`
`Daniel E. Casey, MD, and Stevin H. Zorn, Ph.D.
`
`In general, antipsychotic agents have diverse actions on a wide range of neurotransmitter systems,
`Data strongly suggest that a number ofthese systems may play a role in the regulation ofbody weight.
`n addition to having very distinct pharmacologic profiles, individual agents possess discrete weight
`
`ga‘
`liabilities. This article briefly reviews the evidence for the involvement of specific neurotransx
`: "he; systems in the control of body weight and describes the relevant pharmacologic characteristics
`
`
`
`(J Clin Psychiatry 200162[suppl 7]4—10)
`
`
`
`factors, and other controls of appetite?"4 Other known or,
`as yet, unknown factors may also be involved. Hence,
`
`there are a number of axes along which it may be possible
`
`to interfere with the usual balance of these systems.
`
`Extensive biochemical, pharmacologic, and endocrine
`
`V research into the brain systems regulating food intake and
`
`rgy homeostasis has identified a number of mono-
`well as have beneficial effects on mood, anxiety, and h
`
`hes, neuropeptides, and hormones that may play a role
`tility.2 This article aims to explore the disparity among di
`
`ferent atypical antipsychotics to cause weight gain by“
`deteaimning body weight (Figure 1) Several factors
`looking at their individual effects on neurotransmitter sys—
`olvedin altering their normal function, such as
`
`tems and their specific receptor profiles. The possible im-
`
`pact of these receptor interactions on some of the factors
`currently known to influence weight regulation will also
`be explored. Other nonpharmacologic aspects of weight
`gain are discussed elsewhere in this supplement.
`
`effects of pharmacotherapy.
`is generally thought to be the struc-
`
`
`
`PHYSIOLOGY 0F WEIGHT REGULATION
`
`The regulation of body weight is a complex interplay
`between energy intake,
`energy expenditure,
`satiety
`
`From the Portland Veterans Affairs Medical Center, Oregon
`Health Sciences University, and Oregon Regional Primate
`Research Center, Portland (Dr. Casey); and Groton
`Laboratories, Pfizer Global Research andDevelopment,
`Groton, Conn. (Dr. Zorn).
`This supplement was made possible by an unrestricted
`educational grant from Pfizer Inc and contains the
`proceedings ofthe symposium “Weight Gain:A Growing
`Problem in Schizophrenia Management, ” held August 8, 1.9.9.9,
`in Hamburg, Germany, in conjunction with the 11th annual
`meeting ofthe World Congress ofPsychiatry.
`Reprint requests to: Daniel E. Casey, Ma, Psychiatry
`Research/Psychopharm(zoology, Veterans Affairs Medical
`Center, Psychiatry Service (116A), 3710 SWU.S. Veterans
`Hospital Rd, Portland, OR 97207.
`
`
`
`systems that have distinct
`
`havior and metabolism of spe‘
`
`tems, stimulation results in a ne
`ase in energy intake
`and storage, while for others, stimulation resultsin a net
`decreasein energy intake and storageaitis likely that dis—
`turbancesin monoamines, peptides, and the
`eceptors in
`
`this region may underlie or modulate abno
`ating pat-
`terns, energy metabolism, and body weight changes.
`
`NEUROTRANSMITTER SYSTEMS
`AND SPECIFIC RECEPTOR ACTIVITY
`IMPLICATED IN WEIGHT REGULATION
`
`Serotonergic System
`The serotonin (5-hydroxytryptamine, 5-HT) receptors
`now total at least 14 pharmacologically distinct subtypes
`assigned to 7 different families, located both pre— and post-
`synaptically throughout the mammalian central nervous
`
`J Clin Psychiatry 2001;62 (suppl 7)
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`Exhibit 2028
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`Slayback v. Sumitomo
`|PR2020-01053
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`1
`
`Exhibit 2028
`Slayback v. Sumitomo
`IPR2020-01053
`
`
`
`Cholecystokinin
`
`.
`Somatostati‘
`Glummrfi i “‘5
`
`
`
`Nonselective S—HTIB,1A agonists tend to reduce feeding
`in rats.” Direct injection of 5'HTiB/1A agonists into the rat
`paraventricular nucleus (PVN) has been shown to elicit
`hypophagia.15 Some nonselective 5'HT13/1A antagonists
`have been shown to inhibit D—fenfluramine-induced hypo—
`phagia,16 an effect not produced by selective 5—HT1A
`antagonists. Other preliminary studies reveal no effect
`with more selective 5—HT1B antagonists.17 However,
`knockout of the 5-HT1B receptor in mice is reported to in—
`hibit n—fenflurarnineir induced hypophagia.18
`The 5—HT2C receptor in particular may play an impor—
`tant role in regulating feeding and is a promising target for
`Orexms
`Gal-amn
`Cannabinoids
`antiobesity drug development.” Nonselective 5—HT2C ago~
`
`MCH
`Leptin
`nists such as m-chlorophenylpiperazine (m-CPP) decrease
`a-MSH
`CRH
`feeding in rats,17 These compounds tend to be partial ago—
`
`Central can a body weight
`nists that also block 5—HT2A receptors.19 However, their ef—
`
`fect is potently inhibited by selective 5—HT2C antagonists
`,
`‘Abbreviations: CRH = corticotr
`
`such as SB242084.2° Also, administration of some
`I;
`5-HT = serotonin, MCH = melanin-
`
`u-MSH = alpha-melanocyte-stimulating hor
`
`5—HT2C~selective antagonists alone can increase food in—
`NE = norepinephrine.
`
`take and body weight in rats.“ Knockout mice lacking the
`
`5—HT2C receptor eat more, get heavier, have reduced re—
`
`sponse to D—fenlluramine, and show late—onset diabetes
`system (CNS).5 There are now man ,,
`
`suggest involvement of 5-HT neuro ‘
`mellitus.22 In human subjects, m-CPP is associated with a
`
`decrease in appetite and food intake, and preliminary stud-
`
`ing behavior and body weight regulation.
`ies suggest moderate weight loss in subjects with obesity.23
`In addition to these 5—HT receptors, other subtypes may
`data suggest that 5-HT has a role in the regulatio; of 15
`
`lso be involved in regulating food intake. 5—HT2B receptor
`(an adiposity signal) secretion.6
`
`ivation has been reported to increase food intake in
`The antiobesity agent D—fenfluramine is believed
`elicit its effect through release of 5-HT from nerve ternn
`
`nals and uptake blockade (activating both pre- and post-
`synaptic receptors). However, recent data suggest an asso-
`ciation of chronic elevation of brain 5—HT turnover (as
`measured by internal jugular 5-HT metabolite overflow)
`with human obesity, implying tolerance to the usual re-
`sponse to 5-HT, i.e., a reduction in food intake.7
`Systemic administration and intraraphe injection of
`agonists at
`the 5—HT1A receptor, such as 8—hydroxy-
`dipropylaminotetralin (8—OH-DPAT),
`tend to increase
`food intake in rats fed ad libitum, possibly due to de—
`creased 5-HT release via presynaptic 5-HT1A autorecep—
`torsi‘9 However, in food-deprived rats, 5—HT1A agonists
`decrease feeding”11 Studies also suggest that presynaptic
`mechanisms of 8—OH-DPATiinduced hyperphagia may
`require specific circulating levels of insulin and glucose,
`which are regulated via postsynaptic 5—HT1A receptors.12
`However, there is no clinical evidence to suggest that ago-
`nists at 5—HT1A receptors are associated with effects on ap—
`petite or body weight.13 It should be noted that the 5—HT 1A
`agonists used clinically (e.g., buspirone, gepirone) are full
`agonists at presynaptic receptors (where their activation
`decreases serotonin release), but during chronic adminis—
`tration, these receptors desensitize. At postsynaptic recep-
`tors, these agents are partial agonists, exhibiting antago-
`nist properties when serotonin levels are high and agonist
`properties when they are low.13
`
`
`
`Pharmacology of Weight Gain
`
`Figure 1. Possible Endogenous Central Mediators of Body
`Weighta
`
`Serotonin
`
`5—HT1A' Bv D- E?
`Histamine 5'HT2C‘ Others' Dopamine
`t‘
`H1, H3
`D2
`P ‘
`Nompinephrine
`r0 ac m
`5-HTINE uptake
`“1:“2: l5
`Neuromedins
`Neuropeptide Y
`
`OPiOidS
`Dynorphin,
`enkephalin
`Thyroid hormone
`
` »
`
`hypothalamic histamine
`turnover,29 and activation of histdrn lemneurons in the ven-
`
`
`
`
`inhibition of presynaptic H3 receptors in the
`.
`in rats.”7 One possible mechanism of histamine (HI)—
`induced suppression of feeding in rats is via inhibition of
`norepinephrine (NE) release in the PVN.31 H2 receptor an—
`tagonism has also been implicated in weight gain in rats.
`Although traditional nonselective H1 receptor antagonists
`such as cyproheptadine stimulate appetite and may be as-
`sociated with body weight increase in humans,32 this prop—
`erty may be related to effects on other neurotransmitter
`systems (e.g., cyproheptadine is also a nonselective 5—HT
`receptor antagonist). Many psychotropic drugs with high
`affinities for H1 receptors (and other receptors), such as the
`
`J Clin Psychiatry 2001;62 (suppl 7)
`
`DEF-LURAS-OOO6059
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`2
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`Casey and Zom
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`antidepressants amitriptyline and mirtazapine,
`associated with weight gain.
`
`33,34
`
`are also
`
`Adrenergic System
`Direct injections of selective al—adrenoceptor agonists
`into the PVN of rats result in reductions in food intake,
`whereas intra—PVN injections of selective org-adrenoceptor
`agonists stimulate feeding.35 In the same models, the efiect
`of a2 agonists is reversed by pretreatment with selective
`a,—antagoni,sts___ such as prazosin, suggesting the presence
`of a mutuam (:fantagonistic equilibrium between or,- and
`
`a2-adrenoceptog “frazosin also inhibits
`sibutramine—
`induced (see bblo f») decreases in food intake in rats.36
`
`Clinically, there are
`data to suggest effects on weight
`gain with any a—adré ”agitator antagonists. However, many
`
`psychotropic drugs W1
`affinities for (211- and/or
`(1;——adrenoceptors (e.g, tiic
`5c:jc,ahtidepressants) are asso—
`
`ciated with weight gain, w er
`.
`use with low affinities
`
`for these receptors (e.g., selective
`rt) nin reuptakem—
`hibitors) are not.33 A genetic pol i
`,hism of the
`
`azn—adrencceptor subtype may contri
`,gdlthe pathogen—
`esis of obesity in some populations
`
`
`Dopaminergic System
`
`likely to be a complex derivative of multiple receptor in-
`teractions.
`
`EFFECTS OF ANTIPSYCHOTICS ON BODY WEIGHT
`
`The low—potency phenothiazines have long been asso—
`ciated with weight gain. For example, Amidsen (1964)“1
`observed that patients taking chlorpromazine gained 9 lb
`(4.1 kg) on average over 12 weeks. Chlorpromazine was
`associated with greater increases than perphenazine and
`clopenthixol. The high—potency agents such as haloperidol
`are associated with a comparatively lower weight gain
`liability42 versus lower potency agents and newer genera—
`tion drugs. Many other conventional antipsychotics from a
`range of drug classes are also associated with significant
`weight gain.1 Exceptions to this are molindone and loxa-
`pine, which appear to be associated with weight loss.”3
`Treatment with clozapine, the first atypical antipsy-
`chotic, is associated with clinically significant weight gain
`in a large proportion of patients. The effect appears to be
`more substantial
`than that observed with conventional
`
`agents.44>45 A 10—week study comparing the effects of clo-
`zapine and haloperidol on weight gain in outpatients who
`had been only partially responsive to treatment with tradi—
`tional antipsychotics found that clozapine induced signifi-
`
`cantly more weight gain than haloperidol (mean = 11.7 lb
`
`D2 receptors. However, dopamine facilitates and
`.vs. 1.5 lb [5.3 kg vs. 0.7 kg]).45 Clozapine patients in this
`
`
`forces feeding in mesolimbic areas. D2 agonists in
`'
`1 continued to gain weight during a 1—year follow—up.
`
`Most of the new atypical antipsychotics appear to be
`feeding in both food-deprived rats and those fed ad lib: ..
`tum.3B Nonselective D1 agonists are also associated with
`4
`agar
`d with weight gain liabilities. ”547 The meta-
`reduced food intake and may act synergistically with D2
`agonists. The mixed Dz/D3 antagonist sulpiride induces ro—
`bust feeding and drinking when injected into the LH of
`rats. However, it is worth noting that the extent that this
`behavior is mediated via a specific interaction(s) with the
`dopaminergic or some other neurotransmitter systems is as
`yet unknown.
`
`Monoamine Reuptake Sites
`5-HT and NE reuptake sites are currently a prime target
`in the development of weight—reducing drugs.39 Sibutra-
`mine, a mixed 5-HT/NE reuptake inhibitor, was recently
`approved as a treatment for obesity and purportedly exerts
`its effect by increasing NE at peripheral Bs—adrenoceptors
`and NE and 5-HT at central receptors.“
`However, not all drugs that increase levels of norepi—
`nephrine and serotonin at the synapse induce weight loss.
`The novel antidepressant mirtazapine enhances NE and
`specifically 5—HT1A—mediated serotonergic transmission
`via antagonism at az-adrenoceptor and 5-HT2 and 5—HT3
`receptors.34 This drug possesses a propensity to induce
`weight gain. It has little affinity for al—adrenoceptors,
`dopaminergic receptors, or muscarinic receptors, but is a
`potent antagonist at H1 receptors. A weight gain liability of
`a drug with a broad pharmacologic profile is, therefore,
`
`
`
`
`ght gain Among the conven-
`tional agents, weight charfge
`ged from a reduction of
`
`
`ed with an increase
`thioridazine. Haloperidol was assay
`
`largest gain was
`of 0.48 kg. With the atypical agents,
`
`,ed by olanzapine
`found with olozapine (4.45 kg), fol
`
`(4 15 kg), sertindole (2.92 kg), and risperid‘ ’
`(2.10 kg).
`Ziprasidone was associated with a mean met ‘se of only
`0.04 kg. In the longer term, weight gain with either cloza—
`pine or olanzapine may be substantially higher.“
`Recent studies demonstrate that body weight increase
`with clozapine and olanzapine is associated with increased
`leptin levels, whereas with haloperidol it is notfl9 Whether
`this is a cause or effect of increased food intake is unclear.
`
`ANTIPSYCHOTIC RECEPTOR PROFILES
`
`It is generally accepted that antagonism at central dopa-
`minergic D2 receptors is a key factor in the treatment of
`
`J Clin Psychiatry 2001;62 (suppl 7)
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`
`
`schizophrenia. Indeed, all antipsychotic
`,
`.
`,
`agents possess this feature, and a pos1tive
`,
`correlation between the dose adequate to
`.
`treat positive symptoms and the drug’s D2
`receptor affimty has been repeatedly rep-
`-
`-
`-
`48,50
`.
`heated in the literature.
`The atypical
`antipsychotic agents tend to be character-
`ized by having combined antagonist ac—
`tivity at both D2 and 5-HT2,, receptors and
`generally haVe higher affinities for the
`
`Pharmacology of Weight Gain
`
`
`
`Table 1. Comparative In Vitro Receptor Binding (human receptor affinity)a
`Receptor
`Ziprasidone Risperidone Olanzapine Quetiapine Clozapine Haloperidol
`D2
`W ++++
`++
`+
`+
`++++
`," I) W
`0
`+
`+
`5»HT,,,
`++++
`+
`0
`
`i
`0
`0
`54111»
`'
`i
`i
`‘
`0
`.l
`, t
`.
`_
`+4
`5a
`,A
`+t.—++.+..
`+++H
`_ +_
`
`++++
`5"HTzc
`+++++
`++++
`0
`1+
`0
`,
`i++
`or;
`I
`;
`-, +41 -,
`++++
`++i
`~ +H~
`+i+++ii
`, ‘T‘Li
`$1 _
`y :1
`+0+
`“QT,
`,_
`_
`‘
`,2;
`,
`0
`Sin uptake
`++
`0
`0
`0
`0
`t»
`NEuptake
`we“
`0
`c
`+
`0
`“Adapted from Schmidt et a1.54 and A. W. Schmidt, M. A.; L. A. Lebel, B. 8.;
`H. R. Howard, Jr., M.S.; et al., manuscript submitted.
`Affinity represented as: +++++ (very high, K, < l M); ++++ (high, K, = 1—10 nM);
`++ (moderate, K, 2 11—100 nM); + (low, K,- 2 101—1000 11M); 0 (negligible, K, > 1000 nM).
`
`_
`
`-'
`
`
`
`
`
`
`
`
`I’Bovine.
`
`Table 2, Clinical Implications of Various Receptor Activities of
`Antipsychotic DrugsI
`cologic profiles encompassingavariety
`Possible Clinical Effects
`Receptor Activity
`of effects via interactions with a n
`
`D2 receptor antagonist
`Antipsychotic activity vs positive symptoms,
`
`EPS, endocrine effects
`Antidepressant and anxiolytic activity,
`improved cognition, reduced EPS, increased or
`decreased body weight
`Antidepressant activity
`Antipsychotic activity vs negative symptoms,
`reduced EPS
`Improved antipsychotic efficacy vs positive
`symptoms, body weight gain
`Sedation and hypotension, efi‘ect on body weight gain
`Sedation and body weight gain
`
`of other neurotransmitter receptors. Théi
`
`5-HT1A receptor agonist
`
`
`
`
`
`tor systems may underlie their diff eat
`
`propensities to induce weight gain. In par ..
`tioular, many atypical agents are antago—s
`nists at Hl-histaminergic, al-adrenergic,
`and 5—HT2C-serotonergic receptors. A
`summary of the relative receptor activ-
`ities of various antipsychotic drugs is
`presented in Table 1 and more detailed
`nonhuman and human affinity constants
`have been reported elsewhere (references
`52754 and A. W. Schmidt, M.A.; L. A.
`Lebel, B.S.; H. R. Howard,
`J12, M.S.;
`et al., manuscript submitted). The pos—
`sible relationships of the various neuro-
`transmitter receptor activities of antipsy—
`chotic drugs to weight gain and to other
`potential side effects are summarized in
`Table 2. These effects will vary depending on a drug’s af—
`finity for various neurotransmitter receptors and also by the
`combination of receptor affinities it exhibits. For example,
`a drug with high antagonist affinity at al-adrenergic recep—
`tors (e.g., clozapine) would be predicted to more likely pro-
`duce hypotension and sedation than a drug with more mod—
`erate or lower affinity for this receptor (e.g., ziprasidone).
`It is widely known that thioridazine stands among
`the typical antipsychotics that possess the largest weight
`gain liability. This compound has higher affinity for
`oil—adrenoceptors and Ml—muscarinic acetylcholine recep—
`tors than it does for the D2 receptor,55 Its affinities for
`Hl-histaminergie receptors and 5-HT2A receptors are simi-
`lar to its affinity for the D2 receptor.
`The traditional high-potency antipsychotic haloperidol
`has a high affinity for D2 receptors. It does not, however,
`possess similar or higher affinities at any of the other
`
`Ml-musc
`Memory impairment, GI symptoms, dry mouth,
`
`blurry vision, improved EPS
`antagonist
`
`
`High S-HTZA/D2 rec
`Improved antipsychotic activity and lower BPS
`binding affinity ratio
`than that expected from D2 receptor antagonism alone
`
`,
`Mixed serotonin and
`depressant and anxiolytic activity, reduced body
`norepinephrine neuronala
`
`
`
`reuptake inhibition
`
`aAbbreviations: D = dopamine,
`
`
`GI = gastrointestinal, H ; histamin
`
`
`
`
`
`
`the highest propen51
`Clozapine has
`weight gain of all the antipsychotic drugs.
`binding studies, clozapine demonstrates higher affinity for
`5—HT2A, 5-HT2C, Hl—histaminergic, al—adrenergic, and
`Ml—musearinic receptors than it does for dopaminergic I)2
`receptors (see Table H.525] Its affinity for 5-HT1A recep—
`tors, where it appears to be a partial agonist, is similar to
`that for the D2 receptor (Figure 2).
`Olanzapine is another atypical antipsychotic agent with
`a high propensity to cause weight gain (second only to
`clozapine). Like elozapine, it also has higher affinities
`for 5-HT”, 5-HT2C, Hl-histaminergic, and Ml-muscarinic
`
`J Clin Psychiatry 2001;62 (suppl 7)
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`Casey and Zom
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`
`
`Figure 2. Relative Affinities of Atypical Antipsychotics for Different Receptor Subtypesa
`Ziprasidone
`Risperidone
`
`5-HT2A
`
` 5-HT2C
` a1
`
`
`Clozapine
`
`Quetiapine
`
`
`“’R. Howard, Jr., M.S.; et a]., manuscript submitted. The subtypes
`3Data from Schmidt et a1.“ and A. W. Schmidt, M A.; L. A. Lobe
`
`
`mphasis.
`potentially relevant to weight gain (S-HTZC, a1, and H1) have been gfis
`
`
`
`
`receptors compared with its affinity for the D2 receptor
`(see Table 0.5253 However, unlike clozapine, it has lower
`affinity for the al-adrenooeptor than it does for the D2
`receptor (see Figure 2).
`Another new atypical agent, quetiapine, has higher af—
`finity for Hl—histarnjnergic receptors and aradrenoceptors
`and approximately similar activity at the Ml—muscarinic,
`5—HT1A (partial agonist), and 5-HT2A receptors compared
`with its affinity for the D2 site (see Table l).52'53
`Risperidone, which has a slightly lower weight gain li-
`ability than most atypical agents, displays higher affinity
`for 5-HT2A receptors and ul-adrenoceptors and lower af-
`finity for 5-HT2C receptors compared with its affinity for
`the D2 receptor.
`Ziprasidone, the newest atypical antipsychoticfz’56 has
`a neurotransmitter receptor—binding profile distinct from
`that of the other atypical antipsychotics. Like risperidone,
`it has a high affinity for D2 receptors and an even higher
`affinity for 5—HT2A receptors. However, unlike all the other
`antipsychotic drugs, ziprasidone has a greater degree of
`serotonergic and a lesser degree of adrenergic, histaminer—
`gic, and muscarinic receptor properties (see Table 1) (ref-
`erences 52 and 53 and A.W. Schmidt, M.A.; L.A. Lebel,
`B.S.; HR. Howard, Jr, M.S.; et al., manuscript submit-
`ted). Ziprasidone possesses high affinity for 5-HT1A recep—
`tors, Where it is a full agonist,52 and higher affinity for
`
`
`
`
`
`
`
`inhibitor of rat and human
`
`5-HT and NE reuptake.52
`ity at these neurotrans—
`
`th that of the antide—
`mitter uptake sites is compa
`
`652
`pressants amitriptyline and imip
`
`DISCUSSION
`
`Antipsychotic agents, particularly the riewe atypical
`agents, possess broad pharmacologic profiles with activity
`at a number of receptor sites at therapeutic doses.58 Many
`of these neurotransmitter systems and specific receptor
`subtypes are implicated in the regulation of food intake
`and energy homeostasis and are likely to play a role in
`weight gain associated with antipsychotic use. Potential
`targets for interfering with normal body weight regulation
`may be either central or peripheral and may occur at any
`number of stages in a complex cascade of mediators. This
`plethora of neurotransmitter and neurohumoral systems
`and receptors involved in body weight regulation make the
`
`J Clin Psychiatry 2001;62 (suppl 7)
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`5
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`
`weight gain liability of a potential novel agent diffith to
`predict. However, insight may be gained by comparing
`differences in the receptor-binding profiles of those anti-
`psychotic drugs that cause the most weight gain with those
`that produce the least, and it may be possible to relate a
`drug’s propensity to induce weight gain to its actiw'ty at
`particular receptors.
`This analysis suggests that compounds that antagonize
`several specific receptors,
`in affinity ranges equal to or
`greater than their afiinities at the D2 receptor, may be
`
`
`
`pine, possess relative high'affiniey (defined relative to
`their own affinities for 132 recept
`
`
`Pharmacology of Weight Gain
`
`erties may also contribute to ziprasidone’s weight—neutral
`profile. For example, ziprasidone also differs from the
`other atypical antipsychotic drugs by having a relatively
`higher affinity for the 5—HT”, versus the D2 receptor. How-
`ever, the role of the 5-HT”, receptor in weight regulation
`is unknown at present.
`There are a number of receptors at which antipsychotic
`drugs have high affinity whose role in weight regulation is
`still unclear. Similarly there are a number of neurotrans—
`mitter, hormone, and peptide receptors implicated in the
`control of food intake and weight regulation for which
`there are as yet no pharmacologic data available for
`antipsychotic drugs. Weight gain associated with anti—
`psychotic treatment may have serious long-term conse-
`quences for patient health and compliance. The pharmaco—
`logic mechanisms underlying weight gain are presently
`poorly understood, and there is a need for further under—
`standing of these systems and how antipsychotic agents
`interact with them. This may facilitate selection of appro—
`priate antipsychotic treatment and improve the manage—
`ment of cases in which avoiding significant weight gain is
`of prime importance.
`
`REFERENCES
`
`Drug names: amitriptyline (Elavil and others), buspirone (BuSpar),
`nations ofactivity (see Figure 2). In contras
`chlorpromazinc (Thorazine and others), clozapinc (Clozaril and others),
`
`
`cyproheptadine (Periactin), haloperidol (Haldol and others), loxapine
`lower propensity to cause weight gain re
`(Loxitane and others), mirtazapine (Remeron), molindone (Mohan),
`drugs may be explained by its relatively high a “pity f
`
`olanzapine (Zyprexa), perphenazine (Trilafon and others), prazosin
`
`an
`Id
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