Novel Antipsychotics:
`Comparison of Weight Gain Liabilities
`
`Donna A. Wirshing, M.D.; William C. Wirshing, M.D.; Lisa Kysar;
`M. Andrew Berisford, Ph.D.; Danielle Goldstein; Joanna Pashdag, MA;
`Jim Mintz, Ph.D.; and Stephen R. Marder, M.D.
`
`
`
`Background: We performed a retrospective
`analysis of 122 clinical records of 92 male pa—
`tients with DSM—III—R schizophrenia to examine
`the relative weight gain liabilities of clozapine,
`risperidone, olanzapine, and sertindolc com—
`pared with haloperidol. We hypothesized that
`the unique pharmacodynamic profiles of these
`agents would contribute to different amounts
`and patterns of weight gain.
`Method: Data were analyzed to determine
`differences in weight gain during treatment
`among patients receiving 5 different drug treat-
`ments (clozapine [N = 20], olanzapine [N = 13],
`risperidone [N = 38], haloperidol [N = 43], and
`sertindole [N = 8]). Measures of maximal
`weight gain, final weight, and duration to maxi—
`mal weight gain were calculated.
`Results: Repeated measures analyses of vari-
`ance controlling for age, treatment duration, and
`initial weight revealed statistically significant
`differences between groups on all 3 measures.
`Clozapine and olanzapine had the greatest maxi—
`mal weight gain liability (F = 4.13, df= 4,23;
`p = .01). Weight gain with clozapine, but not
`olanzapine or rispcridone, appears to persist
`(as reflected by final weight) despite behavioral
`interventions (e.g., nutritional consultation, sug-
`gested exercise regimen; F = 5.69, df = 4,23;
`p 7 .003). Clozapine— and olanzapine—treated
`subjects appeared to gain weight over a pro-
`longed period of time, whereas risperidone-
`and sertindole-treated subjects had a more lim-
`ited period of weight gain (F = 2.95, df= 4,25;
`p = .04).
`Conclusion: Clozapine and olanzapine
`caused the most weight gain, risperidone was
`intermediate, and sertindole had less associated
`weight gain than haloperidol. The relative re-
`ceptor affinities of the novel antipsychotics
`for histamine H1 appear to be the most robust
`correlate of these clinical findings.
`(I Clin Psychiatry 1999;60:358—363)
`
`
`Received March 30, 1998; accepted Aug. 24, 1998. From the
`Department ofPsychiatry VA. Greater Las Angeles Healthcane System,
`LosAngeles (Dr's. D. Wirshing, W. Wirshing, Berisfiard, Illintz, undid/larder
`and Mr. Goldstein);
`the Department of Psychiatry and Biobehavioral
`Science, University ofCalifornia at Los Angeles School ofMedicine, Las
`Angeles (Drs. D. Mrshing, W Wzrshing, and Murder and Ms. Kysanl; and
`Pepperdine University, Malibu, Calif (Ms. Pasha'ag).
`Parts of this research were presented at the 19th meeting of the
`Collegium Internationale Neum-Psychophannacologicum, June 27—July
`1, I994, Washingion, DC, and at the I47th annual meeting of the
`American Psychiatric Association, Addy 22—26, 1994, Philadelphia, Pa.
`file outhons‘ thank Sun S. Hwang, MS, for statistical consultation.
`Reprint requesm ta: Donna A. Wirshing, M.D., VA. Greater Las
`Angeles Healthcare dystem, 11301 Wilshire Blvd.
`(BI51-H), Building
`2103, Room 15, LasAngeles, CA 90073 (e—mail: ames@ucla.edu).
`
`any antipsychotic drugs have been associated
`with substantial weight gain and drug—induced
`obesity.“3 Studies
`indicate that antipsychotic drug-
`induced weight gain is a common cause of noncompli-
`ance and discontinuance of treatment, resulting in the re—
`turn of psychotic symptoms."2‘4‘5 Furthermore, excessive
`weight gain and obesity are associated with increased
`morbidity from coronary heart disease, diabetes, hyper-
`tension, gallbladder disease, and some forms of cancer.6
`Monitoring and combating antipsychotic drugwinduced
`weight gain may therefore play a part in promoting treat—
`ment compliance and general health among psychotic pa-
`tients.
`
`Psychotropic drugs that influence serotonin (5—HT)
`neurotransmission have been reported to affect food in—
`take and cause fluctuations in weight. Drugs that facilitate
`serotonin transmission have been found to reduce food
`
`consumption and cause weight loss?“9 In contrast, drugs
`that block serotonin transmission have been found to in—
`
`crease food intake and cause weight gain.‘°"“Hz
`It remains speculative which serotonin receptor type is
`responsible for stimulating food intake and weight gain.
`Aulakh et al.13 suggested that both 5-HT1C and 5-HT2 re—
`ceptors play an important role in the stimulation of food
`intake; these receptors are now referred to as 5-HT2C and
`5-HT,» respectively.14 Tecott and colleagues15 developed
`a strain of mice whose gene for the 5-HT2C receptor was
`removed. These mice became obese and had a propensity
`for seizures.
`
`In addition to animal models for the role of 5—HT”; in
`eating behavior, the medication fenfluramine is thought to
`
`J Clin Psychiatry 60:6, June 1999
`
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`Wirshing et al.
`
`
`
`Table 1. Binding Affinity In Vitro of Antipsychotics for
`
`Neurotransmitter Receptor SubtypesaL
`
`Drug
`5-H“ 5-mzc
`DEL
`D23
`(11
`H1
`Clozapine
`9.6
`13
`192
`147
`23
`0.23
`Olanzapine
`2.5
`7.1
`31
`21
`60
`0.65
`Risperidoue
`0.52
`48
`5.9
`6.2
`2.3
`20
`Haloperidol 196
`> 10,000
`2.2
`1.8
`19
`790
`Sertindole
`0.39
`1.9
`7.0
`5.8
`1.8
`130
`3Reprinted with permission from reference 14. Binding affinity (K)
`values are shown in nmol/L.
`
`exert its chemical activity as a 5-HT2C (formerly 5—HT1C)
`agonist,
`thus
`suppressing
`appetite.16 Additionally,
`m-chlorophenylpiperazine (m-CPP), a serotonin agonist,
`decreases food intake when given to humans.17 This adds
`further evidence that the serotonin blockade of novel anti—
`
`psychoties may do the opposite, i.e., increase food intake.
`Also, some of these novel agents, particularly cloza—
`pine, have strong affinity for histamine H1 receptor
`sites.“19 Links between weight gain, use of antihista—
`mines, and older conventional antipsychotic agents such
`as thioridazine and chlorpromazine have been demon—
`strated in humansz's'zwz
`Clozapine, risperidone, sertindole, and olanzapine are
`novel antipsychotics that have been developed in an effort
`to increase antipsychotic efficacy with fewer side effects,
`particularly extrapyramidal side effects, than conventional
`antipsychotics. In comparison with conventional antipsy—
`chotics, these novel antipsychotics are pharmacologically
`characterized as potent serotonin receptor antagonists with
`a lower affinity for dopamine D2 receptor sites.”26 Specifi—
`cally, clozapine, risperidone, sertindole, and olanzapine
`have high binding affinities for 5-HT2C and 5—Ii’l"2,.,.”’27’28
`Clozapine also has a large amount of activity at choliner—
`gie and histaminergic receptor sites.““19 Previous studies
`have indicated that clozapine, risperidone, and olanzapine
`are responsible for drug-induced weight gain in psychotic
`patients.”33 Table 1 shows the medications’ binding affini—
`ties for neurotransmitter receptor subtypes.
`In contrast, haloperidol is a conventional antipsychotic
`with a low affinity for serotonin receptor binding sites.34
`Studies indicate that haloperidol’s serotonergic properties
`are significantly weaker than those exhibited by cloza—
`pine, risperidone, sertindole, and olanzapirie.25’27‘35"37 It has
`been hypothesized that haloperidol’s limited serotonergic
`properties are responsible for the drug’s lower potential to
`induce weight gain2 and that the different serotonergic af-
`finities exhibited by the novel antipsychotics and haloper—
`idol might explain the variation in the amount of weight
`gained by patients receiving these drugs.31g
`This study is a retrospective analysis of the relative
`weight gain liabilities of clozapine, risperidone, olanza—
`pine, and sertindole compared with that ofhaloperidol. We
`hypothesized that the unique pharmaeodynamic profiles of
`these agents will contribute to different amounts and dif—
`ferent patterns of weight gain.
`
`METHOD
`
`Subjects and Procedures
`The subjects were 92 male patients with schizophrenia
`(DSM-IH-R criteria) who were participants in 8 different
`clinical drug trials conducted over 6 years in our research
`clinic: a study comparing clozapine with haloperidol, 2
`different studies comparing risperidone with haloperidol,
`a study comparing sertindole with placebo, a study com—
`paring olanzapine with placebo, a study comparing 4 dose
`levels of haloperidol decanoate, a study comparing cloza-
`pine with risperidone, and a study comparing olanzapine
`with risperidone. Thirty subjects participated in more than
`1 study over the 6-year period. Thus, 122 clinical records
`were included in the analyses.
`As noted above, some of these clinical trials included
`placebo controls during the initial double—blind phase.
`Placebo-control subjects were not entered into these
`analyses of weight gain because none of them were main-
`tained on treatment with placebo longer than 6 weeks (see
`Table 2 for average duration of treatment). All studies
`were double-blind comparisons that were followed by
`open-label extension phases, with the exception of the
`haloperidol decanoate study (it had no open—label exten—
`sion). The patients in the 2 clozapine-treatrnent studies
`and l of the risperidone versus haloperidol studies were
`classified as treatment resistant; the patients in l of the
`risperidone studies, the sertindole study, and both olanza—
`pine studies were classified as treatment responsive; and
`the patients in the haloperidol decanoate study had a his—
`tory of psychotic decompensation with a need to be main-
`tained on treatment with antipsychotics. The drug studies
`were all conducted at
`the VA. Greater Los Angeles
`Healthcare System. All the patients provided informed
`consent after receiving a full explanation of their respec—
`tive study procedures.
`At the time these data were collected, our clinic was
`running approximately 10 studies. The 8 studies chosen
`were selected because they had the greatest number of pa—
`tients enrolled for the longest period of time. These stud—
`ies have been conducted over a 6-year period.
`Medical charts were reviewed to obtain the following
`information: age, ethnicity, diagnosis, weight changes,
`duration of treatment, and inpatient status. Demographic
`variables are summarized in Table 2. Patients were
`
`weighed as part of routine procedures using the same
`clinic scale.
`
`All patients were subject to the following clinical man—
`agement of weight control during the 6—year period: First,
`patients were instructed to weigh themselves and report
`their weight to our research clinical nurse specialist at each
`Visit (every 1 to 4 weeks). If this simple feedback behav—
`ioral paradigm failed to maintain their weight (a gain of
`10 lb [4.5 kg] in our subjects is generally considered suffi—
`cient to warrant further intervention), they were instructed
`
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`

`Novel Antipsychotics and Weight Gain
`
`Pairwise Comparisons
`Clozapine > hamper-idol.”
`risperidone > haloperidol,”
`olanzapine > haioperidolM
`
`
`
`Table 2. Demographic Variables
`
`Drug
`Olanzapine Risperidone Haloperidol
`(N = 13)
`(N = 38)
`(N = 43)
`44.5 2 1.2
`43921.0
`41.1 a 1.0
`
`Clozapine
`(N = 20)
`Variable
`Age, y. mean a SEM“ 43.1 a 1.0
`
`Sertindole
`(N = 8)
`42.4 a» 1.4
`
`Ethnicity, N (94:)
`5 (62)
`16 (37)
`25 (66)
`5 (38)
`11 (55)
`White
`2 (25)
`10 (23)
`9 (24)
`5 (38)
`5 (25)
`African American
`0(0)
`11 (26)
`1 (3)
`l (8)
`4 (20)
`Hispanic
`1 (12)
`6 (14)
`3 (8)
`2 (15)
`0(0)
`Other
`25.8 t 5.8
`73.1 t 9.9
`27.2 1 8.0
`Treatment duration,
`Olanzapine > clozapine,“
`42.5 x 12.6
`24.7 t 5.4
`wk, mean a: 813leW
`olanzapine > risperidone,”
`
`olanzapine > haloperidolM
`”p 5 .01.
`
`to keep a detailed diary of all food intake over a several
`week period. If this failed to maintain or decrease weight,
`they were then referred to our clinical nutritionist. Subse—
`quent to this, they were referred to the “Wellness Clinic”
`at our medical center, which involves a more rigorous
`evaluation of both dietary and exercise habits and adds
`education, exercise classes, and group support. While it is
`true that not all subjects availed themselves of these ser-
`vices, there is no reason to think that any one drug group
`would have more or fewer “uncooperative” patients.
`
`Statistical Methods
`
`Maximal weight gain was defined as the maximum
`weight a subject obtained at any point in the study minus
`his initial weight. Percentage weight gain was defined as
`maximum weight minus initial weight, divided by initial
`weight. Of note, 12 patients lost weight during the study.
`Thus, the maximum weight change for these patients was
`negative. Final weight change was defined as the final
`weight observed minus the initial weight. Both maximal
`weight change and final weight change were studied to
`see if interventions resulted in a change between maximal
`and final weights. Repeated-measures analyses of vari—
`ance (ANOVAs) were performed using the SAS statistical
`package.3g
`
`RESULTS
`
`Subjects
`There were statistically significant differences be-
`tween the drug treatment groups on the demographic vari-
`ables of age (F = 4.96, df= 4,26; p = .004) and duration
`of treatment (F = 5.27, df= 4,26; p = .003; see Table 2).
`There were no other statistically significant differences
`between groups on demographic variables.
`
`Maximal Weight
`treatment duration, and initial
`Controlling for age,
`weight, we determined average adjusted maximal weights
`for each group (Table 3). Clozapine- and olanzapine-
`
`J Clin Psychiatry 6026, June1999
`
`treated patients had the highest maximal weight gains com-
`pared with other groups (F = 4.26, df= 4,23; p = .01). Fig—
`ure 1 represents the percentage of subjects on each drug
`treatment who gained 10% or more of their baseline
`weight, less than 10%, and had no weight change. Patients
`taking olanzapine or clozapine gained weight over greater
`periods oftime compared with risperidone- and sertindole—
`treated subjects (F = 2.95, df = 4,25; p = .04; see Table 3).
`
`Final Weight
`Controlling for age, treatment duration, and initial
`weight, we found that final weight change was different
`among groups (F: 5.69, df=4,23; p= .003; Table 4).
`At the time of final weight measurement, clozapine—
`associated weight gain remained statistically significantly
`higher than that for all other medications. No other
`pairwise differences were seen.
`
`Relationship Between
`Initial Weight and Weight Gain
`Overall,
`there was no relationship between body
`weight status at baseline and either the maximum weight
`gained or the weight at endpoint. Of the 92 subjects, how-
`ever, 2 who were thin at baseline were clearly outliers.
`These 2 patients gained 45 lb and 55 lb (20 kg and 25 kg),
`respectively, during treatment (with baseline weights of
`128 lb and 151 lb [58 kg and 68 kg]). Including these out-
`liers in a Pearson product moment correlation calculation
`gave only a meager suggestion of an inverse correlation
`between body weight index at baseline and weight gained
`(r = —0. l 4, p = .19). Excluding these outliers, however,
`caused even this suggestion to disappear completely.
`
`Relationship Between
`Maximal Weight and Final Weight
`The correlation between maximal and final weights was
`high for all drugs (overall: I = 0.88, p = .0001; clozapine:
`r = 0.98, p = .0001; haloperidol: r = 0.90, p = .0001; ser-
`tindole: r = 0.94, p = .0004) except olanzapine (r = 0.83,
`p = .0001) and risperidone (r = 0.83, p = .0001).
`
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`Wirshing et al.
`
`
`
`Table 3. Maximum Actual and Adjusted Weight Gain
`
`Drug
`
`Variable
`Clozapine
`Olanzapine
`Risperidone
`Haloperidol
`Sertindole
`Pairwise Comparisons
`Beginning weight, mean 1 SD
`n/a
`1b
`kg
`Adjusted time to maximum
`weight gain, mean 1 SEM, wk"
`
`184.41335
`83.01151
`24.9 1 3.1
`
`19001416
`85.5119.6
`21.2 1 4.1
`
`18161380
`83.51111
`15.0 1 2.3
`
`18601362
`83.71163
`18.5 1 2.1
`
`188.81301
`84.91135
`8.3 1 4.9
`
`Maximum weight gain, mean 1 SD
`lb
`kg
`Maximum adjusted weight gain,
`mean 1 SEM"
`1b
`kg
`Maximum % weight gain,
`mean 1 SD
`Maximum adjusted “/0
`weight gain, mean 1 SEM**
`
`*p 5 .05.
`
`’"p 5 .01.
`
`16.81133
`7.5161)
`
`17.81133
`8016.0
`
`9.1176
`4113.4
`
`15211.8
`6.9 1 0.8
`
`9518.1
`8.8 1 1.1
`
`15012.2
`6.8 11.0
`
`10.51103:
`8.8 1 1.3
`
`11.1114
`5.0 1 0.6
`
`5214.4
`6.4 1 0.8
`
`7.7190
`3514.1
`
`8211.3
`3.7 1 0.6
`
`4114.7
`4.4 1 0.8
`
`5,617.3
`2513.3
`
`6.8128
`3.1112
`
`3214.5
`4.1 1 1.7
`
`Clozapine > risperidone,”
`clozapine > sertindole,""‘I
`olanzapine > sertindole“
`n/a
`
`Clozapine > sertindole,‘
`clozapine > haloperidol."
`olanzapine > sertindolef
`olanzapine > haloperidol**
`
`n/a
`Clozapine > sertindole,*
`clozapine > haloperidol,”
`olanzapine > sertindole,*
`olanzapine > haloperidol*$
`
`Relationship Between 5-HT2C Receptor Affinity,
`H1 Receptor Affinity, and Weight Gain
`No relationship could be established between the rela—
`tive 5-HT2C receptor affinities and weight gain. However,
`an exponential relationship was seen between the medi-
`cations’ H1 receptor affinities and maximum weight gain
`(Figure 2).
`
`DISCUSSION
`
`Novel antipsychotics vary in their weight gain liabili—
`ties. Clozapine and olanzapine appear to cause the most
`weight gain, risperidone is intermediate, and sertindole
`actually has less associated weight gain than haloperidol.
`Clozapine’s effect on weight gain was sustained and un-
`responsive to interventions, whereas olanzapine’s weight
`gain effect was somewhat reversible with dietary and
`other behavioral maneuvers. However,
`the possibility
`that this phenomenon may simply be an artifact of the
`much longer treatment duration of the olanzapine pa-
`tients (73.14 weeks) compared with that of the clozapine
`patients (27.17 weeks) cannot be ruled out.
`the time
`For those patients who did gain weight,
`course was distinct among treatment groups. Risperi—
`done- and sertindole-treated subjects reached a weight
`plateau after a comparatively short initial time period
`(circa 10 weeks), whereas olanzapine— and clozapine—
`treated patients continued to gain weight over a more
`lengthy period (circa 20 weeks.)
`The weight gain liabilities of these drugs appeared
`to be correlated with their relative affinities for the
`
`histamine H1 receptor. Despite our speculation that
`weight gain from these new agents would be linked to
`serotonin receptor activity, no relationship could be es-
`
`
`
`Figure 1. Weight Gain as a Func ion of Drug
`90
`
`
`
`
`
`l Clozapine
`I Oianzapine
`El Risperidone
`El Sertindoie
`CI Haloperidoi
`
`
`—
`
`
`
`50
`
`70
`60
`
`50
`
`40%ofSubjects 30
`
`20
`
`10
`
`
`
`
`
` z 10%
`
`< 10%
`No Change,
`or Lost Weight
`Weight Gain
`Weight Gain
`% Weight Change From Baseline to Maximum Weight
`
`tablished between clinical weight gain and 5-HT2C recep-
`tor affinity.
`The literature is variable in terms of establishing a link
`between weight gain and dose of conventional antipsy-
`chotic medications.”43 Our sample size is too small to
`adequately address the issue of dosage. In future studies,
`we will attempt to have a larger sample to examine dosage
`issues.
`
`Other possible explanations for increased weight gain
`seen in the clozapine—treated patients compared with the
`haloperidol—treated patients may be that, clinically, the
`clozapine-treated patients were ill longer and were thus
`more sedentary. However, over half of the haloperidol—
`treated subjects in this retrospective study were matched
`for severity of illness with the clozapine—treated patients.
`
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`

`Novel Antipsychotics and Weight Gain
`
`
`
`'lable 4. Final Weight Gain
`
`Drug
`
`Variable
`clozapine
`Olanzapine
`Risperidone
`Haloperidol
`Sertindole
`Pairwise Comparisons
`Final weight gain, mean :1: SD
`n/a
`lb
`kg
`Final adjusted weight gain,
`mean 1 SEM**
`lb
`kg
`Final % weight gain,
`mean: SD
`n/a
`Final adjusted % weight gain,
`Clozapine > risperidone,“
`mean = SEM”
`clozapine > sertindole."
`clozapine > haloperidol,"
`clozapine > olanzapine**
`*pg .05. "pg .01.
`
`14.1: 13.5
`6316.1
`
`6.2: 14.1
`2816.4
`
`15.0: 2.3
`6.8: 1.0
`
`8.0:: 8.2
`8.7 :r 1.3
`
`5.3 :29
`2.4: 1.3
`
`42:93
`3.3 x 1.6
`
`4.2:92
`1.9:4.2
`
`5.0: 1.8
`2.3:0.8
`
`2.5:53
`3.1 x 1.1)
`
`3.0: 10.9
`1.4149
`
`3.4: 1.7
`1520.8
`
`1.62:5.7
`1.9 x 1.0
`
`05:86
`0213.9
`
`l.4:3.7
`0.6::1.7
`
`0.63:5.2
`1.2 i 2.0
`
`Clozapine > risperidone,“
`clozapine > sertindole,**
`clozapine > haloperidol,‘H
`clozapine > olanzapine*
`
`
`
`Figure 2. Weight Gain as a Function of H1 Affinity“
`
`10—
`
`Olannpine
`Clozapine
`
`
`Risperidone
`
`
`
`AdjustedMaxlmumWalghtGain('73)
`
`
`
`
`
`Haloperidol
`Serfindole
`
`0%
`
`T
`l
`T
`3
`2
`1
`“H, Receptor Affinity (K‘)
`
`5.4
`
`01
`
`t ain
`= ad'usted maximum wei
`'= 4.7 1 — e425" + 4.1 where
`Y
`g
`J
`(%) and x = 1/I-I, receptor afiinity (K1).
`
`Additionally, the clozapine-treated patients had a better
`clinical response than the haloperidol—treated subjects.38
`Some researchers have postulated that an increase in
`weight during clozapine treatment is linked with good
`clinical response.44 Although we have clinical response
`data for all these patient groups, different rating instru-
`ments were used to measure response in each study. Each
`subset of patients was selected for these studies for their
`difl'erent historical patterns of response; thus, compari—
`sons across these studies would be unfair.
`
`As adults age, weight can naturally increase.45 We be-
`lieve the weight gain seen in our patients treated with the
`new agents exceeds what would be expected as a normal
`aspect of aging. Indeed, some patients in each group
`gained over 30 lb (14 kg).
`The fact that only men were included in this study is a
`limitation, as women may have different weight gain pat—
`terns. Another potential difficulty in interpreting our re-
`sults is that 30 patients were involved in more than 1
`study. Sequential participation may artificially minimize
`
`J Clin Psychiatry 6026, 11111131999
`
`the actual weight gain a patient may have experienced
`with the second medication he was exposed to in the sec-
`ond trial.
`
`A suggestion coming from pharmaceutical companies
`is that weight gain may be most significant in patients
`who were initially underweight. However, we examined
`this in our data set, and we saw no correlation between
`body weight index at baseline and weight gain.
`Future prospective studies could be designed to actu—
`ally measure caloric intake and assess the types of foods
`that patients eat, e.g., are they preferentially increasing
`carbohydrate intake or fat intake?
`Although novel antipsychotic drugs have superiority
`over haloperidol both in increased effectiveness and in re-
`duced side effects,“’47 they carry the liability of potential
`weight gain. Of note, conventional antipsychotic medica—
`tions were also notorious for this effect, particularly
`lower—potency agents."2 Histamine receptor blockade was
`speculated to play a role in this in the past.48 Antihista—
`mines are well known to cause weight gainffidmz2 so anti-
`histamine properties of clozapine and olanzapine may, in
`part, account for the increase in weight caused by these
`medications?0 Indeed, we saw the strongest correlation
`between weight gain and relative histamine H1 receptor
`affinities of the novel agents.
`Clinicians should be aware of this potential liability of
`the new agents. Patients should have nutritional counsel—
`ing and referral to exercise programs while taking these
`medications. Weight should be monitored carefully over
`the course oftreatrnent. Primary care practitioners, family
`members, and other caregivers should be alerted to this
`risk, as the potential complications of weight gain in pa-
`tients with schizophrenia can be serious. Of note, several
`of our patients who have had enormous weight gain on
`treatment with novel antipsychotie medications have de—
`veloped diabetes.49 Greater risk for heart disease may also
`result in patients who develop significant weight gain. It
`is essential that we educate our patients to minimize the
`risks of this important side efi'ect.
`
`362
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`DEF-LURAS-0005919
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`

`Wirshing et a1.
`
`Drug names: chlorprornaziue (Thorazine and others), clozapine (Cloza-
`ril), haloperidol (Haldol and others), olanzapine (Zyprexa), risperidone
`(Risperdal), thioridazine (Mellaril and others).
`
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