Article
`
`Attenuation of Olanzapine-Induced Weight Gain
`With Reboxetine in Patients With Schizophrenia:
`A Double-Blind, Placebo-Controlled Study
`
`Michael Poyurovsky, M.D.
`
`Ilanit Isaacs, M.D.
`
`Camil Fuchs, Ph.D.
`
`Michael Schneidman, M.D.
`
`Sarit Faragian, M.A.
`
`Ronit Weizman, M.D.
`
`Abraham Weizman, M.D.
`
`Objective: Since increased norepineph-
`rine availability may account for the
`weight-reducing effect of appetite sup-
`pressants, the authors hypothesized that
`the addition of the selective norepineph-
`rine reuptake inhibitor reboxetine may
`prevent or attenuate olanzapine-induced
`weight gain.
`
`Method: Twenty-six patients hospitalized
`for first-episode DSM-IV schizophrenic dis-
`order participated in the study. In addition
`to 6 weeks of treatment with olanzapine,
`10 mg/day, patients were randomly allo-
`cated in a double-blind design to receive
`either reboxetine, 4 mg/day, (N=13) or pla-
`cebo (N=13).
`
`Results: Ten patients in each group com-
`pleted the 6-week trial. Patients given
`olanzapine and reboxetine demonstrated
`a significantly lower increase in body
`weight (mean=2.5 kg, SD=2.7) than those
`
`given olanzapine and placebo (mean=5.5
`kg, SD=3.1). Significantly fewer patients in
`the olanzapine/reboxetine group (N=2 of
`10) than in the olanzapine/placebo group
`(N=7 of 10) gained at least 7% of their ini-
`tial weight, the cutoff for clinically signifi-
`cant weight gain. The addition of reboxe-
`tine to olanzapine treatment was safe and
`well tolerated by the patients. A between-
`group difference in the reduction of Ham-
`ilton depression scale scores was seen that
`favored the olanzapine/reboxetine group
`(mean difference=–3.1, SD=1.25).
`
`Conclusions: The selective norepineph-
`rine reuptake inhibitor reboxetine may re-
`duce olanzapine-induced weight gain in
`schizophrenia patients, and activation of
`the adrenergic system may attenuate
`weight gain induced by atypical antipsy-
`chotic agents.
`
`(Am J Psychiatry 2003; 160:297–302)
`
`Neuroleptic-induced weight gain has been suggested
`
`to contribute to patient noncompliance with treatment
`and may adversely affect clinical outcome (1). Obesity and
`being overweight are associated with reduced quality of
`life, greater morbidity (cardiovascular disease, diabetes
`mellitus, osteoarthritis, and some types of cancer), and
`mortality (2).
`Olanzapine, along with clozapine, has the greatest pro-
`pensity of all available atypical antipsychotics to induce
`weight gain (3, 4). It seems that most weight gain occurs
`early in treatment, and young patients previously unex-
`posed to antipsychotic medication appear to be particu-
`larly vulnerable to olanzapine-induced weight gain (5, 6).
`The pathophysiological mechanisms underlying weight
`gain associated with atypical antipsychotic treatment have
`not been clarified. The adrenergic system may be relevant
`to iatrogenic weight gain. An increase in adrenergic tone
`(either through norepinephrine reuptake inhibition or
`stimulation of beta-3 or alpha-1 adrenergic receptors) has
`been associated with reduction of food intake, increase in
`energy expenditure, and weight loss (7). The norepineph-
`rine reuptake inhibitors phentermine and sibutramine,
`which inhibit both norepinephrine and serotonin (5-HT)
`reuptake, are potent appetite suppressants (8). In contrast,
`
`atypical antipsychotics, primarily clozapine and olanza-
`pine, exert an adrenergic antagonistic effect that may con-
`tribute—alone or together with their antagonistic effect at
`the 5-HT2C and the histaminergic H1 receptors—to their
`high propensity to cause weight gain (4, 9).
`Reboxetine is a selective norepinephrine reuptake inhib-
`itor, and its addition to conventional antipsychotics has
`been found to be safe and well tolerated in patients with
`schizophrenia (10). We hypothesized that stimulation of
`adrenergic activity by the selective norepinephrine re-
`uptake inhibitor reboxetine may diminish olanzapine-in-
`duced weight gain. In the present double-blind, placebo-
`controlled study, we sought to determine whether the ad-
`dition of reboxetine would prevent or attenuate olanza-
`pine-induced weight gain in patients with schizophrenia.
`
`Method
`
`Subjects and Study Design
`
`Patients hospitalized at Tirat Carmel Mental Health Center (Is-
`rael) for DSM-IV schizophrenic disorder were enrolled in the
`study. Best-estimate diagnoses were based on information ob-
`tained from the Structured Clinical Interview for DSM-IV Axis I
`Disorders, Patient Edition (11). Other inclusion criteria for the
`study were <4 weeks of antipsychotic drug exposure in the pre-
`
`Am J Psychiatry 160:2, February 2003
`
`http://ajp.psychiatryonline.org
`
`297
`
`1
`
`Exhibit 2096
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`ATTENUATION OF WEIGHT GAIN
`
`TABLE 1. Characteristics of 20 Schizophrenia Patients Randomly Assigned to Receive Either Reboxetine or Placebo for At-
`tenuation of Weight Gain Induced by Olanzapine Treatmenta
`Agent Added to Olanzapine Treatment
`Reboxetine (N=10)
`Placebo (N=10)
`Mean
`SD
`Mean
`SD
`34.6
`13.0
`26.5
`6.7
`6.4
`2.6
`5.5
`2.1
`1.5
`0.4
`1.4
`0.3
`65.75
`15.99
`59.75
`10.51
`22.76
`3.62
`20.30
`3.19
`
`p
`0.10
`0.40
`0.48
`0.35
`0.13
`
`0.23
`0.73
`0.71
`0.07
`
`Variable
`Age (years)
`Duration of illness (years)
`Number of hospitalizations
`Weight (kg)
`Body mass index (kg/m2)
`Rating scale scores
`–1.26
`11.8
`31.7
`17.8
`23.2
`Scale for the Assessment of Positive Symptoms
`–0.35
`9.9
`45.3
`16.5
`43.2
`Scale for the Assessment of Negative Symptoms
`0.37
`0.5
`4.6
`0.7
`4.7
`Clinical Global Impression (for psychosis)
`1.98
`2.3
`11.7
`2.5
`13.8
`Hamilton Depression Rating Scale
`a Olanzapine and reboxetine doses were fixed at 10 mg/day and 4 mg/day, respectively, for the entire 6 weeks of the trial.
`
`Analysis
`t (df=18)
`1.75
`0.86
`0.73
`0.95
`1.61
`
`ceding 6 months, no previous olanzapine treatment, and a rec-
`ommendation for olanzapine treatment by the treating physician
`during the current hospitalization. A double-blind, placebo-con-
`trolled, randomized design was used in the present study. The
`participants were allocated according to entries of a table of ran-
`dom numbers to receive a fixed dose of olanzapine (10 mg at 8:00
`p.m.) with either reboxetine (4 mg/day [2 mg b.i.d.], N=13) or pla-
`cebo (N=13) for 6 weeks.
`Forty patients were screened for eligibility in the study. Four-
`teen patients were excluded for not meeting inclusion criteria (N=
`3), refusal to participate (N=4), uncooperativeness (N=2), aggres-
`sive or suicidal behavior (N=2), diabetes mellitus (which can af-
`fect body weight, N=1), and obesity (body mass index ≥30 kg/m2,
`N=2). Twenty-six patients (17 men, nine women) were included in
`the study. The olanzapine/reboxetine group consisted of 13 pa-
`tients (nine men and four women; mean age=31.5 years [SD=12.9,
`range=19–46]; mean duration of illness=3.1 years [SD=3.0, range=
`0.5–10]; mean number of hospitalizations=1.2 [SD=0.3]). The
`olanzapine/placebo group also consisted of 13 patients (eight
`men and five women; mean age=30.0 years [SD=10.2, range=19–
`49]; mean duration of illness=2.8 years [SD=3.0, range=0.5–10.0];
`mean number of hospitalizations=1.1 [SD=0.2]). Before the be-
`ginning of the study, three patients in each group were drug naive,
`and seven patients in each group had received haloperidol (5–20
`mg/day). Two patients in the olanzapine/reboxetine group had
`received perphenazine (8–24 mg/day), and one patient in the
`olanzapine/reboxetine group and three patients in the olanza-
`pine/placebo group had received risperidone (3–5 mg/day).
`None of the study participants received medications other than
`psychotropic agents. No abnormal findings were seen following a
`routine physical examination or in results of laboratory tests
`(which included an electrocardiograph and drug screening when
`appropriate).
`The study was approved by the Tirat Carmel Hospital Review
`Board. Written informed consent was obtained from all partici-
`pants after they received a full explanation of the nature of the
`study.
`Administration of an anticholinergic agent (trihexyphenidyl,
`5–10 mg/day) for extrapyramidal side effects and administration
`of a benzodiazepine (lorazepam, 1–3 mg/day) for insomnia or ag-
`itation were allowed on an as-needed basis, but no other antipsy-
`chotics, antidepressants, anxiolytics, or mood stabilizers were
`permitted. The doses of all medications remained unchanged
`during the entire study period. Meals were served three times a
`day, and patients were not placed on a special diet or physical ex-
`ercise program for weight reduction.
`
`Assessments
`
`Body weight and body mass index were measured before
`breakfast at baseline and weekly afterwards. All weight measure-
`ments were performed by a research nurse who was blind to the
`patients’ treatment assignment. Clinical assessment instruments
`included the Scale for the Assessment of Positive Symptoms
`(SAPS) (12), Scale for the Assessment of Negative Symptoms
`(SANS) (13), Clinical Global Impression (CGI) scale for psychosis
`(14), and the 17-item Hamilton Rating Scale for Depression (15).
`Extrapyramidal side effects were assessed by using the Barnes
`Akathisia Scale (16) and Simpson-Angus Rating Scale (17). Emer-
`gent nonextrapyramidal drug-induced side effects were moni-
`tored through spontaneous reporting by the patients. Clinical rat-
`ings were completed at baseline and at week 6 by the same
`trained psychiatrist (I.I.), who was blind to the patients’ treatment
`assignments.
`
`Statistical Analysis
`
`Chi-square, two-tailed Student’s t test, and Pearson’s correla-
`tion analyses were used as appropriate. Six of the 26 study pa-
`tients (three in each group) withdrew during the first week (before
`the second assessment) because of agitation that could have been
`related to the switch from typical antipsychotics to olanzapine.
`Since all dropouts were assessed only at baseline and no observa-
`tion could be carried forward as a last observation, no intent-to-
`treat analysis was performed. Final statistical analysis included
`only those patients who completed the study (10 patients in each
`group).
`Although weight and body mass index were measured weekly,
`we did not apply repeated-measures analysis, since the prelimi-
`nary evaluation showed that for the mean values of both weight
`and body mass index, the trends over time were far from linear. In
`particular, there were no differences in the mean values of body
`weight and body mass index between weeks 2 and 3 or between
`weeks 4 and 5. Therefore, the mean changes in body weight and
`body mass index during the trial period (difference between
`baseline and each time point) were analyzed for each group.
`Analysis of the difference from baseline is equivalent to analysis
`of covariance with the coefficient for the covariate set at the value
`of one. Our preliminary analysis showed that for both weight and
`body mass index, those coefficients did not differ significantly
`from the value of 1 (mean=0.99 [SD=0.5] and 0.89 [SD=0.6], re-
`spectively). We also assessed the between-group difference in
`mean change from baseline for scores on the SAPS, SANS, CGI,
`and Hamilton depression scale. All results are expressed as mean
`and standard deviation. All p values are two-tailed at the signifi-
`cance level of 0.05.
`
`298
`
`http://ajp.psychiatryonline.org
`
`Am J Psychiatry 160:2, February 2003
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`

`

`TABLE 2. Change in Weight and Body Mass Index Over 6 Weeks for 20 Schizophrenia Patients Randomly Assigned to Re-
`ceive Either Reboxetine or Placebo for Attenuation of Weight Gain Induced by Olanzapine Treatmenta
`Absolute
`Change From Baseline
`Reboxetine (N=10)
`Placebo (N=10)
`Reboxetine (N=10)
`Placebo (N=10)
`Mean
`SD
`Mean
`SD
`Mean
`SD
`Mean
`SD
`
`Analysisb
`t (df=18)
`
`p
`
`POYUROVSKY, ISAACS, FUCHS, ET AL.
`
`Measure and Week
`Weight (kg)
`Baseline
`Week 1
`Week 2
`Week 3
`Week 4
`Week 5
`Week 6
`Body mass index (kg/m2)
`3.19
`20.30
`3.62
`22.76
`Baseline
`0.68
`0.39
`0.61
`0.21
`3.02
`20.69
`3.47
`22.96
`Week 1
`0.77
`0.80
`0.70
`0.55
`3.06
`21.10
`3.25
`23.30
`Week 2
`0.79
`0.86
`0.64
`0.57
`2.80
`21.16
`3.34
`23.33
`Week 3
`0.93
`1.45
`0.71
`0.75
`2.97
`21.75
`3.37
`23.51
`Week 4
`1.06
`1.62
`0.69
`0.66
`2.80
`21.91
`0.36
`23.42
`Week 5
`0.99
`1.84
`0.88
`0.86
`2.99
`22.14
`3.35
`23.61
`Week 6
`a Olanzapine and reboxetine doses were fixed at 10 mg/day and 4 mg/day, respectively, for the entire 6 weeks of the trial.
`b For the between-group differences in change from baseline.
`
`65.75
`66.25
`67.15
`67.30
`67.80
`67.60
`68.20
`
`15.99
`16.31
`15.74
`16.33
`16.34
`16.74
`17.11
`
`59.75
`61.05
`62.30
`62.35
`64.15
`64.65
`65.20
`
`10.51
`11.10
`11.61
`10.39
`11.25
`11.14
`10.88
`
`0.50
`1.40
`1.55
`2.05
`1.85
`2.45
`
`1.67
`1.91
`1.79
`2.01
`2.06
`2.72
`
`1.30
`2.55
`2.60
`4.40
`4.90
`5.45
`
`2.15
`2.54
`2.39
`3.12
`3.41
`3.09
`
`–0.93
`–1.14
`–1.11
`–2.01
`–2.42
`–2.31
`
`–0.64
`–0.78
`–0.90
`–1.90
`–2.39
`–2.34
`
`0.36
`0.27
`0.28
`0.06
`0.03
`0.03
`
`0.53
`0.45
`0.38
`0.07
`0.03
`0.03
`
`Results
`
`Twenty patients (10 in each group) completed the 6-
`week protocol. There were no differences in demographic
`or clinical characteristics or weight/body mass index val-
`ues between the patients who dropped out of the study
`and those who did not. Each group consisted of six men
`and four women, and completers from the olanzapine/re-
`boxetine group did not differ significantly from their olan-
`zapine/placebo counterparts in clinical characteristics,
`baseline weight/body mass index values, and psychomet-
`ric rating scale scores (Table 1).
`Body weight/body mass index changes from baseline in
`both groups are presented in Table 2. Patients in both
`groups gained weight during the 6-week trial. However, at
`the end of the study, completers in the olanzapine/rebox-
`etine group gained significantly less weight (mean=2.5 kg,
`SD=2.7, range=–0.5 to 7.5) than their counterparts in the
`olanzapine/placebo group (mean=5.5 kg, SD=3.1, range=
`0.5–11) (t=2.31, df=18, p<0.04), a mean between-group dif-
`ference in weight gain of 3.0 kg (SD=1.3). Treatment-in-
`duced change in body mass index was significantly less in
`the olanzapine/reboxetine group (mean=0.86 kg/m2, SD=
`0.88) than in the olanzapine/placebo group (mean=1.84
`kg/m2, SD=0.99) (t=–2.34, df=18, p<0.04), a mean be-
`tween-group difference of 0.98 kg/m2 (SD=0.42). It is note-
`worthy that the between-group difference in changes
`from baseline already emerged by the fourth week of the
`trial for both weight (mean difference=–2.35 kg, SD=1.17)
`and body mass index (mean difference=–0.7 kg/m2, SD=
`0.37); these differences reached the level of statistical sig-
`nificance by the fifth week (Table 2). Two of the 10 olanza-
`pine/reboxetine-treated patients demonstrated weight
`loss, and one had no weight change, whereas all of the pa-
`tients in the olanzapine/placebo group gained weight to
`some degree. Fewer patients in the olanzapine/reboxetine
`
`group (N=2 of 10) than in the olanzapine/placebo group
`(N=7 of 10) increased their initial weight by at least 7%, the
`cutoff for clinically significant weight gain (18), which was
`a significant difference (χ2=5.05, df=1, p<0.03). There was
`no significant correlation between initial body mass index
`and change in body weight at 6 weeks in either the olanza-
`pine/reboxetine group (r=0.34, df=8, p=0.34) or the olan-
`zapine/placebo group (r=0.02, df=8, p=0.96).
`Patients from both groups demonstrated a significant
`reduction from baseline in scores of all psychometric rat-
`ing scales (Table 3). At the end of the 6-week trial, no be-
`tween-group differences in change from baseline scores
`were revealed for the SAPS (mean difference=1.50, SD=
`6.95), SANS (mean difference=–2.20, SD=5.92), or CGI
`(mean difference=0.0, SD=0.43). The improvement in
`Hamilton depression scale scores was significantly greater
`in the olanzapine/reboxetine group than in the olanza-
`pine/placebo group (mean difference=–3.10, SD=1.25).
`The coadministration of olanzapine with reboxetine or
`placebo was well tolerated. Three patients in the olanza-
`pine/reboxetine group and four in the olanzapine/pla-
`cebo group had daytime somnolence. No treatment-in-
`duced motor hyperactivity was observed in either group
`during the study period. Mild akathisia (Barnes Akathisia
`Scale score of 2) was noted at baseline in five patients in
`the olanzapine/reboxetine group and three patients in the
`olanzapine/placebo group but disappeared in all cases by
`the end of the study. Parkinsonian symptoms (as mea-
`sured by the Simpson-Angus Rating Scale) decreased in
`both groups; the between-group difference (mean=1.9,
`SD=2.03) was not significant (t=1.24, df=18, p=0.23). Anti-
`cholinergic medication for extrapyramidal side effects was
`not required by any of the study participants. Lorazepam
`(1–2 mg/day) for insomnia was required by 11 patients (six
`from the olanzapine/reboxetine group, five from the olan-
`zapine/placebo group). No gastrointestinal side effects
`
`Am J Psychiatry 160:2, February 2003
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`http://ajp.psychiatryonline.org
`
`299
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`3
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`

`

`ATTENUATION OF WEIGHT GAIN
`
`TABLE 3. Change in Psychometric Rating Scale Scores for 20 Schizophrenia Patients Randomly Assigned to Receive Either
`Reboxetine or Placebo for Attenuation of Weight Gain Induced by Olanzapine Treatmenta
`Agent Added to Olanzapine Treatment
`Reboxetine (N=10)
`Placebo (N=10)
`Baseline Score
`Endpoint Score
`Baseline Score
`Endpoint Score
`Mean
`SD
`Mean
`SD
`Mean
`SD
`Mean
`SD
`Rating Scale
`23.2
`17.8
`4.8
`3.9
`31.7
`11.8
`11.8
`12.2
`Scale for the Assessment of Positive Symptoms
`43.2
`16.5
`18.9
`13.4
`45.3
`9.9
`23.2
`18.8
`Scale for the Assessment of Negative Symptoms
`4.7
`0.7
`3.1
`1.3
`4.6
`0.5
`3.0
`1.1
`Clinical Global Impression (for psychosis)
`13.8
`2.5
`3.6
`1.8
`11.7
`2.3
`4.6
`3.5
`Hamilton Depression Rating Scale
`a Olanzapine and reboxetine doses were fixed at 10 mg/day and 4 mg/day, respectively, for the entire 6 weeks of the trial.
`b For the between-group differences in change from baseline.
`c Nonsignificant after Bonferroni post hoc test.
`
`Analysisb
`t (df=18)
`0.22
`–0.37
`0.00
`–2.48
`
`p
`0.83
`0.72
`1.00
`0.03c
`
`(e.g., nausea, vomiting, anorexia) were reported by the pa-
`tients. No abnormal changes were noted in the results of
`routine laboratory tests.
`
`Discussion
`
`The present study confirms that olanzapine treatment is
`associated with substantial weight gain in schizophrenia
`patients. Moreover, our results are consistent with an ear-
`lier report that indicates that olanzapine-associated
`weight gain frequently occurs during the initial stage of
`treatment (19).
`The major finding of the present study is that the selec-
`tive norepinephrine reuptake inhibitor reboxetine (4 mg/
`day) administered for 6 weeks attenuates olanzapine-in-
`duced weight gain in schizophrenia patients. Indeed, pa-
`tients given olanzapine and reboxetine gained a mean of
`2.5 kg (SD=2.7), whereas patients given olanzapine and
`placebo gained a mean of 5.5 kg (SD=3.1). It is of note that
`similar increases in body weight were observed in olanza-
`pine/placebo-treated schizophrenia patients in our previ-
`ous study of fluoxetine addition to olanzapine for attenua-
`tion/prevention of weight gain (20). Finally, significantly
`fewer patients in the olanzapine/reboxetine group (N=2 of
`10 [20%]) than in the olanzapine/placebo group (N=7 of 10
`[70%]) increased their baseline weight by more than 7%, a
`cutoff for clinically significant weight gain.
`The limitations of the present study are the small study
`group size, short duration of trial, and fixed doses of both
`olanzapine (10 mg/day) and reboxetine (4 mg/day). In ad-
`dition, further studies should apply a pairwise matching
`for weight/body mass index to avoid between-group dif-
`ferences at baseline. In the present study, despite random-
`ization, the olanzapine/reboxetine group had higher
`baseline weight/body mass index mean values than the
`olanzapine/placebo group. The differences, however,
`were not statistically significant. It is of note that these dif-
`ferences were mainly due to an outlier observation from
`the olanzapine/reboxetine group in which a subject with
`the highest weight/body mass index baseline values (92.5
`kg and 25.09 kg/m2, respectively) still exhibited the great-
`est weight gain in this group at the end of the trial (change
`in weight=7.5 kg; change in body mass index=2.04 kg/m2).
`
`This observation and the lack of correlation between ini-
`tial body mass index and change in body weight at the end
`of 6 weeks in both groups indicate that it is unlikely that
`the lower initial weight in the olanzapine/placebo group
`accounted for the greater weight increase. However, Kinon
`et al. (5) demonstrated in a retrospective analysis of pa-
`tients treated with olanzapine for at least 39 weeks that
`higher baseline body mass index was predictive of a lower
`long-term weight gain. It remains to be studied whether a
`longer duration of trial will be associated with a further
`weight-attenuating effect of reboxetine.
`Reboxetine’s potential to attenuate olanzapine-induced
`weight gain may be explained by enhancement of norepi-
`nephrine neurotransmission through a selective blockade
`of the norepinephrine transporter. This notion is sup-
`ported by evidence that both phentermine and sibutra-
`mine, two FDA-approved appetite suppressants, possess a
`potent inhibitory effect at the presynaptic norepinephrine
`transporter (8). Unfortunately, these agents have not been
`examined in studies of neuroleptic-induced weight gain.
`Sibutramine, however, suppresses appetite and reduces
`weight by combined norepinephrine and 5-HT reuptake
`inhibition, leading to elevation of the availability of both
`monoamines in the hypothalamus (21). It is of note that
`low potential to cause weight gain and even weight reduc-
`tion have been reported in patients treated with the atypi-
`cal antipsychotic ziprasidone, an agent with a unique po-
`tent antagonistic effect at both the norepinephrine and 5-
`HT transporters, in contrast to olanzapine and other atyp-
`ical antipsychotics (22). The relevance of the 5-HT trans-
`porter inhibition to attenuation of olanzapine-induced
`weight gain remains unclear, since in our previous study
`addition of the selective serotonin transporter inhibitor
`fluoxetine (20 mg/day for 8 weeks) was found ineffective
`in diminishing olanzapine-induced weight gain in a
`younger population of first-episode schizophrenia pa-
`tients with a shorter duration of illness (20). Thus, it is pos-
`sible that stimulation of the norepinephrine rather than
`the 5-HT system may contribute to the attenuation of
`olanzapine-induced weight gain. Particularly, reboxetine
`may counteract olanzapine’s antagonistic effect at the al-
`pha-1 and beta-3 adrenoreceptors (9), which may disrupt
`peripheral or central energy homeostasis, resulting in
`
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`

`weight gain. It is of note that sedentary lifestyle has been
`associated with weight gain (4, 23). It seems unlikely that
`reboxetine’s effect on patients’ activity in the ward ac-
`counted for the observed diminished olanzapine-in-
`duced weight gain, since no between-group differences
`were revealed in either treatment-induced somnolence/
`sedation or hyperactivity. In addition, since in the present
`study we did not assess caloric intake (caloric counts,
`meal refusal, etc.), future studies should monitor the bal-
`ance between caloric intake and caloric expenditure in an
`attempt to clarify the mechanism underlying reboxetine’s
`attenuating effect on olanzapine-induced weight gain. Fi-
`nally, it seems unlikely that the significantly lower weight
`gain in the olanzapine/reboxetine group versus the olan-
`zapine/placebo group was related to pharmacokinetic in-
`teractions between the two agents. Both agents exhibit
`only modest effects on hepatic cytochrome enzymes (24,
`25), and, to the best of our knowledge, there are no pub-
`lished data on clinically relevant olanzapine-reboxetine
`interactions.
`On the clinical level, reboxetine addition was safe and
`well tolerated and did not interfere with the antipsychotic
`effect of olanzapine. In contrast, caution is advised when
`currently available appetite suppressants are adminis-
`tered concurrently with neuroleptic agents (26). An addi-
`tional clinically relevant advantage of reboxetine over es-
`tablished appetite suppressants such as phentermine and
`sibutramine is its antidepressive effect, as revealed by the
`reduction in the Hamilton depression scale scores in our
`olanzapine/reboxetine-treated schizophrenia patients
`when compared with their olanzapine/placebo-treated
`counterparts. It is of note, however, that the olanzapine/
`reboxetine superiority did not remain significant follow-
`ing correction for multiple comparisons (Table 3).
`In conclusion, the results of the present study indicate
`that the addition of the selective norepinephrine reuptake
`inhibitor reboxetine may attenuate olanzapine-induced
`weight gain in schizophrenia patients. Reboxetine coad-
`ministration was safe and well tolerated and associated
`with a modest beneficial effect on depressive symptoms in
`this patient population. To the best of our knowledge, this
`is the first study to demonstrate meaningful weight gain
`attenuation with reboxetine in olanzapine-treated pa-
`tients. Determination of the optimal dose and time course
`of reboxetine efficacy in prevention/attenuation of neuro-
`leptic-induced weight gain warrants further large-scale
`controlled studies in first- and recurrent-episode schizo-
`phrenia patients. Since olanzapine doses greater than the
`10 mg/day administered in the present study are common
`in clinical practice, evaluation of reboxetine’s impact on
`weight in a broader range of clinically relevant olanzapine
`doses merits further investigation. A comprehensive bio-
`chemical workup (e.g., cholesterol, lipid profile, insulin re-
`sistance, glucose level) is also needed to clarify whether
`the diminution of weight gain achieved by reboxetine ad-
`
`POYUROVSKY, ISAACS, FUCHS, ET AL.
`
`dition to olanzapine is accompanied by improvement in
`patients’ “metabolic fitness” (8).
`
`Received March 30, 2002; revision received Aug. 27, 2002; ac-
`cepted Aug. 29, 2002. From the Research Unit, Tirat Carmel Mental
`Health Center. Address reprint requests to Dr. Poyurovsky, Research
`Unit, Tirat Carmel Mental Health Center, 9 Eshkol St., Tirat Carmel
`30200, Israel; tyrmichael@matat.health.gov.il (e-mail).
`The authors thank Agis Industries Ltd. (Israel) for providing reboxe-
`tine (Edronax) tablets and Ms. Rena Kurs of Sha’ar Menashe Mental
`Health Center for editorial assistance.
`
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