Antidepressive Effect of Nicergoline on Patients with Mild Post-Stroke Depression

● Original

Antidepressive Effect of Nicergoline on Patients with Mild Post-stroke Depression

Yasuhiro Nishiyama1）, Yuichi Komaba1） Sunao Mizumura2） and Yasuo Katayama1）

Abstract Background and Purpose : Post-stroke depression（PSD）is considered the most frequent and important neuropsychiatric complication in stroke patients. Antidepressants are commonly used in the treatment of severe PSD, but these drugs are not necessarily administered to patients with mild PSD. Nicergoline is an ergoloid mesylate derivative currently used for the treatment of cognitive and behavioral disorders of older people or neuropsychological impairments in cerebrovascular disorders, though antidepressive effects of nicergoline is unknown. We investigated whether nicergoline is effective on patients with mild PSD instead of antidepressants. Methods : We selected 6 patients with mild PSD defined by the Zung’s self-rating depression scale（SDS）1 month after the onset of stroke. Nicergoline（15 mg!day）was administered for four weeks to the patients one month after the onset of cerebral infarction. Depression was also evaluated using SDS after administration of nicergoline. Furthermore, we evaluated the effect of nicergoline on three subscales of SDS, i.e., cognitive, affective and somatic symptoms. Results : The SDS score improved significantly in all patients after treatment（p＝0.0042）. The analysis of three subscales revealed that the cognitive symptom in the SDS scores is a significant improved（p＝0.026）. Conclusions : Our findings suggest that niceijoke nicergoline has antidepressive effect on patients with mild PSD instead of antidepressants and diagnosis of PSD should be performed in early period of stroke. （Cerebral Blood Flow and Metabolism 17 : 11―16, 2005） Key words : nicergoline, depression, cerebrovascular disease

adverse impact on functional recovery2） and sur- Introduction vival3）. It has previously been reported that PSD is an independent predictor of poor long-term func- Symptoms of depression, such as deteriorated mo- tional outcome4,5）. Recent reports underlined the im- tivation and apathy, after stroke are collectively portance of early treatment for PSD that can have a called poststroke depression（PSD）, and the concept positive effect on rehabilitation and functional recov- of PSD has been established in recent years. Post- ery of the patients6,7）. stroke depression（PSD）is considered as the most Nicergoline is an ergoloid mesylate derivative with frequent and important neuropsychiatric complica- pharmacological actions such as cerebral metabo- tion in stroke patients, since 12％ to 64％ of stroke lism-improving action8） and cerebral neurotransmi- survivors experience depression both early and late ssion-improving action9）. Nicergoline is also effective after stroke1） and since this condition can have an from the clinical view point in improving decreased motivation and initiative10）. However, effect of nicer-

1）The Second Department of Internal Medicine, 2）Depart- goline for PSD is unclear. In the treatment of PSD, ment of the Radiology, Nippon Medical School tricyclic, tetracyclic antidepressants, or selective

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Table 1. Background

SDS 1 Age Diagnosis Atrial Case Sex month after Hypertension Hyperlipidemia Diabetes Smoking （yr）（lesion location） fibrillation onset 1 81 F Atherothrombotic infarction 52 ＋＋－－－（left putamen to radio corporis callosi） 2 76 M Atherothrombotic infarction 51 ＋－－－＋（left arteria cerebri media area） 3 55 M Atherothrombotic infarction 46 －－－－＋（left pons） 4 68 M Cardiogenic cerebral embolism 46 －－－＋＋（left arteria cerebri anterior area） 5 67 M Lacunar infarction 44 ＋－＋－－（left medulla oblongata） 6 77 F Cardiogenic cerebral embolism 41 ＋－－＋－（right arteria cerebri posterior area）

serotonin reuptake inhibitors（SSRI）is commonly administered, but cannot be administered to some patients, especially elderly patients, because of their side effects. As a result, these antidepressants are not often administerd to patients with mild PSD. Here we investigate whether nicergoline has antide- presseive effect on mild PSD.

Subjects and Methods

Fig. 1. Changes in Zung self-rating depression scale The present study included 30 of 36 consecutive （SDS）scores after treatment with nicergoline. All pa- patients with their first significant acute-ischemic tients treated with nicergoline had significantly better stroke admitted to the Department of Neurology, scores after treatment with nicergoline（p＝0.0042 ; paired t-test）. The scores changed from 47.17±4.26 to Nippon Medical School between June and Septem- 40.33±4.96. There was a significant reduction of the ber 2002. Diagnosis of stroke was made clinically by scores after treatment with nicergoline. stroke with experienced stroke neurologists using the Trial of ORG 10172 in Acute Stroke Treatrment （TOAST）criteria11）. All patients was underwent CT Of these patients, 4 were male, and 2 were female ; and!or MRI scanning. We selected the 30 patients their mean age±SD was 70.6±9.4 years（range, 55 who met the following criteria（I）no : severe apha- to 81）. The patients’clinical backgrounds data are sia（II）no ; reduced level of consciousness（III）no ; summarized in Table 1. One tablet（5 mg）of nicer- dementia（IV）no ; alcohol abuse（V）no ; psychosis goline was administered three times daily for four or current antidepressant treatment. Six of 36 pa- consecutive weeks. PSD was also evaluated by SDS tients were excluded. All 30 patients were evaluated after the administration of nicergoline. The 20 items using the Zung SDS12） one month after the onset. of SDS were divided into the following three The 20 items of SDS are scored according to a stan- subscales according to the report of Sakamoto et dard 4-point scale（1 to 4）for each item, with a poten- al14）. 1）cognitive symptoms, 2）affective symptoms, tial range of 20 to 80. Mild PSD was defined be- and 3）somatic symptoms. SDS item Nos. 11, 12, 14, tween 40 and 59 points according to the the report 16, 17, 18, and 20, Nos. 1, 3, 10, 13, and 15, and Nos. 4, of Herrmann2） and Ohira13）. From among patients, six 5, 7, and 9 were considered to represent cognitive, patients were remained, meeting mild PSD criteria. affective and somatic symptoms, respectively. Cere- All six patients were administerd with nicergoline. bral blood flow was also quantified in one patient be-

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Fig. 2. Changes in three subscales of SDS after treatment with nicergoline. After treatment with nicergoline, cognitive symptoms were significantly improved（p＝ 0.026 ; paired t-test）. However, no statistically significant differences were found regarding affective symptoms（p＝0.091 ; paired t-test）or somatic symptoms（p＝ 0.095 ; paired t-test）.

Fig. 3. Cerebral blood flow and images obtained by single photon emission computed tomography（SPECT）with N-idopropil-p-［123I］-iodoamphetamine（123I-IMP） before and after treatment with nicergoline in Case 1. A. Cerebral blood flow was quantified before and after treatment with nicergoline in relation to the location of the lesions. B . Imaging of cerebral blood flow by SPECT before and after treatment．（before : before nicergoline treatment ; after : after nicergoline treatment） Little increases of the cerebral blood flow in the occipital cortex and in the thalamus on the left side, as well as approximately 10％ increases in the bilateral striata were noticed, but no other clear changes were observed.

―13― 脳循環代謝第 17 巻第 1 号 fore and after nicergoline treatment using on recovery of functions, some authors4,5） have con- N-idopropil-p-［123I］-iodoamphetamine（123I-IMP）single firmed that PSD is an independent predictor of poor photon emission computed tomography（SPECT）. long-term functional outcome. The influence of PSD The location of the lesion detected by SPECT was on post-stroke outcome has been confirmed by a re- as follows : frontal lobe, temporal lobe, parietal lobe, cent study18）, which has shown that the presence of occipital lobe, white matter, striatum, thalamus, PSD 1 month after stroke increases the risk of mor- brainstem and cerebellum, as previously reported15,16）. tality 12 and 24 months later. Gonzalez-Torrecillas et Changes in SDS scores after nicergoline administra- al6） and, recently Miyai and Reding7） and Chemerin- tion were statistically assessed using a paired t-test. ski et al.19） underlined the importance of early treatment for PSD that can have a positive effect on the Results outcome of the patients. Depression itself is responsi- ble for the delay in rehabilitation and the prevention As illustrated in Figure 1, SDS scores after treat- of functional recovery. Therefore, diagnosis of PSD ment with nicergoline were significantly improved in should be performed in early period of stroke. all the patients（p＝0.0042 ; paired t-test）.Theim- Moreover, we divided the 20 items of SDS into provement shown by the three subscales was statis- three subscales, that is cognitive, affective and so- tically analyzed. As shown in Figure 2, cognitive matic symptoms, and then compared the scores of symptoms showed a significant improvement after these subscales obtained before and after treatment treatment（p＝0.026 ; paired t-test）. No statistically with nicergoline. Our results revealed a significantly significant differences were found regarding affec- better improvement of cognitive symptoms, while tive symptoms（p＝0.091 ; paired t-test）or somatic there was no significant improvement in affective or symptoms（p＝0.095 ; paired t-test）. Cerebral blood somatic symptoms. In a previous study, nicergoline flow in Case 1 is shown in Figure 3. Apart from a lit- was found to inhibit the activity of brain acetyl- tle increases of the cerebral blood flow in the occipi- cholineesteraseinmiceandrats20）. The central tal cortex and the thalamus on the left side and ap- cholinergic system is known to play a fundamental proximately 10％ increases of blood flow in the bilat- role in cognitive function, and extensive evidence in- eral striae, no other noticeable changes were ob- dicates that a disruption of the cholinergic function served. leads to characterisic signs of aging and Alzheimer’s disease. Inhibition of cholinesterase in nicergoline Discussion may result in improvement of cognitive symptom21,22）. In conclusion, we investigated whether nicergoline In the present study, nicergoline was given to pa- is thought to have antidepressive effect on patients tients with mild depression in the early stage of with mild PSD instead of antidepressants and diag- stroke, namely four weeks after the onset. Notably, nosis of PSD is thought to be performed in early pe- SDS scores improved significantly in all the patients. riod of stroke. It is not rare for us to encounter patients with symptoms of depression, such as deteriorated moti- References vation and apathy, in these patients after stroke. 1）Robinson RG, Bolduc PL, Price TR : Two-year longitu- These symptoms are collectively called poststroke dinal study of poststroke mood disorders : diagnosis depression（PSD）. and outcome at one and two years. Stroke 18 : 837― 843, 1987 We evaluated PSD using the Zung SDS, which is 2）Parikh RM, Robinson RG, Lipsey JR, Starkstein SE, widely used as a reliable depression screening in- Fedoroff PJ, Price TR : The impact of poststroke de- 13,17） strument , at a defined timing, four weeks after pression on recovery in activities of daily living over the onset of ischemic stroke. As the timing of PSD a 2-year follow up. Arch Neurol 47 : 785―789, 1990 evaluation, we selected one month after ischemic 3）Morris PL, Robinson RG, Andrzejewski P, Samuels J, stroke, because the benefit of early diagnosis may be Price TR : Association of depression with 10-year reflected in good outcome. In the influence of PSD poststroke mortality. Am J Psychiatry 150 : 124―129,

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1993 Ogawa Y, Imano H, Sato S, Kitamura A, Shimamoto 4）Herrmann N, Black SE, Lawrence J, Szekely C, Szalai T : Prospective study of depressive symptom and risk JP : The sunnybrook stroke study. A prospective of stroke among Japanese. Stroke 32 : 903―908, 2001 study of depressive symptoms and functional out- 14）Sakamoto S, Kijima N, Tomoda A : Factor structures come. Stroke 29 : 618―624, 1998 of the Zung self-rating depression scale（SDS）for un- 5）Pohjasvaara T, Vataja T, Leppavuori A, Kaste M, dergraduates. J Clin Psychology 54 : 477―487, 1998 Erkinjuntti T : Depression is an independent predic- 15）Komaba Y, Mishina M, Utsumi K, Katayama Y, Ko- tor of poor long-term functional outcome post-stroke. bayashi S, Mori O : Crossed cerebellar diaschisis in Eur J Neurol 8 : 315―319, 2001 patients with cortical infarction : logistic regression 6）Gonzalez-Torrecillas JL, Mendlewicz J, Lobo A : Ef- analysis to control for confounding effects. Stroke 35 : fects of early treatment of post-stroke depression on 472―476, 2004 neuropsychology rehabilitation. Int Psychogeriatr 7 : 16）Kamano C, Komaba Y, Sakayori O, Iino Y, Katayama 547―560, 1995 Y : Decreased cerebral blood flow in renal transplant 7）Miyai I, Reding MJ : Effects of antidepressant on recipients. Intern Med 41 : 677―683, 2002 functional recovery following stroke : a double-blind 17）Katayama Y, Usuda K, Nishiyama Y, Katsura K : study. J Neurol Rehabil 12 : 5―13, 1998 Poststroke depression. Jpn J Geriatr 40 : 127―129, 8）Le Poncin-Lafitte M, Grosdemouge C, Rapin JR : Si- 2003 multaneous study of haemodynamic, metabolic and 18）House A, Knapp P, Bamford J, Vail A : Mortality at 12 behavioural sequelae in a model of cerebral ischaemia and 24 months after stroke may be associated with in aged rats : Effects of nicergoline. Gerontology 30 : depressive symptoms at 1 month. Stroke 32 : 696― 109―119, 1984 701, 2001 9）Moretti A, Carfagna N, Caccia C, Carpentieri M, 19）Chemerinski E, Robinson RG, Kosier JT : Improved Amico A, Marchi G, Trunzo F : Neurochemical effects recovery in activities of daily living associated with of ergoline derivatives. In : Proof of therapeutical ef- remission of poststroke depression. Stroke 32 : 113― fectiveness of nootropic and vasoactive drugs. ed by 117, 2001 H Herdrich, Springer-Verlag, Heidelberg, 1985, 20）Matsuoka Y, Fukushima T, Iwata H, Matsumoto M, pp103―110 Shibutani Y, Kawashima K, Kudo Y, Ishida R : Inhibi- 10）Herrmann WM, Stephan K, Gaede K, Apeceche M : A tory action of nicergoline and its major metabolites multicenter randomized double-blind study on the ef- on acetylcholinesterase activity in rat and mouse ficacy and safety of nicergoline in patients with multi- brain. In : Basic clinical and therapeutic aspects of Al- infarct dementia. Dement Geriatr Cogn Disord 8 : 9― zheimer’s and Parkinson’s diseases. ed by T Nagatsu, 17, 1997 Plenum Press, New York, 1990, pp 415―419 11）Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, 21）Davis P, Maloney AJ : Selective loss of central cholin- Love BB, Gordon DL, Marsh EE 3rd : Classification of ergic neurons in Alzheimer disease. Lancet 2 : 1403, subtype of acute ischemic stroke. Stroke 24 : 35―41, 1976 1993 22）White P, Hiley CR, Goodhardt MJ, Carrasco LH, Keet 12）Zung WWK : A self-rating depression scale. Arch Gen JP, Williams IE, Bowen DM : Neocortical cholinergic Psychiatry 12 : 63―70, 1965 neurons in elderly people. Lancet 1 : 668―671, 1977 13）Ohira T, Iso H, Satoh S, Sankai T, Tanigawa T,

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脳梗塞後うつに対するニセハゴリンの抗うつ効果の検討

西山康裕1），駒場祐一1），水村直2），片山泰朗1）

1）日本医科大学第 2 内科 2）同放射線科

脳梗塞後うつ病は最も重要な脳梗塞後遺症の一つである．近年，脳梗塞うつ病患者に対して，早期の治療が機能的あるいは生命的予後に有意な改善をもたらすと報告されている．しかしながら，重症の脳梗塞うつ患者に対しては抗うつ薬での加療が行われるが，軽症な患者は加療されないことが多い．一方，ニセルゴリンは脳梗塞後遺症，特に意欲低下に対して効果的な薬剤とされるが，慢性期早期脳梗塞での投与効果は検討されていない．我々は脳梗塞発症 1 カ月後に Zung の SDS（self-rating depression scale）を用いて軽症うつ病と診断された 6 名に対して，ニセルゴリンを 4 週間投与した．その結果，6 名全例において SDS スコアは有意な改善を認めた（p＝ 0.0042）．さらに SDS の 20 項目から cognitive，affective，somatic symptom を抽出し検討した結果，cognitive symptom にのみ，有意な改善を認めた（p＝0.026）．脳梗塞患者において早期に軽症うつ病を診断し，ニセルゴリンを投与することはうつ改善効果が期待される．キーワード：ニセルゴリン，うつ病，脳梗塞

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