Effects of idebenone on electroencephalograms of patients with cerebrovascular disorders

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1 Arch. Gerontol. Geriatr., 8 (1989) Elsevier AGG Effects of idebenone on electroencephalograms of patients with cerebrovascular disorders Takashi Nakano a Matu6 Miyasaka a, Katsumi Mori a, Tadashi Ohtaka a and Yoshihisa Kifune b a Department of Psychiatry, Dokkyo University School of Medicine, 880 KitakobayashL Mibu-machL Shimotsuga-gun, Tochigi, Japan, and b Biostatistics Section, Takeda Chemical ndustries, Ltd., 3-6 Dosho-machi 2-chome, Chuo-ku, Osaka 541, Japan (Received 2 August 1988; revised version received 22 December 1988; accepted 28 December 1988) Summary A daily dose of 90 mg of idebenone was given to nine patients with cerebrovascular disorders to investigate its effects on clinical symptoms and electroencephalograms (EEG). Changes in EEG before and after the administration were compared quantitatively by computer analysis using the wave-form recognition method. Significant increase in frequency in the a band (O1) and trends of increased appearance of 13 waves, decreased appearance of a 1 bands, and lowered amplitude in the cq and a2 bands were observed after administration of idebenone. The 0 waves of 30/~V and over had a significantly diminished maximum amplitude (C 3) and a tendency to appear less often. Mean frequency of the EEG and appearance of fast waves apparently increased in the patients showing improvement of the clinical symptoms as compared with those not showing improvement. The results suggested that idebenone improved the EEG in the patients with cerebrovascular disorders, causing changes in EEG similar to those observed with psychostimulants. debenone; Cerebrovascular disorder; Computerized EEG analysis; Psychostimulant ntroduction Many drugs are being developed for cerebrovascular disorders, but evaluation of the efficacy of these drugs is based largely on subjective indices such as mental and behavioral symptoms. Abnormalities in EEG, including decreased frequency of waves and increased slow-wave components, are often found in cerebrovascular disorders and dementia of vascular origin (Kiloh et al., 1981; Otomo, 1971). This Correspondence should be addressed to Takashi Nakano, Department of Psychiatry, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, Japan /89/$ Elsevier Science Publishers B.V. (Biomedical Division)

2 356 may reflect dysfunctions of the brain. t has been thought that few drugs affect abnormal EEG favorably, but some have been reported to improve the EEG (Hirasawa et al., 1984; Miyasaka et al., 1982) which indicated that EEG findings might be a useful index to determine the mechanism of their actions. debenone is an enhancer of the cerebral metabolism. t smoothes the function of the electron-transfer system of mitochondria in brain cells and inhibits the nonphysiological lipid peroxidation of the mitochondrial membrane, increasing the respiratory activity (Sugiyama and Fujita, 1985; Suno and Nagaoka, 1984). n addition, idebenone has been reported to improve disorders of energy metabolism and to relieve neurologic signs in experimental cerebral ischemia (Nagaoka et al., 1984). Clinically, it was noted that it improves mental symptoms and subjective symptoms in patients with cerebrovascular disorders indicating the high therapeutic potential of this drug (Otomo et al., 1985). We studied quantitatively the effects of idebenone on the basic activities of EEG in patients with cerebrovascular disorders, using an automated EEG analyzer system. Subjects Nine patients, who were hospitalized at or visiting as outpatients the Department of Psychiatry of Dokkyo University School of Medicine, were our subjects. Written informed consent was obtained from all subjects or their guardians before the start of the study (Table ). There were five men and four women. Ages ranged from 37 to 82 years, with a mean of Diagnosis was made by means of computerized tomography as well as based on the clinical symptoms. There were four patients with sequelae of cerebral infarction, one with sequelae of cerebral apoplexy (uncertain whether it involved hemorrhage or infarction) and four with cerebral arteriosclerosis. The duration of illness was from 10 months to 8 years and 4 months. None of the disorders were acute. The patient with cerebral arteriosclerosis complicated with endogenous depression was hospitalized 2 months before the start of the idebenone treatment and the depressive condition was improved after hospitalization and stabilized by the time when the idebenone treatment began. Most of the subjects had such symptoms as decreased volition and spontaneity, emotional disorders or decreased memory and disorientation. The severity of EEG abnormalities at the start of the study was slight in all the patients. Methods Method of administration One tablet of idebenone was given to the patients three times daily (90 mg/day) after every meal for 12 weeks. Administration of other cerebral metabolism activators, cerebral vasodilators, or minor or major tranquilizers was not started from 4

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4 358 weeks before the study and during the trial. When such drugs had been given for more than 4 weeks before the study began, however, they were continued without changing the drug, dosage or route of administration. A benzodiazepine drug was concomitantly used in three patients. As it was in use since 4 weeks before beginning the idebenone treatment, its influence on EEG was thought to have reached a stabilized state. Evaluation of clinical signs and symptoms n addition to examination of the mental symptoms, subjective symptoms and neurologic signs and disturbances in activities of daily living (ADL), the patients were evaluated by the Hasegawa's Dementia Rating (DR) Scale (Hasegawa, 1977) before the idebenone treatment started, and 4, 8 and 12 weeks after beginning the idebenone treatment. Recording and analysis of EEG EEGs were recorded when the patients were awake, and resting with their eyes closed before the idebenone treatment was started and at the 8th and 12th weeks after the start of therapy, three times in all. We used the nternational system and placed electrodes on FP1, 2, FT. s, T3, 4, C3.4, P_3.4, O1.2, and A1, 2. EEGs were recorded on paper using a monopolar lead system and at the same time on magnetic tape. Later, a stable part of recording of 1 rain without drowsiness was selected by visual inspection for each patient, and the EEGs from the left central (C3) and the left occipital (O1) were analyzed, using an automated EEG analysis system that simulated a manual method of EEG measurement. Frequency (Hz) was classified as follows: 0.5 < 8 wave < 4.0, 4.0 < 02 wave < 6.0, 6.0 < 01 wave < 8.0, 8.0 < c~ 1 wave <9.0, 9.0_<c~, wave<11.5, 11.5<as wave<13, 13</31 wave<18.0, 18</32 wave < 30. Results Effects on EEG The effects of idebenone on the EEG were shown as mean values and standard deviations (SD) of the nine patients. (1) Mean frequency Table shows the mean frequency in all the frequency bands ( Hz), the O~-fll band ( Hz) and the c~ band ( Hz), and the peak frequencies (the frequency band where there are the largest number of waves) before the trial started and at the 12th week. (a) The mean frequency in all the frequency bands at 01 in the group of all patients was Hz (mean + SD) before idebenone therapy was started and Hz at the 12th week; these values at C 3 were 13.5 _+ 1.8 Hz and 14.2 _+ 2.2

5 359 TABLE Changes in mean frequency and peak frequency (12 weeks after beginning the idebenone treatment) Location tems Before idebenone After idebenone O 1 all bands (0,5-30 Hz) 12.4 _ fll band _ 0.8 a band 9.8_ _+0.3 a peak frequency 8.9 _ _+ 2.0 C 3 all bands ( Hz) 13.5 _ _ ill band _+ 0.7 a band 10.0 _ _+ 0.3 peak frequency 9.1 _ Figures indicate mean -+ SD; unit, Hz. The paired t test was used; a p < Hz, respectively. The mean frequency at O 1 was slightly higher but without significant difference. (b) The mean frequency in the 01-/31 bands was 8.8 _+ 0.6 Hz before idebenone and Hz after idebenone at O 1 and Hz before idebenone and Hz after idebenone at C 3. There were no significant changes. (c) The mean frequency of the a band increased significantly (p < 0.05) at 01 from Hz before idebenone to Hz after idebenone. There was a tendency for waves to become faster. At C3, it was Hz before idebenone and Hz after idebenone and showing no significant changes. (d) Peak frequency was Hz before idebenone and Hz after idebonone at 01 and showing no significant changes. Wl~ile the frequency increased at C 3 from Hz before idebenone to Hz after idebenone, but the change was not significant. TABLE Changes in appearance rate (% time) of all bands (12 weeks after beginning the idebenone treatment) O1 before idebenone after idebenone before idebenone after idebenone _ _ _ _ _ _ _ _ _ _ _+ 9.6 a a a a _ ot _ / _ a 29.8 _ Figures indicate mean+ SD; unit, %. Wilcoxon's signed-rank test was used; a, p < C3

6 360 LoCOtlOrl Patients 'with cerebrovosculc]r 8~soroers ] ncrease 6 O2 Decrease.& P<010 ncrease 10 %% F,? 5~ O~ 02 a Decrease Fig. 1. Changes in appearance rates of waves in each frequency band (difference between before and after idebenone): (0 = 0 z + 01, a = a s + a 2 + a 3, /3 =/31 +/32). Results at the 8th week indicated trends similar to those after idebenone (at the 12th week), but changes were slighter. (2) Appearance rates ( % time) of waves and Z-profile for each frequency band A comparison of the appearance rates of waves for each band before idebenone and at the 12th week of the idebenone treatment (Table, Fig. 1) showed a tendency for the a 1 components (the slower component of a) to decrease at O 1 (p < 0.10) and a tendency for the/3 wave to increase at O a (p < 0.10). On the other hand, the appearance rates of waves at C 3 showed a similar tendency but without significant difference. Changes in appearance rates and mean amplitude at the 8th and 12th weeks of the idebenone treatment were compared with those before the idebenone treatment was started and expressed as the Z-profile, based on the normal deviation for each band (Fig. 2). The appearance rate of the a t components at O 1 decreased significantly at the 8th week of the idebenone treatment, and that of the /3 components tended to increase. Similar changes were observed at the 12th week. At C3, significant increases in /32 were noted at the 8th week. The mean amplitude decreased significantly for the a t components at 01 at 12th weeks, and the mean amplitude decreased for a 1 components at 12th weeks, and for a 2 components both at the 8th and 12th weeks at C 3.

7 ' ncrease T + 0 Normal 0 deviation -1.0 Decrease -20 Appearance rate (Oi) p<o J p<0.10 ncrease ~ 1 al a2 2 ~,~, p<o 10 Decrease -2.0 Appearance rate / (c3) t i t a~ /V. W z 03 i t p< 005 p<0.1o p<010 ncrease ~+ 1.0 Normal deviation Decrease -2.0 Mean amplitude Mean amplitude (O1) ( 3) p < 010 J.nc;ease[-- / +10 a s 02 8~ a~ a2a /3, P2 a ~a, a2 P~2.~ Z~ f-" ~ /^~ Norm.el 0 deviatton ~ t~ )1 ;~., / \\ ~1 l -1.0 ~', X p<0.10 Decrease ~ p<o weeks after beginning of administration w e e k s after beginning of administration Fig. 2. Z-profiles in each frequency band. p<olo p<0.10 p<o.05 TABLE V Changes in O waves of 30 ~V and over (12 weeks after beginning the idebenone treatment) Location tems Before idebenone After idebenone 01 appearance rate (%) 23.3 _ maximum amplitude (/-tv) mean amplitude (/~V) C 3 appearance rate (%) maximum amplitude (/~V) 79.4 _ a mean amplitude (ffv) 55.3_ Figures indicate mean + SD. The paired t test was used; a p < 0.05.

8 362 (3) 0 waves of 30 ixv and over Comparison of 0 waves of 30 ~av and over before idebenone and at the 12th week of the idebenone treatment showed significant drops in the maximum amplitude at C 3 at the 12th week (p < 0.05; Table V). Trends were similar at O~ but without significant difference. The results at the 8th week of treatment were almost the same as those at the 12th week. Appearance rates tended to decrease at O h (p < 0.10), and the maximum amplitude at C 3 decreased significantly (p < 0.05). (4) Bird's eye view A bird's eye view, looking down at an angle of 60 to the plane, with the following three axes: frequency bands (45 to the abscissa), amplitude (-45 to the ordinate), and the number of waves corresponding to them (including single and super-imposed waves) (height), were drawn for both 01 and C 3 by a computer, to compare the changes before and after the idebenone treatment. Two such views for patients who had marked changes are shown in Fig. 3. Superimposed bird's eye view, before and after therapy, for a patient (Case No. 8) with sequelae of cerebral infarction, are shown in Fig. 3. There was an increase in the /7 components and tendency for the amplitude to increase. Effects on clinical signs and symptoms The effect of idebenone on clinical signs and symptoms are listed in Table V. Mental symptoms tended to improve in five of the nine patients. The symptoms that improved were anxiety and irritation (5/6), restlessness and excitement (3/4), depressive mood (2/4), disturbances in falling asleep (3/6) and decrease of volition (2/7). Subjective symptoms improved in two of the four patients, and dizziness and faintness on standing (2/2) improved. Neurologic signs improved in only two of the six patients. Disturbances in ADL improved in only two of the seven patients. The overall efficacy of the drug was rated as effective or fair in five of the nine patients. 50 ~ 6O 100 '~'~,i Fig. 3. Bird's eye view... before administration; - - tion. 1oo~, 12 weeks after beginning of administra-

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10 364 ~q > ;> E,',"!,.~ +i '19 ~' +i e,e-, '4; "5 ~..," -7-,~- +J :zk,,6 V +J V [ - ~ +i Y r.~ "" +l +1.=_.fi ]

11 Retention of urine and edema occurred in one patient 7 days after the beginning of the idebenone treatment. However, both signs improved as the treatment was continued and amitriptyline, which had also been given, was stopped. This suggested that these side effects were not related to the administration of idebenone. When a comparison was made in the influence of EEG of idebenone between the patients showing clinical response and those not showing response, there was a tendency for the waves to become faster in the patients whose clinical symptoms improved. n them, increased mean frequencies and increased 13 components or reduced appearance rates of 19 components of 30 /~V or over, were observed. The results suggested that changes in EEG were related to the effects of idebenone on clinical signs and symptoms. 365 Discussion There are few reports on the effects of idebenone on the EEG. Otomo et al. (1985) performed an attentive judgment of EEG before and after idebenone and reported that localized abnormalities, mainly of the 0 waves, improved in many cases when this drug was given. No definite effects of idebenone on basic activities were observed. We studied quantitatively the effects of idebenone on the basic rhythms of EEG in patients with cerebrovascular disorders who had some basic wave abnormalities on EEG, using an automatic EEG analysis system. ncreased fl components and increased mean frequencies in the o band associated with reduced slow a components, particularly the a component, were observed in the patients. Decreased maximum amplitude and reduced appearance rates of 0 waves of 30/~V and over, which correlate well with the results of the Bender Gestalt Test (Miyasaka et al., 1978), were found. toh (1986) administered a single dose of mg of idebenone to patients with sequelae of apoplexy and performed EEG studies to recognize improvement of a rhythm, a decreasing tendency of slow waves and disappearance of the difference between the right and left. Further, they reported that the patients who were given idebenone in a single oral dose of 150 mg after inhibition of brain stem function by intramuscular administration of phenobarbital (0.1 g), showed improvement of a rhythm and a tendency for waves to become faster by increase of fl waves. The results suggest that in patients with cerebrovascular disorders, idebenone activates the remaining unaffected function, increases the fast wave components of EEG, and fastens a waves. These changes seem to be related to improvement of the clinical symptoms. t is generally said that psychostimulants increase the appearance of 13 waves on the EEG, and reduce the appearance of 0 and ct waves (Fink, 1961; til, 1974; Saito, 1984). This is well in agreement with the changes in the EEG caused by idebenone in the patients with cerebrovascular disorders, suggesting that idebenone has a psychostimulant-like action on the EEG. On the other hand, it was also suggested that idebenone has broader activities other than psychostimulation if we take the

12 366 improvement by idebenone of symptoms such as anxiety, restlessness, excitement and disturbances in falling asleep (tranquilizing effect) into account. References Fink, M. (1961): Quantitative electroencephalography and human psychopharmacology, t. Frequency spectra and drug action. Med. Exp., 5, Hasegawa, K. (1977): Clinical evaluation of dementia. Clin. Psychiat., 6, , in Japanese. Hirasawa, H., Okubo, Y., Atsumi, Y., et al. (1984): Effects of amantadine hydrochloride on clinical symptoms and EEG of patients with dementia. Clin. Psychiat., 13, 81-88, in Japanese. til, T.M. (1974): Quantitative pharmaco-electroencephalography (use of computerized cerebral biopotentials in psychotropic drug research). Psychotropic drugs and the human EEG, pp Editor: T.M. til. Karger, A.G., Basle. toh, T. (1986): Personal communication. Kiloh, L.G., McComas, A.J., Osselton, J.W. and Upton, A.R.M. (1981): Clinical electroencephalography, 4th edn., pp Butterworth, London. Miyasaka, M., Nakano, T., Ohmori, K., et al. (1978): The mental deterioration in the aged and computerized EEG analysis. Folia Psychiat. Neurol. Jpn., 32, Miyasaka, M., Nakano, T., Matsuura, M., et al. (1982): Effects of lisuride hydrogen maleate on EEG of patients with cerebrovascular disorders and senile dementia -- statistical study of analysis of computerized EEG analysis. Clin, Psychiat., 11, , in Japanese. Nagaoka, A., Suno, M., Shibota, M. and Kakihana, M. (1984): Effects of idebenone (CV-2619) on neurologic symptoms and regional cerebral blood flow and energy metabolism caused by experimental cerebral ischemia. Jpn. J. Pharmacol., 84, , in Japanese. Otomo, E. (1971): EEG of the aged. Clin. Electroencephalogr., 13, , in Japanese. Otomo, E., Araki, G., Hasegawa, K., et al. (1985): Usefulness of CV-2619 tablets for cerebrovascular disorders -- multi-institute double-blind calcium hopantenate-controlled test. gaku no Ayumi 134, , in Japanese. Saito, M. (1984): Psychotropic drugs and EEG. Neurol. Psychiat. Pharmacol., 3, , in Japanese. Sugiyama, Y. and Fujita, T. (1985): Stimulation of the respiratory and phosphorylating activities in rat brain mitochondria by idebenone (CV-2619), a new agent improving cerebral metabolism. FEBS Lett., 184, Suno, M. and Nagaoka, A. (1984): nhibition of lipid peroxidation by a novel compound, idebenone (CV-2619), in rat mitochondria and mode of action of the inhibition. Biochem. Biophys. Res. Commun., 125, Yamamoto, K., Shimazono, Y., Miyasaka, M., et al. (1975): The system construction on a newly developed automatic EEG diagnosing system -- with special regard to the wave-form recognition method. Psychiat. Neurol. Jpn., 77, , in Japanese.

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