New atypical antipsychotic medications

\ PERGAMON

Journal of Psychiatric Research 21 "0887# 104Ð117

New atypical antipsychotic medications Michael D[ Jibson\ Rajiv Tandon Schizophrenia Program\ Department of Psychiatry\ University of Michigan School of Medicine\ Ann Arbor\ MI 37098!9019\ U[S[A[

Abstract Conventional antipsychotics were the _rst treatments e}ective in controlling psychotic symptomatology and revolutionized management of psychotic disorders when introduced in the 0849|s[ The use of these agents has\ however\ been marked by several shortcomings\ including limited e.cacy in treating the negative and cognitive symptoms of schizophrenia\ and by signi_cant extrapyramidal and other side!e}ects[ There appears to be justi_able excitement about the introduction of the newer atypical antipsychotics\ which may represent the second pharmacological revolution in the treatment of psychotic disorders[ But how are these agents really di}erent from their neuroleptic predecessors< How is their pharmacological pro_le di}erent< Are there clear di}erences in e.cacy< How do side!e}ect pro_les di}er< These issues are reviewed in this manuscript[ Atypical agents are phar! macologically distinct from their neuroleptic predecessors[ Their primary advantage is their superior side e}ect pro_les\ particularly with regard to EPS[ The implications of EPS reduction touch virtually every domain of pathology in schizophrenia\ including short! and long!term movement disorders\ negative symptoms\ noncompliance\ relapse rate\ cognitive dysfunction\ and dysphoria[ It should be emphasized that while atypical antipsychotics share some clinical attributes\ there are substantial clinical di}erences between them as well[ These di}erences are reviewed in this article as well[ The drugs| unique pro_les with regard to other side e}ects may make it possible to tailor treatment more individually to patients[ Further re_nement of our understanding of the clinical utility of these drugs awaits their widespread use in mainstream clinical settings[ Controlled studies comparing them to one another should be of particular interest[ Þ 0887 Elsevier Science Ltd[ All rights reserved[

0[[ Introduction The past few years have witnessed an unprecedented development of new antipsychotic medications[ As with their neuroleptic predecessors\ these medications are e}ective in reducing the delusional thinking\ hallucin! atory experiences\ and thought disorganization which are the hallmarks of psychosis[ Compared to older medi! cations\ however\ these agents are chemically and phar! macologically unique\ have fewer side e}ects\ and hold the promise of greater clinical e.cacy[ The older\ or conventional\ antipsychotics all consistently caused extra! pyramidal side!e}ects\ leading to their being referred to as neuroleptics "{{seizing the neuron||#[ The introduction of clozapine and other atypical antipsychotics has dem! onstrated that it is possible to have antipsychotic e.cacy without these neurologic adverse e}ects^ in fact these agents are called {atypical| because they separate the therapeutic antipsychotic e}ect from the extrapyramidal side!e}ect[ Conventional antipsychotics or neuroleptics have been  Corresponding author[ 9911!2845:87:,08[99 Þ 0887 Elsevier Science Ltd[ All rights reserved[ PII] S 9 9 1 1 ! 2 8 4 5 " 8 7 # 9 9 9 1 2 ! 4 7

exceedingly useful in the treatment of schizophrenia and other psychotic disorders[ Although they vary widely in potency and chemical composition\ they share numerous signi_cant features "Tandon\ 0887a#[ Their primary phar! macologic activity is blockade of the dopamine D1 recep! tor[ Among their bene_ts are control of active psychotic symptoms\ reduction of assaultive behavior\ man! agement of severe agitation\ and decrease in risk of psy! chotic relapse in patients su}ering from schizophrenia and other psychotic disorders during maintenance treat! ment[ All conventional antipsychotics appear to be equ! ally e}ective in accomplishing these objectives[ Neuroleptics also have inherent limitations of e.cacy[ They leave up to 29) of psychotic patients without sig! ni_cant clinical improvement "Cole et al[\ 0853#[ Even among responding patients\ their spectrum of therapeutic activity is somewhat narrow "Tandon et al[\ 0887#] "i# fairly e}ective in treating positive symptoms^ "ii# limited e}ectiveness in treating the negative symptoms of schizo! phrenia "Jibson and Tandon\ 0884#^ and "iii# minimally e}ective or ine}ective in treating the cognitive de_cits associated with schizophrenia "Bilder\ 0886#[ In fact\ neu! roleptics simultaneously ameliorate and worsen di}erent components of negative and cognitive symptoms\ con!

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tributing to their relative lack of net e.cacy on these symptom dimensions[ Their side e}ects also limit patient compliance\ worsening long!term relapse rates[ Even among patients who both respond to and comply with treatment\ there is a 19) annual relapse rate "Gilbert et al[\ 0884#[ Neuroleptics cause prominent and pervasive side e}ects[ These include signi_cant anticholinergic e}ects\ such as constipation\ dry mouth\ blurred vision\ and uri! nary hesitancy[ Neuroleptics are commonly associated with erectile and orgasmic dysfunction "Milner et al[\ 0887#[ These medications cause persistent elevations in serum prolactin\ which can result in menstrual and sexual side!e}ects[ They cause short!term movement disorders\ including bradykinesia\ cogwheel rigidity\ sti}ness\ aki! nesia\ and akathisia "extrapyramidal side e}ects * EPS#\ and have the potential for long!term side e}ects such as tardive dyskinesia[ The importance of EPS in the course of schizophrenia should not be underestimated[ Acute dystonic reactions are common during neuroleptic treatment\ particularly with initial doses of the medication\ and patients are predictably resistant to continuing the medication fol! lowing such an event[ Dystonic reactions can also occur later in treatment\ and this too can result in poor patient compliance[ Akathisia is common\ often goes unrecog! nized by patients and physicians\ and is likewise associ! ated with premature treatment termination "Van Putten et al[\ 0889#[ Among patients who continue to take the medication\ bradykinesia and rigidity impair social and occupation function\ adding to the likelihood of deterio! ration in these areas[ Early expression of EPS sig! ni_cantly increases the likelihood of subsequently developing tardive dyskinesia "Chatterjee et al[\ 0884#^ tardive dyskinesia adds to the stigma associated with the illness\ is dis_guring\ and may hasten the patient|s decline in social function[ Bradykinesia may contribute to the reduced facial expression\ loss of expressive gestures\ and ~attening of vocal in~ection which are among the nega! tive symptoms of the illness[ This contribution of {sec! ondary| negative symptoms may o}set the bene_ts of these medications in this regard "Jibson and Tandon\ 0884^ Miller and Tandon\ 0887#[ In addition to their motor symptoms\ neuroleptics have been associated with cognitive dysfunction\ attributable directly to EPS\ to their inherent anticholinergic properties\ and to the adjunctive use of other anticholinergic agents "Bilder\ 0886#[ It is not surprising that signi_cant EPS may be correlated with dysphoria[ The {costs| of EPS are thus not limited to parkinsonian motor manifestations\ but extend to increased negative and cognitive symptoms\ more dysphoria\ higher likelihood of noncompliance\ and greater risk of developing tardive dyskinesia[ Despite these limitations\ the bene_ts of neuroleptic medications are substantial\ and their use in the treatment of psychotic disorders has been of enormous clinical sig!

ni_cance[ It is reasonable\ however\ to seek medications with greater bene_t and reduced risk[ Assessment of the new generation of antipsychotic medications must include consideration of each of these issues[ Potential bene_ts to be sought from new medications include] "i# e}ectiveness in a greater proportion of patients\ par! ticularly those refractory to conventional medications^ "ii# broader spectrum of e.cacy\ with increased e}ec! tiveness in treating negative and cognitive symptoms^ "iii# reduced risk or absence of EPS^ "iv# minimal risk of tardive dyskinesia^ and "v# absence of prolactin elevation and related side!e}ects[ The broadest de_nitions of {atypical| antipsychotic include elements of each of these factors[ More narrowly\ atypical agents are de_ned sim! ply as those associated with minimal risk of EPS[ The approval in 0878 of clozapine for use in the United States made the possibility of atypical antipsychotic treat! ment a reality[ Clozapine "ClozarilTM or LeponexTM# is more e}ective than its predecessors in treating both posi! tive and negative symptoms of schizophrenia particularly in those patients refractory to neuroleptic treatment\ and does so without the risk of movement disorders "Kane et al[\ 0877#[ Although the utility of clozapine has been limited by its potential for agranulocytosis and conse! quent need for frequent blood count monitoring\ it remains the standard against which all newer anti! psychotics are compared[ The introduction of risperidone "RisperdalTM# in 0883 marked another step toward the widespread use of atypical antipsychotic medications[ The absence of agranulocytosis as a major clinical issue made it possible to use the drug in routine clinical settings\ while the reduction in EPS made the medication more acceptable to a large number of patients and clinicians than conventional neuroleptics[ Since then\ the atypical antipsychotics olanzapine "ZyprexaTM# and quetiapine "SeroquelTM# have been introduced\ and two additional agents\ sertindole "SerlectTM# and ziprasidone "ZeldoxTM# have completed clinical trials[ Although the manu! facturer|s application for approval of sertindole in the USA has been withdrawn\ the medication is available in Europe\ and it may be reconsidered for release in the USA in the future[ It is anticipated that ziprasidone will soon be available in the USA for clinical use[ This review will examine the pharmacology\ clinical e.cacy\ and side! e}ect pro_les of the atypical antipsychotics\ and will dis! cuss the implications of each of these areas for the treat! ment of schizophrenia[

1[ Pharmacology and pharmacokinetics The pharmacologic pro_les of the atypical anti! psychotics are shown in Fig[ 0[ Receptor pro_les are usually presented in terms of the binding a.nities of the particular compound to various neurotransmitter recep! tors[ In!vitro binding studies\ in!vivo binding studies\ and

M[D[ Jibson\ R[ Tandon : Journal of Psychiatric Research 21 "0887# 104Ð117

106

Fig[ 0[ Receptor pro_les of typical and atypical antipsychotic agents[ Typical serum concentrations of the drugs are shown as shaded areas on the graphs for reference[ Data from Beasley et al[ "0885a\ 0885b#\ Saller and Salama "0882#\ Seeger et al[ "0884#\ Baldessarini and Frankenburg "0880#\ Thyrum et al[ "0885#\ Dahl "0875#\ Heykants et al[ "0883#[

in!vivo behavioral assays can all provide a comparative measure of the activity of the compounds at the di}erent receptors[ While there is a fairly good correspondence between these di}erent estimates of the neuro! pharmacological pro_le\ discrepancies are evident as well "Arnt and Skarsfeldt\ 0887#[ Furthermore\ while anti! psychotics are generally considered to be antagonists at all the sites for which they show high a.nities\ clozapine acts as a partial agonist at some muscarinic receptors "Zeng et al[\ 0886^ Tandon\ 0887b# and ziprasidone is a weak agonist at the 4HT0A receptor "Tandon et al[\ 0886#[ With these caveats\ it is evident that there are some simi! larities\ and also pronounced di}erences\ in the phar! macological pro_les of the various atypical anti!

psychotics[ These agents retain the {neuroleptic| property of dopamine D1 antagonism\ albeit to di}ering extents\ with risperidone and olanzapine being potent antagonists and clozapine being a relatively weak antagonist[ The atypical antipsychotics possess the common additional property of potent 4HT1A antagonism[ On the other hand\ these agents exhibit signi_cant di}erences in activity at various muscarinic cholinergic\ histaminergic\ noradrenergic and other serotonergic receptors[ It has been suggested that the group of atypical anti! psychotics be divided into a subgroup of {selective| sero! tonin!dopamine antagonists "e[g[\ risperidone\ sertindole\ ziprasidone# and a subgroup of multiple receptor antag! onists "e[g[\ clozapine\ olanzapine\ quetiapine# "Gerlach

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and Peacock\ 0884^ Busatto and Kerwin\ 0886#[ This classi_cation system is inadequately descriptive and inac! curate as the serotonin!dopamine antagonists are not completely selective\ there is considerable overlap across subgroups\ and there are potentially clinically signi_cant pharmacological di}erences between agents within each subgroup[ The probable clinical signi_cance of blockade of various receptors is shown in Table 0 "Richelson\ 0874#[ From a therapeutic standpoint\ dopamine D1 receptor blockade appears to be necessary for an anti! psychotic e}ect^ currently\ there is no e}ective anti! psychotic that is devoid of this property "Tandon\ 0887a#[ 4HT1A antagonism appears to confer the lesser propensity for EPS that distinguishes atypical from typical anti! psychotics "Meltzer et al[\ 0878#^ possible bene_ts of other pharmacological activities are speculative "Tandon and Kane\ 0882#[ The receptor pro_les of the atypical agents are consistent with the observation that each of these drugs has a distinct set of side e}ects[ The pharmacokinetics of the atypical antipsychotics are summarized in Table 1 along with an assessment of their relative antipsychotic potency in terms of chlor! promazine equivalents "that dose of the atypical anti! psychotic whose activity is approximately equal to that of 099 mg of chlorpromazine#[ The biological half!life of the various agents is depicted in Fig[ 1[ The major advantage of a longer elimination half!time is reduced frequency of administration\ with its possible impli! cations for patient compliance[ It should be noted\ however\ that receptor occupancy may be of signi_cantly longer duration than the elimination half!time would imply\ making less frequent dosing of short half!life drugs an option to be explored[ At this time\ clozapine\ ris! peridone\ and olanzapine "sertindole as well\ when avail! able# are approved for once!a!day dosing whereas queti!

apine "and likely ziprasidone\ when available# is approved for twice!a!day dosing[ The time from administration of the drug to maximum level "Tmax# relates to the rapidity of development and likelihood of persistence of side! e}ects such as hypotension and sedation[ The atypical antipsychotics are eliminated predominantly by hepatic metabolism\ utilizing the P!349 cytochrome system "Pre! skorn and Magnus\ 0883#^ the speci_c P!349 enzyme uti! lized by each agent is noted[ Clozapine produces signi_cant blockade at 4! hydroxytryptamine "4!HT#1A\ a0 and a1 adrenergic\ mus! carinic\ and histamine H0 receptors[ Blockade of dopa! mine D0 and D1 receptors is somewhat lower[ The stan! dard dose range for clozapine is 299Ð599 mg:day\ usually given in two doses to minimize side e}ects[ Despite an elimination half!time of 03 h\ there is no evidence that clinical e.cacy is compromised by once!daily dosing[ Lower doses may be e}ective in some patients\ including the elderly[ Doses up to 899 mg:day may be used in treatment!refractory patients[ The drug is 84) protein! bound[ Bioavailability is not a}ected by food "Choc et al[\ 0889#[ Clozapine is eliminated principally by the hep! atic P!349 0A1 and 2A3 cytochrome enzymes^ 0A1 inducers such as smoking can reduce its half!life\ while 0A1 inhibitors such as ~uvoxamine can increase its dur! ation of action[ Risperidone is primarily active in blockade of the 4! HT1A receptor\ with lower a.nity for a0 adrenergic\ dopa! mine D1\ histamine H0\ and a1 adrenergic sites "Janssen et al[\ 0877^ Leysen et al[\ 0877#[ Its pharmacologic pro_le is markedly di}erent from both conventional anti! psychotics and clozapine[ As expected from the 19!h half! life of risperidone and its active metabolite\ 8!hydroxy! risperidone "Huang et al[\ 0882#\ once!daily dosing is as e}ective as multiple doses[ The dose range of 2Ð5 mg:day

Table 0 Clinical implications of blockade of various receptors by antipsychotics Receptor

Possible bene_ts

Possible side e}ects

Dopamine D1

Antipsychotic e}ect\ E.cacy on positive symptoms

Serotonin 4HT1A Serotonin 4HT1C Histamine H0

Reduced EPS Not known Not known

Muscarinic

Reduced EPS

a0!Adrenergic

Not known

a1!Adrenergic

Not known

Extrapyramidal side e}ects "EPS#] dystonia\ parkinsonism\ akathisia\ tardive dyskinesia\ rabbit syndrome[ Endocrine changes] prolactin elevation\ galactorrhea\ gynecomastia\ menstrual changes\ sexual dysfunction Sexual disturbances Weight gain Sedation\ increased appetite\ weight gain\ hypotension Blurred vision\ dry mouth\ constipation\ urinary retention\ sinus tachycardia\ memory dysfunction Postural hypotension\ dizziness\ re~ex tachycardia Drug interactions

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M[D[ Jibson\ R[ Tandon : Journal of Psychiatric Research 21 "0887# 104Ð117 Table 1 Pharmacokinetics and clinical potency of atypical antipsychotic medications Typical neuroleptics

Clozapine "ClozarilTM#

Risperidone "RisperdaITM#

Olanzapine "ZyprexaTM#

Quetiapine "SeroquelTM#

Drug class

Various

Benzioxazol

Potencya Time to peak plasma concentration "hours# Protein binding ")# Active metabolites Route of metabolism

1Ð099 Various

Dibenzo! diazepine 49 2

0 0[4

Thienobenzodia! zepine 3[9 4

Dibenzothiazepine Imidazidoline Benzisothiazolyl piperazine 79 3 19 0[4 09 3

64Ð88 Variable CYP0A1\ CPY1D5 Various

81!84 No CYP0A1\ CYP2A3 09Ð099

89 Yes CYP1D5

82 No CYP0A1\ CYP1D5

72 No CYP2A3

5Ð13

19Ð69

3Ð09

Elimination half!life "hours# a

Sertindole "SerlectTM#

84Ð86 No CYP1D5\ CYP2A3 19Ð199

Ziprasidone "ZeldoxTM#

87Ð88 No CYP2A3 2Ð090

Mg of drug 099 mg chlorpromazine equivalents[

appears to be optimal for most patients[ Lower doses may be e}ective in selected patients\ including the elderly\ for whom the recent introduction of a 0 mg:ml oral solution may prove advantageous[ Although several studies have been conducted at doses up to 05 mg:day\ the side e}ect pro_le of the medication is signi_cantly worse at doses greater than 5Ð7 mg:day\ making these higher doses less well tolerated "Marder and Meibach\ 0883#[ Bioavailability of both tablet and solution is about 54) "Gutierrez et al[\ 0886#[ Food and smoking do not modify its pharmacokinetics[ Olanzapine has high a.nity for 4!HT1A\ muscarinic M0\ histamine H0\ dopamine D0\ and a0 adrenergic recep! tors\ somewhat lower blockade at dopamine D1 sites\ and minimal a1 adrenergic antagonism "Bymaster et al[\ 0885#[

A dose range of 09Ð19 mg:day appears to be optimal for most patients "Tran et al[\ 0886a#[ For patients in whom a lower dose might be preferable\ a 1[4 mg tablet has recently been introduced[ Once!a!day dosing appears to be as e}ective and well tolerated as divided daily doses\ consistent with the drug|s 29 h elimination half!life "Kas! sahun et al[\ 0886#[ Olanzapine is readily oxidized in air when its protective coating is removed\ which occurs when the tablets are cut or crushed[ In these cases\ the portion of the medication not consumed immediately must be discarded[ Olanzapine shows minimal capacity to inhibit cytochrome P349 isoenzymes "Ring et al[\ 0885#[ It is eliminated principally by the hepatic P!349 0A1 and 2A3 cytochrome enzymes[ Consequently 0A1 inducers such as smoking can reduce its half!life necessitating

Fig[ 1[ Pharmacokinetics of atypical antipsychotic medications] elimination half!times[

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higher doses^ since there is a high prevalence of cigarette smoking among patients su}ering from schizophrenia\ the modal dose of olanzapine used to treat schizophrenic patients in the clinic "04Ð19 mg per day# is substantially higher than that indicated by clinical trials "09 mg:day#[ Quetlapine|s pharmacologic pro_le includes somewhat greater a.nity for 4!HT1A than dopamine D1 receptors\ high a.nity for a0 adrenergic and histamine H0 receptors\ lower a.nity for a1 adrenergic and dopamine D0 recep! tors\ and no muscarinic M0 activity "Saller and Salama\ 0882#[ Quetiapine has been shown to act selectively on the limbic system[ The steady!state half!life of the drug is relatively short\ 5[8 h\ and clinical studies have used two! or three!times!daily dosing schedules "Borison et al[\ 0885^ Small et al[\ 0886#[ Twice!a!day dosing appears to be adequate[ Its optimal dose range is 199Ð649 mg per day\ although lower doses may be e}ective in older pati! ents[ A 14 mg tablet is available to facilitate dose titration[ Quetiapine is metabolized predominantly by the 2A3 cytochrome P!349 enzyme\ and therefore its blood levels are not modi_ed by smoking[ Sertindole|s primary activity is blockade of 4!HT1A receptors\ with moderate a.nity for dopamine D1 and a0 adrenergic receptors\ low a.nity at dopamine D0 sites\ and minimal activity at a1 adrenergic\ histamine H0\ and muscarinic M0 receptors "Hyttel et al[\ 0881#[ Its dopa! mine D1 blockade appears to be selective for mesolimbic neurons "Skarsfeldt and Perregaard\ 0889#[ The serum half!life is approximately 2 days[ Sertindole is 88) pro! tein!bound[ Its bioavailability is close to 099) with or without food "Wong et al[\ 0886a#[ Its pharmacokinetics are unchanged by renal impairment "Wong et al[\ 0886b# and not modi_ed by smoking[ Ziprasidone|s primary pharmacologic activity is block! ade of 4!HT1A receptors\ with moderate a.nity for dopa! mine D1\ a0 adrenergic\ and histamine H0 sites[ Activity at dopamine D0\ muscarinic M0\ and a1 adrenergic recep! tors is low[ It is unique in being a potent 4!HT0A receptor agonist and in having signi_cant norepinephrine reup! take inhibition "Seeger et al[\ 0884#[ The serum half!life is 4Ð09 h\ without active metabolites "Prakash et al[\ 0886#^ clinical trials have accordingly focused on twice! daily dosing[ The baseline bioavailability of ziprasidone is 29)\ which increases to 59) when the drug is taken with food[ Ziprasidone does not inhibit cytochrome P! 349 isoenzymes at clinically relevant concentrations\ nor is it metabolized by cytochrome P!349 0A1\ suggesting that cigarette smoking will not a}ect the levels of the drug "Miceli et al[\ 0883#[

2[ Clinical ef_cacy Schizophrenia is an extremely heterogeneous disorder\ with a broad range of symptoms[ While experts disagree about the number of relevant symptom domains and their

relationship to one another "Carpernter and Buchanan\ 0878^ Tandon et al[\ 0884#\ there appear to be at least three distinct psychopathologic dimensions that warrant separate consideration] "i# positive symptoms\ consisting of delusions\ hallucinations\ and thought disorder^ "ii# negative symptoms\ including lack of motivation and social drive\ impaired emotional expression and experi! ence\ impoverished speech and thought\ and anhedonia^ and "iii# cognitive and neuropsychological impairments\ which are fairly pervasive among patients su}ering from schizophrenia "Bilder\ 0886#[ It is reasonable to consider the e}ect of antipsychotic medications on each of these symptom domains[ Within each of these symptom domains\ several speci_c areas of comparison among the medications merit atten! tion] , Is there a di}erence in speed of response< , Is there a di}erence in the proportion of patients responding< In particular\ do neuroleptic!refractory patients respond to a particular atypical antipsychotic agent< , Is there a di}erence in spectrum of activity< Speci_! cally\ are the atypical agents more e}ective in treating negative and cognitive symptoms that respond poorly to conventional neuroleptics< 2[0[ Speed of response There are no data to suggest that the speed with which schizophrenic patients respond to treatment with various antipsychotic agents is di}erent[ Symptoms of sleep dis! turbance\ agitation\ motoric hyperactivity\ and aggress! ive behavior tend to respond most rapidly[ Positive symp! toms "delusions\ hallucinations\ thought disorder# and inattention tend to respond somewhat less rapidly\ with maximal response occurring over 3Ð7 weeks[ Negative symptoms respond more slowly\ with maximal response occurring over 5Ð01 weeks[ Cognitive and neuro! psychological improvement\ related signi_cantly to the improvement in attention\ may progress for up to six months "Sweeney et al[\ 0880#[

3[ Positive symptoms 3[0[ Proportion of patients respondin` Each of the atypical antipsychotics reviewed here has proven to be as e}ective as conventional agents in treating psychotic symptoms in short!term "3Ð5 week# trials "Beasley et al[\ 0885a\ 0885b\ 0886^ Marder and Meibach\ 0883^ Peuskens\ 0884^ van Kammen et al[\ 0885^ Borison et al[\ 0885^ Small et al[\ 0886^ Tamminga et al[\ 0886^ Tandon et al[\ 0886^ Tollefson et al[\ 0886a^ Zimbro} et al[\ 0886#[ Some studies "with almost all the atypical

M[D[ Jibson\ R[ Tandon : Journal of Psychiatric Research 21 "0887# 104Ð117

antipsychotics considered here# suggest a {better response| during treatment with atypical antipsychotics in comparison to neuroleptics in terms of either a higher proportion of responding patients\ a greater proportion of patients showing a greater degree of response\ or a greater mean reduction in symptom scores[ Preliminary data from various studies also suggest at least equal e.! cacy and perhaps an advantage for atypical agents over neuroleptics in _rst!episode schizophrenic patients[ Methodological limitations of such studies\ and the fact that such _ndings are not consistently obtained\ suggest that any conclusion of di}erential rates of e.cacy are premature at this time[ 3[1[ Response of neuroleptic!refractory patients to atypi! cal antipsychotics Clozapine has clearly been demonstrated to be more e}ective than conventional antipsychotics in the treat! ment of neuroleptic!refractory patients "Kane et al[\ 0877#\ working in approximately 29Ð49) of such pati! ents[ To date\ no persuasive evidence has been presented to suggest that other atypical antipsychotic agents share clozapine|s e.cacy in patients refractory to treatment with conventional neuroleptics[ Although several clinical trials with various atypical agents to study this question are underway\ no results have been reported thus far[ Clinical experience with risperidone and olanzapine sug! gest some utility but not the decisive level of e.cacy in treatment!refractory patients associated with clozapine\ and therefore these should be considered as alternatives to clozapine therapy only in cases in which clozapine is not tolerated or has been completely ine}ective[ Thus\ the degree of bene_t that new atypical antipsychotics o}er treatment!refractory patients must still be con! sidered an unresolved question[

110

4[0[ Response of ne`ative symptoms to atypical anti! psychotics Negative symptom improvement with clozapine is modest\ but still superior to conventional agents "Breier et al[\ 0883#[ The components of negative symptoms most likely to improve with clozapine include symptoms sec! ondary to EPS and secondary to active psychosis\ since clozapine is superior to conventional agents in both those areas "Tandon et al[\ 0882#[ There is as yet no direct evidence of improvement in de_cit symptoms "either pre! morbid or deteriorative components#[ Several studies demonstrate improvement in negative symptoms with risperidone "Marder and Meibach\ 0883^ Peuskens\ 0884#\ olanzapine "Beasley et al[\ 0885b^ Tollefson et al[\ 0886a#\ quetiapine "Borison et al[\ 0885^ Small et al[\ 0886#\ sertindole "Zimbro} et al[\ 0886^ Tamminga et al[\ 0886#\ and ziprasidone "Tandon et al[\ 0886#[ In all cases negative symptom improvement is modest\ but is generally superior to that seen with con! ventional agents[ Most improvement may be attributed to reduction in secondary negative symptoms associated with EPS[ Reports of a path!analytical approach to statistically separate the e}ects of risperidone "Moller et al[\ 0884# and olanzapine "Tollefson and Sanger\ 0886#\ on primary versus secondary negative symptoms have indicated a signi_cant direct e}ect on primary symptoms[ Path analysis\ however\ does not examine primary symp! toms directly\ but instead considers all e}ects not attri! butable to secondary symptoms "Meltzer et al[\ 0887#[ It is unclear\ therefore\ whether path analysis is su.cient to distinguish primary from secondary symptoms\ and any conclusion that atypical antipsychotics are more e}ective "or e}ective at all;# than neuroleptics in treating de_cit symptoms of schizophrenia is very premature[ On the other hand\ atypical antipsychotics are clearly superior to conventional agents in reducing the total complement of negative symptoms[

4[ Negative symptoms

5[ Cognition

The negative symptoms of schizophrenia may arise from a variety of causes\ some inherent to the illness "primary symptoms#\ and some secondary to treatment or other psychosocial factors "Jibson and Tandon\ 0884# "Fig[ 2#[ Residual psychotic symptoms in a patient treated with conventional neuroleptics may contribute to per! sistent negative symptoms similar to de_cit or primary enduring negative symptoms[ The pathophysiological mechanisms underlying the di}erent components of negative symptoms are poorly understood "Miller and Tandon\ 0887# EPS caused by these agents are a major contributor to secondary negative symptoms[ EPS may partially o}set gains in negative symptoms associated with resolution of active psychosis "Fig[ 3#[

Cognitive impairment has long been described as a feature of schizophrenic illness\ independent of positive or negative symptoms "Saykin et al[\ 0880^ Harvey and Keefe\ 0886#[ In addition to premorbid cognitive impair! ment\ there is evidence that cognition may progressively deteriorate for several years following the onset of psy! chotic symptoms "Bilder et al[\ 0881#[ Functional impair! ment in social and occupational roles appears to be even more highly correlated with de_cits in cognition than with negative symptoms "Breier et al[\ 0880#[ The neuro! biologic basis for cognitive dysfunction in schizophrenia is not entirely clear\ but may be modulated in part by various neurotransmitter systems "Harvey and Keefe\ 0886#[ It is reasonable\ therefore\ to consider phar!

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M[D[ Jibson\ R[ Tandon : Journal of Psychiatric Research 21 "0887# 104Ð117

Fig[ 2[ Components of negative symptoms[

Fig[ 3[ E}ect of antipsychotic treatment on negative symptom components[ Adapted from Tandon et al[ "0882#[

M[D[ Jibson\ R[ Tandon : Journal of Psychiatric Research 21 "0887# 104Ð117

macologic intervention as a possible approach to reduce cognitive de_cits or limit their progression "Bilder\ 0886#[

5[0[ Response of co`nitive impairment to atypical anti! psychotics Conventional neuroleptics have only minor e}ects on most aspects of cognition in schizophrenia "Medalia et al[\ 0877^ Spohn and Strauss\ 0878#[ There is some ben! e_cial e}ect of typical neuroleptic treatment on measures of attention and distractibility "Marder et al[\ 0873#[ Anticholinergic medications\ in contrast\ are known to exacerbate cognitive de_cits\ especially problems with memory "Tune et al[\ 0871^ Strauss et al[\ 0889#[ There are several studies that suggest that atypical anti! psychotics may have a greater bene_cial e}ect on cog! nitive function in schizophrenic patients[ Clozapine has been found to be more e}ective than typical anti! psychotics in improving attention and verbal ~uency\ even among patients whose psychotic symptoms respond well to conventional agents "Lee et al[\ 0883#[ Risperidone is also more bene_cial than haloperidol for schizophrenic patients taking the trail!making test\ a measure of execu! tive functioning "McGurk et al[\ 0886#[ Subtle di}erences between di}erent atypical agents on cognitive dysfunction in schizophrenic patients are being reported[ Ziprasidone has been found to improve measures of immediate recall and reaction time "Serper and Chou\ 0886#[ Although these studies show only modest e}ects on cognition\ they represent a promising development with the new medications[ Cognitive dysfunction is thus an important dimension of schizophrenic psychopathology\ strongly related to the severity of functional impairment[ Cognitive function in schizophrenia can be positively or negatively impacted by antipsychotic treatment[ Improved attention associated with antipsychotic control of positive symptoms results in a broad but modest improvement in various neu! ropsychological measures[ Blockade of mesocortical

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dopamine transmission results in slower response in cer! tain timed neuropsychological tests and adversely impacts aspects of cognitive function^ this is akin to par! kinsonian symptoms due to unattenuated antipsychotic blockade of nigrostriatal dopamine neurotransmission[ Anticholinergic activity "either intrinsic to the anti! psychotic agent or due to the addition of an anti! cholinergic antiparkinsonian agent such as trihexy! phenidyl or benztropine to treat parkinsonian side! e}ects# adversely a}ects memory\ learning\ and other cognitive functions[ Since atypical agents are less likely than conventional neuroleptics to cause extrapyramidal side!e}ects "EPS# or require the addition of adjunctive anticholinergic to treat EPS\ modest cognitive advan! tages of these agents could be expected[

6[ Adverse effects 6[0[ Extrapyramidal side effects "EPS# Extrapyramidal side e}ects remain a signi_cant obstacle to e}ective treatment of schizophrenia\ and their reduction or absence with atypical antipsychotics is a major advantage of these drugs[ With neuroleptics\ EPS occur in the same dose range at which psychotic symp! toms respond\ making it very di.cult to obtain clinical bene_ts in the absence of side e}ects[ In fact\ approxi! mately half of all patients receiving conventional anti! psychotic treatment exhibit EPS[ Among the newer agents\ symptom relief occurs in the absence of EPS\ or at doses of medication below those at which EPS become signi_cant "Fig[ 4#[ The degree of separation between dose response and EPS may be a di}erentiating factor among these medications\ and may be useful in predicting the risk of tardive dyskinesia associated with each medi! cation "Casey\ 0884#[ EPS have not been reported with clozapine\ even at higher doses[ Similarly\ tardive dyskinesia does not

Fig[ 4[ DoseÐresponse curves for antipsychotic and EPS e}ects for neuroleptics and atypical antipsychotics[

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appear to be a risk of clozapine treatment "Lieberman et al[\ 0878#[ Among other atypical drugs the presence of EPS and tardive dyskinesia are more variable[ Risperidone in its standard dose range of 1Ð5 mg:day is associated with signi_cantly fewer EPS than conventional antipsychotics\ as measured both in clinical rating scales and in use of anticholinergic medication[ While risks of EPS are at placebo level below doses of 5 mg:day\ a dose!dependent increase in EPS becomes clinically signi_cant at 7Ð01 mg:day\ and the risk of EPS at 05 mg:day risperidone is not much less than that with haloperidol 09Ð19 mg:day "Marder and Meibach\ 0883^ Peuskens\ 0884#[ Akathisia has been noted even at standard doses[ Tardive dys! kinesia has been reported in patients treated only with risperidone\ although the risk of TD appears to be sub! stantially lower than with conventional agents "Brecher\ 0885#[ Olanzapine has consistently been shown to produce signi_cantly fewer EPS than haloperidol\ and in most studies was not di}erent in this regard from placebo "Beasley et al[\ 0885a\ 0885b^ Tran et al[\ 0886a#[ In these studies\ signi_cantly fewer patients dropped out of treat! ment because of EPS while taking olanzapine than while using haloperidol[ A comparison of olanzapine to ris! peridone showed a slightly lower level of EPS with olanzapine\ but comparable rates of akathisia and acute dyskinesia with the two drugs "Tran et al[\ 0886b#[ These studies are complicated by a dose!dependent increase in EPS for both risperidone and\ to a lesser extent\ olan! zapine\ while dose equivalencies between the two drugs have not been determined[ A review of long!term studies indicates that the risk of tardive dyskinesia with olanza! pine is signi_cantly lower than with haloperidol "Tollefson et al[\ 0886b#[ In most studies of quetiapine\ EPS have been minimal[ Reports of akathisia have also been rare\ in some studies comparable to placebo[ There has been no evidence of a dose!dependent increase in EPS in the 64Ð799 mg:day dose range used in clinical trials "Borison et al[\ 0885^ Small et al[\ 0886#[ While preclinical data predict a sig! ni_cantly lower occurrence of tardive dyskinesia with quetiapine\ clinical data are lacking thus far[ Sertindole shows signi_cantly less propensity for EPS than haloperidol\ and has been found to be indis! tinguishable from placebo in most studies "van Kammen et al[\ 0885^ Zimbro} et al[\ 0886#[ No dose!dependent increase in EPS has been found in the clinical range of 7Ð 13 mg:day[ Akathisia has been reported\ but signi_cantly less often than with haloperidol[ Clinical data regarding tardive dyskinesia are not yet available\ but preclinical _ndings suggest a lower incidence than with conventional agents[ EPS have not been prominent during clinical trials of ziprasidone[ Dystonic events occurred in less than 4) of patients[ Akathisia was slightly more frequent\ but was

not di}erent than placebo "Tandon et al[\ 0886#[ As with quetiapine and sertindole\ preclinical data suggest that there will be a low incidence of tardive dyskinesia with ziprasidone\ but no clinical data are available[ The importance of EPS in the context of treatment of schizophrenic illness tends to be underestimated[ Not only do the motor parkinsonian side!e}ects limit function and cause distress in their own right\ EPS are also associ! ated with several other adverse consequences[ Expression of EPS signi_cantly increases the likelihood of sub! sequent tardive dyskinesia "Chatterjee et al[\ 0884#^ tardive dyskinesia\ in turn\ is associated with increased morbidity and mortality[ EPS contribute to secondary negative symptoms\ increasing the severity of this symp! tom dimension and attendant dysfunction[ EPS are associated with cognitive dysfunction\ attributable directly to unattenuated mesocortical dopamine block! ade of the antipsychotic or to the adjunctive use of other anticholinergic agents "Bilder\ 0886# to treat EPS[ It is not surprising that signi_cant EPS may be correlated with dysphoria[ The {costs| of EPS are thus not limited to parkinsonian motor manifestations\ but extend to increased negative and cognitive symptoms\ more dys! phoria\ higher likelihood of noncompliance\ and greater risk of tardive dyskinesia[ The de_ning characteristic of atypical antipsychotics is at least equal e.cacy with a signi_cantly lower liability of EPS then conventional agents^ consequently\ their use would be predicted to yield several bene_ts that go beyond reduction in motor Parkinsonian side!e}ects "Fig[ 5#[ Many of these advan! tages have been con_rmed in clinical studies[ Therefore\ to derive optimal bene_ts from the use of atypical anti! psychotics\ it is essential that they be used in a way that EPS not occur^ if EPS occur in the course of treatment with an atypical antipsychotic\ consideration should be given to a reduction in dose or change to another agent[ Adequate control of psychotic symptoms with avoidance of EPS without adjunctive antiparkinsonian medication should be the objective[

7[ Other side effects The incidence of other side!e}ects di}er among the atypical antipsychotics\ and to a great extent this is pre! dictable from the di}erences in their respective phar! macological pro_les[ The side!e}ect pro_les of the atypi! cal antipsychotics are compared to one another and to the conventional neuroleptics in Table 2[ The overall side!e}ect pro_le of clozapine is signi_cant[ Hypotension is common\ especially early in treatment\ and usually necessitates gradual titration of the dose over several days or weeks[ Anticholinergic e}ects\ especially constipation\ may remain problems throughout the course of treatment[ Hypersalivation occurs in about one! third of the patients[ Sedation\ weight gain\ and tachy!

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Fig[ 5[ The EPS advantage of the atypical antipsychotics[

cardia are other common problems[ The risk of seizures with clozapine is dose!dependent\ increasing from 1) at low!range doses to 5) at high doses[ The risk of agranulocytosis is 0Ð1)\ primarily in the _rst 5 months of treatment[ The risk of agranulocytosis has currently limited clozapine|s use to patients unresponsive to other antipsychotics and patients with signi_cant tardive dys! kinesia^ however\ as the scope and uniqueness of its thera! peutic activity are further elucidated "Busatto and Kerwin\ 0886#\ its applicability may increase[ The major side e}ects of risperidone include drowsi! ness\ orthostatic hypotension\ lightheadedness\ anxiety\ akathisia\ constipation\ nausea\ nasal congestion\ weight gain\ and prolactin elevation "Marder and Meibach\ 0883^ Peuskens\ 0884#[ Prolactin elevation is dose!related^ any relationship to potential clinical adverse e}ects "such as amenorrhoea\ galactorrhoea\ sexual dysfunction\ etc[# is unclear "Kleinberg et al[\ 0886#[ The risk of EPS is at placebo!level at low doses but increases in a dose!related manner[ Consequently\ daily doses of risperidone should optimally be limited to less than 5 mg per day[

Side!e}ects frequently noted with olanzapine include somnolence\ dry mouth\ nausea\ lightheadedness\ ortho! static hypotension\ dizziness\ constipation\ headache\ akathisia\ substantial weight gain\ and transient elevation of hepatic transaminases "Beasley et al[\ 0886^ Tran et al[\ 0886a#[ Prolactin elevation occurs transiently\ but generally does not persist "Beasley et al[\ 0886#[ A number of patients who developed agranulocytosis on clozapine have been challenged with olanzapine\ and there appears to be no increased risk of signi_cant reduction in white blood cell count[ Frequently reported side!e}ects with quetiapine include somnolence\ postural hypotension\ dizziness\ agi! tation\ dry mouth\ elevated hepatic transaminases\ and weight gain "Borison et al[\ 0885^ Small et al[\ 0886#[ Sustained serum prolactin elevation has not been reported "Small et al[\ 0886#[ The most frequently reported adverse e}ects with ser! tindole include nasal congestion\ decreased ejaculatory volume\ akathisia\ weight gain\ and tremor "van Kam! men et al[\ 0885^ Zimbro} et al[\ 0886#[ The decreased

Table 2 Side e}ect pro_les of atypical antipsychotic agents

Agranulocytosis Anticholinergic ALT:AST elevation EPS Dose!related EPS Orthostatic hypotension Prolactin elevation QT prolongation Sedation Seizures Tardive dyskinesia Weight gain

Typical neuroleptics

Clozapine "ClozarilTM#

Risperidone "RisperdalTM#

Olanzapine "ZyprexaTM#

Quetiapine "SeroquelTM#

Sertindole "SerlectTM#

Ziprasidone "ZeldoxTM#

2 to ¦ 2 2 ¦ to ¦¦¦ ¦¦ 2 to ¦¦¦ ¦¦ to ¦¦¦ 2 to ¦ ¦ to ¦¦¦ 2 ¦¦¦ 2 to ¦¦

¦¦ ¦¦¦ ¦ 2 9 ¦¦¦ 9 ¦ ¦¦¦ ¦¦ to ¦¦¦ 9 ¦¦¦

9 2 2 2 ¦¦ ¦ ¦¦ 2 to ¦ ¦ 2 2 to ¦< ¦¦

9 ¦ 2 2 2 2 2 2 to ¦ ¦¦ 2 2 to ¦< ¦¦¦

9 2 2 2 9 to 2 ¦ 2 2 to ¦ ¦¦ 2 < ¦¦

9 2 2 2 9 ¦ to ¦¦ 2 ¦¦ ¦ 2 < ¦¦

9 2 2 2 2 2 2 2 to ¦ ¦ 2 < 2

9] Absent^ 2] Minimal^ ¦] Mild^ ¦¦] Moderate^ ¦¦¦] Severe^ <] Incomplete data[ ALT] alanine aminotransferase^ AST] aspartate amino! transferase^ EPS] extrapyramidal side e}ects[

115

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ejaculatory volume appears to be an isolated problem\ not associated with other sexual dysfunction\ such as retrograde ejaculation\ erectile dysfunction\ loss of libido\ or anorgasmia[ Tachycardia occurs frequently during dose titration\ and is especially associated with rapid titration schedules "3 mg:day#\ but not with titration at a rate of 3 mg every second or third day[ Prolactin elevation does not occur[ Questions regarding ser! tindole|s cardiac safety initially delayed its approval for clinical use in the United States\ and more recently led to the manufacturer|s withdrawal of the new drug appli! cation in that country[ Sertindole can cause prolongation of the QT interval^ the average QT prolongation is 10 ms[ The precise relationship to increased cardiac mortality or morbidity is unclear[ The most prominent side e}ects of ziprasidone are headache\ somnolence\ nausea\ and dyspepsia[ Uncom! mon or mild adverse e}ects include dizziness\ weakness\ nasal discharge\ orthostatic hypotension\ and tachy! cardia[ There was no evidence of increased incidence of weight gain or sexual dysfunction[ Laboratory abnor! malities include transient\ asymptomatic elevation of liver enzymes and asymptomatic elevation of serum tri! glycerides and cholesterol "Tandon et al[\ 0886#[ There is a transient elevation of serum prolactin with each dose\ which returns to baseline within the dosing interval "Bench et al[\ 0885#[

8[ Use of atypical antipsychotics Unquestionably\ atypical antipsychotics are preferred for patients who do not adequately respond to con! ventional agents[ To date\ clozapine is the only atypical agent with proven e.cacy in this population[ For patients in whom EPS are a major consideration\ these side e}ects can be signi_cantly reduced or com! pletely eliminated with the newer drugs[ This EPS advan! tage has many potential rami_cations for patients\ including improvement in negative symptoms\ less cog! nitive impairment\ better mood\ fewer motor problems\ better compliance\ and reduced risk of tardive dyskinesia[ To maximize the bene_ts of the newer atypical agents\ it is crucial that EPS and the need for adjunctive anti! parkinsonian medication be avoided[ The question of atypical antipsychotic use in other situations remains open[ Their clear EPS advantage and its many rami_cations warrant consideration of their use as _rst!line agents in the treatment of schizophrenia and other psychotic disorders[ The primary advantage of atypical agents in initial treatment is their superior side e}ect pro_le compared to conventional drugs\ par! ticularly EPS[ In clinical trials\ fewer patients receiving atypical antipsychotics dropped out of treatment than did patients receiving neuroleptics[ In long!term treatment studies of conventional antipsychotics\ side e}ects have

been cited as the major reason for treatment non! compliance leading to relapse[ The clinical bene_ts of continuous treatment and relapse prevention\ par! ticularly early in the course of schizophrenia\ are not limited to avoidance of hospitalization\ but may also include improved long!term course\ less severe negative symptoms\ reduction of cognitive impairment\ and less functional deterioration[ These considerations make use of atypical agents early in treatment highly advantageous[ For patients who have other limiting side e}ects\ the availability of several medications with distinct side e}ect pro_les makes it possible to select the single drug with the most favorable pro_le for the individual patient[ It is important to recognize that the class of atypical anti! psychotics is not homogeneous\ and that there are sub! stantial pharmacological and clinical di}erences between the di}erent atypical antipsychotic agents[

09[ Conclusion The new atypical antipsychotic medications represent a major step forward in the treatment of schizophrenia and other psychotic disorders[ These agents are phar! macologically distinct from their neuroleptic prede! cessors[ The primary advantage of the new agents is their superior side e}ect pro_les\ particularly with regard to EPS[ The implications of EPS reduction touch virtually every domain of pathology in schizophrenia\ including short! and long!term movement disorders\ negative symptoms\ noncompliance\ relapse rate\ cognitive dys! function\ and dysphoria[ The drugs| unique pro_les with regard to other side e}ects may make it possible to tailor treatment more individually to patients[ Preliminary evi! dence suggests that this advantage may lead to improved patient compliance\ and a superior long!term outcome in patients treated with these medications[ Further re_ne! ment of our understanding of the clinical utility of these drugs awaits their widespread use in mainstream clinical settings[ Controlled studies comparing them to one another should also be of interest[

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M[D[ Jibson\ R[ Tandon : Journal of Psychiatric Research 21 "0887# 104Ð117

among patients with serious mental illness\ American Psychological Association Press\ 0887[ In press[ Moller H!J\ Muller H\ Borison RL\ Schooler NR\ Chouninard G[ A path!analytic approach to di}erentiate between direct and indirect drug e}ects on negative symptoms in schizophrenic patients[ Eur! opean Archives of Psychiatry and Clinical Neuroscience 0884^134]34Ð38[ Peuskens J[ Risperidone in the treatment of patients with chronic schizophrenia^ a multinational\ multicentre\ double!blind\ parallel! group study versus haloperidol[ British Journal of Psychiatry 0884^055]601Ð615[ Prakash C\ Kamel A\ Gummerus J\ Wilner K[ Metabolism and excretion of a new antipsychotic drug\ ziprasidone\ in humans[ Drug Metabolism and Disposition 0886^14]752Ð761[ Preskorn SH\ Magnus RD[ Inhibition of hepatic P!349 isoenzymes by serotonin selective reuptake inhibitors] in vitro and in vivo _ndings and their implications for patient care[ Psychopharmacology Bull! etin 0883^29]140Ð148[ Richelson E[ Pharmacology of neuroleptics in use in the United States[ Journal of Clinical Psychiatry 0874^35]7Ð03[ Ring BJ\ Binkley SN\ Vandenbranden M\ Wrighton SA[ In vitro inter! action of the antipsychotic agent olanzapine with human cyto! chromes P349 CYP1C8\ CYP1C08\ CYP1D5 and CYP2A[ British Journal of Clinical Pharmacology 0885^30]070Ð075[ Saller CF\ Salama AI[ Seroquel] biochemical pro_le of a potential atypical antipsychotic[ Psychopharmacology 0882^001]174Ð181[ Saykin AJ\ Gur RC\ Gur RE\ Mozley PD\ Mozley LH\ Resnick SM\ Kester DB\ Sta_niak P[ Neuropsychological function in schizo! phrenia[ Selective impairment in memory and learning[ Archives of General Psychiatry 0880^37]507Ð513[ Seeger TF\ Seymour PA\ Schmidt AW\ Zorn SH\ Schulz DW\ Lebel LA\ McLean S\ Guanowsky V\ Howard HR\ Lowe 2rd[ JA\ et al[ Ziprasidone "CP!77\948#] a new antipsychotic with combined dopamine and serotonin receptor antagonist activity[ Journal of Pharmacy and Experimental Therapeutics 0884^164]090Ð002[ Serper MR\ Chou JCY[ Novel antipsychotics improve attentional func! tioning in schizophrenic patients] ziprasidone and aripiprazole[ CNS Spectrums 0886^1]45Ð48[ Skarsfeldt T\ Perregaard J[ Sertindole\ a new neuroleptic with extreme selectivity on A09 versus A8 dopamine neurones in the rat[ Eur! opean Journal of Pharmacology 0889^071]502Ð503[ Seroquel Study Group\ Small JG\ Hirsch SR\ Arvanitis LA\ Miller BG\ Link CGG[ Quetiapine in patients with schizophrenia[ Archives of General Psychiatry 0886^43]438Ð446[ Spohn HE\ Strauss ME[ Relation of neuroleptic and anticholinergic medication to cognitive functions in schizophrenia[ Journal of Abnormal Psychology 0878^87]256Ð279[ Strauss ME\ Reynolds KS\ Jayaram G\ Tune LE[ E}ects of antic! holinergic medication on memory in schizophrenia[ Schizophrenia Research 0889^2]016Ð018[ Sweeney JA\ Haas GL\ Keilp JG\ Long M[ Evaluation of the stability of neuropsychological functioning after acute episodes of schizo! phrenia] one!year follow!up study[ Psychiatry Research 0880^27]52Ð 65[ Tamminga CA\ Mack RJ\ Granneman GR\ Silber CJ\ Kashkin KB[ Sertindole in the treatment of psychosis in schizophrenia] e.cacy and safety[ International Clinical Psychopharmacology 0886^01 "Suppl[ 0#]S18ÐS24[ Tandon R[ Antipsychotic agents[ In] Klein DF and Rowland LP\ editors[ Current psychotherapeutic drugs[ New York] Brun! ner:Mazel Publishers\ 0887a[ pp[ 019Ð043[ Tandon R[ Cholinergic aspects of schizophrenia[ British Journal of Psychiatry 0887b[ In press[ Tandon R\ Kane JM[ Neuropharmacological basis of clozapine|s unique pro_le[ Archives of General Psychiatry 0882^49]046Ð048[ Tandon R\ Goldman R\ DeQuardo JR\ Goldman M\ Perez M\ Jibson

M[ Positive and negative symptoms covary during clozapine treat! ment in schizophrenia[ Journal of Psychiatry Research 0882^16]230Ð 236[ Tandon R\ Jibson MD\ Taylor SF\ and DeQuardo JR[ Conceptual models of the relationship between positive and negative symptoms[ In] Shriqui CL and Nasrallah HA\ editors[ Contemporary issues in the treatment of schizophrenia[ Washington\ D[C[] American Psychiatric Press Inc[\ 0884\ pp[ 098Ð013[ Tandon R\ Harrington E\ Zorn SH[ Ziprasidone] a novel antipsychotic with unique pharmacology and therapeutic potential[ Journal of Serotonin Research 0886^3]048Ð066[ Tandon R\ DeQuardo JR and Taylor SF Neurobiology of Schizo! phrenia[ In] Ananth J\ editor[ Textbook of psychopathology[ New Delhi] Jaypee Brothers\ 0887[ Thyrum PT\ Fabre LF\ Wong J\ Ewing BJ\ Yeh C[ Multiple!dose pharmacokinetics of ICI 193\525 in schizophrenic men and women[ Psychopharmacology Bulletin 0885^21]414[ Tollefson GD\ Sanger TM[ Negative Symptoms] a path analytic approach to a double!blind\ placebo! and haloperidol!controlled clinical trial with olanzapine[ American Journal of Psychiatry 0886^043]355Ð363[ Tollefson GD\ Beasley Jr[ CM\ Tran PV\ Street JS\ Krueger JA\ Tamura RN\ Gra}eo KA\ Thieme ME[ Olanzapine versus haloperidol in the treatment of schizophrenia and schizoa}ective and sch! izophreniform disorders] results of an international collaborative trial[ American Journal of Psychiatry 0886^043]346Ð354[ Tollefson GD\ Beasley Jr[ CM\ Tamura RN\ Tran PV\ Potvin JH[ Blind\ controlled\ long!term study of the comparative incidence of treatment!emergent tardive dyskinesia with olanzapine or halo! peridol[ American Journal of Psychiatry 0886^043]0137Ð0143[ Tran PV\ Dellva MA\ Tollefson GD\ Beasley Jr[ CM\ Potvin JH\ Kiesler GM[ Extrapyramidal symptoms and tolerability of olanzapine ver! sus haloperidol in the acute treatment of schizophrenia[ Journal Clinical Psychiatry 0886^47]194Ð100[ Tran PV\ Hamilton SH\ Kuntz AJ\ Potvin JH\ Andersen SW\ Beasley Jr[ C\ Tollefson GD[ Double!blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders[ Journal of Clinical Psychopharmacology 0886^06]396Ð 307[ Tune LE\ Strauss ME\ Lew MF\ Breitlinger E\ Coyle JT[ Serum levels of anticholinergic drugs and impaired recent memory in chronic schizophrenic patients[ American Journal of Psychiatry 0871^028]0359Ð0351[ van Kammen DP\ McEvoy JP\ Targum SD\ Kardatzke D\ Sebree TB[ A randomized\ controlled\ dose!ranging trial of sertindole in patients with schizophrenia[ Psychopharmacology "Berl# 0885^013]057Ð064[ Van Putten T\ Marder SR\ Mintz J[ A controlled dose comparison of haloperidol in newly admitted schizophrenic patients[ Archives of General Psychiatry 0889^36]643Ð647[ Wong SL\ Linnen P\ Mack R\ Granneman GR[ E}ects of food\ antacid\ and dosage form on the pharmacokinetics and relative bioavai! lability of sertindole in healthy volunteers[ Biopharmaceutics and Drug Disposition 0886^07]422Ð430[ Wong SL\ Menacherry S\ Mulford D\ Schmitz PJ\ Locke C\ Granneman GR[ Pharmacokinetics of sertindole and dehydrosertindole in vol! unteers with normal or impaired renal function[ European Journal of Pharmacology 0886^41]112Ð116[ Zeng XP\ Le F\ Richelson E[ Muscarinic m3 receptor activation by some atypical antipsychotic drugs[ European Journal of Pharmacology 0886^210]238Ð243[ Sertindole Study Group\ Zimbro} DL\ Kane JM\ Tamminga CA\ Daniel DG\ Mack RJ\ Wozniak PJ\ Sebree TB\ Wallin BA\ Kashkin KB[ Controlled\ doseÐresponse study of sertindole and haloperidol in the treatment of schizophrenia[ American Journal of Psychiatry 0886^043]671Ð680[