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Changes in the electroencephalogram during chronic administration of tranquilizing drugs
C H A N G E S IN T H E E L E C T R O E N C E P H A L O G R A M D U R I N G C H R O N I C A D M I N I S T R A T I O N OF T R A N Q U I L I Z I N G D R U G S LEo E. HOLI2ISTER, M.D. a n d CAgL A. BARTHEL
Veterans Administration Hospital, Palo Alto, California (Received for publleation: Deeember 13, 1958) Despite widespread use of tranquilizing drugs for long periods, few studies have determined the chronic effects of these drugs on electroencephalograms of patients. Such studies might be relevant to exacerbation of seizures by the drugs, their extrapyramidal effects and their mode of action. We chosed for study 40 chronic schizophrenic patients with normal eleetroencephalographic tracings prior to treatment with tranquilizing drugs. Treatment ranged in duration from 7 to 36 months (15 months median). Twenty-six patients received chlor-
show a normal pattern. The details of these 11 cases are noted in table I. The changes were variable, with focal slowing the most frequent (fig. 1). Slowing of alpha rhythm has been noted previously in a study of chronic chlorpromazine administration (Liberson 1955). Acute administration of chlorpromazine has also produced slowing, especially in the temporal areas (Shagass 1955; Szatmari 1956). Although scalp tracings showed no changes, some patients treated with Reserpine have shown slowing (2-3/see.) in the basal EEG (Arellano and 5eri 1956). Meprobamate in
TABLE I Electroeneephalographic Abnormalities in Eleven Patients on Long-Term Therapy with Tranquilizing Drugs
Case
Age
Drug
Daily Dose ~
Duration (Months)
1 2 3 4 5
62 57 31 31 25
CP CP CF CP CP
400 300 800 200 400
16 14 16 15 29
6
59
CP
200
12
7 8 9 10 11
57 32 32 58 52
Res Res Res Res Mep
2 3 2 1 1200
36 27 24 26 10
Changes in EEG
Gen. dysrhyth.; focal slow (4/sec. L.T.) Focal slow L.A.T. and L.T ................... Focal slow (4-6/see.); A.T., bil . . . . . . . . . . Focal slow (temporals 4-7/see. L.) ......... Focal slow (frontals 4-7/see.); amp. assym . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T. Mild gen. dysrhyth. Focal slow (5-7/ses L.T.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Focal slow (2-3/see.); L.F . . . . . . . . . . . . . . . . Gem slow (6-7/see.) ........................... Gen. and focal slow, especially on left Gen. and focal slow (A.T., bil.) ......... Mild gen. fast (15-20/sec.) . . . . . . . . . . . . . . .
Possible contributing factor Age None None IST previously See text Age None None None Age Alcoholism
Dose at time EEG taken. Usually had been higher earlier. CP : chlorpromazine - - Res : Reserpine - - Mep : meprobamate. promazine 100 to 800 mg. daily (median 400 mg.), 10 Reserpine 2 to 10 mg. daily (median 1200 rag.). Both pre- and post-treatment electroencephalograms were read independently by each of two observers, one of whom was unaware of the sequence of the tracings or the identity of the patients. Eleven patients had changes toward an abnormal EEG pattern, the other 29 patients continuing to The authors wish to express their appreciation to Dr. Richard Wortington and to G. Lawrence Mowery, who read the tracings.
single oral doses of 1600 to 2000 mg. produced low voltage (20-30/sec.) fast activity resembling that from barbiturates ( P f e i f f e r et al. 1957). There was no correlation between the degree of clinical improvement produced by tranquilizing drugs and the presence or absence of eleetroencephalographie changes. As is usual after prolonged administration of these agents, none of the patients showed clinical evidences of oversedation or excessive sleepiness. I t should be emphasized that factors other than the drugs might have contributed to the changes noted. Previous convulsive therapy, alcoholism, or advancing
[ 792 ]
EEG AND T R A N Q U I L I Z I N G DRUGS
793
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LEFT aUTIRIOR TNfPORAL
MIaBT U T I R I 0 ~ I'EPORAL lIGHT POS79RIOR TBfPG~I£L
LEPT ~
PAIlIZTAI~
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Fig. 1 Cas~ 3, table I. Left: Tracing taken on 4-10-56, normal. Right: Repeat tracing on 9-10-57 after 16 months of Chlorpromazine (current dose 800 mg. dally), focal slowing both anterior temporal leads, especially left. Reference electrode consists of 220,000 ohms resistance as an average reference taken, and all of the so-Called monopolar runs go to this resistance and thence to the other grid. TABLE
II
E f f e c t of Acute (500 m g ) Dose of Thioridazine D u r i n g Chronic A d m i n i s t r a t i o n Thioridazine
Eiectroencephalographic Changes
.
Case
Dose D u r a t i o n ASe/Sex rag/day mos.
A f t e r chronic dose
A f t e r added acute dose
1
27/M
500
5
Gen. parox, slow ( 3 - 6 / s )
Same
2
34/M
200
5
Normal
Same
3
42/M
450
2
Mild gen. slow ( 5 - 6 / s )
4
25/M
300
4
Normal
Gem and foe. slow (2-5/sec.)
5
48/M
600
4
Minimal slow, L A T
Foc. slow, A T
6
45/M
150
6
Normal
7
22/M
600
5
Normal
8
46/M
200
5
Normal
9
49/M
200
5
Parox. slow ( 4 - 5 / s )
P a r o x . slow (2-5/sec.)
10
27/M
200
4
Foe. slow ( 4 - 6 / s ) , L P T , LO
Gen. and foc. slow (2-6/see.)
Normal
Same Foc. slow, LC, L A T Normal
Clinical Changes Mnrked Imp. Slight Imp. Moderate Imp. Marked Imp. Unchanged Slight Imp. Moderate Imp. Moderate Imp. Unchanged Marked Imp.
794
L E O E. H O L L I S T E R
a n d C A R L A. B A R T H E L
L.Le'!
I,&,T,
L,T°
il,t
I,,IP.~o
lI,P.to
J 80qzV.
l.O.
l~'ig. 2 case 4, table II. Left: Tracing taken on 12-8-58 after 4 months of thloridazlne (current dose 300 rag. daily), normal. Right: Tracing same day, 4 hrs. after, added acute dose of 500 rag., generalized and focal slowing, especially on left side. Reference electrode consists of 220,000 ohms resistance as an average reference taken, and all of the so-called monopolar runs go to this resistance and thence to the other grid. y e a r s are f a c t o r s to be reckoned with. N o n e of these p a t i e n t s h a d a h i s t o r y of epilepsy, t h o u g h one (case 5) h a d a seizure a c c o m p a n y i n g a severe e x t r a - p y r a m i d a l s y n d r o m e d u r i n g a n earlier period of i n t e n s i v e chlorpromazine therapy. A new p h e n o t h i a z i n e derivative, thioridazine, is of i n t e r e s t because it does n o t produce a n y extrap y r a m i d a l effects. F o r t h i s reason, electroencephalog r a m s were o b t a i n e d on 10 schizophrenic p a t i e n t s who h a d been chronically t r e a t e d w i t h t h e drug. I m m e d i a t e l y a f t e r these t r a c i n g s were obtained, a n a d d i t i o n a l 500 mg. dose of the d r u g w a s a d m i n i s t e r e d . F o u r h o u r s later, a n o t h e r t r a c i n g w a s obtained. All t r a c i n g s were read blindly. T h e results are shown in table I I . l~ive p a t i e n t s h a d c h a n g e s (generalized or f o c a l slowing) a f t e r chronic a d m i n i s t r a t i o n of t h i o r i d a z i n e s i m i l a r to those observed a f t e r chronic t r e a t m e n t w i t h chlorpromazine or Reserpine. W h e n t h e a d d e d a c u t e dose w a s given, t h e c h a n g e s were m a d e worse in all b u t one case. A b n o r m a l i t i e s n o t p r e s e n t on t h e i n i t i a l t r a c i n g
were elicited b y t h e a c u t e dose in 2 cases (fig. 2). B o t h t h e s e p a t i e n t s showed e v i d e n t drowsiness of m o d e r a t e degree following t h e a c u t e dose of d r u g . A s with the o t h e r d r u g s , t h e r e w a s no correlation b e t w e e n the e f f e c t of the d r u g on t h e p s y c h o s i s a n d t h e occurrence of e l e c t r o e n c e p h a l o g r a p h i c a b n o r m a l i t i e s . CONCLUSION Chronic a d m i n i s t r a t i o n of t r a n q u i l i z i n g d r u g s in t h e r a p e u t i c doses m a y be a s s o c i a t e d w i t h electroe n c e p h a l o g r a p h i c a b n o r m a l i t i e s . I n t h e case of chlorp r o m a z i n e a n d Reserpine, generalized d y s r h y t h m i a a n d focal slowing are m o s t c o m m o n l y observed. Similar c h a n g e s follow chronic t r e a t m e n t w i t h thioridazine, a d r u g which does n o t produce e x t r a p y r a m i d a l effects. T h e s i g n i f i c a n c e of these c h a n g e s is n o t known, b u t t h e i r presence m a y lead to d i a g n o s t i c c o n f u s i o n unless considered as a possible d r u g e f f e c t . F u r t h e r s t u d i e s of t h e chronic e f f e c t s of t h e s e d r u g s on electroencephalographic p a t t e r n s should be done.
EEG
AND
TRANQUILIZING
REFERENCES ARELLAN0, A. P. and JERI, R. Scalp and basal electroencephalogram during the effect of reserpine. Arch. Neurol. Psychiat., Chicago, 75: 252. LIBERSO~¢, W. T. E f f e c t s of chlorpromazine hydrochloride (Thorazine) on EEG and on skin galvanic activity. - - A preliminary report. EEG Clin. NeurophysioL, 1955, 7: 474. PFEIFFER, C. C. et al. Comparative study of the effect of meprobanmte on the conditioned response, on
DRUGS
795
strychnine and pentylenetetrazol thresholds, on the normal electroencephalogram, and on polysynaptic reflexes. Ann. N. Y . Acad. Sci., 1957, 67 : 734-745. SHAGASS, C. E f f e c t of intravenous chlorpromazine on the electroencephalogram. EEG Clin. Neurophysiol., 1955, 7: 306-308. SZAT~ARI, A. Clinical and electroencephalographic investigation on Largactil in psychoses (Preliminary Study). Amer. J. Psyehiat., 1956, 112: 788.
Reference: HOLLISTER, L. E. and BARTHEL, C. A. Changes in the electroencephalogram during chronic administration of tranquilizing drugs. EEG Clin. Neurophysiol., 1959, 11 : 792-795.
Veterans Administration Hospital, Palo Alto, California (Received for publleation: Deeember 13, 1958) Despite widespread use of tranquilizing drugs for long periods, few studies have determined the chronic effects of these drugs on electroencephalograms of patients. Such studies might be relevant to exacerbation of seizures by the drugs, their extrapyramidal effects and their mode of action. We chosed for study 40 chronic schizophrenic patients with normal eleetroencephalographic tracings prior to treatment with tranquilizing drugs. Treatment ranged in duration from 7 to 36 months (15 months median). Twenty-six patients received chlor-
show a normal pattern. The details of these 11 cases are noted in table I. The changes were variable, with focal slowing the most frequent (fig. 1). Slowing of alpha rhythm has been noted previously in a study of chronic chlorpromazine administration (Liberson 1955). Acute administration of chlorpromazine has also produced slowing, especially in the temporal areas (Shagass 1955; Szatmari 1956). Although scalp tracings showed no changes, some patients treated with Reserpine have shown slowing (2-3/see.) in the basal EEG (Arellano and 5eri 1956). Meprobamate in
TABLE I Electroeneephalographic Abnormalities in Eleven Patients on Long-Term Therapy with Tranquilizing Drugs
Case
Age
Drug
Daily Dose ~
Duration (Months)
1 2 3 4 5
62 57 31 31 25
CP CP CF CP CP
400 300 800 200 400
16 14 16 15 29
6
59
CP
200
12
7 8 9 10 11
57 32 32 58 52
Res Res Res Res Mep
2 3 2 1 1200
36 27 24 26 10
Changes in EEG
Gen. dysrhyth.; focal slow (4/sec. L.T.) Focal slow L.A.T. and L.T ................... Focal slow (4-6/see.); A.T., bil . . . . . . . . . . Focal slow (temporals 4-7/see. L.) ......... Focal slow (frontals 4-7/see.); amp. assym . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T. Mild gen. dysrhyth. Focal slow (5-7/ses L.T.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Focal slow (2-3/see.); L.F . . . . . . . . . . . . . . . . Gem slow (6-7/see.) ........................... Gen. and focal slow, especially on left Gen. and focal slow (A.T., bil.) ......... Mild gen. fast (15-20/sec.) . . . . . . . . . . . . . . .
Possible contributing factor Age None None IST previously See text Age None None None Age Alcoholism
Dose at time EEG taken. Usually had been higher earlier. CP : chlorpromazine - - Res : Reserpine - - Mep : meprobamate. promazine 100 to 800 mg. daily (median 400 mg.), 10 Reserpine 2 to 10 mg. daily (median 1200 rag.). Both pre- and post-treatment electroencephalograms were read independently by each of two observers, one of whom was unaware of the sequence of the tracings or the identity of the patients. Eleven patients had changes toward an abnormal EEG pattern, the other 29 patients continuing to The authors wish to express their appreciation to Dr. Richard Wortington and to G. Lawrence Mowery, who read the tracings.
single oral doses of 1600 to 2000 mg. produced low voltage (20-30/sec.) fast activity resembling that from barbiturates ( P f e i f f e r et al. 1957). There was no correlation between the degree of clinical improvement produced by tranquilizing drugs and the presence or absence of eleetroencephalographie changes. As is usual after prolonged administration of these agents, none of the patients showed clinical evidences of oversedation or excessive sleepiness. I t should be emphasized that factors other than the drugs might have contributed to the changes noted. Previous convulsive therapy, alcoholism, or advancing
[ 792 ]
EEG AND T R A N Q U I L I Z I N G DRUGS
793
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II(IHT lqq~ TAL
RIGHT l~(RqTAL
L Z ~ ~OSTBtXOa T m ~ a a C
LEFT aUTIRIOR TNfPORAL
MIaBT U T I R I 0 ~ I'EPORAL lIGHT POS79RIOR TBfPG~I£L
LEPT ~
PAIlIZTAI~
~ltaL
RI(~T PAI~JlI~AL
LIFI ~ OC¢IPZTAL LEPT OCCrPITAL
R I ( I T OCCtIPITAL
lIGHT OCCIPITAL
JJOtaV. I I
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Fig. 1 Cas~ 3, table I. Left: Tracing taken on 4-10-56, normal. Right: Repeat tracing on 9-10-57 after 16 months of Chlorpromazine (current dose 800 mg. dally), focal slowing both anterior temporal leads, especially left. Reference electrode consists of 220,000 ohms resistance as an average reference taken, and all of the so-Called monopolar runs go to this resistance and thence to the other grid. TABLE
II
E f f e c t of Acute (500 m g ) Dose of Thioridazine D u r i n g Chronic A d m i n i s t r a t i o n Thioridazine
Eiectroencephalographic Changes
.
Case
Dose D u r a t i o n ASe/Sex rag/day mos.
A f t e r chronic dose
A f t e r added acute dose
1
27/M
500
5
Gen. parox, slow ( 3 - 6 / s )
Same
2
34/M
200
5
Normal
Same
3
42/M
450
2
Mild gen. slow ( 5 - 6 / s )
4
25/M
300
4
Normal
Gem and foe. slow (2-5/sec.)
5
48/M
600
4
Minimal slow, L A T
Foc. slow, A T
6
45/M
150
6
Normal
7
22/M
600
5
Normal
8
46/M
200
5
Normal
9
49/M
200
5
Parox. slow ( 4 - 5 / s )
P a r o x . slow (2-5/sec.)
10
27/M
200
4
Foe. slow ( 4 - 6 / s ) , L P T , LO
Gen. and foc. slow (2-6/see.)
Normal
Same Foc. slow, LC, L A T Normal
Clinical Changes Mnrked Imp. Slight Imp. Moderate Imp. Marked Imp. Unchanged Slight Imp. Moderate Imp. Moderate Imp. Unchanged Marked Imp.
794
L E O E. H O L L I S T E R
a n d C A R L A. B A R T H E L
L.Le'!
I,&,T,
L,T°
il,t
I,,IP.~o
lI,P.to
J 80qzV.
l.O.
l~'ig. 2 case 4, table II. Left: Tracing taken on 12-8-58 after 4 months of thloridazlne (current dose 300 rag. daily), normal. Right: Tracing same day, 4 hrs. after, added acute dose of 500 rag., generalized and focal slowing, especially on left side. Reference electrode consists of 220,000 ohms resistance as an average reference taken, and all of the so-called monopolar runs go to this resistance and thence to the other grid. y e a r s are f a c t o r s to be reckoned with. N o n e of these p a t i e n t s h a d a h i s t o r y of epilepsy, t h o u g h one (case 5) h a d a seizure a c c o m p a n y i n g a severe e x t r a - p y r a m i d a l s y n d r o m e d u r i n g a n earlier period of i n t e n s i v e chlorpromazine therapy. A new p h e n o t h i a z i n e derivative, thioridazine, is of i n t e r e s t because it does n o t produce a n y extrap y r a m i d a l effects. F o r t h i s reason, electroencephalog r a m s were o b t a i n e d on 10 schizophrenic p a t i e n t s who h a d been chronically t r e a t e d w i t h t h e drug. I m m e d i a t e l y a f t e r these t r a c i n g s were obtained, a n a d d i t i o n a l 500 mg. dose of the d r u g w a s a d m i n i s t e r e d . F o u r h o u r s later, a n o t h e r t r a c i n g w a s obtained. All t r a c i n g s were read blindly. T h e results are shown in table I I . l~ive p a t i e n t s h a d c h a n g e s (generalized or f o c a l slowing) a f t e r chronic a d m i n i s t r a t i o n of t h i o r i d a z i n e s i m i l a r to those observed a f t e r chronic t r e a t m e n t w i t h chlorpromazine or Reserpine. W h e n t h e a d d e d a c u t e dose w a s given, t h e c h a n g e s were m a d e worse in all b u t one case. A b n o r m a l i t i e s n o t p r e s e n t on t h e i n i t i a l t r a c i n g
were elicited b y t h e a c u t e dose in 2 cases (fig. 2). B o t h t h e s e p a t i e n t s showed e v i d e n t drowsiness of m o d e r a t e degree following t h e a c u t e dose of d r u g . A s with the o t h e r d r u g s , t h e r e w a s no correlation b e t w e e n the e f f e c t of the d r u g on t h e p s y c h o s i s a n d t h e occurrence of e l e c t r o e n c e p h a l o g r a p h i c a b n o r m a l i t i e s . CONCLUSION Chronic a d m i n i s t r a t i o n of t r a n q u i l i z i n g d r u g s in t h e r a p e u t i c doses m a y be a s s o c i a t e d w i t h electroe n c e p h a l o g r a p h i c a b n o r m a l i t i e s . I n t h e case of chlorp r o m a z i n e a n d Reserpine, generalized d y s r h y t h m i a a n d focal slowing are m o s t c o m m o n l y observed. Similar c h a n g e s follow chronic t r e a t m e n t w i t h thioridazine, a d r u g which does n o t produce e x t r a p y r a m i d a l effects. T h e s i g n i f i c a n c e of these c h a n g e s is n o t known, b u t t h e i r presence m a y lead to d i a g n o s t i c c o n f u s i o n unless considered as a possible d r u g e f f e c t . F u r t h e r s t u d i e s of t h e chronic e f f e c t s of t h e s e d r u g s on electroencephalographic p a t t e r n s should be done.
EEG
AND
TRANQUILIZING
REFERENCES ARELLAN0, A. P. and JERI, R. Scalp and basal electroencephalogram during the effect of reserpine. Arch. Neurol. Psychiat., Chicago, 75: 252. LIBERSO~¢, W. T. E f f e c t s of chlorpromazine hydrochloride (Thorazine) on EEG and on skin galvanic activity. - - A preliminary report. EEG Clin. NeurophysioL, 1955, 7: 474. PFEIFFER, C. C. et al. Comparative study of the effect of meprobanmte on the conditioned response, on
DRUGS
795
strychnine and pentylenetetrazol thresholds, on the normal electroencephalogram, and on polysynaptic reflexes. Ann. N. Y . Acad. Sci., 1957, 67 : 734-745. SHAGASS, C. E f f e c t of intravenous chlorpromazine on the electroencephalogram. EEG Clin. Neurophysiol., 1955, 7: 306-308. SZAT~ARI, A. Clinical and electroencephalographic investigation on Largactil in psychoses (Preliminary Study). Amer. J. Psyehiat., 1956, 112: 788.
Reference: HOLLISTER, L. E. and BARTHEL, C. A. Changes in the electroencephalogram during chronic administration of tranquilizing drugs. EEG Clin. Neurophysiol., 1959, 11 : 792-795.