Treatment of schizophrenia current issues and future possibilities

Future possibility about the treatment of schizophrenia

1. Treatment of schizophrenia:
current issue
&
future possibilities

2. Evolution of Antipsychotic(AP) Drugs
•Psychoticdisordershavebeenrecognizedsince
ancienttimesandtherehavebeenongoingattemptsat
discoveringeffectivetreatmentsforthese.
•Themoderneraoftreatingpsychosisevolvedthrough
insulincoma,camphorcoma,electroconvulsive
therapy,andantipsychoticmedications(AP)beginning
withreserpineandculminatingintheintroductionof
chlorpromazine(CPZ)in1952.
•CPZandotherfirst-generationantipsychotics(FGAs)
thatfollowedhadaheterogeneousreceptor-binding
profileandlowpotency,requiringhigherdosesfora
therapeuticresponse.

3. •SubsequentdevelopmentofselectiveD2antagonistslike
haloperidolandfluphenazineledtohighpotency/lowerdose
APs.
•In1990sthesecond-generationantipsychotics(SGAs)were
introduced.Theirdevelopmentwasbasedonclozapine,which
hadasubstantiallydifferentreceptor-bindingprofile,resultingin
someefficacyinrefractorypatients,andlowermotoricside
effects(MSE)likeextrapyramidaleffects(EPS),neuroleptic
malignantsyndrome(NMS),andtardivedyskinesia(TD)

4. Timeline of Major
Antipsychotic Therapies
Ziprasidone
1950 1960 1970 1980 1990 2001 2003 2007
ECT, etc.
Chlorpromazine
Fluphenazine
Thioridazine
HaloperidolClozapine
Risperidone
Olanzapine
Quetiapine
Aripiprazole
Consta
Paliperidone
Consta = Long-acting injectable risperidone

5. •TheSGAshavevirtuallybecomethefirsttreatmentof
choiceforschizophrenia,buttheyhavenotliveduptohigh
expectationsbasedoninitialgratifyingexperiencewith
clozapineintreatmentrefractorycases.
•EventhoughtheycarryanalmostnegligibleriskofMSE
comparedtoFGAs,theirefficacyintreatingnegative,
cognitive,anddepressivesymptomsisonlymodestly
betterthanthatofFGAs.
•ManyFGAsandSGAslikerisperidone,amisulpride,and
paliperidoneinducehyperprolactinemiawhichmaybe
eitherasymptomatic,orassociatedwithclinicaleffects
suchasgynecomastia,galactorrhea,menstrual
irregularities,andsexualdysfunction.

6. •MostSGAs(andsomeFGAs)arealsoassociatedwithweight
gainandmetabolicdisordersincludingglycemicdysregulation
andanatherogeniclipidprofile.
•Thesemetabolicdisordersareinturnariskfactorfor
microvascularandmacrovasculardiseases,leadingto
increasedriskofmorbidityandmortality.
•Thus,thereisaneedforanewgenerationofAPsfreeofthe
listeddrawbacks.
•ThenewerAPsarebeingdevelopedformarketinginthenear
future,focusingontheirefficacy,adverseeffects,and
pharmacodynamicandpharmacokineticprofiles.

8. Past Areas of
Concern
Current Medical Realities
Shift in Risk Perception
of Antipsychotics
Sedation
Weight
Gain
Insulin
Resistance
CHD
Hyper-
lipidemia
Weight Gain
Diabetes
Prolactin
Insulin
Resistance
Sedation
Hyperlipidemia
Coronary Heart
Disease
Tardive
Dyskinesia
TD
Prolactin

9. A critical appraisal of available AP drugs
•Despitetheshort-termefficacyofAPs,theoveralltreatmentoutcome
remainspoorwiththemajorityofpatientswithschizophrenia
experiencingpoorerqualityoflifeduetorelapses,enduring
symptoms,anddeficitsincognitiveandpsychosocialfunctioning.
•WhileRCTsseemtosuggestthatSGAssignificantlyimprove
cognition,thereissomeevidencethattheimprovementsmay,at
leastinpartbeduetopracticeeffects.
•TheserealizationshaveledtoaninitiativeintheUnitedStatesto
facilitatethedevelopmentofnewerAPsfocusingonmitigationof
cognitiveimpairmentsinschizophrenia(MeasurementandTreatment
ResearchtoImproveCognitioninSchizophrenia,orMATRICS).
•Thisprojecthasidentifiedthreedrugmechanismsforparticular
attention:cholinergic,dopaminergic,andglutamatergic.Clinical
efficacytrialsarecurrentlyunderwayevaluatingpotentialcognitive-
enhancingagents

10. 3 basic approaches in new target
Glutamate receptor and related targets
Cholinergic system related drugs
Dopaminergic and serotoninergic related drugs
Other mechanisms : H2 receptor antagonism, Valacyclovir,
Minocycline, SERM, Omega-3 fatty acids, Cannabinoid
agents, Neuropeptides, Sigma receptor antagonist, COX-2
inhibitors, Alpha 2 agonists, GABA-A receptor modulation
Non pharmacological : rTMS, tDCS, Maintenance ECT,
Avatar therapy, psychotherapy

11. What’s New?

12. September 01, 2001
The Emerging Role of Glutamate in the Pathophysiologyand Treatment of
Schizophrenia
Donald C. Goff, M.D.; Joseph T. Coyle, M.D.Am J Psychiatry 2001;158:1367-1377
Glutamatergicneuronsarethemajorexcitatorypathwayslinkingthe
cortex,limbicsystem,andthalamus,regionsthathavebeenimplicatedin
schizophrenia.
TheN-methyl-D-asparticacid(NMDA)subtypeofglutamatereceptormay
beparticularlyimportantasblockadeofthisreceptorbythedissociative
anestheticsreproducesinnormalsubjectsthesymptomaticmanifestations
ofschizophrenia,includingnegativesymptomsandcognitiveimpairments,
andincreasesdopaminereleaseinthemesolimbicsystem.
AgentsthatindirectlyenhanceNMDAreceptorfunctionviatheglycine
modulatorysitereducenegativesymptomsandvariablyimprovecognitive
functioninginschizophrenicsubjects.
Glutamate and schizophrenia

13. Glycine : Future treatment for schizophrenia?
AgonistsattheglycinesiteofNMDAreceptorsincludethe
naturallyoccurringaminoacidsglycineandd-serineaswellas
ananalogueofd-serine,calledd-cycloserine,whichisalso
activeattheglycineco-agonistsiteofNMDAreceptors.Allof
theseagentshavebeentestedinschizophrenia,withevidence
thattheycanreducenegativeand/orcognitivesymptoms.
Furthertestingisinprogress,andsyntheticagonistswith
greaterpotencyareindiscovery.
PerhapsstimulatingtheglycinesitewillboostNMDAreceptor
activityinamannerthatissufficienttoovercomeits
hypotheticalhypofunctionandtherebyreducenegativeand
cognitivesymptoms,butpossiblyevenpositivesymptomsin
schizophrenia.

14. OnepossiblewaytoindirectlyimproveNMDAreceptorfunction
istoincreasetheavailabilityofthereceptorco-factorglycine.
Aseriesofdouble-blind,placebo-controlledcrossoverstudies
byJavittandcolleagues(asreportedinCoyle2004)administered
30-60g/dayofglycinetoschizophreniapatientsontraditional
neuroleptic.Eachgroupofpatientsreceivedeitherplaceboor
glycinefor4weeks;forthefollowing4weeks,theoriginalplacebo
groupwasgivenglycineaswell.
Resultsreportedasignificantdecrease(17%)innegativeand
cognitivesymptomsfortheglycinegroup,andfortheplacebo
groupfollowingthe4-weekcrossover.

15. DCS(d-cycloserine),genericallyanantituberculardrug,cross-reacts
withtheNMDAreceptorGLYsitetoactasapartialagonistwitha30-
-60%oftheefficacyofGLY.
D-serineappearedtoimprovepositivesymptomsaswellasnegative
andcognitiveinschizophreniapatientswhodidnotrespondwellto
traditionalneuroleptics(studybyTsaietal1998,quotedinCoyleet
al2004)
Atleastforsomepeople,glycineord-cycloserinetreatmentaddedto
astandardregimenofantipsychoticscouldhavesubstantialbenefits
intermsofmitigationofschizophrenia’snegativesymptoms.
D-serinehasbeenreportedtocauserenaltubularnecrosisin
rodents;thus,itisstillundertoxicologyinvestigationbytheFDA

16. •Twomajorapproachesfortargetingglutamatesignalingarenow
advancinginpreclinicalandclinicaldevelopment.
1.FirstareinhibitorsforatransporterforglycinetermedGlyT1.Glycine
isaco-agonistwithglutamateforaspecificsubtypeofglutamate
receptor,termedtheNMDAreceptor,whichisthoughttobecritically
involvedinbraincircuitsthataredisruptedinschizophreniapatients.
(InhibitingGlyT1increasesglycinelevelsandcanselectively
increaseNMDAreceptorsignaling.)
2.Anotherpromisingapproachistoincreaseactivityofanotherfamily
ofglutamatereceptors,termedmetabotropicglutamatereceptors
(mGlus),whichplayimportantmodulatoryrolesinbraincircuitsthat
arethoughttobedisruptedinschizophreniapatients.Activationof
thegroupI(mGlu
5)andthegroupII(mGlu
2andmGlu
3)mGlusis
hypothesizedtonormalizethedisruptionofaberrantsignalingin
thesecircuits.
Modulation of Glutamatergic signalling

17. Glycine transporter inhibitor
GlyT1terminatingtheactionofglycinereleasedbyglial
cellsintothesynapsestoactattheglycinesiteofNMDA
receptors.
SeveralGlyT1inhibitorsarenowinclinicaltesting,
includingthenaturalagentN-methylglycine,alsoknownas
sarcosine,RG1678(bitopertin),andOrg25935/SCH
900435,aswellasothersinpreclinicaltestingsuchas
SSR504734,SSR241586,andJNJ17305600.
GlyT1inhibitors,sometimescalledselectiveglycine
reuptakeinhibitorsorSGRIs.WhenGlyT1pumpsare
blockedbyaGlyT1inhibitor,thisincreasesthesynaptic
availabilityofglycine,andthusenhancesNMDA
neurotransmission.
ThedownstreamconsequenceofGlyT1inhibitionisto
reversethehypofunctionalNMDAreceptor.

18. Inonestudy,65risperidone-treatedin-patientswithacute
exacerbationsofschizophreniaweregivena6-week,
randomized,double-blindtrial(DBT)comparingadjuvants
sarcosine(aglycinetransporterinhibitor)2g/day,DSR2g/day,
andplacebo.Thesarcosinegroupshowedsignificantlymore
symptomsimprovementthantheothertwogroups.
Ina6-week,controlledtrialwithchronicschizophreniapatients,
sarcosine2g/dayadjuvanttreatmentledto17%(P<0.0001),
14%(P<0.0001),and13%(P<0.0001)reductionsinpositive,
negative,andcognitivesymptoms,respectively,without
inducinganysignificantsideeffects.

19. mGluR (metabotropic glutamate
receptors) modulators
mGluRsareGprotein-coupled-receptorsthatincludeeight
subtypestermedmGluR1-8.
GroupIreceptors=potentiatebothpresynapticGLUrelease
andpostsynapticNMDAneurotransmission
GroupsIIand3receptors=servetolimitGLUrelease,particularly
duringconditionsofGLUexcess.
Thus,groupIagonistsorpositivemodulatorsareexpectedto
stimulateNMDAreceptor-mediatedneurotransmission,and
groupIantagoniststoinhibitit.
PresynapticmGluR2/3agonistcouldpotentiallyprevent
excessiveglutamatereleasefromglutamateneuronsasis
postulatedtooccurasthedownstreamconsequenceofNMDA
hypoactivityandtherebyimprovethesymptomsof
schizophrenia.Onesuchcompound,LY2140023,hasbeen
testedwithproofofconceptofefficacyinschizophreniabuthas
beendroppedfromclinicaldevelopment.

20. AMPA kines
AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid)
receptorsareoneoftheglutamatereceptorsubtypes,andthey
regulateionflowandneuronaldepolarizationthatcanleadto
NMDA(N-methyl-d-aspartate)receptoractivation.Anumberof
modulatorsoftheAMPAreceptorareunderdevelopment,
includingthosethatdonotactdirectlyattheglutamatesiteof
theAMPA receptor,butatpositiveallosteric
modulating(i.e.,PAM)sitesonthisreceptor,e.g.,CX516.
TheseAMPAPAMsarealsocalledAMPAkines.
Preliminaryevidencefromanimalstudiessuggeststhat
AMPAkinesmightenhancecognition,butearlyresultswith
CX516inschizophreniaaresomewhatdisappointing..

21. However,morepotentAMPAkinesarebeingdeveloped
(CX546,CX619/Org24448,Org25573,Org25271,Org24292,
Org25501,LY293558)andthesemighthavemoreefficacyfor
cognitivesymptomsinschizophreniawithoutshowingactivation
ofpositivesymptomsorneurotoxicity.

22. Cholinergic agents
Alpha-7nicotinicreceptorpartialagonists.
Inpatientswithschizophreniapreclinical,genetic,and
humanpostmortemstudiessuggestreducedfunctionof
alpha-7receptors,whichisassociatedwithdeficitsin
variouspsycho-physiologicalmeasureslikesensory
inhibitionoftheP50auditory-evokedresponse,auditory
sensorygating,andvoluntarysmoothpursuiteye
movements.
Nicotineisknownfortransientcognitiveenhancingclinical
effectinschizophrenia.{Alpha-7nicotinicreceptorisone
ofthenicotinicacetylcholinereceptors(n-AChRs),alarge
familyofligand-gatedionchannels.}

23. Concurringwiththisfact,DMXBA,apartialagonistatthealpha-
7nicotinicreceptorwasnotedtoenhanceauditorysensory
gatinginanimalmodels.
ThisledtospeculationthatDMXBAmightimproveP50auditory
gatingandcognitioninschizophrenia.
Galantamine,anotheralpha-7nicotinicreceptormodulator,isin
PhaseIIclinicaltrialsforselectivebenefitsinprocessingspeed
andverbalmemoryinpatientswithschizophrenia.
Similarly,alpha4beta2nAChRpartialagonistVarenicline,
meantfortreatingnicotinedependence,isbeingevaluatedfor
cognitivedysfunctioninschizophrenia.

24. MuscarinicM1agonists
Post-mortemandneuroimagingstudiesinschizophreniashow
asignificantdecreaseofmuscarinicreceptordensity,especially
forM1subtype,inthefrontalcortex,basalganglia,and
hippocampus.
M1receptorknockoutmiceshowspecificbehavioralchanges
thataretypicalinanimalmodelsofschizophrenia.
Conversely,administrationofselectiveM1receptorantagonists
producessignificantcognitiveimpairment..

25. •Xanomeline,amuscarinicagonistwithhighM1activity,is
effectiveinthecognitiveandpsychoticsymptomsofpatients
withAlzheimer'sdisease(psychotics>cognitive).
•Thisdrugselectivelyinhibitsthefiringofmeso-limbicdopamine
cellsevenafteracuteadministrationandwouldhaveafaster
onsetofactioncomparedtocurrentAPsandwouldnotinduce
extrapyramidalsideeffects.Thus,preclinicaldataare
suggestiveofanAP-likeprofileofthisdrugthatmaybecome
availableintransdermalpatches,withlessadverseeffects.

26. Newer dopaminergic and dual acting
(serotonergic and dopaminergic) agents
Dopamine D2 receptor antagonist and 5-HT1A
receptor agonist (SSR181507 and SLV3313)
BothdopamineD2receptorantagonistand5-HT1Areceptor
agonist(SSR181507andSLV3313)haveaunique
neurochemicalandelectrophysiologicalprofilethatislinkedto
dualpropertieswhichareexpressedinthesamedoserange.It
ishypothesizedthatthesedrugsshouldbewithouttheliability
ofextrapyramidalsideeffectsandbeefficaciousagainst
positive,negative,andcognitivesymptomsofschizophrenia,
andschizophrenia-associatedmoodandanxietydisorders.

27. D2/D3 antagonist, 5-HT1A agonist, and D4 partial
agonist properties (F15063)
Inrodent,modelF15063potentlyreversedmethylphenidate-
inducedstereotypedbehaviorsandattenuatedapomorphine-
inducedPPI(prepulseinhibition)deficitswithoutinducing
catalepsy.SoitshouldhavelowEPSliability,complemented
byafavorableprofilefornegativesymptomsandcognitive
deficitsofschizophrenia.

28. l-stepholidine
AsanaturallyoccurringdopaminereceptorD1agonistandD2
antagonistitshouldcontrolpsychosisandtreatcognitive
symptomsbyenhancingcorticaldopaminetransmission.
Inanimalstudies,itiseffectiveinreducingamphetamineand
phencyclidine-inducedlocomotionaswellasconditioned
avoidanceresponse,withcatalepsyandprolactinelevationas
themainsideeffects.Thisactionprofileislikethatofan
atypicalAP.

29. Asenapine
Asenapine,beingdevelopedfortreatingschizophreniaand
bipolardisorder,isinthepreregistrationphasewiththeFDA.
Itshowshighaffinityforandbehavesasapotentantagonistat
serotoninreceptors(5-HT1A,5-HT1B,5-HT2A,HT2B,5-HT2C,
5-HT5,5-HT6,and5-HT7),adrenoceptors(α1,α2A,α2B,and
α2C),DAreceptors(D1,D2,D3,andD4),andhistamine
receptors(H1andH2).
Itdisplays5-HT1Apartialagonisticactivitywithregion-specific
anddose-dependenteffectsonionotropicglutamatergic
receptorsubtypesintheratforebrain,predictingAPactivitywith
lowmotorsideeffectpotentialandapossiblepro-cognitive
effect.

30. Ina6-weekPhaseIIRCT,asenapine5mgb.i.d.wasassessed
againstplacebob.i.d.andrisperidone3mgb.i.d.in174
patientswithacuteschizophrenia.
MeanimprovementsonPositiveandNegativeSymptomScale
(PANSS)total,positive,negative,andgeneralpsychopathology
subscalescoresandClinicalGlobalImpression---Severity
(CGI-S)wereallsignificantlygreaterwithasenapinethanwith
placebo(P<0.005,P=0.01,P=0.01,P<0.005and,P<
0.01,respectively).
Adverseevent(AE)ratesweresimilarforasenapineand
placebo,whilesubstantialweightgainandprolactinelevation
wereobservedwithrisperidone.

31. Inanother6-weekRCT,450subjectswithacuteschizophrenia
werecomparedusingfixeddosesofasenapine5or10mg
b.i.d.orplaceboorhaloperidol4mgb.i.d.
Atendpoint,asenapine5mgb.i.d,butnot10mgb.i.d.,was
significantlybetterthanplaceboforPANSStotalscore
reduction.
Akathisiawastheonlydose-relatedAEs.
ThemotorAEswerehigherwithasenapine(15and18%at5
and10mgtwicedaily,respectively)comparedwithplacebo
(10%),butlowerthanthatwithhaloperidol(34%).

32. Along-termstudyonsafetyassessed1219patientswithacute
exacerbationofschizophreniaorschizoaffectivedisorderon
olanzapineandasenapine.
AEsinbothtreatmentgroupswereinsomnia,worseningof
psychoticsymptoms,weightgain,anddepression.
BothtreatmentgroupsshowedimprovementinmotorAEs
althoughEPS-relatedAEsweremorecommonwithasenapine
(18%)thanwitholanzapine(8%).Bothtreatmentshadminimal
effectsonprolactinlevels.

33. Iloperidone
Iloperidoneisanorallywell-absorbed5-HT2A/D2antagonist
targetingschizophreniaandbipolardisorderthathascompleted
PhaseIIItrialsindosesranging4-24mg/day.PhaseIIandIII
clinicaltrialsindicateitsabilitytoreducepositiveandnegative
symptomsofschizophrenia,comparabletohaloperidoland
risperidone.
Likeziprasidoneandaripiprazole,ithasminimaleffectson
weightandalowincidenceofdiabetesandEPS.Development
ofalong-actingdepotformulationmayimprovecompliance,in
additiontoagenerallylowAEprofile.
Thetwobiggestfactorssupposedtopredictitsclinicalsuccess
are:QTcintervalchangesandanynoveleffectithasin
personalizedmedicineinregardtoresponsetospecific
genotypesinschizophrenicpatients.

34. Norclozapine
Clozapineundergoesextensivehepaticmetabolismleadingtotwo
majormetabolites,norclozapine(N-desmethylclozapine-NDMC)and
clozapineN-oxide.NorclozapinehasauniqueAPefficacyinvitroas
a5-HT2antagonistandasapartialagonisttodopamineD2and
muscarinicreceptors.
Despitehighexpectations,resultsfromarecent6-week,multicentre,
placebo-controlled,phaseII,DBTofnorclozapineweredisappointing.
Thetwodosesused(100or200mgtwicedaily)didnotdemonstrate
efficacyasmeasuredbyPANSStotalscoreandPANSSsubscales
andCGIscale,respectively.
MostcommonAEsweredose-relatedhypersalivation,tachycardia,
anddyspepsia.Also,importantlynosignificantdecreasesin
neutrophilcountswereobserved

35. Other Targets:
•Anti histaminics
•Anti viral
•SERM
•Minocycline
•Omega 3 fatty acids
•Cannabinoid agents
•COX-2 inhibitors
•Neuropeptides
•Sigma receptor antagonist
•Alpha 2 agonists
•GABA-A receptor modulation

36. Thefirst,double-blind,placebo-controlled,parallel-group,randomizedtrial
inwhichthirtysubjectswithschizophreniawererandomizedtohaveeither
famotidine(100mgtwicedaily,n=16)orplacebo(n=14)orally,addedto
theirnormaltreatmentregimenfor4weeks.
.Inthefamotidinegroup,theSANSscorewasreducedby5.3(SD,13.1)
points,whereasintheplacebogrouptheSANSscorewasvirtually
unchanged(meanchange,+0.2[SD,9.5])-nostatisticalsignificance
ThePANSSTotalscoreandtheGeneralsubscoreaswellastheCGI
showedsignificantly(P<0.05)greaterchangeinthefamotidinegroupthanin
theplacebogroup.
Ref Article: A Randomized Clinical Trial of Histamine 2 Receptor Antagonism in
Treatment-Resistant Schizophrenia
(J ClinPsychopharmacol.2013 Aug;33(4):472-478.)

37. Inadouble-blindplacebo-controlleddesign,theyrandomized
24HSV1-seropositiveschizophreniasubjectstoreceiveeither
valacyclovir(n=12)orplacebo(n=12)for18weeksin
additiontostabledosesofAntiPsychotics.(Valacyclovirdose
wasstabilizedat1.5gtwicedailyorally)
Valacyclovirgroupimprovedinverbalmemory,working
memory,andvisualobjectlearningcomparedwithplacebo
group.
Supplementalvalacyclovirmayalleviateimpairmentsin
cognitivedomainsthatareoftenobservedinschizophreniabut
notpsychoticsymptomsinthoseexposedtoHSV1.
Antiherpes virus-specific treatment and cognition in schizophrenia: a test-of-
concept randomized double-blind placebo-controlled trial.
(Schizophr Bull2013 Jul;39(4):857-66 Epub 2012 Mar 23.)

38. PILOTING THE EFFECTIVE THERAPEUTIC DOSE OF
ADJUNCTIVE SELECTIVE ESTROGEN RECEPTOR
MODULATOR TREATMENT IN POSTMENOPAUSAL
WOMEN WITH SCHIZOPHRENIA
Toprovideanindicationofthepotentialtherapeuticdosefor
raloxifenehydrochlorideinpostmenopausalwomenwith
schizophrenia,thisstudypoolsdatafromanongoing
randomizedcontrolledtrialofadjunctive120mg/dayoral
raloxifenehydrochloride(n=13)versusoralplacebo(n=13),
withdatafromapreviouspilotstudyadministering60mg/day
raloxifenehydrochloride(n=9).
Analysisofvariancefoundsignificantinteractioneffectsfortotal
(p=.01)andgeneral(p=.02)PositiveandNegativeSyndrome
Scale(PANSS)symptomatology.
Psychoneuroendocrinology Volume 35, Issue 8, September 2010, 1142–1147
Jayashri Kulkarni,Caroline Gurvich

39. Participantsrandomizedtoreceive120mg/dayraloxifene
hydrochlorideexperiencedasignificantlymorerapidrecovery
oftotalandgeneralpsychoticsymptomscomparedtoboth
60mg/dayraloxifenehydrochlorideandplacebo.
Thedemonstratedbenefitofadjunctivetreatmentwith
120mg/dayraloxifenehydrochlorideofferssupportforthe
potentialroleofthisselectiveestrogenreceptormodulatorin
treatingpostmenopausalwomenwithschizophrenia.
JayashriKulkarni,CarolineGurvich
PsychoneuroendocrinologyVolume35,Issue8,September2010,1142–1147

40. Minocyclineisasecond-generationtetracyclinethathasa
beneficialeffectinvariousneurologicdisorders.Recentfindings
inanimalmodelsandhumancasereportssuggestitspotential
forthetreatmentofschizophrenia.
MECHANISM:theeffectofminocyclineontheglutamatergic
system,throughinhibitionofnitricoxidesynthase(beinga
caspaseinhibitor,decreasesinduciblenitricoxidesynthase)
andblockingofnitricoxide-inducedneurotoxicity
Itshowedabeneficialeffectonnegativesymptomsand
generaloutcome(evidentinSANS,ClinicalGlobalImpressions
scale).

41. MinocyclineasAdjunctiveTherapyforSchizophrenia:AnOpen-LabelStudyMiyaokaTsuyoshi
ClinicalNeuropharmacologySept/Oct2008-Volume31-Issue5-287-292
Authors:LevkovitzY,MendlovichS
JClinPsychiatry.2010Feb;71(2):138-49.
Asimilarpatternwasfoundforcognitivefunctioning,mainlyin
executivefunctions(workingmemory,cognitiveshifting,and
cognitiveplanning).
Minocyclinewaswelltolerated,withfewadverseevents.
Minocyclinetreatmentwasassociatedwithimprovementin
negativesymptomsandexecutivefunctioning,bothrelatedto
frontal-lobeactivity.Overall,thefindingssupportthebeneficial
effectofminocyclineadd-ontherapyinearly-phase
schizophrenia

42. Omega-3 fatty acids
Decreasedomega-3fattyacidlevelshavebeenreportedinpatientswith
depression,schizophrenia,andAlzheimer'sdisease.Recently,
eicosapentaenoicacid(EPA)hasbeenusedtotreatseveralpsychiatricand
neurodegenerativediseasesduetoitsanti-inflammatoryand
neuroprotectiveeffects.
AcasestudyshowedEPAtreatmentat2g/daytoimproveschizophrenia
intermsofSchedulefortheAssessmentofPositiveSymptoms(SAPS)
decreasedfrom46to7andtheSchedulefortheAssessmentofNegative
Symptoms(SANS)16to3respectivelybymonths1and2.
Peetetal.evaluatedtheefficacyofomega-3fattyacidsintwostudiesusing
thePANSS.TheEPAgroupshowedgreaterimprovementcomparedto
placeboonthePANSS-positivesymptomscore.
OnlyminimalAEssuchasfishyeructationorbreath,andgastrointestinal
effectssuchasdiarrheawerereportedwithEPAtreatment.

43. Cannabinoid agents
Theendogenouscannabinoidsystem,thatincludestheGprotein
coupledreceptorsCB1andCB2,hasbeenimplicatedinthe
etiopathogenesisofschizophrenia.Increasedcerebrospinalfluid
levelsofanandamide(anendogenouscannabinoid)foundinpatients
withschizophrenia.
ThecannabinoidCB1genealtersthebehavioraleffectsoftheNMDA
antagonistphencyclidine.Rimonabant,aselectivecannabinoidCB1
receptorantagonist,reducesstimulant-inducedhyperactivityinrats.
SR14176andAM251,whicharecannabinoidCB1receptor
antagonists,reversedeficitsofsensorimotorgatinginducedby
phencyclidinebutwerenotbeneficialagainstplacebo.
AVE1625,aselectivecannabinoidCB1antagonist,hasgoneonto
PhaseIIclinicaltrialasanadd-ontoSecondGeneration
Antipsychotics

44. COX-2 inhibitors
COX-2isknowntoinfluencethebalancebetweentypes1
and2immuneresponses.
CelecoxibisanNSAIDwithhighlyselectiveCOX-2
inhibitorproperty.An8-week,DBPCtrialinvestigating
celecoxibasanadd-ontorisperidoneinthetreatmentof
chronicschizophreniademonstratedsignificantsuperiority
ofthecombinationoverrisperidoneinthetreatmentof
positiveandgeneralpsychopathologysymptoms.
ThisstudyhasbeenthroughaPhaseIIRCT.

45. Non-Pharmacological approaches:
rTMS
TRANSCRANIAL DIRECT -CURRENT
STIMULATION (TDCS)
Avatar therapy
Newer approaches in psychotherapy

46. rTMS
Ina4-weekrandomizeddouble-blindsham-controlledpilotstudydesign,
27medicatedschizophreniapatientsweretestedbymakingthemperform
theverbalworkingmemoryn-backtaskbeforeandafterrTMS(magnetic
resonanceimagetargetedbilaterallysequentiallytoleftandrightdorsolateral
prefrontalcortex750pulses/sideat20Hzfor20treatments.)
TherTMSsignificantlyimprovedn-backaccuracyfortargetscompared
withplacebosham(Cohen’sd=.92).Theimprovementinn-backaccuracy
wasalsofoundtobeatalevelcomparabletohealthysubjects
ThesepilotdatasuggestthatbilateralrTMSmightbeanovel,efficacious,
andsafetreatmentforworkingmemorydeficitsinpatientswith
schizophrenia.
Biological Psychiatry vol73,issue6:510-17

47. Am J Psychiatry.2012 Jul 1;169(7):719-24.
TRANSCRANIAL DIRECT -CURRENT STIMULATION
(tDCS) IN SCHIZOPHRENIA.
Thepossibilitythatapplicationoftranscranialdirect-currentstimulation
(tDCS)withinhibitorystimulationoverthelefttemporo-parietalcortexand
excitatorystimulationovertheleftdorsolateralprefrontalcortexcouldaffect
hallucinationsandnegativesymptoms,respectively.
AuditoryverbalhallucinationswererobustlyreducedbytDCSrelativeto
shamstimulation,withameandiminutionof31%(SD=14;d=1.58,95%
CI=0.76–2.40).Thebeneficialeffectonhallucinationslastedforupto3months.
TheauthorsalsoobservedanameliorationwithtDCSofothersymptomsas
measuredbythePositiveandNegativeSyndromeScale(d=0.98,95%
CI=0.22–1.73),especiallyforthenegativeandpositivedimensions.Noeffect
wasobservedonthedimensionsofdisorganizationorgrandiosity/excitement
theresultsshowpromisefortreatingrefractoryauditoryverbalhallucinations
andotherselectedmanifestationsofschizophrenia.
Brunelin J,Mondino M,Gassab L

48. AreviewofpublishedliteratureontheuseofmaintenanceECT(M-
ECT)wasconducted.Itfocusedprimarilyontrialspublishedsince1997,
meetingthefollowingadditionalcriteria:randomizedcontrolledtrialor
cohortstudywithacomparison(matchedgrouporbeforeandafter),
andatleast10patientsreceivingM-/continuationECT.
MaintenanceECTisanunderusedtreatmentoptionthatcan
substantiallyreducerisksofrelapseinpatientswithmajordepressive
disorderandlikelyinbipolardisorderandschizophrenia.
Thereisnowagrowingbodyofevidencetosuggestthatforthose
whohavenotrespondedwelltomedicationsbuthaveresponded
toECT,M-ECTmustbepresentedasanoptiontothepatientandthe
familyforconsideration.
JECT.2012 Mar;28(1):39-47.

49. Thecomputer-basedsystemcouldprovidequickandeffective
therapythatisfarmoresuccessfulthancurrentpharmaceutical
treatments,helpingtoreducethefrequencyandseverityof
episodesofschizophrenia
Inanearlypilotofthisapproachinvolving16patientsandupto
seven30-minutesessionsoftherapy,almostallofthepatients
reportedareductioninthefrequencyandseverityofthevoices
thattheyhear.
Threeofthepatientsstoppedhearingvoicescompletelyafter
experiencingthemfor16,13and3.5years.

50. PSYCHOTHERAPY –NEWER APPROACHES
Preliminarystudypresentsanovelapproachofsocialskills
training(SST)linkthetreatmenttosevenspecifictarget
behaviours:socialperception,socialinformationprocessing,
respondingandsendingskills,affiliativeskills,interactional
skills,andbehaviourgovernedbysocialnorms.
ResultsofthissupporttheefficacyofthebriefSSTfor
outpatientswithschizophreniaandshowtheneedtoimplement
empiricallysupportedinterventionsinmentalhealthservicesto
enhancepatients'socialfunctioningandqualityoflife.
A brief cognitive–behavioural social skills training for stabilised outpatients with
schizophrenia: A preliminary study
Mar Rus-Calafell et. all
Schizophrenia Research 143 (2013) 327–336

51. OTHER APPROACHES COMING UP IN
SCHIZOPHRENIA PSYCHOTHERAPY :
CBTINSCHIZOPHRENIA
Recentdevelopmentsincognitivetreatmentsbrandedasthird-
waveapproachesillustratetheadvantageofnotonlytargeting
thecontentofthoughtsandbeliefsbutalsodeveloping
alternativemethodsofchangingthewayinwhichpeoplerelate
totheirthoughtsandfeelings.
WHATBEYONDCBT!!!
Mindfulness,metacognitiveapproaches,compassionatemind
training,andmethodoflevelsarepostulatedasusefuladjuncts
forCBTwithpsychoticpatients.

52. Conclusions
•Thenewmoleculeslistisincreasingdaybyday,buthow
fartheywillproveouttobeuseful,wearestillnotverysure.
•Onethingveryclearthatnowasweareknowingmoreand
moreaboutneurobiologyandneurophysiologyof
schizophrenia,therearemoreexpecteddrugstargeting
specificareasinnearfuture.
•Thedayisnottoofarwhenwemaysoondeclaredisease
modifyingagentsinschizophreniamanagementandmove
aheadofsyndromicandsymptomaticmanagement.

53. Refrences:
1.Lewis S, Escalona R, Keith SJ. Phenomology of Schizophrenia. In: Sadock
BJ, Sadock VA, Ruiz P, editors. Kaplan & Sadock’s Comprehensive
Textbook of Psychiatry
2.Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA.
Recent advances in the development of novel pharmacological agents
for the treatment of cognitive impairments in schizophrenia. Schizophr
Bull 2007;33:1120-30.
3.Newer molecules in the treatment of schizophrenia: A clinical update :
Abhishek Ghosh, Kaustav Chakraborty, Surendra Kumar Mattoo
4.CNS & Neurological Disorders -Drug Targets, 2007, 6, Novel Targets
for Drugs in Schizophrenia J.M. Stone* and L.S. Pilowsky