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ﬂ e c t t h o s e o f h i s e m p l o y e r s . C a r b a m a z e p i n e ( T e g r e t o l ) , c l o z a p i n e ( C l o z a r i l ) , a n d [ n e t h

y l p h e n i d a t e ( R i t a l i n ) a r e m a r k e t e d b y N o v a r t i s .

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HadaptedFromParacelsus, 1 5 3 8

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SELECIE¥IREFERENCF§

PPinel, A TreatiseonInsanity, 1 8 0 6 , reprinted 1 9 8 3 , Birmingham,Alabama, GryphonEditionsLtd,p 1 0

Paracelsus,FourTreatisesTranslatedC.LilianTemkin,EditedbyHenryE.Sigerist B HopkinsUniversityPress, 1 9 4 1 , p22:“Allthingsarepoison . poison”

ClassicsofMedicineLibrary, altimore:Johns . theDosisalonemakesathingnota WilliamOsler,CounselsandIdeals,editedHumphreyNﬁlford,London:OxfordUniversityPress,2ndedi‘ tion, 1 9 2 1 , 1 3 1 1 6 .

Preface l Prlegomena'TenFallaciesandTenTruthsofPsychopharmacoogy

A NewPsychopharmacologyNomenclature

5.Evidence~BasedMedicine:ProandC011

6.IVIaintenanceTreatmentDesigns:“Enriched,”ButNotBetter

7.NegativeStudies:'IheFailuretoICnowWVhatIsn’tICnown 8 SideEffectsandGeneralizability:BeyondPValues

5‘ g Dogemine

lODopa‘mlz'seBlockers(Cit‘antipsyci‘lotics”)

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77/31:1}Chile

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Appendixl‘:i‘inxedStates

AppendixII:BipolarorBorderline?

Preface

Thiskindoftextbookofclinicalpsychopharmacologyﬂdirectlyfocusedonminimizing symptomatictreatmentandmaximizingdiseaseorientedtreatmenthasnotbeen writtenpreviously

Itisadifferentkindoftextbookofpsychopharmacology,notmeanttoreﬂectthe commonconsensusofWhatmostcliniciansbelieveorpractice.ItisnotamerecompendiumofcommonlyacceptedViewsInthatsense,itisnotatextbook,astypically conceived,butachallengeTruthisnotamatterofmajorityvote,HenryDavidThoreau saidVVhatisthestatusgun,orthemainstreamView,isnotnecessarilytrue,includingin clinicalmedicineThistextbookseekstopresentwhatistrue,asbestasitsauthorcandi vine,irrespectiveofpopularityorcommonality.Doubtlesstherewillbemistakesthatthe futuremightcorrect,buttheywillnotbedrivenbypreferenceforconventionalWisdom Itishopedthatreaderswillseeksuchanapproach,evenifitchallengesorconﬂictswith someoftheirownviewpoints,andthattheymightusethistextbookaccordingly,not merelytoacceptitasawhole,nortorejectitasaWhole,butrathertouseittothinkabout theirassumptionsandbeliefs,soastobecomebetterclinicians

Clinicalpsychopharmacologyispracticedtodayinamanneropposedtotherestof themedicalprofession.Psychiatricpracticetendstoanon~Hippocraticapproach(the Galenicapproach),whichtherestofInedicineputasideacenturyago(Chapter 1 6 ) . Othertextbooksofpsychopharmacologyunconsciouslyandwithoutapologyteachthe Galenic,nonHippocraticapproach.Inthisview,biologicaltheoriesarethebasisfor decisionmaking.Oneofthebestaspectsofrelianceonbiologicaltheoryprimarilyisthat factscanbedistortedtoﬁtthetheoryItmatterslittlewhetheroneusesfourhumors,or threemonoamines,ortheegoandtheidmanyfactscanbedistortedtojustifyafavored theory

Incontrast,theHippocraticapproachprioritizedclinicalobservationoverbiolog icaltheory.Itfocusedonsymptomsinrealclinicalpractice,notspeculationsabout

Preﬁzcc

bodilycausesOvertilne,thisclinicalapproachinspiredthefoundersofclinicalre searchinmedicine,leadingtotheuseofstatisticstorevolutionizeclinicalmedicine, aswiththediscoveryofthemethodofrandomizationtoproveordisprovetreatment efﬁcacy.

Yetbiologyalwayshasbeenseductive,andclinicalresearchcanappearpedestrian ResearchpublicationsandfundingaremuchgreaterintheformertOpicthanthelatter Intheend,biologicalresearchstillneedstobetranslatedintoclinicalpractice.Biological speculationitselffailstoachievethattranslation.

TruthsoftheoryaretransientNotonlyisGalenoutofdate,butsoaremanybiolog icaltheoriesofrecentvintage,likethecatecholaminehypothesisofdepressionorthe dopaminehypothesisofschizophrenia.Clinicalobservationandresearch,incontrast,is steadier:thesamemelancholiathatl-lippocratesdescribedcanbediscernedindepres siontoday,-thesamemaniathatArateusofCappadociaexplainedinthesecondcentury ADisvisibleincurrentmania

Clinicalresearchisthesolidgroundofmedicine,-biologicaltheoryisanecessary butchangingsuperstructureIftheserelationsarereversed,thenmerespeculationtakes over,andthemoresolidgroundofscienceislost.Thistextbookwilltakethatclinical approach,explicitlyeschewingthecommonstandardbiologicaltheoryapproachto teachingpsychopharmacology.

Innon-Hippocraticmedicine,manytreatmentsareprovidedaggressivelyathigh dosesandforindeﬁnitedurations,andallsymptomsaretreatedinthisaggressivemanner equallyInHippocraticmedicine,thereisascientiﬁcallyandclinicallysoundrationale forwhentobeaggressivewithdosingandtypeofmedication(fordiseases)andwhento bemoreconservativeandcautious(fornondiseases).HencetheWisdomofParacelsus, Whocanbeparaphrasedtosaythat:allmedicationsaretoxic;itisonlytheirdosingand indicationwhichmakesthemtherapeutic.

Thistextbookwilltrytodotwothings:Oneidentifyanddiiferentiatepsychiatric diseasesfromsymptomsandfrom“clinicalpictures,”which,althoughreceivingpsychiatricattention,arenotdiseasesTwoteachthepracticeofpsychopharmacologyof diseasesbasedonexaminationoftheclinicalresearchevidence,notthroughbiological speculationaboutneurotransmittersystems

Aboveall,thistextbookofpsychopharmacologywillbeclinical,-itwillnottreatall symptomsequallyandadvocateaggressiveindeﬁnitetreatmentWithmanydifferent medicationsbasedonbiologicalspeculationsdrawnfromanimalstudiesofquestionablerelevancetohumansTherecommendationsmadehereWillbebasedprimarilyon humanstudies,ondirectclinicalresearchthatshowsbeneﬁtorharm,andwilldifferen tiallyemphasizecautionversusmoreaggressivetreatmentofsymptomsversusdiseases, respectively.

ThegoalistohelppsychiatriststopracticenotjustinaInodernmanner,butina moreethicallyandscientiﬁcallysoundmannerthanhasbeenthecasepreviously.Many proposalsinthistextWillnodoubthaveshortcomingsandwillneedcorrectionand

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S,NagshGhaemij:MD’NIPH,

Professor,PsychiatryandPharmacology TuitsUniversitySchooloflviedicine Lecturer,Psychiatry ElarvardMedicalSchool Boston,Nlassachusetts

P r o l e g o m e n a

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1 . M o r e i s b e t t e r . ( I f a l o w d o s e h e l p s a l i t t l e , a higher d o s e h e l p s m o r e . N o t s o . )

2 . W h a t g e t s y o u w e l l keeps y o u w e l l . ( H a p p i l y ) ever a f t e r : b u t m a n y d r u g s w o r k

a c u t e l y b u t n o t p r e v e n t i v e l y , a n d V i c e v e r s a . )

3 . T r e a t t o r e m i s s i o n . ( I f o n e d r u g h e l p s s o m e w h a t , a n d t w o d r u g s h e l p m o r e , k e e p

g o i n g u n t i l a l l s y m p t o m s a r e g o n e c o m p l e t e l y ; t h e y r a r e l y d o , b u t s i d e e f f e c t s i n

c r e a s e i n e v i t a b l y . )

4 . P o l y p h a r m a c y i s g o o d . ( A v a r i a n t o n t h e ﬁ r s t f a l l a c y : I f o n e d r u g h e l p s s o m e w h a t , t w o d r u g s w i l l h e l p m o r e . )

5 . M a k e o n e c h a n g e a t a t i m e . ( C l i n i c a l p r a c t i c e i s n ’ t r e s e a r c h ; o n e c a n g o t o o s l o w l y . )

6 . F o u r t o e i g h t w e e k s i s a s u f ﬁ c i e n t t r i a l o f a d r u g . ( P o s s i b l y c o r r e c t f o r s o m e a c u t e

t r i a l s , b u t n o t f o r m a i n t e n a n c e t r i a l s . )

7 . D o s e l o w , g o s l o w . ( I f c o m m o n , t h i s a p p r o a c h p r o d u c e s u n d u e s u f f e r i n g ) .

8 . A l w a y s t a p e r a d r u g . ( S o m e t i m e s v e r y h a r m f u l e f f e c t s c a l l f o r i m m e d i a t e d i s e o n t i n u a t i o n ; n o t a l l d r u g s h a v e w i t h d r a w a l s y n d r o m e s . )

9 . T r e a t t h e m o s t s e v e r e s y m p t o m . ( T h i s o f t e n h a s n o r e l a t i o n s h i p t o t h e u n d e r l y i n g d i s e a s e . )

1 0 . A l w a y s i n c o r p o r a t e t h e p a t i e n t ’ s p r e f e r e n c e . ( T h e p a t i e n t c a n b e W r o n g . )

E V E N T R F J I H § . . . Q E P § ¥ § § 9 § 3 E € + B M § 9 § E 9 9 X

1 . Y o u r t r e a t m e n t i s a s g o o d a s y o u r d i a g n o s i s .

2 , . T r e a t d i s e a s e s , n o t s y m p t o m s .

x v i i

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P I ' D I E g D m e n d .

A l l d r u g s a r e g u i l t y u n t i l p r o v e n i n n o c e n t . ( ' l h e d e f a u l t p o s i t i o n i s : D o n o t p r e

s c r i b e , - y o u I n u s t h a v e p r o v e n b e n e ﬁ t s t h a t e x c e e d h a r m s t o p r e s c r i b e . )

A l l d r u g s a r e t o x i c ; o n l y t h e d o s i n g a n d i n d i c a t i o n m a k e s t h e m t h e r a p e u t i c .

A l w a y s h a v e a n e x i t s t r a t e g y ( D o n o t p r e s c r i b e a c u t e l y , a n d a s s u m e i n d e ﬁ n i t e t r e a t ”

m e n t l ‘ l a v e a n e n d p o i n t i n m i n d , o r a s t r o n g s c i e n t i ﬁ c r a t i o n a l e f o r l o n g t e r m u s e ) .

I v l o s t c u r r e n t p s y c h o t r o p i c d r u g s h a v e s y i n p t o n l a t i c b e n e ﬁ t s , b u t a r e n o t d i s e a s e

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

O l d e r d r u g s a r e m o r e e f f e c t i v e t h a n n e w e r d r u g s .

N e w e r d r u g s a r e m o r e t o l e r a b l e t h a n o l d e r d r u g s .

T r e a t m e n t ‘ r e s i s t a n c e ’ u s u a l l y r e ﬂ e c t s e i t h e r m i s d i a g n o s i s o r a n i n v a l i d d i a g n o s i s .

C o u r s e , n o t s y m p t o m s , r e v e a l s t h e d i a g n o s i s .

R e a d e r s c a n t u r n t o C h a p t e r 4 9 f o r f u r t h e r e x p l a n a t i o n o f t h e s e f a l l a c i e s a n d t r u t h s o f

p s y c h o p h a r m a c o l o g y .

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N INNOVATIVE T E X T B 0 O K O F PSYCH O P H A R M A C O L O G Y WOULD F A I L I F I T

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

a r e n o t a n t i d e p r e s s a n t s ; a n t i p s y c h o t i c s a r e n o t j u s t f o r p s y c h o s i s , - a n x i o l y t i c s a r e n o t j u s t

a n x i o l y t i c ; s t i m u l a n t s d o n ’ t s t i m u l a t e ,“ m o o d s t a b i l i z e r ” h a s n o s c i e n t i ﬁ c m e a n i n g .

A l l t h e s e t e r m s b e g a n a s c l i n i c a l s h o r t h a n d i n t h e 19605 f o r p o s s i b l e c l i n i c a l e f f e c t s o f

a n e x c i t i n g n e w c r o p o f m e d i c a t i o n s , m o s t o f w h o s e m e c h a n i s m s w e r e u n k n o w n . T h e u n

e d u c a t e d g u e s s e s o f t h a t e r a h a v e b e e n r e i ﬁ e d i n t o p h r a s e s t h a t p a t i e n t s a n d c l i n i c i a n s u s e

a s i f t h e y a r e t r u e . I n f a c t , h a l f a c e n t u r y l a t e r , t h i s c l i n i c a l s h o r t h a n d h a s b e e n d i s p r o v e n ,

e i t h e r a s s i m p l y f a l s e , o r a s i n s u f ﬁ c i e n t l y c l e a r , o r s o m e t i m e s a s s i m p l y n o t m e a n i n g f u l

S c i e n t i ﬁ c a l l y . I t ’ s t i m e t o s t a r t a t e x t b o o k o f p s y c h o p h a r m a c o l o g y w i t h c l e a r , s c i e n t i ﬁ c a l l y

s o u n d t e r m s f o r d r u g c l a s s e s .

I n c o n t r a s t t o t h e p a r r o t e d r e p e t i t i o n o f d r u g c l a s s n a m e s f o r h a l f a c e n t u r y , t h e p s y

v c h i a t r i c p r o f e s s i o n h a s b e e n o b s e s s e d f o r o v e r t h r e e d e c a d e s w i t h h o w t o c l a s s i f y i t s

d i a g n o s e s . C e n t e r e d a r o u n d r e v i s i o n s o f t h e A m e r i c a n P s y c h i a t r i c A s s o c i a t i o n ’ s ( A P A )

D i a g n o s t i c a n d S t a t i s t i c a l M a n u a l o f M e n t a l D i s o r d e r s ( D S M , v a r i o u s e d i t i o n s ) , m u c h o f

t h i s d e b a t e h a s b e e n a b o u t t h e p r a c t i c a l i m p l i c a t i o n s o f h o w w e d i a g n o s e m e n t a l i l l n e s s e s .

I t i s p r e s u m e d f r e q u e n t l y t h a t i f a c o n d i t i o n h a s a n o f ﬁ c i a l D S M d i a g n o s i s , t h e n i t W i l l b e

t r e a t e d m o r e a s s i d u o u s l y , o f t e n w i t h m e d i c a t i o n s , a n d , d e p e n d i n g o n w h e t h e r o n e l i k e s

o r d i s l i k e s p s y c h o t r o p i c d r u g s , i n t e r e s t g r o u p s a r r a y t h e m s e l v e s f o r o r a g a i n s t p r o p o s e d

d i a g n o s t i c r e v i s i o n s .

I n c o n t r a s t , t h e c l a s s i ﬁ c a t i o n o f p s y c h o t r o p i c m e d i c a t i o n s h a s b e e n i g n o r e d u n t i l r e c e n t l y . T h e t e r m s u s e d f o r p s y c h o t r o p i c d r u g c l a s s e s a r e i m p r e c i s e a n d m i s l e a d i n g : “ a n t i d e p r e s s a n t s , a n t i p s y c h o t i c s , a n x i o l y t i c s , s t i m u l a n t s . ” “ A n t i d e p r e s s a n t s ” o f t e n a r e i n e f f e c t i v e f o r m a n y d e p r e s s i v e c o n d i t i o n s ; “ a n t i p s y c h o t i c s ” a r e o f t e n e f f e c t i v e

i n m a n y n o n p s y c h o t i c c o n d i t i o n s ,“ a n t i d e p r e s s a n t s ” a r e o f t e n a s e f f e c t i v e f o r a n x i e t y

s y m p t o m s a s “ a n x i o l y t i c s . ” A n d t h e t e r m s “ m o o d s t a b i l i z e r ” a n d “ s t i m u l a n t ” a r e d e v o i d o f

s c i e n t i ﬁ c m e a n i n g a l t o g e t h e r , a s w i l l b e s h o w n i n t h i s c h a p t e r .

C u r r e n t p s y c h i a t r i c d r u g c l a s s i ﬁ c a t i o n i s b a s e d o n c l i n i c a l t e r m s d e v i s e d a n d

p o p u l a r i z e d o v e r h a l f a c e n t u r y a g o , w i t h c o d i ﬁ c a t i o n b y a s p e c i a l c o m m i t t e e o f t h e I / V o r l d

H e a l t h O r g a n i z a t i o n i n 1 9 6 7 . I t ’ s c e r t a i n l y t i m e f o r a n u p d a t e .

I n t h e l a s t f e w y e a r s , t h e m a i n p s y c h o p h a r m a c o l o g y o r g a n i z a t i o n s i n t h e U n i t e d

S t a t e s a n d E u r o p e ( t h e A m e r i c a n C o l l e g e o f N e u r o p s y c h o p h a r m a c o l o g y [ A C N P ] a n d

t h e E u r o p e a n C o l l e g e o f N e u r o p s y c h o p h a r r n a c o l o g y [ECNPD c o n v e n e d a t a s k f o r c e f o r

j u s t s u c h a n u p d a t e . T h e c o n c l u s i o n s o f t h a t t a s k f o r c e w e r e t h a t d r u g c l a s s d e ﬁ n i t i o n s

s h o u l d b e b a s e d o n t h e i r b i o l o g i c a l ; i e c h a n i s m , n o t c l i n i c a l p u r p o s e . T h e r a t i o n a l e f o r

t h i s a p p r o a c h i s t h a t c l i n i c a l p u r p o s e s c a n v a r y a n d c h a n g e , b u t b i o l o g i c a l m e c h a n i s m s ,

o n c e i d e n t i ﬁ e d , a r e ﬁ x e d .

' I h i s t e x t b o o k a g r e e s w i t h t h i s b a s i c n o t i o n , b u t d i f f e r s f r o m t h e A C N P / E C N P t a s k

f o r c e a p p r o a c h b e c a u s e t h e l a t t e r s e e k s t o i d e n t i f y d r u g s i n g r e a t d e t a i l , b a s e d o n t h e i r

b i o l o g i c a l m e c h a n i s m s , a n d , f u r t h e r , t o c o n n e c t s u c h m e c h a n i s m s t o D S M b a s e d c l i n ‘

i c a l i n d i c a t i o n s . S u c h d e t a i l e d b i o l o g i c a l d e ﬁ n i t i o n s w i l l b e t o o c l u m s y a n d i n e f ﬁ c i e n t f o r

c l i n i c i a n s . F u r t h e r m o r e , t h e p r o b l e m w i t h t o o m u c h e m p h a s i s o n b i o l o g i c a l m e c h a n i s m s

i s t h a t e a c h d r u g h a s m a n y b i o l o g i c a l m e c h a n i s m s , n o t j u s t o n e . S e r o t o n i n r e u p t a k e

i n h i b i t o r s ( S R I S ) a l s o a r e c y t o k i n e i n h i b i t o r s , a n d c l o t t i n g f a c t o r i n h i b i t o r s , a n d n i t r i c

o x i d e i n h i b i t o r s , a n d s o o n . H o w d o W e k n o w w h i c h b i o l o g i c a l m e c h a n i s m i s t h e m o s t

i m p o r t a n t ?

T h e V i e w t a k e n h e r e i s t h a t b i o l o g i c a l m e c h a n i s m s s h o u l d b e u s e d , b u t i n a b r o a d

a n d ﬂ e x i b l e w a y . I t m a y t u r n o u t t h a t s o m e b i o l o g i c a l m e c h a n i s m s t h a t a r e u s e f u l f o r d e

ﬁ n i n g a d r u g c l a s s a r e n o t t h e a c t u a l m e c h a n i s m s o f c l i n i c a l e f f e c t . F o r i n s t a n c e , t r i c y c l i c

a n t i d e p r e s s a n t s ( d e ﬁ n e d b y t h e i r c h e m i c a l s t r u c t u r e ) h a v e e f f e c t s o n n e u r o p a t h i c p a i n

t h a t m a y h a v e t o d o w i t h t h e i r i m p a c t o n b l o c k i n g s o d i u m a n d c a l c i u m c h a n n e l s p e r i p h

e r a l l y , n o t t h e i r e f f e c t s o n n o r e p i n e p h r i n e a n d s e r o t o n i n .

S o b i o l o g i c a l m e c h a n i s m s m a y b e b e t t e r t h a n c l i n i c a l d e ﬁ n i t i o n s , b u t t h e f o r m e r

c a n l e a d t o c o n f u s i o n t o o i f o v e r d o n e . F u r t h e r m o r e , d r u g c l a s s d e ﬁ n i t i o n s s h o u l d h a v e

n o t h i n g t o d o w i t h D S M d i a g n o s t i c d e ﬁ n i t i o n s , b e c a u s e , a s d i s c u s s e d i n C h a p t e r 1 6 , t h e

l a t t e r c a n c h a n g e a s w e l l , a n d , m o r e i m p o r t a n t l y , t h e y a r e w e a k i n t h e i r s c i e n t i ﬁ c v a l i d i t y .

T h e p r o p o s e d n e w d r u g n o m e n c l a t u r e i n t h i s c h a p t e r w i l l b e b a s e d o n b i o l o g i c a l m e c h

a n i s m , b u t w i t h t h e b r o a d e s t s u c h d e ﬁ n i t i o n s , b o t h f o r c l i n i c a l u t i l i t y a n d f o r ﬂ e x i b i l i t y

i n r e l a t i o n t o t h e r a n g e o f s p e c i ﬁ c m e c h a n i s m s t h a t e a c h d r u g m a y h a v e f o r d i f f e r e n t

c l i n i c a l u s e s .

E ﬂ

h g ﬁ N I P § é § E t 5 F ? Y E P B P L G E L é S S E §

I n c u r r e n t u s a g e , t h e r e a r e ﬁ v e m a j o r d r u g c l a s s e s i n t h e t r a d i t i o n a l p s y c h o p h a r m a

c o l o g y n o m e n c l a t u r e : a n t i d e p r e s s a n t s , a n t i p s y c h o t i c s , m o o d s t a b i l i z e r s , a n x i o l y t i c s , a n d

s t i m u l a n t s . A m a j o r p r o b l e m w i t h c u r r e n t u s a g e i s t h a t t h e p h r a s e s u s e d a r e n o t a c c u r a t e

s c i e n t i ﬁ c a l l y , a n d c a n b e m i s l e a d i n g i n t h e i r u s e s , a s d e s c r i b e d i n B o x 1 . 1 .

‘ n ‘ d e i c s s r v c c o n d i t i o i , a n t i d e p r e s s a n t s c a n w o r k f o r n o p

4 ) H I 3 6 ( ) 0 ) ()EH C L I I t ) C r $ 3 c " C C ( 3 ( C ‘ ) 1 € S b V 6 1 5 l < ( ‘ 1 ' x 1 S 1 ( 1 l l l t f l V 6 [ 0 S ( )

0 d S ) ; l ( 3 1 1 1 “ H ‘ l O O C l $ 0 I 3 > ‘ - l l l C l L ‘ y ( 0 1 1 . 0 1 1 1 0 t 1 6 ‘ C l b y t h e P h a l H i a C E L I E l C a S 1 ” b t l E l l i S d e ﬁ n e

s t a b i l i z e r ” ) ; . D

6 C a n b e a s s o c i a t e d W i t h s t i g m a ( ‘ a n t i p s y c h o t i c ) , . c y P 5 ’ C l ( ) E I V E a

7 l V l U l l S l C E L C l a t i e n t J l O O C l s t a b i l i z e r » C a l 1 1 ’ 1 1 n o t b e l g a l l o w e l ' 1 ‘ S ( ( p

r a n g e o f m o o d s ) ; ﬂ . r e s s a n t s ”

8 M y b i a s r e s e a r c h ( “ m o o d s t a b i l i z e r s ” m a y n o t b e s e e n a s a n t i d e p . a

w o r t h y o f s t u d y f o r d e p r e s s i v e c o n d i t i o n s ) .

r t l n ( : 1 1

S C E S N 7 1 1 , N 3 1 0 N 1 7 ’ ! ” G L L 6 f I S A I L / 1 ' O P I C 1 " g 5 , 0 1 1 ! c h O f C m i c a 5 y ( ) - 0 “ ? ( ” 7 6 1 6 1 A 0 6 a t 7 0 P 0 t ? D L ! L l P

h a r i n a c o l o g y ‘ 7 0 1 5 ' 3 5 ( 4 ) . R e p r i n t e d w i t h p e r m i s s i o n o f W o l t e r s K l m u e r . P_ ; . . . f

T h ﬁ v e c l a s s e s o f d r u g s t e n d t o h a v e t y p i c a l c o r r e s p o n d i n g d i a g n o s e s o r s e ‘ e e 6 “ m a j o r d e p r e s s i v e d i s o r d e r ” ( M D D ) , s c h i z o p h r e n i a , b i p o l a ; i l l n e s s , x a m : w t § s a : e

1 d i a g g n o s e s a n d a t t e n t i o n d e ﬁ c i t d i s o r d e r ( A D D ) . E a c h c o m m o n c a s s i s a m I

' T b l e 1 1 a l o n g w i t h b a c k g r o u n d r e g a r d i n g t h e i r h i s t o r i c a l o r i g i n s , s e c o n d a r y i n a . , ' ' ' ' h a n i s m s . . ' i n d i c a t i o n s a n d b i o l o g i c a l m e c . ‘ . d l c a t l o n s

A s c a n b e s e e n i n T a b l e 1 . 1 , i t s e e m s t o b e t h e c a s e i n g e n e i a l t h a t p r n n a r y i n ’ t i o n s . T w o f r t h e d r u g c l a s s e s d o n o t d e m o n s t r a t e m o r e e f ﬁ c a c y t h a n s e c o n d a r y i n d i e : 1 1 b t t w o

0 ' . u o f ﬁ v e d r u g c l a s s e s h a d r e l a t i v e l y c o n s i s t e n t p h a r m a c o l o g i c a l . s t r u c t p l r e s h a n i s m s

( a m h e t a m i n e s a n d s e d a t i n g a g e n t s ) h a d r e l a t i v e l y c o n s 1 s t e n t b i o l o g i c m l e c t thod m e

' l l h i s a n a l y s i s ﬁ n d s t h a t 3 d r u g s b i o l o g i c a l m e c h a n i s m i s t h e m p s t g o n i s t e n h C O

' ‘ o v e e i t e r p a r m a '‘ ' d i c a t 1 o n s . T h e t w o e x c e p t i o n s 1 n v f o r c l a s s r f y i n g p s y c h o t r o p i c m e ‘ t l o g i c a l s t r u c t u r e ( a m p h e t a m i n e s ) a n d / o r c l i n i c a l e f f e c t ( s e d a t i n g a g e n ) A N E W N Q M E N L Q E é T P R E

T a b l e 1 2 p r o v i d e s a n a l t e r n a t i v e n o m e n c l a t u r e b a s e d o n b r o a d b i o l o g i g a l m i l - 1 : 2 1 : 1 3 ; . ' ' h c l a s s a l t h o u g h s u b c l a s s e s a n s p e c c ' I h s e m e c h a n i s m s a p p l y t o a l l d r u g s i n e a c ‘ , . m a :

d i f f e r f r o m e a c h o t h e r i n h a v i n g o r n o t h a v m g o t h e r m e c h a n l s t i c e ﬁ c e c t s .

“ A n t i d e ” w a " a ” a " l a p r e s s a n t s : i z i g fl fl e l f fl i i i fi A g u n i s i s t J l r " d i l l d e p i e c 3 ) 1 5 P c a l l 0 c J c i . P L C I [ E e 9 3 1 e l l ’ l 1 P " l l l B “ h a " . i n ‘ l e ' i C l i 1 : 3 ( 1 f l ’ ) S y ( 1 0 l l r l l [ e r O O y S \ f l ) : L y u c 1 : P a u c i 1 1 , l > 7 C E l ) P S ” ? l . 1 ( I e i ( I ( J [ 6 ‘ S EQ Q ‘ C O A M ] l l ) 6 S i H7 l l 1 l - a t 3 ’ 1 ' 1 0

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* T h e s e a g e n t s a r e p u r e S R I : a t l o w d o s e , b u t h a v e N R I a c t i v i t y a d d e d a t u s u a l d o s e :

c h z / J P a w / 7 0 1 7 1 7 5 1 . ) ' i 7 7 a c u l n g y 1 V 0 m 2 7 1 v i a m m 9

t h a t i t d i d n o t i m p r o v e d e l u s i o n s o r h a l l u c i n a t i o n s i n a n u m b e r o f p a t i e n t s w i t h s c h i z o .

p h r e n i a , b u t o n e p a t i e n t , w h o w a s d e l u s i o n a l b u t q u i e t a n d r e l a t i v e l y l o w i n a f f e c t , s u d ;

d e n l y b e c a m e e x c i t e d a n d r a n a r o u n d a n d b e c a m e v e r y a c t i v e . K u h n c o r r e c t l y j u d g e d t h a t

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

o b s e r v a t i o n h a p p e n e d i n p a t i e n t s p u t a t i v e l y d i a g n o s e d w i t h s c h i z o p h r e n i a i n t h e 1 9 5 0 3

( a n e r a i n w h i c h m a n y s u c h p a t i e n t s i n s t e a d o f t e n h a d i n a n i c d e p r e s s i v e n i n e s s ) . D r . A l a n

B r o a d h u r s t o f G e i g y , w h o w a s i n v o l v e d i n t h o s e i n i t i a l o b s e r v a t i o n s , r e c o u n t e d w h a t

h a p p e n e d i n a n o r a l h i s t o r y :

S o m e p a t i e n t s b e g a n t o d e t e r i o r a t e w i t h i n c r e a s i n g a g i t a t i o n a n d a f e w w e n t i n t o f r a n k

h y p o m a n i a .

O n e g e n t l e m a n , i n s u c h a s t a t e , m a n a g e d t o o b t a i n a b i c y c l e a n d r o d e i n h i s n i g h t

s h i r t t o a n e a r b y v i l l a g e , s i n g i n g m e r r i l y , m u c h t o t h e a l a r m . o f t h e i n h a b i t a n t s . T h i s w a s

n o t v e r y g o o d P R e i t h e r f o r t h e h o s p i t a l o r f o r G e i g y . [ I t w a s ] s o e x c i t i n g t h a t a d r u g

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

b e g a n t o w o n d e r i f t h e f l a t t e n e d a f f e c t o f s c h i z o p h r e n i a w a s s o m e h o w e l e v a t e d b y t h e

d r u g t o h y p o m a n i a , m i g h t a s i m i l a r e l e v a t i o n o f m o o d b e p o s s i b l e i n p a t i e n t s w i t h

d e p r e s s i o n . ( F r o m “ P s y c h o p h a r m a c o l o g y t o n e u r o p s y c h o p h a r n i a c o l o g y i n t h e 1 9 8 0 5

a n d t h e s t o r y o f C I N ' P a s t o l d i n a u t o b i o g r a p h y . ” T h o m a s A . B a n , B u d a p e s t : A n i m u l a

P u b l i s h i n g H o u s e , 2 0 1 O , p 3 3 9 )

T h e G e i g y r e s e a r c h e r s a n d K u h n d i d n ’ t k n o w t h a t h i s p a t i e n t w a s p r o b a b l y a m i s d i a g n o s e d

p a t i e n t w i t h m a n i c d e p r e s s i o n , w i t h i m i p r a m i n e r e v e a l i n g t h e u n d e r l y i n g s u s c e p t i b i l i t y

t o m a n i a , b u t t h e y a p p r e c i a t e d t h a t t h e m a n i c e f f e c t o f i r n i p r a m i n e s u g g e s t e d p o t e n t i a l

b e n e ﬁ t f o r d e p r e s s i o n , r a t h e r t h a n f o r s c h i z o p h r e n i a . K u h n c o n d u c t e d t h e ﬁ r s t s y s t e m a t i c

t r i a l i n d e p r e s s i o n i n 1 9 5 6 , a n d n o t e d b e n e ﬁ t i n s e v e r e m e l a n c h o l i a .

G i v e n t h e c l e a r m a n i a i n d u c i n g e f f e c t s o f t h e s e d r u g s , t h e t e r m “ m o o d e l e v a t o r ”

w o u l d h a v e b e e n c l i n i c a l l y a p p r o p r i a t e , o r p e r h a p s “ p s y c h i c e n e r g i z e r " a s s u g g e s t e d

b y s o m e . E v e n t u a l l y t h e t e r m " a n t i d e p r e s s a n t , ” i n a n a n a l o g y t o “ a n t i b i o t i c , ” c a u g h t o n

m o s t . I t w a s t h o u g h t t h a t a n t i d e p r e s s a n t s w o u l d t r e a t a l l k i n d s o f d e p r e s s i v e s t a t e s , j u s t a s

a n t i b i o t i c s t r e a t e d a l l k i n d s o f i n f e c t i o n s . T h i s a s s u m p t i o n h a s b e e n p r o v e n u n t r u e , b u t

t h e n a m e p e r s i s t s a n d c o n t i n u e s t o g i v e p a t i e n t s a n d c l i n i c i a n s t h e s a m e f a l s e i m p r e s s i o n

t h a t i f y o u a r e d e p r e s s e d , t h e n y o u s h o u l d t a k e a n “ a n t i d e p r e s s a n t . ” I t s o u n d s l o g i c a l i n

E n g l i s h , i t ’ s j u s t f a l s e s c i e n t i ﬁ c a l l y .

T h i s i s s o b e c a u s e t h e e f ﬁ c a c y o f “ a n t i d e p r e s s a n t s ” a s a c l a s s h a s b e e n d i s p r o v e n i n

b i p o l a r d e p r e s s i o n , a c u t e l y i n m o s t s t u d i e s , a n d f o r m a i n t e n a n c e p r e v e n t i o n e v e n m o r e

d e ﬁ n i t i v e l y ' l h e “ a n t i d e p r e s s a n t ” c l a s s i s a l s o d i s p r o v e n a s e f f e c t i v e i n M D D w i t h m i l d

b a s e l i n e d e p r e s s i v e s e v e r i t y , b a s e d o n a m e t a a n a l y s i s o f a l l e x t a n t p u b l i s h e d a n d u n p u b

l i s h e d F o o d a n d D r u g A d m i n i s t r a t i o n ( F D A ) d a t a . A b o u t o n e h a l f o f a l l a n t i d e p r e s s a n t

r a n d o m i z e d c l i n i c a l t r i a l s o f a c u t e d e p r e s s i o n h a v e b e e n n e g a t i v e . I n v a s c u l a r d e p r e s s i o n ,

a n d d e p r e s s i o n i n t h e s e t t i n g o f c a r d i o v a s c u l a r d i s e a s e , a n t i d e p r e s s a n t s o f t e n a r e f o u n d t o

b e i n e f f e c t i v e c o m p a r e d t o p l a c e b o ( s e e C h a p t e r 1 9 ) .

I n c o n t r a s t t o t h e i r r e g u l a r a n d o f t e n a b s e n t b e n e ﬁ t o f s o ~ c a l l e d a n t i d e p r e s s a n t s

f o r a r a n g e o f d e p r e s s i v e s t a t e s , t h i s c l a s s o f m e d i c a t i o n s i s m o s t c o n s i s t e n t l y e f f e c t i v e

i i j 1

I O B A S I C P S Y C H O P H A R I V I A C O L O G Y

f o r i m p r o v e m e n t o f a n x i e t y s y m p t o m s . S u c h i s t h e c a s e f o r s t u d i e s o f g e n e r a l i z e d a n X ~

i e t y , p a n i c , a n d o f t e n o b s e s s i o n s o r c o m p u l s i o n s . B a s e d o n t h e i r b e s t c o n s i s t e n t C l i n i c a l

b e n e ﬁ t s , “ a n t i d e p r e s s a n t s ” s h o u l d b e c a l l e d “ a n x i o l y t i c s ” i n s t e a d .

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

b y i t s p h a r m a c o l o g i c a l s t r u c t u r e i s t h e t r i c y c l i c a n t i d e p r e s s a n t ( T C A ) c l a s s . Y e t o t h e r

a g e n t s t h a t a r e s i m i l a r i n t r i c y c l i c s t r u c t u r e , l i k e c h l o r p r o m a z i n e a n d c a r b a m a z e p i ’ n e , d o

n o t h a v e n o t a b l e b e n e ﬁ t s f o r d e p r e s s i v e s t a t e s .

B i o l o g i c a l m e c h a n i s m i s t h e m o s t c o n s i s t e n t ﬁ n d i n g i n t h i s d r u g c l a s s ; n a m e l y , m o n o a

m i n e a g o n i s m . T h e s e a g e n t s i n c r e a s e a c t i v i t y o f o n e o r m o r e o f t h e t h r e e m o n o a m i n e s : d o -

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

s t i m u l a t i o n , o r i n d i r e c t l y v i a b l o c k a d e o f r e u p t a k e p u m p s i n t h e s y n a p s e . W h a t e v e r t h e

m e c h a n i s m , t h e r e s u l t i s t o i n c r e a s e a c t i v i t y o f o n e o r m o r e o f t h e m o n o a m i n e s . H e n c e ,

t h e p r o p o s e d d r u g c l a s s n a m e f o r t h e s e m e d i c a t i o n s i s “ m o n o a m i n e a g o n i s t s . ”

F u r t h e r s p e c i ﬁ c a t i o n b y b i o l o g i c a l m e c h a n i s m c a n o c c u r , s i n c e s o m e S R I s a r e a l s o

n o r a d r e n e r g i c ( ﬂ u o x e t i n e , v e n l a f a x i n e , d u l o x e t i n e ) o r d o p a m i n e r g i c ( s e r t r a l i n e ) , a n d

s o m e T C A s a r e h a v e b o t h s e r o t o n i n a n d n o r e p i n e p h r i n e r e u p t a k e i n h i b i t i o n (NRI; t e r -

t i a r y a g e n t s ) a n d s o m e o n l y h a v e N R 1 ( d e s i p r a m i n e , n o r t r i p t y l i n e ) . A n o t h e r p u r e N R 1 i s

a t o m o x e t i n e , d e s p i t e t e c h n i c a l F D A i n d i c a t i o n f o r n o n - d e p r e s s i o n u s e s ( a d u l t a t t e n t i o n

d e ﬁ c i t h y p e r a c t i v i t y d i s o r d e r [ A D H D ] ) . B u p r o p i o n h a s v e r y m i l d d o p a m i n e a g o n i s t a n d

n o r e p i n e p h r i n e a g o n i s t e f f e c t s , b u t t h e p o t e n c y o f t h e s e e f f e c t s i s s m a l l ( m u c h l e s s t h a n

s e r t r a l i n e f o r d o p a m i n e r g i c e f f e c t s ) . B u p r o p i o n a l s o h a s a n a m p h e t a m i n e s t r u c t u r e , - h e n c e ,

o n t h i s s c h e m a i t w i l l b e c a t e g o r i z e d a s a n a m p h e t a m i n e , w h i c h , a s n o t e d l a t e r , i s t h e o n l y

d r u g c l a s s i n t h i s p r o p o s e d n o m e n c l a t u r e i n w h i c h t h e p h a r m a c o l o g i c a l s t r u c t u r e i s r e t a i n e d

a s i t s m a i n c l a s s i f y i n g f e a t u r e . I V I i r t a z a p i n e i s a n a l p h a 2 , a d r e n e r g i c r e c e p t o r a n t a g o n i s t ,

w h i c h i n c r e a s e s n o r e p i n e p h r i n e a v a i l a b i l i t y , i t i s a l s o a s e r o t o n i n 2 a n d 3 r e c e p t o r b l o c k e r ,

w h i c h i n c r e a s e s s e r o t o n i n ~ l n e u r o t r a n s i n i s s i o n , t h o u g h t t o e x e r t a n t i d e p r e s s a n t e f f e c t s .

H e n c e i t c a n b e c l a s s i ﬁ e d a s a n o r e p i n e p h r i n e / s e r o t o n i n a g o n i s t , a s a r e SRI/ N R 1 a g e n t s .

“ A n t i p s y c h o t i c s ” : D o p a m i n e B l o c k e r s

I n t h e e a r l y 1 9 5 0 s , c h l o r p r o m a z i n e w a s f o u n d t o r e d u c e a g i t a t i o n i n h o s p i t a l i z e d p a t i e n t s

w i t h s c h i z o p h r e n i a . T h i s g e n e r a l a n t i a g i t a t i o n e f f e c t l e d t o t h e d r u g c l a s s n a m e o f “ m a j o r

t r a n q u i l i z e r s , " i n c o n t r a s t t o t h e b e n z o d i a z e p i n e s , w h i c h h a d c o m e t o t h e m a r k e t a f e w

d e c a d e s b e f o r e h a n d , t e r m e d “ m i n o r t r a n q u i l i z e r s . " S o o n , i t w a s n o t e d t h a t c h l o r p r o m a

z i n e a n d i t s a n a l o g u e s p r o d u c e d e x t r a p y r a m i d a l s i d e e f f e c t s , w h i c h w e r e u s e d t o d e ﬁ n e t h e

c l a s s a s “ n e u r o l e p t i c s ” ( “ b r e a k i n g n e u r o n s , ” i n L a t i n ) . T h i s t e r m i n o l o g y w a s m o r e c o m m o n

i n F r a n c e , b u t p s y c h i a t r i s t s i n t h e U n i t e d S t a t e s a n d U n i t e d K i n g d o m p r e f e r r e d t o u s e a

p h r a s e t h a t d i d n ’ t r e l a t e t o s i d e e f f e c t s , a n d t h u s t h e t e r m “ a n t i p s y c h o t i c ” g a i n e d v o g u e . I t w a s ﬁ r s t i n t r o d u c e d b y t h e C a n a d i a n p s y c h i a t r i s t H e i n z L e h m a n n i n t h e 1 9 6 0 5 , a n d g a i n e d

i n c r e a s i n g u s a g e . L e h m a n n w a s a w a r e t h a t t h e t e r m w a s b a s e d o n l i m i t e d e v i d e n c e : “ I n

- 1 9 5 6 , w h e n I w a s a d d r e s s i n g t h e C a n a d i a n M e d i c a l A s s o c i a t i o n , I i n t r o d u c e d t h e t e r m ‘ a n t i p s y c h o t i c ’ a p o l o g e t i c a l l y , a n d m o r e a s a m e t a p h o r t h a n a d e s i g n a t i o n . ” T i m e h a s p r o v e n

L e h m a n n m o r e c o r r e c t t h a n h e k n e w : t h e s e a g e n t s w o r k f o r p s y c h o t i c s y m p t o m s ; t h e y a l s o b e n e ﬁ t n o n p s y c h o t i c m a n i a a n d s o m e t i m e s n o n p s y c h o t i c d e p r e s s i v e s t a t e s . T h e t e r m

N e w P s y c h o p h a r m a c o l o g y N o m e n c l a t u r e 1 1

“ n e u r o l e p t i c ” i s m o r e c o n s i s t e n t c l i n i c a l l y b e c a u s e a l l a g e n t s i n t h i s c l a s s h a z l e d a ] : l e a s t : 3 c h :

e x t r a p y r a m i d a l s i d e e f f e c t s . H o w e v e r , u s i n g s i d e e f f e c t s f o r c l a s s n a m e s : v l o b 1 ' e ‘ e x p r e c C i s e

t o p r o d u c e n e g a t i v e a t t i t u d e s t o w a r d t h o s e a g e n t s . T h e . a n t i p s y c h o t i c a . e a g a p e a r e

t h o u g h , s i n c e t h e s e a g e n t s a r e e f f e c t i v e i n n o n - p s y c h o t i c s t a t e s , l i k e m a n i a , a n y

m o s t w i d e l y u s e d f o r b i p o l a r i l l n e s s a n d d e p r e s s i v e c o n d i t i o n s S T a b l e 1 . 4 ) . . ” . a h a

l f o n e h a d t o c h o o s e a m o n g t h e s e c l a s s n a m e s , t h e t e r m n e u r o l e p t i c “ i s m o r e v 1 ’

s i n c e a l l t h e s e a g e n t s h a v e e x t r a p y r a m i d a l s i d e e f f e c t s ( B P S ) , w h i l e t h e a n t 1 P § Y C h 0 ¥ £

“ n e u r o l e p t i c ” c l a s s n a m e a l s o h a s m o r e v a l i d i t y , g i v e n t h a t a n i m a l m o d e l s o f a n t i p s y c 0 1 c

t e r m d o e s n o t c a p t u r e t h e f r e q u e n t u s e o f t h e s e a g e n t s i n n o n p s y c h o t i c c o n d i t i o n : l t ‘ e

e f f e c t a r e b a s e d o n t h e m o t o r e f f e c t s o f d o p a m i n e b l o c k a d e ( c a t a l e p s y ) . f d

I f o n e t u r n s t o b i o l o g i c a l m e c h a n i s m , a l l d r u g s i n t h i s c l a s s h a v e b e e n b l o c k e r s o . c ; —

p a r n i n e r e c e p t o r s , t o a g r e a t e r o r l e s s e r d e g r e e , w i t h o n e r e c e n t e x c e p t i o n ( p i m a v g n s e r i c n 1

H e n c e , t h e t e r m “ d o p a m i n e b l o c k e r ” i s p r o p o s e d h e r e a s t h e b e s t c o n s i s t e n t a n n e l u r :

t e r m f o r t h e d e ﬁ n i t i o n o f t h i s d r u g c l a s s . T h i s d o p a m i n e b l o c k a d e i s s t r o n g e s t f o r D d a n

D 2 r e c e p t o r s , b u t i t c a n a l s o a f f e c t o t h e r r e c e p t o r s . P r i o r a t t e m p t s t o d e v e l o p p ' u i r e f o p :

m i n e b l o c k e r s t h a t e x c l u d e d D 1 o r D 2 , s u c h a s t h e p u r e D 4 b l o c k e r r e m o m c p g e , a ; e i

t o p r o d u c e c l i n i c a l e ﬁ i c a c y f o r p s y c h o s i s . A g a i n , s p e c i ﬁ c a g e n t s i n t h e c l a s s 1 b e i ; “ 7 : 1 1 ; :

i n p h a r m a c o l o g i c a l s t r u c t u r e ; e a r l y a g e n t s w e r e p h e n o t h i a z a n e s i n s t r u c t u g e , 1 u 0 m e )

( l i k e h a l o p e r i d o l ) w e r e b u t y r o p h e n o n e s , a n d s t i l l o t h e r s ( l i k e c l o z a p i n e a n o a n z a p

d i b e n z o d i a z e p i n e s ; o t h e r c o m p l e x s t r u c t u r e s a l s o a b o u n d . . ‘

S u b c l a s s e s w i t h t h e o v e r a l l d o p a m i n e b l o c k i n g c l a s s c a n b e i d e n t i ﬁ e d m o s t p r o m r

n e n t l y o n W h e t h e r o r n o t t h e r e i s a l s o s u b s t a n t i a l s e r o t o n i n 2 r e c e p t o r b l o c k a d e , a e a t u r e

T A B L E 1 . 4 N o m e n c l a t u r e f o r D o p a t n i n e B l o c k e r s ( F o r m e r l y C a l l e d “ A n t i p s y c h o t i c s ” )

S u b c l a s s

D o p a m i n e b l o c k e r s *

D o p a m i n e / s e r o t o n i n b l o c k e r s

D o p a m i n e / s e w t o n i n b l o c k e r s w i t h p a r t i a l a g o n i s m

S p e c i ﬁ c a g e n t s

H a l o p e r i d o l

C h l o r p r o m a z i n e

T h i o t h i x e n e

T r i f l u o p e r a z i n e

T h i o r i d a z i n e

C l o z a p i n e

O l a n z a p i n e

R i s p e r i d o n e

Q u e t i a p i n e

A s e n a p i n e

I l o p e r i d o n e

L u r a s i d o n e

C a r i p r a z i n e

A r i p i p r a z o l e

B r e x p i p r a z o l e

Z i p r a s i d o n e

ofthesecondgenerationofantipsychoticsinthelasttyvodecades.Theterm"atypical”is usedforthatclass,butgiventhatitisusedmuchmorefrequentlythantheoriginal(“typ ical”)class,andthatnowmoresecond-generationthanfirst generationagentsexist,it wouldseemoddtocall"atypical”whatisnowstandardandtypical.Ivloreimportantly, somedifferencesexistin b i o l o g i c a l mechanismsamongspecificagentsinthedopamine/ serotoninblockers.Specifically,aripiprazoleandbrexpiprazole d i s p l a y somedopamine agonism;ZiprasidonehasnotableSRl/NR}:eitects;andlurasidoneisaserotoninagonist.

“MoodStabilizers”:Secondh/lessengerModifiers

Thephrase“moodstabilizer”hasnoscientificmeaningitwasusedcolloquiallyinthe 19505forthecombinedprescriptionofan"upper,”dextroamphetamine,anda“downer,” phenobarbital,Thisamphetamine/barbituratecombinationobviouslyhasnothingtodo withlithiumandbenefitsforbipolarillness.Rather,thetherapeuticconceptinvolved raisingandloweringmoodssimultaneouslyandsymptomatically(Table1.5).Thisidea doesn’tcapturelithium’seflectofpreventingfuturemanicanddepressiveepisodes,while havingfewimmediatesymptomaticeffects.

Infact,formanyyears,theterm“moodstabilizer”wasn’tusedmuchinpsychiatry,nor appliedtobipolarillness,sincelithiumwastheonlyagentavailableforthisconditionfrom the1960sintothe19803.Whencarbarnazepinewasdevelopedinthe19803,andthen valproatewasmarketedformaniaintheearly19905,theterm“moodstabilizer”beganto beusedfortheclass,drivenprimarilybymarketingofvalproatebyitsmanufacturer.This usageobfuscatedthefactthatlithium’smainefﬁcacywasinpreventionoffutureepisodes, nottreaUnentofcurrentsymptoms,asthephrase”moodstabilizer”implied.

Later,pharmaceuticalcompaniesobtainedindicationsformostnewantipsychoticsfor acutemaniaaswell.Sincemostsuchagentswerewidelyusedinbipolardisorder,theterm “moodstabilizer”wasappliedtothem,despiteabsenceofevidenceofprophylacticefﬁcacy.

Ifagentsinthisclassarelimitedtothedrugsthathaveeﬂ'icacyinpreventionofmanicor depressiveepisodes,thenincludedagentswouldbelithium,valproate,carbamazepine,and lamotrigine.Thedopamineblockerswouldbeexcludedsincetheirmaintenancepreven~ tionstudiesmaybeinvalidduetoabiased“enriched”design,Whereonlydrug responsive patientsarepreselectedtoentermaintenancestudies,asdescribedinChapter6.

Ifthisclinicaldeﬁnitionisaccepted,andthesefouragents(lithiumandthree anticonvulsants:valproate,carhamazepine,andlamotrigine)areincludedasaclass

TABLE1.5NomenclatureforSecondMessengerModiﬁers(FormerlyCalled “MoodStabilizers”)

Subclass Speciﬁcagents

Secondmessengermodiﬁers

t0cretherforPIEVBDlZlVEtreatmentofbipolarillness,thenonecanaslt:vhethirthseyns:1:: qr:pharmacologicalorbiologicalproperties.Theirphaririacologica strucure :1, trelnelyvariableevenamongthislimitedgroupofagents,rangingfiotl:1r:::%c:rll:: (lithium),toaSimplecarbohydratestructure(valproate),toatiicyc,icslin inazeplne),toacomplexmolecule(larnotrigine), 1’m flt1 6 ‘ 9 8 0 8 W h e n it

Biologicalmechanismswerelargelyunknowninthiscdboun1 , 1 -p .t;“gunk“ becameclearthatlithiumhadmanifoldandpowerfulsecondmessengerinrail;.er; effects,whichhadmajorneuroprotectiveeffects,andultimatelycaaliusedcnarégeirbagnai‘ activityleadingtoneuroplasticalterationotaxonalconnections.Vproatean‘c; ﬁveas epinewerealsofoundtohavesomesecondmessengereilects,thoughriota:ererilslimo:1 lithiun’i’s(affectingproteinslikeproteinkinase C forvalproate,andcyc1caenosy ophosphate [ A M P ] activityforcarbarnazepine). 1 1 8mfor t h o s e t h r e e r[111.15,themostconsistentﬁndingisthatthebiologicamec1amd a dmen“

agentsinvolvesSecondmessengers.Theclassthereforecouldbedeﬁne asseconth 1:; sengermodiﬁers,”sincetheseagentsappeartoallmodifysecondmeetingeipatitgys Withoutmuchactivityinsynapticneurotransmittersandtheirreceptors.1eexcep ' ‘ onistlamotrigine,which18apotentglutamatereceptorantag

“Anxiolytics/Hypnotics”:GABAergicAgonists

Theterm“anxiolytics/hypnotics”isusedmainlyforthebenzodiazepinedrugclass,“which wasinitiallyintroducedinthe19308and1940s(Table1.6).TheywereViewedasminor

TABLE 1 6 NomenclatureforGABAergicAgonistsandOtherDrugClasses withAnxiolyﬁcorSedatingEﬁects

Subclass Speciﬁcagents

GABAergicagonists: Benzodiazepines(diazepam,lorazepam,alprazolarn,clonazepam, amongothers)

Gabapencin

Zolpidem

Zaleplon

Other Antihistamines: Quetiapine*

Doxepirﬁ

Diphenhydramine

Hydroxyzine

Adrenergicblockers: Propanolol

Clonidine

Melatoninagonist: Ramelteon

*Predominantmechanismatlowdose.