ATYPICAL
`ANTIPSYCHOTICS
`
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`Current Medicinal Chemistry
`
`Editor:
`Atta-ur-Rahman (HEJ Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan)
`
`Co-Editors:
`David Fairlie (University of Queensland, Brisbane, Australia)
`William J. Hoekstra (GlaxoSmithKline, R & D, Research Triangle Park, NC, USA)
`Graeme Semple (Arena Pharmaceuticals, San Diego, CA, USA)
`Hakan V. Wikstrom (University ofGroningen, Groningen, The Netherlands)
`
`Associate Editors:
`Bernard Pirotte (Universite de Liege, Liege, Belgium)
`Susanna Fiirst (Semmelweis Univ. of Med., Budapest, Hungary)
`Koichi Shudo (ltsuu Laboratory, Tokyo, Japan)
`Francis Johnson (State Univ. of New York, New York, USA)
`Alan P. Kozikowski (Univ. of Illinois at Chicago, Chicago, USA)
`Editorial Advisory Board:
`John A. Lowe III (Pfizer, Groton, USA)
`Pier Giovanni Baraldi (Universita di Ferrara, Ferrara, Italy)
`James William Lown (Univ. Alberta, Alberta, Canada)
`Fatima Z. Basha (Abbott, Abbott Park, USA)
`Philip D. Magnus (Univ. Texas at Austin, Texas, USA)
`Wesley G. Bentrude (Univ. of Utah, Salt Lake City, USA)
`Sohail Malik (BioFrontiers, Inc., Redmon, W A, USA)
`Mark S. Berridge (Univ. Hospital of Cleveland, Cleveland, USA)
`Ian A. McDonald (Structural GenomiX, San Diego, CA, USA)
`Mark G. Bock (Merck, Westpoint, USA)
`Alan R. Morgan (PDT Pharmaceuticals, Santa Barbara, USA)
`Nicholas Bodor (University of Florida, Florida, USA)
`Kenji Mori (Science University of Tokyo, Tokyo, Japan)
`Gunther Bonn (University oflnnsbruck, Innsbruck, Austria)
`D.W. Oliver (Potchefstroom Univ., Potchefstroom, South Africa)
`John K. Buolamwini (Univ. of Mississippi, Mississippi, USA)
`Krysztof W. Pankiewicz (Pharmasset, Inc., Atlanta, GA, USA)
`Terrence R. Burke Jr. (National Inst. of Health, Bethesda, USA)
`George Perry (Case Western Reserve University, Cleveland, USA)
`David J. Craik (University of Queensland, St. Lucia, Australia)
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`
`Current Medicinal Chemistry
`Volume 11, Number 3, February 2004
`Contents
`Pharmacological Treatment of_Schizophrenia:
`Recent Antipsychotic Drugs and New Therapeutic Strategies
`Guest Editor: Maria Augusta Raggi
`Preface
`Schizophrenia: From Dopamine to Glutamate and Back
`ML. Carlsson, A. Carlsson and M Nilsson
`Atypical Antipsychotics: Pharmacokinetics, Therapeutic Drug
`Monitoring and Pharmacological Interactions
`Maria Augusta Raggi, Roberto Mandrioli, Cesare Sabbioni and
`Vincenzo Pucci
`Pharmacogenomic-Guided Rational Therapeutic Drug Monitoring:
`Conceptual Framework and Application Platforms for Atypical
`Anti psychotics
`Lawrence J Albers and Vural Ozdemir
`A Critical Review of Atypical Antipsychotic Utilization: Comparing
`Monotherapy with Polypharmacy and Augmentation
`S.M Stahl and MM Grady
`Naturalistic Studies of Second Generation Antipsychotics in the
`Treatment of Schizophrenia
`C. Simon Sebastian, William Glazer and Peter F. Buckley
`New Antipsychotics and Schizophrenia: A Review on
`Efficacy and Side Effects
`Alessandro Serretti, Diana De Ronchi, Cristina Lorenzi and
`Domenico Berardi
`
`267
`
`279
`
`297
`
`313
`
`329
`
`343
`
`General Articles
`Mode of Action of Endotoxin: Role of Free Radicals and
`Antioxidants
`Jharna Bhattacharyya, Sabyasachi Biswas and Asoke G. Datta
`Oxidative Stress-Induced Ischemic Heart Disease: Protection
`by Antioxidants
`·
`Debashis Bandyopadhyay, Aindrila Chattopadhyay, Goutam Ghosh
`and Asoke G. Datta
`The NMDA Receptor NR2B Subunit: A Valid Therapeutic
`Target for Multiple CNS Pathologies
`PaulL. Chazot
`
`359
`
`369
`
`389
`
`This is to acknowledge that the slide shown on the front cover of this journal was kindly supplied by
`Prof. Maria Augusta Raggi, Head of the Pharmaco. Toxicological Analysis Laboratory, Department of Pharmaceutical
`Sciences, Faculty of Pharmacy, University of Bologna, 40126 Bologna, Italy. The cover slide shows the different
`receptor systems involved in the pharmacological action of atypical antipsychotics.
`
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`Aims and Scope
`Current Medicinal Chemistry aims to cover all the latest and outstanding
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`
`Preface
`
`The pharmacological treatment of schizophrenia has made great strides in the last few decades.
`Many new drugs have been synthesized and commercialized, and these agents have notably
`improved the quality of life of many psychotic patients. Unfortunately, the aetiology of this
`disease is yet largely unknown, and the therapy is still symptomatic. Furthermore, a small
`percentage of patients do not respond to therapy, thus remaining outside the possibility of
`intervention of current medicinal practice.
`
`New developments in the field of antipsychotic drugs arc a very interesting and topical subject
`in today's medicinal chemistry, from pharmacodynamic, pharmacokinetic, pharmacological and
`clinical point of view.
`
`First of all, the most recent perspectives for the design and development of innovative dopamine stabiliser agents will be
`presented. As reported in the first review, these compounds have the advantage of producing much less or none of those side
`effects that are a consequence ofhypodopaminergia: they can thus alleviate abnormal motor and mental hyperactivity with only
`a slight risk of attaining activity levels below baseline.
`
`Next, the recent drugs already available on the market will be widely discussed in the following reviews of this issue, with
`special attention for the main atypical antipsychotics, such as clozapine, rispcridone, olanzapine and quetiapine. We will focus
`on the advantages and importance of carrying out an accurate therapeutic drug monitoring (TDM) of schizophrenic patients
`undergoing pharmacologic therapy with atypical antipsychotics. The new pharmacogenomic-guided TDM, that will be
`presented in the third article, could complement and expand the scope of traditional TDM by providing a more complete
`portrayal of sources of variability in psychotropic drug response and will probably make important contributions to medical
`therapeutics in the future.
`
`New therapeutic strategies will be compared and discussed, such as polypharmacy with different anti~sychotics or
`augmentation with drugs of other classes (e.g. antiepileptics). These practices are currently becoming more widely used.
`Nevertheless, experimental evidence at the basis of these practices is not unequivocal and the available literature on the subject
`will be critically reviewed.
`
`Finally, clinical data from both naturalistic and controlled studies regarding the efficacy and safety of atypical antipsychotics
`will be presented in the last two reviews. The naturalistic studies of second generation anti psychotics can provide information
`on the pattern of use, patient response, and tolerability ofthese recent drugs, and are useful tools because ofthe scarcity oflong
`term comparative studies. The last article will focus on the advantages of atypical agents when compared to classical
`antipsychotics, and on the efficacy and side effects of the different new antipsychotics when compared to one another.
`My most heartfelt thanks go to the invited contributors for spending so much of their time and efforts for this Thematic Issue.
`My many thanks also go to the qualified experts who have significantly contributed to our efforts by acting as referees.
`
`Maria Augusta Raggi
`Alma Mater Studiorum- University of Bologna
`Faculty of Pharmacy- Department of Pharmaceutical Sciences
`40126 Bologna
`Italy
`E-mail: raggima@alma.unibo.it
`
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`
`Current Medicinal Chemistry, 2004, 11, 279-296
`
`279
`
`Atypical Antipsychotics: Pharmacokinetics, Therapeutic Drug Monitoring
`and Pharmacological Interactions
`
`Maria Augusta Raggi*, Roberto Mandrioli, Cesare Sabbioni and
`Vincenzo Pucci
`
`Alma Mater Studiorum - University of Bologna, Faculty of Pharmacy, Department of
`Pharmaceutical Sciences, Via Belmeloro 6, 40126 Bologna, italy
`
`Abstract: The development of new "atypical" antipsychotic agents, which are safer than
`classical neuroleptics and also active against
`the negative symptoms and
`neurocognitive deficits caused by the illness, has produced a significant advancement
`in the treatment of schizophrenia.
`
`The atypical (or "second generation") antipsychotics have several therapeutical properties in common, however
`they can significantly differ with regard to clinical potency and side effects. The main features regarding
`pharmacodynamics, pharmacokinetics and pharmacological interactions of the most important atypical
`antipsychotics, namely clozapine, olanzapine, quetiapine and risperidone, are treated herein. Several analytical
`methods available for the therapeutic drug monitoring of these drugs are also presented, as well as the novel
`formulations, which can notably improve the therapy of schizophrenia. Other very recent atypical agents, such
`as ziprasidone, aripiprazole, iloperidone, sertindole and zotepine will also be briefly described.
`Keywords: Atypical antipsychotics, Pharmacokinetics, Pharmacological Interactions, Therapeutic Drug Monitoring, Analytical
`methods.
`
`INTRODUCTION
`Schizophrenia is a severe mental disorder affecting about
`1% of the world population, that can gravely impair the
`social and working life of patients by causing a gross
`distortion of reality, loss of identity and mental capacity [1].
`
`many efforts in this direction, its etiology remains still
`largely unknown. Nevertheless, great strides have been made
`in the treatment of this invalidating mental disorder in the
`last fifty years, thanks to the introduction of numerous
`antipsychotic drugs in therapy.
`
`Positive symptoms
`
`.(' Hallucinations
`
`.(' Delusions
`
`.(' Disorganised behaviour
`
`.('
`
`Incoherence of speech
`
`Negative symptoms
`
`.(' Apathy
`
`.(' Poverty of speech
`
`.(' Emotional withdrawal
`
`.(' Anhedonia (lack of pleasure)
`
`Other symptoms
`
`.(' Cognitive symptoms
`
`.(' Aggressive sympt~ms
`
`.(' Depression
`
`.(' Anxiety
`
`.(' Agitation
`
`.(' Asociality (inability to initiate or maintain social contacts)
`
`.('
`
`Incongruity of emotions
`
`.(' Difficulty in abstract thinking
`
`.(' Thought broadcast, thought insertion
`Scheme 1. Main symptoms of schizophrenia.
`
`.(' Attention impairment
`
`This illness is considered an organic disorder of the brain
`where neuroanatomical investigations and positron-emission
`tomography (PET) studies have shown structural alterations
`and reduced glucose metabolism in the thalamus and frontal
`cortex, respectively [2]. Several studies on genetic and
`environmental factors during the early processes of
`neurodevelopment and maturation of the brain have been
`carried out and are currently in progress to understand the
`biological causes of schizophrenia [3]; however, despite the
`
`*Address correspondence to this author at the Alma Mater Studiorum -
`University of Bologna, Faculty of Pharmacy, Department of
`Pharmaceutical Sciences, Via Belmeloro, 6, 40126 Bologna, Italy; Tel:
`+39 051 2099700; Fax: +39 051 2099734; E-mail: raggima@alma.unibo.it
`
`Chlorpromazine (Fig. (la)), introduced in therapy in the
`early 1950s, was the first antipsychotic agent effective in
`controlling the positive symptoms of schizophrenia [ 4 ], such
`as delusions and hallucinations (Scheme 1 ).
`From its discovery, several other phenothiazine drugs
`were developed (e.g. levomepromazine, Fig (lb)), as well as
`other classes of antipsychotics such as butyrophenones, e.g.
`haloperidol Fig. (lc); and thioxanthenes, e.g. clopenthixol
`Fig. (ld). All these drugs, which are collectively known as
`conventional antipsychotics (or "neuroleptics "), are
`dopamine 0 2 antagonists [5, 6]; no substantial differences in
`efficacy between the different classes have been evidenced [6,
`7]. Their mechanism of action originated the so-called
`"dopamine hypothesis" of schizophrenia, which implies that
`
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`
`280 Current Medicinal Chemistry, 2004, VoL I 1, No.3
`
`Raggi etaL
`
`(a) - Chlorpromazine
`
`(b) - Levomepromazine
`
`(c)- Haloperidol
`
`(d) - Clopenthixol
`
`Fig. (I). Chemical structure of (a) chlorpromazine, (b) levomepromazine, (c) haloperidol and (d) clopenthixol.
`
`/
`
`Cl
`
`the disorder arises from a hyperactivity of the meso limbic
`dopaminergic system.
`
`Conventional antipsychotics are helpful in controlling
`the positive symptoms of schizophrenia and in reducing
`both morbidity and mortality. Side effects due to a non-
`selective dopamine receptor blockade are common: up to
`50% of patients treated with conventional antipsychotics
`develop pseudoparkinsonism, and akathisia and acute
`[8]. Moreover,
`frequent
`relatively
`dystonias are
`approximately 30% of patients receiving conventional
`
`:::~t:~~~f:~~: :~~~~:ui1~~1~o b~~~f~yf~~:i~~fl~~:~ifi;!~~
`
`symptoms [7, 9]. In addition, conventional antipsychotics
`have demonstrated to have scarce effect in treating negative
`symptoms of schizophrenia such as apathy, withdrawal and
`lack of pleasure (Scheme 1).
`A breakthrough in the treatment of schizophrenia was
`achieved with the introduction of clozapine, which is the
`parent drug of a new class, that of the so-called "atypical", or
`"second generation", antipsychotics. Clozapine exhibits a
`peculiar action profile with respect to conventional (or
`"classical") antipsychotics. In particular, it has demonstrated
`to be effective against both positive and negative symptoms
`of schizophrenia and the associated neurocognitive deficits,
`and it tends to not cause extrapyramidal side effects (EPSs),
`tardive dyskinesia or hyperprolactinemia, which are the most
`frequent cause of discontinuation of therapy with classical
`antipsychotics [10]. Furthermore, clozapine is effective in a
`high percentage of patients who are non-responders to
`classical treatment. Clozapine and all the other atypical
`antipsychotics subsequently developed can be considered
`Serotonin (5-HT2A· 5-HT2B• S-HT2c) and Dopamine
`Antagonists (SDAs), as opposed to classical antipsychotics,
`
`which as already noted are mainly D2 recept,antagonists
`and do not usually show strong S-HT2 receptor antagonism
`(however exceptions exist). This fact in tum, combined with
`the observation of 5-HT agonists causing schizophrenic-like
`symptoms, has led to the f<;>rmulation of the "serotonin
`hypothesis" or, more recently, the "serotonin/dopamine
`hypothesis". According to this theory, blocking the 5-HT2A
`receptors (which are dopamine inhibitors) reverses the
`blockade of D2 receptors by disinhibiting dopamine
`neurones. Thus, incomplete inhibition of these neurones is
`achieved, which supposedly leads to a broader therapeutic
`
`~:c~~~o~~~~e0![~~s~~l~ ~!r~;;;~~; ~~: ~;~;~~~;~{:~;
`
`negative symptomatology of schizophrenia [2]. Recently,
`imbalances in other neurotransmitter systems have been
`implicated as the cause of schizophrenia, in particular
`imbalances in the glutamate, y-aminobutyric acid (GABA)
`and acetylcholine systems. One of the most recent and
`accredited of these theories is that of glutamate: according to
`theory, since glutamate antagonists such as
`this
`phencyclidine can cause psychotic symptoms in healthy
`subjects, hypofunction or dysfunction of the glutamate
`transmission system could be at least one of the causes of
`schizophrenia [11]. Nowadays, many researchers believe that
`schizophrenia is a multi-factorial disease and that it
`originates from simultaneous imbalances in several different
`neurotransmitter systems, as summarized in Fig. (2). Even if
`until now none of these hypotheses has been confirmed, the
`introduction of atypical antipsychotics acting on multiple
`neurotransmitters has surely greatly improved the quality of
`life of psychotic patients. These drugs, similarly to
`clozapine, have several advantages in common with respect
`to conventional neuroleptics (efficacy against negative and
`neurocognitive symptoms, low incidence of EPSs, no
`
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`
`Atypicul Amip~yclloth·.•·
`
`Current Medicinal Chemistry, 20114, Vol. I I, No.3 281
`
`ATYJPJIC AJL
`ANTJIJPS~CHOTJICS
`
`Fig. (2). The different receptor systems involved in the pharmacological action of /\typical 1\ntipsychotics.
`
`increase in prolactin levels), as well as some side effects in
`common, such as weight gain, insomnia. agitation, dry
`mouth and constipation (12). Each atypical antipsychotic,
`however, possesses unique characteristics in terms of
`pham1acodynamics, pham1acokinctics, clinical potency and
`toxicity, which will be discussed herein.
`Since all these drugs arc rather recent, a constant
`Therapeutic Drug Monitoring (TDM) of the patients
`undergoing therapy is advisable [13] to avoid toxtctty,
`especially that caused by pharmacological interactions during
`polypharmacy: the data thus obtained can be very useful in
`clarifying pharmacokinetic variations
`in different
`populations.
`In fact, the pharmacokinetics of drug interactions and the
`genetic variability of drug-metabolizing enzymes has
`received great attention in the last few years [14]. The
`hepatic metabolizing system o f cytochrome P450 (CYP),
`which is involved in the biotransformation of classical and
`atypical antipsychotics, has been the most studied [ 15].
`CY P enzymes exist as different subtypes, which exhibit
`preferential affinity/activity toward one or more xenobiotics;
`for example, c lozapine is preferentially metabolized by
`
`CYP I A2 enzymes, while risperidone is preferentially
`oxidi..:ed by the CYP2D6 isoform [41 (Table 1). For this
`reason, the eflicacy and tolerability of these drugs could be
`directly inOucnced by genetic variations in cytochrome CYP
`enzymes. Their activity may also be inOuenced by genetic
`alterations affecting the drug target mo lecule, such as
`dopaminergic and serotonergic receptors, neurotransmitter
`transporters and other receptors and enzymes involved in
`psychiatric disorders [ 16 J. Further investigations on the
`efTect of genetic polymorphism in metabolic enzymes and
`neurotransmiller receptors on psychiatric treatment outcome
`would lead to a better understanding of the rational basis for
`the personalization of psychiatric treatment. Thus innovative
`disciplines, such as pharmaeogenomics and pharmaco(cid:173)
`genomics-guided therapeutic drug monitoring, could provide
`many advantages for the optimization o f antipsychotic
`therapy; this topic will be treated in another review of this
`volume, by L. AI bers et at. It should be noted that the
`knowledge of the multiple symptom dimensions of
`schizophrenia (Scheme I) is importalll to understand the
`possibility of clinical application of atypical anti psychotics.
`The study of the mechanisms and the genetic basis of
`pharmacological interactions has particular importance
`
`Table I. Atypical Antipsychotic Substra tes of Different Cytochrome P~SO lsocnzymes
`
`Isoenzyme
`Antipsychotics
`metabolized
`
`CYPIA2
`Clozapinc
`Olanzapine
`Ch/orproma:i111f1
`
`CYP3A4
`Cloatpinc
`Rispcridonc
`QLtctiapine
`I /aloperidofl
`
`CYI'2U(>
`Rispcridono
`Olan,apino
`I laloperidof1
`Chlorproma::imfl
`
`a The classical antipsychotics haloperidol and chlorpromazine arc reponed for comparison.
`
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`282 Current Medicinal Chemistry, 2004, Vol. 11, No. 3
`
`Table II. Usual Doses and Plasma levels of Atypical Antipsychotics
`
`Raggi eta/.
`
`Drug
`
`Chemical class
`
`Clozapine
`
`Risperidone
`
`Olanzapine
`
`Quetiapine
`
`Ziprasidone
`
`Aripiprazole
`
`!loperidone
`
`Sertindole
`
`Zotepine
`
`Chlorpromazine b
`
`Dibenzodiazepine
`
`Benzisoxazole
`
`Thienobenzodiazepine
`
`Dibenzothiazepinc
`
`Dihydroindolone
`
`Dihydroquinolinone
`
`Benzisoxazole
`
`Indole, imidazolidinone
`
`Diben.~:othiepine
`
`Aliphatic phenothiazine
`
`Daily dose range
`(mg/day)
`
`Therapeutically effective plasma levels (ng/mL)
`
`Minimum
`
`Maximum
`
`200-600
`
`4-16
`
`5-20
`
`300-500
`
`20-80
`
`5-30
`
`4-24
`
`12-20
`
`75-300
`
`50-1000
`
`300
`
`lOa
`
`8
`
`50
`
`20
`
`80
`
`5
`
`3
`
`10
`
`30
`
`3
`
`700
`
`60 a
`
`50
`
`400
`
`200
`
`450
`
`25
`
`140
`
`90
`
`1100
`
`30
`
`Haloperidol b
`a Concentration of the "active moiety" (i.e., the sum of risperidone and 9-hydroxyrisperidone concentrations).
`b The classical anti psychotics haloperidol and chlorpromazine are reported for comparison.
`
`B utyrophenone
`
`2-60
`
`because currently about 30% of antipsychotic prescriptions
`concerns patients undergoing polypharmacy (17]. The use of
`two antipsychotics simultaneously, however, is a debated
`practice in psychiatry [ 18]. In fact, while antipsychotic
`monotherapies are well accepted because their efficacy is
`based on compelling evidence from controlled trials and
`meta-analyses (19, 20], antipsychotic polypharmacy is a
`practice mostly derived from clinical experience [21]. This
`controversial issue will be treated more deeply in another
`review of this volume, by S.M. Stahl et al.
`
`It should be noted that TDM of second generation
`antipsychotics in the clinical setting is usually carried out
`only as a possible strategy under defined conditions, such as
`poor response and polypharmacy. On the contrary, it is our
`opinion that a wider application of TDM to the patients
`could provide very useful information on the pharmacology
`of the drugs, as well as preventing side and toxic effects,
`thus potentially reducing the number of hospitalization cases
`and consequently the cost of therapy.
`
`Table Ill. Clinical potency and characteristics of Atypical Antipsychotics
`
`Drug
`
`Minimum effective dose
`(mg/day)
`
`Clinical
`Potency
`
`Advantages
`
`Disadvantages
`
`Clozapine
`
`Risperidone
`
`Olanzapine
`
`Quetiapine
`
`Ziprasidone
`
`Aripiprazole
`
`Iloperidone
`
`Sertindole
`
`Zotepine
`
`Chlorpromazine a
`
`50
`
`4
`
`5
`
`150
`
`20
`
`5
`
`4
`
`5
`
`75
`
`50
`
`++
`
`+++
`
`+++
`
`+
`
`++
`
`+++
`
`+++
`
`+++
`
`+
`
`+
`
`Effective on non-responders, little or no EPS,
`generic
`
`Possible agranulocytosis, seizures at
`very high doses, weight gain
`
`Active on pos. and neg. symptoms, little or no
`EPS at low doses
`Active on pos. and neg. symptoms, little or no
`EPS
`Active on pos. and neg. symptoms, little or no High doses if hypotension present; short
`t112 (multiple daily administrations)
`EPS, safe in overdosage
`QTc prolongation
`
`EPS and hypotension at high doses
`
`Weight gain. sedation
`
`Little or no EPS, no hyperprolactinemia, no
`body weight gain
`No EPS, no hyperprolactinemia, no body
`weight gain
`
`Little or no EPS
`
`Little or no EPS, no hyperprolactinemia, no
`sedation
`
`Anxiety, insomnia, headache
`
`QTc prolongation
`
`QTc prolongation, weight gain
`
`Haloperidol a
`+ - low; ++ - medtum; +++ - h1gh
`a The classical antipsychotics haloperidol and chlorpromazine are reported for comparison.
`
`2
`
`+++
`
`Generic, parenteral form available
`
`Little or no EPS, useful for depressive
`symptoms
`
`Short half-life, convulsions at high
`doses
`
`Generic, inexpensive
`
`Several side effects (EPS,
`hyperprolactinaemia)
`
`Severe EPS, cardiac effects
`
`Roxane Labs., Inc.
`Exhibit 1021
`Page 009
`
`

`
`Atypical Antipsyc/wtics
`
`The present paper considers the main atypical
`antipsychotics, namely clozapine, olanzapine, quetiapine and
`risperidone, with respect to their pharmacodynamic and
`pharmacokinetic properties, and to their side and toxic
`effects. Attention will also be paid to novel formulations,
`metabolism and pharmacological interactions, and analytical
`methods useful for the therapeutic drug monitoring (TDM)
`of atypical antipsychotics. The main characteristics of other,
`very recent atypical antipsychotics (such as ziprasidone,
`iloperidone, zotepine, sertindole and aripiprazole) will be
`briefly presented as well.
`A summary of the chemical-clinical properties of atypical
`antipsychotics, such as usual dose ranges and typical
`effective plasma levels, is reported in Table II. The main
`therapeutical advantages and disadvantages of these drugs, as
`weJI as their clinical potency, are summarized in Table III.
`The characteristics relative to two classical antipsychotics
`(chlorpromazine and haloperidol) are also reported in both
`Tables for the purpose of comparison.
`
`CLOZAPINE
`Clozapine (8-chloro-11-( 4-methyl-1-piperizinyl)-5H(cid:173)
`dibenzo[b,e][l,4]diazepine, CLZ), Fig. (3a), was the first
`"atypical antipsychotic" to be introduced into therapeutical
`practice in the 1970s. Clozapine (ClozariJ®, Leponex®, by
`Novartis Pharma) (21] has demonstrated to be very effective
`against the negative and positive symptoms of schizophrenia
`and in reducing suicidal tendencies [22], and has been
`successfuiiy used in patients who are "non-responder" to the
`classical neuroleptic drugs (23, 24]. CLZ is still one of the
`most widely used atypical antipsychotics, despite its
`complex and not entirely known mechanism of action: in
`
`Current Medicinal Chemistry, 2004, VoL 11, No. 3
`
`283
`
`fact, it interacts with several subtypes of dopaminergic (Dr,
`D2, D3, D4), serotonergic (5-HTtA• 5-HT2A• 5-HT2c, 5-
`HTJ, 5-HT6, 5-HT7), adrenergic (aJ, a2), histamine (Ht)
`and