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Cl oz ap i ne - Induc e d E l e c tr oe nc e pha l ogr am Change s asa F unc t i on o f C l oz ap i ne Se r um L e ve l sOliver Freudenreich, Richard D. W einer, and Joseph P. M cEvoy

Spec i f i c e lec t roencephalogram ( EEG) changes du r ing c lozapine therapy were prospec t ive lys tud ied in a cohor t o f 50 chronic s ta te hosp i ta l pa t ien t s w i th s ch i zophren ia w ho w ere random lyass igned to one o f three nonover lapping c lozapine s erum leve l ranges ( 50- 150 ng /mL ,200- 300 ng /mL , and 350- 450 ng /mL ) . EEGs were ob ta ined be fore c lozapine was ins t i tu ted ,and a f te r 10 weeks o f tr ea tment. F i f t y - three percen t o f pa t ien t s sho wed EE G cha nges dur ingthe lO- wee k s tudy per iod . We observed three s e izures ( 6%) , one in a pa t ien t on 900 m g ( serumleve l 320 ng /mL ) c lozapine , and two in pa t ien t s w i th low er c lozapine s erum leve l s ( 20 0- 3 00ng/mL ) who had pr ior h i s tor ie s o f s e i zures and inadequate va lproate coverage. T h ir teenpercen t o f pa t ien t s deve lop ed sp ikes wi th no re la tionsh ip to dose or s erum leve l o f c lozapine .F i f t y - three percen t o f pa t ien t s deve loped s lowing on EE G. Comp ared to p lasm a leve l s be low300 ng /mL , a c lozapine s erum leve l be tween 350 and 450 n g /mL led to more f r eque nt and m oresevere s lowing . T he EEG s lowing cor re la ted wi th observed s leep iness , a l though th i s fac torwa s not suf f ic ient to explain the sever i ty of high-dose ef fects . 1997 Socie ty of Biolog icalPsych ia t ryKey Words: Clo zap in e , s e i zu res , e l ec t ro en cep h a lo g ram, sch i zo p h ren i a , s e ru m l ev e lBIOL PSYCHIATRY 1997 ;42 :1 32-1 37

IntroductionR e c e n t r e v i e w s h a v e e s t i m a t e d c r u d e i n c i d e n c e r a t e s f o rs e i z ur e s d u r i n g c l o z a p i n e t r e a tm e n t o f 2 . 8 % ( D e v i n s k y e ta l 1 9 9 1 ) an d 1 .3 % (P ac i a an d Dev in sk y 1 9 94 ). F o r t h e i rr e t r o s pe c t i v e r e v ie w , P a c i a a n d D e v i n s k y u t i li z e d t h e h u g ed a t a b a s e f r o m t h e C l o z a r il P a t i e n t M a n a g e m e n t S y s t e mwi th 5 6 2 9 p a t i en t s , wh i l e Dev in sk y e t a l an a ly zed t h eS an d o z d a t ab ase o f 1 4 1 8 p a ti en t s p r i o r t o U .S . mark e t i n go f c l o zap in e . U s in g l i f e - t ab l e an a ly s i s , t h e l a t t e r ca l cu l a t edFrom t he John U mst e a d Hosp i t a l , Bu rner , Nor t h Ca ro l i na (OF, JPM) ; a nd Du keUni ve r s i t y Me d i c a l Ce n t e r a nd Durha m V A M e d i c a l Cen t er , Durha m, Nor t hCa ro l i na (RDW) .Addre ss r e p r i n t s t o Jo se ph P . Mc E voy , MD, John Umst e a d Hosp i t a l . Adu l tAd mis sion Uni t , Butner , NC 27509.Re c e i ve d Se p t e mbe r 7 , 1995 ; r e v i se d Ma y 27 , 1996 .

a cu mu la t i v e 1 0 % r i sk o f se i zu res a f t e r 3 .8 y ear s o ft r e a t m e n t . O t h e r s h a v e r e p o r t e d e v e n h i g h e r o c c u r r e n c era t es o f se i zu res i n mo re se l ec t ed p o p u l a t i o n s su ch as s t a t eh o sp i t a l p a t i en t s (Wi l so n an d C lau ssen 1 9 9 4 ) o r b r a in -i n ju red p a t i en t s (M ich a l s e t a l 1 9 9 3 ) . Th e ex p er i en ceb ased main ly o n case r ep o r t s an d case se r i es su g g es t s t h a tt h e r i sk fo r se i zu res i s d o se - r e l a t ed (Ha i l e r an d B in d er1 9 9 0 ; Bak er an d Co n ley 1 9 9 1 ) , a l t h o u g h se i zu res cano ccu r i n a l l d o se r an g es (W i l so n an d C lau ssen 1 9 9 4 ) an de v e n a t v e r y l o w d o s e s ( T h o m a s a n d G o u d e m a n d 1 9 92 ) .S o m e o f t h e s e s e e m i n g l y c o n t r a d i c t o r y o b s e r v a t io n s m i g h tb e e x p l a i n e d b y c l o z a p i n e ' s w i d e r a n g e o f p l a s m a l e v e l f o ra g iv en d o se (Har in g e t a l 1 9 9 0 ) .

C lo zap in e a l so h as an u n u su a l l y l a rg e p ro p en s i t y t oi n d u c e e l e c t r o e n c e p h a l o g r a m ( E E G ) c h a n g e s , r a n g i n g

1997 Socie ty of Biolog ica l Psyc hia t ry 0006-3223/97/$17.00PII S0006-3223(96)00298-3

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Clozapine-Induced EEG Changes BIOL PSYCHIATRY 1331997;42:132-137

f r om 53 % ( G un t he r e t a l 1993) and 59% ( Sp a t z e t a l 1978)t o 74% ( W el ch e t a l 1994) . O f t he s e , gene r a l i z ed s l ow i n gi s t he m os t p r om i nen t f i nd i ng ( e . g . , Spa t z e t a l 1978 ;Ma l ow e t a l 1994 ; We l ch e t a l 1994) , w i t h s ha r p ac t i v i t yoccu r r i ng i n a s m a l l e r p r opo r t i on ( e . g ., 16% i n G un t he r e ta l 1993) . Som e bu t no t a l l s t ud i e s f ound E EG change s t obe dos e - r e l a t ed ( e . g . , We l ch e t a l 1994 ; G un t h e r e t a l 1993;B r a u n - S c h a r m a n d M a r t i n i u s 1 9 9 1 ) .

O n l y one s t udy w as done t ha t r e l a t ed EEG a l t e r a t i onsw i t h c l ozap i ne p l a s m a l eve l s ( H a r i ng e t a l 1994) . Theg r oup s t ud i ed 29 i npa t i en t s and f ound an i nc i dence o f 52%f o r c l o z a p i n e - i n d u c e d E E G c h a n g e s . U s i n g d i s c r i m i n a n tana l ys i s , t hey f ound c l ozap i ne p l a s m a l eve l s bu t no tc l ozap i ne dos e t o be a va l i d i nd i ca t o r o f t he appea r ance o fpa t ho l og i ca l EEG changes . The s t udy w as na t u r a l i s t i c i nt he s ens e t ha t pa t i en t s w e r e t r e a t ed w i t h c l ozap i ne on ac l i n i ca l l y open ba s i s . I n add i t i on , on l y l ow t o m ode r a t er a n g e s o f c l o z a p in e l e v e l s w e r e e n c o u n t e r e d ( g r o u p m e a n so f 8 1 . 6 a n d 2 3 5 . 7 n g / m L ) .

N o p r o s p e c t i v e , s y s t e m a t i c s t u d y w i t h r a n d o m a s s i g n -m e n t t o s p e c i f i c c l o z a p i n e s e r u m l e v e l r a n g e s h a s b e e nd o n e i n w h i c h c l o z a p i n e s e r u m l e v e l s a n d s p e c i f i c E E Gc h a n g e s w e r e c o r r e l a t e d . A s p a r t o f a n o n g o i n g r a n d o m -i zed , doub l e - b l i nd , 12 - w eek t r i a l i n adu l t s w i t h t r e a t m en t -r e s i s t an t s ch i zophr en i a com par i ng t h r ee d i f f e r en t c l oza -p i ne s e r u m le v e l r a n g es ( 5 0 - 1 5 0 n g / m L , 2 0 0 - 3 0 0 n g / m L ,a n d 3 5 0 - 4 5 0 n g / m L ) , w e o b ta i n ed E E G s b e f o r e ra n d o m -i za t i on and aga i n a f t e r 10 w eeks o f c l ozap i ne t he r apy . W er e p o r t t h e i n c i d e n c e o f s e i z u r e s a n d p r e v a l e n c e o f E E Gchanges i nc l ud i ng e s pec i a l l y ep i l ep t i f o r m ac t i v i t y ( s p i ke s /s ha r p w aves ) and s l ow i ng i n ou r f i r s t 50 pa t i en t s .

M e t h o d s

EligibilitySub j ec t s w e r e a l l hos p i t a l i z ed pa t i en t s w i t h ch r on i cs ch i zophr en i a o r s ch i zoa f f ec t i ve d i s o r de r a cco r d i ng t oD S M - I I I - R c r i te r i a . A l l pa t ien t s w e r e t r e a t m en t - r e s i s tan t ,a s de f i ned by hav i ng f a i l ed r epea t ed t r i a l s o f a t l e a s t t w od i f f e r en t neu r o l ep t i c s i n t he pa s t . N o pa t i en t had r ece i vedc l ozap i ne be f o r e . Tw o pa t i en t s w i t h a s e i zu r e h i s t o r y w how er e i n need o f t r e a t m en t w i t h an an t i convu l s an t w e r es w i t ched t o va l p r o i c ac i d p r i o r t o en t r y . N o o t he r pa t i en t shad any ava i l ab l e h i s t o r y o f p r i o r s e i zu r e ac t i v i t y .

T h e p r o t o c o l w a s r e v i e w e d a n d a p p r o v e d b y t h e i n v e s -t i ga t io n a l r e v i e w b o a r d s o f b o t h D u k e U n i v e r s it y a n d J o h nU m s t ead H os p i t a l . A l l pa t i en t s gave w r i t t en i n f o r m edcons en t .Patient PopulationFi f t y pa t i en t s ( 11 w om en and 39 m en) pa r t i c i pa t ed i n t hes t u dy ; 2 6 w e r e w h i te , 2 4 w e r e b l a c k . T h e i r m e a n a g e w a s

3 8 y e a r s ( r a n g e f r o m 2 1 t o 5 6 ) . T h e y h a d h a d b e t w e e n 2and 44 l i f e t i m e adm i s s i ons ( m ean 10 ) , w e r e be t w een 2 and33 yea r s pa s t t he i r f ir s t hos p i t a l i z a t i on ( m e an 15 ), and hada G l o b a l A s s e s s m e n t o f F u n c t i o n i n g b e t w e e n 1 5 a n d 4 0( m ea n 29 ) a t ba s e l i ne . A s s i g nm en t t o one o f t he th r eec l o z a p i n e s e r u m r a n g e g r o u p s w a s n o t a s s o c i a t e d w i t hs i gn i f i c an t i n t e r g r oup d i f f e r ences i n any o f t he dem o-g r aph i c va r i ab l e s .

Study Design and Treatment RegimenI n an e f f o r t t o a ch i eve cons i s t ency o f conven t i ona l an t i -p s ycho t i c t r e a t m en t du r i ng ba s e l i ne a s s e s s m en t s , e l i g i b l epa t i en t s w e r e s w i t ched ove r t o ha l ope r i do l o r f l uphenaz i nea n d t r e a t e d f o r 1 - 2 w e e k s b e f o r e b a s e l i n e a s s e s s m e n t sw er e done . P a t i en ts w e r e t ape r ed o f f al l o t he r m ed i ca t i onexcep t i f g i ven t o t r e a t a conc om i t an t m ed i ca l cond i t ion .Pa t i en t s w e r e t hen r ando m l y a s s i gned t o one o f t h r een o n o v e r l a p p i n g c l o z a p i n e s e r u m l e v e l r a n g e s ( g r o u p I :5 0 - 1 5 0 n g / m L , g r o u p II : 2 0 0 - 3 0 0 n g / m L , a n d g r ou p I II :3 5 0 - 4 5 0 n g / m L ) . P a t i e n t s w e r e s l o w l y ( b y 2 5 - 5 0 - m gi n c r e m e n t s e v e r y d a y o r e v e r y o t h e r d a y ) t i t r a t e d u p t ot h e ir a s s i g n e d s e r u m l e v e l ra n g e . B l o o d w a s d r a w n w e e k l yt h r ougho u t t he du r a t i on o f the s t udy , and a phys i c i an no ti n v o l v e d i n t h e p a t i e n t a s s e s s m e n t s m a d e t h e n e c e s s a r ydos e ad j us t m en t s t o keep each pa t i en t i n h i s o r he ra s s i gned s e r um l eve l r ange . We dec i ded a p r i o r i t o g i ve am a x i m u m o f 9 0 0 m g a s a d a i l y do s e . N o s e d a t i v em ed i ca t i ons ( e . g . , benzod i azep i ne s , ba r b i t ua t e s ) w e r e pe r -m i t t ed t h r oughou t t he s t udy . D os es o f ha l ope r i do l o rf l u p h e n a z i n e w e r e g i v e n a s n e c e s s a r y o n r a r e o c c a s i o n sdu r i ng t he f i r s t 2 w eeks o f c l ozap i ne dos e t i t r a t i on .

Assessments of PsychopathologyS e v e r i t y o f p s y c h o p a t h o l o g y w a s a s s e s se d a t t h r ee t i m epo i n t s by a phys i c i an b l i nd t o t he a s s i gned s e r u m l eve l andt he dos e : du r i ng t he ha l ope r i do l l e ad - i n pe r i od , and aga i nbo t h 6 and 12 w ee ks a f t e r r andom i za t i on . Fo r th i s repo r t ,w e ex am i n ed r e s pon s e a t a c r i t e ri on l eve l o f a 33% dec l i nei n t o ta l b r i e f p s ych i a t r i c r a t i ng s ca l e ( B PR S) s co r e . Thet r e a tm e n t o u t c o m e d a t a w i l l b e r e p o r t e d e l s e w h e re .

I n add i t ion , s l e ep i ne s s w as a s s e s s ed b y a r e s ea r ch nu r s et h r ee t i m es du r i ng t he s t udy w i t h an o r d i na l s ca l e f r om 0to 3 (0 , energet ic ; 1 , a ler t but ca lm; 2 , s l ight ly s leepy; 3 ,ve r y s l e epy ) .

E E G sA 21- channe l EEG w as r eco r ded , u s i ng a l l 19 s t anda r ds ca l p l oca t i ons o f t he I n t e r na t iona l 10 / 20 s ys t em o f e l ec -t r o d e p l a c e m e n t a n d a 2 1 - c h a n n e l N i h o n K o h o n E E Gm a c h i n e . T h e E E G w a s r e p e a t e d a f t e r 1 0 w e e k s a n d , f o r2 4 s u b j e c ts , a n i n t e r m e d i a r y r e c o r d in g w a s m a d e w h e n t h e

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134 BIOLPSYCHIATRY O . Freudenreich et al1997;42:132-137

Table 1. Mean Clozapine D oses and Mean Achieved Clozapine Serum Lev els from 50 Schizophrenic Patients for Each of ThreeDesignated Clozapine Serum Lev el RangesCloz a p ine dos e in m g S e rum le ve l in ng /m LGroup Ass igned c lozapine se rum leve l # pa tients Mean (SD) Rang e [mean (SD)]

I 50-1 50 ng/m L 16 157 (75.9) 64 -3 50 94 (13.5)II 200 -300 ng/m L 22 421 (229.2) 150 -900 248 (15.0)III 35 0- 450 ng/m L 12 594 (175.6) 30 0-9 00 391 (26.8)

pa t i en t f i r st r e ached t he a s s i gned t a r ge t s e r um l eve l range .T h i s e x t r a r e c o r d in g , p e r f o r m e d b e t w e e n t h e b a s e l in e a n d1 0 - w e e k f o l l o w - u p s t u d y , w a s i n st it u te d m i d w a y t h r o u g ht he p r o t oco l becaus e o f t he app r ec i ab l e i nc i dence o fs e i zu r e s ( s ee be l ow ) i n t h i s popu l a t i on . A l l EEG s w er ei n t e r p r e t ed b l i nd t o s ub j ec t , g r oup a s s i gnm en t , and t i m e i ns t udy by a boa r d - ce r t i f i ed c l i n i ca l e l ec t r oencepha l og r a -p h e r ( R D W ) . E E G s w e r e r a te d o n a n c h o r e d 5 - l e v e l o rd i n a lsca les f ro m 0 to 4 (0 , absent ; 1 , bord er l ine ; 2 , mi ld ; 3 ,m ode r a t e ; 4 , s eve r e ) f o r po l ym or ph i c s l ow i ng , f r on t a li n t e r m i t t en t r hy t hm i c de l t a s l ow i ng ( F I R D A ) , o t he r r hy t h -m i c s l ow i ng , s ha r p / s p i ke ac t i v i t y , and ove r a l l a s ym m et r y( We i ne r e t a l 1986) . F o r t he pu r pos e o f t h is s t udy , f ou rm eas u r e s w e r e u s ed : 1 ) ove r a l l abno r m a l i t y ; 2 ) ove r a l la s ym m e t r y ; 3 ) s p i ke / s ha r p ac t i v i t y ; and 4 ) a s l ow i ng i ndex( s um o f s co r e s f o r t he t h r ee s l ow i ng r a t i ngs ) .

D i f f e r ence s co r e s f o r e ach o f t he f ou r va r i ab l e s w e r eca l cu l a t ed t o i nd i ca t e changes a t w eek 10 com par ed t obas e l i ne EEG s . S i nce a l l bu t 4 pa t i en t s had no r m a lbas e l i ne EEG s , t h i s ba s i ca l l y co r r e s ponded t o t he r ead i ngsa t w eek 10 .Special Lab StudiesB l o o d w a s d r a w n i n t h e m o r n i n g b e f o r e b r e a k f a s t a p p r o x -i m a t e l y 12 hou r s a f t e r t he l a st c l ozap i ne dos e . C l ozap i new as quan t i f i ed i n s e r um a t N a t i ona l Med i ca l Se r v i ce s ,I n c ., W i l l o w G r o v e , P A , u s i n g c a p i l la r y g a s c h r o m a t o g r a -p h y ( S i m p s o n a n d C o o p e r 1 9 7 8 ) .

W e c a l c u l a t e d a n a v e r a g e c l o z a p i n e d o s e a n d s e r u ml eve l f o r e ach pa t i en t by t ak i ng t he m ean s o f the dos e s an dac t ua l l y ach i eved s e r um l eve l s f o r on l y t hos e t i m es w hent ha t pa t i en t ' s b l ood l eve l s w e r e i n h i s o r he r a s s i gnedt a r ge t r anges .

Statistical AnalysesC o m p a r a b i l i t y o f t r e a t m e n t g r o u p s w a s e s t a b l i s h e d u s i n ga n a l y s e s o f v a r ia n c e ( A N O V A s ) f o r c o n ti n u o u s v a r i a b l e sa n d c h i - s q u a r e s f o r c a t e g o r i c a l v a r i a b l e s . W e e x a m i n e do u r E E G r a t i n g s w i t h A N O V A s , f o l l o w e d u p w i t h t h eN e w m a n - K e u l s p r o c e d u r e a s o u r p o s t h o c t es t. C h i -s q u a r e s w e r e u s e d i f f re q u e n c i e s w e r e t o b e c o m p a r e d .

When i nd i ca t ed , t he B onf e r r on i co r r ec t i on w as u s ed . Thea l pha l eve l w as s e t a t - < .05 ; a l l t e s t s w e r e t w o t a i l ed .

Resu l t sD ur i ng t he ha l ope r i do l l e ad - i n pe r i od , pa t i en t s r e ce i ved ana v e r a g e o f 2 2 m g h a l o p e r i d o l e q u i v a l e n t s d a i l y ( r a n g i n gf r o m 5 t o 6 0 m g ) w i t h n o s i g n i f i c a n t d i f f e r e n c e a m o n gt r ea t m en t g r oups .

F i f t y pa ti en t s w e r e r ando m i zed . Th r e e ou t o f 15 pa t i en t sa s s i gned t o t he h i gh c l ozap i ne s e r um l eve l r ange cou l d no tr each i t becaus e o f e i t he r i n t o l e r ab l e hypo t ens i on ( 1p a t ie n t ) o r b e c a u s e t h e y h a d r e a c h e d t h e m a x i m u m d o s e o f900 m g ( 2 pa t i en t s ) . They a r e g r ouped acco r d i ng t o t he i ra c t u a l a c h i e v e d s e r u m l e v e l ( m e d i u m r a n g e f o r a l l 3p a t ie n t s) . O n e p a t i e n t w h o r e a c h e d 3 2 7 n g / m L o n 9 0 0 m gw as i nc l uded i n t he h i gh g r oup . Thus , 16 pa t i en t s w e r et r ea t ed i n t he l ow r ange , 22 i n t he m ed i um r ange , and 12i n the h i gh r ange . I t c an be s een i n Tab l e 1 t ha t m ean da i l yc l ozap i ne dos e s neces s a r y t o m a i n t a i n pa t i en t s i n t he i ra s s i gned c l ozap i ne s e r u m l eve l r anges va r i ed w i de l y . S t i l l,c l ozap i ne dos e and s e r um l eve l w e r e s i gn i f i c an t l y co r r e -la ted ( r = .64; p < .001) .

T w o p a t i e n t s w h o w e r e b o t h a s s i g n e d t o t h e m e d i u ms e r u m l e v e l r a n g e b e g a n t h e s t u d y o n v a l p r o a t e b e c a u s e o fs e i zu r e h i s t o r i e s . Th r ee m or e pa t i en t s w e r e s t a r t ed onva l p r oa t e du r i ng t he cou r s e o f t he s t udy e i t he r a f t e r as e i zu r e occu r r ed ( 1 pa t i en t ) o r becau s e o f ep i l ep t i f o r ma c t i v i t y s e e n o n E E G s o b t a i n e d b e f o r e o u r w e e k l 0 E E G(2 pat ient s ) .

O ve r a l l , 3 ou t o f 50 pa t i en t s ( 6% ) had s e i zu r e s . R epor t so f t h e s e s e i z u re s w e r e s u g g e s t i v e o f th e t o n i c - c l o n i c t y p e ;h o w e v e r , n o n e w e r e w i t n e s s e d b y a h i g h l y e x p e r i e n c e do b s e r v e r w h o c o u l d r e l i a b l y d i s t i n g u i s h m y o c l o n i c f r o mt o n i c - c l o n i c s e iz u r e s. B o t h p a t i e n ts w h o w e r e p r o p h y l a c -t i c a l l y s t a r t ed on va l p r oa t e had s e i zu r e s . O ne s e i zu r eoccu r r ed du r i ng t he t i t r a t i on pe r i od w hen va l p r oa t e w asd i s con t i nued becaus e o f a m ed i ca t i on e r r o r , and t he o t he ro n e t o w a r d t h e e n d o f th e s t u d y w h e n v a l p r o a t e le v e l s f el li n t o the s ub t he r ape u t i c r ange ( 38 I xg / m L ) w h i l e t he pa t i en tw a s o n 6 5 0 m g c l o z a p i n e ( l e v e l 1 2 0 n g / m L ) . T h e o n l yo t he r s e i zu r e occu r r ed i n a pa t i en t f r om t he s e r um l eve lg r o u p I I I w h i l e o n 9 0 0 m g c l o z a p i n e ( 3 2 0 n g / m L s e r u m

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l e v e l) a t w e e k 8 . T h e s e i z u re i n c i d e n c e i n o u r c o h o r t f o r a llp a t i e n t s w i t h o u t a p r e e x i s t i n g s e i z u r e d i s o r d e r r e q u i r i n gv a l p r o a t e w a s 1 o u t o f 4 8 ( 2 % ) .

F i v e p a t i e n t s w h o e n t e r e d t h e s t u d y o n v a l p r o a t e o rw e r e p u t o n v a l p r o a t e d u r i n g t h e s t u d y w e r e e x c l u d e df r o m t h e f o l l o w i n g a n a l y s e s . T h u s , 4 5 p a t i e n t s w e r ea n a l y z e d w i t h n o c o n c o m i t a n t m e d i c a t io n .

T w e n t y - f o u r o u t o f 4 5 p a t ie n t s ( 5 3 % ) d e v e l o p e d s o m ed e g r e e o f o v e r a ll E E G a b n o r m a l i t y d u r i n g th e s t u d y .G r o u p m e a n s ( S D ) w e r e s i g n i f i c a n t l y d i f fe r e n t f o r t h et h r e e g r o u p s ( F = 4 . 0 ; d f = 2 , 4 2 ; p = . 0 2 5 ), w i th p o s t h o ca n a l y s i s s h o w i n g t h a t t h e h i g h s e r u m l e v e l g r o u p ( I I I ) w a ss i g n i f i c a n t ly m o r e a f f e c t e d t h a n e i t h e r g r o u p I o r g r o u p I I .I f o n l y o v e r a l l a b n o r m a l i t i e s m o r e s e v e r e t h a n t h e b o r d e r -l i n e r a t i n g w e r e e x a m i n e d , 1 5 o u t o f 4 5 p a t i e n ts ( 3 3 % ) h a dn e w E E G f i n d i n g s w i t h a s i g n i f i c a n t s e r u m l e v e l - d e p e n -d e n t d i s t ri b u t i o n ( g r o u p I 2 0 % , g r o u p I I 2 1 % , a n d g r o u pI I I 7 3 % ; c h i - s q u a r e = 1 0 . 2; d f = 2 ; p = . 0 0 6 ). T h e h i g h e s ts e r u m l e v e l g r o u p h a d s i g n i f i c a n t l y m o r e a b n o r m a l i t i e st h a n e i t h e r g r o u p I o r I I. T h e r e w a s n o d i f f e r e n c e b e t w e e ng r o u p I a n d I I .

W e t h e n e x a m i n e d s p i k e / s h a r p a c t i v i t y a n d s l o w i n gs e p a r a t e l y .

S p i k e / s h a r p w a v e s w e r e s e e n i n 6 s u b j e c t s ( 1 3 % ) . T h ed e v e l o p m e n t o f s h a rp w a v e s a n d s p ik e s w a s n o t c o n f i n e dt o h i g h e r s e r u m l e v e l g r o u p s ; 1 s u b j e c t i n s e r u m l e v e lg r o u p I d i s p l a y e d t h e s e f i n d i n g s , 3 i n g r o u p I I , a n d 2 i ng r o u p I I I ( c h i - s q u a r e = 0 . 9 , d f = 2 , n o n s i g n i f i c a n t) . O n ep a t i e n t f r o m g r o u p I I h a d m o d e r a t e s p i k e / s h a r p w a v e s t h a tw e r e c l e a r l y e p i l e p t i f o r m i n n a t u r e , w h e r e a s t h e o t h e r 5h a d m o r e e q u i v o c a l b o r d e r l i n e r a t i n g s . T h e r e w a s n or e l a t i o n s h i p t o d o s e .

A f r e q u e n c y d i s t r i b u t io n f o r t h e ra t i n g s o f s l o w i n g i sg i v e n i n F i g u r e 1 . T w e n t y - f o u r o u t o f 4 5 p a t i e n t s ( 5 3 % )s h o w e d s o m e d e g r e e o f s l o w i n g o n t he i r E E G r a ti n g s;h o w e v e r , t h i s e f f e c t w a s n o t u n i f o r m a c r o s s a l l s e r u ml e v e ls : 3 3 % o f p a t ie n t s i n g r o u p I s h o w e d s l o w i n g , 5 3 %f r o m g r o u p I I, a n d 8 2 % f r o m g r o u p I I I ( c h i - s q u a r e = 6 . 0 ;d f = 2 ; p = . 0 4 9) . E E G s l o w i n g c o r r e l a t e d p o s i t i v e l y w i t hb o t h c l o z a p i n e d o s e ( r = . 3 6 ; p = . 0 2 ) a n d c l o z a p i n es e r u m l e v e l ( r = . 4 4 ; p = . 0 0 2 ). T h e g r o u p m e a n s a s am e a s u r e o f s ev e r it y o f E E G s l o w i n g [ m e a n s ( S D ) f o rg r o u p s I t h r o u g h I I I , r e s p e c t i v e l y : 0 .9 ( 1 .8 ) , 1 .0 ( 1 .5 ) , 3 .4( 1 .9 ) ] w e r e s i g n i f i c a n t l y d i f f e r e n t ( F = 8 .7 ; d f = 2 ,4 2 ; p