Folia Psychiatrica et Neurologica Japonica, Vol. 30, No. 2, 1976

Effects of L-Dopa and Vitamin )3(, on Electroencephalograms of Schizophrenic Patients: A Preliminary Report Michi Yarnauchi, M.D. Department of Neuropsychiatry, Kurume University School of Medicine, Kuriitne and Kai Hospital, Yanagawa

INTRODUCTION

The present author has been pursuing studies of the effect of L-Dopa on electroThe L-dihydroxyphenylalanine (L-Dopa) encephalograms since some years ago, which therapy has been acquiring importance in failed to reveal any significant EEG changes clinical neuropsychiatry since L-Dopa," a during prolonged periods of observation therapeutic agent for parkinsonism, was following administration of L-Dopa in a found empirically to be endowed with psy- single oral dose. The study reported herein chotropic actions. The drug was first ap- was undertaken to investigate EEG changes plied for the treatment of depressione l o and and changes in clinical manifestations in reported to have the clinical effects of schizophrenic patients receiving low doses elevating mood and activating behavior.l2 of L-Dopa daily in combination with neuIts application to the treatment of schizo- roleptic agents for a period of eight weeks. phrenic patients began with the use against Group B vitamins have long been reparkinsonism which occurs as an untoward cognized to play important roles in the effect of certain neuraleptic agents, where metabolism of the nervous system' l o 24 and, it has been described that the symptoms of schizophrenia may be either alleviated or, among these vitamins, vitamin Ba is known on the contrary, aggravated in response to to serve the function as coenzyme in the process of decarboxylation of L-Dopa to administration of L-Dopa." In 1971, Inanaga and co-workers re- dopamine (dihydroxyphenylethylamine). On ported a marked improvement in clinical the presumption that this vitamin might manifestations of schizophrenia, especially have some neuropharmacologic bearing decrease of spontaneity and disturbance of upon the L-Dopa therapy, we conducted contact, observed in patients receiving neu- analysis of electroencephalograms recorded roleptics combined with low doses of L- with twenty schizophrenic patients who Dopa. There have been numerous reports were given this vitamin, as pyridoxal-5'of clinical trials of low-dose L-Dopa phosphate (referred to hereinafter as Plp). therapy in schizophrenia s ~ b s e q u e n t l y , ~ ~ In addition, a series of eight patients with 27 Zn $!I :ii :in which describe that the thera- chronic schizophrenia with an average dupeutic response was related to duration of ration of illness of 18 years were treated illness, the rate of clinical improvement with low doses of L-Dopa combined with being low in chronic cases. Plp and their EEG changes and changes in clinical manifestations observed, with the gratifying results that could not be obtained Received for publication Mar. 4, 1976. ~~

M. Yamauchi

122

by the therapy with L-Dopa or Plp alone. The present communication deals with the findings in these three studies along with some discussion. SUBJECTS A N D METHODS

All studies were performed at Kai Hospital, Yanagawa City, Fukuoka Prefecture. The subjects admitted to the study were inpatients with schizophrenia at the psychiatric wards of Kai Hospital. Practically all these cases were of chronic schizophrenia with a duration of illness over five years, details of which will be given below in respective sections as well as those of age and sex distribution. Their principal manifestations included decreased spontaneity, abulia, emotional blunting and disturbance of contact. Throughout the study, psychotropic drugs that had been given to the patients up to the time of admission to this study were continued as basal treatment. These included chlorpromazine, levomepromazine, thioridazine, haloperidol, triperidol, floropipamide, carpipramine, perphenazine, propericiazine, spiclomazine, diazepam, promethazine, trihexyphenidyl and biperiden which were administered at usual dosage levels. No alteration in the variety of drug or dose level was made as to these psychotropic medications in any of the cases during the study. Electroencephalograms were recorded with 13-channel Model ME-1 35D (Nihon Koden) with voltage calibration of 5 mm deflection for 50 microvolts, with the time constant set at 0.3 sec. and at a paper speed of 3 cm/sec., using elastic band-restrained electrodes arranged in accordance to the 1O/ 20 system. The EEG tracings were analyzed by means of an automatic frequency analyser, Nihon Koden Model MAF 5 which is a standard device for analysis of EEG into five frequency bands, 6(2-4Hz),

0(4-8Hz), a(8-I 3Hz), PI(13-2OHz) and P2(20-30Hz). The incidence of each frequency band was expressed as energy % which represented a percentage of the squared amplitude of each band to the sum of squared amplitudes of all bands. The regions of scalp of electrode placement and time subject to analysis, which vary with sections, will be described in respective sections. RESULTS 1. EEG and Symptomatic Changes during

L-Dopa Therapy ( I ) Subjects and Procedure Ten patients, five males and five females, were studied. They ranged in age from 24 to 48 years with an average of 37 years. The duration of disease varied between seven and 32 years, averaging 12.4 years and being from five to less than 10 years in four cases, from 10 to less than 15 years in five cases and over 15 years in one case. During the period of observation, we made it a rule to administer G D o p a as adjunctive therapy to the previously instituted psychotropic medication which was continued without alteration in the variety of drug or dose level whereas the dose of LDopa was adjusted according to symptom. L-Dopa was started with dosage of three 100-mg capsules per day, given in three divided doses orally after meals. In every case the drug was administered daily over a period of eight weeks, with the dosage increased 100 mg/day biweekly up to 600 mg/day. Electroencephdlograms and automatic frequency analysis were recorded with the above-described devices before and at twoweek intervals after initiation of L D o p a medication. The frequency analysis was carried out on ten 10-sec. epochs each of

Effects of L-Dopa and Vitamin BB

tracings from the three selected scalp regions Fz-Cz, Pz-Oz and Cz-A1 of each patient. Clinical assessments were made on each schizophrenic inpatient at two-week intervals by using the Psychiatric Evaluation Scale (PES) of Tokumaruf" the assessment of psychic symptoms was made by the attending physician and observation of behavior by the nursing staff, respectively. The physician rated each patient on a five point scale as to degree of clinical improvement, i.e. excellent (remarkable symptomatic amelioration, permitting the patient to return to normal community life), good (considerable symptomatic improvement, yet requiring continued treatment by confinement), fair (a slight degree of symptomatic alleviation), unchanged (virtually no change in the patient's condition) or worsened (aggravation as compared with the condition prior to study treatment). (2) Behavioral and Electroencephalographic Changes Behavioral Changes: Each patient's condition was assessed by the above-described criteria at conclusion of the L-Dopa therapy. The therapeutic response was rated as good in one patient, fair in one, unchanged in seven and worsened in one; thus the condition remained unchanged in the majority of inpatients. Statistical data analysis made with the attempt to find relationship of the patients' sex, age, duration of current institutionalization, duration of disease (Table 1) or concomitant psychotropic medicaments to the therapeutic response failed to reveal any significant relation with the only exception of the fact that the duration of hospitalization was less than twelve months in both cases showing fair to good therapeutic responses. As for periods at which changes in the patients' conditions were observed and in-

123

dividual symptoms in the three cases including the one which showed exacerbation, the moderately improved patient (Case No. 3) became to smile, occasionally seen humming, and stated that he became to feel cheerful about two weeks of L-Dopa medication. He also exhibited a trend toward improvement in respect of volition, saying that he became able to do something by little and little whereas nothing could induce him to do anything before. The patient continued to be improved gradually in cheerfulness and liveliness over the ensuing weeks (4th to 6th weeks); he came to chat with other patients and take active part in outdoor exercises, being diverted in a loud voice at times. Clinical amelioration of the patient was in evidence both to the patient himself and to the observers. In about six weeks the patient tended to display elevation of mood alone, talked much and moved well but appeared to be somewhat flippant. However, this trend was rather transient and he regained his composure spontaneously in the seventh to eighth weeks, thus showing clinical improvement in respect of volition, contact with others, facial expression, amount of conversation, interpersonal relations, work, behavior, recreation, insight, efc. as compared with the conditions prior to initiation of the L-Dopa medication. In the slight improved case (No. 9), increased facial expressiveness became evident about the fourth week of L-Dopa therapy; she became to be seen talking with other patients even in the ward and stated that she thought she had been ill because of bashfulness and lack of positiveness. In the sixth week she became increasingly active in expression and general attitude, saying that she became to feel more composed than before and showing clinical improvement as to contact, expression, insight and personal relations as compared with the

Table 1: Interrelation Between EEG Change-Therapeutic Response and .mrations of Disease and Hospitalization in the Ten Patients With Schizophrenia Duration of

Illness(yrs)

Duration of Hospitalization(yrs)

EEG Changes

Therapeutic Response

8

32

13

nil

unchanged

11

nil

unchanged

nil

good unchanged

No. Subject Sex Age 1

F.K.

f

4

2

S.O.

f

35

12

3

Y.H.

m

28

11

4

S.K.

f

45

13

13

5

A.T.

m 4 0

14

9

Slight increase in activity (* *)

6

T.I.

m

36

9

3

Slight increase in a activity

unchanged

7

M.S.

m

48

over 7

2

Slight increase in a activity

unchanged

8

T.S.

m

26

8

8

diminution in a activity

unchanged

9

M.K.

f

0

11

3 mo.

during treatment with

10

K.K.

f

24

7

7

500-600 mg L-Dopa q.d.

4

7 mo.

increase in a activity (*) (r

unchanged

fair worsened

*: “Increase in a activity” denotes more than 15% increase in appearance of a frequency bands following treatment with L-Dopa. (I! activity” denotes 5 to 15% increase in emergence of a bands following treatment with L-Dopa.

**: “Slight increase in

Effects of L-Dopa and Vitamin B6 condition prior to the L-Dopa therapy. She continued to be in this improved state at the eighth week of therapy. As for the worsened case (No. lo), the patient became to display rather impassive features, to be abulic and clinomaniac and to assume a negative attitude when she was spoken to, from about 25 days of LDopa therapy onward. On the 47th day she shouted “Somebody’s laughing at me,” throwing a thing at the observer all of a sudden, and thereafter became completely abulic. We, therefore, were inclined to discontinue the L-Dopa medication temporarily but, thc next day but one, the tension and excitability subsided and she became to

respond composedly; this composure lasted till the eighth week. Of the seven unimproved patients, two showed improvement in respect of contact, interpersonal relations, expression, behavior, volition and emotional disturbance from the second to third weeks or from the third week of L-Dopa medication onward, respectively, although, in both cases, the improvement was of a slight degree and the overall therapeutic response rated as unchanged. Four of the seven patients displayed virtually no changes in their conditions. EEG Changes: Shown in Figs. 1 and 2 are EEG changes, or frequency analysis

L- DOPA = I . TO

Fz- Cz t

Pr-

125

Or

N= 10

ct-

Al

60

50

40

Fig. 1

Solid lines represent values before therapy while broken lines show those after ), SO0 mg/day therapy with dosage, 300 mg/day ( - - - - - - ), 400 mg/day (----(-x-x-) or 600 mg/day ( - 0 - 0 - ) ,

M. Yamauchi

126

values expressed as energy %, observed in the patients during L D o p a medication. Fig. 1 illustrates average values of 10 cases. As can be seen, the tracings from all three regions (Fz-Cz, Pz-Oz and &-A1) of the scalp showed virtually no changes as compared with those recorded before LDopa medication. Inasmuch as the region Pz-Oz was thought to be most suitable for detection of changes in alpha activity, we investigated EEG changes as to tracings from the region Pz-Oz in 10 cases. This study revealed the following tendencies (Fig. 2).

YO

80

ro

A

L-DOPA

a Y. Pz

Three of the 10 patients (Nos. 1, 2 and 3) with whom virtually no EEG changes were observed displayed a high incidence of alpha waves even prior to start of LDopa therapy, i.e. 8 5 % , 80% and 66%. Fig. 2-a illustrates a typical example. Of the remaining four cases (Nos. 4, 5 , 6 and 7), one case showed a distinct increase in alpha activity and three a slight increase following institution of L-Dopa medication. (Fig. 2-b illustrates an example.) W t h dosage increase to 500 mg or 600 mg q.d., the amount of alpha frequency band emergence conversely diminished in the three

b

H.

M. S.

- oz

Pz- 01

C

K. Pr

K.

- Or

Solid lines represent values before therapy while broken lines show those after therapy at dosage, 300 ( - - - ), 400 (----), 500 (-X-x-) or 600 mg/day

- --

(-0-0-)*

Effects of L-Dopa and Vitamin BB remaining cases (Nos. 8, 9 and 10) as compared with the initial level. (Fig. 2-c illustrates an example.) In Table 1, the results of data analysis to look for correlation between the EEG changes and therapeutic response and the durations of disease and hospitalization are summarized. As viewed with respect to clinical manifestations, Case No. 3 which was a good responder among the three cases with symptomatic changes (including a worsened case) showed virtually no EEG changes (Fig. 2-a) whilst a fair responder (No. 3) displayed EEG changes similar to those in Fig. 2-c, with an increase in alpha activity at L-Dopa dosages of 300-400 mg/ day and with depression of this activity at 500-600 mg/day. (However, the depression of alpha activity did not accompany any significant symptomatic exacerbation.) In the aggravated case (No. lo), depression and decrease in alpha' activity occurred in keeping with aggravation of symptoms and subsequent spontaneous recovery in composure accompanied restoration to the control EEG pattern (Fig. 2-c). Thus it was only in Case No. 10 (K.K.) that symptomatic changes correlated EEG changes. When viewed with respect to EEG changes, Case No. 4 showed a distinct increase in alpha activity, with alpha frequency band emergences of 60, 48 and 52%, respectively, at L-Dopa dosage levels of 400, 500 or 600 mg/day in contrast to an initial level of 34%, but no significant improvement of psychic symptoms was noted. As viewed from the angle of duration of disease or hospitalization, either the duration of disease or the duration of institutionalization was less than 10 years in all three cases in which symptomatic changes were observed. As for interrelation between EEG changes and durations of illness and

127

hospitalization, two of the three cases with which virtually no EEG changes were observed had durations of disease and hospitalization over 10 years while the duration of hospitalization of the third case was seven months. All three patients showed a high incidence of alpha activity of 85, 80 and 66% from before administration of L-Dopa onward. There were four patients who exhibited a slight increase in alpha activity in the EEG irrespectively of the dosage increase of L-Dopa. The durations of illness and hospitalization were both 13 years in one of these four cases whilst the remaining three cases had durations of illness for seven to 14 years and those of institutionalization for less than 10 years. Three patients displaying diminution of alpha activity in the EEG with L-Dopa dosage not less than 500 mg q.d. had durations of disease and hospitalization both for less than 10 years. (3) Therapeutic Efficacy Low-dose L-Dopa therapy for schizophrenia is generally indicated for cases with relatively recent onset except for a report by Asano et d 2The study herein described was undertaken to ascertain whether administration of L-Dopa in low doses might offer clinical benefit and any favorable effect upon the EEG in chronically schizophrenic patients. The results were a low rate of clinical improvement, i.e. only two slightly to moderately improved cases out of ten cases treated, and a generally dearth of EEG changes. The data, nevertheless, suggest that the EEG changes were likely to be related to the duration of disease or hospitalization as was the symptomatic improvement. In patients with both durations of illness and institutionalization less than 10 years, there occurred diminution of alpha frequency bands following L-Dopa

128

M. Yamauchi

dosage increase over 500 mg/day. It was inferred from this finding that, in such patients with the duration of disease less than 10 years, the increase in alpha activity might be depressed when the dosage of L-Dopa exceeds a certain level, which might in an occasional case eventuate even in exacerbation of symptoms as in Case No. 10. In patients with durations of illness over 10 years, susceptibility to pharmacologic actions of drugs is undoubtedly altered and, consequently, the drugs perhaps are less liable to influence the EEG pattern. The three patients with durations of illness less than 10 years displayed 10 to 15% increase in alpha activity and one patient with a duration of 13 years more than 15% increase in alpha activity. Three of the six patients with durations of illness over 10 years had high rates of emergence of alpha waves, 66 to 8 5 % , from before initiation of L-Dopa medication as described above and it seemed that EEG changes by the drug medication could hardly be expected in such cases. At any rate, although the small number of 10 cases involved would fail to form a convincing ground for conjecture, there seems to remain the therapeutic possibility of LDopa medication in schizophrenic patients with a duration of illness or hospitalization less than 10 years as well as in those with a duration over 10 years showing not significantly high rate of emergence of alpha activity in the EEG. 2. EEG Changes during Treatment with Vitamin B,, (1) Subjects and Methods

Twenty chronically schizophrenic inpatients, 10 males and 10 females, at Kai Hospital were admitted to the study. They ranged in age from 24 to 47 years, with a

median age of 30 years. Their durations of illness were between three and 32 years, averaging 13 years and being not longer than 10 years in six cases and from 1 1 to 32 years in the remaining 14 cases. Principal psychic symptoms of these patients included abulia, autism, emotional blunting, diminished volition, decrease of behavior and disturbance of contact. None of the patients admitted to the study had psychomotor excitement or marked hallucination or delusion. The patients received vitamin B,, as pyridoxal-5’-phosphate (PIP) in oral doses of 20 mg t.i.d. after meals daily for a period of four weeks. Throughout the study no alteration was made as to the variety of drug or dose level of basal neuroleptic medications as was the rule with L-Dopa therapy; the pyridoxine therapy served as adjunct to the neuroleptic medications. Electroencephalograms were recorded once before start of Pip therapy (to obtain a control pattern) and two, three and four weeks after the start of P l p therapy. Frequency analysis was made on 10 epochs each of tracings from regions Pz-A, and Oz-A,, and the rates of emergence of respective frequency bands were determined and expressed as energy %. (2) Electroencephalographic Changes In Fig. 3 are shown the mean EEG changes observed in the 20 patients. As can be seen, a slight extension of alpha frequency band (4.6%) and decrease in theta band (2.1 %) even in the parietal and occipital regions. The same data are illustrated in Fig. 4 with the patients divided into two groups according to duration of disease, over 10 years or not longer than 10 years. There was a slight extension of alpha band by about 5 % in the EEG from the parietal

Effects of L-Dopa and Vitamin Bo region and from the occipital region in the less-than- 1 0-year group (six cases) while the over- 10-year-group (14 cases) showed a tendency of slight decrease of theta band with increase of alpha band. In Table 2, the data concerning changes in the EEG pattern following treatment with P l p in all individual cases are summarized. When classified according to EEG pattern from the occipital region (Oz-A,), I0 patients were alpha dominant with the most frequent emergence of alpha bands

and seven were theta dominant with the most frequent emergence of theta waves whereas the remaining three displayed peak emergence of delta and alpha bands or frequent appearance of delta bands. The latter two categories are included in the slow wave dominant pattern. Following institution of Plp medication, five of the 10 patients with the alpha dominant pattern showed a further increase in alpha activity (an example in Fig. 5-a). Conversely, there occurred decrease in alpha

Vitamin Be %

Pz

70

129

N=20

- Ai

02- AI

50

40 \

30

x

20

10

6

0

oc

#I

6

8 2

8

d

PI

82

Fig. 3 (

Solid lines represent values before therapy and broken lines show those at 2 or 4 weeks (-x-x-) of treatment.

- - - - - - - ), 3 (------I

M. Yamauchi

130

activity following P l p treatment in two of the remaining five cases, and two others exhibited extension of alpha bands in the parietal region in every week of Plp medication but such extension of alpha bands occurred in the occipital region only four weeks after start of Plp therapy; these changes were interpreted tentatively as representing a trend to improvement in the EEG pattern. The remainder showed rather inconsistent EEG changes during the P l p therapy .

Of the seven patients with the theta dominant pattern prior to treatment with Plp, one patient (Fig. 5-b) showed a tendency to EEG improvement (theta dominant over the first three weeks, followed by changes into alpha dominant pattern in the 4th week with extension of alpha activity in the occipital region) whilst no EEG change could be observed in the remaining six cases where theta bands increased or inconsistent EEG changes were observed following treatment with Plp.

Vitamin Be % 70

Pz

- Al

Pz- AI

60

50

10

s

t3

5

81

6

8 2

t,

d

sI

8 2

Fig. 4(1) Less than .lo years Over 10 years Solid lines represent values before therapy and broken lines show those at 2 ( - - ), 3 (----) or 4 weeks (-x-%-) of treatment.

- -. I

-I

Effects of L-Dopa and Vitamin Bn The patient with delta dominant pattern displayed virtually no change in the EEG after the start of Plp therapy. Of the two patients with peak frequencies in appearance of delta and theta bands, the one showed increased alpha activity in the occipital region with frequent emergence of delta bands as before and the other displayed a trend to decrease in alpha activity with increase of theta waves. It follows that EEG improvement occurred in five (25%) of the 20 chronic schizophrenic inpatients after

131

treatment with Plp or, with those showing a trend to EEG improvement inclusive, in eight patients (40%). There was no significant difference in age or sex among these patients. Trend analysis revealed that the EEG improvement was likely to be more frequent among patients with a duration of illness not longer than 10 years, in that there were five cases with durations not longer than 11 years and two cases with durations over 16 years. Symptomatic improvement was noted in

Vitamin BS ?4

02- AI

70

02- AI

60

50

10

R

6

i

PI

6

P2

e

d.

PI

8 2

Fig. 4(2)

Over 10 years Less than 10 years Solid lines represent values before therapy and broken lines show those at 2 ( - - - - __. .), 3 or 4 weeks (-X-x-) of treatment.

-

(--om-)

Table 2: EEG Changes During Treatment With Vitamin B6 (To be Continued) Alpha Dominant Pattern No.

Patient

Duration of Sex Age Disease(yrs)

1

K.M.

m

30

4

EEG Changes Parietal increase in a activity (*)

Overall (* * *) assessment

Occipital

no change in

a!

*

activity at

4 weeks of treatment

+ + + +

2

H.T.

f

32

7

slight increase in a activity (**)

no change

3

M.R.

f

34

6

no change

slight increase in a activity

4

K.K.

f

26

9

slight increase in a activity

increase in

5

K.I.

f

39

11

slight increase in a activity

slight increase in

6

Y.K.

f

41

-33

slight increase in a activity

slight increase in a! activity at 4 weeks of treatment

+

7

C.T.

m

43

16

increase in 8 activity from week

decrease in a activity

-

a!

activity a!

activity

4 onward

8

T.O.

m

41

16

increase in a activity

increase in

a!

activity

+

9

R.K.

f

41

11

no change

decrease in

a!

activity

-

10

K.T.

m

44

20

decrease in a activity

decrease in a activity

* “Increase in

a! activity” denotes more than 15% increase in the appearance of frequency bands following treatment with vitamin B,. “Slight increase in a activity” denotes 5 to 15% increase in the emergence of a bands following treatment with vitamin B6. a!

+*

I

_

5 5

2c

n

z

Table 2: EEG Changes During Treatment With Vitamin Be (Continued) Slow-Wave Dominant Pattern EEG Changes

Duration of

No. Patient

Sex Age Disease(yrs)

11

M.K.

m

36

13

12

I.T.

m

47

32

13 14

Y.A.

m f

44

23

K.K.

31

10

15 16

A.T. K.S.

m f

41 33

20 12

17 18 19

A.T.

25

10

T.S.

D.Y.

f m m

29 42

10 3

20

C.H.

f

24

6

*** Criteria:

Parietal decrease of 8 waves during weeks 2-3; no change at 4 weeks of treatment still 8 dominant pattern although increase in a activity evident at 4 weeks

increase in a activity during weeks 2-3; decrease in a activity during 4th week at 4 weeks of treatment, converted to a dominant pattern with increased a activity slight increase in a activity only in the third week decrease in 8 activity, yet no increase in a activity during entire course further increase in 8 activity only in the third week increase in 8 activity at 3 weeks no change of treatment no change no change no change no change no change decrease in a activity at 3 weeks of treatment decrease in a activity; slight slight increase in a activity increase in 8 activity

+ (EEG improvement)-Greater increase in a activity in both regions,

or in o w region with no change in the other region, over the control level in all weeks of medication; (EEG tendency to improvement)-Increase in a activity in both regions, or in one region with no change in the other region, at 4 weeks of treatment; - Virtually no change in EEG or no distinct trend of EEG change.

*

Occipital

Overall (* *) Assessment

M. Yamauchi

134

only one patient (No. 4) during Plp therapy, i.r. increase in personal relations and improved contact. Thus the EEG improvement was correlated with symptomatic amelioration in this case, whereas in the remaining cases, no significant change in clinical manifestation occurred. In no case was there evidence of somatic symptoms which could be regarded as side-effects of the drug medication. (3) Clinical Efficacy The clinical trial of vitamin Bo (as Plp) in schizophrenic patients represents a tentative plan to enhance the efficacy of LDopa therapy for this condition. The present study was conducted to evaluate the effect

a

of administration of Plp alone on the EEG as a step toward clinical trials of combined L-Dopa-Plp therapy regimens. It has been recognized that group B vitamins play important roles in the metabolism of nervous tissues' l o and these vitamins are extensively used for the treatment of cerebral disorders and disturbance in the peripheral nervous system. Our previous studies with group B vitamins (B1, Ba and BIZ)in patients with involutional psychoses (including chronic schizophrenia) demonstrated normalization of EEG following administration of these vitamins in various combinations (unpublished data).

Vitamin Be

K. K. Oz- At

%

70

b I . T. Oz - AI

A

60

I

6

0

I .

d

81

8a

Fig. 5 (

Solid lines represent values before therapy and broken lines show those at 2 or 4 weeks (-x-x-) of treatment.

- - - - - - - ), 3 ( - - - - - - )

Effects of L-Dopa and Vitamin B, By comparative assessments of responses in EEG changes after treatment with Plp alone vs. those after treatment with L-Dopa alone, practically no EEG changes were observed on the average of 10 patients during L-Dopa medication whereas the group of 20 patients receiving Plp exhibited a trend to slight increase in alpha activity with modest decrease of theta bands (especially in those with a duration of illness over 10 years). Of these 20 patients, five (or eight inclusive of those showing this trend) were found to exhibit increase in alpha activity. It would follow that the administration of Plp alone appears to be more beneficial in obtaining EEG changes when compared with that of L-Dopa alone. From these findings it may be inferred that, in schizophrenic patients with extended durations of illness and neuroleptic medication, not only depletion of dopamine but diminution of dopa decarboxylase activity exist in their brain tissue and, consequently, administration of L-Dopa alone fails to bring about any significant EEG changes but Plp medication temporarily elevates the activity level of dopa decarboxylase, thereby normalizing the metabolism of the existing L-Dopa to dopamine. Although the short period of observation for only four weeks did not allow determination of whether the EEG improvement brought about by Plp medication might immediately link into clinical (symptomatic) amelioration, it would be deducible that such EEG changes may precede clinical improvement. There was one patient, K.K., a 26-yearold woman, who was admitted, by chance, to both of these clinical trials (Figs. 2-c and 5-a). The patient developed exacerbation of symptoms during administration of LDopa and came to show negativism, mutism and excitement shortly after dosage increase to 500 mg/day. The patient’s EEG tracings

135

displayed increase of alpha bands at dosage levels from 300 to 400mgq.d. and, after dosage increase to 500-600 mg q.d., exacerbation occurred in the EEG such as decrease in alpha activity with increased theta bands in the Cz-A, region. During treatment with Plp, on the contrary, extension of alpha bands was evident in both the parietal and occipital regions and, clinically, improvement of contact disturbance and personal relations was observed. The fact of aggravation during L-Dopa therapy and amelioration durling Plp medication has suggested the possibility that, in this case where diminished dopa decarboxylase activity already existent in the cerebral tissue hindered L-Dopa from normal metabolic decarboxylation to dopamine, administration of L-Dopa facilitated abnormal metabolism (viz., excess of L-Dopa supply is metabolized to 6-hydroxydopamine which, according to the hypothesis of Stein and Weis,:i2 causes schizophrenia-like symptoms), thus giving rise to exacerbation of clinical manifestations. It was inferred accordingly that normalization of the metabolic process from L-Dopa to dopamine was facilitated by the administration of Plp with the consequent clinical and EEG improvements. 3. EEG Changes During Combined Treatment With L-Dopa and Vitamin Be

(1) Subjects and Methods As shown in Table 3, the subjects studied were eight schizophrenic inpatients, four males and four females, at Kai Hospital. They ranged in age from 34 to 48 years with an average of 40.3 years and their durations of disease averaged 18.3 years with a range from eight to 34 years, being between eight and 10 years in two cases and over 10 years in the remaining six cases. Almost all patients, therefore, were cases of long standing. Principal symptoms

Table 3: EEG Changes and Therapeutic Response in the Patients Receiving L-Dopa Plus Vitamin Bs Duration of Age Disease (yrs) Principal Clinical Manifestation

Neuroleptics

EEG Changes

autism, inappropriate laughter without evident cause, poriomania, disturbance of contact,-abnorrnal experiences, emotional blunting

levomepromazine, promethazine, chlorpromazine, trihexyphenidyl, diazepam

marked disturbance of contact, inexpressiveness, markedly autistic abulia, autism, marked disturbance of contact, tension, inordinate laughter without evident cause, frequently poriomaniac

haloperidol, promethazine, thioridazine haloperidol, promethazine, floropipamide, biperiden, thioridazine, nitrazepam haloperidol, promethazine, floropipamide, trihexyphenidyl, levomepromazine

slight increase in a activity during weeks 1-2; marked increase in a activity from week 4 onward increase in a activity from week 4 onward increase in a activity from week 4 onward

No.

Subject

Sex

1

T.O.

m

42

17

2

K.T.

m

45

22

3

M.K.

m

38

14

4

I.T.

m

48

5

M.R.

f

35

autism, abulia, apathia, superficial contact, negative attitude

6

H.T.

f

34

hypokinesia, poor contact, inexpressiveness, autism, diminished interest in surrounding affairs

Therapeutic Response

~

34

abulia, marked autism, inordinate laughter without evident cause, poriomania, disturbance of contact, devastation, auditory hallucination (++)

8 dominant pattern during weeks 1-4; increased a activity subsequently chlorcarpipramine, increase in a activity from promethazine, week 4 onward thioridazine 8 dominant floropipamide, pattern with promethazine, amitriptyline, increased a activity during trihexyphenidy 1, weeks 1-2; thioridazine marked increase in a activity from week 4 onward

good

~ood fair

ic:

fair

excellent excellent

Effects of L-Dopa and Vitamin B,,

137

of these patients included decreased spontaneity, abulia, blunted emotion and disturbance of contact and, in some cases, hallucination, delusions and disturbance of self-consciousness as well. All patients but one, Case No. 7, were identical with those in the foregoing study with the administration of vitamin Bo alone. As for dosage of L-Dopa and vitamin Be, each patient received L-Dopa in a dose of 200 mg (orally in two divided doses post cibum, morning and noon) and 3 0 m g of pyricbxal-5'-phosphate (Plp) q.d. (orally post cibum, morning alone) daily over a period of 12 weeks. Throughout the study the basal neuroleptic medications, of course, were continued without alteration in the variety of drugs or the dose (Table 3). The same electroencephalograph, automatic frequency anaIyser and related devices as those employed in the above-described studies were used. EEG's were recorded before and biweekly after initiation of the combined L-Dopa-Plp therapy, and frequency analysis was made of tracings of five epochs each from regions Pz-A2 and OZ-AZ.

00 3

m m ' I

Each patient's therapeutic response was assessed as to clinical manifestations virtually in accordance with the procedure described by Inanaga et al.,I7 i.e. rating on a five point scale - excellent, good, fair, unchanged or worsened. As for degree of improvement of individual psychic symptoms, each patient was rated as to the six psychic symptoms or the twelve psychiatric symptomatologic parameters indicated in the evaluation sheet on a five point scale. Response with a decrease in the rating score by not less than two following the 12week study treatment as compared with the initial (pretreatment) level, such as 5+2 or 1, 4-1, 3-1 or 2+1, was rated as excellent. Similarly, response with 5-3, 4-2, or 3-2 improvement was assessed

138

M. Yamauchi

N

I i

d n a N

P

P Vi

n ul 0

0

"

m

-

0

Q

Effects of L-Dopa and Vitamin B,{

as good, that with 5+4 or 4-3 amelioration as fair, and that with a 4-5, 3+4 or 5, or 2+3, 4, or 5 increase as exacerbation.

(2) Therapeutic Response and Its Interrelation With EEG Changes The therapeutic response and course of symptomatic changes observed in the patients have been reported by K a P elsewhere and I would like to describe here the EEG changes and their relations to clinical manifestations noted. As can be seen from Table 3, the therapeutic response was excellent in two cases, good in three, fair in three and unchanged or worsened in none; five patients showed good to excellent responses. Amelioration of symptoms became evident about two to six weeks after the start of combined medication. As for interrelation between the duration of illness and the therapeutic response, the duration of disease was less than 10 years in the two markedly improved cases (eight and nine years, respectively) and the cases of long standing with durations over 10 years also displayed a satisfactory rate of improvement, viz. moderately improved in three cases (.I 7, 22 and 25 years) and slightly improved in three (14, 18 and 34 years). Fig. 6 illustrates mean EEG changes observed in the eight cases. In contrast to the theta dominant pattern noted before the start of combined treatment with L-Dopa and vitamin B,, (during which period the patients had received neuroleptics alone as basal medication), a marked increase in alpha band-macroscopically, increase of a activity (emergence, increase in amplitude and/or continuity) - became evident after four weeks of study treatment and this condition lasted till the last week. These EEG changes became clearly demonstrable in two weeks of study medication in one case and four weeks in the

139

remaining seven cases and continued to be observable in all cases till the final week of study treatment. In Figs. 7-a, b and c are shown the clinical courses of psychic symptoms and EEG changes observed in three of these eight cases. The data presented in Fig. 7-a are from a patient with excellent therapeutic response (No. 5 , M.R., female). In the EEG, theta frequency bands continued to be dominant during the two weeks of study medication, though there was an increase in alpha activity as compared with the initial (pretreatment) tracings. The EEG pattern became alpha dominant with a marked extension of alpha bands in four weeks of study medication. In about two weeks of study treatment, she exhibited an increase in motility, presented softened facial expressions and responded in increased words at the interview instead of previous stereotyped expressions; hence signs of symptomatic improvement. About four to five weeks after the start of combincd medication, she came to show satisfactory contact with others, smiled in an appropriate way and became able to conduct daily activities and look after herself of her own accord; she participated for the first time in outdoor exercise. In about the sixth week of study treatment, EEG tracings showed increased delta and theta frequency bands and diminished alpha bands, although, symptomatologically, her condition remained satisfactorily improving. During the eighth to twelfth weeks there occurred again a marked extension of alpha frequency bands in the EEG and she showed a further increase in indoor motility and in contact with other patients, kept herself wellgroomed and came to take care not only of her own personal appearance but of hair dressing of fellow patients as well; the satisfactory condition lasted up to the final twelfth week of combined medication. In Fig. 7-b the clinical data from a mode-

CL

P

0

M. R.

50

40

ic cc

10

2 0

patients with natural expression and behavior and keeping tidy personal

smiling more naturally.

v. 2

A

I

Fig. 7-a

appearance.

Effects of L-Dopa and Vitamin B,

' 4 9

d 8

'*

r

B

N

141

M. K.

x 60

20

10

i\ abulia, autism. conspicuous disturbance of contact uith others: tension, giggling, poriomania

increased motor act.ivity. improved contact with others, participating in both w o r k and recreation. I I

A

corn01

2

w

4

w

CC P i5-

C

0

2:

giggling and poriomania reduced. L

6

Fig. 7-c

W

I

o

w

A

10

w

I2

w

Effects of L-Dopa and Vitamin Bs rately improved case (No. 8, Y.K., female, 45 years of age) are summarized. As can be seen, an EEG pattcrn characterized by a peak in the appearance of theta frequency bands was noted during the first two weeks of study treatment, whereas during the ensuing period from the fourth to twelfth weeks, she displayed a conspicuous increase in alpha bands in the EEG. Before the study treatment the patient’s motility was in such an extent that she did the necessary minimum only after being urged: thus a rating score of five for this parameter. Moreover, she fell off from group activities because she was remarkably slow in every motion and there were marked disturbance of contact, tension, emotional blunting and compulsive conduct (hand washing repeated 15 times a day), etc. About four weeks after the study treatment had been instituted, the patient became gradually relieved of tension, so as to be able to smile and show reduction in the frequency of washing her hands from 15 to about seven times a day and to be fairly sprucely dressed. Aftcr about six weeks of study medication, she was seen making contacts with her roommates and asking the nurse for cakes; hence, improvement took place in respect to contact, facial expression, amount of conversation, alertness and compulsive conduct. The data shown in Fig. 7-c are from a slightly improved case (No. 3, M. K., male, 38 years of age). In four weeks of medication the patient’s EEG tracings were still dominated in pattern with delta and theta frequency bands but there was a significant increase in alpha activity as compared with those recorded two weeks earlier. From the sixth week on, there occurred diminution of delta frequency bands and increase in alpha bands thus with an alpha dominant pattern in the EEG which lasted till the 10th week. During the 10th week there was an increase

143

in delta frequency bands, but, again, a fairly alpha dominant pattern was observed during the 12th week of study treatment. After about five weeks of combined medication, he stated that he felt relieved of pains deep in the head. He took part in volleyball matches in which he had been very reluctant to participate ear1:er despite being repeatedly urged to do so. He, thereafter, joined the games almost every day, occasionally showing a vivacious expression while playing. Inordinate laughter without evident cause and poriomania which had been frequently observed became less frequent but marked tension and disturbance of contact continued to be present. In all these cases changes in the EEG pattern became evident about four weeks after institution of combined medication whereas symptomatic improvement occurred almost simultaneously or subsequently, indicating that the EEG changes usually preceded the amelioration in clinical manifestations. The author would like to draw comparison of the EEG changes between the group of patients treated with vitamin B,, alone and that of patients given the combined LDopa-vitamin B8 therapy regimens inasmuch as seven of the eight subjects in the latter group had also served as subjects in the former group. The comparison pertains to the changes in the EEG recorded from the OZ-Al region in the fourth week of study medication, although the procedures of study adopted differ and the group treated with vitamin B,, alone might include subjects who showed EEG changes after the lapse of the 4th week. As can be seen from Table 4, all the eight patients receiving combined therapy regimens of L-Dopa and vitamin B,, displayed increase in alpha frequency bands whereas increased alpha activity was demonstrable in only four of the seven cases treated with vitamin B,, alone. Furthermore, the increase in alpha

M. Yamauchi

144

Table 4: Comparison of EEG Changes between Vitamin BIITherapy and Combined L-Dopa-Vitamin BIITherapy

No. Subject

-~

1

T.O.

Vitamin Be Therapy increase in a activity

Combined L-Dopa-Vitamin BB Therapy increase in a activity (+38.5%)

(+26.3%) 2

K.T.

decrease in a activity

increase in a activity (+35.3%)

(-5.7%) 3

M.K.

no change

increase in a activity (+17.7%)

4

I.T.

slight increase in a activity (+8.7%)

increase in a activity (+26.8%)

5

M.R.

slight increase in a activity (+ 12.1%)

increase in a activity (+34.8%)

6

H.T.

no change

increase in a activity (+29.1%)

7

Y.K.

slight increase in a activity (+4.8 % )

increase in a activity (+36.4%) ~

Changes in EEG tracings from the occipital region observed four weeks after initiation of treatment are compared; figures in parentheses denote per cent increase (or decrease) in the emergence of a frequency bands over the pretreatment level.

activity in the EEG pattern observed following administration of L-Dopa combined with vitamin B,, was conspicuous, i.e. 17.7 % at the minimum and mainly between 20% and over 30%, in contrast to 5 % to 12% in the group treated with vitamin Bo alone with the exception of one case that showed a 26% increase. (3) Clinical Efficacy Since the report of lnanaga and his associates describing efficacy of L-Dopa administercd in combination with conventional neuroleptic agents to schizophrenic patients,"' many reports of the clinical effects of L-DoPa therapy in schizophrenia have appeared.17 27-31 35 The clinical effectiveness of L-Dopa has also been confirmed recently by a controlled double-blind trial in a series of 104 patients with schizophrenia.'" In all these reported studies, nevertheless, the rates

of improvement were noted to be higher among patients with relatively short durations of illness and low among chronic cases of schizophrenia with durations over 10 years. It has been pointed out that this fact constitutes information of prime importance in evaluating the effects of L D o p a on schizophrenia.31 The fact that the duration of disease serves as an important factor affecting the therapeutic effectiveness of the drug would suggest that the mechanism of action of the lowdose L-Dopa adjunctive therapy might vary with the duration of illness when viewed with respect to the disease state of schizophrenia. That is to say, the favorable clinical effects might be brought about as a result of normalization of the process of intracerebral NA metabolism by the administration of LDopa alone in patients with a relatively short duration of illness, whilst disturbance of

Effects of L-Dopa and Vitainin B,,

other enzyme systems might probably be involved in cases with prolonged durations of disease. The results of thc present study seem to provide some data which support this view. Namely, it is inferable that depression of the activity of Dopa-decarboxylase which catalyzes the synthesis of dopamine from LDopa may be present in chronic schizophrenic subjects from the fact that administration of low doses of L-Dopa and vitamin B,, in combination with the conventional neuroleptic mcdications brought forth EEG improvement and symptomatic amelioration in such cases which could not be attained by the administration of either drug alone. It would follow that vitamin B,, administered probably enhanced the activity of L-Dopa, which failed to produce any significant clinical effect when singly administered, and consequently facilitated the ensuing metabolic process with the therapeutic effects. The data obtained in the study described hercin indicate satisfactory clinical benefit from thc use of L-Dopa in combination with vitamin B,, in the small number of the eight cases involved and it is considered necessary to ascertain the efficacy by studies in greater numbers of cases. It also remains to be questioned whether the doses and the mode of administration of L-Dopa and vitamin B,, employed were optimal. Particularly, it might as well be advisablc to use higher dosage of L-Dopa in schizophrenic cases of long standing with durations of illness over 10 years, and it may be necessary to make further assessment of the dosage of vitamin B,, in the combined adjunctive treatment. As for the mode of administration and dose, it might be desirable to administer Plp two to four hours after L-Dopa in order to allow for the time of absorption and metabolism of the latter.33

145

DISCUSSION

The hope that therapeutic effects can be expected from the use of L-Dopa in low doses in chronic schizophrenic cases of long standing has been aroused by the three clinical studies described above. However, the mechanism of action of the drug as yet is obscure at the present stage where the etiology of schizophrenia is not known. The following interpretation may be possible, nevertheless, on the ground of the theory of disturbance of amine metabolism. Stein ef al. postulated the following hypothesis as to etiology of schizophrenia.:i2 That is, a marked depression of activity of dopamine/3-hydroxylase, an enzyme essential to the metabolism of dopamine (DA) to norepinephrine (NE) as a result of genetic enzymatic error is present in schizophrenic subjects. Conscquently, the metabolic process of DA hydroxylation to norepinephrine is impaired to cause accumulation of DA in excess in the synaptic vesicles of the nerve-ending, which is then liberated into the adjoining synaptic cleft where it is abnormally metabolized to 6-hydroxydopamine (6-HD). This abnormal metabolite of DA gives rise to catecholamine depletion in the brain and may cause the basic symptoms and the prolonged down-hill course of schizophrenia. Stein et al. also describe that chlorpromazine exerts its antipsychotic effect perhaps by its ability to interfere with the action of 6-HD on the NE receptor. In connection with the mechanisms of action of neuroleptic agents, Bruno and Allegranza reported that high doses of reserpine, chlorpromazine or haloperidol produced a significant elevation of urinary DA metabolites which could be associated with the akinetic-hypertonic side effects of these drugs, suggesting that haloperidol administered in large doses might probably cause decrease in the DA content of the cerebral

I46

M. Yamauchi

basal ganglia.5 However, phenothiazines and butyrophenones have been described as a cause of a marked increase in urinary homovanillic acid (HVA) even without noticeable changes in the cerebral DA concentration, and this has been attributed to accelerated metabolic turnover of DA in the wake of recompensation through the feedback mechanism associated with the blocking action of neuroleptics upon the DA receptor and with inhibition of reuptake into the nerveending.' Inanaga et af. carried out clinical trials of low-dose therapy with L-Dopa, a precursor of DA, in combination with neuroleptic agents on the rationale that such conditions as abulia, diminished spontaneity, emotional blunting and disturbance of contact which were noted in schizophrenic patients who had undergone prolonged neuroleptic medication might be the result of CA deficiency in the brain tissue. In view of the therapeutic effectiveness of the compound demonstrated in their study, the investigators explained the underlying mechanism of action of LDopa as follows.ln The clinical benefit from the administration of L-Dopa in conjunction with neuroleptic medications might exert some favorable influence upon the metabolism of CA besides protection by neuroleptics against cerebral NE depletion due to 6-HD formation as well as making up for cerebral CA deficiency by small doses of L-Dopa. There exist limits to the clinical application of the low-dose L-Dopa therapy (where the duration of disease seems to constitute a major contributory factor), however, and the present author has made re-evaluation of the L-Dopa therapy from this angle and conducted a clinical trial of vitamin Bll in combination with L-Dopa which has customarily been contraindicated. Vitamin B,,is one of the group B vitamins which is well known as antidermatitic factor. This vitamin is universally recognized to

have the biochemical function as an important coenzyme related to transaminases, aromatic- 1-amino acid decarboxylase, amine oxidase, enzymes catalyzing which participate in the catalysis of reactions of tryptophan metabolism and lipid metabolism."' 2.1 The vitamin was first demonstrated as coenzyme of amino acid decarboxylase in bacterial cells. It is known to be synthesized in rats by intestinal bacteria, whereas in man, it should be supplied orally. Since it is widely distributed in practically all varieties of foodstuff, ordinary dietary feeding is said to suffice for its usual nutritional requirements, 2-3 mg/day, unless the food has been drastically processed by some physical or chemical means. Vitamin B,,functions as the coenzyme for Plp-dependent L-Dopa decarboxylase which catalyzes the decarboxylation of L-Dopa and 5-hydroxytryptophan in the brain tissue. While the decarboxylase shows no specific localization in its tissue distribution, the intracerebral activity level of decarboxylase parallels to some degree, the amine content of the brain tissue and that both the decarboxylase activity level and the amine content have been described to be high in the brain stem.Is Vitamin B,, has been applied in the treatment of various diseases, where the therapeutic dose levels employed were by far higher than the daily nutritional requirement. Efficacy of the vitamin given at high dosage levels, i.r. a few hundred milligrams q.d., has been observed in a considerably wide variety of diseases.'" The attempt of assessing the clinical effects of vitamin B,,as adjunct to the lowdose L-Dopa therapy was based on the views as follows. In patients with chronic schizophrenia failing respond to the L-Dopa therapy, it might not be improbable that disturbance of other enzyme systems such as, for example,

Effects of L-Dopa and Vitamin B,, in the metabolic process of L-Dopa-DA preceding the process of DA-NE exists in addition to the above-described, although the cause of such disorder is not known yet. It might be the consequence of the chronic ailment or that excessively prolonged neuroleptic medication which caused chronic enhancement of compensatory metabolism of L-Dopa to DA probably eventuated as a homeostatic response in progressive slowing of the metabolic turnover with the consequent depression of intracerebral DA and NE metabolism and decrease in decarboxylase activity. Therefore, it was assumed that the administration of L-Dopa alone did not provide significant clinical benefit in such circumstances and concomitant administration of vitamin B,, which activates the enzyme activity rendered the administered L-Dopa into a biochemically utilizable state. Vitamin B,, has been generally believed to bring to naught or substantially reduce the therapeutic effect of L-Dopa in parkinsonismn "0 "9 and, therefore, combined use of these drugs has been practically avoided. As for the reason of this antagonistic action of vitamin B,,against LDopa, Duvoisin" and Leonz3 ventured a hypothesis that L-Dopa administered might be decarboxylated in peripheral tissues to dopamine before reaching the brain tissue. However, the observed fact of a remarkably rapid passage of vitamin B,,through the blood brain barrier has raised a question against this hypothesis that decarboxylation of administered L-Dopa is accelerated selectively in tissues outside the central nervous system, and another hypothesis has been suggested concerning the antagonistic activity of vitamin B,,."' The dosage level at which vitamin B,, is administered constitutes an important factor determining the degree of the antagonism and Duvoisin describes in this regard that vitamin B,, given in high doses (750-1,000

147

mg/day) causes a complete abolition of the antiparkinsonism effect of L-Dopa but, when administered in small doses (5-10 mg/day), diminishes the effect of L-Dopa and at the same time also reduces the degree of dyskinesia associated as a side effect with LDopa. The alleviative effect of small doses of pyridoxine against dyskinesia has been subsequently confirmed."" It follows that there exists no established theory of contraindication for small doses of pyridoxine in combination with L-Dopa. Recent reports have suggested the possibility of vitamin B,, deficiency state occurring in patients with parkinsonism maintained on L-Dopa over an extended period." Bianchine et uL4 observed a significant increase in urinary L-Dopa metabolite excretion in patients with parkinsonism given combined medication of pyridoxine and L-Dopa, in contrast to normal subjects who did not show any such increase (indicating absence of the effect of pyridoxine), and have thereby conjectured that the patients with parkinsonism might have functional deficiency of pyridoxine. MawatarP described that complete abolition of the effect of L-Dopa occurred in patients with paralysis agitans receiving 90 mg of pyridoxine per day whereas no significant reduction of the antiparkinsonism effect of L-Dopa was noted in those given 10 mg of the vitamin daily. The investigator also describes that tryptophan loading tests revealed elevation of urinary xanthurenic acid in the patients maintained on L-Dopa, suggesting relative deficiency of vitamin B,, possibly brought about by the L-Dopa therapy. Thus it is considered practicable to use small doses of vitamin B,,even in cases of parkinsonism undergoing L-Dopa therapy and that the data reported seem to suggest necessity for the concomitant administration of this vitamin in low doses in such patients who are possibly in a deficiency state. In the study herein reported, the combined

148

M. Yamauchi

medication of L-Dopa and vitamin B,; in low doses for schizophrenic patients was considered theoretically reasonable on account of the possibility of diminished cerebral dopa decarboxylase activity as a factor pertaining to the disease state. The therapeutic application of vitamin B,, was carried out in the present investigation with emphasis laid on the possible decrease in dopa decarboxylase activity in the brain tissue. Activity of the various enzyme systems participating in the entire course of mctabolism from tyrosine to L-Dopa-DA +NE should be subject to discussion in this regard and, moreover, relations to the serotonin metabolism are also considered probable since L D o p a decarboxylase is related to 5-hydroxytryptophan as well. In addition, influence upon other hormonal systems may also have bearing upon the problem. These are the subjects that remain to be investigated. Noticeable EEG improvement and symptomatic amelioration, which had not been attained by the treatment with vitamin B,, alone or with low-dose L-Dopa therapy alone, were observed in a series of eight chronically schizophrenic patients by the administration of vitamin B,, in combination with low-dose L-Dopa therapy in the present clinical trial and the results might represent data suggesting the possibility of diminution of cerebral dopa decarboxylase activity in schizophrenia although the number of cases involved was small and the duration of observation relatively short. In this study, EEG changes were expressed as energy percent. Previously, Mukasa and 1nanaga”I have reported the relation between the changes of EEG pattern and the clinical improvement in schizophrenic patients treated with chlorpromazine. They pointed out that the frequency curves of EEG were evidently altered from those before treatm’ent in the patient with clinical

improvement and that the peak of the curve was almost in normal range, at 9-10 Hz. Therefore, the author observed the changes of EEG pattern (energy percent), especially the change of a band, as indicators for the clinical improvement. The three clinical studies described above were performed not in a continued series but separately at Kai Hospital, Yanagawa City, Fukuoka Prefecture, and, therefore, differ in subjects and procedure. All three clinical trials are summarized together in this report inasmuch as they all concern L-Dopa therapy for schizophrenia. SUMMARY

1. To assess the therapeutic effect of low-dose L-Dopa therapy and associated EEG changes in chronic schizophrenia, 10 patients with a mean duration of illness of 12.4 years were treated with L-Dopa for a period of eight weeks during which the dosage was increased progressively from an initial level of 300 mg q.d. biweekly up to 600 mg q.d. The treatment was moderately effective in one case and slightly efficacious in one, produced no significant change in the conditions of seven patients while the remaining patient showed exacerbation; hence a noticeably low rate of improvement. There occurred no significant changes in the EEG pattern in the scries of 10 patients on the average. The individual patients’ responses, nevertheless, could be classified into threc groups: one with no observable EEG changes, the second showing a slight degree of increase in alpha activity and the third exhibiting diminution of alpha activity in the EEG. The patients in the latter two groups all had durations of disease less than 10 years.

2. Observations were made primarily of ch,anges in the EEG in 20 chronically schizophrenic patients with a mean dura-

Effects of L-Dopa and Vitamin B,, tion of disease of 13 years receiving 60 mg of vitamin Bo (as pyridoxaL5’-phosphate) daily over a period of four weeks. Slight increase of alpha activity and decrease of theta activity in the EEG were noted on the average of the 20 cases, in response to the vitamin B,; therapy. The increase of alpha activity was frcquently seen among patients with a duration of illness less than 10 years whose pretreatment EEG pattern had been alpha dominant (five out of 10 cases), whereas a slight ameliorative tendency of EEG was observed only in one out of 10 patients whose pretreatment EEG pattern had been slow-wave dominant. Symptomatic improvement was evident only in one of the 20 cases studied. 3. Observations were made of the therapeutic effect and associated EEG changes in eight patients receiving combined medication of 200 mg L-Dopa and 30 mg vitamin B,, (as pyridoxaL5’-phosphate) daily for a period of 12 weeks. Of these eight patients with a mean duration of disease of 18.3 years, two showed excellent response, three good and three fair; hence good to excellent responses attained in five out of the eight cases or 62.5%. A marked increase in alpha activity in the EEG occurred from the 2nd to 4th weeks onward in all eight cases. The EEG changes were likely to precede the symptomatic improvement. 4. To sum up the results of these three clinical trials, administration of L-Dopa alone resulted in practically no symptomatic improvement or EEG changes in patients with chronic schizophrenia whilst vitamin Bn administered singly as pyridoxal-5’-phosphate scarcely produced significant symptomatic improvement but brought about a slight amcliorative tendency in the EEG of such patients. Both symptomatic amelioration and EEG improvement occurred following combined medication of L-Dopa

149

and vitamin Be. The findings suggest that diminution of the activity of decarboxylase essential to the metabolism of L-Dopa to DA might be present in chronically schizophrenic patients. ACKNOWLEDGMENT The author wishes to extend heartfelt gratitude to Dr. K. Inanaga, Professor of Neuropsychiatry, for valuable suggestions and review of the manuscript. Thanks are also due to Dr. Y. Kai, Director of Kai Hospital, for helpful advice and guidance in connection with this investigation. The collaboration of thc medical staff of Kai Hospital is gratefully acknowledged. REFERENCES 1 AndBn, N. E., Butcher, S. G., Corrodi, H., Fuxe, K. and Ungerstedt, U.: Receptor ac-

tivity and turnover of dopamine and noradrenaline after neuroleptics, European J Pharmacol, 11: 303-3 14, 1970. 2 Asano, T., Noma, T., Matsuda, K., Ikeda, H., Otsuki, S.: Effect of L-Dopa on the hypochondriac complaints of the chronic psychotics, Clinical Psychiatry, 15: 74575 I , 1973 (in Japanese). 3 Barbeau, A.: L-Dopa therapy in Parkinson’s disease: A clinical review of nine years’ experience, Canad Med Ass J, 101: 79 1-800, 1969. 4 Bianchine, J.

R. and Sunyapridakul, L.: Interactions between Levo-dopa and other drugs: Significance in the treatment of Parkinson’s disease. Drugs, 6: 364-388, 1973.

5 Bruno, A. and Allegranza, A: The effect

of haloperidol on the urinary excretion of dopamine, homovanillic and vanilmandelic

acids in schizophrenics. Psychopharmacologia (Berl), 8: 60-66, 1965.

6 Bunney, W.E., Janowsky, D.S., Goodwin, F. K., Davis, J. M.,Brodie, H. K. H., Murphy, D. L. and Chase, T. N.: Effect of L-

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7

8

9 10

11

12

13

14

15

16

17

18

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