4

（＊：Wilcoxon’s検定 p＜0.05）

投与前

投与後

＊

＊

＊ ＊

Fig.2 ハミルトン不安評価尺度の推移

体験することによって引き起こされる PTSD

についても，いくつかの報告がなされている．

近年の臨床睡眠医学の進歩により，これら感

情障害や不安障害における不眠については，

その病態によって引き起こされる生理学的な

変化であることが明らかになってきてい

る．1,4,8,12-15)

一方，老年期の感情障害，不安障害におい

て 1990 年代より CT，MRIなどの神経放射

線学の発達とともに，「無症候性脳梗塞」

（Silent Cerebral Infarction：SCI）と呼ばれる

病態の存在が注目されるようになり，米国

ad hoc committee の脳血管障害の分類に加

えられた経緯がある．これらの病態は局所神

経症状や卒中発作などの臨床症状がみられな

いために，脳ドックなどの画像診断において

発見される．1990 年代後半より，この「無症

候性脳梗塞」を認める者は，うつ状態をはじ

めとする感情障害が高率に認められるとの報

告が数多くなされ，脳血管性うつ病（Vascu-

lar Depression）の概念が提唱された．近年

においては，MRI 機器の高性能化や PET，

SPECTあるいは PET-CT の進歩，脳磁図な

どの生理学的検査技術の向上により，認知機

能やこれらの無症候性脳梗塞の時系列的な病

態の変化に及ぶまで，様々な報告がなされて

いる．7,8,10,16-20)

塩酸トラゾドンは 1980 年代にイタリアで

開発された非定型抗うつ薬である．塩酸トラ

ゾドンはセロトニン 2c のアンタゴニストで

あるが，体内でその代謝産物であるｍ− CPP

（ｍ− chlorophenyl-piperazine）がセロトニ

ン 1a に作用するという臨床薬理学的作用を

有する．臨床的に塩酸トラゾドン短回投与し

た場合（50〜100mg：成人男子），血中ドラゾ

ドン濃度は 3-4時間で最高値を示し，半減期

は 6-7 時間である．代謝産物である m-CPP

もそれよりやや遅れた動態を示す．（50mg

短回投与：塩酸トラゾドン T max 2.6，m-

CPP Tmax 3.4hr）また，miannserinなどと

同様にセロトニン 2c への拮抗作用から，不

久留米大学文学部紀要社会福祉学科編第 10 号・第 11 号合併号44

Table 1 EQ尺度，職場サポート，社内評価，活気の性別比較の結果

Case Age 投与前HAM 投与後HAM 頭部MRI所見

1 61 26 19 ラクナ梗塞、PVH2 58 20 15 ラクナ梗塞、PVH3 64 25 19 ラクナ梗塞、PVH4 66 28 25 ラクナ梗塞、PVH5 68 25 24 ラクナ梗塞6 61 26 19 ラクナ梗塞7 69 21 18 ラクナ梗塞8 67 26 18 ラクナ梗塞9 68 22 15 ラクナ梗塞10 68 26 14 ラクナ梗塞11 65 22 1712 60 26 13

Fig.3 基底核を中心としたラクナ梗塞と PVH，前

頭から側頭にかけての委縮が認められる

Case 4 の頭部MRI 画像

眠改善作用や疼痛抑制作用が期待されてい

る．欧米では，睡眠調整剤としての塩酸トラ

ゾドンの使用が一般的であり，抑うつ状態と

類似した睡眠構造の変化を有する加齢による

不眠にも効果が期待される．12,21-28)

今回，初老期の不安障害の患者に対して塩

酸トラゾドンの夜間短回投与を行った．対象

患者への脳器質性病変を除外するために行っ

たMRI検査では，12名中 10名で無症候性脳

梗塞や PLM などの虚血性病変の存在を認

め，感情障害だけでなく不安障害，さらには

老年期における様々な精神症状においても，

これら Aging による病態形成において虚血

性病変の関与の可能性が示された．今後，こ

れらの病態形成の過程について，認知機能や

それらの病態マーカー（ApoE42など）との

関連性についても検討が必要である．

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久留米大学文学部紀要社会福祉学科編第 10 号・第 11 号合併号46

Natural killer cell activity and thyroid function

in depressed patients

Fukuyama H., Egami H.,Tomita M., Matsunaga M., Chikama K., Tsukamoto H.,

Uematsu K., Matsunaga M., Horikawa K., Tsujimaru S. and Uchimura N.

【Abstracts】An association between depressive symptoms and altered immunity or thyroid

function has been suggested in many studies. We examined here, NK cell activity and thyroid

function in depressed patients before and after the treatment. The subjects were a homogeneous

group of 14 unmedicated, ambulatory adults who met the DSM-IV criteria for unipolar major

depressive episode. Clinical symptoms concerning the severity of depression were assessed with

the 17-item Hamilton Depression Rating Scale. All subjects had laboratory tests including CBC,

automated biochemical blood analysis (SMAC), thyroid function(TSH), and NK cell activity. NK cell

activity and serum TSH level were decreased in unmedicated depressive patients compared to

after treatment. the serum concentration of TSH showed a negative correlation to the total HAMD

score. These results suggest that major depressive symptoms are associated with alternations in

aspects of the immune system and Hypothalamus-Pituitary-Axis functions.

【Key words】Depression, Natural killer cell, tlyroid function

Introduction

Depression is usually over whelmingly

burdensome. The World Health Organization

(WHO) ranked all major medical disorders in

the world by disability adjusted life years, a

new, standardized measure of burden. The

lifetime prevalence of depression was asses-

sed in a large national sample by Kessler et

al.1) More than 340 million people worldwide

and 18 million people in the United States

alone are estimated to have depression at any

one time. Teen suicides, long a concern, in the

United States have increased fourfold in the

past several decades, ranging from a low of 2.

3 per 100,000 in 1956 to 9.5 per 100,000 in

1997.2)

The association between depressive symp-

toms and altered immunity has been sug-

gested by many studies, although the findings

have not been consistently demonstrated.

Differences between studies may relate to

the patient subgroup investigated.3,4)

Furthermore, many studies suggested that

thyroid function (i. e. TSH, TRH) were sup-

pressed in depressive state, and core rated

with severely of depression. For the depress-

ive patients who did not make the remark-

able response to antidepressants medication,

adding thyroid hormone also deserves

consideration.5) In rapid-cycling patients

whose main problem is frequent break-

through depressions on antidepressants,

thyroid may be helpful either to augment

treatment with a mood stabilizer plus an

antidepressant or may be added to the mood

stabilizer alone. Thus, thyroid function may

be biological markers of unipolar affective

disorders that have an important role of those

etiologies.6,7)

But, there were few evidence that con-

cerned about the association between im-

mune system and thyroid function. In present

study, we examined NK cell activity and the

thyroid function in depressed patients, at the

before and after treatment.

Natural killer cell activity and thyroid function in depressed patients 47久 留 米 大 学 文 学 部 紀 要

社会福祉学科編第10号・第11号合併号 (2011)

Method

Subjects were the homogeneous group of

unmedicated, amburately adults who met

DSM-IV criteria for unipolar depressive

episode (Male N = 7, Female N = 7, Mean

age56. 4 ; Male 55. 6, Female 56. 4). After

adequate explanation, informed consent was

obtained from all subjects. None of the

depressed patients fulfilled criteria for alco-

hol abuse in the last 3 months. All subjects

had physical and neuropsychiatric examina-

tion and laboratory test (complete blood cell

count, blood chemistry screen, thyroid func-

tion tests, CRP, NK activity) with in normal

limit. Blood was collected between 11 and 12

AM. Subjects had neither histories of recent

(< 20 days) viral infections nor histories of

disease (e.g. Autoimmune disorders or can-

cer) that could affect. Subjects were free of

medications known to affect sleep structure

and immune function for at least 2-week

period. Remarkably, all patients were first

episode of mood disorder. Clinical symptoms

severity of depression was assessed with 21-

items Hamilton Depression Rating Scale. 18

of subjects, who had agreed, had neurop-

sychiatric examination and laboratory test in

the state of remission after treatment (i. e.

Total HAM-D score under 10) To test for

differences between before and after treat-

ment, Wilcoxson's Test were used. And to

examine the relationships between values of

NK activity, TSH and HAM-D score, nonpar-

ametric Spearman correlation procedures

were used.

Results

Fourteen patients (7 men and 7 women)

who met the inclusion criteria participated.

Their mean age was 56.3 (SD 5.07) years. All

patients were the first episode of depressive

mood in their life experience. The mean

HDRS depression score at study entry was

25. 1 (SD 7. 1 ; range 17-42). Subjects were

taking antidepressants drugs from various

classes (7 paroxyetine HCL, 4 mianserine

HCL, 3 tarzodone HCL). After the antide-

pressants medication, the mean HDRS was

significantly reduced comparing to the before

drug therapy (p ＜ 0.01 wilcoxon's test ; see

Fig. 1)

At baseline, all patients shouwed serum

TSH and other Labo data levels within the

久留米大学文学部紀要社会福祉学科編第 10 号・第 11 号合併号48

Fig.1 Total HAM-D score in 14 patients at baseline

and follow-up study

0

5

10

15

20

25

30

Before Medication After Medication

Fig.2 Serum TSH level in 14 patients at baseline

and follow-up study

0

0.5

1

1.5

2

Before Medication After Medication

Μg/ml

p<0.05 wilcoxon’s matched pairs test

normal range. The mean of serum TSH, NK

cell activity at the entry were 1.27 ug/ml, 36.

8% before medication.

After the treatment, patients had signifi-

cantly higher serum TSH levels (p < 0. 05

wilcoxon's matched pairs test; see Fig. 2) and

higher NK cell activity (p < 0. 05 wilcoxon's

matched pairs test; see Fig. 3).

In addition, there were siginificant correla-

tion between serum TSH level and the total

HAMD score at the before treatment (p＜ 0.

05 nonparametric Spearman correlation proc-

edures; see Fig. 4)

Discussion

For a long time, standard medical teaching

has been that thyroid function is associated

with mood. Medical guidelines for clinical

practice for Clinical Endocrinologists, state

that ʻthe diagnosis of subclinical or clinical

hypothyroidism must be considered in every

patient with depression.8,9) It is, therefore,

common practice to test patients presenting

with depressive symptoms for thyroid dys-

function. There are biological reasons why

low thyroid function could cause depression.

Brain 5-HT activity may be reduced by

hypothyroidism or thyrotropin-releasing hor-

mone (TRH)may itself be a neurotransmitter

with antidepressant properties. There is

particular debate about whether patients

with major depressive disorder are predis-

posed to hypotharamic-pituritary-thyriod

(HPT) system abnormalities and whether

such dysfunction may contribute to the

pathophysiology of the illness.10)

Natural killer cell activity and thyroid function in depressed patients 49

Fig.3 NK activity in 14 patients at baseline and

follow-up study

0

10

20

30

40

50

60

Before Medication After Medication

%

p<0.05 wilcoxon’s matched pairs test

Fig.4 Significant correlation between serum TSH level and the total HAM-O score

0

.5

1

1.5

2

15 20 25 30 35 40 45HAM-D Score

Serum TSHΜｇ/ml

p<0.05 nonparametric Spearman correlation procedures

Otherwise, there are many pros&cons

about the thyroid function and depressed

provided that threre are no evidence that low

thyroid function is associated with depression

over the life course, in contrast, that high

normal thyroid function (lower TSH and

higher T4) is associated with depression. In

the patient, who ere medicated by lithium,

SSRIs, TSH and T4 may predict response to

treatment.11) Forthermore, in the Postpar-

tum mood disturbances subject, and the

patients medicated by TMS, there are a

significant negative correlation between TSH

levels at pretreatment and decrease (%) in

the HDRS score.12-14)

This study revealed 2 result of interest.

First, the common antidepressants therapy

was associated with the a significant reduc-

tion of HPT system activity, and second, they

was possible concerned with psycho-immune

systems.

Natural killer cell are a heterogeneous

subset of large granular lymphocytes that

show cytoxicity which is not restricted by the

major histcompatibility complex. These cells

are believed to be involved in the natural

resistance to tumor growth and microbial

infection and other important immunoregu-

latry functions, such as the production of

lymphokines. Natural killer (NK) cells are

referred to as large granular lymphocytes

(LGL) expressing CD16 and CD56 as surface

markers. The NKcell functions include im-

munological surveillance against tumors,

control of viral infections, production of

cytokines, and regulation of killer activity.

Impaired NK cell activity can generally be

identified in patients with congenital im-

munodeficiency, malignant tumors, autoim-

mune diseases, acquired immunodeficiency

syndrome (AIDS), HTLV-1-associated myelo-

pathy/tropical spastic paraparesis (HAM/

TSP), chronic fatigue fatigue syndrome ,

depression, and by stress.15-17)

More than 30 studies have examined

immune parameters in depression. A number

of investigators have reported depression-

related alterations in peripheral blood im-

mune cell numbers and decreases in

peripheral blood mitogen responses and

natural killer cell activity. However, the

studies have led to disagreement and confu-

sion regarding conceptualizations, methods,

experimental designs, and results. Several

recent clinical investigations have demons-

trated that circulating NK activity is abnor-

mally low in depression compared to normal

controls. In our study, NK cell activity were

decreased in unmedicated depressive pa-

tients compared to after treatment. These

observation suggested that NK activity may

be as one important not ʻtraitʼ but ʻstateʼ

marker of severity of depression.18-20)

Basic studies have found that NK activity

is sensitive to many factors, including classic

immunomodulators (eg. interferon), as well as

neural (e.g. catecholamine, GABA) and neuro

endocrine (e. g. corticotrophin releasing fac-

tor, ACTH, cortisol, endorphin) modulator

that have been implicated in the neurobiology

of depression. Viral infections and chronic

diseases have been associated with psychiat-

ric disorders. Among these infections, in-

creased mood disorder has been reported in

HTLV-1,3 patients. HIV, HTLV carriers with

persistently low NK cell activity, NK cell

subsets (CD16 +, CD56 +) were reduced. In

many studies suggest that, 10-20% of AIDS

carrier complained of many physical and

mental symptoms, with persistently low NK

cell activity.21-24) Interleukin-1 (IL-1), which

transmits immunological information to the

久留米大学文学部紀要社会福祉学科編第 10 号・第 11 号合併号50

central nervous system, is produced under

stress. IL-1 also directly promotes secretion

of corticotrophin-releasing-hormone (CRH)

from the hypothalamus, leading to the

activation of the hypothalamus-pituitary-

adrenal (HPA) axis. Cortisol, produced by the

activated HPA axis, was reported to inhibit

the NK cell activity. CRH activates the

sympathetic system, and increased nore-

pinephrine suppresses the NK cell activity.

The hypothalamus is known to play a role of

physiological pacemaker by regulating the

NKcell activity via neuroendocrine hor-

mones. CRH appears to be produced in

excess under stimulation by IL-1, if stress is

not managed appropriately and chronic

fatigue or depression and anxiety persist.

From the neuroimmunological viewpoint, it is

thought that CRHcauses reduction.25-29)

In this study, we found that NK cell activity

was altered by antidepressants medication.

Many studies suggested that thyroid function

( including TSH, TRH), HPA system were

biological marker in depression. Neural and

endocrine changes associated with depress-

ion may mediate this function of cellular

immunity. Those results suggested that

major depressive symptoms are associated

with alternation in aspects of the immune

system and hypothalamus- pituritary func-

tions. Future research should identify diffe-

rent behavioral endophenotypes characteris-

tic for depression, which would greatly

facilitate delineating the biological phe-

nomena associated with this psychiatric

illness.

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