Edited by: Gerfried Karl Hans Nell, NPC Nell Pharma Connect Ltd, Austria
Reviewed by: Domenico Criscuolo, Genovax S.r.l., Italy; Fathi M. Sherif, University of Tripoli, Libya
*Correspondence: Min Zhao
Xiaoduo Fan
This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology
†Co-first authorship.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
ClinicalTrials.gov identifier: NCT02736474.
Schizophrenia is a devastating neuropsychiatric disease with a prevalence of 1% worldwide. The rates of obesity are two times higher, and the rates of cigarette smoking are three to five times higher in this patient population compared to the general population, (Marder et al.,
Bupropion is an approved medication for depression and smoking cessation treatment. Bupropion can enhance subcortical dopamine and norepinephrine effects and mitigate the effects of nicotine-evoked dopamine transmission, therefore reduce nicotine reward and withdrawal experiences (Mansvelder et al.,
The mechanisms underlying weight gain post cessation in smokers are likely related to the results of heightened food reward (Lerman et al.,
Research on central nervous system pathways that regulate food intake and body weight has identified two key systems: the hypothalamic melanocortin system, which integrates input related to energy balance and produces anorexigenic signaling, and the mesolimbic reward system, which modulates reward value and goal-oriented behavior. Bupropion stimulates hypothalamic proopiomelanocortin (POMC) neurons while naltrexone can prevent inhibition of POMC neurons by blocking the action of β-endorphin (Billes et al.,
The combination of sustained-release naltrexone and bupropion (NB) (Contrave, Orexigen, CA) has received FDA-approval for weight loss in people who are overweight or obese (Greenway et al.,
This study was approved by the ethics committee of Shanghai Mental Health Center. Each participant provided written informed consent. Male patients with schizophrenia were recruited from the inpatient unit at Xuhui Mental Health Center located in Shanghai, China. Each patient had 7 smoking breaks throughout the day from 6:15 a.m. to 7:30 p.m. During these 15-min breaks, patients were allowed to smoke cigarettes freely.
The inclusion criteria were: (1) diagnosis of schizophrenia by the International Classification of Diseases 10th Revision (ICD-10); (2) age between 18 and 65 years old; (3) on stable antipsychotic medication treatment for at least 1 month; (4) BMI > 28 kg/m2 according to BMI criterion for obesity in the Chinese population (Wu,
The exclusion criteria were: (1) eating disorders; (2) currently taking weight loss medications; (3) substance use (except caffeine or nicotine); (4) clinically significant liver disease; (5) clinically significant thyroid dysfunction; (6) history of epilepsy; (7) history of unstable heart diseases or other unstable medical conditions.
A total number of 330 male patients with schizophrenia were approached and screened between July 2016 and March 2017. Among 28 patients who fit the inclusion and exclusion criteria, 22 of them were enrolled in the study. One patient in the placebo group dropped out of the study after week-12 because of loss of follow up after being discharged from the inpatient unit. Therefore 21 patients (11 in the treatment group, 10 in the control group) completed the 24-week trial and were included in the final analysis.
Following screening and confirmation that inclusion and exclusion criteria were met, participants were randomized to receive the combination treatment or placebo. Participants were started with naltrexone 15 mg and bupropion sustained release 150 mg daily in the first 2 weeks. Then naltrexone was increased to 15 mg in the morning, 10 mg in the afternoon, and bupropion increased to 150 mg twice per day as tolerated during the remaining weeks of the study. Dosing targets were determined based on the efficacy and side effects associated with various dosing strategies reported in previous studies (Anderson et al.,
Medical and psychiatric histories were obtained, and physical exam was performed for each participant. Urine drug screen and 12-lead EKG were performed at baseline. The following measures were completed at baseline and week 24: (1) height, weight and waist circumference; (2) fasting lipids, fasting glucose, HbA1c, and insulin; (3) breath CO level; (4) smoking craving using the Visual Analogue Scale; (5) number of cigarettes smoked in the past week; (6) the Positive and Negative Syndrome Scale (PANSS), (7) the side effects questionnaire.
Laboratory assays were performed by the Bio-Chemistry Lab of Shanghai Mental Health Center. Fasting plasma glucose was measured with a hexokinase reagent kit. Hemoglobin A1C (HbA1c) was measured by high performance liquid chromatography with an automated analyzer. Fasting total plasma cholesterol and triglyceride levels were measured enzymatically, and the HDL cholesterol fraction was measured after precipitation of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) with dextran sulfatemagnesium, LDL levels were determined by the direct LDL reagents. Fasting insulin was measured using immunochromatography.
Data were analyzed using SPSS 24.0 (IBM Corp., Armonk, NY). For baseline between-group comparisons, independent student
There were no significant differences between the two groups on age, illness time duration, smoking time duration, breath CO level, number of cigarettes smoked per week, smoking craving, body weight, BMI, waist circumference, HbA1c, fasting glucose, HDL, LDL and insulin, and the PANSS total and subscale scores (
Baseline demographic and general clinical characteristics.
Age (years) | 54.3 ± 5.7 | 56.2 ± 4.8 | 0.418 |
Education (years) | 11.0 ± 2.8 | 8.1 ± 3.5 | 0.049* |
Illness time duration (years) | 29.8 ± 4.6 | 27.0 ± 8.8 | 0.400 |
Smoking time duration (years) | 28.6 ± 7.8 | 32.4 ± 4.9 | 0.211 |
Breath CO Level (ppm) | 27.1 ± 23.2 | 23.8 ± 9.0 | 0.679 |
Number of cigarettes smoked per week | 72.5 ± 5.7 | 77.0 ± 22.1 | 0.526 |
VAS smoking craving | 6.3 ± 1.0 | 7.0 ± 1.4 | 0.202 |
Weight (kg) | 74.7 ± 8.4 | 78.4 ± 10.6 | 0.380 |
BMI (kg/m2) | 26.1 ± 2.9 | 27.6 ± 2.6 | 0.229 |
waist circumference (cm) | 94.9 ± 4.5 | 98.8 ± 6.3 | 0.118 |
PANSS-Total | 51.5 ± 17.4 | 55.9 ± 20.3 | 0.602 |
PANSS-Positive | 10.0 ± 3.4 | 11.2 ± 6.1 | 0.579 |
PANSS-Negative | 15.9 ± 5.4 | 19.9 ± 7.9 | 0.188 |
PANSS-General | 24.3 ± 9.1 | 25.3 ± 11.1 | 0.819 |
Glucose (mmol/l) | 5.5 ± 1.1 | 5.6 ± 2.3 | 0.903 |
HbA1c (%) | 6.1 ± 0.6 | 6.4 ± 1.9 | 0.729 |
Triglyceride (mmol/l) | 2.3 ± 1.1 | 1.4 ± 0.6 | 0.050* |
HDL (mmol/l) | 0.9 ± 0.2 | 0.8 ± 0.1 | 0.163 |
LDL (mmol/l) | 2.8 ± 0.8 | 2.4 ± 0.9 | 0.234 |
Insulin (pmol/l) | 106.8 ± 65.8 | 66.4 ± 20.2 | 0.095 |
After controlling for education level and baseline value, the ANCOVA analysis showed no significant differences between the two groups in week 24 changes for metabolic measures including body weight, BMI, waist circumference, fasting glucose, HbA1c, triglycerides, HDL, LDL, and insulin (
Comparison of change values from baseline to week 24 on outcome measures.
Body weight (kg) | 0.2 ± 5.3 | −0.9 ± 3.1 | 0.779 |
BMI (kg/m2) | 0.0 ± 1.9 | −0.3 ± 1.1 | 0.314 |
Glucose | 0.5 ± 1.5 | 1.0 ± 1.6 | 0.264 |
HbA1c | 0.05 ± 0.6 | 0.4 ± 1.1 | 0.385 |
Triglycerides | −1.0 ± 0.9 | −0.4 ± 0.6 | 0.591 |
HDL | 0.0 ± 1.1 | 0.0 ± 0.1 | 0.657 |
LDL | −0.4 ± 0.7 | −0.2 ± 0.7 | 0.900 |
Insulin | 3.5 ± 74.4 | 11.0 ± 35.3 | 0.262 |
Breath CO level (ppm) | −5.3 ± 22.4 | −7.2 ± 7.4 | 0.289 |
Cigarettes per week | −6.2 ± 16.3 | −6.3 ± 23.0 | 0.621 |
Craving scores | −1.0 ± 2.9 | −1.9 ± 3.1 | 0.481 |
During the 24-week study time period, five participants reported dry mouth and1 participant reported mild abdominal discomfort in the treatment group; 1 participant reported tachycardia in the placebo group. There were no serious adverse events reported during the study. No participants withdrew from the study because of side effects.
Obesity and tobacco dependence are two major clinical challenges in patients with schizophrenia. To date studies have generally focused on addressing one or the other but not both. Identifying effective strategies to address both problems simultaneously would have great clinical value and public health implication. The current pilot study was designed to test naltrexone and bupropion combination treatment to address obesity and tobacco dependence together in individuals with schizophrenia. To our knowledge, this was the first study to target two difficult-to-treat conditions simultaneously in this population. Our study suggests that naltrexone and bupropion combination is well-tolerated in patients with schizophrenia.
Our study failed to demonstrate benefit of naltrexone and bupropion combination treatment for weight loss or smoking cessation in patients with schizophrenia. Possible reasons may include the small sample size, dosing of study medication, peer pressure to engage in cigarette smoking in the inpatient environment, and the absence of a psychosocial intervention combined with the pharmacological intervention. Another possibility is that the mechanisms related to obesity and cigarette smoking in patients with schizophrenia may not be responsive to naltrexone and bupropion combination treatment. The high rates of tobacco dependence in individuals with schizophrenia are believed to result from a range of neurobiological vulnerability factors that likely act in concert (Wing et al.,
Obesity and tobacco dependence are two major clinical challenges in patients with schizophrenia. To date studies have singly focused on addressing one or the other. Novel strategies to address both problems simultaneously would have high clinical value and considerable public health implication. Future studies with larger sample sizes and in combination with psychosocial interventions, such as motivational interviewing and/or nutritional counseling, are warranted to further explore potential benefits of naltrexone and bupropion combination treatment in treating obesity and cigarette smoking in patients with schizophrenia.
FJ, XF, MZ: conceived and designed the experiments; XL, GZ, YW, HS, YZ: performed the experiments; XL: analyzed the data; XL, JD: contributed reagents, materials, analysis tools; XL, JD, XF: wrote the paper.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.