Prog. Neuro-Psychophormocol & Biol. Psychiot. 1982. Vol. 6, pp. 243--248 0278-58461821030243-06503,0010 Printed in Great Britain. All rights reserved. Copyright © 1982 Pergamon Press Ltd.

THE VALUE OF CYTIDINE-5-DIPHOSPHATE-CHOLINE IN THE PREVENTION OF IMPAIRMENT OF MEMORY FUNCTION AFTER ELECTRIC CONVULSIVE THERAPY.

A DOUBLE-BLIND STUDY

1 JOSE LUIS AYUSO-GUTIERREZ and JERONIMO S A I Z - R U I Z

Department of Psych ia t ry . Complutense Un ivers i t y . Medical School Madr id-Spain

(Final form, May 1982)

Abstract

1. A double-bl ind study of the effect of CDP-chol ine on memory impairment fo l lowing b i la tera l ECT was performed on 22 inpatients suffer ing from endogenous depression.

2. Memory scores were checked af ter 2 and 4 ECT sessions, and the length of the post-ECT confusional state was also measured.

3. The resul ts showno s ta t i s t i ca l l y s igni f icant d i f fe rences between the reduced memory scores obtained by both groups. Our f indings do not support the hypothesis that CDP-chol ine affords protect ion against ECT-induced memory dysfunction in depression cases.

Keywords: CDP-chol ine; b i la tera l ECT; memory impa i rment .

Abreviat ior ,s: Q, t id ine-5-d iphosphate-chol ine (CPD-chol ine); E lec t r i c convuls ive therapy (ECT); Memory test , T~cnicos Especia l is tas Asociados (TEA).

I ntroduct ion

Since Kennedy and Weiss (1956) descr ibed the importance of cy t id ine-5-d iphosphate-chol ine (CDP-cho l ine) in the synthesis os phosphol ipids, exper iments with animals have shown its effect iveness in st imulat ing consciousness and its capaci ty to fac i l i ta te the arousal react ion (Ya- suhara and Nai to, 1974). S im i l a r l y , its use in patients has shown it to be ef fect ive in comba- t ing impairment of consciousness, especia l ly in recent head injur}.es (Uyama et a l . , 1968). More- over , the use of CDP-chol ine in patients with post - t raumat ic sequelae has made it possible to achieve improvements in memory d isorders (Watanabe, 1966).

On the basis of these experimental an c l in ical observat ions, we consider the hypothesis that CDP-chol ine may afford protect ion against memory impairment, which continues to be the chief undesiderable s ide-ef fect of e lec t roconvu ls ive therapy (Squire et a l . , 1979).

Methods

Subjects.

We have studied 22 consecutive patients suf fer ing from endogenous depression for whom e lec t ro convuls ive therapy had been prescr ibed. We have excluded subjects who showed signs of severe

1 Present Address: Department of Psych ia t ry . Centro "Ram6n y Ca ja l " . Madr id-Spain .

243

244 J.L. Ayuso-Gutierrez and J. Saiz-Ruiz

in te l lec tua l impai rment , those whose re ta rda t i on or negat ive at t i tude rendered the i r coopera t ion in

the f i r s t i nsu f f i c ien t , and those who had undergone ECT dur ing the three months p r i o r to the study. Al l were inpat ients in the department of psych ia t r y of a genera l hospi ta l (Hospi ta l C l [n i co ,

Madr id ) .

Exper imenta l technique. The technique employed is t ha to f a doub le -b l i nd study. Al l the pat ients rece ived a da i l y in jec t ion

of 100 cc of phys io log ica l serum, admin is te red e a r l y in the morning ove r a pe r iod of eight days , conta in ing e i the r a p lacebo o r act ive medicat ion (800 rag. of CDP-cho l i ne ) .

ECT app l i ca t ion . B i l a te ra l ECT was appl ied on a l t e rna te days inmediate ly a f t e r admin is t ra t ion of the serum, f o l -

lowing the technique rou t ine ly employed in the depar tment . The doc tor r e s p o n s i b l e - a l w a y s the sa- me- ensured that f ac to rs such as in tens i ty of c u r r e n t , t ime of app l i ca t ion , humid i ty , pos i t ion of e lec t rodes , e t c . , were constant in al l cases . A l l sub jects rece ived ident ica l p re -med ica t ion : 250 mg of 2,5% solu t ion of th iopenta l , 35 mg of succ iny l chol ine and 0 ,5 mg of a t rop ine . Constant oxygen supply was not used e i the r be fo re o r a f t e r the convuls ions (pat ients with these requ i rements were thus excluded f rom the s tudy ) . In al l cases, ass is ted b rea th ing by means of a f a c e - m a s k was given both be fore and a f t e r the app l i ca t ion of ECT .

Ins t ruments and eva luat ion of r esu l t s . The fo l low ing two aspects h a v e b e e n studied: the memory impai rment , and the a l t e ra t i ons in

the level of consc iousness fo l l ow ing EC]- ( p o s t - c r i t i c a l confus ional s ta te) .

I ) To determine the degree of inmediate memory impai rment , we have used two scales of the TEA memory test (1969)wh ich sco re numer ical and assoc ia t i ve memory. Th is test is based on

the co r respond ing sub- tes ts of the WF-SCHLER sca le (1958). In al l cases these memory tests were appl ied in th ree d i f f e ren t occas ions: a) on the f i r s t day, be fo re t reatment , b) 24 hours a f t e r the second ECT (4th day) and c) 24 hours a f t e r the fou r th ECT (8th day) .

2) To determine the poss ib le ef fect of CDP-cho l i ne on the length of the t ime requ i red to r e c o - ve r f rom the pos t - convu l s i ve confus ional s tate we have appl ied the fo l l ow ing two paramete rs used b y d ' E l i a (1970) and m e a s u r e d b y us a f t e r the second and fou r th ECT . a) Length of time between f i r s t convu ls ion and s ta r t of effect iv.e spontaneous r e s p i r a t i o n . b) Length of t ime between app l i ca t ion of ECT and the moment the subject is ab le to g ive c o r - rec t answers to a s e r i e s of quest ions designed to test his s p a t i o - t e m p o r a l o r i en ta t i on . These quest ions (name, age, name of hosp i ta l , number of bed, day of week, month) a re f i r s t asked be fo re t reatment is s ta r ted , and then, fo l l ow ing ECT, they a re asked at 5 minute i n te rva l s unti l c o r r e c t answers to al l of them a re obta ined.

S ta t i s t i ca l ana l ys i s . S ta t i s t i ca l ana lys is was done by c h i - s q u a r e tests and Student 's t - tes t where approp ia te .

Resu l ts

CPD-cho l ine e f f i cacy .

a) Memory sco res . Table 1 shows that there a re not s ign i f i can t d i f f e rences between the p lacebo and CPD-cho l i ne groups rega rd ing age, sex of pa t ien ts , and in i t ia l memory sco res .

Tab le 2 shows the sco res obta ined by the two groups a f t e r second and fou r th ECT sess ions . It can be seen that in both the numer ica l memory sco re a f t e r the second ECT is the same as be fo - re t rea tment , and is s l i gh t l y lower a f t e r the fou r th ECT . As f a r as the assoc ia t i ve memory sco re is concerned , th is is h igher in both groups a f t e r the second ECT and no t i ceab ly l ower

a f t e r the f o u r h t .

Electric convulsive therapy impairment of memory 245

TABLE 1

C H A R A C T E R I S T I C S OF THE P A T I E N T S AND ASSESSMENT OF THE I N I T I A L MEMORY SCORES

Total Placebo CDP-chol ine S ign i f i cance N=22 N=] ] N=I 1

9 3 6 n . s .

13 8 5

32.86 34.?3 31.00 n .s .

(+l I. 25) (+ 15.14)

9.00 8.73 9.2? n . s .

(+1.66) (+ 2.46)

21.13 19.09 23.18 n . s .

(+_5.54) (+__ 5.54)

Male

F e,ua I e

Mean age (years)

In i t ia l mean memory score (digi ts)

In i t ia l mean memory score (associat ive)

TABLE 2

MEAN MEMORY SCORES A F T E R TWO AND FOUR ECT S E S S I O N S

Memory score (digi ts)

Memory score (associat ive)

Placebo CDP-chol i re

A f te r 2 ECT 8.73 9.2? (+ 2.86) (+ 1.86)

Af ter 4 ECT 8.30 8.80 (+2.26) (+ 1.61)

Af ter 2 ECT 21.00 25.00 (+9.06) (+3.16)

Af ter 4 ECT 12.80 20.10 (+10.1(2) (+_10.10)

Table 3 compares the degree of memory impairment in each gr:oup from tbe.pre- t r l la tment stage to the f inal score, s-. The reduced capacity, to remember d i g i t s i s p r a c t i c a l l y tdentio-¢l, in both groups. In the assoc ia t ive memo~'y tests, IDsses are h[ghe.r i~ the 'placeb(~ group (6,29 as against 3 ,08)a l though th~ ~i f ference is not s ta t i s t i ca l l y s igni f igant .

b) Pos t -ECT confusional state. Table 4 summarises the resul ts obtained fo l lowing computation of the per iods requ i red for the recove ry of resp i ra t i on and or ienta t ion af ter the second and fourth ECT sessions. No s igni f icant d i f ferences in the length of the pos t -ECT confusional state between

246 J,L. Ayuso-Cutierrez and J. Saiz-Ruiz

CDP-chol ine and placebo condit ions were revealed in the s ta t is t ica l treatment of the data.

TABLE 3

MEMORY SCORE REDUCTION AFTER FOUR ECT S E S S I O N S

Placebm, CDP-chol ine Signif icance

Mean memory s.core reduct ion af ter /4 ECT

(digi ts)

Mean memory score reduct ion af ter 4 ECT

(associat ive)

0.43 0.47 n.s.

6.29 3.08 n.s.

MEAN RECUPERATION

TABLE 4

TIME (sec) OF BREATHING AND O R I E N T A T I O N

F i r s t spontaneous breathing

Af ter 2 ECT

Af te r 4 ECT

Placebo CDP-cho l ine

130.73 171.09 (Z 66.54) (±91.80)

131.00 158.90 (±69.47) ( !79.93)

Orientation recovery

Af ter 2 ECT

Af ter 4 ECT

2094.00 1567.20

(±1125) (±825.6)

1534.00 1942.80 (+_841.80) (+1049.40)

Side-ef fects

Although CPD-chol ine was administered in re l a t i ve l y e levated were observed in any of the pat ients who rece ived i t .

doses, no adverse side-effects

Discussion

a) Memory scores.

Psychological studies of the performance in memory tests of subjects suffering from depression (Cronholm and Ottoson, ]961) show that their learning ability is frequently impaired while, in contrast, their retention is not significantly affected.

Electric convulsive therapy impairment of memory 247

Elec t roconvu ls i ve therapy has two d i f ferent effects on the memory of pat ients suf fer ing from endogenous depress ion. On the one hand, it increases the learning since it a l lev ia tes the ef fect ive d i so rde r and consequent ly reduces in ter ference caused by the depress ion, increases mot ivat ion and st imulates concent ra t ion. On the other hand, it f requent ly provokes an adverse r e a c t i o n - it reduces re tent ion , a phenomenon which is completely independent of its therapeut ic effects (Ottoson, 1979).

The fact that the numerical memory scores remain constant af ter the second ECT whi le the as - soc ia t ive memory scores improve, may be seen as the resu l t of increased learn ing which, in the case of the assoc ia t ive memory test , is g rea te r than the degree of memory impairment involved.

The fact that both numerical and assoc ia t ive memory scores are lower af ter the f inal ECT than at the p re - t rea tment s t a g e - a phenomenon observed in both our g roups- resu l ts from impairment of retent ion insuf f ic ient ly compensated for by improvement in learn ing. This imbalance is most c l e a r - ly observed in the wo rd -pa i r memory s c a l e , s ince this is a more d i sc r im ina t i ve test of impa i r - ment of retent ion (Cronholm and Ottosson, 1961).

The absence of any s ta t i s t i ca l l y s ign i f icant d i f ferences between the CDP-cho l ine and placebo groups in respect of the i r reduced memory scores , does not permi t us to reach any va l id con- c lus ions. Our f indings do not support the hypothesis that CDP-cho l ine affords protect ion against memory dysfunct ion induced by ECT.

b) Pos t -ECT confusional state.

The seemingly con t rad ic to ry nature of the resul ts obtained af ter measurement of the length of time requ i red for the recovery of resp i ra t i on and or ienta t ion may be a t t r ibu ted to va r iab les such as indiv idual react ions to anaesthet ic, enzymatic fac to rs , drug in terac t ion , etc. which it was not possib le to control in spi te of the r igorous un i formi ty it was attempted to achieve.

Conclusions

Our f indings do not support the hypol~hesis that CDP-cho l ine af fords protect ion against E C T - i n - duced memory impairment. This fact may be expla ined as the resul t of var ious factors such as insuf f ic ient ly sens i t ive measuring methods, va r i e t y of indiv idual pat ient react ions, or even perhaps unknown pharmacokinet ic aspects of CDP-cho l ine . Fu r the r research in this area would be necessary.

Acknowl edgment

We are indebted to Ferrer Internat ional Chemical Indus t r ies , of Barce lona, fo r the i r kindness in supply ing us with the act ive medicat ion and placebo used in this study.

References

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248 J.L. Ayuso-Gutierrez and J. Saiz-Ruiz '

UYAMA, T . , SHIGEMOTO, K . arid YANAGISAWA, T. (1968). Therapeut ic effect of CDP-cho l ine on sequelae of head in jury on cerv ica l in ju ry in pa r t i cu la r . Paper presented to the symposium on the chernu[herapies of the sequelae of head in ju r ies . 27th. Annual meeting of Japan Neuro log i - cal Soc ie ty . Tok io .

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WESCHLER, D. (1958). The measurement and appraisal of adult in te l l igence. Will iams C- Wilkins. Ba l - t imore.

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Inqui r ies and repr in t requests should be addressed to:

J .L . Ayuso -Gu t i e r rez , M.D. Department of Psych ia t r y , Hospital Cl [n ico - 8 a- p lanta, Madr id-3 (Spain).