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Sibutramine in the treatment of antipsychotic-induced weight gain: a pilot study in patients with schizophrenia Falko Biedermanna, W. Wolfgang Fleischhackera, Georg Kemmlera, Christoph F. Ebenbichlerb, Monika Lechleitnerc and Alex Hofera Weight gain represents a frequent side effect of antipsychotic drug treatment. The current trial investigated the effect of add-on treatment with sibutramine in schizophrenia outpatients who had gained more than 7% of weight during the course of treatment. This 24-week placebo-controlled study evaluated the effects of sibutramine added to ongoing antipsychotic treatment. Weight, waist–hip ratio, BMI, blood pressure/pulse and ECG were monitored regularly. In addition, several laboratory tests were performed. Psychopathological symptoms and side effects were assessed frequently. Fifteen patients were assigned randomly to add-on treatment with sibutramine 10 mg or placebo. The two groups did not differ in weight, sociodemographic, or clinical data. Eleven patients were considered for statistical analysis. Significant weight loss was observed in the sibutramine group (mean = – 6.1 kg), whereas patients on placebo experienced a mean weight gain of 1.9 kg. A reduction in HbA1c was apparent in the sibutramine

but not in the placebo group. No significant between-group differences were found in changes in psychopathology or drug safety. This pilot trial suggests that adjunctive treatment with sibutramine may be safe and effective in schizophrenic patients with antipsychotic-induced weight c 2014 gain. Int Clin Psychopharmacol 29:181–184 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Introduction

Patients and methods

Antipsychotic treatment has frequently been associated with weight gain, especially in patients treated with newgeneration compounds (Tschoner et al., 2009; Balt et al., 2011). To date, most pharmacological approaches for weight reduction have yielded little success. Positive effects were found for metformin and sibutramine (Baptista et al., 2007; Henderson et al., 2007; Khan et al., 2010).

Patients

Sibutramine blocks serotonin, noradrenalin and dopamine reuptake and leads to a decrease of appetite (Ryan et al., 1995). Cardiovascular side effects such as supraventricular tachycardia and ventricular ectopic beats (Sharma, 2001; Kim et al., 2003; Dogangun et al., 2008) led to a recommendation of the European Medicines Agency against its use in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias as well as to a ‘black box’ warning by the US Food and Drug Administration. Short-term studies investigating the effect of sibutramine in antipsychotic-induced weight gain yielded conflicting results (Henderson et al., 2005, 2007). Therefore, the current placebo-controlled, 24-week, double-blind study investigated the effect of sibutramine in schizophrenic patients using different antipsychotics in the medium term. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-1315

International Clinical Psychopharmacology 2014, 29:181–184 Keywords: antipsychotics, schizophrenia, sibutramine, weight gain a

Department of Psychiatry and Psychotherapy, Biological Psychiatry Division, Department of Internal Medicine I, Medical University Innsbruck, Innsbruck and Department of Internal and Geriatric Medicine, Hochzirl Hospital, Zirl, Austria

b c

Correspondence to Falko Biedermann, MD, Department of Psychiatry and Psychotherapy, Biological Psychiatry Division, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria Tel: + 43 512 504 23669; fax: + 43 512 504 25267; e-mail: [email protected] Received 6 June 2013 Accepted 7 November 2013

Fifteen schizophrenic outpatients (following ICD-10) between 19 and 65 years of age who had gained at least 7% of their initial weight during the course of antipsychotic treatment and whose current BMI was more than 27 were included in the study. They did not have any other axis I disorder. Except for benzodiazepines, no concomitant medication was accepted. Exclusion criteria were hypersensitivity to sibutramine, any other severe somatic or psychiatric disorder, concurrent treatment with tricyclic antidepressants SSRIs, MAO inhibitors or lithium, other appetite suppressants, sympathomimetics and substances influencing the metabolism of cytochrome P450 (3A4), ECG abnormalities, history of vascular diseases, pregnancy, or breastfeeding. Participants signed informed consent in accordance with the local Ethical Committee. Medical check and laboratory analyses

Patients included in the study underwent investigation by a specialist for internal diseases. Next to the performance of routine blood tests leptin, HbA1c, insulin, C-peptide and plasma level of the antipsychotic medication administered were analysed regularly. In addition, weight, waist–hip ratio, BMI, blood pressure/pulse and DOI: 10.1097/YIC.0000000000000022

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182 International Clinical Psychopharmacology 2014, Vol 29 No 3

ECG were monitored. A study drug-free final visit was planned half a year after completion of the trial; however, this was neglected by all participants.

Compared with placebo, sibutramine led to a significant decrease in HbA1c after 24 weeks (Table 1). All other laboratory parameters did not show any significant fluctuations during the course of the study.

Procedures

Diastolic blood pressure decreased significantly after 12 weeks of treatment with sibutramine compared with treatment with placebo. This difference was not found at week 24.

Patients were assigned randomly to the two groups (adjunctive treatment with sibutramine 10 mg or placebo) and were maintained on their previous antipsychotic drug. During the course of the study, 11 assessments were performed. Psychopathological symptoms were assessed by the means of the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987), side effects by the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale (Lingjaerde et al., 1987) and hunger, appetite and satiety by a Visual Analogue Scale. Statistical analysis

Eleven patients were eligible for statistical analysis. Repeated-measures analysis of variance (within-patient factor time, between-patient factor group) was used to compare the two treatment groups with respect to the time course of the outcome variables of interest, with a special focus on the group-by-time interaction; this interaction reflects differences between the two groups in the course of time. Individual missing values of the dependent variable were replaced using the last observation carried forward method. For comparison, we also carried out an analysis ‘according to protocol’ including only those patients who completed the entire 24 weeks of treatment.

Results Demographic data, clinical characteristics and laboratory assessments

Fifteen patients were enrolled into the study. Five patients (three from the placebo group, two from the sibutramine group) did not complete the study for the following reasons: in the placebo group, one patient (clozapine) developed QTc prolongation, one (quetiapine + haloperidol) relapsed and one developed nausea and withdrew consent. In the sibutramine group, one patient withdrew informed consent without stating the reason and one became noncompliant with antipsychotic medication and relapsed. The remaining patients (five placebo/five sibutramine) completed the trial. The patient in the placebo group who withdrew informed content after week 8 was considered eligible for analysis. Hence, a total of 11 patients were eligible for statistical analysis. The two groups were comparable with respect to age, sex and PANSS scores (Table 1). All were treated with approved doses of second-generation antipsychotics. Regular plasma level monitoring did not show any significant fluctuations during the study period.

Weight change

In patients eligible for analysis, the mean prestudy weight gain during antipsychotic treatment was 25±11.6 kg. After 24 weeks of treatment, weight decreased significantly in the sibutramine, but not in the placebo group (P < 0.05, repeated-measures ANOVA) (Table 2). Patients on adjunctive sibutramine lost 6.1 kg; those on placebo gained 1.9 kg. A similar pattern was also observed with respect to BMI, although only at a trend level.

Overview of psychopathology, HbA1c, glucose, blood pressure and pulse rate in sibutramine-treated and placebotreated patients

Table 1

Group Sibutramine (N = 6) Variables

Mean

PANSS total Week 0 46.2 DWeek 0–12 – 3.0 DWeek 0–24 – 4.4 PANSS-positive symptoms Week 0 8.4 DWeek 0–12 – 0.4 DWeek 0–24 – 0.6 PANSS-negative symptoms Week 0 14.8 DWeek 0–12 – 1.2 DWeek 0–24 – 1.0 PANSS general Week 0 23.0 DWeek 0–12 – 1.4 DWeek 0–24 – 2.8 HbA1c Week 0 5.58 DWeek 0–12 – 0.08 DWeek 0–24 – 0.38a Glucose Week 0 94.60 DWeek 0–12 + 2.20 DWeek 0–24 + 6.20 Blood pressure systolic Week 0 115.0 DWeek 0–12 – 4.0 DWeek 0–24 1.6 Blood pressure diastolic Week 0 81.0 DWeek 0–12 – 6.6 DWeek 0–24 – 5.4 Pulse rate Week 0 72.4 DWeek 0–12 1.8 DWeek 0–24 10.8

Placebo (N = 5)

SD

Mean

SD

17.2 6.3 16.9

55.4 – 4.9 – 4.6

23.5 7.9 12.5

1.9 0.9 1.3

12.2 – 1.7 – 2.0

8.2 2.7 3.4

7.9 2.3 6.5

16.2 + 0.3 1.0

7.5 4.1 2.8

9.1 3.6 9.3

27.1 – 3.6 – 3.6

11.0 7.5 7.4

0.66 0.25 0.29

5.78 + 0.10 + 0.12

0.32 0.35 0.22

5.37 6.06 11.95

98.33 + 4.20 + 3.60

11.69 16.80 10.62

20.0 15.2 21.8

120.8 – 9.2 0.6

15.9 13.9 18.8

16.0 12.2 8.3

81.7 3.3 4.6

11.3 4.1 13.0

9.0 10.7 9.0

77.5 3.4 7.8

8.1 9.7 10.2

a Significantly stronger decrease in the sibutramine group than in the placebo group, P = 0.032. No further significant differences between the two groups for any of the variables listed.

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Sibutramine in antipsychotic-induced weight gain Biedermann et al. 183

Table 2

Time course of weight, BMI and waist–hip ratio in patients treated with sibutramine or placebo Statisticsc

Group Sibutramine (N = 5) Variables

Assessment time

Weight (kg)

Week Week Week Week Week Week Week Week Week

BMI

Waist–hip ratio

0 12 24 0 12 24 0 12 24

(vs. 0) (vs. 0) (vs. 0) (vs. 0) (vs. 0) (vs. 0)

Placebo (N = 6)a,b

Mean

SD

Mean

SD

F

d.f.

P

99.2 – 4.5e – 6.1d 35.1 – 1.7e – 2.3e 0.895 – 0.019d + 0.014

21.6 4.7 6.7 8.3 1.8 2.6 0.115 0.024 0.038

94.4 – 0.2 + 1.9 32.5 + 0.0 + 0.6 0.933 + 0.007 + 0.015

11.3 2.0 3.5 6.0 0.7 1.1 0.098 0.008 0.044

0.22 3.77 6.21 0.35 3.55 5.15 0.35 6.04 0.01

1.9 1.8 1.8 1.9 1.8 1.8 1.9 1.8 1.8

0.647 0.088 0.037 0.567 0.096 0.053 0.571 0.039 0.916

Bold indicates significant P values. a One patient dropped out before week 24 [analysis by the last observation carried forward (LOCF) method]. b Waist–hip ratio at week 24 was only available for four patients of the placebo group (analysis by LOCF method). c Analysis on the basis of repeated-measures ANOVA with adjustment for baseline differences. For week 12 vs. 0 and week 24 vs. 0, the statistics of the time-by-treatment interaction are shown. d Significantly stronger decrease in the sibutramine group than in the placebo group (P < 0.05). e Stronger decrease in the sibutramine group than in the placebo group attaining trend-level significance (P < 0.1).

In addition, a larger decrease in the waist–hip ratio was apparent on sibutramine compared with placebo at week 12 that disappeared at week 24. Hunger, appetite and satiety as assessed by the Visual Analogue Scale were comparable between groups at all assessments.

Similar to our study, sibutramine was found to be safe in both trials. Baptista et al. (2008) investigated the effect of adjunctive metformin plus sibutramine versus placebo in 18 schizophrenic patients treated with olanzapine and found no impact on weight, but sibutramine was found to be safe in this trial as well.

Side effects

In contrast to earlier studies, we conducted a trial of longer duration and included patients who were currently treated with different antipsychotics. We were able to confirm the positive results as patients on adjunctive sibutramine lost weight and showed a reduction in the waist–hip ratio when compared with those on placebo.

Throughout the course of the study, all side effects rated by the UKU were comparable between groups. As mentioned above, in the placebo arm, one patient dropped out because of nausea and another one because of QTc prolongation. No patient dropped out because of severe adverse events caused by sibutramine.

Discussion Antipsychotic-induced weight gain and its consequences have consistently been associated with reduced life expectancy, stigma, decreased quality of life and lowered self-esteem in patients with schizophrenia (Masand and Gupta, 2003; Heald, 2010). Accordingly, weight gain represents a common reason for noncompliance, which may result in relapse, hospital admission as well as treatment resistance and the development of chronic psychosis (Hofer and Fleischhacker, 2011). In addition, relapse because of compliance problems has been associated with suicide and dangerous behaviours (Besnier et al., 2009; Volavka and Citrome, 2011). For these reasons, next to mental health outcomes, the management of physical health represents a major challenge in the treatment of schizophrenic patients. Henderson et al. (2005, 2007) conducted two trials to investigate the effect of sibutramine coadministered to olanzapine or clozapine and reported on a weightreducing effect in the olanzapine group but not in the clozapine group. They suggested that different mechanisms might be responsible for weight gain in these agents.

Complementary to dietary recommendations, adjunctive pharmacological support for weight control may often be indicated in antipsychotic-induced weight gain. So far, metformin, nizatidine, topiramate, reboxetine and aripiprazole have been investigated with limited success, whereas metformin shows the most promising evidence (Fiedorowicz et al., 2012). Reports on a potential sibutramine-induced deterioration of psychopathology are inconsistent. There are several case reports and case series reporting on an exacerbation of psychotic symptoms, mood disorders and manic episodes (Litvan and Alcoverro-Fortuny, 2007; Gazdag and Szabo´, 2008; Naik et al., 2010). However, similar to the findings of Henderson et al. (2005, 2007), we found no significant psychopathological changes in our sample. Despite the use of the lowest approved dosage (10 mg/day), sibutramine led to a significant weight reduction compared with placebo. In addition, it was well tolerated and safe, although it was administered over a longer period than in former trials; therefore, our results allow no statement on drug safety because of the small sample size. Previous studies had reported on return to the baseline weight level after discontinuation of add-on treatment

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with sibutramine. We had therefore planned a study drugfree final visit half a year after the completion of the trial. However, this was neglected by all participants. When interpreting our data, one clearly has to consider that the patients investigated in the current trial were healthy from a somatic point of view. Accordingly, nonfatal myocardial infarction or stroke that had led to withdrawal of sibutramine from the market was not expected in our sample. That is, sibutramine may be useful and safe to treat antipsychotic-induced weight gain in patients with schizophrenia, who are not cardiac highrisk patients. Consequently, only a selected group of patients comes into consideration for this treatment.

Acknowledgements This study was supported by the ‘Medizinischer Forschungsfonds Tirol’. Sibutramine was provided by Knoll Pharmaceuticals (Abbott Laboratories) and placebo medication was provided by the Pharmacy of the University Hospital of Innsbruck. The authors thank Nadja Eltanaihi-Furtmu ¨ller and Regina Huber for their commitment and for the medical attendance of the study participants.

Conflicts of interest

F.B. has received financial support for congress participation from the following companies: Janssen-Cilag and Eli Lilly. W.W.F. has received research grants from Alkermes, Janssen-Cilag, Eli Lilly, BMS/Otsuka and Pfizer. He has received honoraria for educational programmes from Janssen-Cilag, Pfizer and AstraZeneca, speaking fees from AstraZeneca, Pfizer, Janssen-Cilag, Roche, Lundbeck, BMS/Otsuka and advisory board honoraria from BMS/Otsuka, Wyeth, Janssen-Cilag, Neurosearch, Amgen, Lundbeck, Endo, United BioSource, Targacept, MedAvante, and AstraZeneca and owns MedAvante stocks. M.L. has received speaking fees from Sanofi, Novartis, ESK, as well as financial travel support. A.H. has received research grants from Janssen-Cilag. He has received speaking fees from AstraZenca, BMS/Otsuka, Janssen-Cilag, Lundbeck and Pfizer. For the remaining authors there are no conflicts of interest.

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Sibutramine in the treatment of antipsychotic-induced weight gain: a pilot study in patients with schizophrenia.

Weight gain represents a frequent side effect of antipsychotic drug treatment. The current trial investigated the effect of add-on treatment with sibu...
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