Psychopharmacology (2007) 192:441 448
`DOI 10.1007/s00213 007 0731 1
`
`ORIGINAL INVESTIGATION
`
`Attenuating effect of reboxetine on appetite and weight
`gain in olanzapine-treated schizophrenia patients:
`a double-blind placebo-controlled study
`
`Michael Poyurovsky & Camil Fuchs &
`Artashez Pashinian & Aya Levi & Sarit Faragian &
`Rachel Maayan & Irit Gil-Ad
`
`Received: 12 December 2006 / Accepted: 26 January 2007 / Published online: 20 February 2007
`# Springer Verlag 2007
`
`Abstract
`Rationale Search for safe and effective strategies to
`diminish weight gain associated with second generation
`antipsychotics (SGAs) is imperative. In the present study,
`we sought
`to replicate our preliminary findings, which
`indicated that coadministration of the selective norepineph-
`rine reuptake inhibitor reboxetine attenuates olanzapine-
`induced weight gain.
`Materials and method Fifty-nine patients hospitalized for
`first-episode DSM-IV schizophrenic disorder participated in
`this randomized double-blind study. Reboxetine (4 mg/day;
`
`M. Poyurovsky : A. Pashinian : A. Levi : S. Faragian
`Research Unit, Tirat Carmel Mental Health Center,
`P.O. Box 9, Tirat Carmel 30200, Israel
`
`M. Poyurovsky (*)
`Rappaport Faculty of Medicine,
`Israel Institute of Technology Technion,
`Haifa, Israel
`e mail: poyurovs@tx.technion.ac.il
`
`C. Fuchs
`Department of Statistics and Operations Research,
`Tel Aviv University,
`Tel Aviv, Israel
`R. Maayan : I. Gil Ad
`Laboratory of Biological Psychiatry,
`Felsenstein Medical Research Center,
`Geha Psychiatric Hospital,
`Petah Tiqva, Israel
`
`Present address:
`C. Fuchs
`Department of Statistics, University of Pittsburgh,
`Pittsburgh, PA, USA
`
`31 patients) or placebo (29 patients) was coadministered
`with olanzapine (10 mg/day) for 6 weeks. Analysis was by
`intention-to-treat.
`Results Nine patients in each group prematurely discontin-
`ued the trial. Olanzapine/reboxetine-treated patients showed a
`significantly lower increase in body weight (mean=3.31 kg,
`SD=2.73) than their olanzapine/placebo-treated counterparts
`(mean=4.91 kg, SD=2.45). Significantly fewer olanzapine/
`reboxetine-treated patients gained at least 7% of their initial
`weight,
`the cutoff for clinically significant weight gain
`(6 [19.4%] of 31 patients vs 13 [46.4%] of 28 patients).
`Seven (22.6%) olanzapine/reboxetine-treated patients com-
`pared to only one patient (3.6%) in the olanzapine/placebo
`group revealed no weight change or even modest weight loss.
`Appetite increase was significantly lower in the olanzapine/
`reboxetine than olanzapine/placebo group and was correlated
`with attenuation of weight gain. Reboxetine addition was safe
`and well tolerated.
`Conclusions The results confirm that coadministration of
`reboxetine promotes a clinically meaningful attenuation of
`olanzapine-induced weight gain in schizophrenia patients.
`If substantiated in long-term studies, along with behavioral
`management and diet counseling, reboxetine may have a
`clinical utility in controlling SGA-induced weight gain.
`
`Keywords Second generation antipsychotics . Olanzapine .
`Reboxetine . Weight gain
`
`Introduction
`
`Weight gain is one of the major drawbacks of treatment
`with second generation antipsychotic agents (SGAs). SGA-
`
`1
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`Exhibit 2097
`Slayback v. Sumitomo
`IPR2020-01053
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`442
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`Psychopharmacology (2007) 192:441 448
`
`induced weight gain is associated with patient nonadher-
`ence to medication, reduced quality of life,
`increased
`morbidity (e.g., cardiovascular disease, type 2 diabetes),
`and mortality (Newcomer and Haupt 2006).
`Olanzapine, along with clozapine, has the greatest
`propensity of all available SGAs to induce weight gain.
`Despite extensive research during the last decade, a
`pathophysiological mechanism underlying olanzapine-
`induced weight gain remains unclear. Neurotransmitter
`systems, primarily serotonergic (5-HT), noradrenergic
`(NE), and histaminergic (H), apparently play a role (Elman
`et al. 2006). It was suggested that the antagonistic effect of
`olanzapine on NE neurotransmission contributes, along
`with its 5-HT2C and H1 receptor blockade,
`to its high
`propensity to cause weight gain (Kroeze et al. 2003;
`Poyurovsky et al. 2003). In contrast, phentermine and
`sibutramine, both potent appetite suppressants and antiobe-
`sity agents, facilitate adrenergic tone by stimulating NE
`release and NE and 5-HT reuptake inhibition (Henderson et
`al. 2005). Increased NE neurotransmission has consistently
`been implicated in regulation of food intake, body weight,
`and energy expenditure in preclinical models of obesity
`(Ste Marie et al. 2005).
`Reboxetine, a selective norepinephrine reuptake inhibitor
`(NRI), is broadly used as an antidepressant and antianxiety
`agent. Overall,
`in these patient populations, reboxetine
`produced a neutral effect on body weight, but weight loss has
`also been reported (Schatzberg 2000; Bertani et al. 2004).
`Based on the assumption that stimulation of NE activity by
`the selective NRI reboxetine may diminish olanzapine-
`induced weight gain, we conducted a pilot study in which
`reboxetine was coadministered with olanzapine in schizophre-
`nia patients (Poyurovsky et al. 2003). In accordance with our
`assumption, patients given olanzapine and reboxetine demon-
`strated a significantly lower increase in body weight than
`those given olanzapine with placebo. The addition of
`reboxetine to olanzapine treatment was safe and well tolerated
`by the patients. Noteworthy, the participants were young first-
`episode schizophrenia patients previously unexposed to
`antipsychotic medication who seem to be particularly vulner-
`able to olanzapine-induced weight gain (Kinon et al. 2001).
`In the present double-blind placebo-controlled study, we
`sought to replicate, in a larger sample, our preliminary findings
`indicating that reboxetine coadministration attenuates olanza-
`pine-induced weight gain. In addition, as increased appetite
`and food intake seem to be a major behavioral pathway by
`which olanzapine produces weight gain (Gothelf et al. 2002;
`Kinon et al. 2005; Cope et al. 2005), we also assessed the
`effect of reboxetine on appetite and its relationship to weight
`gain. To increase comparability of the results, similar to the
`previous study, we recruited first-episode predominantly
`drug-naïve schizophrenia patients for whom olanzapine
`treatment was indicated.
`
`Subjects and methods
`
`Subjects and study design
`
`This study was conducted in Tirat Carmel Mental Health
`Center (Tirat Carmel, Israel) between October, 2003 and
`October, 2006. The study protocol was approved by the
`local ethics committee and was undertaken in accordance
`with Good Clinical Practice and the provisions of the
`International Conference on Harmonization, with all
`patients providing written informed consent after they
`received a full explanation of the study procedures. Patients
`hospitalized for a first psychotic episode were enrolled in
`the study. All met the DSM-IV criteria for schizophrenia or
`schizophreniform disorder. The diagnosis was based on
`information obtained from the Structured Clinical Interview
`for DSM-IV Axis-I Disorders, Patient Edition (First et al.
`1995). Similar to the previous pilot study, inclusion criteria
`in the present study were none or less than 4 weeks of
`antipsychotic drug exposure and a recommendation for
`olanzapine treatment by the treating physician. Exclusion
`criteria included major mood disorders, aggressive or
`suicidal behavior, medical illnesses that could affect body
`weight (e.g., diabetes mellitus and hypothyroidism), and
`obesity (body mass index [BMI]≥30 kg/m2). Of the 85
`patients who were screened for participation in the study,
`69 met entry criteria, 59 patients (38 men, 21 women) were
`randomized, whereas ten patients refused to participate
`(Fig. 1). There were no differences in socio-demographic or
`clinical variables between participants (N=59) and those
`who refused to participate (N=10).
`The olanzapine/reboxetine group consisted of 31 patients
`(23 men, 8 women; age 30.3±8.5 years, range 19–48 years),
`and the olanzapine/placebo group consisted of 28 patients
`(15 men, 13 women; age 29.5±7.2 years, range 19–
`46 years). Before the beginning of the study, 13 patients
`in the olanzapine/reboxetine group were drug-naïve, eight
`patients received risperidone (2–4 mg/day), five patients
`received haloperidol (5–10 mg/day), and five patients
`received perphenazine (8–24 mg/day). In the olanzapine/
`placebo group, 12 patients were drug-naïve, five patients
`received risperidone (2–6 mg/day), five patients received
`haloperidol (10 mg/day), five patients received perphena-
`zine (8–16 mg/day), and one patient received quetiapine
`(600 mg/day). None of the participants received medica-
`tions other than psychotropic agents during the study. None
`of
`them had abnormal
`findings on routine physical
`examination and laboratory tests, including electrocardiog-
`raphy and drug screening, when appropriate.
`A double-blind placebo-controlled randomized design
`was used in the present study. The participants were
`allocated according to entries on a table of random numbers
`to receive olanzapine (fixed dose of 10 mg at 8:00 P.M.)
`
`2
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`

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`Psychopharmacology (2007) 192:44] 448
`
`443
`
`
`
` 3] patients
`
`olarrzapindrebmetine
`WP
`
`
`
`1, rrrinirnal increase; 2, moderate increase; 3, substantial
`increase; -1, rrrinirnal decrease; —2, moderate decrease; -3,
`
`substantial decrease. Appetite ratings were complewd at the
`end of the trial. Clinical assessment instruments included the
`
`Scale for the Assessment of Positive Symptoms (SAPS;
`Andreasen 1984), Scale for the Assessment of Negative
`Symptoms (SANS; Andreasen 1983), Clinical Global
`Impression scale for psychosis (CGI; Guy 1976), and the
`Hamilton Rating Scale for Depression (HAM-D; Hamilton
`1960). EPS were assessed using the Barnes Akathisia Scale
`(BAS; Barnes 1989) and Simpson—Angus Scale (SAS;
`Simpson and Angus
`I970). Emergent non-EPS drug-
`induced side effects were closely monitored Clinical ratings
`were completed at baseline and at week 6 by the same
`trained psychiatrist (A. Pashiniarr) who was blinded to the
`patients’ treatment assignments.
`
`Statistical analysis was carried out using SPSS for
`Windows 13 (SPSS, Chicago, Ill). The sample size of
`approximately 30 in each group was determined to provide
`80% power in detecting a between-group difference of at
`least 2 kg, when the significance level of the two-sided test
`is a=0.05, and the pooled SD is 2.9, as obtained in our
`previous pilot study (Poyurovsky et al. 2003), and allowing
`for a 25% attrition rate. The primary statistical analysis was
`by intention to treat and included all randomized partic-
`ipants. A complementary analysis of weight/BM] changes
`in completers was also performed. We used analysis of
`variance with repeated measurements (ANOVA-RM) to
`evaluate between-group differences in weight and BM]
`during the 6-week trial with time as a within-subject factor
`and group as a between-subject factor. In addition, similar
`to the previous study, the mean changes in weight/BM]
`during the trial period (difference between baseline and
`each time point) were analyzed for each group.
`We used the regression method to treat missing data. In
`this method, for each week with missing weight/BM], the
`values were substituted by those obtained from the fitted
`values based on the regression of the values of the
`participants with complete data for the given week on the
`data for the previous week. This imputation method takes
`into account the direction and the effect size of weight/BM]
`changes in the group to which the patients with missing
`data were wcribed. We also carried out an alternative
`
`method of imputation based on the last observation carried
`forward (LOCF).
`We used the changes in weight and BMI as the primary
`continuous outcome variable and the proportion of patients
`who gained 7% of their initial body weight, the established
`cut-off for clinically significant weight gain (Kanders et a1.
`1991), as a primary categorical outmme variable. Between-
`
`@ Springer
`
`trial
`
`Statistical analysis
`
`22 completed
`
`31 evalufled for
`primary outcome
`
`28 evaluated for
`
`primary orrwome
`
`Fig. 1 Trial profile. Primary analysis was done on the intention to
`treat population
`
`with either reboxetine (4 mg/day, administered in 2-mg
`doses twice daily) or placebo (twice daily) for 6 weeks. All
`study rrredications were dispensed in identical capsules, and
`patients received two capsules per day. Clinical and
`research staff and patients were unaware of and could not
`determine the study drug assignment by appearance or
`otherwise. The reboxetine dose was determined based on
`
`our previous report (Poyurovsky et al. 2003). Administra-
`tion of an anticholinergic agent (trihexyphenidyl 5 mg/day;
`biperiden 2—4 mg/day) for extrapyrarnidal side effects
`(extrapyramidal symptoms, EPS) and benzodiazepines
`(lorazeparn 1—3 mg/day; diazepam 5 mg/day) for insomnia
`or agitation were allowed on an as-needed basis; no other
`antipsychotics, antidepressants, or mood stabilizers were
`permitted. The doses of all medications remained un-
`changed during the entire study period. Meals were served
`three times a day, and patients were not placed on a special
`diet or physical exercise program for weight reduction.
`
`Assessments
`
`Body weight and BMI were measured before breakfast at
`baseline and that weekly. All weight measurements were
`performed by a research assistant blinded to the patients’
`treatment assignment. To assess a change ofappetite, we used
`a visual analog scale with the following scores: 0, no change;
`
`

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`444
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`Psychopharmacology (2007) 192:441 448
`
`group differences in the proportion of patients who gained
`7% of their initial body weight were tested by χ2 test and
`odd ratios. Between-group differences in demographic and
`clinical variables and in changes from baseline to endpoint
`in the appetite visual analog scale, SAPS, SANS, CGI,
`HAM-D, SAS, and BAS scores were analyzed using t test
`or χ2 test, as appropriate. Pearson’s correlation analysis was
`used to assess the relationship between appetite and
`weight changes at the end of the trial and the relationship
`between baseline weight and weight change at the end of
`the trial. All tests were two-tailed with a significance level
`of α=0.05. Measures are given as mean±SD.
`
`Role of the funding source
`
`The study was funded by the Stanley Medical Research
`Institute. The funding source had no role in gathering,
`analyzing, or interpreting the data or in deciding to submit
`the paper for publication in Psychopharmacology.
`
`Results
`
`Figure 1 depicts the flow of patients through the study.
`There were no significant between-group differences in
`demographics, baseline clinical characteristics, body
`weight, and BMI (Table 1). Nine patients in each group
`discontinued the study medication because of a lack of
`efficacy of olanzapine (seven patients in each group),
`withdrew consent (olanzapine/reboxetine: one patient; olan-
`zapine/placebo:
`two patients), and discharge from the
`hospital (olanzapine/reboxetine: one patient). The missing
`data patterns for weight/BMI values were similar between
`the two groups. None of the patients discontinued the study
`because of weight gain, and the majority (olanzapine/
`reboxetine: eight of nine patients; olanzapine/placebo: six
`
`of nine patients) dropped out before the fourth assessment
`(third week). There were no differences in demographic or
`clinical characteristics or weight/BMI values between the
`patients who dropped out of the study and those who did not.
`Body weight/BMI changes from baseline in both groups
`are presented in Table 2. ANOVA-RM revealed a highly
`significant effect of time (weight: F=88.89; df=5,287,
`p<0.01; BMI: F=84.35; df=5, 287, p<0.01) and effect of
`group (weight: F=6.46, df=1, p=0.014; BMI: F=6.37;
`df=1, 57, p=0.014) but not the interaction between time
`and group (weight: F=1.77, df=5, 287, p=0.12; BMI:
`F=1.83; df=5,287, p=0.11). Analysis of the changes in
`weight gain in the two groups (Table 2) revealed a gradual
`cumulative effect in weight gain from the baseline in favor
`of reboxetine, resulting in statistically significant between-
`group differences in each of the weeks starting from week 2
`through the end of
`the 6-week trial. Although the
`cumulative effect
`from baseline was significant,
`the
`between-group week-to-week differences in weight were
`relatively small and not statistically significant, accounting
`for the failure of ANOVA-RM to detect significant group ×
`time interaction for the sample sizes. Overall, at the end of
`the trial, patients in the olanzapine/reboxetine group gained
`significantly less weight
`than their counterparts in the
`olanzapine/placebo group (3.31±2.73 and 4.91±2.45 kg,
`respectively; t=2. 55; df=57; p=0.013), namely, a between-
`group difference in mean weight gain of 1.61±0.62 kg. The
`corresponding increase in BMI was 1.12±0.87 kg/m2 in
`the olanzapine/reboxetine group and 1.71±0.91 kg/m2 in
`the olanzapine/placebo group (t=2.56, df=57, p=0.013),
`with a between-group mean difference of 0.59±0.23 kg/m2.
`Table 2 highlights the statistically significant between-
`group difference in body weight and BMI in favor of
`reboxetine, which was evident in the first week, strength-
`ened by the third week and which remained significant until
`the end of the trial. The LOCF analysis also yielded a
`
`Table 1 Demographics and
`baseline clinical characteristics
`of the study participants
`
`Variables
`
`Olanzapine/reboxetine
`(n=31)
`
`Olanzapine/placebo
`(n=28)
`
`Statistic
`
`p
`
`Age (years)
`Gender (male/female)
`Education (years)
`Duration of illness (years)
`No. of hospitalizations
`Weight (kg)
`BMI (kg/m2)
`Rating scales
`SAPS
`SANS
`CGI
`HAM D
`SAS
`BAS
`
`30.3 (8.5)
`23/8
`11.7 (1.8)
`4.0 (5.6)
`1.7 (1.3)
`67.1 (12.0)
`22.6 (3.21)
`
`6.4 (3.2)
`12.9 (3.6)
`4.2 (0.5)
`10.0 (3.5)
`11.3 (2.7)
`0.7 (1.0)
`
`29.5 (7.2)
`15/13
`11.6 (1.7)
`3.0 (4.0)
`1.3 (0.5)
`68.4 (13.2)
`23.3 (3.36)
`
`5.8 (2.4)
`12.9 (3.0)
`4.1 (0.6)
`(4.3)
`11.5 (2.6)
`0.6 (1.0)
`
`t(57)=0.40
`χ2=2.73
`t(57)=0.08
`t(57)=0.75
`t(57)=1.78
`t(57)= 0.38
`t(57)=0.82
`
`t(57)=0.82
`t(57)= 0.06
`t(57)=0.13
`t(57)=0.67
`t(57)= 0.31
`t(57)=0.55
`
`0.69
`0.10
`0.94
`0.46
`0.08
`0.71
`0.42
`
`0.42
`0.96
`0.90
`0.50
`0.76
`0.59
`
`BMI Body Mass Index; SAPS
`Scale for the Assessment of
`Positive Symptoms; SANS
`Scale for the Assessment of
`Negative Symptoms; CGI
`Clinical Global Impression for
`psychosis; HAM D Hamilton
`Rating Scale for Depression;
`SAS Simpson Angus Scale;
`BAS Barnes Akathisia Scale
`
`4
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`

`Psychopharmacology (2007) 192:441 448
`
`445
`
`significant between-group to difference in weight gain
`(olanzapine/reboxetine: 2.68±2.62 kg; olanzapine/placebo:
`4.14 ± 2.85 kg; Δweight = 1.46 ± 0.61,
`t = 2.05, df = 57,
`p=0.045) and BMI (olanzapine/reboxetine: 0.92±0.96 kg/
`m2; olanzapine/placebo: 1.45±1.04 kg/m2; ΔBMI=0.53±
`t=2.03, df=57, p=0.047). Complementary
`0.26 kg/m2,
`analysis in completers revealed a similar to intent-to-treat
`population trajectory and effect size of weight/BMI changes
`in the olanzapine/reboxetine (N=22) and olanzapine/place-
`bo (N=19) group (Δweight=1.78±0.80 kg; t=2.22, df=37,
`p = 0.032; ΔBMI = 0.65 ± 0.30 kg/m2;
`t = 2.17, df = 37,
`p=0.036).
`The two groups were unbalanced with respect to gender,
`with less women in the olanzapine/reboxetine group than in
`the olanzapine/placebo group (8 and 13, respectively).
`Using gender as a fixed factor in a two-way analysis of
`variance, there was no effect of gender (p=0.96) on the
`between-group difference in weight gain (Δweight: olan-
`zapine/reboxetine, men=3.38±2.12 kg, women=3.09±
`3.16 kg; olanzapine/placebo, men=4.81±2.68 kg, women=
`5.04±2.26 kg).
`The weight-attenuating effect of reboxetine is further
`supported by the fact that significantly less patients in the
`olanzapine/reboxetine group than in olanzapine/placebo
`group increased their initial weight by at least 7%, the
`cut-off for clinically significant weight gain (Kanders et al.
`1991; 6/31 [19.4%] and 13/28 [46.4%], respectively; χ2=
`4.94, df=1, p=0.026; odds ratio=3.61 [95%CI 1.13–
`11.52]). These patients did not differ significantly from
`their counterparts who gained weight in any of demograph-
`ic or clinical characteristics and baseline weight/BMI
`indices. Noteworthy, 7 (22.6%) of the 31 olanzapine/
`reboxetine-treated patients compared to only one patient
`(3.6%) in the olanzapine/placebo group revealed no weight
`change from baseline or even minor weight loss (χ2=4.54,
`df=1, p=0.033).
`No significant correlation between initial BMI and
`change in body weight at 6 weeks in either group (r=0.02,
`df = 29, p = 0.92 for
`the olanzapine/reboxetine group;
`r=0.01, df=26, p=0.97 for the olanzapine/placebo group)
`was found.
`Regarding reboxetine’s effect on appetite, there was a
`significantly lower increase in appetite in the olanzapine/
`reboxetine than in the olanzapine/placebo group (0.82±1.13
`and 1.50±0.88, respectively; t=−2.49; df=57, p=0.016).
`Specifically,
`less patients in the olanzapine/reboxetine
`group reported moderate to substantial increase in appetite
`at the end of the trial, as reflected by the scores “2” and “3”
`on the appetite scale (olanzapine/reboxetine=8/31 (25.8%);
`olanzapine/placebo = 15/28 (53.5%); χ2 = 4.77, df = 1,
`p=0.02; odds ratio=3.32 [95%CI 1.11–9.92]). Notably,
`there was a strong positive correlation between increase in
`appetite and weight gain in each group (olanzapine/
`
`aBetweengroupdifferencesinweight/BMI
`
`0.013
`0.023
`0.026
`0.017
`0.028
`0.044
`
`2.56
`2.33
`2.29
`2.46
`2.25
`2.06
`
`1.71(0.91)
`1.47(0.84)
`1.22(0.72)
`1.04(0.73)
`0.80(0.69)
`0.49(0.58)
`
`1.12(0.87)
`0.96(0.82)
`0.76(0.83)
`0.56(0.78)
`0.40(0.62)
`0.23(0.37)
`
`p
`
`(df=57)
`tStatisticsa
`
`(n=28)
`placebo
`Olanzapine/
`
`(n=31)
`reboxetine
`Olanzapine/
`
`25.05(3.53)
`24.80(3.45)
`24.56(3.42)
`24.38(3.39)
`24.13(3.43)
`23.82(3.45)
`23.34(3.36)
`
`(n=28)
`placebo
`Olanzapine/
`
`23.80(3.37)
`23.51(3.27)
`23.31(3.27)
`23.11(3.25)
`22.96(3.20)
`22.78(3.16)
`22.55(3.21)
`
`(n=31)
`reboxetine
`Olanzapine/
`
`0.013
`0.022
`0.024
`0.015
`0.030
`0.051
`
`2.55
`2.34
`2.31
`2.51
`2.23
`2.00
`
`4.91(2.45)
`4.21(2.33)
`3.53(2.04)
`3.01(2.03)
`2.26(1.92)
`1.36(1.58)
`
`3.31(2.73)
`2.81(2.26)
`2.22(2.29)
`1.64(2.15)
`1.19(1.77)
`0.68(1.01)
`
`73.28(13.00)
`72.58(13.04)
`71.90(13.19)
`71.40(13.12)
`70.63(13.09)
`69.73(13.05)
`68.36(13.18)
`
`70.44(12.25)
`69.95(11.80)
`69.35(11.94)
`68.77(11.96)
`68.33(11.88)
`67.81(11.90)
`67.13(11.97)
`
`p
`
`(df=57)
`tStatisticsa
`
`(n=28)
`placebo
`Olanzapine/
`
`(n=31)
`reboxetine
`Olanzapine/
`
`(n=28)
`placebo
`Olanzapine/
`
`(n=31)
`reboxetine
`Olanzapine/
`
`Week6
`Week5
`Week4
`Week3
`Week2
`Week1
`Baseline
`
`Week
`
`BodyMassIndex(BMI):differencefrombaseline
`
`Weight:differencefrombaseline
`
`Table2Weight/BMIvalues(mean±SD);changesfrombaselineinolanzapine/reboxetineandolanzapine/placebogroups
`
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`446
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`Psychopharmacology (2007) 192:441 448
`
`Table 3 Changes from baseline in psychometric rating scale scores (mean±SD) for olanzapine/reboxetine and olanzapine/placebo groups
`
`Rating scales
`
`Olanzapine/reboxetine (n=31)
`
`Olanzapine/placebo (n=28)
`
`Between group mean differences
`
`SAPS
`SANS
`CGI
`HAM D
`SAS
`BAS
`
`3.19 (3.74)
`4.52 (3.82)
`0.82 (0.90)
`4.65 (3.73)
`2.10 (2.49)
`0.68 (0.94)
`
`3.14 (3.88)
`4.04 (4.47)
`0.96 (0.84))
`1.5 (5.07)
`2.36 (2.45)
`0.50 (0.92)
`
`t Statistics
`
`t(57)= 0.05
`t(57)= 0.43
`t(57)=0.56
`t(57)= 2.69
`t(57)=0.40
`t(57)= 0.73
`
`p
`
`0.96
`0.67
`0.58
`0.01
`0.69
`0.47
`
`SAPS Scale for the Assessment of Positive Symptoms; SANS Scale for the Assessment of Negative Symptoms; CGI Clinical Global Impression
`for psychosis; HAM D Hamilton Rating Scale for depression; SAS Simpson Angus Scale; BAS Barnes Akathisia Scale
`
`reboxetine: r=0.77, df=29, p<0.01; olanzapine/placebo:
`r=0.71, df=26, p<0.01, respectively).
`Patients from both groups demonstrated a comparable
`reduction in scores of SAPS, SANS, and CGI rating scales,
`and no between-group differences in change from baseline
`scores were revealed (Table 3). In contrast, the improve-
`ment in the HAM-D scores was significantly greater in
`the olanzapine/reboxetine group than in the olanzapine/
`placebo group (Table 3). Noteworthy, no correlation
`between changes in HAM-D scores and body weight in
`the olanzapine/reboxetine-treated patients was revealed
`(r=0.14, p=0.46).
`The coadministration of olanzapine with reboxetine or
`placebo was safe and well
`tolerated. There was a
`significant reduction in scores in BAS and SAS rating
`scales in both groups without between-group difference
`(Table 3). Anticholinergic medication for EPS was required
`by two patients in the olanzapine/reboxetine group and
`three patients in the olanzapine/placebo group. Lorazepam
`(1–2 mg/day) or diazepam (5 mg/day) for insomnia was
`required by 12 patients from the olanzapine/reboxetine
`group and nine from the olanzapine/placebo group. No
`abnormal changes were found in routine laboratory tests.
`
`Discussion
`
`Weight gain associated with SGAs, primarily clozapine and
`olanzapine,
`is a frequent adverse effect and a major
`contributor to patient morbidity and noncompliance with
`medication. Effective and safe approaches to control SGA-
`induced weight gain remain major unmet needs in SGA
`treatment. The major finding of the present study is that the
`selective NRI reboxetine (4 mg/day) given for 6 weeks
`attenuates olanzapine-induced weight gain in first-episode
`schizophrenia patients. Reboxetine coadministration with
`olanzapine resulted in significantly less weight gain
`compared to olanzapine/placebo treatment as reflected in
`mean between-group difference of 1.6 kg by the end of the
`
`the olanzapine/placebo than
`trial. Twice as many of
`olanzapine/reboxetine-treated patients (46.4 vs 19.4%)
`increased weight by more than 7%, a cut-off for clinically
`significant weight gain. Importantly, reboxetine prevented
`weight increase or led to a minor weight loss in a clinically
`meaningful proportion (22.6%) of olanzapine/reboxetine-
`treated patients. Finally, we corroborated our preliminary
`findings indicating that reboxetine coadministration with
`olanzapine is safe and well-tolerated by schizophrenia
`patients and does not interfere with olanzapine’s effect on
`core schizophrenia symptoms. The beneficial effect of
`reboxetine on depressive symptoms revealed in our
`schizophrenia patients, as reflected by a significant reduc-
`tion in HAM-D scores, is also of clinical value.
`The short duration of the trial and a relatively high
`attrition rate are major limitations of the present study.
`Roughly 30% of the participants prematurely discontinued
`the trial. To substitute for missing data, we used two
`imputation strategies, regression model and LOCF, and in
`addition, we compared the results in the intention-to-treat
`population and the completers. Overall, regardless of the
`statistical strategy employed, the revealed between-group
`difference in weight gain was remarkably similar. This
`may be accounted for by the fact
`that
`reasons for
`discontinuation were unrelated to weight gain in this
`short-term study.
`It remains to be evaluated whether reboxetine maintains
`its weight-attenuating effect throughout a longer period of
`administration. If substantiated, rapid weight attenuation
`achieved by reboxetine may be of particular clinical utility,
`as olanzapine-induced weight gain seems to manifest
`during the initial period of treatment (Kinon et al. 2005).
`Whether weight gain induced by other SGAs would be
`attenuated by reboxetine and whether administration of a
`different NRI (e.g., atamoxetine) would also be associated
`with the weight-attenuating effect merit further investiga-
`tion. As female patients seem to be more vulnerable to
`antipsychotic-induced weight gain (Ascher-Svanum et al.
`reboxetine’s
`2005), explicit comparative evaluation of
`
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`
`in male and female
`
`attenuating effect on body weight
`schizophrenia patients is warranted.
`The magnitude of reboxetine’s weight-attenuating effect
`was less, although not statistically significant, than in our
`previous study (1.6 vs 3.0 kg). Visual analysis of the group
`behavior revealed a similar monotonic increase in mean
`weight difference in favor of reboxetine during both trials.
`In our previous study, unexpected mean weight decrease in
`the olanzapine/reboxetine group between weeks 4 and 5
`resulted in a larger magnitude of
`the between-group
`difference in weight gain by the end of
`the trial.
`Considering this fact and a threefold larger power of the
`present study, the effect size of 1.6 kg seems to approxi-
`mate the true weight-attenuating effect of reboxetine. Such
`magnitude of effect is apparently modest; however, even a
`modest weight attenuation may potentially be beneficial for
`olanzapine-treated patients. The impact of
`reboxetine
`coadministration on biochemical indices relevant to weight
`gain (e.g., lipid profile, insulin resistance, and leptin) is
`essential and is currently under investigation by our group.
`The mechanism of reboxetine’s weight-attenuating effect
`is unknown. Appetite increase was substantially less
`pronounced in the olanzapine/reboxetine than olanzapine/
`placebo group and was strongly correlated with the
`attenuation of weight gain. These findings support
`the
`assumption that one of the possible pathways by which
`olanzapine produces weight gain is by increased appetite
`(Gothelf et al. 2002; Kinon et al. 2005; Cope et al. 2005). It
`is conceivable that reboxetine like other norephinephrine
`enhancers (e.g., phentermine) acts as an appetite suppressant
`by facilitating NE neurotransmission by a selective blockade
`of the NE transporter. In addition, reboxetine may counteract
`olanzapine’s antagonistic effect at the alpha-1 and beta-3
`adrenoreceptors, which may disrupt peripheral and/or central
`energy homeostasis resulting in weight gain (Bymaster et al.
`1999). The evaluation of energy expenditure and energy
`intake during reboxetine treatment may clarify its effect on
`energy homeostasis. Pharmacogenetic aspects of NE neuro-
`transmission in weight regulation apparently play a role,
`based on the revealed contribution of beta 3 subunit gene
`(C825T) polymorphism and alpha 2a-adrenergic receptor
`1,291 C/G polymorphism to olanzapine-induced weight gain
`(Bishop et al. 2006; Park et al. 2006). Finally, the possibility
`of pharmacokinetic interactions between olanzapine and
`reboxetine should be considered. However, reboxetine
`appears to have low propensity for clinically meaningful
`pharmacokinetic interactions with atypical antipsychotics,
`particularly olanzapine (Spina et al. 2003).
`In conclusion, the results of the present study confirm
`that the addition of the selective NRI reboxetine is safe and
`well-tolerated and result in clinically meaningful attenua-
`tion of olanzapine-induced weight gain in schizophrenia
`patients. As weight management programs including
`
`physical exercises and diet counseling proved effective in
`olanzapine-treated patients (Kwon et al. 2006),
`their
`combination with pharmacological approaches such as
`add-on reboxetine merit further evaluation.
`
`Acknowledgments The study was supported in part by grant no.
`03T 294 from the Stanley Medical Research Institute. The authors
`thank Rena Kurs for assistance in preparation of the manuscript.
`
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