Weight Change and Atypical Antipsychotic Treatment
`in Patients With Schizophrenia
`
`Barry Jones, M.D.; Bruce R. Basson, M.S.; Daniel J. Walker, Ph.D.;
`Ann Marie K. Crawford, Ph.D.; and Bruce J. Kinon, M.D.
`
`
`
`ehizophrenic patients who have been prescribed atypical antipsychotics have a potential risk of
`w nihg weight. The implications of weight gain for clinical care may differ depending on whether a
`
`
`
`(J Clin Psychiatry 2001;6215appl 21.4144)
`
`
`
`tients to drink large quantifies of high-caloric liquids that
`may lead to weight gain.10
`
`In this article, we compare changes in body weight of
`
`Some patients can show large increases in b
`schizophrenic patients during treatment with olanzapine,
`_ an atypical antipsychotic, with those observed during
`during drug treatment, while others show little cigan
`
`treatment with other atypical and typical antipsychotics.
`even a loss in body weight, Weight gain has been cite W
`
`e also review factors that can help predict which pa-
`major reason for treatment noncompliancef although th
`ls repay gain weight during antipsychotic treatment and
`,’
`is evidence suggesting that some patients with the m ,
`w
`
`idenae that behavioral interventions are useful in con—
`weight gain may also have the best clinical response};
`
`These observations illustrate the complexity of changes in
`body weight as a response to antipsychotic medications.
`The precise physiologic mechanism underlying weight
`gain in patients treated with antipsychotics is presently
`unknown, although antagonism of several neurotransmit—
`ter systems has been proposed. For example, antagonism
`of the serotonergic 5-HT2C receptor has been shown to
`
`play a major role in increasing food consumption and
`
`leading to weight gain.7 It has also been demonstrated that
`histaminergic H1 receptor antagonists increase food intake
`and weight gain in both humans and rats,8 an effect that
`may be associated with increased release of norepineph-
`rine.9 Furthermore, it has been suggested that some pa—
`tients experience anticholinergic adverse events such as a
`dry mouth, which has been attributed to a blockade of
`muscarinic M1 receptors. Dry mouth may cause some pa-
`
`tween 6 weeks and 2 years) {d{iig on file, Eli Lilly and
`Company, Indianapolis, Ind, 20m“?
`In addition, in some
`
`of the clinical trials, patients treate
`th olanzapine were
`
`compared with patients treated with haipperidol, a typical
`
`antipsychotic (1—year endpoint; N: 386’
`lanzapine;
`N = 85, haloperidol), or risperidone, an atypi‘al antipsy-
`chotic (28—week endpoint; N: 102, olanzapiiie; N= 79,
`risperidone).
`
`RESULTS AND DISCUSSION
`
`From Lilly Research Laboratories, Eli Lilly and Company,
`Indianapolis, Ind.
`Supported by an unrestricted grant from Eli Lilly and
`Company.
`Reprint requests to: Barry Jones, MD, Lilly Research
`Laboratories, Eli Lilly and Company, Lilly Corporate Center,
`Drop Code 1758, Indianapolis, IN 46285
`(e—mail: Jones_Barry@lilly.com).
`
`The amount of weight gained during drug treatment is
`variable. For example, results from the entire olanzapine
`database of trials sponsored by Eli Lilly and Company in
`which patients were treated for 2 years showed that a ma—
`jority ofpatients (66%) gained less than 10 kg (Figure 1).11
`Approximately 7% of the patients gained more than 20 kg
`
`1 Clin Psychiatry 2001;62 (suppl 2)
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`41
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`Slayback v. Sumitomo
`|PR2020-01053
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`Exhibit 2036
`Slayback v. Sumitomo
`IPR2020-01053
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`Jones et al.
`
`
`
`
`
`Figure 1. Distribution of Weight Change During Long—Term
`Olanzapine Treatment After 2 Years (observed cases)1
`25
`
`Figure 2. Weight Gain and Plateau During Long-Term
`Olanzapine Treatment“
`
`NO
`
`a 01
`
`
`
`%Olanzapine—TreatedPatients 8
`
`
`
`
`
`
`
`Weight Change, kg
`
`aData fiom Basson et a1.”
`
`MeanWeightGain,kgmwaoro:«Aon
`
`_\
`O
`
`14
`38
`0
`60
`92
`124
`156
`“Data from Kinon et alf2
`
`
`
`Figure 3. Relationship Between Starting Dose of Olanzapine
`and Weight Gaina
`
`
`
`A Olanzapine, 5 mg/day (N = 68)
`I Olanzapins. 20 mglday (N = 68)
`O Placebo (N = 34)
`
`
`
`
`
`
`cameo-halo:
`‘canWeightChange,kg I
`
`
`
`
`after 2 years. However, approximately 1 in 4 patie
`
`ally lost weight or gained no weight at all.
`
`For both the clinician and the patient, it is important
`
` 15 20 30
`
`
`know when weight gain may occur, if at all, during trea
`Relative Week of Therapy
`ment with antipsychotic medications. For example, in pa-
`tients treated with olanzapine for up to 3 years, the increase
`in body weight trended toward a plateau at approximately
`36 weeks of drug exposure, with no significant further in—
`creases occurring on subsequent treatment, on average
`(Figure 2).12
`Dose was not a significant predictor of long-term
`changes in weight in patients treated up to 3 years.12 There—
`fore, decreasing the dose will probably not affect weight
`change and may negatively affect clinical response if it re—
`sults in a subtherapeutic dose. Likewise, starting dose also
`appears not to affect weight gain. A 6-month study com—
`pared fixed doses of olanzapine (5 and 20 mg/day) with
`placebo in schizophrenic patients displaying prominent
`negative symptoms (data on file, Eli Lilly and Company,
`Indianapolis, Ind, 2000). The results demonstrated that
`weight gain was very similar between the 2 starting doses
`of olanzapine (Figure 3).
`Differences have been observed in the amount of
`
`
`
`
`
`'lly and Company, Indianapolis, Ind, 2000.
`
`o of haloperidol—treated patients
`
`
`
`igure 4) (data on file, Eli Lilly
`
`
`and Company, Indianap
`Ind, 2000). Conversely, 20%
`of olanzapine— and 45% ofhalo egdol—neamd patients ac—
`tually lost weight. However, it3
`portant to realize that,
`
`even though haloperidol—treate p,
`ts may experience
`
`less weight gain, patients with olanzap
`, as well as other
`
`atypical antipsychotics, have a lower rdte of extrapyrami—
`dal symptoms.”17
`’
`All of the currently available atypical arfifisychotics
`have been reported to cause weight gain to varying de-
`grees.18 One recent survey reported that clozapine—treated
`patients experienced the greatest amount of weight gain.19
`Olanzapine-treated patients have generally experienced
`more weight gain than patients treated with risperidone,
`although the differences can be fairly small depending on
`the clinical trial. For example, in a study by Tran et al.,20 a
`higher percentage ofrisperidone patients (88%) compared
`with olanzapine patients (78%) gained less than 10 kg.
`More olanzapine patients had weight gains greater than 1 0
`kg (20.0%) compared with risperidone patients (8.6%).
`
`weight gained during treatment with typical and atypical
`antipsychotics. Comparison of weight gain following ex—
`posure to olanzapine or haloperidol revealed that 72% of
`olanzapine—treated patients versus 91% of haloperidol-
`treated patients lost weight, had no weight change, or
`gained less than 10 kg at 1 year, while 6% of olanzapine-
`
`42
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`J Clin Psychiatry 2001;62 (suppl 2)
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`Figure 4. Weight Change With Olanzapine Versus Haloperidol
`at 1 Yeari
`
`Figure 6. Behavioral Interventions: Weight Gain by
`Antipsychotic‘
`
`Weight Change and Atypical Antipsychotics
`
`I Olanzapine (N = 386)
`
`E Haloperidol (N = 85)
`
`
`
`Gained
`Gained
`Gained
`Gained
`io<15 kg 15<20 kg 20<25 kg 25<30 kg
`
`Lost
`Weight
`
`45
`40
`35
`30
`25
`20
`15
`1o
`
`5 o
`
`”InPatients
`
`No Change
`aha;
`or Gained 55“ 0’
`
`0 <5 kg
`
`8Data on file, Eli Lilly and Comp
`polis, 1nd,, 2000.
`
`
`Figure 5. Weight Change With Olanzap eV
`s Risperidone
`
`at 28 Weeksa
`
`
`
` Olanzapine (N =
`@ Rispendone (N — 7
`
`
`
`
`I Ciozapine (N = 20)
`I Oianzapine (N = 13)
`E Risperidnne(N=38)
`El Haioperidol (N =43)
`El Sertindcla (11:3)
`
`7
`
`3’ 6
`c"
`g 5
`.4 4
`‘5:
`g 3c 2
`S2 1
`0
`
`
`
`Maximum Weight Gain
`Final Weight Gain
`After Behavioral Interventions
`During Therapy
`
`”Data from Wirshing et a1.”
`
`aged a weight gain of less than 4 kg compared with about
`8 kg for the low—BMI group. Because many schizophrenia
`patients are thin and have a low BMI, weight gain may be
`a benefit if it results in a BMI that is normalized.
`
`To determine if baseline BMI has an influence on weight
`gain during treatment vsn'th other atypicals, a retrospective
`analysis compared olanzapine and risperidone from 3 ran—
`domized, double-blind studieszo":2 The results demon-
`. strated that patients with low BMI gain the most weight
`whether they are receiving olanzapine or risperidone (data
`on file, Eli Lilly and Company, Indianapolis, Ind, 2000).
`-Qbreover, patients who were considered overweight
`
`
`
`as as
`
`as
`Gained
`Gained
`Gained
`Gained
`Lost
`Gained
`>5—1O kg >10—15 kg >15—20 kg >20 kg
`Weight
`0—5 kg
`“Data from Tran et al.20
`
`
`
`About 20% and 25% of patients lost weight in the olanza—
`pine and risperidone groups, respectively (Figure 5). At
`endpoint (28 weeks), the mean weight gains were 4.1 kg
`and 2.3 kg in the olanzapine and risperidone groups, re-
`spectively. This absolute difference of 1.8 kg over 28
`weeks was statistically significant (p = .015), although the
`data were based on the last observation carried forward.
`
`What factors can help predict whether weight gain may
`occur during treatment with olanzapine? One important
`variable appears to be the patient’s baseline body mass in-
`dex (BMI) prior to drug treatment. The results of a recent
`study12 showed that patients with a high baseline BMI had
`significantly lower (p < .002) mean weight gains than the
`medium— and low—BMl patients, beginning at 13 weeks. By
`endpoint (3 years), the high—BMI patients had a significantly
`lower (p > .001) mean weight gain than the medium— and
`low-BMI patients. At endpoint the high—BMI group aver—
`
`] Clin Psychiatry 2001;62 (suppl 2)
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`
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`
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`an increased ap—
`even better predictor. Those patients131/
`petite gained significantly (p= .0001)?ignoreweight com-
`
`pared with patients with normal appetites
`é
`esting to note that patients prone to gain Wagiht during
`treatment with other antipsychotics often base a robust
`clinical improvernentzz“26 and/or low baseline BMI.27’28
`In the same analysis,‘1 olanzapine was compared with
`haloperidol or risperidone, and it was found that a better
`clinical outcome and low baseline BMI were indicators of
`
`weight gain for all 3 drugs. in addition, younger patients
`gained more weight than older patients with the atypicals,
`but this was not observed with haloperidol. When compar-
`ing only olanzapine with haloperidol, the predictive factor
`with the greatest effect on weight change was initial ran—
`domization to atypical versus conventional therapy. More—
`
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`Jones et :11.
`
`over, predictors of weight gain for olanzapine, but not
`haloperidol, were increased appetite and male sex.
`Can weight gain during antipsychotic drug treatment be
`controlled? Arecent study incorporated a variety ofbehav—
`ioral interventions for patients who had gained consider—
`able amounts of weight during treatment with antipsy—
`chotics (maximal weight gain between 2.5 and 8.0 kg,
`depending on the drug)“2 A stepwise approach was taken
`such that patients were subject to increasingly intensive
`interventiopstself—weighing, food diary, nutrition consul—
`tation, educ
`tin, group support, exercise classes), depend-
`ing on their ’hiliryto control their weight The maximum
`weight gained during therapy and final weight gain after
`interventions are depicted for diiferent drugsin Figure 6.
`Only those patientstakingclozapme failed to have any re-
`
`sponse to the intervenno
`
`phtipsychofics and weight
`A comprehensive revie
`gain by Baptism” includes curfe‘ and future interventions
`in managing this adverse event. We‘g. gain control may
`e
`include both pharmacologic and noii’pfiaxinacologic inter—
`ventions (e.g., diet, exercise) Irnpo artilyf and as noted
`
`
`
`
`
`
`
`
`Holden JMC, Holden UP. Weight changes with schizophrenic psychosis
`and psychotropic drug therapy. Psychosomatics 1970;9z551—561
`Gordon 1-11., Groth C. Weight change during and after hospital treatment.
`Arch Gen Psychiatry 1964;10:187—191
`Gordon HL, law A, Hohmen KE, et al. The problem of overweight in hos—
`pitalized psychotic patients. Psychiatr Q 1960;34:69—82
`Bernstein JG. Induction of obesity by psychotropic drugs. Ann N Y Acad
`Sci 1987;499:203—215
`Leadbetter R, Shutty M. Pavalonis D, et a1. Clozapine—induced weight gain:
`prevalence and clinical relevance. Am J Psychiatry 1992;149:6842
`Stahl SM. Neurophannacology of obesity: my receptors made me eat it
`[BRAINSTORMS]. J Clin Psychiatry 1998;59:447—448
`Sahara T, Fukagawa K, Fujimoto K, et al. Feeding induced by blockade of
`histamine Ill-receptor in rat brain. Experienu'a 1988;44:216~218
`Oishi R, Shishido S, Yarnori M, et a1. Comparison of the effects of eleven
`histamine Hrreceptor antagonists on monoamine turnover in the mouse
`brain. Naunyn Schmiedebergs Arch Pharmacol 1994;349:1411—1114
`. Wetterling T, Mfibigbrodt HE. Weight gain: side efiect of atypical neuro—
`leptics? J Clin Psychopharmacol 1999;19:316—321
`. Basson BR, Kinon BJ, Taylor CC, et al. Factors influencing weight change
`in patients with schizophrenia treated with olanzapine versus halcperidol
`or risperidone. Presented at the Slst Institute on Psychiatric Services; Oct
`29, 1999; New Orleans, La
`Kinon BJ, Basson BR, Tollefson GD, et a1. Eifect of long-term olanzapine
`treatment on weight change in schizophrenia. Schizophr Res 2000;41:
`195—196
`. Beaumont G. Antipsychotics: the future of schizophrenia treatment. Curr
`Med Res Opin 2000;16:37—42
`Worrcl JA, Markcn PA, Beckman SE, et a1. Atypical antipsychotic agents:
`a critical review. Clin Rev 2000;57:238455
`. Tollefson GD, Beasley CM 11', Tran PV, et a1. olanzapine versus haloperi—
`dol in the treatment of schizophrenia and schizoafi‘ective and schizophreni-
`form disorders: results of an international collaborative trial. Am J Psychi-
`atry 19973541457465
`. Tran PV, Dellva MA, Tollefson GD, et a1. Extrapyramidal symptoms and
`tolerability of olanzapine versus haloperidol
`in the acute treatment
`of schizophrenia. J Clin Psychiatry 1997;58:205—211. Correction 1997;58:
`
`
`
`
`additional and more precise interventions in controliihg
`weight gain.
`1
`Beagle”): CM, Tollefson G, Tran P, et a1. Olanzapine versus placebo and
`moperidol: acute phase results ofthe North American double—blind olan—
`
`
`
`SUMMARY
`
`
`
`Weight gain has been reported during treatment with
`nearly all the atypical antipsychotics. Over a period of 2
`years, nearly half of the patients in the clinical trial data—
`base either lost weight, remained stable, or gained 5 kg or
`less. Treatment-emergent weight gain in patients treated
`with up to 3 years of olanzapine therapy trended toward a
`plateau after about 36 weeks of treatment. Predictors of
`weight gain dining olanzapine treatment include good
`clinical response, low baseline BMI, increased appetite,
`and, possibly, age of less than 40 years and male sex. Daily
`and starting drug dose do not appear to be correlated with
`weight gain in olanzapine-treated patients. Finally, pa-
`tients for whom weight gain is an issue should be encour-
`aged to follow healthy diet and exercise habits.
`
`Drug names: clozapine (Clozaril and others), haloperidol (Haldol and
`others), olanzapine (Zyprexa), risperidone (Risperdal).
`
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