Department of Psychiatry,University of Toronto Faculty of Medicine, Toronto, Ontario, Canada
Department of Psychiatry,University of North Carolina School of Medicine, Chapel Hill, North Carolina
Department of Psychiatry, Dartmouth Medical School, Hanover, New Hampshire
Department of Psychiatry,University of North Carolina School of Medicine, Chapel Hill, North Carolina
Lilly Research Laboratories, Indianapolis, Indiana
Department of Psychiatry, Duke University School of Medicine, Durham, North Carolina
Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA
Clinical Neuroscience Research Centre, Kent, UK
Department of Psychiatry, University of Utrecht Medical School,Utrecht,The Netherlands
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Lilly Research Laboratories, Indianapolis, Indiana
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York,USA
on behalf of the HGDH Study Group
Correspondence: Dr Robert B. Zipursky, Schizophrenia Programme,Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8. Tel: +1 416 979 6913; fax: +1 416 979 4676; e-mail: robert_zipursky{at}camh.net
Declaration of interest This work was financially supported by Lilly Research Laboratories. M.F.T. and G.D.T. are employees of Lilly Research Laboratories.
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ABSTRACT |
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Aims To evaluate the extent, time course and predictors of weight gain and its effect on study retention among people with first-episode psychosis treated with olanzapine or haloperidol.
Method Survival analysis assessed time to potentially clinically
significant weight gain (7%) and the effect of weight gain on study
retention. Weight gain during the 2-year study was summarised using
last-observation-carried-forward (LOCF), observed cases and study completion
approaches.
Results After 2 years of treatment, LOCF mean weight gain was 10.2 kg (s.d.=10.1) for olanzapine (n=131) and 4.0 kg (s.d.=7.3) for haloperidol (n=132); observed cases mean weight gain was 15.4 kg (s.d.=10.0) for olanzapine and 7.5 kg (s.d.=9.2) for haloperidol. Change in body massindex was significantly predicted only by treatment group (P < 0.0001).
Conclusions Olanzapine was associated with significantly greater weight gain than haloperidol, with both leading to greater weight gain than previously described.
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INTRODUCTION |
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METHOD |
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Participants
Study participants met DSMIV criteria for schizophrenia,
schizophreniform disorder or schizoaffective disorder
(American Psychiatric Association,
1994) and were between 16 and 40 years of age. All had experienced
psychotic symptoms for at least 1 month but no more than 60 months, met
predefined criteria for being at least moderately ill, and were determined to
be in clinical need of an antipsychotic medication. All participants or their
authorised legal representative provided written informed consent for this
study after the procedures had been fully explained. The appropriate
institutional review boards approved the study.
Individuals were excluded from participating if they met any of the study exclusion criteria (Lieberman et al, 2003). They were excluded if they had received prior antipsychotic treatment for more than 16 cumulative weeks, had ever received clozapine, or were currently in need of treatment with anticonvulsants, antidepressants, benzodiazepines (except for treatment of agitation and extrapyramidal symptoms), or other psychotropic medications.
Study design and procedures
Participants were randomly assigned to olanzapine or haloperidol under
double-blind conditions. In the first 6 weeks of the study, doses could be
titrated in the range of 510 mg/day (olanzapine) and 26 mg/day
(haloperidol); for the second 6 weeks of the study, doses could be further
adjusted in the range of 520 mg/day (olanzapine) and 220 mg/day
(haloperidol). Antidepressants and mood stabilisers could not be used during
the first 12 weeks of the study. Following the 12-week acute treatment period,
fluoxetine 1060 mg/day could be prescribed for individuals meeting
DSMIV criteria for major depressive disorder. Lithium carbonate or
valproate could be added if they failed to respond to fluoxetine or if they
developed mania or a mixed affective state.
Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1992) as the primary efficacy variable. The PANSS was administered at study entry, on the day of randomisation, weekly for the first 6 weeks, every 2 weeks for the next 6 weeks and then monthly for the remainder of the study. Body weight was measured at each of these visits. Non-fasting serum glucose and cholesterol levels were measured on the day of study entry, on the day of randomisation, at 12 weeks, 6 months, 12 months, 18 months and 24 months.
Statistical analyses
We identified the primary outcome to test treatment group differences as
the event of clinically significant weight gain, defined as
7% increase in weight (kg) from baseline; this definition is consistent
with the US Food and Drug Administration guidelines
(Sachs & Guille, 1999).
The primary analysis was able to use the intent-to-treat population of all
randomised participants and compared the KaplanMeier survival curves of
the two treatments using the log-rank test. A Cox regression elaborated the
findings by modelling the treatment effects jointly with other potentially
important covariates selected from baseline body mass index (BMI), age,
gender, ethnicity, smoking status, premorbid functioning, diagnosis, age at
onset, duration of untreated illness and history of previous antipsychotic
treatment (backward model selection, P<0.05 to stay).
The descriptive statistics for amount of weight gained were plotted using
data for LOCF, observed cases and completers to examine the effect of early
withdrawal on weight gain estimates. A more sophisticated approach was taken
to model growth curves of BMI change in the first 12 weeks using a random
coefficient mixed model, and to identify significant clinical predictors (as
described above) for the course of BMI change. The correlation of weight gain
and clinical outcome (as assessed by PANSS total score) was calculated at each
time point and summarised using mixed models with repeated measures. A
hierarchy of Cox regression models was carried out to assess the difference in
study retention between the two treatment groups, as well as the contribution
of symptom improvement and weight gain to withdrawal from the study. Only the
primary analysis on treatment effect was tested at a two-sided level
of 0.05. The supplemental exploratory analysis was undertaken to expand our
understanding of clinical aspects of weight gain, and no adjustment for
multiple comparisons was considered necessary. The statistical analysis was
performed using SAS version 8.01 for Windows (SAS Institute, Cary, North
Carolina, USA).
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RESULTS |
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Time to clinically significant weight gain
Among olanzapine-treated participants, 95 met the clinically significant
weight gain criterion by the end of the 2-year study; one individual remaining
on treatment and 35 who had discontinued treatment did not meet this
criterion. Among haloperidol-treated participants, the numbers were 51, 3 and
78, respectively. Figure 2
shows the percentage of participants who were expected to have clinically
significant weight gain at each time point, adjusting for withdrawal rates as
calculated by KaplanMeier estimates. Olanzapine-treated participants
met the clinically significant weight gain criterion at a significantly faster
rate than haloperidol-treated individuals (2(1)=67.9,
P<0.0001; log-rank test). The median treatment time before meeting
the clinically significant weight gain criterion was 5 weeks for the
olanzapine-treated group (95% CI 46) and 28 weeks (95% CI 1640)
for the haloperidol-treated group. Results from the Cox regression model
confirmed the treatment-group differences in the likelihood of developing
clinically significant weight gain. The hazard was more than five times
greater for olanzapine-treated participants than for those treated with
haloperidol (hazard ratio=5.19,
2(1)=66.3,
P<0.0001). Participants with higher baseline weight took longer to
gain 57% of their baseline body weight, representing a 12% reduction in hazard
(
2(1)=20.9, P<0.0001). In addition, Black
participants and those from minority ethnic groups demonstrated a
significantly faster rate of clinically significant weight gain (hazard ratio
1.58,
2 = (1)=6.28, P=0.01). The effects of baseline
weight and ethnicity on the likelihood of developing clinically significant
weight gain were not related to treatment group, as indicated by the
non-significant interactions between these variables and treatment group
(P>0.23).
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Figure 3c shows the time course for weight gain among olanzapine- and haloperidol-treated participants who completed 12 weeks, 1 year and 2 years of treatment. The time course for weight gain for the three completer groups is remarkably similar and is similar to the results of the observed-cases analysis.
The BMI change during the study follows a pattern similar to that for weight gain (kg) when analysed using LOCF, observed cases and completers. Last-observation-carried-forward analysis showed that in the olanzapine group the mean BMI increased from 23.6 (s.d.=4.8) at baseline to 26.0 (s.d.=5.1) at 12 weeks, 27.0 (s.d.=5.6) at 1 year and 27.0 (s.d.=5.6) at 2 years, compared with an increase from 23.9 (s.d.=4.5) to 24.8 (s.d.=4.5), 25.3 (s.d.=5.0) and 25.3 (s.d.=5.1) in the haloperidol group. However, according to analysis of observed cases, BMI increased from a mean of 23.6 (s.d.=4.8) at baseline to 26.4 (s.d.=4.6) at 12 weeks, 28.8 (s.d.=4.5) at 1 year and 28.3 (s.d.=4.0) at 2 years in the olanzapine group and from 23.9 (s.d.=4.5) to 24.8 (s.d.=4.1), 26.2 (s.d.=4.3) and 26.6 (s.d.=4.4) in the haloperidol group.
Growth curve modelling for clinical predictors of time course for weight gain
Overall, the time course of weight gain from baseline could be best
described as an increasing binomial curve, whose rate of increase stabilised
gradually over time. Body mass index change was not predicted by age, gender,
smoking status, diagnosis, premorbid functioning, age at onset, duration of
illness or history of previous antipsychotic treatment. Individuals with
higher pre-treatment BMI had larger BMI increases in the first week of
treatment but followed the same rate of weight gain as the others thereafter.
Olanzapine-treated participants gained weight significantly faster than
haloperidol-treated individuals but seemed to have greater propensity to
stabilise over time, as indicated by both the significantly larger positive
linear slope and larger negative quadratic slope in the growth curve models on
BMI. The model-estimated linear slopes were 0.14 BMI units/week for
haloperidol v. 0.41 BMI units/week for olanzapine (s.e.=0.03,
t(1394)=6.5, P<0.0001); the estimated quadratic slopes
were -0.005 BMI units/week2 for haloperidol v. -0.02 BMI
units/week2 for olanzapine (s.e.=0.002, t(1396)= 4.22,
P<0.0001). Black participants and those from minority ethnic
groups gained weight faster than White participants and maintained the high
rate of weight gain longer. The effects of baseline BMI and ethnicity on the
BMI increase rate did not differ significantly between the olanzapine- and
haloperidol-treated groups (P>0.40).
Laboratory correlates of weight gain
Body mass index changes did not significantly correlate with changes in
non-fasting glucose levels. The correlation coefficients ranged from -0.21 to
0.18, with none significant for either treatment group at the 12-week,
6-month, 12-month, 18-month and 24-month points. However, change in BMI did
significantly correlate with changes in non-fasting cholesterol levels. The
Pearson correlations between BMI and cholesterol changes were 0.53
(P<0.001), 0.41 (P<0.01), 0.54 (P<0.001),
0.64 (P<0.01) and 0.29 (P=0.29) for the haloperidol group
at the 12-week, 6-month, 12-month, 18-month and 24-month points, respectively;
and 0.17 (P=0.11), 0.25 (P<0.05), 0.30
(P<0.05), 0.27 (P=0.17) and 0.54 (P<0.01) for
the olanzapine group.
Weight gain and clinical response
Overall, we found evidence that higher weight gain was associated with
greater symptom improvement before week 12, but the association was diminished
thereafter. At weeks 1 and 6, a modest correlation was observed
(r=0.21, P=0.02) between weight gain and clinical
improvement in both treatment groups; after 12 weeks, this association could
no longer be detected. The mixed model with repeated measures confirmed this
observation. Changes in BMI were significantly associated with clinical
improvement for both olanzapine- and haloperidol-treated participants
(F(1,3364)=50.05, P<0.001). The association was
significantly reduced at later stages of treatment (F(31,3364)=2.12,
P<0.001).
Weight gain and study retention
In separate Cox regression models, olanzapine treatment, higher BMI
increase and greater symptom improvement each predicted a significantly
smaller hazard of early withdrawal from the study (see models 13,
Table 2). When modelled jointly
(see model 4, Table 2),
reduction in the PANSS total score remained the most significant predictor of
better study retention. With every 10 points of PANSS improvement, the hazard
rate of early study discontinuation was reduced by 29%; even after controlling
for weight gain and drug effect, the reduction remained at 28%. Greater BMI
increase also reduced the hazard ratio for study discontinuation by 11%, but
the effect was reduced to 7% after the effects of drug and PANSS improvement
were taken into account.
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DISCUSSION |
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The magnitude of weight gain observed is of clinical concern;
Table 3 uses criteria
established by the US National Heart, Lung, and Blood Institute to describe
the number and percentage of participants at each time point of the study who
would be categorised as of normal weight (BMI<25), overweight
(BMI5<30) or obese (BMI
30). After 1 year of treatment, 36.7% of
olanzapine-treated participants and 20.5% of haloperidol-treated participants
had BMIs in the obese range; in addition, 40.8% of the olanzapine-treated
group and 35.9% of the haloperidol-treated group had BMIs in the overweight
range.
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Clinical predictors of weight gain
There has been much interest in the possibility that weight gain associated
with antipsychotics may be related to a range of clinical parameters (for
review see Blin & Micallef,
2001). To date, such correlations have been mainly studied among
people treated with clozapine. Clozapine-associated weight gain has been
reported to be more likely in people who started treatment at a lower weight,
in women, in younger people, in those treated with higher doses of clozapine
and in people receiving antipsychotic treatment for the first time
(Blin & Micallef, 2001). In
this study, we were unable to identify predictors of the amount of weight
gained other than treatment group. However, our data clearly demonstrate that
virtually all of the participants treated with olanzapine and approximately
three-quarters of those treated with haloperidol were predicted to gain >7%
of their baseline body weight after 1 year of treatment.
Metabolic correlates of weight gain
Elevations in glucose levels have been described in people receiving some
atypical and some typical antipsychotics
(Wirshing, 2001;
Newcomer et al, 2002;
Lindenmayer et al,
2003). Increases in cholesterol and triglyceride levels have also
been described in individuals receiving clozapine and olanzapine
(Wirshing, 2001; Lindenmayer et al,
2003). In our study, weight change was not significantly
correlated with changes in non-fasting glucose levels, but was significantly
correlated with increases in non-fasting cholesterol levels at some time
points for both treatment groups. Given the extent of the weight gain in both
treatment groups, it would clearly be important to assess fasting glucose and
complete lipid profiles in future clinical trials of antipsychotic medications
for first-episode psychosis to further evaluate the extent to which there is a
significant correlation between weight gain and changes in glucose and lipid
levels.
Weight gain and clinical outcome
Some recent publications have also observed that weight gain associated
with atypical antipsychotics may correlate with clinical outcomes, although
findings have been inconsistent (Blin &
Micallef, 2001). We were able to demonstrate the previously
reported association between weight gain and clinical response. However, our
analysis found that this association was present only in the early weeks of
treatment and that even at these points it was small, accounting for only 4%
of the variance in clinical improvement observed in both treatment groups at
weeks 1 and 6. After 12 weeks, weight gain did not account for any variance in
clinical improvement in either treatment group.
There are a number of possible explanations for this finding. Use of LOCF data for studying this association is problematic because participants who withdraw early may experience both little clinical improvement and little weight gain, whereas those who remain in the study for longer periods are expected to have both greater clinical improvement and higher weight gain. Use of LOCF data may therefore lead to a spurious association between weight gain and clinical response. Why weight gain and clinical response may be associated only in the early weeks of treatment is not clear. This may in part be due to individual pharmacokinetic parameters: people whose absorption and metabolism of antipsychotics resulted in relatively higher plasma drug concentrations very early in the study might be expected to have greater symptom improvement and possibly higher weight gain, whereas those with lower plasma drug concentrations in the early weeks may have neither. A small correlation could thus be generated early in treatment and be expected to disappear once doses have been adjusted to provide therapeutic drug concentrations for all participants. However, this presumes a relationship between weight gain and drug dose/concentrations that has not yet been established. It is possible that other mechanisms may account for the small and transient association between weight gain and clinical response.
Weight gain and study adherence
The weight gain associated with antipsychotic medications, particularly
some atypical antipsychotics, is of concern both because of the potential
health consequences associated with weight gain and because weight gain may
affect the long-term adherence to these medications. In this clinical trial,
olanzapine-treated participants were significantly more likely to complete the
2-year trial despite their higher mean weight gain; haloperidol-treated
participants were significantly more likely to withdraw because of adverse
events and lack of efficacy (Lieberman
et al, 2003). Furthermore, BMI increases were associated
with higher study retention during the first 12 weeks of treatment for both
treatment groups. Our data do not support the view that weight gain
contributes to non-adherence in the short term. Rather, they suggest that for
younger people with first-episode psychosis the degree of clinical improvement
may be the best predictor of adherence to medication in the short term
regardless of adverse events, including weight gain. After controlling for the
effect of clinical improvement, BMI increase (but not treatment group)
remained a significant predictor of study retention. Although it is not known
what features of olanzapine explain the higher study retention associated with
this treatment, it may be that this is mediated through a mechanism that also
contributes to weight gain.
In summary, we have demonstrated that the weight gain associated with extended treatment of a first-episode psychosis with either olanzapine or haloperidol is greater than has been previously estimated. Our results highlight the importance of evaluating weight gain in clinical trials using data derived from observed cases in addition to LOCF procedures. The observed weight gain was significantly greater for olanzapine-treated participants, but no other clinical factors were predictive of the amount of weight gained. Our results suggest that weight gain is associated with clinical improvement but in a minor and transient way, which is unlikely to be of clinical significance. Nor is it clear whether weight gain adversely affects short-term treatment adherence. However, it is clear that the extent of weight gain observed justifies additional study of the potential health consequences that may be experienced by young people who are being treated for a first-episode of psychosis.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication October 25, 2004. Revision received March 15, 2005. Accepted for publication March 21, 2005.
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