`
`Novel antipsychotics:
`issues and controversies.
`
`Typicality of atypical antipsychotics
`
`Emmanuel Stip, MD, MSc, CSPQ
`
`Centre tie Recherche Fernand Seguin, Hopital L.-H. Lafontaine, Universite de Montreal, Montreal, Que. and University of
`British Columbia. Vancouver. BC
`
`The typically of atypical antipsychocic drugs remains debatable. Preclinical studies and findings from ran-
`domized. controlled and open trials of clozapine. olanrapine, risperidone. quetiapine. sertindole. ziprasi-
`done and a substituted benzamide were examined. A MEDLlNE search was conducted using key words.
`including “extrapyrarnldal side effeCts." "cognition," “schizophrenia" and the generic drug names. Over I40
`articles from peer-reviewed journals were reviewed, some of which were based on a meta-analysis. New-
`generation neuroleptic agents were found to have greater efficacy on the negative symptoms of schizo.
`phrenia and to cause fewer unwanted extrapyramidal side afiecrs (E95) than the traditional antipsychotic
`drugs. On one hand, atypical neuroleptic agents could be strictly defined as any neuroleptic agent with
`antipsychotic effects at a dosage that does not cause extrapyramidal side effects. Thus. ciozapine is regard~
`ed as the “standard“ atypical antlpsychotic drug. On the other hand, typicality is about dimension rather
`than category. and we suggest the use of the term “spectrum of atypicality." For example. an emphasis is
`placed on quetiapine to illustrate where a new compound fits in this spectrum. Although close-related.
`atypicality may be more a quesu‘on of prescription attitude drain of a specific characteristic of a compound.
`The degree to which a new compound is clinically superior to another atypical antipsychotic drug, in terms
`of improving positive. negative or affective symptoms, cognitive function and long-term outcome. will
`require further a priori‘ hypotheses based on conceptual frameworks that are clinically meaningful. in addi-
`tion. the results from industry-sponsored trials should be more comparable to diose obtained from inves-
`tigator-leading trials. Finally. the patient characteristics that define a panel-It's response to a specific antlpsy-
`chotic drug are unknown.
`
`Le caractere typique des neuroleptiques atypiques susclte touiours des débats. On a analysé des études
`précllniques et les résultats d‘études randomisées, controlees et ouvertes portant sur la clozapine. l’olan—
`zapine. la rispéridone. la quetiapine. Ie serflndole, Ie ziprasidcme et une benzarnide substituée. On a affec—
`tué dans MEDLINE une recherche en moyen tie mom clés cornme «extrapyrumidal side effects», «cognition».
`«schizophrenia» et des noms generiques des medicamenu. On a analyse plus de I40 articles provenant de
`ioumaux critiques par des pairs, dont terrains fondés sur um: meta-analyse. On a constaté que les neu-
`
`
`
`Correspondenca to: Dr. Emmanuel Ssip. Centre de Recherche Fernand-Seguln. 733I Hochelaga. Montreal, PQ HIN 3V2; fax 5 I4
`ZSl-fl I T: ommanuel.sflp@umonu-eai.ca
`Medical subject headings: antipsychotic agents: cloupine: cognition: receptors. dopamine: rlsper‘idone: schizophrenia
`
`j Psychiatry Neurosci 2000;25{2):i3?~53.
`
`Submitted fan. 2?, l9”
`Revised Oct. 5. I999
`Accepted Aug.
`| I. I999
`® 2000 Canadian Medical Association
`
`
`
`1
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`LATUDA04354653
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`Slayback v. Sumitomo
`|PR2020-01053
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`1
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`Exhibit 2014
`Slayback v. Sumitomo
`IPR2020-01053
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`roleptiques de la nouvelle generation agissent plus efficacement sur les symptomes negadfs de la schizophrénle et
`causeot mains d‘elfets secondaires mpyzamidaux (ESE) indesires que les neuroleptiques classtques. On pour-
`rait d’une part définir les neurolepflquas atyplquas a Mutant parler comme tour neuroleptique qui a des elfets
`antipsychotiques a one dose ne provoquam pas d‘eflets secondaires extnpyramidaux. La cloupine est ainsi con-
`sidérée comme un neuroleptique atypique «standard». Par ailleurs, le caractere typique pone sur la dimension
`plurot que sur la categorie et nous sugarcane d'ufiliser I'expmslon «spectre atyplque». Par exemple, on met
`t'accent sur la quétiap‘me pour illustrer la place «for: nooveau compose dans ce spectre. meme s'il est lit a Ea dose.
`Ie mam atypique pent etre lie Men plus a one attitude do prescripteur qu’a use communique spectfique d'un
`compose. it faudra poser d’autres hypotheses fondees a priori sur dos cas conceptual: significadfs sur Ie pian clini-
`que pour determiner le degré auquel le nouveau composé est cliniouement Superieur a un autre neuroleptique
`atypique pour ce qul es: d'améliorer les symptom posiziis, négattfs ou affectifs. la function cognitive et les resul-
`tant a long tenne. En outre, tee résultats d'emdes commanditees par I'industrie devraient acre plus comparable:
`a ceux que l'on a obtenus a la suite d'etudes dirigéns par des chercheurs. Enfin. on he connait pas les caracréris-
`tiques do patient out definissent 5a reaction a on neuroleptique en pardculler.
`
`Introduction
`
`The commercial advent of a new class of psychotropic
`drugs, the so-called “atypical” neurolepfics, has already
`begun to change the prescription habits of the medical
`community. These drugs are unique because they affect
`different brain receptors and do not inhibit the same
`neurotransmitters as their ”typical" counterparts. But
`how are they atypical? Does this qualification corre—
`spond to a biological and clinical reality? The answer is
`not immediate, because very often receptor profiles dif-
`fer quantitatively rather than qualitafivelyf for exam-
`ple, chlorpromazine basically inhibits many of the same
`receptors as clozapine or olanzapine.1 At present, there
`is no consensus regarding the "atypical" classification
`of these drugs, and clinicians are divided over the issue.
`One side favours the term "anfipsychotios," whereas
`others prefer the terms “atypical neuroleptic agents,"
`“novel neuroleptic agents,” ”second-generation” or,
`more recently, "mud-generation neuroleptic agents."
`Schizophrenia was first treated with neuroleptic agents
`in the 19505 and 19605 after the discovery of (11110er
`mazine. At that time, one of the defining criteria of neu-
`roleptirs was the induction of an extrapyramidal syn-
`drome. The more recent trend in the development of
`new pharmacologic agents has been to avoid this prop»
`erty. and thus new neuroleptics could rightly be
`labelled "atypica ."3
`Until recentiy in North America, the various classes of
`classical or traditional neuroleptics tie, phenotl‘fiazines.
`butyrophenones, thioxanthenes and other compounds
`Such as pimozide) were the only antipsychoiics avail-
`able. These drugs are primarily effective against the peer
`itive symptoms of schizophrenia (e.g., delusions and
`
`hallucinations). Few psychiatrists would dispute the use
`of antipsychotic drugs in controlling the more florid or
`positive symptoms of schizophrenia and in preventing
`psychotic relapse. A review of 24 placebocontrolled
`trials found that 65% of patients relapse without anti-
`psychotic treatment compared with 30% of those who
`continue treatment.4 The traditional neuroleptics are,
`however, less satisfactory in treating the negative symp-
`toms of schizophrenia, thus opening an interesting ther-
`apeutic niche for “atypical neuroleptics.”M
`The interpersonal and socioprofessional repercus-
`sions of schizophrenia are probably primarily related to
`the disorders negative symptoms, which generally
`determine the patients prognosis and rehabilitation.
`The cognitive dysfunctions associated with schizophre-
`nia (e.g., memory, attention and abstract thought) must
`also be considered: when Kraepeljn first described
`schizophrenia in 1396, he labelled the disorder ”demen-
`tia praecox," precisely on account of the cognitive dis-
`turbances presented by young adults.
`The clinical picture of schizophrenia also has an affec-
`tive component. About 25% of patients with schizo-
`phrenia will experience at least 1 depressive episode in
`their lifetime” «- the suicide rate of 10% holds true for
`
`the overall population of patients with schizophrenia,
`whereas the suicide rate in those without schizophrenia
`is 0.01% to 0.25%:a patients who suffer from comorbid
`depression most likely have a higher suicide rate. As
`with all medications, the undesirable side effects of
`
`atypical neuroleptics must be assessed. Unlike their tra-
`ditional counterparts, may produce fewer and less—
`pronounced extrapyramidal effects, which constitutes
`their strong advantage over traditional neuroleptics.1‘”3
`These new drugs are also atypical in terms of their
`
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`cost. Given the existing climate of budgetary cuts, we
`interviewed a representative sample of 1001 people
`from Quebec by telephone in March 1997: "Neuro-
`lepn'cs H drugs used in the treatment of Schizophrenia
`w are different one from another. The more recent ones
`
`produce fewer side effects, are more effective against
`symptoms and afford a better quality of life, but can be
`up to 20 times as expensive as the older ones. Do you
`think that, in the case of a disorder such as schizophre-
`nia, new neuroleptics should be prescribed from the
`start?" Seventy-seven per cent responded yes and 12%
`responded no.“
`
`Classical or typical agents:
`receptors and symptoms
`
`From the outset, researchers have wondered how neu-
`roleptics differ from one another in terms of mode of
`action and efficacy against the symptoms of schizo-
`phrenia (e.g., hallucinations, anxiety, agitation and
`deficit or negative symptoms). French clinicians classi-
`fied neuroleptios as either ”incisive” (effective against
`delusions) or “sedative” (effective primarily against
`anxious agitation), thereby justifying the combined use
`of these compounds. In the United States, it was gener~
`ally tacit that all neuroleplics were mterchangeable in
`terms of dirucal efficacy,m5 and questions about the
`combined use of neuroleptics were first asked in the
`19805, after clinicians saw that neuroleptics did not all
`produce the same side effects, such as extrapyramidal,
`cardiovascular or vegetative symptoms.“ It was sug-
`gested that this was probably owing to the different
`antagonistic effect of each neuroleptic on the brain’s
`dopaminergic and serotoninergic receptors. Research
`suggests that the antagonist action of traditional neuro-
`leptics on the dopamine (1),) receptors is directly
`responsible for their efficacy against positive symptoms
`such as hallucinations, but also for the induction of cer«
`tain side effects.ms
`
`However, there is no consistent evidence that any
`classical antipsychotic is more effective than another.”
`Indeed, approximately 30% of patients do not respond
`to treatment with classical antipsychotics and are cate»
`gorized as nonresponders or treatment resistant. These
`include patients who have had either at least 3 6-week
`periods of neuroleptic treatment over the past 5 years,
`with neuroleptics from 2 or more chemical classes, at
`dosages equivalent to at least 1000 mg per day of chlor-
`promazine, or no period of good functioning over the
`
`past 5 years?" In addition, approximately 30% to 40% of
`patients are partial responders to neuroleptic therapy,“
`and 20% to 30% of patients who benefit initially relapse
`within 2 years of starting drug treatment. Some of these
`patients even become treatment resistant.22 Notably, the
`traditional antipsychotics have little effect on primary
`negative symptoms.” These drugs are also associated
`with side effects, such as the extrapyramidal syndrome,
`which includes parkinsonisrn, dystonia, akathisia and
`tardive dyskinesia, in up to 75% of patients .2‘ The levels
`of extrapyramidal side effects (BPS) in patients signifi-
`cantly predicts reluctance to take antipsychotic drugs.15
`Also, drugs prescribed to counter EPS have their own
`spectrmn of side effects and thus can cause further com-
`plications.
`According to the dopamine hypothesis,” schizophre-
`nia is caused by increased dopaminergic transmission in
`the brain, and the ability to block postsynaptic D2 recep»
`tors is a biochemical effect characteristic of all classical
`
`antipsychotics. In 1986, See-man” linked the efficacy of
`these drugs to their D2 receptor binding affinity. More
`recently, Kapur et all“8 in Toronto used positron emission
`tomography (PET) to confirm the correlation between
`the I), receptor occupancy rate and the clinical efficacy
`and onset of EPS. Blockade of 60% to 70% of the E)2
`dopamjnergic receptors appears sufficient for optimal
`clinical efficacy, that is, a significant improvement in
`symptoms?” When the D, receptor occupancy rate of
`80% is exceeded, BPS become manifest." The ideal neu-
`
`roleptic agent would, flierefore, have to block approxi-
`mately 60% to 80% of D2 receptors to obtain maximum
`efficacy without inducing undesirable side effects.
`This outlook is appealing in principle, but in every-
`day clinical practice it is still impossible to accurately
`estimate the proportion of D2 receptors that will be
`blocked when prescribing medication in schizophre—
`nia."3 However, experimental evidence suggests that the
`dosage of haloperidol which results in 60% to 80% occu-
`pancy of D2 receptors is 2 to 3 mg per day.Bl Although
`theoretically this dosage should be enough for optimal
`clinical efficacy correlated to an optimal D, receptor
`blockage rate, dosages 5 to 20 times as high are pre-
`scribed in current clinical practice.
`The negative symptoms of schizophrenia can be
`either primary or treatment related.32 The deleterious
`effect of haloperidol on paranoid patients might corre-
`spond to a bradykmesia.” To the extent that blunted
`affect, avolition, aboulia in schizophrenia, bradyphenia
`or athymia in parkinsonism are phenomenologically
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`similar, a dopaminergic deficit may be seen as a com-
`mon feature of these subcortical illnesses. Deficit symp—
`toms in schizophrenia may be related to decreased
`dopaminergic neurotransmisaion.”
`
`Atypicality
`
`Atypical neuroleptic drugs are divided into various
`family groups, including:
`0 Dibenzodiazepines, such as clozapine, olanzapine,
`quetiapine, zotepine and amoxapine? loxapine
`belongs to this chemical group, and in combination
`with cyproheptadine it becomes less typical"5
`0 Substituted benzamides, such as remoxipride (sold in
`Canada, but withdrawn from the market because it
`
`was associated with the risk of aplastic anemia), and
`amisulpride (popular in Europe, effective against
`negative symptoms and associated with few EPS.‘
`' Benzisoxazole derivatives, such as risperidone.
`0 Ziprasidone.
`‘I Sertindole.
`
`Clozapine was the first antipsychofic agent to be
`termed atypical because it was clinically effective but
`associated with much lower levels of EPS than seen
`
`with other antipsychotic agents.”38 However, ciozapine
`also showed atypical effects on serum prolaclin icvels,
`which increased only transiently after administration of
`the drug. interestingly, clozapine is currently the lead-
`ing neuroleph'c prescribed in China; its use since 1977 in
`the major psychiatric hospitals of Shanghai and Beijing
`shows an efficacy rate greater than that of other neuro-
`leptics, and it presents few problems with agranulocy-
`tosis.” Notably, no case of dyskinesia attributable to
`ueatment by clozapine per se has been reported world-
`wide to date.
`
`traditional antipsychotics increase serum pro-
`All
`lactin, an effect assodated with D1 receptor inhibition. 1n
`
`1988, Kane et al” demonstrated the superior efficacy of
`clozapine in patients with neaurlent-resistant Schizo-
`phrenia, namely those patients who were unresponsive
`to classical antipsychotics. Clozapine has a complex
`receptor binding profile and affects multiple brain
`receptors (Table 1).“H3 The serotinin mdopamine (5.
`H'I‘,:D,) ratio of affinities is thought to be a good indicar
`tor of possible atypicaiity. [n 1998 Karim"1 proposed a
`model (a further development of the Meitzer’s model)
`that takes in account the SHE/D; occupancy thresl'loldw
`Low SHE/high D; is related to conventional neurolep-
`tics, high 5-HTz/high D2 is related to clanzapine and
`risperidone, high 5vl-IT2/low D, to clorapine and low 5-
`l-sz/lcw D2 to quetiapine. However, this model is as yet
`unable to explain the efficacy on negative symptoms
`and the safety on EPS of anusulpride, which has high
`potential for blocking the D2 and D, meptcrs and low
`potential for blocking 5-HT, receptors.“ Amisulpride
`has important actions on 1), receptors, which might
`account for some of its peculiarities. However, the rela»
`tively low levels of D2 receptor occupancy (48% versus
`78% for classical agents) and high affinity for 5-HT“
`receptors are believed to be important in reducing the
`ext-apyramidal-syndrome liability of Cloisapu'rief“5 This
`has challenged the notion that efficacy is directly related
`to 0; receptor blockade and encouraged the develop-
`ment of new agents with activity at multiple receptors.
`
`The clozapine model of neuroleptics
`
`On a more neurobiologic and morphologic level,
`Chakos et al“ found that the caudate nuclei of patients
`treated with a classical neuroleptic increased in volume,
`whereas the caudate nuclei volume of patients treated
`with clonpine diminished. Researchers had demon-
`strated for the first time that neuroleptics had a direct
`effect on the brain’s structures.
`
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`As part of the basal ganglia, the caudate nuclei are
`directly involved in the genesis of EPS or negative
`symptoms.”*‘”’ Procedural memory requires intact
`basal ganglia to operate properly.”"‘” Procedural learn-
`ing refers to the process of learning either a cognitive or
`motor procedure in which the strategy of execution can-
`not be explicitly described (is, learning by doing).
`Procedures are then progressively learned over succes»
`s'we trials until there is an automation of the optimal
`performance.
`Studies of neurodegenerative disorders such as
`Huntington’s and Parkinson’s diseases show that a stri~
`atai dysfunction could affect procedural learning.” In
`patients with schizophrenia treated with neuroieptics,
`some studies have reported that procedural learning is
`affected, whereas others uncovered no such deficit? It
`is very clear from neuropsychological research that
`schizophrenia itself leads to cognitive deficits. This is
`therefore not a matter of contention. 0n the other hand,
`
`the influence of traditional and novel antipsychotics on
`these cognitive deficits is still a matter of contention.“
`In normal volunteers, acute administration of chlorpn}
`mazine induces a deficit in procedural learning, which
`suggests a direct effect of neuroleptics, presumably via
`a D, blockade in the striatum?‘ Recently we have shown
`that patients with schizophrenia who were treated with
`haloperidol showed many deficits in procedural learn
`ing tasks, whereas clozapine— or risperidonetreated
`patients experienced no such difficulties.55
`Clozapine is the prototype for atypical antipsychotics.
`Although it blocks B, receptors and induces few BPS, it
`causes agranulocytosis, weight gain and sedation.”
`Putative atypical drugs must still be proven against the
`criteria of “atypicality” established by clozapine, name-
`ly their efficacy in patients resistant to classical antipsy-
`chotics, a lower incidence of EPS than is associated with
`
`classical antipsychotics, no sustained increase in serum
`prolactin levels and efficacy against negative symp-
`toms. To outperform clozapine, new atypical drugs
`must not be associated with agranulocytosis, which
`requires costly and inconvenient blood monitoring.
`
`Atypical drugs today and tomorrow
`
`Antipsychotic drugs in development are being judged
`initially on their preclinical profiles to assess potential
`atypicalil‘y. All the tests described below (Table 2) are
`considered useful in predicting efficacy and side-effect
`profiles. Binding affinities at a range of receptors for
`
`ciozapine, risperidone and putative atypical drugs are
`shown in Table 1.5"“
`
`A new wave of atypical antipsychotic drugs, such as
`quetiapine, risperidone, oianzapine, sertindole and
`ziprasidone, are available to treat schizophrenia.“s Data
`from preclinical and clinical trials indicate that these
`new drugs offer significant advantages over current
`treatments and are available for use or will be shortly.
`For example, a recent meta—analysis of 17 randomized
`controlled trials which compared the effect of typical
`versus atypical neuroleptics on negative symptoms
`shown that atypical compounds reduce the degree of
`severity of negative symptoms.5
`
`Risperidone
`
`Risperidone is a benzisoxazole derivative with an affin-
`ity for both D2 and 5-HT2 receptors. For example, ris-
`peridone is as effective as haloperidol against positive
`and negative symptoms,6M and can have a non-durable
`”awakening” effect.la Although it causes few EPS at 6
`mg per day, at dosages above 10 mg per day it induces
`FPS as frequently as haloperidol." Since these effects are
`dose dependent,
`its dosages are currently being
`"revised downward?” Risperidone treatment is also
`associated with hyperprolact‘inemia,m”’ sexual dys-
`functionm and significant weight gain." Thus, although
`risperidone is a useful addition to the antipsychoiic
`drug arsenal, there is some debate regarding its classifi-
`cation as an "atypical" antipsychotic agent.“
`Although the efficacy and, indeed, EPS of classical
`neuroleptics are dose dependent, this is not the case for
`the atypical neuroleptics, except risperidone where EPS
`reappear at dosages of 6 mg per day or more." PET scans
`show that 6 mg per day risperidone blocks 80% of the D2
`receptors, so the appearance of EPS at this dosage is not
`surprising. Risperidone is an atypical neuroleptic at
`doses up to 4 mg per day but begins to lose its atypical
`profile at dosages greater than 8 mg per day."""”“’ In
`some studies, risperidorie did not show superiority in
`terms of EPS when compared with perphenazine,
`zuclopenthixol and methotrirneprazine.MS Neverthe-
`less, risperidone is, and has been, the leading neurolep-
`tic prescribed in Canada since 1996 when it supplanted
`haloPeridol.“ Canadian psychiatrists seem to have rec-
`ognized the value of atypical neuroieptics, particularly
`with respect to their low BPS profiles, but the question of
`the dosage is unresolved. In the Canadian group study
`of Chouinard et al,’1 6 mg risperidone was clearly supe-
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`riot in efficacy and EPS incidence (specifically tardive
`dyskinfiia) to that of other doses of risperidone (2 mg,
`10 mg and 20 mg). However, since PET data from
`patients using 6 mg rispeiidone showed a D, occupacy
`above 80%,” EPS should become more prominent and
`mereforetheseclirficalfindingsofEPSatémgremain
`open to discussion.
`As Impala“5 stressed: "A more complete understand-
`ing of the optimal dose of risperidone requires investi-
`gation of seiect groups of patients,
`including first-
`episode as well as refractory patients." In her study
`with first—break patients, the symptom response rate
`was better at tower (2 to 4 mg) than higher {5 to 8 mg)
`doses of risperidone for all 3 symptom clusters of the
`Positive and Negative Syndrome Scale (PANSS). A
`more recent factor analysis on the 5 dimensions of
`schizophrenia has shown that dosages of 6 to 16 mg per
`day of risperidone yielded better factor scores on posi-
`tive symptoms, disorganized uncontrolled hostih'ty and
`
`than lower dosages of risperi-
`anxiety/ depression,
`done.” The response rate on PANSS total scores at
`weeks 6 and 8 were similar for risperidone and
`haioperidol (“both at doses of 2 mg), and during treat—
`ment with risperidone;
`the mean time to the best
`response was 3.7 months.W
`
`Olanzapine
`
`Olanzapine is a dibenzodiazepine with combined sero-
`tonin—dopamine antagonist actions and a wide spec-
`trum of binding affinities for other neurotransmitter
`binding sites." Preclinical studies have shown that olan-
`zapine produces dozapine-appropriate responses in
`animal drug discrimination model.” It is also more
`potent in irflubiting avoidance responses than in induc-
`ing catalepsy and causes selective depolarization of tim-
`bic A18 dopamine cells, suggesting low BPS liability.”
`However, olanzapine produces dystonic reactions (sug-
`
`
`
`
`
`
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`as increase is the fl‘squemy oi active twosome behaviour anti
`is suggesceo as a mode‘i for paranoid eeimsioss.
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`other mtipaychotic drugs {egg risperitficm‘,
`xiiiorprosmzsns Ehsgfizsnariue} suggest: :9 sate-m
`cermiarion between the ahéiit’; eta: composes to iridme
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`and a iistsiiiry tor pmcacing W5.
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`negatEve smiptom: of schuofireoia,
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`time CE?TE€9‘6§%£5F with FPS. amt? :Mresxsryd hiodéim'h
`rm: or: time correisces with a. psychotic «efficacy.
`
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`gesiive of EPS} in the haloperidolwsensitized monkey
`within the predicted human antipsychotic dose range,“
`but causes fewer EPS clinically than haloperidol,95
`Although olanzapine shows a well-established efficacy
`and causes minjn'tal elevation of prolactin levels,
`patients do experience significant weight gain.“
`
`Quetiapine
`
`Quetiapine is a dibenzodiazepine with an affinity for
`multiple brain receptors. it is active in behavioural and
`electrophysiological tests believed to predict antipsy-
`chotic activity. Quetiapine also satisfies a number of
`phannacologic criteria that are putative predictors of
`atypicaljty, such as its higher affinity for central 5-HT2
`than 13, receptors?”8 Like clozapine, quetiapine shows
`limbic selectivity,"9 causes minimal dystonic liability in
`haloperidoisensifized and drug-naive Cebus mon~
`keys“ and is associated with only transient eleva~
`tions in plasma prolactin after acute administration in
`rats.” Furthermore, quetiapine is selected in a dose—
`dependent manner by Squirrel monkeys trained to dis-
`tinguish clozapine from saline?“ it restores pro-pulse
`inhibition in apomorphine—treated rats with a potency
`comparable to that of clozapine,“2 and it produces
`induction patterns of neuronal Pos expression simiiar to
`that
`induced by clozapine but different from that
`induced by haloperidol."5 Case reports and clinical trials
`suggest that quetiapine has the potential to improve
`certain components of memory and attentiorrm'l”5
`Clinical trials have shown that quetiapine is effective
`against positive and negative symptoms of schizophre—
`In clinical studies, sertindole produces EPS compara-
`nia)“ is associated with fewer BPS than haiopericlol,W
`ble to placebo at all tested doses, although it has been
`
`
`shows EPS levels comparable to placebo across the
`entire dosage range‘““” (Fig. 11m“) and is not associated
`with sustained increases in serum prolactin.“2 Quetia-
`pine has the lowest incidence rate of akathisia of the
`atypical neuroleptics (Table B‘W't'”). The optimal
`dosage is probably greater than 250 mg per day.“ To
`summarize, quetiapine is an analogue of clozapine and
`blocks dopamine, 5-HT and other receptors. Its receptor
`binding profile is dose to that of clozapine, suggesting
`a similar degree of efficacy, and its propensity to cause
`fewer adverse effects than clozapine {such as agranulo—
`cytosis} indicates potential therapeutic benefit.”" The D2
`occupancy is lower than what is observed with typical
`or atypical antipsychotics.”‘ The patients subjective
`experience with quetiapine has also been noted as very
`specific by several. clinicians, and patient satisfaction
`has been confirmed as high during a long-term treat-
`ment.“
`
`Settindole
`
`Serfindole is unusual in that, unlike clozapine, it has lit-
`tle or no effect in acute tests for dopamine antagonism,
`whereas its effects on 5-HT“ receptors are potent and
`iong lasting.m lt selectively depolarizes A10 dopamine
`cells only at low doses,””" fails to reverse oamphetw
`mine- or apomorphine-induced inhibition of rnidbrain
`dopamine ceils (a standard test for antipsychotic activi-
`ty)m and produces dystom'c reactions in haioperidol-
`sensitized monkeys at doses that are inactive in the
`conditioned avoidance test.“‘
`
`Pooled data
`
`King
`
`In-‘—-—— —--—-----uua-—
`
`-5
`
`-10
`
`45
`
`I: Mew-analysis of change in Brief Psychiatric Rating Scale (BPRS) total score from
`Fig.
`baseline for quetiapine compared with placebo (data represent mean 44- 95% confidence
`Interval; where necessary, 25 mg quefiapine has been considered a placebo dosage equiva-
`lent). (Adapted. with permission. from Meatsg'” King et al"'.)
`
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`associated with undesirable cardiovascular effects such
`
`as hypotension and a prolonged Q—T interval.m To our
`knowledge, the core clinical trials with sertindole are
`the only ones to have compared the new drug with dif-
`ferent doses of haloperidol: 4 mg, 8 mg and 16 mg. Such
`a design is assent-ta} for obtaining objective data on EPS
`and improvement of negative symptoms. In these triais,
`serfindole proved significantly better than haioperidoi
`with respect to BPS, even against 4 mg of haloperidol.
`However, it was not different in terms of improvement
`of negative symptoms, although a trend of improve
`ment did emerge with 20 mg of serfindole.’”-‘” A path
`analysis technique was performed on these results and
`showed a direct effect on negative symptoms.“ A very
`large study with almost 20 000 patients, designed to
`specifically assess the QT interval issue, was planned
`to be completed in 2005, but it has been halted.ml ’Ihe
`drug is currently under review at the European regis-
`tration agency.
`
`Ziprasidone
`
`mine hyperactivity is 10 times the dose required to pro-
`duce cataiepsy, which is indicative of a low BPS liabili-
`ty at antipsychotic doses. In contrast, however, data
`show that dystonic reactions occur in haloperidol—
`sensitized Cebus monkeys at projected antipsychotic
`dosesW“ (aithough halopeiidolwinduced dystonia can
`be reversed by a combination of a selective 5-HT“ ago-
`nist with haloperidol in rats”). This agonistic property,
`which is inherent to ziprasidone, needs to be studied
`hirther. Data from phase II and phase In clinical trials
`have shown zipraSidone to be effective in reducing the
`positive and negative symptoms of schizophrenia,
`reducing depression associated with schizophrenia,
`and in diminishing anxiety“: Moreover, a parenteral
`fonnuiation of ziprasidone has been developed to facil-
`itate the administration of antipsychotic therapy to
`acutely agitated patients.
`In summary, atypical anfipsychotics shotdd have the
`following: EPS at levels comparable to placebo, global
`efficacy at least equal to that of classics} anfipsychotics
`and a specific effect on negative symptoms. A broader
`definition might
`include: no sustained increase in
`serum prolactin after administration, although efficacy
`in treatment-resistan