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Ten years of chlorpromazine
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By MAx"HaMILTOrr ,][ T : ! S NOT : O ~ E N : : t h a t a •busy .:~li~!!ci~:I!iaS t h e inczentiye, to..:Stop land t!iink ] t a b o u t thetlmra]Deptic .weapons: flmt are placcd.:ion his handS. :by:the /:syntheticchemist a n d tlie p lmrma~logist,, and the tenth year after.~the appearanee Of iit,lie tranquiiiize r :ichlorp r°m a zinOi.-on.ille, ~ a r k e f p#o~Jdesaniex C!Use-t0~:~si~:and Stare:and it]~ink..Ofwl~at~orie iS.doi~g~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ::The: mOSt:.ob~vioUs%haractmSsficlof...clflorprOmazine/iand:this :to :a grdat ex: tent [applies t6 ia!ii:pi~nOfifia~ne:!i~mpo~ I.ilig:iits.,wide, Irapge:iOf:¢Mnig~!iap ! " libations. These-arise froin its peculiar :- r0pertieS The most ob~;dous :roperty is t h e great g a y between:: the'sedative -and-the :llypnotic :effect of this. drug, and of th?i others w!liCh:are similar, a n d .that is .why .it iis ?2ailed 'a. tranquilli~r, T h e a n t i e m e t i c e f f e c t : o f tliese d r u s i s w e l l - k n 0 w n : a n d . s 0 i s t h e p e C u l i a r potentiating, effect.on .dep!;ess~ants of !ttae ~entral nervous.system: (CNS):~They are centr~flly a6ting analgesics. S0me~ o f t h e oddities, .it:S.a c t i 0 n o n ~the h y ~ : thalmus .wliidl aff~dts the ituitary and:the e n d o c ~ e s , - a r e alsol -of:: " e a t importance and it is ::to :be r e g r e t t e d t h a t ~these have -n0tyet:-been ::adequately explored. :Usrzs r~ MrzmcL~E ,Atop SuRcmly There is no d o u b t about the value:ofehlorpromazinel and similar.substances in the deliria and" confusional :states. Its value i n excitement, -particularly in schiz~0phrenia- and ,mania is outstanding: its usei"as .a "treatment' for:sChizophrenia forms One of:the .most powerful-weapons .:in o u r a r m a m e n t a r i u m . I t also has some(effects on chronic::schizophrenia and has played an important, although here not -so clear, p a r t in new devel0pments a n d treatmen[: Undoubtedl);:the d r u g is o f v a l u e i n the-treatment of anxiety, IWhere this.is .Seeonda~, t o other disorders, alth0ugh:it :is n o t s o muelaiiuse :-~ the- treatment ~of:chronic anxiety States as~sueh. F i n a l l y , a s a n ~.-idju~,ant-inthetreatm~tlof- alc0holism:~and:dru ~:dddiCtion during the withdrawal periodsit~is again-one: Of the ~mostusefUl:drugsav~lable. I n general medicine," "t h e " sade "~ " effects " " " ......... ~ ~ " . . . . . . amportant.. "" ' ..... ~'I t is :used, :are particularly and is o f somehelp, i n all conditions Where- an~eta¢ and (tension:'in ~:thepatient l~lay a part in t h e d e v e t o p m e n t : o f ~ p t ~ m s , e.g.,: it"is of!some:value in.asthma 0r deixnatological conditions.: I t s a n t i ~ e t l C e f f e c t i s :impOrtant in theltreatrnent of all chronic conditions,' Such ~as-tirmia , Wherethe patientsuffers~:fmm"much • omitingand, of course, it counterbalancesthe effect'of other drugs ~and treat ~ mcnts : " such as. . radiotherapy . . : . , wllieh .... g a"re . . . .rise ... -t .o. . v . 0 m i ~, n g " In the treatment of diseases 'of the C N S i t i s of.vii|ue 'in: chorea, a vani~;hing disorder in thispart of the wodd, andalso, ~bocause~of its potentiating :effe6ts, .in flae treatment of tetanus. In surge~, it potentiates anesthetics-and analgesics "
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Leeds, England. 291
CO.~IPn~IEN.~IVE PS~(.'qlIATi~Y. VOL. 6. NO. 5 {OC~nE1A), ]~$5
• I A X . l - l A g l l L 1 ON'
a n d this, is its main: i use, It helps,, of...course_, in.. posto. [~erative~. , ~..vomiting,: .Post-, op(q:atiVe.~ ~xmfusi.on/i zmd e-xcitement a r e relie.ved::by :'t!m drug~:: ::and, oddly enough~ i e i s effective in: hiceu ~s;' ma action ~r0babl " r e l a t e d - t o the:,matiemetic :effevt.i:,:In:-.0bst~tt:ics'.~and,, pediatries.:its, actions are simi!ari(to, those i n :general m e d i c i n e alid: sut-,~4erv.2;These. are: a. few.~0f. tim ast0nishin~Iv. wide :range of :atDp Ii ca t i.()n s of ..:ithis: ( iru ~ :~t Iid. its. d eri Va t i ves~ S IDI~":N FF!gG-'I~
,Rost~.:have,-th.etr.thortxs, a n d t-hese-drugs have. thetr.,sldel effects,, "lhe m o s t . v¢,ell~kim~,wais-.parkinSonism?~'and: it-,i s easilv/deatt,-:with,.~:A:;, less-:obiAotLsLone .is iak.amiSla:/; !a:.:fm'm.:"of o d d rest lessness, which: :is:,eaSily;/iCemm~ized : o n e : ~it .,:h as been; s.eena.~:There, are manvl mhlor: sial,e-effects whieh.m~vone>who uses .the drugs, k u o . w s i X b i S u t - : ; b r • - h a s ., to aaasvcer-questions about-.:., th/~ I: ossibilitv-of :e )ilepsv•: and headixehes;:, dizzin,ess: and, drowsiness:2weakness ,and-.!hypotgnia; ! oee-asionMLde: ~:dopnlerii:: Of:. 2.~dsed:::temperatures+: rashes. ).aud {photogensitivi~,,::::S ! d e effects w.htch:: are;: wcir~?ing; :'but *vb~eh 'fortunately::: are~{rare;, d~'e:: toxic effeCts, on.( th e liver and!)a~:mul0eytosis2.' A ~minor o u t wh g-h .is: ,:,e.~¢ alarming: i s oroptam)'nge a! s )asm:. IThe-.patient wtt/-be-..brou ht.,-hurnedlv-.mto, the' Casual ". Department,. with:his: {ongue ~ i e k i n g 0ut-;Unable: to. sav:a :.word: and! barelv::ableto breathea: Fortttra~-{el~:/:the s~,~m, iS Very. 6uieklV::-irelie~;t~d l.~V;anti2Darkinsonism,,dru~s, O f c0urs< : t}mre: "~S uo,. limit: ::to[the/side -:effects o f dn,g's}_ A -new ,,,o n e : has: recentl'J: beert:i described!! the-lappe/o~anee- of. pimnentation: in :thee:skin. and cornea.a Ttiis. develsaps in- the-:skill:chiefly i n t h e mreas exposed to-light, ap; parent~- Only :ffter mare.v years of" ver3/tiigh-•dosage:.. At-preseni. s i d e effects ;~-u-e gt~qng rise,to" much-concern; b u t . they must,: be regarded :as ii~herent in. d n , g a c t i 0 n : any,; drug-: that: is active naust f h a v e side effects; if.it c a n a l t e r m e t a b o l i s m i n a w a y tO produce, some k h i d of effedt;.then it w i l l h a v e " s i d e effects. A. d r n g that c~n-be:- ~m,.!arant~d to. llave,no negative effects v~431 llave no" positive 'effects: either. T h e - v M u e of the. dung, depends on me ratio o~ th~ aartieut'~ e f f e c t s i r e g a r d e d : a s d e s i r a b l e in-i kriven :eircumsVance~, to those.: reg~uxted ias tmdesirabIe i n - t h e iame.:eirenmstances,-If:xve v~ish tomake, a patient V0mit; . ~ e n an mltiemetie-effect is depiobable; an in" convenient side: effect; . .:-.ff w e 4 - , v a n t : N m Cease vomitin : then.: i t i s a-hi hly de~irable therat'4eutie effect. ~iFrom'this point ,of.4¢iew, ;it would.-appear: tha t the sem-eh: for.: drugs w i t h n6:Mde.- e f f e ~ , iS- the ~pursuit ~'of a n - - i m a ~ a a r y ; entity: W h a t Ls requiredi is ' t h a t a p a t t i , ! t a r MdeTeff~ S h o u l d b e : m i n i m ' a l under-cer -~ r a i n ' g i v e n :circumstances, f iS when" it "is:desirabie to h a v e available: a series :of Similar compounds,, m e m ~ r s : of :a farnilv:of"drt,gs: from which; on'e can c h o o s e t h e most useful' for a .particular' purpose( A n example o f this :Stile :. morphine family:of drugsi " • Side" effects • m u s t b e differentiated ! from idiosyncrasy, Strictly. speaking; a,gTannlo%vtosis a n t i j a u n d i e e m e n t i o n e d - a b o v e a r e examples, of idiosyncrasy. ld~osynerat~'e responseto: d r a g s c a n never be. eliminated, for it arises frorn l the inherene Variability o f h u m a n beings: :-The variability of the h u m a n species i s greater than almost any. other, m u c h g r e a t e r t h a n any domesticated animal. It in extremely unlikely that idiosyncwatie response to dungs will be e l i m i n a t e d hy altering the dungs. Side effects and idiosyneracT will always be a p r o b l e m .
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aild the )rotesmon wJ]] haw" to acce )t th~s and .deal :with Jt f o r exampk, t h e n e w l ' d e s e r i b d sideeffect o f chlor r o m a z i n e ( i * n e n t a t i o n ) h a s ~ iven .rise tO soine alarm. Oj~ee agaii~, if lias been: m a d e clear: t h a t p r o l o n g e d a ~ i n l s t ~ a tioli ~61:]arg~( q Uantifies-6fa drug ~¢~an ]lave spec~a]:}.dangers,"b6t- this i.i.s:t:ruei-0f • any ti,ij:ag f r o m as: ~h.ins:to b i s m d t h m a d e v e r / t o the:::c0n~sumpiloli: 0fi:inilk: " ~' : Usv: L'~.PsYc!~IA-n~y I-Iow c a n the effects of 10 'yc~ars:o£ iahlorpromazine:and..phC~notl~iazincs-be summarized '~ .Psychiatrists ~mJ ht find.' fliis" ,digicUlt,' but-feW. 'would '~like !to praati~.psychiatry without:it. I f one w e r e to narrow .the answer d 6 ~ n l.o:eleat: a l ! d :Specific poi~!t.s; .there: would .inot .be ~;many,~;:~e.re.;:is::;lm; d~bt:.(:a~ixt/, the: v a l u e of pllen0thiazi,le~s if=in~aqute .sch~op~e~a:;!.:~ey!ih~Ve~ire.~olUtibni~X~d/its treatmcn!, a n d :have: ldlled -insulin: shoek.:.treatment/s~one., :dead:::.:It:.~i.::~¢ :/~.a] •[ h e corpse still q u i v e r s oa~si0naliy ::in One:: or:::tiv6::rem0te: pIa~:;:i.vh~e :;t'here .are- Sfili One..ori.:twO .insui~: ShbCk~ ~--nters, :bUt :iJt/C~n:sfill: be/zaidt]~At :~.~lin ' Stmck~'l'trcatment:ihas:disappeared::i~rgm./psy~iia~i:ii~e: ~Mue:of.:/~e):d~g i n lmndling :.manias i:and.:acute:..COnf.usio~l~:States.:has ::~remark,abLv~ic~.ged::-:Our attitude anf, l appr0ach, t o :.thesc conditionsi:;~e.greatesqc::af=hie~!ement!o ~i:;ehlof )romazine i n general medicine and sUrge~:- i s probably•:its u s e . t o potcmtiate analgesics trod: ane.sthetik.~: T h i s : n ! a y : s e e m an ~ i m p r e s s i v e list:ibut ~:!t/:.d~kg with outstanding:acl~ievements; not merely: file (fact/thatl tlie :drug has. ~ n used. ComparedTwitJa daese, d m i~effeetS: On:ehronie.s6h~oplire~ai:~e~-iile~s:ob~ vious, and:it: has even been. Said..:to.be':very:.,doubfful,.:;and.: i ~ .~:~'aI,pd:.iin: ~ ~xie~? states ;is also _not so irnpressive.:ThedrUg::hasnot s01vedall :problems 5n. medi~:ine an¢l n o drug.ever will... The si nifieance o f t h e phenothiazines lies in t h e p e r s p e c ~ v e s the~,;haverevealed F o r example, psychiatrists now:: think h 0 efullv o f d r a g s - w h i c h ;would potentiate other treatments i n m e n t a t , disorder, e,g4:bySnereasing the i~powerl and applicability o f rehabilitation land } psTchOtherapy.-iThat; phenothiazinesl have such a n effect is 'doubt_fuLl There !As ;eonflic~Sng:evidenceland :it ~Iis-:Still very much a question u n d e r discussion.X0 Contradic~to results from :different researches cause quite, u n n ~ , 'al~/ •~rdmnsion T o m a n y it-mav..appear ~thati the] result::in:nothing b u t : c o ~ 0 n , but it ma :bebetter, to i=egardeon~adietoryresults'~from-reseaxeh as a SUbstitU= ti6n of ign6ranoe.by .confusion: This:is n o t ne~aH]y::tO::bei:dep]ored,:~iProb= iems in :.biolOgy, an d:-psy claiatry:in :.,p a ~ c u l a r ; : a r e ~.~mplic~te~-: :~d--~e!- ~ hdvanee :from i - ::Or~n~:.i enerally!is~!VdD,::eonf~in ,:Evahmtind::the •phe-n~ thiazines is !.particularly 10i~efilt::iibec~use d ~ g s : ia~gion!i:tlie:?CNS :present problems v e r y different :'from,:"Say,-,:.those" actingon;the::pe~pher~ner~;ous System(:In the!latter ease~it :is/:eas);: to~olatel-al s ~ e ! a e t i ~ i ~ ; ! ~ d : ! d e t e ~ e the:influence,: on it of, . eig., a t r o P i n e o r adrenaline~ :_In ithei~ormer, it h e s i t u a t i 0 n is very different. ~In the firstplaee, w h a t m a y : b e l t h o u g h t 0f: as a ~ g l e ! f i i n e t i o n is often t h e end r e m i t Of m a n y different alternative! ~ d s : o f f i c t i ~ ; a n d i n the: Second place, the =.CNS compensates {or interference, u s i n g infomiation-SUl~i plied by feedback. Of course, a good deal of the eontradietoi'y materials published arises:from one very simple cause: bad Work. s The level, of researches, of-published re-
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s6arche,.,~;: is;.iust-,not:hi~h .e,nou~l~,! Sometimes flae doses. :of drtuz:'! trtalLcomparhag, chlorpromazine~/reserpine,:, plmno,bar.bitone:..m~d:, a.~:blanki,dumm~,,,. .:R he< net~..,re.sult~<:~;aS...:that::nonci, of.-.ttiese,:i, dfUg,s laad?-:an~);~effeCt:.~:The, deseription (!,of: -the;::experiment ~,showed/that::.il the,se; d r u g~ w ere: ~.':)en !in Irandom.,Order;to- )atients as-,thev-we~, admitted (int o t h e lios ~itali: This ~ e i O f e : eriihent::could:" -Si+m,e:::.that. .~enicillin: wa:siuat3tive,: . . . . . • A- drug'actia!m,.on::.:the:~GNSqs~, mterfenn~r:.,xvath-, on-gore ,,activity.- and th~s: ~s ve~,,.i~ff6~.ntT:~ffom~:,=slO~{ing,! :~:0ri: accelerating: ~imi:,:.endi-.;:.fimOUon~;~:~Cont~di~?tot~,i: res u lts/-fmin:;:id~erlanm~Ni-SimiSly::.~.mean; :,:.aSst[m~g-i,:that:-:: t hd~! ex~efiments!i?:xvere) god;!~-!tIiilt+ thew:':"i~;-ere;;,:'deali.g~i~wi{B~,~:verV:/:eompla!.~ ' ,roblenls.::::il~*' :.:which:;~m a n y factorsi::~ire-~:,a~tiri~g`~n~;~an`~im~6i~tar~<7.itistead:~f{~`a~i:~ri~a~`;;~x~/a~`;and{.~sudi~;eontra~ :dictorv:.:~rdsutt~S;:~S~ioutdi::aet:.,aS::.a~:=sUmulUs-:~t6.further>~ sVsteniatic": feseard~-d. . . . . Much" Of:tl~e :,;Vbrk-:oii?[h~ ~,;,alUe~6f"-treatmimt::in i~psychiatrv.i consists,::Of:ma-i! ~i~
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I t is possible to reconcile t h e hypothesis: that the dlaag acts b y anterfering with on,going activity and the fact t h a t patients improve under its influence, b y a s s u m i n g t h a t t h e interference Witll cerebral fimcti0n is equivalent t o a temporary "lesion,'~ the symptoms Of Which counteract 0r bahmce tile symptoms o f the patient. T h e maalogy i s with the surgical treatment o f ~parkinsonism, whereby a lesion is produced in the brain which improves tile patients" tremor. Obviously, t h e lesion m u s t produce some impairment iof function, b u t this is cotmterbalanced b y the diminution in tremor. I t is possible that ehlorpromazine acts in this way. I n one controlled t r i a l w h i c h a t t e m p t e d to investigate the interaction between drug-s and occupational therapy in chronic schizophrenic patients, it was found that chlorpromazine inhibited the effect of the additional treatanent.T T hi s is not true o f all phenothiazines, a n d sometimes treatment by drug trod by intensive rehabilitation may indeed summate. 6 It is possible t h a t this may be trne of chlorpromazine as well, under appropriate circumstances. What is needed is systematic investigation o f the effect of rehabilitation techniques and the circumstances in which drugs may help or hinder. It should not b e thought that it is only the pharmacologists, the animal behaviorists .and the ~europhysiologists t h a t have been faced with problems by the appearance of chlorpromazine. The clinicians, too, have become aware of deficiencies in their work. First, the methods of assessing improvement have been found wanting. In fact, it would not be ~:n exaggeration to say that they are grossly inadequate. J u d g m e n t of "over-all" improvement is very crude and too coarse for most purposes when it is assessed as present or absent. In any ~ase, it forms a kind of Procrustean bed. Changes in behavior are bluntly classified as "improvement" or "worsening," and i t becomes too easy t o assume that the patient who becomes easier to look after is therefore "'better." By the use of m o d e m techniques, Overall ,-uad Gorham 1~ were able to s h o w that improvement in behavior ,and symptoms were independent and were differently affected by drugs. Crude over-all m e t h o d s of assessment are now being replaced by rating scales, and as with all innovations, t h e y have been g r e e t e d with uncritical enthusiasm ,and ununderstanding scepticism. The critics do not see how the formal summation of scores on individual items represents the intuitive process of judgement of the practicing clinician; the enthusiasts do not recognize that since a rating scale is m e r e l y a m e t h o d o f recording, it cannot exceed the value of the clinician's judgement r Rating scales are easily quantified, a n d this makes them particularly useful for research. This quantification has also m a d e clear t h e comple~ties of handling many symptoms simultaneously, N e a r l y all scales can be used to give a:sum of sc~res whibh is a measure of the severity of the illness, b u t t h i s loses a g o o d deal of the information available. Much of this information can be retained b y using appropriately weighted sums of the scores on the items: S u c h s u m s can be used as indices of change in the symptoms, but w h a t these changes mean is not a t all clear. 4,-~ After World W a r II t h e r e were few r a t i n g scales available and most of those were primitive. By 10 years a g o , there had been some improvements. The arrival of the new psyehotropie drugs, Of which chlorpromazine was the first, have led to considerable improvements, but the scales available for as,
TEN Y E A B S
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sessing schizophrenia can still not be regarded as satisfactory. Anyi psychiatrist who has attempted t o rate the condition o£ a chronic: sehizophrenic :patient knows how diflacult i t i s to:make a satisfactory judgernent, andl the i.eliability of such ratings :is low :compared with ratings~for other:Iconditions. The new drugs are forcing the clinician to flfinkanew about his way of lookingatthe symptoms of schizophrenia. 'J It m a y well b e tliat the old):cai~egoriesa r e inadequate and perhaps even :misleading. T h e careful: a n d prolonged observations of patients by the pioneers of clinicalpSychiatryWill haxSeltobe repeatedunder present, day conditions and with the aid of tlae new diSCriminations provided by the response to treatments. StrM~artY Chlorpromazine was the first of the ,'major tranquillizers., These drugs have an extensive and varied use in general medicine but their main application is in psychiatry. In this field theyare of greatimp0rtance, but even more so is the impetus they have given to t h e development of research and theories. R E F E a E N C E S
1; Casdy, J . . F . , Lasky, J. j., Klett, G . J . , and Hollister, L. E.: Treatment o f schizophrenic reactions with p h e n o thiazine derivatives. Amer. J . Psychiat. 117:97-105, 1960. 2. Clark, M. L., Ray, T. R., and Paredes, A:: Chlorpromazine in chronic schizophrenic women and a note on predicting response. T.r. Sixth Res. Conf. on Coop. Chemother. Studie; in l%ychiat., pp. 331--339, 1961. 3. Greiner, A. G., a n d Berry; K.: Skin pigmentation and corneal and lens opacities w i t h prolonged chlorpromazine therapy. Canad. M. A. J. 90: 66,3-665, 1964. 4. Hamilton, M.: Treatment of a n x i e t y states. IIL J. Ment.. Sci. 104:106o_1068, 1958. 5. = : An experimental approach to the identification of f~.ctors. Brit, J. Stat. Psyehol. 11:101"169, 1 9 5 8 . 6 . - - , H o r d e r n , A., Waldrop, 17. N . , a n d Lofft, J.: A controlled trial on the value of proehlorperazine, trifluoperazine a n d i n t e n s i v e gToup treatment. Brit. J . Psychiat. 109:510--5P..% ~1903. 7 . - - , Smith, A. L, G., Lapidus , H . E . , and Cadogan, F , P.: A controlled trial of thiopropazate dihydrochlo-
8.
9.
10.
11.
12.
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ride ( D a r t a l a n ) , chlprPromazine and occupational therapy in chronic schizophrenics. J. M e n t . Sci. 106: 4 0 - 5 5 , 1960. Hei!izer, F.: A critical review of some published experiments with ehlorpromazine in schizophrenic, neurotic and normal humans. J. Chron. Dis. 11:109,--148, 1960. Klein, D. F., and Fink, M.: Behavioural reaction patterns v~dth phenothiazines. Ard~. Gen. Psychiat. 7 : 449--459, 1962. Klernaan, G. L.: Assessing the influence of the hospital milieu upon the effectiveness of psychiatric drug therapy: problems of conceptualization and o f research methodology. J. Nerv. Ment, Dis. 137:143-154, 1983. Oberall, J., and Gorham, D. R.: F a c t o r . s p a c e D "2 a n a l y s i s a p p l i e d t o the study of i ehanges in sdaizophrenic syrnptomatology during chemotherapy. J . Clin. Exp, Psychopath. 21-187-195, 1900. Toman, J. E. P . : Some aspects of central ~ nervous pharmacology. A n n . Rev. Pharmae. 3:153-184, 1963.
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By MAx"HaMILTOrr ,][ T : ! S NOT : O ~ E N : : t h a t a •busy .:~li~!!ci~:I!iaS t h e inczentiye, to..:Stop land t!iink ] t a b o u t thetlmra]Deptic .weapons: flmt are placcd.:ion his handS. :by:the /:syntheticchemist a n d tlie p lmrma~logist,, and the tenth year after.~the appearanee Of iit,lie tranquiiiize r :ichlorp r°m a zinOi.-on.ille, ~ a r k e f p#o~Jdesaniex C!Use-t0~:~si~:and Stare:and it]~ink..Ofwl~at~orie iS.doi~g~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ::The: mOSt:.ob~vioUs%haractmSsficlof...clflorprOmazine/iand:this :to :a grdat ex: tent [applies t6 ia!ii:pi~nOfifia~ne:!i~mpo~ I.ilig:iits.,wide, Irapge:iOf:¢Mnig~!iap ! " libations. These-arise froin its peculiar :- r0pertieS The most ob~;dous :roperty is t h e great g a y between:: the'sedative -and-the :llypnotic :effect of this. drug, and of th?i others w!liCh:are similar, a n d .that is .why .it iis ?2ailed 'a. tranquilli~r, T h e a n t i e m e t i c e f f e c t : o f tliese d r u s i s w e l l - k n 0 w n : a n d . s 0 i s t h e p e C u l i a r potentiating, effect.on .dep!;ess~ants of !ttae ~entral nervous.system: (CNS):~They are centr~flly a6ting analgesics. S0me~ o f t h e oddities, .it:S.a c t i 0 n o n ~the h y ~ : thalmus .wliidl aff~dts the ituitary and:the e n d o c ~ e s , - a r e alsol -of:: " e a t importance and it is ::to :be r e g r e t t e d t h a t ~these have -n0tyet:-been ::adequately explored. :Usrzs r~ MrzmcL~E ,Atop SuRcmly There is no d o u b t about the value:ofehlorpromazinel and similar.substances in the deliria and" confusional :states. Its value i n excitement, -particularly in schiz~0phrenia- and ,mania is outstanding: its usei"as .a "treatment' for:sChizophrenia forms One of:the .most powerful-weapons .:in o u r a r m a m e n t a r i u m . I t also has some(effects on chronic::schizophrenia and has played an important, although here not -so clear, p a r t in new devel0pments a n d treatmen[: Undoubtedl);:the d r u g is o f v a l u e i n the-treatment of anxiety, IWhere this.is .Seeonda~, t o other disorders, alth0ugh:it :is n o t s o muelaiiuse :-~ the- treatment ~of:chronic anxiety States as~sueh. F i n a l l y , a s a n ~.-idju~,ant-inthetreatm~tlof- alc0holism:~and:dru ~:dddiCtion during the withdrawal periodsit~is again-one: Of the ~mostusefUl:drugsav~lable. I n general medicine," "t h e " sade "~ " effects " " " ......... ~ ~ " . . . . . . amportant.. "" ' ..... ~'I t is :used, :are particularly and is o f somehelp, i n all conditions Where- an~eta¢ and (tension:'in ~:thepatient l~lay a part in t h e d e v e t o p m e n t : o f ~ p t ~ m s , e.g.,: it"is of!some:value in.asthma 0r deixnatological conditions.: I t s a n t i ~ e t l C e f f e c t i s :impOrtant in theltreatrnent of all chronic conditions,' Such ~as-tirmia , Wherethe patientsuffers~:fmm"much • omitingand, of course, it counterbalancesthe effect'of other drugs ~and treat ~ mcnts : " such as. . radiotherapy . . : . , wllieh .... g a"re . . . .rise ... -t .o. . v . 0 m i ~, n g " In the treatment of diseases 'of the C N S i t i s of.vii|ue 'in: chorea, a vani~;hing disorder in thispart of the wodd, andalso, ~bocause~of its potentiating :effe6ts, .in flae treatment of tetanus. In surge~, it potentiates anesthetics-and analgesics "
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a n d this, is its main: i use, It helps,, of...course_, in.. posto. [~erative~. , ~..vomiting,: .Post-, op(q:atiVe.~ ~xmfusi.on/i zmd e-xcitement a r e relie.ved::by :'t!m drug~:: ::and, oddly enough~ i e i s effective in: hiceu ~s;' ma action ~r0babl " r e l a t e d - t o the:,matiemetic :effevt.i:,:In:-.0bst~tt:ics'.~and,, pediatries.:its, actions are simi!ari(to, those i n :general m e d i c i n e alid: sut-,~4erv.2;These. are: a. few.~0f. tim ast0nishin~Iv. wide :range of :atDp Ii ca t i.()n s of ..:ithis: ( iru ~ :~t Iid. its. d eri Va t i ves~ S IDI~":N FF!gG-'I~
,Rost~.:have,-th.etr.thortxs, a n d t-hese-drugs have. thetr.,sldel effects,, "lhe m o s t . v¢,ell~kim~,wais-.parkinSonism?~'and: it-,i s easilv/deatt,-:with,.~:A:;, less-:obiAotLsLone .is iak.amiSla:/; !a:.:fm'm.:"of o d d rest lessness, which: :is:,eaSily;/iCemm~ized : o n e : ~it .,:h as been; s.eena.~:There, are manvl mhlor: sial,e-effects whieh.m~vone>who uses .the drugs, k u o . w s i X b i S u t - : ; b r • - h a s ., to aaasvcer-questions about-.:., th/~ I: ossibilitv-of :e )ilepsv•: and headixehes;:, dizzin,ess: and, drowsiness:2weakness ,and-.!hypotgnia; ! oee-asionMLde: ~:dopnlerii:: Of:. 2.~dsed:::temperatures+: rashes. ).aud {photogensitivi~,,::::S ! d e effects w.htch:: are;: wcir~?ing; :'but *vb~eh 'fortunately::: are~{rare;, d~'e:: toxic effeCts, on.( th e liver and!)a~:mul0eytosis2.' A ~minor o u t wh g-h .is: ,:,e.~¢ alarming: i s oroptam)'nge a! s )asm:. IThe-.patient wtt/-be-..brou ht.,-hurnedlv-.mto, the' Casual ". Department,. with:his: {ongue ~ i e k i n g 0ut-;Unable: to. sav:a :.word: and! barelv::ableto breathea: Fortttra~-{el~:/:the s~,~m, iS Very. 6uieklV::-irelie~;t~d l.~V;anti2Darkinsonism,,dru~s, O f c0urs< : t}mre: "~S uo,. limit: ::to[the/side -:effects o f dn,g's}_ A -new ,,,o n e : has: recentl'J: beert:i described!! the-lappe/o~anee- of. pimnentation: in :thee:skin. and cornea.a Ttiis. develsaps in- the-:skill:chiefly i n t h e mreas exposed to-light, ap; parent~- Only :ffter mare.v years of" ver3/tiigh-•dosage:.. At-preseni. s i d e effects ;~-u-e gt~qng rise,to" much-concern; b u t . they must,: be regarded :as ii~herent in. d n , g a c t i 0 n : any,; drug-: that: is active naust f h a v e side effects; if.it c a n a l t e r m e t a b o l i s m i n a w a y tO produce, some k h i d of effedt;.then it w i l l h a v e " s i d e effects. A. d r n g that c~n-be:- ~m,.!arant~d to. llave,no negative effects v~431 llave no" positive 'effects: either. T h e - v M u e of the. dung, depends on me ratio o~ th~ aartieut'~ e f f e c t s i r e g a r d e d : a s d e s i r a b l e in-i kriven :eircumsVance~, to those.: reg~uxted ias tmdesirabIe i n - t h e iame.:eirenmstances,-If:xve v~ish tomake, a patient V0mit; . ~ e n an mltiemetie-effect is depiobable; an in" convenient side: effect; . .:-.ff w e 4 - , v a n t : N m Cease vomitin : then.: i t i s a-hi hly de~irable therat'4eutie effect. ~iFrom'this point ,of.4¢iew, ;it would.-appear: tha t the sem-eh: for.: drugs w i t h n6:Mde.- e f f e ~ , iS- the ~pursuit ~'of a n - - i m a ~ a a r y ; entity: W h a t Ls requiredi is ' t h a t a p a t t i , ! t a r MdeTeff~ S h o u l d b e : m i n i m ' a l under-cer -~ r a i n ' g i v e n :circumstances, f iS when" it "is:desirabie to h a v e available: a series :of Similar compounds,, m e m ~ r s : of :a farnilv:of"drt,gs: from which; on'e can c h o o s e t h e most useful' for a .particular' purpose( A n example o f this :Stile :. morphine family:of drugsi " • Side" effects • m u s t b e differentiated ! from idiosyncrasy, Strictly. speaking; a,gTannlo%vtosis a n t i j a u n d i e e m e n t i o n e d - a b o v e a r e examples, of idiosyncrasy. ld~osynerat~'e responseto: d r a g s c a n never be. eliminated, for it arises frorn l the inherene Variability o f h u m a n beings: :-The variability of the h u m a n species i s greater than almost any. other, m u c h g r e a t e r t h a n any domesticated animal. It in extremely unlikely that idiosyncwatie response to dungs will be e l i m i n a t e d hy altering the dungs. Side effects and idiosyneracT will always be a p r o b l e m .
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aild the )rotesmon wJ]] haw" to acce )t th~s and .deal :with Jt f o r exampk, t h e n e w l ' d e s e r i b d sideeffect o f chlor r o m a z i n e ( i * n e n t a t i o n ) h a s ~ iven .rise tO soine alarm. Oj~ee agaii~, if lias been: m a d e clear: t h a t p r o l o n g e d a ~ i n l s t ~ a tioli ~61:]arg~( q Uantifies-6fa drug ~¢~an ]lave spec~a]:}.dangers,"b6t- this i.i.s:t:ruei-0f • any ti,ij:ag f r o m as: ~h.ins:to b i s m d t h m a d e v e r / t o the:::c0n~sumpiloli: 0fi:inilk: " ~' : Usv: L'~.PsYc!~IA-n~y I-Iow c a n the effects of 10 'yc~ars:o£ iahlorpromazine:and..phC~notl~iazincs-be summarized '~ .Psychiatrists ~mJ ht find.' fliis" ,digicUlt,' but-feW. 'would '~like !to praati~.psychiatry without:it. I f one w e r e to narrow .the answer d 6 ~ n l.o:eleat: a l ! d :Specific poi~!t.s; .there: would .inot .be ~;many,~;:~e.re.;:is::;lm; d~bt:.(:a~ixt/, the: v a l u e of pllen0thiazi,le~s if=in~aqute .sch~op~e~a:;!.:~ey!ih~Ve~ire.~olUtibni~X~d/its treatmcn!, a n d :have: ldlled -insulin: shoek.:.treatment/s~one., :dead:::.:It:.~i.::~¢ :/~.a] •[ h e corpse still q u i v e r s oa~si0naliy ::in One:: or:::tiv6::rem0te: pIa~:;:i.vh~e :;t'here .are- Sfili One..ori.:twO .insui~: ShbCk~ ~--nters, :bUt :iJt/C~n:sfill: be/zaidt]~At :~.~lin ' Stmck~'l'trcatment:ihas:disappeared::i~rgm./psy~iia~i:ii~e: ~Mue:of.:/~e):d~g i n lmndling :.manias i:and.:acute:..COnf.usio~l~:States.:has ::~remark,abLv~ic~.ged::-:Our attitude anf, l appr0ach, t o :.thesc conditionsi:;~e.greatesqc::af=hie~!ement!o ~i:;ehlof )romazine i n general medicine and sUrge~:- i s probably•:its u s e . t o potcmtiate analgesics trod: ane.sthetik.~: T h i s : n ! a y : s e e m an ~ i m p r e s s i v e list:ibut ~:!t/:.d~kg with outstanding:acl~ievements; not merely: file (fact/thatl tlie :drug has. ~ n used. ComparedTwitJa daese, d m i~effeetS: On:ehronie.s6h~oplire~ai:~e~-iile~s:ob~ vious, and:it: has even been. Said..:to.be':very:.,doubfful,.:;and.: i ~ .~:~'aI,pd:.iin: ~ ~xie~? states ;is also _not so irnpressive.:ThedrUg::hasnot s01vedall :problems 5n. medi~:ine an¢l n o drug.ever will... The si nifieance o f t h e phenothiazines lies in t h e p e r s p e c ~ v e s the~,;haverevealed F o r example, psychiatrists now:: think h 0 efullv o f d r a g s - w h i c h ;would potentiate other treatments i n m e n t a t , disorder, e,g4:bySnereasing the i~powerl and applicability o f rehabilitation land } psTchOtherapy.-iThat; phenothiazinesl have such a n effect is 'doubt_fuLl There !As ;eonflic~Sng:evidenceland :it ~Iis-:Still very much a question u n d e r discussion.X0 Contradic~to results from :different researches cause quite, u n n ~ , 'al~/ •~rdmnsion T o m a n y it-mav..appear ~thati the] result::in:nothing b u t : c o ~ 0 n , but it ma :bebetter, to i=egardeon~adietoryresults'~from-reseaxeh as a SUbstitU= ti6n of ign6ranoe.by .confusion: This:is n o t ne~aH]y::tO::bei:dep]ored,:~iProb= iems in :.biolOgy, an d:-psy claiatry:in :.,p a ~ c u l a r ; : a r e ~.~mplic~te~-: :~d--~e!- ~ hdvanee :from i - ::Or~n~:.i enerally!is~!VdD,::eonf~in ,:Evahmtind::the •phe-n~ thiazines is !.particularly 10i~efilt::iibec~use d ~ g s : ia~gion!i:tlie:?CNS :present problems v e r y different :'from,:"Say,-,:.those" actingon;the::pe~pher~ner~;ous System(:In the!latter ease~it :is/:eas);: to~olatel-al s ~ e ! a e t i ~ i ~ ; ! ~ d : ! d e t e ~ e the:influence,: on it of, . eig., a t r o P i n e o r adrenaline~ :_In ithei~ormer, it h e s i t u a t i 0 n is very different. ~In the firstplaee, w h a t m a y : b e l t h o u g h t 0f: as a ~ g l e ! f i i n e t i o n is often t h e end r e m i t Of m a n y different alternative! ~ d s : o f f i c t i ~ ; a n d i n the: Second place, the =.CNS compensates {or interference, u s i n g infomiation-SUl~i plied by feedback. Of course, a good deal of the eontradietoi'y materials published arises:from one very simple cause: bad Work. s The level, of researches, of-published re-
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I t is possible to reconcile t h e hypothesis: that the dlaag acts b y anterfering with on,going activity and the fact t h a t patients improve under its influence, b y a s s u m i n g t h a t t h e interference Witll cerebral fimcti0n is equivalent t o a temporary "lesion,'~ the symptoms Of Which counteract 0r bahmce tile symptoms o f the patient. T h e maalogy i s with the surgical treatment o f ~parkinsonism, whereby a lesion is produced in the brain which improves tile patients" tremor. Obviously, t h e lesion m u s t produce some impairment iof function, b u t this is cotmterbalanced b y the diminution in tremor. I t is possible that ehlorpromazine acts in this way. I n one controlled t r i a l w h i c h a t t e m p t e d to investigate the interaction between drug-s and occupational therapy in chronic schizophrenic patients, it was found that chlorpromazine inhibited the effect of the additional treatanent.T T hi s is not true o f all phenothiazines, a n d sometimes treatment by drug trod by intensive rehabilitation may indeed summate. 6 It is possible t h a t this may be trne of chlorpromazine as well, under appropriate circumstances. What is needed is systematic investigation o f the effect of rehabilitation techniques and the circumstances in which drugs may help or hinder. It should not b e thought that it is only the pharmacologists, the animal behaviorists .and the ~europhysiologists t h a t have been faced with problems by the appearance of chlorpromazine. The clinicians, too, have become aware of deficiencies in their work. First, the methods of assessing improvement have been found wanting. In fact, it would not be ~:n exaggeration to say that they are grossly inadequate. J u d g m e n t of "over-all" improvement is very crude and too coarse for most purposes when it is assessed as present or absent. In any ~ase, it forms a kind of Procrustean bed. Changes in behavior are bluntly classified as "improvement" or "worsening," and i t becomes too easy t o assume that the patient who becomes easier to look after is therefore "'better." By the use of m o d e m techniques, Overall ,-uad Gorham 1~ were able to s h o w that improvement in behavior ,and symptoms were independent and were differently affected by drugs. Crude over-all m e t h o d s of assessment are now being replaced by rating scales, and as with all innovations, t h e y have been g r e e t e d with uncritical enthusiasm ,and ununderstanding scepticism. The critics do not see how the formal summation of scores on individual items represents the intuitive process of judgement of the practicing clinician; the enthusiasts do not recognize that since a rating scale is m e r e l y a m e t h o d o f recording, it cannot exceed the value of the clinician's judgement r Rating scales are easily quantified, a n d this makes them particularly useful for research. This quantification has also m a d e clear t h e comple~ties of handling many symptoms simultaneously, N e a r l y all scales can be used to give a:sum of sc~res whibh is a measure of the severity of the illness, b u t t h i s loses a g o o d deal of the information available. Much of this information can be retained b y using appropriately weighted sums of the scores on the items: S u c h s u m s can be used as indices of change in the symptoms, but w h a t these changes mean is not a t all clear. 4,-~ After World W a r II t h e r e were few r a t i n g scales available and most of those were primitive. By 10 years a g o , there had been some improvements. The arrival of the new psyehotropie drugs, Of which chlorpromazine was the first, have led to considerable improvements, but the scales available for as,
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sessing schizophrenia can still not be regarded as satisfactory. Anyi psychiatrist who has attempted t o rate the condition o£ a chronic: sehizophrenic :patient knows how diflacult i t i s to:make a satisfactory judgernent, andl the i.eliability of such ratings :is low :compared with ratings~for other:Iconditions. The new drugs are forcing the clinician to flfinkanew about his way of lookingatthe symptoms of schizophrenia. 'J It m a y well b e tliat the old):cai~egoriesa r e inadequate and perhaps even :misleading. T h e careful: a n d prolonged observations of patients by the pioneers of clinicalpSychiatryWill haxSeltobe repeatedunder present, day conditions and with the aid of tlae new diSCriminations provided by the response to treatments. StrM~artY Chlorpromazine was the first of the ,'major tranquillizers., These drugs have an extensive and varied use in general medicine but their main application is in psychiatry. In this field theyare of greatimp0rtance, but even more so is the impetus they have given to t h e development of research and theories. R E F E a E N C E S
1; Casdy, J . . F . , Lasky, J. j., Klett, G . J . , and Hollister, L. E.: Treatment o f schizophrenic reactions with p h e n o thiazine derivatives. Amer. J . Psychiat. 117:97-105, 1960. 2. Clark, M. L., Ray, T. R., and Paredes, A:: Chlorpromazine in chronic schizophrenic women and a note on predicting response. T.r. Sixth Res. Conf. on Coop. Chemother. Studie; in l%ychiat., pp. 331--339, 1961. 3. Greiner, A. G., a n d Berry; K.: Skin pigmentation and corneal and lens opacities w i t h prolonged chlorpromazine therapy. Canad. M. A. J. 90: 66,3-665, 1964. 4. Hamilton, M.: Treatment of a n x i e t y states. IIL J. Ment.. Sci. 104:106o_1068, 1958. 5. = : An experimental approach to the identification of f~.ctors. Brit, J. Stat. Psyehol. 11:101"169, 1 9 5 8 . 6 . - - , H o r d e r n , A., Waldrop, 17. N . , a n d Lofft, J.: A controlled trial on the value of proehlorperazine, trifluoperazine a n d i n t e n s i v e gToup treatment. Brit. J . Psychiat. 109:510--5P..% ~1903. 7 . - - , Smith, A. L, G., Lapidus , H . E . , and Cadogan, F , P.: A controlled trial of thiopropazate dihydrochlo-
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9.
10.
11.
12.
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ride ( D a r t a l a n ) , chlprPromazine and occupational therapy in chronic schizophrenics. J. M e n t . Sci. 106: 4 0 - 5 5 , 1960. Hei!izer, F.: A critical review of some published experiments with ehlorpromazine in schizophrenic, neurotic and normal humans. J. Chron. Dis. 11:109,--148, 1960. Klein, D. F., and Fink, M.: Behavioural reaction patterns v~dth phenothiazines. Ard~. Gen. Psychiat. 7 : 449--459, 1962. Klernaan, G. L.: Assessing the influence of the hospital milieu upon the effectiveness of psychiatric drug therapy: problems of conceptualization and o f research methodology. J. Nerv. Ment, Dis. 137:143-154, 1983. Oberall, J., and Gorham, D. R.: F a c t o r . s p a c e D "2 a n a l y s i s a p p l i e d t o the study of i ehanges in sdaizophrenic syrnptomatology during chemotherapy. J . Clin. Exp, Psychopath. 21-187-195, 1900. Toman, J. E. P . : Some aspects of central ~ nervous pharmacology. A n n . Rev. Pharmae. 3:153-184, 1963.