`
`F
`
`S
`
`POINTS
`
`¢ The mechanistic inner-workings thought to under-
`lie both pharmacologic andclinical class actions
`possessed by atypical antipsychotics may ultimately
`oweto the inherent utility of each compound's
`5-HT2a2 receptor-relative-binding affinity ratio.
`* Rapid dissociation of atypical antipsychotics from
`Dz receptors is also believed to contribute to over-
`all antipsychotic efficacy and decreased incidence
`of extrapyramidal symptoms.
`¢ Appropriate dosing remains a critical issue and
`ultimately a prerequisite for optimizing the ther-
`apeutic effects and tolerability profile of each
`atypical antipsychotic.
`
`Academic Supplement
`Atypical Antipsychotics:
`Matching ReceptorProfile to Individual
`Patient’s Clinical Profile
`By Darius K. Shayegan, BS, and Stephen M.Stahl, MD, PhD
`
`dalside effects (EPS). Furthermore, theutility of these
`agents as mood stabilizers with application for treatment
`within bipolarillness has also recently been recognized.
`Understanding individual differences among the various
`atypical antipsychotics may provide manyof the answers
`to commonclinical questions. Whydoes one patient
`tespond to one agent, and not another? Why do some
`patients experience side effects with one agent, yet others
`do not? Are these drugs interchangeable in their antipsy-
`chotic or mood-stabilizing effects? How well dodifferent
`agents address other independent symptom domains of
`disease? This review will examinethe similarities and dif-
`ferences among atypical antipsychotics in terms of their
`mechanismsof action andclinical efficacy. The strategy
`of matching the best receptor profile to each individual
`patient's clinical profile as a means for obtaining a favor-
`able treatment outcomewillalso be assessed.
`
`ABSTRACT
`Understanding common pharmacologic and clinical
`“class” actions associated with atypical antipsychotics cer-
`tainly reveals how these agents are alike, but what about
`unique differences from one agent to another? Atypical
`antipsychotics are also a heterogeneous group of agents that
`have complex pharmacologic entities, acting upon multiple
`dopamine receptors (Dz, D,, D3, and D4) and multiple
`serotonin receptors (S-HT, 5-HT2c, 5-HT4, and 5-
`HT, among others). Atypical antipsychotics also interact
`with noradrenergic (0t,- and ,-adrenergic receptor block-
`ade), histaminergic (H,-receptor blockade), and cholinergic
`(muscarinic M, blockade) neurotransmitter systems as
`well as with monoamine (D, 5-HT, and norepinephrine
`reuptake blockade) transporters. However, no two atypical
`antipsychotics possess the same portfolio of actions upon all
`of these additional neurotransmitter systems.
`CNSSpectr. 2004;9(Suppl 1 1):6-14
`
`BACKGROUND
`Having now celebrated the 50th anniversary of the
`introduction of classical neuroleptics intoclinical prac-
`tice, these conventionalantipsychotics very successfully
`demonstrated the relationship between dopamine (D,)
`receptor blockade andclinically robust antipsychotic
`action. In fact, all available antipsychotic agents tar-
`get the key hypothetical neurochemicaldisturbance in
`psychosis—excessive dopamine neurotransmission at
`D,receptors in the mesolimbic pathway ofthe brain—
`presumably responsible for the positive symptoms of
`schizophrenia. Building upon theclassical modelof
`mesolimbic D, antagonism, present day atypical anti-
`psychotics extend upon this theme,offering comparable
`if not better control over positive symptoms of psycho-
`sis, while maintaining a dramatically reduced propen-
`sity for causing motorside effects typically associated
`I
`INTRO.
`with conventional agents.
`Atypical antipsychotics are the preferredfirst-line
`This more clinically desirable therapeutic and
`treatmentsfor schizophrenia, owing to their ability to
`tolerability profile of the five first-line atypical anti-
`effectively manage the positive and negative symp-
`psychotics—-aripiprazole,ziprasidone, quetiapine, olan-
`zapine, and risperidone—is duelargely to their serotonin
`toms of schizophrenia while minimizing extrapyrami-
`This article is based on information presented at the 157th Annual Meeting ofthe American Psychiatric Association, held May 1-6, 2004, in New York
`City. Since the data were presented,aripiprazole, quetiapine , and ziprasidone were approved by the US Food and Drug Administrationfor the treatment
`ofacute bipolar mania. Other atypical antipsychotics previously approved for the wearmentofacute bipolar mania include olanzapine and risperidone.
`All graphic illustrations/tables/figures in this feature, ©2003-2004 Neuroscience Education Institute. All Rights Reserved.
`Please direct all correspondence to: Darius K. Shayegan, BS, Neuroscience Education Institute, 5857 Owens Ave, Suite 102, Carlsbad, CA
`92008; Tel: 760-931-8857; Fax: 760-931-8713; E-mail: darius@neiglobal.com.
`Volume 3 - Number 10 (Supp! 11)
`6
`
`CNS Spectrums — October 2004
`
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`
`1
`
`Exhibit 2045
`Slayback v. Sumitomo
`IPR2020-01053
`
`Exhibit 2045
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Atypical Antipsychotics: Matching Receptor Profile to Individual Patient’s Clinical Profile
`
`(5-HT)>4/D) antagonist or D> receptor partial agonist
`actions-—properties that contribute to improved anti-
`psychotic efficacy, reduced motorside effects, and a
`variety of potential mood-stabilizing effects.'? In fact,
`in addition to having properties of 5-HT,/D, antago-
`nistn/partial agonism, atypical antipsychotics also exert
`substantial blockade of D) receptors with concomitant
`comparable or greater functional blockade of 5-HTz4
`receptors at clinically therapeutic doses. It is predomi-
`nantly these features that are considered pharmaco-
`logic actions sharedby all atypical antipsychotics as
`a class; they are thought to account for the universal
`ability of these agents to mitigate the positive symp-
`toms of schizophrenia and otherdisorders of psychosis
`and potentially exert a variety of other mood-stabiliz-
`ing effects. The mechanistic inner-workings thought to
`underlie both pharmacologic and clinical class actions
`possessed by atypical antipsychotics may ultimately owe
`to the inherentutility of each compound's 5-HT),/Dy
`receptor-relative-bindingaffinity ratio (Figure 1).°*
`When maximized through optimal dosing of
`each agent,it is the fundamental bindingaffinity
`relationship between drug and receptor that allows
`atypical antipsychotics to leverage and applytheir
`associated class properties of D) and 5-HT>4 antag-
`onismor partial agonism within key neurocircuits
`involved in the pathophysiology ofdisease.
`
`WHATIS SO GREAT ABOUT 5-HT34
`ANTAGONISM?
`Although 5-HT;,4 antagonismalonehas been asso-
`ciated with the potential for antipsychotic activity, by
`
`itself this property does not appear to confer antipsy-
`chotic effects comparable to those attributed to clas-
`sical D, antagonism.”'° Rather, 5-HT> antagonism
`functions to reduce dopamine D) antagonism in key
`pathways, which can help to avoid motor symptoms
`without reversing antipsychotic activity. In the meso-
`limbic dopamine pathway, 5-HT,4 antagonism does
`not reverse D, antagonism to the extentthat it would
`interfere with antipsychotic actions. In the mesocorti-
`cal pathway, 5-HT),4 antagonism may help to increase
`dopamine release enough to improve negative and
`cognition symptoms mediated in this pathway. In the
`nigrostriatal dopamine pathway, the opposition of
`dopaminerelease by serotonin would act to decrease
`the likelihood of causing motor side effects. Thus, the
`superimposition of 5-HT>, antagonism on D, antago-
`nism in this pathway reduces D, bindingsufficiently
`that enough D, receptor blockadein the striatumis
`reversed, ultimately reducingliability for EPS.
`This concert of 5-HT),4/D) antagonist/partial ago-
`nist actions has been previously analogized as a kind
`of seesaw that “teeters” and “otters” until achieving
`balance in the distressed circuits outlined above.!!
`Rapid dissociation of atypical antipsychotics from D,
`receptors is also believed to contribute to overall anti-
`psychotic efficacy and decreased incidence of EPS."
`These agents—clozapine and quetiapine, in particu-
`lar—-are thought to exhibit a “hit-and-run” action at
`the dopamine D, receptor, hitting this receptor with
`sufficient force (bindingaffinity) to result in antipsy-
`chotic effects, yet binding weakly enough to run (dis-
`sociate) off the receptor before causing EPS."
`
`
`
`
`
`ReceptorAffinities(1/K)x100
`
`
`
`
`
`
`
`ReceptorAffinities(1/K)x100
`
`Risperidone
`
`x BHT SHI, SHITE
`
`NAT
`
`
`
`
`
` 2ReceptorAffinities(WK)x100
`
`Olanzapine
`
`DT
`
`SHY” SHI. SHT" SHI, SHIT”
`
`NAT
`
`Quetiapine
`
`0,
`
`SMT” SHY,” SH,” SHT,”
`
`SHIT”
`
`NAT
`
`Aripiprazole
`
`Binding
`
`
`
`
`
` 2fieceptorAffinities(17K)x100
`
`Ziprasidone
`
`D, ST, ST,”
`
`SME” SHY,” SHIT
`
`NAT
`
`g
`
`8 3
`
`-
`
`8 ¥3
`
`é=
`
`FIGURE1. All Atypical Antipsychotics Have Relevant 5-HT2 and D2, Binding®*
`Represented here for comparison are individual receptor-binding-affinity profiles for five first-line atypical antipsychotic agents. Binding
`affinity of these agents for the D2, and 5-HT2za receptors are plotted on a logarithmic scale for the purpose ofrelative comparison. Each of the
`agents has binding affinity
`for the 5-HT2a receptor, which approaches or exceedsits bindi
`affinity for the D2 receptor. A dashed line labeled
`ustrate the hypothetical functional activity
`“Functional Activity” has
`been added to the receptoraffinity plot for aripiprazole in an effort toif
`, consistent with
`of this compound at various dopamine receptor subt
`e hypothesis proposedbyLawler and colleagues® that aripiprazole
`maintains
`functionally selective activation of D2 (and
`possibly D3)-dopamine receptors expressed in
`humantissue.
`D=dopamine; 5-HT=serotonin; NAT=noradrenaline transporter.
`Shayegan DK, Stahi SM. CNS Spectr. Vol 9, No 10 (Suppl 11). 2004.
`
`Volume 9 ~ Number 10 (Suppl 11)
`
`CNS Spectrums ~ October 2004
`
`
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`€
`

`

`D.K. Sh
`
`, 5.M.Stahl
`
`Undoubtedly,all 5-HT,4/D) antagonists share the
`same treatmenttargets: to quiet hyperactive dopa-
`mine neurons that mediate psychosis (mesolimbic
`pathway); to spark underactive dopamine neurons
`that mediate negative and cognitive symptoms (meso-
`cortical pathway); and to preserve physiologic func-
`tion in dopamine neurons that regulate movement
`(nigrostriatal pathway) and prolactin secretion (tuber-
`oinfundibular pathway)—accomplishing each ofthese
`goals concurrently in the brain.
`
`assessments of D) and 5-HT) receptor occupancy
`across multiple doses of ziprasidone indicate that doses
`ofat least 120 mg/day are required to optimize antipsy-
`chotic action.” These findings perhaps also explain
`empiric limitations in clinical response reported by
`clinicians to occur when ziprasidone is administered
`in the lower end of the dosing range. In light of this
`information and recent data showing an apparentlack
`of a dose-response curve for QTc interval prolongation,
`ziprasidoneis even beginning to be utilized at doses of
`160-320 mg/day in difficult cases.”
`CLASS ACTIONS ARE IMPORTANT: WHAT
`In the case ofaripiprazole, it may be too early to
`
`DOSEISNEEDEDTOENLISTTHEM? ___
`define optimal dosing in schizophrenia,bipolarillness,
`As mentioned previously, how favorably a clinician
`and special patient populations. While doses of 10, 20,
`is able to take advantage of the pharmacologic and asso-
`and 30 mg/day have been proven efficacious in patients
`ciated clinical class actions of atypical antipsychotics
`treated within clinicaltrials, it is not yet clear whether
`depends largely on howeach agentis dosed in practice.
`these same doses provide the best combined antipsy-
`However, each of thefivefirst-line agents entered the
`chotic efficacy andtolerability profile with respect to
`market with dosing recommendations that did not nec-
`treating antipsychotic-naive patients and children, for
`essarily provide the best aim toward establishing both
`example, or if lower doses of aripiprazole may be more
`maximal antipsychotic efficacy and tolerability of these
`clinically desirable.!* It is through trial and error of both
`agents in patients treated within our own clinical prac-
`on- andoff-label uses that clinicians are helping to fine-
`tice. The discrepancies betweeneffective doses of these
`tune aripiprazole dosing in regard to optimizing treat-
`agents determined within earlier clinical trials, and the
`ment not only in schizophrenia, but in acute mania and
`optimal therapeutic dosing models we have nowrefined,
`softer indications, such as bipolar I] and in children.
`Appropriate dosing remainsa critical issue and ulti-
`given the benefitof time and clinical experience, are pos-
`mately a prerequisite for optimizing the therapeutic
`sibly due to the notion that the subpopulation of patients
`effects andtolerability profile of each individual atypi-
`studied in trials may not precisely represent the whole
`of patients seen in real-world practice. In any event, we
`cal antipsychotic. Although the dosing tips summarized
`both above and in the Table can certainly help clini-
`have nowlearned thatit is a good idea to dose risperi-
`doneless than whatwas initially predicted (16 mg/day),
`cians obtainpositive and acute manic symptomefficacy,
`namely within 2-6 mg/day to help avoid unwanted EPS
`not every patient responds to the same agent at the
`same dose, nor does each patient necessarily have the
`withoutsacrificing antipsychotic efficacy.
`sameflavor of response to each agentat the same dose.
`Similarly, olanzapine 10 mg/day wasinitially
`thought to be the mosteffective dose; however, wide-
`Clarification on this issue requires the identification of
`other porentialclinically relevant receptor actions of
`spread clinical experience suggests thar 15-20 mg/
`atypical antipsychotics, beyond the 5-HT>,4/D) antago-
`day may be more efficacious. Even higher doses may
`nist/partial agonist properties shared bytheclass.
`be more effective for patients refractory to antipsy-
`chotic treatment. Olanzapine also appears to share a
`dose-response curve for efficacy, but not necessarily
`WHATIS SO GREAT ABOUT ALL OF
`THE OTHER BINDING PROPERTIES OF
`for weight gain, suggesting that moreefficacy might
`potentially be gained with higher doses without neces-
`
`ATYPICALANTIPSYCHOTICS?
`Understanding common pharmacologic andclinical
`sarily incurring moreside effects.'*
`Quetiapine, though, historically has not been dosed
`“class” actions associated with atypical antipsychotics
`certainly reveals how these agents are alike, but what
`correctly. This atypical was initially expected to work
`between 200-300 mg/day, but nearly every clinician
`about unique differences from one agentto another?It
`in practice now knowsit takes 2500 mg/day toopti-
`turns out thatatypical antipsychoticsare also a hetero-
`mize antipsychotic efficacy, tolerability, and mood-sta-
`geneous group of agents that have complex pharmaco-
`bilizing effects. Dosing quetiapine up to 2750 mg/day
`logic entities, acting upon multiple dopamine receptors
`(not just D, but also D,, D3, and Dy) and multiple sero-
`may potentiallybe useful in treating difficult cases.”
`tonin receptors (not just 5-HT,4 but also 5-HT20,
`To date,ziprasidone has been gloriously underdosed
`5-HT,4, and 5-HTp, among others). Atypical
`in clinical practice. Initial studies of D, receptor occu-
`pancy data predicted antipsychotic efficacy ofziprasi-
`antipsychotics also interact with noradrenergic
`(a,- and a-adrenergic receptor blockade), histamin-
`doneat doses of 20-40 mg.''® However, more recent
`
`Volume 9 — Number 10 (Suppl 11)
`
`CNS Spectrums ~ October 2004
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`

`

`
`
`
`tor Profile to Individual Patient's Clinical Profile
`
`
`ergic (H,-receptor blockade), and cholinergic (musca-
`rinic M, blockade) neurotransmitter systems as wellas
`with monoamine (DA, 5-HT, and NEreuptake block-
`ade) transporters. However, no two atypical antipsy-
`chotics possess the sameportfolio of actions upon all of
`these additional neurotransmitter systems.
`The path to unveiling the clinical usefulness of
`unique secondary pharmacologic actionsofatypical
`antipsychotic agents begins with understanding the
`candidate models of polygenicillness for selective affec-
`tive disorders such as schizophrenia andbipolardisorder.
`The framework underlying these models encompasses
`multiple interacting symptom domains(positive, nega-
`tive, cognitive, affective, behavioral, and functional
`symptomsof schizophrenia) and phases (acute mania,
`hypomania, depression, and mixed states associated
`with bipolar illness) that limit the capacity of affected
`individuals to participate in meaningful social engage-
`mentor achieve their desired quality oflife.’ In the
`case of schizophrenia and schizoaffective disorder, such
`theories suggest that the earlier and more globally these
`symptoms are bombarded with treatment,the better the
`long-term prospect that patients will become meaning-
`fully reintegrated into the workplace, community, and
`family life. These same models might also be expected
`to predict similar trends with regard to mood stabiliza-
`tion, as various areas of overlap in the genetics, neuro-
`circuitry, and neurochemistry underlying schizophrenia
`andbipolarillness have now been identified.” To date,
`however,theeffects of early atypical antipsychotic-
`based therapeutic intervention in bipolar disorders
`are considerably less well-understood in terms of their
`impact upon long-term patient outcomes.
`Nowequipped with a neurobiologically informed
`appreciation of current hypotheses linking genes,
`
`TABLE. ADJUSTING THE DOSE OF ATYPICAL
`ANTIPSYCHOTICSIN CLINICAL PRACTICE
`
`Spectr. Vol 9, No 10 (Suppl 11). 2004.
`
`Attaining The Goal of Substantial D, and
`5-HT>, Blockade
`* Risperidone (original dosing of 16 mg reduced to 2-6 mg)
`* Olanzapine (original dosing of 10 mg increased to
`15-20+ mg)
`* Quetiapine (original dosing of 200-300 mg needs to
`be adjusted to >500 mg and up to 800+ mg)
`¢ Ziprasidone (average dose still often <80 mg; >50%
`of use is below 120 mg; dose needs to be >120 mg for
`optimalefficiency)
`* Aripiprazole (who knows yet? 20-30 mg may be too
`high for children, mood disorders and those withour
`prior antipsychotic dosing; 5mg?)
`D=dopamine; 5-HT=serotonin.
`
`Shayegan DK, Stahl SM. CNS Spectr Vol 9, No 10 (Supp! 11). 2004.
`CNS
`
`neurocircuitry, and neurochemistry to the manifesta-
`tions of psychotic illness, the strategy of selectively
`leveraging pharmacologic actions which function to
`stabilize and reduce symptom domains mostclosely
`correlated with best treatment outcomes—cogni-
`tive andaffective symptoms in schizophrenia—will
`ultimately serve to maximize the chances of these
`benefits, and thus of a favorable outcome.
`
`WHAT RECEPTOR-BINDING PROPERTIES
`MIGHT ENHANCE THE ABILITY OF AN
`ATYPICAL ANTIPSYCHOTIC TO IMPROVE
`M
`DC
`ITION?
`
`5-HT2, and 5-HT2- antagonist properties
`5-HT>, receptors are most highly concentrated
`on pyramidal neurons (and to a lesser extent y-ami-
`nobutyric acid [GABAlergic interneurons) residing
`in the cortex.”* More specifically, these receptors are
`found densely populated about the apical dendrite and
`somal portions of cortical pyramidalcells (Figure 2a).?>
`Current theories suggest that both dopaminergic and
`serotonergic input to cortical pyramidal cells—poten-
`tially mediated through D,/Ds, and 5-HT>, receptor
`mechanisms—are thoughtto play an importantrole
`in the endogenous modulation of cognitive processes.
`Furthermore, deficits in executive cognition and work-
`ing memory are associated with hypothesized altera-
`tions in local prefrontal information-processing circuits
`that involve cortical pyramidal neurons—the same
`neurons implicated in the pathogenesis of schizophre-
`nia.”6"? Such developments have led many who study
`5-HT3, receptors to believe that the salutatory effects
`of 5-HT,4 antagonism are conferred via effects on cor-
`tical pyramidal neurons. Blocking 5-HT>, receptors in
`these neuronsappears to enhance aspects of working
`memory, whereas activation of the 5-HT, receptor in
`this context impairs cognition.”* Whetheror notclini-
`cally relevant, pro-cognitive effects associated with
`atypical antipsychotics are mediated (either entirely
`or in part) through actions upon 5-HT2, receptors
`located on cortical pyramidal neurons. Although not
`fully understood, the role of 5-HT>4 receptor signaling
`in cortical processes remains an important therapeutic
`target for future drug discovery, and perhaps may be
`compelling enoughfor the neurobiologically informed
`clinician to consider when tailoring individual phar-
`macologic treatments to individual patients.
`Anotherpossibility to explain the potential impor-
`tance of 5-HT>, antagonist properties in the enhance-
`mentof cognition and mood through the dopaminergic
`and noradrenergic pathwaysis illustrated in Figure 2b.
`Serotonin neurons projecting from the raphe provide
`inhibitory control over dopamine neurons in the ven-
`
`Volume 9— Number 10 (Suppl 11)
`
`CNSSpectrums — October 2004
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`

`

`D.K. Shayegan, $.M.Stahl
`
`
`tral tegmental area (VTA).” These dopamine neurons
`project from the VTA to the cortex andare inhibited
`directly via 5-HT4 receptors located on the dopa-
`mine neurons themselves. Similarly, serotonin neurons
`projecting from the raphe mayalso provide inhibitory
`control over noradrenaline (NA) neuronsin the locus
`coeruleus (LC) via a 5-HT3, receptor mechanism,*"!
`Noradrenaline neurons which project from the LC to
`the cortex may be inhibited directly via 5-HT, recep-
`tors located on the noradrenaline neurons themselves,
`and possibly indirectly via 5-HT4 receptors located on
`GABAinhibitory interneurons.
`5-HT4 antagonist actions that block binding of
`serotonin to these receptors in these (and perhaps
`other) pathways might theoretically be expected to
`“disinhibit” both dopaminergic and noradrenergic out-
`put to cortex.>28 Thatis, enhancing dopaminergic and
`noradrenergic neurotransmission may contribute to
`improvementof cognitive symptoms whenthis occurs
`in dorsolateral prefrontal cortex**”? and to improve-
`ment ofaffective symptoms, such as the reduction of
`apathy and anhedonia, whenthis occurs in medial
`prefrontal cortex, anterior cingulate cortex, and
`orbitofrontal cortex.*°*? Although specific circuitry
`and pathways are not as well-characterized, similar
`enhancement of dopamine and noradrenaline release
`in the cortex by way of antagonist actions at 5-HT2¢
`receptor sites, may also theoretically be expected to
`producedesirable clinical effects, including improve-
`ments in both cognition and mood(Figure 2c).
`
`
`
`FIGURE 2A.Cortical Pyramidal Neuron”
`Artist’s representation of cortical pyramidal neuron physiology.
`D=dopamine; 5-HT=serotonin; VTA=ventral tegmental area.
`chic” neuron of the
`Adapted from: Goldman-Rakic PS.The ”
`cerebral cortex. Ann N Y Acad Sci. 1999;868: 13-26.
`Shayegan DK,Stahl SM. CNS Spectr. Vol 9, No 10 (Supp! 11). 2004.
`
`Eachofthefivefirst-line atypical antipsychotics
`have bindingaffinity for the 5-HT4 receptor, which
`approachesor exceeds their binding affinity for the D>
`receptor (Figure |). Risperidone, olanzapine, andzipra-
`sidone each possess binding affinity for the 5-HT2¢.
`receptor, which approaches or exceeds their affinity
`for the dopamine D, receptor (Figure 4). These agents,
`having considerable affinity for the 5-HT¢ receptor,
`likewise have high 5-HT/D> affinityratios. Thus,
`these agents possess the desirable pharmacologic action
`of 5-HT_, antagonism in the presence of concomi-
`tant D, receptor and 5-HT, receptor blockade—all at
`
`S-HT,
`
`a,
`
`SH,
`
`ny
`
`/
`
`“
`GABA neuron
`
`5-HT,w”
`
`/
`
`Shayegan DK, Stahi SM. CNS Spectr. Vol 9, No 10 (Supp! 11). 2004.
`Shayegan DK, Stahi $M. CNS Spectr. Vol 9, No 10 (Suppi 11). 2004.
`
`FIGURE2B. 5-HT2, Antagonist Properties”
`§-HT=serotonin; DA=dopamine; NA=noradrenaline; GABA=y-
`aminobutyric acid.
`
`|c
`
`GABAneurons
`
`FIGURE 2C. 5-HT2- Antagonist Properties”
`5-HT=serotonin; DA=dopamine; NA=noradrenaline; GABA=y-
`aminobutyric acid.
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`Volume 9— Number10 (Supp! 11)
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`CNS Spectrums — October 2004
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`
`tor Profile to Individual Patient’s Clinical Profile
`
`clinically effective antipsychotic doses. Although not
`completely understood, the simultaneous occurrence
`of these pharmacologic actions together is thought to
`be important in orchestrating cognitive and mood-
`enhancing/stabilizing effects associated with atypical
`antipsychotic treatment as observed in clinical practice.
`
`5-HT,, Agonist/Partial Agonist Properties
`Agonist or partial agonist actions at presynaptic 5-
`HT}, receptors have been shown to contribute to anti-
`depressanteffects, possibly through the enhancement
`of 5-HT neuronaldisinhibition through this mech-
`anism.** Furthermore, agonist and/or partial agonist
`actions at postsynaptic 5-HT, 4 receptors have been
`shown to facilitate cortical dopaminerelease, particu-
`larly when occurring in the presence of concomitant
`D, and 5-HT>, receptor blockade.”In addition to
`affect and cognition, actions of atypical antipsychotics
`at the 5-HT; receptor mayultimately play a more del-
`icate role in tempering other nonpsychotic features of
`schizophrenia such as anxiety, hostility, problems with
`working memoryand attention, and inadequate social
`interaction.Quetiapine, ziprasidone, and aripipra-
`zole each possess bindingaffinity for the 5-HT}4 recep-
`tor, which approaches or exceedstheir affinity for the
`D, receptor, and are summarized in Figure 3.
`
`5-HT;p Antagonist Properties
`The 5-HT})5 receptoris a presynaptic autoreceptor
`that inhibits serotonin release. Blocking this receptor
`
`disinhibits serotonin release, which would theoreti-
`cally have both antidepressant and anxiolytic effects
`is certain parts of the brain.” However, can 5-HTjp
`autoreceptor antagonist properties enhancethe ability
`of an atypical antipsychotic to improve mood and cog-
`nition! Theevidence to date is quite limited, however,
`preclinical evidence suggests the potential of rapid
`increases in serotonin release and other antidepressant
`actions to be associated with 5-HTjp autoreceptor
`antagonist actions. Early clinical indications of anti-
`depressantactions are also perpetuating further clini-
`cal analysis of compounds having 5-HTjp antagonist
`properties. Ziprasidone possesses bindingaffinity for
`the 5-HTjpreceptor, which approaches or exceeds
`its affinity for the dopamine D, receptor (Figure 3).
`However,the extent to which blockade of this recep-
`tor byziprasidoneat clinical antipsychotic doses may
`ultimately contribute (if at all) to procognitive, antide-
`pressant, or anxiolytic actions is presently unknown.
`
`5-HT and NE Reuptake-Blocking Properties
`Can 5-HT- and norepinephrine (NE)-reuptake—
`blocking properties enhance the ability of an atypical
`antipsychotic to improve mood and cognition? This
`makes sense hypothetically, given our understand-
`ing of the effects of serotonin and/or noradrenaline
`selective reuptake inhibitors that possess similar phar-
`macologic properties. However, if these transport-
`ers are occupied at <50% atclinical doses of atypical
`antipsychotics, it is not presently known whether this
`
`
`
`
`
`ReceptorAffinities(LAK)x100
`
`Risperidone
`
`*
`0, Si, SH, SHY, SH, SATT
`
`*
`NAT
`
`
`
`
`
`ReceptorAffinities(1/K)x100
`
`Quetiapine
`
`Olanzapine
`
`*
`*
`SHI, SHI, SHI SHIT
`
`*
`NAT
`
`0,
`
`SHT
`
`
`
`
`
`ReceptorAffinities(1K)x100 2
`
`
`
`
`
`Ziprasidone
`
`3
`
`8 $
`
`3
`
`
`
`
`
`éé
`
`
`
`
`
`°
`e
`D, SMT” Sut," Surt”NATSHY,” SHT,”
`©,
`"SHY, SHY,” SHt, SHI, SHIT”
`NAT
`
`8
`
`Aripiprazole
`
`~38
`
`ReceptorAffirsties(17K)x100
`
`FIGURE 3. Summary of Potentially Important Therapeutic Receptor Actions of Atypical Antipsychotics®®
`ents. A summary of receptor binding
`es
`Represented here are individual receptor-binding-affinity profiles for five first-line atypical antipsychotic ag
`affinities
`of these agents for the Dz, 5-HT2a,2¢,14,10, and serotonin and norepinephrine transporters are plotte
`on a logarithmic scale for the purpose
`nding the individual and unique differences in these pharmacologic properties from one
`ent to the next is key
`of relative comparison, Ui
`ie treatment outcome
`in attempting to maximize the
`ential for enhancing cognition and mood in patients and thus achieve the most favor
`for each patient. A dashed line labeled “Functional Activity” has been added to the receptoraffinity plot for aripiprazole in an effort to illustrate
`the hy
`consistent with the hypothesis proposed by Lawler
`thetical functional activity of this compoundat various dopamine receptor sul
`and co ae that aripiprazole maintains functionally selective activation of Dz (and possibly D3)-dopamine receptors expressed in humantissue.
`* (ki)x1
`D=dopamine; 5-HT=serotonin; 5-HTT=serotonin transporter; NAT=noradrenaline transporter.
`Shayegan DK, Stahl SM. CNS Spectr. Vol 9, No 10 (Supp! 11). 2004.
`
`Volume 9 - Number 10 (Supp! 11)
`
`CNSSpectrums — October 2004
`
`
`
`

`

`D.K. Shayegan, S.M.Stahl
`
`blockade of monoaminetransporters will result in a
`clinically recognizable effect. It is also not yet clear
`if these transporters are occupied at <50%, but 5-HT
`and NE are bothdisinhibited by other, concomitant
`actionsat clinical doses—-whetheror not this would
`have a meaningfulclinical effect upon mood and cog-
`nition. With ample data supportingthe clinicaleffects
`of monoamine transporter blockade by atypicalanti-
`psychoticsstill lacking, clinicians must rely on their
`ownclinical experience and understanding of the
`theoretical basis for optimizing 5-HT and NE neuro-
`transmission to develop the best treatment approach
`for each individual patient. Ziprasidone appears to be
`the only first-line atypical antipsychotic that inhibits
`both NE and 5-HT reuptake with a potencysimilar to
`that of imipramine and amitriptyline.®
`
`CAN OTHER RECEPTOR PROPERTIES
`INTERFERE WITH THE ABILITY OF AN
`ATYPICAL ANTIPSYCHOTIC TO IMPROVE
`ITION OR MOOD?
`
`Muscarinic Cholinergic Antagonist Properties
`Muscarinic (M,) cholinergic antagonist actions
`may theoretically interfere with procognitive, pro-
`cholinergic actions on acetylcholine release in the
`brain, to the extent that inhibiting acetylcholine
`release via this mechanismhas clinically remarkable
`impact on cognition and memory.Olanzapine and
`quetiapine possess bindingaffinity for the M, recep-
`tor, which exceeds their affinity for the D3 receptor,
`
`indicating marked potency of both compounds for
`blocking these receptors at clinically relevant anti-
`psychotic doses (Figure 4). Interestingly, however,
`atypical antipsychotics as a class have been shown
`to improve cognition (to varying degrees) as well as
`increase acetylcholine release in the medial prefrontal
`cortex (mPFC).** Although the role of M; receptors
`in cognition is not entirely understood, a lowaffinity
`for M, receptors would theoretically predict a low
`propensity for causing anticholinergic side effects,
`including cognitive dysfunction and gastrointestinal
`disturbances, at clinically relevant doses.
`
`Histamine and @.,-Adrenergic
`Antagonist Properties
`Antihistamine (H, antagonist) and a, (adrener-
`gic)-blockingactionseither alone or in combination
`mayinterfere with pro-cognitive effects and may cause
`sedation. Furthermore, recent data have shown strong
`correlation with weight gain and blockade of H; and
`@, receptors in patients treated with atypical antipsy-
`chotics.** Agents with lower propensity to block H,
`or ,-adrenergic receptors relative to their ability to
`block D, receptors may thus be expected to cause less
`sedation, orthostatic hypotension, and weight gain,
`which add to a more favorable tolerability profile in
`clinical practice.*? Olanzapine and quetiapine both
`possess binding affinity for the histamine H, recep-
`tor, which exceeds their affinity for the dopamine
`D, receptor (Figure 4). All five of thefirst-line atypi-
`cal antipsychotics passess potent a, receptor-binding
`
`Olanzapine
`
`2
`
`
`
`
`
`ReceptorAffinities(WK)x100
`
`Quetiapine
`
`2
`
`
`
`
`
`ReceptorAffinities(1/K)x10%
`
`Ziprasidone
`
`Aripiprazole
`
`b,
`
`a
`
`4,
`
`*
`mM,
`
`
`
`5
`
`Risperidone
`
`§
`
`3 S
`
`$
`
`2
`
`g ¢2i:é
`
`
`
`
`
`ReceptorAlfinities(18)x190
`
`FIGURE 4. Summary of Potentially Important Side-Effect Receptor Actions of Atypical Antipsychotics
`Represented here are individual receptor-binding~affinity profiles for five first-line atypical entipaycheticagents. A summary of receptor binding
`nities of these agents for the Dz, 5-HT2a,2¢14,10, and serotonin and norepinephrinetransporters are
`on a logarithmic scale for the purpose
`of relative comparison. Unde:
`rstanding the individual and unique differences in
`pharmacologic properties from one
`agent to the next is key
`in attempting to maximize the
`potential for enhancing cognition and mood in patients and thus achieve the most favorable treatment outcome
`for each patient. A dashed line
`fabeled “Functional Activity” has been added to the receptor affinity plot for aripiprazole in an effort toillustrate
`type:
`the hypothetical functionalactivity of this compound at various dopamine receptor sub!
`s, consistent with the hypothesis pro
`by Lawler
`and colleagues" that aripiprazole maintains functionally selective activation of Dz (and possibly D2)-dopamine receptors expressed in humantissue.
`* (1ki)x100<0