Control led Evaluat ion o f Lithium and Chlorpromazine in the T r e a t m e m of M a n i c States: An Interim Report

By Go,too,'," Jor ixso,,,', SA~tUEL GERSHON AND LEOn j. HE~I~tlAN

S " ' : { ' ther~pt~utie act ion Of lithium salts in INCE T H E DISCOX, E1 ~ of the states of psychotic excitement, '-~ a nu~aber of sta~dies h a v e shown the

consistent clhaicaI eflqeaey of this drug in the manic phase of xnanic depressive 111heSS? ... . . . . . . . . . ~,.a Only one report has shown unfavorable results, aa

However, o~ly two of these studies have been controlled, ar.zs and no trials of treatment have been undertaken to compare the" eflects of lithium against a known therapeutic agent. The' hnportanee of th is has been stressed by pre- vious invest igatorsS ,:~ Its therapeutic action in non-manic excitation has not been the subject of controlled investigation and reports of its action va~,. Most reports state that it has some efficacy in the ~:ontrol of the psychomotor excita- tion. ~',~z.e~; However. two investigators found lithium to have greater efficacy in states other than manic excitement. "~-au In the present controlled investiga- tion,, a neuroleptic chlorpromazine has been used i,z a double blind trial w i t h lithium carbonate in the treatment of manic states. A control group of schizophrenics with psychomotor excitation and elation has %een used.

X'IETltODS

Pa t ienk~ cons ide red su i tab le were se lec ted f rom admiss ions to Be l l evue Psych ia t r i c Hos- pi ta l or d i rec t referr,'ds and h o u s e d on one of t w o research wards . T h o s e u n d e r g o i n g in- tensive ba lance stxtdies were p l aced on the me tabo l i c unit. Pat ients we re assessed b y three psychia t r i s t s and classified as man ia or sehizo-affectSve. The diagnaosis o f m a n i c de- pre~ssive illness, naax~ic~ p h ~ e , v , '~ b a s e d on tJ~e eri ter ia as de ta i l ed in Mayer -Gross . 20

SeP, izo-affec-tive illness is taken to mean the o c c u r r e n c e of p s y c h o m o t o r excitatiotx and he igh tened affect in associat ion w i th c lear cu t sch izophren ic s y m p t o m s such as formal t hough t disorder , i nappropr i a t e behavior , inc-ongruity o f af fec t and ideat ion, systemati .sed de lus ions and hal luc inat ions of more than t ransient na ture . A total o f 42, pa t i en t s x ~ r e in- e l u d e d in the s tudy. B e ~ t u s e of the na tu re of thei r illness m a n y o the r pa t ien ts w e r e lost to the s tudy ,as they w e r e unab le or unwi l l ing to consen t to par t ic ipa te .

Of the 4:2 pat ients , 07 we re marAe-depressive, mr.~nie phase , o.ne " 'chronic ma~tia'" and 14 schizo-affect ive. Fo l lowing t r ea tmen t th ree of the schizo-affec t ive g roup w e r e rediag- nosed sch izophren ic react ion, pa r ano id type. O n e pa t i en t first diag, nosed a.s m a n i c on her first admLssion was r6~lia~nosed ,as schizo-affe~:tive on her se~'ond admiss ion 18 montI~s later. T h e age and sex of the pa t ien ts is s h o w n in T a b l e 1. E thn ic distrib~ttion s h o w e d an absence of man ic -depress ive iHnem in Negroes .

This work was sttpported by USPHS, N I M H Grants ~IH 04669 and 3111 08618. ( ; o tu )oy J o H x s o x , 31.B.B.S., M.A.N.Z.C.P . . D.P..M.: Re, earch ,-L~sociate, Depdrtnvent of

I'.~.yehie.try and No'urology, New Ytirk Unit~ersit!t School of 3tediciTJe, New )'qrk, N.)', SAxtt'l~t. (,~:ltsttO.'~, XI.B.B.S. ] ) .P .M.: Ht:.~varch Proft's.sor, Del~arlrnctzt o] P.~ychiatrtj and NelJrologv, New York UniverMty School o/ .'tlvdici1~e. I,v:o~ J. llEKt.~ftAx, M.D. : Assistant Pro[e&sof I)epar!~nc~d o/ P.vychiatnj t:l~d Nt'ttrolog!l, Nt'tt" York [tnit:,-r.sittj School ojf 3tedieinc.

(;o~tvr~r:~:,x~lvv. ] ' sYc~:vrnY, VOI.. 9. No. 6, (Noveml:~r): 1.~.~; 5~3

564 J O H N S O N , CEIISHON AN1) HEKINIIAN

T a b l e 1 . - - A g e a n d S e x D a t a

0 - 2 0 21 -30 3 1 - 4 0 41-50 51 -60 60.-t-

5Ianie -depres~s ive - - 2 8 10 5 "2 S c h i z o - a f f e c t i v e I 7 1 2 3

S E X

M ale F e m a l e T o t a l

N l a n i c - d e p r e ~ i v e 13 15 28 S c h i z o - a f f e c t i v e 6 8 14 T o t a l 19 23 42

On admiss ion to the research ward. all medicat io , ,s were s topped and pat ients p laced on placebo. Only seda t ion a l lowed was ctfloraI l lydra te or pa r ah l ehyde . T h e basel ine per iod averaged five f l ays and d u r i n g this t ime a clinical and b iochemica l work-up was done. Basel ine estinaates o f electrolytes and blc~)d chemistD' inc lud ing SCOT. and SCPT. b lood urea, b lood sugar, se rmn proteins full blood count and differential , a lkal ine phospha tase and urinalysis were done. T h r m l g h o u t the s~it ly senml electrolytes ~md l i th ium were (le- termi~led twice week ly and blood chemistr ies weekly. Elec t ro ly te estimation.~ were done hy tim Atomic Absorpt iou Method .

A t o m i c A b s o r p t i o n

In this me thud a hol low c a t h o d e l amp prod~wes a specific wave l eng th whic'l~ is to lw absorbed. T h e beam from the l amp passes thmmzh a hmtr pa th of the flame to the photo- tube. k gra t inK insures a na r row band pass.

As the sample is a tomized in a tvo l flame, a few a toms are raised to an excite~l state. Re turn ing to its original state, the a toms emi t light (flame emission). T h e daopper of the A.A. cuts out this fraction. T h e major i ty of the a toms (in the cool flame) are unexc i ted and are capab le of absorb ing l ight (from the beam). The [inal intensiW of tiffs absorbed lit~ht reaches the pho to tube . T h e a m o u n t absorbed hy the flame is propc, rtional to the concen- t rat ion of the e l emen t in the sample.

T w e n t y - f o u r - h o u r ur ine collections were s ta r ted in the basel ine per iod and estimation.s of ur inao" cortisol excret ion were unde r t aken in ore" group and e lec t ro ly te excretion patten~s were. mlalysed in those unde rgo ing ha lance studies. Saliva was col lec ted and es t imat ions of vo lume anti e lec t ro ly te pa t te rns ( luring t r ea tmen t were made . F .K .C . xv~m done at basel ine and r epea t ed a~ain at t emf ina t ion and if toxic synq~toms appeared .

Cl in ica l A s s e s s m e n t

On a d m i ~ i o n to the s t u d y and at w t ~ k l y intervals throug.hout, pa t ien ts were r a t e d by two psychiatr is ts who were u n a w a r e of the med ica t ion the pa t ien t wa_s recwiving, t l owever , owing to the different ial effects of these two drug's, on occasions it was impossible not to have Knu~sed wi th a reasona})le degree of certain~" which medica t ion ,~wks be ing used. This was recognized and recent ly the rater .has been record ing w h i c h ¢lru~ he feels the pa t ient is receiving.

T h e ra t ing scudes used were the Brief Psychia t r ic Ra t ing Scale (BPRS) and T r e a t m e n t Response A.~sessment .Method (TRAM). I " Addi t ional assessments wen- m a d e by the psy- chologist, w h o adminis ter txl a Stralctured Clinical In te rv iew (SC 1) "~ at baseline, 3 - 5 days, 11t--12 days and 1 6 - 1 8 days of t rea tment . T h e ~,Vittenborn scale was filled out weekly by the residt,nt anti X, Vard Behavior I nven to ry (VtBI) and Nurses Obse~ ' a t ion Scale for In- pat ient Evahmt ion (NOSIE) by the n u r s i n g stall . Ill recent months addi t ion;d scales such as Trea t Jnen t Emergelzt Symptonts (TICS). D r u g Record (DR) :rod Pa t ien t Data l n v e n t o ~ {P1)I) and Clinical ( ; lohal I m p r o v e m e n t (CCI) have been inc luded. T w e n t y - f o u r - h o u r dt~.p-act ivi ty record w~ts kept and a lox ic i |y c h e c k list was enq)loved dai ly by the nurs ing s t a l l All .qaif imolve~! in ratim~s were lillit%va[e i[}~ t~ie corn-ct medicat i tm.

L 1 T I t l U . N I A N D C H L O t l P I 1 O N ] [ A Z I N E

T a t d e 2 . - - G l o b a l ln~ p r o r e m e n t o / / l l a n i c Depress ives and Schizo-A f f ee t i res

565

Global Claange Manic-Depr~,sive Schizo-Affeetive Chronic Mania . . . . . . . . . . . . . . . . . . Lithium Chlorpromazine " 'Lit hium Chh~rpromazine 'Lithium ehiorpr0ma~ine'

NI arked Improvemen t 14 4 0 3 - - ~- Modera te Improvemen t 2 4 ] 5 ~ - - ~I i n i m a l I m p r o v e m e n t 1 3 0 2 ~ - - No Change 1 0 0 0 1 I Worse ~ a___ 6 . . . . . . . Tota l IS I 1 7 10 1 1

Drug Administration Patients were assigned in a random nmnner to eithe~ dzaz~. Mc,dication was dispensed in

identical capsules containing e i ther 250 ntg. of lithimn earlmnate or ehlolT~romazine 50 or 100 rag. Initial dosage of medication ran~ed from 200~t00 nag. of ehlorpromazine or 1-2 rag, of l i thium carbonate per day dependi.ug on clinical severity. Dosage was inereased until a therapeutic response occurred or toxic symptoms were manifested. The lithium blood level attained was 1.0 m E q . / L , or greater iri all cases. The psyehiatrist rating the patient was mmware of the semm~ levels of lithium, this being known only to tim laboratory" staff antl psychiatrist assigming treatmc'nt. On two occasions lithimn dosage was reduced based on elevated blood levels alone, viz: 2,.0 m E q / I , , or above, at which point no elinieal signs of toxieit3" were manifest.

11 t,;.s Lrg'l\S

T h e d o s a g e s o f l i t h i u m e m p l o y e d in b o t h m a n i c a n d s e h i z o - a f f e e t i v e p a t i e n t s r a n g e d f r o m 1 . 5 - 4 . 5 ( h n . p e r d a y . N l a x i m u m b l o o d l e v e l s v a r i e d f r o m 1 . 0 0 - 2 .55 m E ( t . / I ~ , in b o t h g r o u p s . T h e m e a n d u r a t i o n on a c t i v e m e d i c a t i o n w a s :3-4 w e e k s . T h e m e a n d u r a t i o n fo r i n i t i a l r e m i s s i o n in m a n i c s t a t e s w a s e i g h t d a y s w i t h e x t r e m e s o f f r o m t w o to f o u r t e e n d a y s . O n c e i n i t i a l i m p r o v e m e n t o c c u r r e d , r e m i s s i o n w a s u s u a l l y r a p i d . O p t i m u m t h e r a p e u t i c d o s e s v a r i e d f r o m I-2. .5 C m . , m o s t p a t i e n t s t ) e i n g m a i n t a i n e d f o l l o w i n g r e m i s s i o n o n 1 , 5 - 2 G in . p e r d a y , C h l o r p r o m a z i n e w a s g i v e n in d o s e s r a n g i n g f r o m 2 0 0 - 1 8 0 0 n a g .

p e r day.., R e m i s s i o n t o o k l o n g e r to a t t a i n a n d w a s m o r e g r a d u a l , o c c u r r i n g , u s u a l l y in 2 - 3 w e e k s in b o t h g r o u p s .

I n t h e 42 p a t i e n t s i n c l u d e d , t h e r e w e r e 48 t r i a l s o f t r e a t m e n t : 37 p a t i e n t s h a d o n e t r i a l o f t r e a t m e n t . F o u r p a t i e n t s h a d t w o t r i a l s o f t r e a t m e n t , t w o o f t h e s e f o l l o w i n g r e a d m i s s i o n i n t o t h e s t u d y , a n d t w o f o l l o w i n g f a l u r e o f o n e t r i a l m e d i c a t i o n w h e n p a t i e n t s w e r e e r o s s e d o v e r o n t o t h e o t h e r m e d i e a r i o n . O n e p a t i e n t w i t h t h r e e t r i a l s w a s r e a d m i t t e d a n d h a d a c r o s s - o v e r t r i a l o f m e d i c a t i o n . T h e r e s u l t s a r e s h o w n in T a l ) l e 9. a n d e x p r e s s e d as g l o b a l c h a n g ~ T h e a n a l y s i s o f t h e m o r e d e t a i l e d r a t i n g s w i l l l )e i n c l u d e d in a l a t e r r e v i e w . M a r k e d i m p r o v e m e n t s ign i f i e s a c o m p l e t e o r n e a r l y e o m p l e k e r e m i s s i o n . X l o d e r a t e i m p r o v e m e n t signifi~,s a p a r t i a l r e m i s s i o n a n d minirr : 'a l a s l i g h t im- p r o v e m o n t , w h i c h is in su f l ' i c i en t to a l t e r t h e p a t i e n t ' s s t a t u s . ":No c h a n g e " a n d " 'wor se" a r e s e l f e x l ) l a n a t o r y .

O f 18 m a n i e s t r e a t e d w i t h l i t h i u m 1-I s h o w e d a e o m p l e t e o r n e a r l y c o m p h q e r e m i s s i o n , i.e., 78 p e r c e n t . In o n l y o n e e a s e w a s t h e r e d o u b t as to s p e c i f i c ¢tru~ of fee t . I n th i s c a s e in i t i a l i m p r o v e m e n t o c c u r r e d w i t h i n 2 - 3 d a y s , a n d a n a t u r a l r e m i s s i o n c o u l d n o t be e x e l u d e d . O n e p a t i e n t who l ind a p a r t i a l r~ ,miss ion

, ~ ( J ~ J O I - t N S O N , ( ; E R S I , I O N A N D I - I E K I N I ~ I A N

d e m a n d e d he r d i scha rge af ter 17 days on act ive med ica t ion . T h e m a n i a h a d b roken on the 1 0 t h - t 4 t h day a n d she h a d a t t a ined a b lood level of 1.5 m E q . ] L . w i thou t any signs of toxici~,.

The one p a t i e n t m i n i m a l l y i m p r o v e d h a d e loped On day 14 of act ive mediea - lion a n d h a d a t t a ined a b lood lewd of 1.05 m E q . / L : The re was doub t t lmt he was tak ing all his medica t ion . T h e pa t i en t showi ng no c h a n g e refused m e d i c a - tion on day 1.,. M e d i c a t i o n h a d b e e n cut on d a y 10 fo l lowing d e v e l o p m e n t of d i a r rhea and drowsiness . Blood levels of ] . 2 8 m E q . / L . of l i t h ium were a t ta ined .

O n l y four out of 11 or 36 pe r cen t of m a n i c pa t ien t s s h o w e d e o m p l e t e or nea r c o m p l e t e remiss ion on eh lo rp romaz ine . One of flae four showi ng m o d e r a t e improvemm'~t h a d e loped on day 12 of ac t ive t rea tment .

The. one put ien t wi th ch ron ic m a n i a showed no change . On l i th ium, blood ,l;* C . -r levels of 2.0 mm t-ti-,, p r o d u c e d side effects and doses had to be r e d u c e d wi th no

the rapeu t i c response. On c h l o r p r o m a z i n e 1500 nag. per day, drowsiness was p r o d u c e d bu t no i m p r o v e m e n t ,

In the g roup of schizo-affect ive pa t ien ts who rece ived l i th ium, six of the seven pa t ien ts or 85 per cent got worse. The i r de ter iora t ion was associa ted in fi,~'e cases wi th signs of ear ly o rgan ic b ra in s y n d r o m e such as r educed com- prehens ion , l ab i l i ty of mood and disor ienta t ion. T h e one pa t ien t sho w ing par t ia l remiss ion still s h o w e d d i s t u r b a n c e of th ink ing and some- prossuro of s p e e c h , b u t mo to r aetiviD~ was normal .

No sch izo-a f fec t ive pa t ien ts on e h l o r p r o m a z i n e s h o w e d worsen ing of their condit ion. Of the" two pa t ien ts who showed m i n i m a l i mprovemen t , one e loped af ter 17 days on m e d i c a t i o n and there was some d o u b t as to w h e t h e r she was tak ing all he r m e d i c a t i o n and tlm second re fused med ica t i on af ter 15 days.

T h e specific p h a r m a c o l o g i e act ion of l i t h ium is ,,,,,ell i l lus t ra ted in the follow- ing cases:

Case I

D . t t . ,,,,'as a 32-year-old wh i t e male , who h a d sho,,wn inc reas ing moto r exci tement , h e i g h t e n ~ affect, p ressure of speech and i m p a i r e d j u d g e m e n t for two mon ths before admiss ion . O n e yea r p rev ious ly he h a d a m a r k e d depres- sive i l lness wifla s u i c i d a l ideat ion . O n admiss ion he ,,,,,as loud, exci ted and aggressive. I l i s speech was pressm-ed, his idea t ion grandiose , l i e showed h e i g h t e n e d a f f e c t w i t h a l t e n m t i n g good h n m o u r and i r r i tabi l i ty , l i e was diag- nosed as m a n i c depressive , m a n i c state, t i e was c o m m e n c e d on 400 nag. per day of e h l o r p r o m a z i n e w h i c h was inc reased rap id ly , and by dav 22, he was s luggish a n d d rowsy wi th some musc le r ig id i ty and was t ak ing 1800 rag. chlor- p romaz ine . However , h e still s h o w e d pressure of speech, g rand iose ideat ion. h e i g h t e n e d affect and hosti l i ty. It b e c a m e necessaQ" to t e rmina te his mcdieat icm and l i th ium was c o m m e n c e d on day 24 and inc reased over 7 days, vchile c h l o f p r o m a z i n e yeas dec reased and ceased on day 31. W i t h i n 5--1.0 days of com- m e n c e m e n t of l i th ium, his grandiosit? ' , e la t ion and host i l i ty d i m i n i s h e d and a comple t e remiss ion ,,,,'as ach ieved in l-I daS's. The changes citc'd wero s t r iking and it is h i g h l y unl ike ly that they co inc idod wi th a na tura l remission.

LrI'I-IIU3,I AND CI-ILOI1PttON.IAZINE 56"7

The effect of l i thium on non-manic exci tement showed a marked contrast which has been commented on previously.

Case 2

A,R. w,-~s a 54-year-old white female who had manifes ted dis turbed behavior of abrupt onset one month previously to her admission. She had been talkative and hostile. Dur ing the day her behavior was drn:,tic, and unpred ic tab le and on many occasions she bought goods she did not wan t and then gave them away. At night she slept l i t t le and spent a considerable t ime Out of bed adorning herself. On the day of admission s h e had packed her bags to leave as she insisted he r husband and niece were plot t ing against her. Two years previously she had shown a similar disturbmace and was :admi t t ed to the staldy and ob- tained a complete remission on ehlorpromazine. On admission she was hype r ' active wi th pressure of speech, Her affect was he igh tened at t imes but inappropriate. She showed formal thought disorder a n d p a r a n o i d ideation. She was placed on l i thium carbonate 1..,5 Gin. per d a y increasing over 13 days to 3.5 Gin. per day. Her m a x i m u m blood level was 1.9 m E q . / L . Her behavior became more bizarre; she ba thed herse l f excessively app ly ing antiseptic to he r arms and face, prayed incessantly and c la imed she was a saint and had spoken to God. She insisted her body had changed and she became restless, i rr i table and disoriented. IAthium was stopped on day t4 and chlorpromazine com- menced, t t e r condition improved slowly as chlorpromazine was inc reased to :i00 rag. per day. At this dose she showed ankle edema and drowsiness and evaluation of her cardiac status showed idiopathic cardiac enlargement . On discharge from the sta~dv her behavior was still inappropriate, but she was no longer grand iosenor showed increased psychomotor aetivi~,,

Toxic Effects

In the manic patients treated with l i th ium, the common side effects were gastro-intestinal with anorexia and nausea , diarrhea and vomiting. Next in order of f requency \vere dizziness, tremor, slurred speech and ataxia. Some side effects were seen with blood levels of 1.2.5 m E q . / L . Howex,er, in near ly every case pa~cnts whose blood levels exceeded 2.0 mEq . /L , mm~ifested toxic effects in various degrees. These were easily corrc-eted by stopping m e d i c a t i o n for :24-48 hours mid recommeneing at a lower dose.

The incidence of toxicity, in tile sehizo-affecfive group was much higher. The Ioxie confusional changes seen in sehizo-affeetive patients seem similar to the. changes observed by some authors in severe l i thium poisoning with blood levels of :3-4 mEq. / I , . ][owever, in these patients b lood levels ranged from 1.16--1.97- mEq,/T~. In onh" one manic patient was a s imilar dis tur lmnce seen and signs of acute brain syndrome occurred within the first 7 days and blood lever rose quickly to :2.25 ml'~q./L.

Chlorpromaziru~ produced side efteels in both groups. The commonest were drowsiness, s luggishness and ext rapyramidal symptoms. The latter occurred only in doses .-:bore 800 rag. per day. t [ypotension and syncope were seen in two cas~-s. Pruritus ,~ccurrcd ill one case.

568 JOHNSOn, GERSHON AND nEgI.X~IAN

In two eases on m a i n t e n a n c e l i th ium med ica t ion possible late side effects o c c u r r e d . O n e t:ernale m a n i c depress ive on mah-t tenanee l i thium medica t /on

i d e v e l o p e d n o d u l a r goi t re wi th h y p o t h y r o i d i s m ;and as he r condi t ion is u n d e r eva lua t ion no definite conclusion as to the re la t ionship wi th l i th ium can yet be drawaa. 4 A n o t h e r f ema le m a n i c depress ive on l i th ium m a i n t e n a n c e medica t ion deve loped a d iabe tes insipidus-l ike s y n d r o m e w h i c h d i s a p p e a r e d on cessatioll of l i thium. 1

Laboratory Analysis No consis tent changes were no ted ill blood ehemista-y. O n e ease on l i th ium

h a d increased a lkal ine p h o s p h a t a s e a n d bi l i rubin wh ich on inves t iga t ion was a t t r i bu t ed to c h r o n i c a l c o h o l i s m . I n one ease e l eva t ed \,V.B.C. was seen t h r o u g h o u t an ted a ring t rea tment . No consis tent e levat ion of ~V. 13.(2. occur red in t h e w h o l e g roup , con t r a ry to Mayf ie ld ' s repor t . ~

T rans i en t a b n o r m a l E K G s w e r e seen in two pat ients . Both eases occur red wi th b lood l eve l s o f 2~0 m E q . / L . O n e s h o w e d p r o l o n g e d Q T intervals and a second low T waves . T h e la t te r w a s assoc ia ted wi th id iopa th ic ca rd i ac enlarge- ment . One p a t i e n t on ch lo rp rom a z i ne shoveed increased S G P T and SGOT.

DISC-~USSION

T h e results of this s t u d y show unequ ivoca l ly tile super io r the rapeu t i c e ~ e a e y of l i th ium earl~onate in m a n i c s ta tes . The remiss ion ra tes ob ta ined wi th liflfimn were 78 pe r cent as c o m p a r e d w i t h 36 pe r cen t of those pa t ien ts t r ea t ed wi th ch lorpromaTine . -Al l m a n i c depress ive pa t i en t s w h o comple t ed :4 trial of treat- men t remi t ted , g iv ing 100 per cen t response . O f the th ree w h o did not it can be a s s u m e d wi th a r ea sonab l e d e g r e e of ce r ta in ty tha t the one pa t ient who had initial remiss ion be fo re d e m a n d i n g d i scha rge w o u l d have m a d e a full recovery . x, Vith the o the r two the p red ic t ion of ou t come w o u l d be less cer ta in. H o w e v e r , fl~e pa t i en t w h o s h o w e d no change on l i th ium medica t ion a n d re fused to coop- c ra te was hosp i ta l i zed du rh lg a s u b s e q u e n t i n t e rphase a n d c o m m e n c e d on l i thium w i t h excel lent results , w h e n h y p o m a n i a b e c a m e manifes t . T h e case of chronic m a n i a co;asti tuted a s o m e w h a t doub t fu l d iagnos t ic ent i ty ha v i ng neve r exhib i ted c y d o t h y m i e episodes previously , this b e i n g a necessa ry cr i ter ia for diagnosis . ~° I t was b e c a u s e of this fllat dfis case w a s p l a c e d in a s e pa ra t e ca tegory .

I t w a s also ev iden t tha t ~the ~vo d rugs dif fered in their p s y c h o p h a n n a c o l o g i - cal effects. Both d rugs p r o d u c e d a dec rease in m o t o r activi ty, this occur r ing ear l ie r w i th chloq~romazine . Norma l i za t i on of affect a n d idea t ion was consis- tent ly ob t a ined wi th l i th ium c a r b o n a t e and m a i n t a i n e d at o p t i m u m doses wi th no signif icant side effects. This r e sponse w a s ev iden t ini t ia l ly on an a v e r a g e wi th in e ight days of c o m m e n c i n g medica t ion . W i t h ch loq~romazine re turn of affect and ideat ion to no rma l was less clear , less consis tent a n d s lower in onset. O p t i m u m m a i n t e n a n c e doses w e r e usua l ly a c c o m p a n i e d by a s ignif icant de- c rease in alert~mss a n d m o t o r perform,-mce.

On ly ear ly theral~eutie response , t ha t is, wi th in one to two weeks, can be a t t r i bu ted wi th ce r t a in ty to speeifie d r u g effect, ~z and b e y o n d this n o n - d r u g

1..lq'ItIUSI AND Ct~[LOItPIIO.X.IAZINE 5 6 9

r e l a t ed co i l t r ibu t ions l~eeome increas ingly impor tan t . T h e specific a n d direct effect of l i th ium on m a n i c b e h a v i o r is invar iab ly p r o d u c e d wi th in one to two weeks, whe rea s wi th ch lo rp romaz ine remissions tha t occur are s lower to evolve a v e r a g i n g two to th ree weeks or longer.

In n o n - m a n i c s ta tes a s t r ik ing diss imilar i ty of ac t ion was seen. C h l o r p r o m a - zinc p r o d u c e d s imilar results in those cases as, it d id in m a n i c states, showing

H o ~ e v e r , wi th l i th ium c a r b o n a t e tha t its t ranqui l iz ing effect is non-specific. ~ : $5 per cen t of the pa t ien ts showe d an overal l wor sen ing of their c l in ica l s t a t u s , The most s ignif icant f ea tu re of this g r o u p was the d e v e l o p m e n t of s y m p t o m s of an acu te braial syndrome , such as disor ientat ion, confusion and r e duc e d com- prehension. C o n e o m i t t a n t wi th this c ha nge an increase in sever i ty of the bas ic p s y c h o p a t h o | o g y was u s u a l l y seen, de lus ions becoming more florid and th ink ing d i s t u rbance more gross. O n e ease showing a s imilar clinical c h a n g e wi th I i thimn has b e e n r e p o r t e d by Mayfie ld . 2~ The occur rence of these severe toxic effects wi th b lood levels of less than 2 m E q . / L , in these cases sugges ts differ- enees in dose- response b e t w e e n non-man ic and m a n i c states. T h a t there is a different ial pat-tern of re ten t ion and excret ion of l i th imn in manies and n o n n a l s was no ted by T r a u t n e r et alY ° M a n i c pat ients s eem able to to lera te very h igh doses unti l remission occurs, wh ich is a c c o m p a n i e d b y inc reased excret ion of l i thium, ~:~ a n d then usua l ly the dose mus t be lowered to avoid toxicity, In t h e non-man ic s tates these signs of toxicity occur red be fo re clinical i m p r o v e m e n t was manifes t . This resul t m a y be re la ted to the des ign of the expe r imen t, dosages be ing increased progress ive ly until cl inical i m p r o v e m e n t o r toxicity occurs. Unfo r tuna t e ly , all of these pa t ien t s b e c a m e m a n a g e m e n t p rob lems a n d h a d to t:~e t r ans fe r red off the research ward , so it was not possible to con t inue l i thium a t r educed dosages to obsela, e ff any the rapeu t i c effects m i g h t be ob- ta ined fo l lowing the d i s a p p e a r a n c e of oxieity.

T h a t l i t l l ium has a specific p s y c h o p h a n n a c o l o g i c a l act ion was first s u g g e s t e d by C a d e ha 1949; howeve r , he t e n d e d to a t t r ibu te this to a specific def ic iency of the ion in the body . t i e ,also n o t e d in his las t case, R.T., a different ial response, in tha t this pat ient , cons idered to be d iagnos t ica l ly d o u b t f u l a t the outset , s h o w e d some decrease in p s y c h o m o t o r activib~, b u t was still hal lucin- a ted a n d delusional . Schou in his rev iew of the l i t e ra tu re -"a was ab le to rough ly g r o u p toge ther 18 inves t igat ions showing overa l l an " i m p r o v e m e n t " ra te of 80 p e r cen t in cases of m a n i c exc i tement .

Ge.rshon and Yuwiler in dle i r r e v i e w of the l i t e ra ture ~' s t a t ed t h a t l i th imn h a d b e e n used in the t r e a t m e n t of 446 eases of man ia , 269 sch izophren ics a n d 87 misce l laneous disorders . The i m p r o v e m e n t ra te in man ic pa t i en t s was 84 pe r cent. Sixty p e r cen t of sch izophren ic pa t i en t s i m p r o v e d b u t in the ma jo r i ty of these eases the i m p r o v e m e n t was p r imar i l y a dec rease in p s y c h o m o t o r excitat ion.

W h i t e et al. "~2 in their s t udy sh ow e d a d rop in i m p r o v e m e n t ra tes f rom 71 to 58 per cen t in their g roup of m a n i c pat ients w h e n eases wi th o the r "signif icant p s y c h o p a t h o l o g y " were included. On ly two s tudies have r e po r t e d super io r the rapeu t i c e ~ c a c y of l i th ium in cases o the r than non -man ic exci tement , a,'-" In nei t l ,er s t u d y is there a control g roup , and in Gles inger ' s s tudy he does not

5 7 0 J O I t N S O N , GER_C.IION A N D I IF .KI . ' , I b~X"

state his cr i ter ia for improvemen t . In only 14 per cent of our series was there any benef ic ia l e f fec t of l i th ium on n o n - m a n i c exc i t emen t as c o m p a r e d to figures of 60 per cen t in the l i terature . 1I

It is c lear tha t l i t h ium tins a specifi c t he r apeu t i c act ion in m a n i c states and tha t if carefu l se lect ion does not p reeeed t rea tment , i m p r o v e m e n t rates will fall. Recen t s tudies "-'.sl have s h o w n that l i t h ium produces a t he r apeu t i c response ill cases t ha t have been unrespons ive to neuro lep t ics or E C T , w h i c h has for the mos t pa r t b e e n the accep t t r e a tmen t for s ta tes of mania . -'°,'-'s Both these w i d e l y used t r ea tmen t m e t h o d s a r e non-specific, a n d they also have the dis- advan tages of b e i n g u n p l e a s a n t e n o u g h to m a k e it diflqcu]t to obta in the pa t ien t ' s coopera t ion for ear ly in i t ia t ion of t r e a tmen t a t the first sign of an attack. ~ R e a d y accep tance of l i t h i um was not fo r thcoming unt i l recent ly m a i n l y because of its seriot~s toxic effects. However , if careful cl inical :and laborator3~ control is ma in t a ined , u n t o w a r d react ions shou ld be avoided. Toxic effects occur usua l ly du r ing the per iod of ini t ia l s tabi l iza t ion, and d i s a p p e a r on p rompt a d j u s t m e n t of dosage. All pa t ients whose Mood level exceeded 2 mEq. / I~. deve loped toxic effects, so that a t t a i n m e n t of this level should be fo l lowed l~y . temporary w i thd rawa l , unt i l b lood level d r o p s .and s tabi l iza t ion at a lower dose is .effected.

L o n g term main tenm~ce has been satisfactorv, pa t ien ts b e i n g m a i n t a i n e d wi th b lood levels of .5-1 m E q . / L , wi thou t mishap . Fo l low-ups have var ied f rom 1--8 week intm.~,als, d e p e n d i n g upon c l in ical condit ion, b lood levels ,and pa t i en t re l iabi l i ty .

Marked e thn ic d i l fe rences occur red wi th in the m a n i c depress ive group. No n e g r o m a n i c depress ives were found over the three y e a r per iod of this sta~dy. References to e thn ic d i s t r ibu t ions are s o m e w h a t contradic tory . Mayer -Gross e'~ states there are cons ide rab le regional and racia l d i f ferences wh ich a re p r o b a b l y no t only due to differences in d iagnosis and cites that there is genera l agree- m e n t that tile d isease is m o r e f r e q u e n t a m o n g Jews. R ed l i eh a n d F r e e d m a n '-':~ s tate that the repor ted f indings on e t h n i c d i f ferences m a y be a t t r ibu ted for t i le most par t to i n a d e q u a t e or b ia sed samples . In Arieti 's American I[andbook e l ° ¢ Psych tarsi, N l a l l zbe rg 1"~ states tha t the i n c i d e n c e of ma~or m e n t a l i l lness in Jews in N e w York State is less than the ave rage bu t makes no specif ic men t ion of m a n i c depress ive i l lness and e thn ic groups, iHowever, M a l l z b e r g !8 s h o w e d that in first admiss ions to hospi ta ls in N e w York State the ra te for m a n i c depress ive i l lness in n e g r o s was on ly 30 pe r cent of tha t for whites . Caro thers 7 in his su rvey of m e n t a l i l lness in Afr icans found this psychosis vel 3, rarely. and w h e n presen t it m,-mifested wi th recur ren t m a n i a wi th no depress ive cycles. This d i f ference he a t t r ibu ted to e i ther a gene t i c i nhe r i t ance of d i f ferent types of man ic -depress ive d i so rder or tha t the Af r i can e n v i r o n m e n t m a y in some w a y prevent :its mani fes ta t ion as depress ion. T he admiss ion rate in Be l levue Psychi- atr ic I tosp i ta l for 1967 was 14,500, and a p p r o x i m a t e l y 40 pe r cen t of these w e r e Negroes. l Iowevt'r , the inc idence of man ic -depres s ive d i sorder in the

. OC l O - e ( , o t q o m l c u p p e r s '" • "" groups m a y account for a sma l l e r pe rcen tage b e i n g admi t t ed to a p u b l i c hospital , bu t this wou ld opera te across e thn ic groups and

" s ' r ' s " 1 could not account for the s t r ik ing absence of Negro mame-deprcs , l~t . . . . F~e

1 . ] ' F I I I U ~ I A N D CI tLOl lP I10 .~ . I :AZINE 5 ' 7 1

data concerning ethnic dill:crences are too inadequa te to draw definite con- clusions; however , the figures point to a much lower incidence, or even an extreme rarity of this condition ill Negroes, than has been assumed. The fact that the condition has a significant genetic component is well documented and differences in ethnic dis tr ibut ion migh t be expected. Fur the r ca re fu l s tudy should help clarify this problem.

In conclusion then, l i th ium exerts a specific therapeut ic action in man ic phase, manic-depressive disease and appears perhaps to be disease specific. Drugs cannot effect behavior 15 directtv, but only through biochemical altera- tions at a cellular or sub-cel lular level. As l i th ium is closely related chemical ly to s o d i u m and potassium its action m,~y be associated wi th an alteration of electn-olyte distribution. As the concentration :gradients of these two ions are fundamenta l to nerve function, dist~urbanee at the nem-onal level would be ex-peeted to produce far reaching changes. In mhnia, Coppen et al. 9 have shown electrolyte dis turbances with increased residual sodium wl!ich possibly returns to nmwnal with the patient 's elinieaI reoovery. Trautner et al. a° and recent ly Greenspan ~a have shown significant differences in retention and excretion of l i thium in manics and normals with increased retention of l i th ium i n manies. Alterations in monoamine levels and serotonin i n bra in in affective disorders have been shown -'* m~d there is suggested evidence that l i th ium will alter these levels. These findings suggest a possible l ink be tween the specific psycho- pharmacological action of l i th ium and disturbances of electrolyte metabol ism either related or unrelated to other biochemical or endocrinologieal changes. In connection with the elinica] s tudy we have been under tak ing deta i led ba lance studies of electrolyte patterns in selected patients, changes in excretion of eatecholamines and steroids and E.E.G. s tudies . These wi l l be reported in later papers.

A n / a l t e r i m report of a double bli~d study of the action of l i th ium ,and ehlor- promazine in man ic states is presented. A control group of schizo-affeetive pat ients has been included.

To date 48 trials of t reatment have been under taken in 42 patients. There were 27 manic depressives, manic phase, one chronic man ia and 14 sehizo- affeetive patients. The absence of negro manic depressives is discussed.

Total remission in manic pat ients occurred in 78 per cent x~dth l i th ium and 36 per cent with ehlorpromazine. Signif icant differences were noted be tween the two drugs in qual i ty of action. Both agents produced a reduction in over- activity but in opt imum doses chlorpromazine tended to produce sluggishness and drowsiness. L i th ium produced normalizat ion of affect and ideation; the action of chlorpromazine on affect and ideation was less consistent, legs clear and slower in onset.

T o x i c effects occurred with l i th ium during periods of stabil ization but at op t imum doses no significant side effects appeared. The occurrence of late toxic effects in two patients was noted.

In tile control group of schizo-af[ectives, 85 per cent of patients on l i thium

5 7 ~ JOI1NSON, (;EI/St.ION AND I iEKINIIAN

s h o w e d d e t e r i o r a t i o n o f t h e i r c l i n i c a l c o n d i t i o n . P r o b a b l e r e a s o n s f o r t h i s a r e

d i s c u s s e d .

T h e s p e c i f i c p s y c h o p h a r m a c o l o g i c a l a c t i o n o f l i t h i u m is d i s c u s s e d .

R E F E R E N C E S

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:2. B a a s t r u p , P. C., and Schou, M.: Lithi- mn as a p rophy lac t i c agent . Arch. Gen. l}sy - chiat. 16 : I62 , 1967.

3. Bel ' skaya, G. M., and Mura tovea , I. D.: Exp'.wienee wi th using l i thium iodide for the t r ea tmen t of some psycho t i c states. Zh. Nevropa t . Psikhiat. Korsakov. 63 :92-95 . 19~3.

4. Bhma, .XI., and Shopsin, B.: Personal eonm-mnieation.

5. Burdock , E. I., and I t a rdesb ' , A. S.: A psychological test for ps~ 'chopatholo~y. J. Abnorrn. Psychol . 73:6"2, 19f%S.

6. Cade , J, F.: L i t h imn salts in the treat- ment of psych ia t r i c exci tement . Med . J. Aust. 2:349, 1949. "

7. Carothers , J. C.: , A s t u d y of menta l d e r a n g e m e n t in Africans, and an a t t e m p t to explain its pecnl iar i t ies , more especia l ly ira relation to the African a t t i tude to life. Brit. J. Psyehiat . 93:548, 1948.

8. Coppen , A.: Minera l me tabo l i sm in af-. fee-tire disorder. Brit. J. Psyehia t . 111:113.3, 1965.

9. Coppen , .A., _Malleson, A., and Costain, It.: Mineral me tabo l i sm in mania. Brit. Med. J. 1:71, 19f~.

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12. Clesin.ger, B.: E v a h m t i o n of l i thimn in tire t rea tment of p sycho t i c exci tement . .Med. J. Aust. 41:277, 19.54.

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14. Guist ino, P.: I1 c i t ra to di litio nel t ra t /amt 'n to dcgli stati. (li cee i taz ione p s i e o f i:a. Nolt" Psychiat . l(Pesaro) 79:.'?~7, 195~.

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17. Maggs , R.: T r e a t m e n t of manic illness with l i thium carbonate . Brit. J. Psychiat . 109:56, 1963.

18. Malzl}erg. B.: Statist ical da ta for the s t u d y of menta l disease a m o n g Negroes in N e w York State, 1949-1951 . Albany, N e w York Sta te Menta l H y g i e n e Research Foma- dat ion.

19. Ma]zberg, B.: In Arieti, S. ted.): Amer ican H a n d b o o k of Psychia t ry , N e w York, Basic Books, 1959, p. 171.

:20. Mayer-Gross , VV. et al.: Clinical Psy- chiatr3" ted. 2). London , Casswel l & Co.. 1960, p. 22 I.

21. Mayfield, D., and Brown, R. C,.: Tire clinical l abora tory" and e lec t roeneepha lo- g raphic effects of l i thium. J. Psychiat . Res. 4:207. l 9f'.'f;.

2:2-. Noack, C. Ill., and Trau tner , E. M.: IAthium t rea tment of manic psychosis . .Xled. J. Aust. :2:219, 1951.

23. ] ledl ich, R. C.. and F r e e d m a n . D. X.: The Theory" and Prac t ice of Psychia t ry . N e w York, Basic Books, 1966, p. 557.

2,t. Sch i ldk rauk J. J.: The ea techo lamtne h~T~othesis of affect ive disorder: A rev iew of supl-or t in~ evidence.. Amer. J. Psychia t . 1PZ:2:509, 1965.

P.5. Sch lagenhauf , G., Tnpin , J. P.. and Vthi te , R. I/.: The use of l i th ium ca rbona te in the t rea tment of man ic psychosis . : \mer . J . Psychiat . 123:201-2137, 1967.

26. Sol,on, M.: L i th imn in l}sychi:dric therapy. P sychopha rmaco log i a 1:65, 1959.

27. Schou, M.: L i t h i u m in psychia t ry . P resen ted at the A C N P rrneeting, San Juan, Pue r to Rico, Decernt)er, 1967.

:28. Schou, M., Jvel -Nielsen, N.. Strom- ~ren, E., and Voldby , 1I.: The t rea tment of manic psychoses lay the adminis t ra t ion of l i th ium salts. J. Neurol . Nenrosur~. l}sychiat. 17: ~50. 1934.

I , ITtI1UM AND CHLORI'ItO~,£AZINE 573

29. Teulie, M. et ,'11.: Etude de l'aetion des sel.s de lithium dans etats d'excitation psycho-motrice. Enc6phale 44:266, 1955.

30. Trautner, E. M., Morns, R., Noack, C. II., and Gershon, S.: The excretion and retention of ingested lithium and its effects on the ionic balance of man. Med~ J. Aust. 42:2,80, 1955.

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use of lithium in tile affective psychoses. Amer. J. Psyehiat. 123:706, 1966.

32. White, R. B., Schlagenhauf, G. K., and Tupin, J. P.: The treatment of manic depressive states with lithium carlx)nate. h~ Masserman, J. H. (ed.): Current Psychia- tric Therapies, Vol. 6. New York, Orune &

s

Strattoh, 1966, p. 2,30.