Academic Supplement
`Atypical Antipsychotics:
`Matching Receptor Profile to Individual
`Patient’s Clinical Profile
`
`By Darius K. Shayegan, BS, and Stephen M. Stahl, MD. PhD
`
`dal side effects (EPS). Furthermore, the utility of these
`agents as mood stabilizers with application for treatment
`within bipolar illness has also recently been recognized.
`Understanding individual differences among the various
`atypical antipsychotics may provide many of the answers
`to common clinical questions. Why does one patient
`respond to one agent, and not another? Why do some
`patients experience side effects with one agent, yet others
`do not? Are these dmgs interchangeable in their anripsy‘
`chotic or mood—stabilizing effects? How well do difierwt
`agents address other independent symptom domains of
`disease? This review will examine the similarities and dif—
`ferences among atypical antipsychotics in terms of their
`mechanisms of action and clinical efficacy. The strategy
`of matching the best receptor profile to each individual
`patient’s cliniml profile as a means for obtaining a favor—
`able treatment outcome will also be assessed.
`
`F
`
`S
`
`lNTS
`
`
`
`o The mechanistic inner-workings thought to under~
`lie both pharmacologic and clinical class actions
`possessed by atypical antipsychotics may ultimately
`owe to the inherent utility of each compound's
`5-HT2NDI receptor-relative—binding affinity ratio.
`0 Rapid dissociation of atypical antipsychotics from
`02 receptors is also believed to contribute to over—
`all antipsychotic efficacy and decreased incidence
`of extrapyramidal symptoms.
`0 Appropriate dosing remains a critical issue and
`ultimately a prerequisite for optimizing the ther—
`apeutic effects and tolerability profile of each
`atypical antipsychotic.
`
`ABSTMQI
`Understaiuling common pharmacologic and clinical
`“Chis" actions associated with atypical antipsychotics ccr‘
`tainly reveals how these agents are alike, but what about
`unique differences from one agent to another? Atypical
`amipsychotics are also a heterogenewts group of agents that
`have complex phm'macologic entities, acting upon multiple
`dopamine receptors (DZ, D], D, and D4) and multiple
`serotrmin receptors (5rHTZA. 5—l-iTzc. 5—HTiA. and 5.
`HT”), among others) . Atypical ancipsyclwtics also interact
`with noradrenergic ((l1- and ayadrenergic receptor block
`ads), histaminergic (H l-recepi‘or blockade) , and cholinergic
`(muscarinic M1 blockade) neurotransmitter systems as
`well as with monoamine ( D, 5—HT, and norcpinephn'ne
`reupmkc blockade) transporters. However, no two atypical
`antipsychotics possess the same portfolio ofactitms upon all
`of dicsc additional neurotransmitter systems.
`CNS Spectr. 2004;9(Suppl l l):6—l4
`
`INT 0
`
`l
`
`BACK ‘ROUND
`Having now celebrated the. 50th anniversary of the
`introduction of classical neuroleptics into clinical prac-
`tice, these conventional antipsychotics very succeSfully
`demonstrated the relationship between dopamine (D2)
`receptor blockade and clinically robust antipsychotic
`action. In fact, all available antipsychotic agents tar»
`get the key hypothetical neurochemical disturbance in
`psychosis——excessivc dopamine neurotransmission at
`DZ receptors in the mcsolimbic pathway of the brain—-
`presumably responsible for the positive symptoms of
`schizophrenia. Building upon the classical model of
`mesolimbic D2 antagonism, present day atypical anti-
`psychotics extend upon this theme, offering compamble
`if not better control over positive symptoms of psycho—
`sis, while maintaining a dramatically reduced propen-
`sity for causing motor side effects typically associated
`with conventional agents.
`Atypical antipsychotics. are the preferred first-line
`This more clinically desirable therapeutic and
`treatments for schizophrenia, owing to their ability to
`tolerability profile of the live first—line atypical anti.
`effectively manage the positive and negative symp-
`psychotiw—aripiprazole. ziprasidonc, queriapine. olanv
`zapinc, and rispcridone—is due largely to their serotonin
`toms of schizophrenia while minimizing extrapyramiv
`This article is based on inflmnatiim [nesenmdm the 157th Annual Moedngofthe American Psychiatric Axum, heldMa)‘ 1—6. 2034. in New York
`City. Since thcdatawere presented, wipipramle, quenzqine, and zitrrasidmte were Wand by the US FooclmtIDugr'ldmmisn’atiimflrr the treatment
`ofacwe bimlar mania Other arypical armlmics [warmly Miriam for the traummt ofacurc bipolar mania include olmzapinc and um.
`All graphic illmn'amms/tables/frgures in this feature, “200}2004 Neuroscience Education Institute. All Rights Reserved
`Please direct all corresprmdaice to: Darius Ki Shaycgan, BS. Neuroscience Education lnsa'tute, 5857 Owens Ate, Suite l 02, Carlsbad, CA
`92008; Tel: 760931—8857; Fax: 760331497”; Email: Miamigbbalxomi
`Volume 9 - Number 10 (Suppl 11)
`
`CNS Spectrums - October 2004
`
`
`
`Exhibit 2045
`Slayback v. Sumitomo
`|PR2020—01053
`
`Exhibit 2045
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Am’al Antipggotics: Matching Recggtor Profile to Individual Patient’s Clinical Profile
`
`(S-HThAIDZ antagonist or D2 receptor partial agonist
`actions—properties that contribute to improved anti-
`psychotic efficacy, reduced motor side effects. and a
`variety of potential mood'stabilizing effects. "5 in fact.
`in addition to having properties of 5-HTZA/Dz antago‘
`nisui/partial agonism. atypical antipsychorics also exert
`substantial blockade of D2 receptors with concomitant
`comparable or greater functional blockade of 5-HT“
`receptors at clinically therapeutic doses. It is predomi-
`nantly these features that are considered pharmacor
`logic actions shared by 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 other disorders 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 inherent utility of each compounds SvHTZA/DZ
`receptor-relative—binding affinity ratio (Figure 1).”
`When maximized through optimal dosing of
`each agent, it is the fundamental binding affinity
`relationship between drug and receptor that allows
`atypical antipsychotics to leverage and apply their
`associated class properties of D2 and 5—HT“ antagv
`oanm or partial agonism within key neurocircuits
`involved in the pathophysiology of disease.
`
`Rlsperidone
`
`itself this property does not appear to confer antipsy—
`choric effects comparable to those attributed to clas'
`sical DZ antagonism.9J0 Rather, S'HTZA antagonism
`functions to reduce dopamine D3 antagonism in key
`pathways, which can help to avoid motor symptoms
`without reversing antipsychotic activity. In the meso—
`limbic dopamine pathway. 5—HT;A antagonism does
`not reverse Dz antagonism to the extent that it would
`interfere with antipsychotic actions. In the mesocorti—
`cal pathway. 5-HT2A 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
`dopamine release by serotonin would act to decrease
`the likelihood of causing motor side effects. Thus. the
`superimposition of 5—HT2A antagonism on D; antago—
`nism in this pathway reduces D3 binding sufficiently
`that enough D2 receptor blockade in the striatum is
`reversed, ultimately reducing liability for EPS.
`This concert of S—HTzA/Dz antagonist/partial ago-
`nist actions has been previously analogized as a kind
`of seesaw that “teeters" and "toners" until achieving
`balance in the distressed circuits outlined above.”
`Rapid dissociation of atypical antipsychotics from D2
`receptors is also believed to contribute to overall anti-
`psychotic efficacy and decreased incidence of EPS.”
`These agenIsMclozapine and quetiapine. in particu’
`lat—are thought to exhibit a “hit-and-nm" action at
`the dopamine D3 receptor. hitting this receptor with
`sufficient force (binding affinity) to result in antipsy'
`chotic effects, yet binding weakly enough to run (dis
`sociate) off the receptor before causing EPS.”
`E
`
`Quetiapine
`
`Olanzapine
`
`o
`
`,
`
`”a" you w,‘ sin. S-NTT w
`
`aa§
`
`a
`
`9. wt" SW" w, sun, 5m NAT
`
`humorAfilnlu‘es(UK)nran
`
`
`
`
` ReamerAfhnhlesmox100
`
`m, m, sul,‘ “in, sun m
`
`
`
`Arlpiprazole
`
`Binding
`
`Ziprasidone
`
`5,
`
`sat“ sun sari, 5-H» sm rur
`
`3
`
`a 5
`
`a
`
`g g8 i E3
`
`FIGURE 1. All Atypical Antipsychotics Have Relevant 5-HT“ and DZA Binding“3
`3 inity of these
`ents for the 02. and 5-HT“ receptors are plotted on a logarithmic scale for the purpose of relative comparison. Each of the
`Rafiresented here for comparison are individual receptor«hindlng—afflnity profiles for five first-line atypical antipsychotic agents. Binding
`a
`is has binding affinitgeiorthe 5—HTu receptor. which approaches or exceeds its bindi
`affinity tor the Dz receptor. A dashed line labeled
`“ unctional Activity" has
`ustrate the h pothetical functional activity
`an added to the receptor affinity plot for aripl razole in an e on to il
`, consistent with
`oi this com und at various dopamine receptor subt
`a hypothesis proposed
`Lawler an colleagues‘ that aripiprazole
`maintains
`nctionally selective activation of Dz (a
`possibly Da)—dopamine receptors expressed in man tissue.
`Dadopamine; S-HTmrotonin; NATunoradrenaline transporter.
`Shayegan DK, Stahl SM. (W5 Spear, Vol 9. No 10 (Suppl 11). 2004.
`
`Volume 9 — Number 10 (Suppl 11)
`
`CNS Spectrums — October 2W4
`
`
`
`WHAT rs so GREAT ABOUT 5-HT2A
`ANTAQQNISM.’
`Although 5»HTZA antagonism alone has been asso
`ciated with the potential for antipsychotic activity, by
`3
`3
`§
`§
`
`WAWIWKJx‘00 5
`
`a
`_ saw sat“ sun. wrr an
`
`
`
`
`
`humorMinna(UK)Iwe 5
`
`8
`
`

`

`BK. Sh
`
`, S.M. Stahl
`
`Undoubtedly, all 5-HTM/Dl antagonists share the
`same treatment targets: to quiet hyperactive dopa-
`mine neurons that mediate psychosis (mesolimbic
`pathway); to spark underactive dopamine neurons
`that mediate negative and cognitive symptoms (mead
`cortical pathway); and to preserve physiologic funo
`tion in dopamine neurons that regulate movement
`(nigrostriatal pathway) and pmlaetin secretion (tuber—
`oinfundibular padrwayFaccomplishing each of these
`goals concurrently in the brain.
`
`CIASS ACTIONS ARE IMPORTANT: WHAT
`WMLOWSM? _ _
`As mentioned previously. how favorably a clinician
`is able to take advantage of the phannacologic and 3890'
`ciated clinical class actions of atypical antipsychotics
`depends largely on how each agent is dosed in practice.
`However, each of the five first’line agents entered the
`market with dosing recommendations that did not nec—
`essarily provide the best aim toward establishing both
`maximal antipsychotic efficacy and tolerability of these
`agents in patients treated within our own clinical prac-
`tice. The discrepancies between effective doses of these
`agents determined within earlier clinical trials, and the
`optimal therapeutic dosing models we have now refined,
`given the benefit of time and clinical experience, are pos-
`sibly due to the notion that the subpopulation of patients
`studied in trials may not precisely represent the whole
`of patients seen in real'world practice. In any event, we
`have now learned that it is a good idea to dose risperir
`done less than what was initially predicted (16 tug/day),
`namely within 2-6 trig/day to help avoid unwanted EPS
`without sacrificing antipsychotic efficacy.
`Similarly, olanzapine 10 mg/day was initially
`thought to be the most effective dose; however. wide—
`spread clinical experience suggests that 15—20 mg]
`day may be more efficacious. Even higher doses may
`be more effective for patients refractory to antipsy'
`chotic treatment. Olanzapine also appears to share a
`dose-response curve for efficacy, but not necessarily
`for weight gain, suggesting that more efficacy might
`potentially be gained with higher doses without neces-
`sarily incurring more side effects.”
`Quetiapine. though. historically has not been dosed
`correctly. This atypical was initially expected to work
`between 200—300 mg/day, but nearly every clinician
`in practice now knows it takes 2500 mg/day to opti-
`mize antipsychotic efficacy. tolerability, and mood—sta—
`bilizing effects. Dosing quetiapine up to 2750 mg/day
`may potentially be useful in treating difficult cases."
`To date, ziprasidone has been gloriously underdosed
`in clinical practice. lnitial studies of D2 receptor occu-
`pancy data predicted antipsychotic efficacy of ziprasi—
`done at doses of 20—40 mg!"{8 However, more recent
`
`assessments of D2 and 5—HT; receptor occupancy
`across. multiple doses of ziprasidone indicate that doses
`of at least 120 rug/day are required to optimize antipsyr
`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
`infonnation and recent data showing an apparent lack
`of a dose—response curve for QTc interval prolongation,
`ziprasidone is even beginning to be utilized at doses of
`[60-320 mg/day in difficult cases.20
`In the case of aripiprazole, it may be too early to
`define optimal dosing in schizophrenia, bipolar illness,
`and special patient populations. While doses of 10, 20,
`and 30 mg/day have been proven efficacious in patients
`treated within clinical trials, it is not yet clear whether
`these same doses provide the best combined antipsy’
`chotic efficacy and tolerability profile with respect to
`treating antipsychotic—na'ive patients and children, for
`example, or if lower doses of aripiprazole may be more
`clinically desirable.” It is through trial and error of both
`on- and off-label uses that clinicians are helping to fine—
`tune aripiprazole dosing in regard to optimizing treat-
`ment not only in schizophrenia, but in acute mania and
`softer indications, such as bipolar ll and in children.
`Appropriate dosing remains a critical issue and ulti-
`mately a prerequisite for optimizing the therapeutic
`effects and tolerability profile of each individual atypi—
`cal antipsychotic. Although the dosing tips summarized
`both above and in the Table can certainly help clini«
`cians obtain positive and acute manic symptom efficacy,
`not every patient responds to the same agent at the
`same dose, nor does each patient necessarily have the
`same flavor of response to each agent at the same dose.
`Clarification on this issue requires the identification of
`other potential clinically relevant receptor actions of
`atypical antipsychotics, beyond the 5-1"szA/Dz antago—
`nist/partial agonist properties shared by the class.
`
`WHAT IS SO GREAT ABOUT ALL OF
`THE OTHER BINDING PROPERTIES OF
`
`WWW
`Understanding common pharmacologic and clinical
`"class" actions associated with atypical antipsychotics
`certainly reveals how these agents are alike, but what
`about unique differences from one agent. to another? It
`turns out that atypical antipsychotics are also a hetero—
`geneous group of agents that have complex pharmaco—
`logic entities, acting upon multiple dopamine receptors
`(not just D3 but also D1, D5, and D4) and multiple sero—
`tonin receptors (not just 5-HT“ but also S’I'ITZC,
`5-HT“, and S‘HTID, among others). Atypical
`antipsychotics also interact with noradrenergic
`(Cll— and az-adrenergic receptor blockade), histamin—
`
`(flames—Number 10 (Suppl 11)
`
`CNS Spectrurns — October 200:
`
`
`
`

`

`
`
`
`tor Profile to Individual Patient’s Clinical Profile
`
`
`crgic (Hlvreceptot blockade). and cholinergic (musca'
`rinic My blockade) neurotransmitter systems as well as
`with monoamine (DA. 5—HT, and NE reuptake block-
`ade) transporters. However, no two atypical antipsy-
`chotics possess the same portfolio of actions upon all of
`these additional neurotransmitter systems.
`The path to unveiling the clinical usefulness of
`unique secondary pharmacologic actions of atypical
`antipsychotic agents begins with understanding the
`candidate models of polygenic illness for selective affec—
`tive disorders such as schizophrenia and bipolar disorder.
`The framework underlying these models encompasses
`multiple interacting symptom domains (positive. nega—
`tive, cognitive, affective. behavioral, and functional
`symptoms of schizophrenia) and phases (acute mania,
`hypoinania, depression, and mixed states associated
`with bipolar illness) that limit the capacity of affected
`individuaLs to participate in meaningful social engage—
`ment or achieve their desired quality of life.21 In the
`case of schizophrenia and schizoaffective disorder, such
`theories suggest that the earlier and more globally these
`symptoms are bombarded with trmtment, 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 neuttmhemistry underlying schizophrenia
`and bipolar illness have now been identified?3 To date.
`however. the effects of early atypical antipsychotic—
`based therapeutic intervention in bipolar disorders
`are considerably less well‘understood in terms of their
`impact upon long‘t'crm patient outcomes.
`Now equipped with a neurobiologically informed
`appreciation of current hypotheses linking genes,
`
`TABLE. ADJUSTING THE DOSE OF ATYPICAL
`ANTIPSYCHOTICS IN CLINICAL PRACHCE
`
`Specu Vol 9. N010($upp 11). 2004,
`
`Attaining The Goal of Substantial D2 and
`5—HT» Blockade
`9 Rispendone (original dosing of 16 mg reduced to 2—6 mg)
`0 Olanzapine (original dosing of 10 mg increased to
`15—20+ mg)
`0 Quetiapine (original dosing of 200—300 mg needs to
`be adjusted to >500 mi; and up to 800+ mg)
`0 Ziprasidone (average dose still often <80 mg; >50%
`of use is below 120 mg; dose needs to be >120 mg for
`optimal efficiency)
`0 Aripiprazole (who knows yet? 20-30 mg may be too
`high for children, mood disorders and those without
`prior antipsychotic dosing; 5mg?)
`Dadopamine; MTasermonin.
`
`C
`Sha egan DK. Stahl SM. CNS Spectn Vol 9. No 10 (Suppl 11). 2004.
`
`neurocircuitry, and neumchemistry to the manifesta'
`tions of psychotic illness, the strategy of selectively
`leveraging pharmacologic actions which function to
`stabilize and reduce symptom domains most closely
`correlated with best treatment outcomes—ocogni‘
`tive and affective 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
`D C
`ITION.’
`
`5-HT“ and 5-HT25 antagonist properties
`5—HT;A receptors are most highly concentrated
`on pyramidal neurons (and to a lesser extent y-ami-
`nobutyric acid [GABAlergic intemeurons) residing
`in the cortex?!" More specifically, these receptors are
`found densely populated about the apical dendrite and
`somal portions of cortical pyramidal cells (Figure 2a).25
`Current theories suggest that both dopaminergic and
`serotonergic input to cortical pyramidal cells—potenr
`rially mediated through 01/135, and S‘l'lTZA receptor
`mechanisms—are thought to play an important role
`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.z"-'37 Such developments have led many who study
`S—HTZA receptors to believe that the salutatory effects
`of 5—HT;A antagonism are conferred via effects on CO?!
`tical pyramidal neurons. Blocking 5-HT“ receptors in
`these neurons appears to enhance aspects of working
`memory. whereas activation of the 3—HT2A receptor in
`this context impairs cognition}8 Whether or not clini‘
`cally relevant, pro—cognitive effects associated with
`atypical antipsychotics are mediated (either entirely
`or in part) through actions upon 5—HT2A receptors
`located on cortical pyramidal neurons. Although not
`fully understood, the role of Sal-[TM receptor signaling
`in cortical processes remains an important therapeutic
`target for future drug discovery, and perhaps may be
`compelling enough for the neurobiologically informed
`clinician to consider when tailoring individual phar-
`macologic treatments to individual patients.
`Another possibility to explain the potential impor—
`tance of 5—HT2A antagonist properties in the enhance;
`ment of cognition and mood through the dopaminergic
`and noradrenergic pathways is illustrated in Figure 2b.
`Serotonin neurons projecting from the raphe provide
`inhibitory control over dopamine neurons in the ven-
`
`Volume 9 e Number 10 (Suppl 1t)
`
`CNS Spectrums — October 2004
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`
`
`

`

`,S.M.Stahl
`D.K. Sh c
`
`
`Each of the five first—line atypical antipsychotics
`have binding affinity for the 5+le receptor, which
`approaches or exceeds their binding affinity for the DJ
`receptor (Figure I). Risperidone, olanzapinc, and zipra—
`sidonc each possess binding affinity for the S'HTZLZ
`receptor, which approaches or exceeds their affinity
`for the dopamine D2 receptor (Figure 4). These agents,
`having considerahlc affinity for the 5—HT2C receptor.
`likewise have high 5-HT3C/D2 affinity ratios. Thus,
`these agents possess the desirable phamtacolqgic action
`of 5rl'lT2C antagonism in the presence of concomi—
`tant D2 receptor and 5+le receptor blockadea-all at
`
`tral tegmental area (VTA).N These dopamine neurons
`project from the WA to the cortex and are inhibited
`directly via 5-HT“ receptors located on the dopa-
`mine neurons themselves. Similarly, serotonin neurons
`projecting from the mphe may also provide inhibitory
`control over noradrenaline (NA) neumns in the locus
`coeruleus (LC) via a S’HTZA receptor mechanism.“‘-"
`Noradtenalinc neurons which project from the LC to
`the cortex may he inhibited directly via 5-HT“ recep
`tors located on the noradrenaline neurons themselves,
`and possibly indirectly via S’HTM receptors located on
`GABA inhibitory interneurons.
`5—HT“ 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 noradrcnergic out
`put to cottexfi“ That is, enhancing dopaminergic and
`noradrenergic neurotransmission may contribute to
`improvement of cognitive symptoms when this occurs
`in dorsolateral prefrontal cortex “”5 and to improve’
`ment of affective symptoms, such as the reduction of
`apathy and anhedonia. when this occurs in medial
`preftontal cortex, anterior cingulate cortex, and
`orhitofrontal cortex.“"‘7 Although specific circuitry
`and pathways are not as well—characterized, similar
`enhancement of dopamine and noradrenaline release
`in the cortex hy way of antagonist actions at 5—HTZC
`receptor sites, may also theoretically be expected to
`produce desirable clinical effects, including improve-
`ments in both cognition and mood (Figure 2c).
`
`
`
`FIGURE 2A. Cortical Pyramidal Neuron’5
`Artist's representation of conical pyramidal neuron physiology.
`D=dopamine; 5-HT=serotonin; vrA=venttaI tegmental area.
`chic" neuron of the
`Ada ted from: Goldman~Rakic PSJ'he "
`care altortex.AnnNYAcadSci.1999;
`:13-26i
`Shayegan DK. Suhl SM. CNS Spear. Vol 9. No 10 (Suppl 11). 2004.
`
`5+"
`
`n \
`
`5-HT
`
`u
`
`/
`
`/
`GABA neuron
`
`5+"u.
`
`/
`
`Shayegan OK Stahl 5M. CNS Specu Vol 9. No IO (Supp! It). 2004.
`Shayegan DK. Stahl SM. CNS Spent. Vol 9, No 10 (Suppl H). 2004.
`
`FIGURE 23. S-HTZA Antagonist PropertiesZS
`5-HTsserotonin; DA=dopamine; NA=noradrenaline; GABA=y-
`aminobutyrit add.
`
`n;I‘
`
`GABAneurons
`
`FIGURE 2C. 5-HT2C Antagonist Properties25
`5-HT=serotonin; DA=dopamine; NAznoradrenaline; GABAs-y-
`aminobutyrlc acid.
`
`Volume 9 — Number 10 (Suppl 11)
`
`10
`
`CNS Spectrums — October 2004
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`
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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-HTM Agonist/Partial Agonist Properties
`Agonist or partial agonist actions at presynaptic 5’
`HTIA receptors have been shown to contribute to anti—
`depressant effects, possibly through the enhancement
`of S—HT neuronal disinhihirion through this mech—
`anism.“ Furthermore. agonist and/or partial agonist
`actions at postsynaptic S—HTM receptors have been
`shown to facilitate cortical dopamine release. particu—
`larly when occurring in the presence of concomitant
`D2 and SIHTM receptor blockade.we In addition to
`affect and cognition. actions of atypical antipsychotics
`at the S-HTIA receptor may ultimately play a more del—
`icate role in tempering other nonpsychotic features of
`schizophrenia such as anxiety. hostility, problems with
`working memory and attention, and inadequate social
`interaction.”“‘ Quetiapine, ziprasidone. and aripipra—
`zole each possess binding affinity for the 5»HTI A recep—
`tor. which approaches or exceeds their affinity for the
`D3 receptor. and are summarized in Figure 3.
`
`5-HT", Antagonist Properties
`The 5vHT1D receptor is a prcsynaptic auroroceptor
`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.‘2 However. can SrHTlD
`autoreceptor antagonist properties enhance the ability
`of an atypical antipsychotic to improve mood and cog-
`nition! The evidence 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 S—HT”) autorcceptor
`antagonist actions Early clinical indications of anti—
`depreSsant actions are also perpetuating further clini—
`cal analysis of compounds. having 54le antagonist
`properties. Ziprasidonc possesses binding affinity for
`the 5+le receptor. which approaches or exceeds
`its affinity for the dopamine [)1 receptor (Figure 3).
`However, the extent to which blockade of this recep-
`tor by ziprasidone at 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 S‘HTv and norepinephrine (NE)»rcuptake—
`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% at clinical doses of atypical
`antipsychotics, it is not presently known whether this
`
`Risperidone
`
`Olanzaplne
`
`Quetia pine
`
`
`
`
`
`ReceptorAnnuities(UK)1lm
`
`
`
`
`
`
`
`humorAffinm'es(IIK)inim
`
`
`
`
`
`RumorAffinitim(UK)it1(1) 9
`
`Aripiprazole
`
`a
`o
`I
`5m, son, w“ sun m
`
`S
`
`0.1
`
`
`
`WAWflmUK):rm
`
`
`
`Ziprasidone
`
`5
`
`§ 5
`
`9
`
`D
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`,
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`5K!“ 9n, 9!!! on.“ sun
`
`rut
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`i i
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`
`FIGURE 3. Summary of Potentially Important Therapeutic Receptor Actions of Atypical Antipsythotics‘r8
`ems. A summary of receptor binding
`es
`a
`niti
`of these agents for the Dz, S-HTiucuuo, and serotonin and norepinephrine transporters are plot!
`ngmented here are individual receptor-binding—affinity profiles for five first-line atypical antipsychotic
`:3 on a logarithmic scale for the purpose
`the individual and unique differences in these pharmacologic properties from one
`em to the next is key
`of relative comparison. Understanding
`e treatment outcome
`in attempting to maximize the
`entlal for enhancing cognition and mood in patients and thus achieve the most favor
`for each patient. A dashed line abeled "Functional Activity” has been added to the receptor affinity plot for aripiprazole in an effort to illustrate
`the hy
`thetical functional activity of this compound at various dopamine receptor subtypes. consistent with the hypothesis pro
`sad by Lawler
`" (ilkllx‘l
`and (O b38305: that anoiprazole maintains functionally selective activation of D2 (and possibly Dantopamine receptors expressed n human tissue.
`D=dopamlne; 5HT=serotoniru SAHTTaerotonin transporter; NAT=noradrenaline transporter.
`Shayegan DK. Stahl SM CNS Spear. Vol 9, No 10 (Suppl 11). 2004.
`
`
`11
`CNS Spectrums — October 2004
`Volume 9 — Number 10 (Suppl 11)
`
`
`
`

`

`D.K. 811123111, SM. Stahl
`
`blockade of monoamine transporters 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 both disinhibited by other, concomitant
`actions at clinical doses—~whether or not this would
`have a medningfiil clinical effect upon mood and cogv
`nition. With ample data supporting the clinical effects
`of monoamine transporter blockade by atypical anti—
`psychotics still lacking, clinicians must rely on their
`own clinical 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 potency similar to
`that of imipramine and amitriptyline.6
`
`CAN OTHER RECEPTOR PROPERTIES
`INTERFERE WITH THE ABILITY OF AN
`ATYPICAL ANTIPSYCHOTIC TO IMPROVE
`ITI NOR 00D?
`
`Muscarinic Cholineryic Antagonist Properties
`Muscarinic (MI) cholinetgic 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 mechanism has clinically remarkable
`impact on cognition and memory.“-“4 Olanzapine and
`quetiapine possess binding affinity for the MI recep—
`tor, which exceeds their affinity {or the D2 receptor.
`
`indicating marked potency of both compounds for
`blocking these receptors at clinically relevant anti—
`psychotic doses (Figure 4). lntetestingly, however,
`atypical antipsychotics as a class have been shown
`to improve cognition (to varying degrees) as well as
`increase acetylcholine release in the medial pnefrontal
`cortex (mPFC).“ Although the role of M 1 receptors
`in cognition is not entirely understood. a low affinity
`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 a] -Adrenergic
`Antagonist Properties
`Antihistamine (I‘ll antagonist) and (11 (adrener—
`gic)—hlocking actions either alone or in combination
`may interfere. with pro-cognitive eil'ects and may cause
`sedation. Furthenuore. recent data have shown strong
`correlation with weight gain and blockade of H] and
`orI receptors in patients treated with atypical antipsy»
`chotics.46 Agents with lower propensity to block H]
`or al—adrenergic receptors relative to their ability to
`block D2 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 HI recep'
`tor. which exceeds their affinity for the dopamine
`D2 receptor (Figure 4). All five of the firstrline atypi—
`cal antipsychotics possess potent a] receptor—binding
`
`Risperidone
`
`5
`
`Olanzapine
`
`Quetiapine
`
`Wflfinitiu(ill):I“)
`
`.0
`
`
`
`ReceptorAffmiaWK)x100
`
`—58
`
`9
`
`lerasidone
`
`n,
`
`u
`
`u,
`
`u,
`
`8
`
`§ 3
`
`P
`
`a :
`
`2E S i5
`
`W‘ME§(IK)Imo
`
`p
`
`
`
`
`
`Aripiprazole
`
`E
`é
`
`P
`
`mmmilfljxlw
`
`l)1
`
`
`
`FIGURE 4. Summary of Potentially Important Side-Effect Receptor Actions of Atypical Antipsychotics
`
`nltles of these agents for the 01. S—HTutzcraw, and serotonin and norepinephrine transporters are plan
`on a logarithmic scale for the purpose
`resented here are individual mcepror-binding-affinity profiles for five first-line atypical antipsychotic gents. A summary of receptor binding
`R
`of relative comparison. Understanding the indivrdual and unique differences in these pharmacologic properties from one
`em to the next is key
`in attempting to maximize the
`tential for enhancing cogn
`‘
`ition and mood in patients and thus achieve the most favorab 2 treatment outcome
`beled 'Functlonal Activrty“ has been added to the receptor affinity plot for aripiprazole in an effort to illustrate
`t e
`{gr e‘ach patient. A dashed line l?
`kal functional activity of this compound at various dopamine receptor subtype
`5, consistent with the hypothesis pro
`by Lawler
`and colleagues' that aripiprazole maintains functionally selective activation of Dz (and possibly DsHopamlne receptors expressed n human tissue.
`' (1/kl)1100<0.1.
`Dadopamine; u-alpha adrenergic; Hahistamine; M=mustarinlc<hoilnergic
`Shayegan DK. Sta