Importance of Early Weight Changes to Predict Long-Term Weight Gain During Psychotropic Drug Treatment
See commentary by Tohen
Importance of Early Weight Changes to Predict Long-Term Weight Gain During Psychotropic Drug Treatment
Background: Psychotropic drugs can induce substantial weight gain, particularly during the first 6 months of treatment. The authors aimed to determine the potential predictive power of an early weight gain after the introduction of weight gain-inducing psychotropic drugs on long-term weight gain.
Method: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 351 psychiatric (ICD-10) patients, with metabolic parameters monitored (baseline and/or 1, 3, 6, 9, 12 months) and with compliance ascertained. International Diabetes Federation and World Health Organization definitions were used to define metabolic syndrome and obesity, respectively.
Results: Prevalences of metabolic syndrome and obesity were 22% and 17%, respectively, at baseline and 32% and 24% after 1 year. Receiver operating characteristic analyses indicated that an early weight gain > 5% after a period of 1 month is the best predictor for important long-term weight gain (≥ 15% after 3 months: sensitivity, 67%; specificity, 88%; ≥ 20% after 12 months: sensitivity, 47%; specificity, 89%). This analysis identified most patients (97% for 3 months, 93% for 12 months) who had weight gain ≤ 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months. Its predictive power was confirmed by fitting a longitudinal multivariate model (difference between groups in 1 year of 6.4% weight increase as compared to baseline, P = .0001).
Conclusion: Following prescription of weight gain-inducing psychotropic drugs, a 5% threshold for weight gain after 1 month should raise clinician concerns about weight-controlling strategies.
J Clin Psychiatry 2015;76(11):e1417-e1423
© Copyright 2015 Physicians Postgraduate Press, Inc.
aUnit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Hospital of Cery, Prilly, Switzerland
bCenter for Psychiatric Epidemiology and Psychopathology; cService of General Psychiatry; dService of Old Age Psychiatry, Department of Psychiatry; and eMultidisciplinary Team of Adolescent Health, Lausanne University Hospital, Prilly, Switzerland
fSchool of Pharmacy, Department of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
*Corresponding author: Chin B. Eap, PhD, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neurosciences, Hospital of Cery, 1008 Prilly—Lausanne, Switzerland .
A high prevalence of obesity (body mass index [BMI] ≥ 30 kg/m2, World Health Organization definition) is reported in psychiatric populations, reaching 49% and 55% of bipolar and schizophrenic patients, respectively.1 Obesity can lead to several metabolic complications, such as hypertension, lipid profile perturbation, or both, contributing to the reported 20-year shorter life expectancy in psychiatric patients as compared to the general population.2 Several factors contribute to the high prevalence of metabolic disorders in psychiatry, such as the illness itself as well as lifestyle factors. In addition, antipsychotics (most atypicals but also some typicals), mood stabilizers (eg, valproate and lithium), and some antidepressants (eg, mirtazapine) can induce important weight gain.3,4
Several factors have been shown to be associated with drug-induced weight gain, including female gender, low baseline BMI, young age, or nonwhite ethnicities.5 A high interindividual variability of drug-induced weight gain is observed, explained in part by genetic variability (eg, in H1 receptor, M3 receptor, or CRTC1 gene),6,7 underlining the importance of monitoring metabolic parameters.
The Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes guideline8 considers that a weight gain > 5% during treatment should be a sign to reconsider the treatment. However, no notion of time was defined, so that a weight gain of 5% after 1 month may be inappropriately compared to a comparable weight gain after 1 year of treatment. A joint statement of the European Psychiatric Association, the European Association for the Study of Diabetes, and the European Society of Cardiology defines a weight gain of 7% after 6 weeks of treatment as a clinically significant weight gain.1 This 7% threshold was chosen for its clinical significance and not for its predictive value for an important weight gain during long-term treatment. To our knowledge, 3 studies have investigated the predictive values of an early weight gain. The first two studies9,10 found that a 2-kg increase after 1 month was a good predictor for a 10-kg increase after 6 months in patients treated for schizophrenia with olanzapine, ziprasidone, and aripiprazole. The third study11 in bipolar patients treated with olanzapine found that a 2-kg weight gain after 3 weeks will predict a 7% increase after 30 weeks of treatment. Notably, the above-mentioned studies were post hoc analyses of clinical trials examining the effects of specific drugs, with restrictions on the number of drugs that could be prescribed, conditions that are not comparable to usual clinical practice. In addition, nonobservance of the pharmacologic treatment is poor, particularly during long-term treatment.12 In the above-mentioned studies, compliance was assessed by patient self-declaration,13-15 which can be overestimated. Finally, the longest study duration was of 30 weeks, with no long-term data (1 year).
Because of the high mortality and morbidity associated with obesity, early detection of patients who have a higher risk of developing an important weight gain during psychotropic treatment is of major clinical relevance. In the present study, we sought to determine, in a cohort of psychiatric patients with compliance ascertained by therapeutic drug monitoring, how weight change during short-term treatment (1 month) could predict intermediate (3 months) and long-term (1 year) weight evolution during treatment with psychotropic drugs known to potentially induce important weight gain. Self-reported increase of appetite and modification of physical activity during the first month after drug introduction were also examined as possible weight gain predictors.
- Psychotropic drug-induced weight gain is associated with high morbidity and mortality.
- Rapid detection of high risk patients is of major clinical significance.
- Weight gain of more than 5% after 1 month of treatment was found to be a good predictor for important long-term weight gain.
A longitudinal observational study has been ongoing since 2007 in the Department of Psychiatry of the Lausanne University Hospital in which inpatients starting a pharmacologic treatment with clozapine, olanzapine, risperidone, quetiapine, aripiprazole, amisulpride, lithium, valproate, and/or mirtazapine are included. Baseline clinical data were obtained during hospitalization, and follow-up data (1, 3, 6, 9, and/or 12 months) were obtained in the hospital or in outpatient centers during a medical examination based on the department guideline for metabolic follow-up performed on a routine basis.16 When a treatment was stopped for more than 2 weeks, or if a drug was replaced by another drug on the list, the follow-up was restarted from baseline. In case of the introduction of a second studied drug, the follow-up was restarted and the last introduced drug considered as the main treatment (for more information, see eMethods 1). If 2 or more follow-ups were available for the same patient, only the longest one was included in the analysis (Supplementary eFigure 1). Diagnoses were based on the ICD-10 classification (F00-F09, organic disorder; F20.0-F24.9 and F28-F29, psychotic disorders; F25.0-F25.9, schizoaffective disorder; F30.0-F31.9, bipolar disorder; F32.0-F33.9, depression; F10-F19, drug addiction). Anxiety, personality disorder, and mental retardation were classified together as "others." Compliance was evaluated by therapeutic drug monitoring (more information in eMethods 2). The study was approved by the ethics committee of the Lausanne University Hospital. Because of the noninterventional post hoc analysis study design, no informed consent was requested.
Mean values were presented with their respective standard error (SE), and significance threshold was fixed at P < .05.
To assess the predictive value of an early weight gain during the first month of treatment on long-term weight gain (3 and 12 months), sensitivity, specificity, positive predictive value, and negative predictive value were calculated using the pROC R package.17 Sensitivity was defined as the percentage of correctly predicted high-risk patients among all truly long-term high-risk patients. Specificity was defined as the percentage of patients predicted as low-risk patients among all truly low-risk patients. Positive predictive value indicates the percentage of patients with an important long-term weight gain and who were classified as having a high early weight gain. Negative predictive value indicates the percentage of patients who did not have an important long-term weight gain and were classified as having a low early weight gain.
Thresholds for early weight gain were examined in 1% increments (from 2% to 8%) to find the best predictors for long-term weight gain as defined by a minimal weight gain of 10%, 15%, or 20% at 3 and 12 months of treatment (more information in eMethods 3). The same analysis was made to predict the effect of activity and appetite increase on long-term weight gain.
A linear mixed-effect model was fitted on the weight gain percentage after separating patients into 2 groups based on their initial weight gain after 1 month of treatment, physical activity, and appetite increase (eMethods 4).
Three hundred fifty-one patients were included (selection criteria in Supplementary eFigure 1). Male subjects (47%) were significantly younger (mean [SE] = 39 [1.6] years) than female subjects (51 [1.6] years, P < .001), which probably explains the lower prevalence of obesity in men (9%) than in women (23%, P = .003) (Supplementary eTable 1). No significant differences in other demographic variables were found between genders. Psychotic disorders (F20.0-F24.9 and F28-F29) were the most frequent diagnosis (41%), and quetiapine was the most frequently prescribed psychotropic drug (32%) (Table 1). Data were available for 313 subjects at 3 months and for 154 subjects at 12 months.
Twenty-one percent of patients were overweight (BMI = 25-30 kg/m2) and 17% were obese (BMI ≥ 30 kg/m2) at baseline (Supplementary eTable 2). In patients with 1-year follow-up, prevalence of patients with normal weight (BMI < 25 kg/m2) decreased from 61% to 49% (P = .007) (Table 2). Mean BMI increase after 1 year of treatment was dependent on age, being 2.7 kg/m2 in young patients (aged ≤ 25 years), 2.2 kg/m2 in young adults (aged 25-45 years), 1.8 kg/m2 in adult patients (aged 45-65 years), and 1 kg/m2 in elderly patients (aged > 65 years) (Supplementary eTable 3). Prevalence of metabolic syndrome (MetS [International Diabetes Federation definition]) was 22% at baseline and 32% after 1 year (Supplementary eTable 2). In patients with baseline and 1-year data, a trend for an increased prevalence during treatment was observed (from 9% to 23%, P = .07) (Table 2). Other metabolic traits, including their evolutions during treatment, are described in eResults 1.
Short-Term Weight Gain as Predictors of Long-Term Weight Gain
The best early weight gain predictor (highest area under the curve [AUC] values, integrating both sensitivity and specificity of the predictor) was found to be a weight gain of more than 5% (Figure 1) after 1 month of treatment (mean [SE] = 31 [0.4] days) for predicting a weight gain of 15% or more after 3 months of treatment (mean [SE] = 102  days). This threshold had a sensitivity of 67%, specificity of 88%, positive predictive value of 29%, and negative predictive value of 97%. Prevalence of a 15% weight gain after 3 months was 7.5%. The 5% threshold was also found to be the best predictor for a weight gain of 20% or more after 1 year of treatment (mean [SE] = 393  days; sensitivity, 47%; specificity, 89%; positive predictive value, 30%; negative predictive value, 93% [Supplementary eTable 4]). A weight gain > 20% was observed in 10% of patients after 1 year. Patients who had a weight gain > 5% at 1 month and who did not reach a 15% weight gain at 3 months (false positives) had still a higher weight gain than patients with ≤ 5% weight gain (8.1% vs 2.4%, P = .000005). However, the difference was not significant anymore after 1 year (6.1% vs 3.9%, P = .2). In young adults and adults combined (age, 25-65 years), this threshold was also found to be the best predictor for a 20% weight gain after 3 months (sensitivity, 100%; specificity, 82%; positive predictive value, 7%; negative predictive value, 100%) and after 12 months (sensitivity, 55%; specificity, 83%; positive predictive value, 30%; negative predictive value, 93%) (Supplementary eTable 5). Due to an insufficient number of observations, no specific threshold could be calculated in young (aged ≤ 25 years) and elderly (aged > 65 years) subjects or in different diagnostic and medication groups.
Using the 5% threshold, 18% of patients had a > 5% weight gain after 1 month. By integrating the 5% threshold in a generalized additive mixed model (Figure 2), patients with an early weight gain > 5% had a strong and fast increase of weight gain during the first 3 months of treatment, with a much slower increase thereafter (Supplementary eFigure 2). On the other hand, patients with an early weight gain ≤ 5% had a slower but steady 1-year weight gain. No differences of age, gender, follow-up duration, illness duration, or diagnosis were observed between the 2 groups. Medication was similar between the 2 groups except for olanzapine, which was present in 24% and 10% of the patients gaining more weight versus those gaining less than 5%, respectively (P = .006) (Table 1). When considering MetS traits at baseline, only BMI was significantly different between both groups (P = .001), being lower in the > 5% group. After 1 year, mean (SE) BMI increases of 1.2 (0.3) kg/m2 and 3.1 (0.8) kg/m2 were observed in the low and high weight-gain group, respectively (P = .01) (Supplementary eTable 6). A stronger decrease of high-density lipoprotein (HDL) cholesterol (Î² = −0.3 mmol/L, Padjusted < .0001) and increase of triglyceride (Î² = 1.5 mmol/L, Padjusted < .0001) were also observed in the > 5% group by using a linear model controlled by several confounders (Table 3). In the final linear mixed model with an early weight gain > 5% as predictor, it was confirmed that this threshold was a significant predictor of long-term weight gain over 1 year of treatment (difference between groups in 1 year [Î²] of 6.4% weight gain as compared to baseline, Padjusted = .0001). This predictor was also found significant for a stronger long-term weight gain in young patients (aged ≤ 25 years) (Î² = 8.7%, Padjusted < .0001), young adults (aged 25-45 years) (Î² = 7.3%, Padjusted = .0001), adults (aged 45-65 years) (Î² = 7.4%, Padjusted = .005), and elderly patients (aged > 65 years) (Î² = 13.6%, Padjusted < .01). This predictor was also found significant in patients with psychotic or schizoaffective disorder (Î² = 7.0%, Padjusted < .0001), bipolar disorder or depression (Î² = 9.1%, Padjusted = .0006), and in the other diagnoses (Î² = 11.6%, Padjusted < .01). Significant results were also observed in patients treated with amisulpride or aripiprazole (Î² = 6.6%, Padjusted = .003); mirtazapine, lithium, quetiapine, or risperidone (Î² = 8.4%, Padjusted < .0001); and finally with clozapine, olanzapine, or valproate (Î² = 7.4%, Padjusted < 0.0001) (Supplementary eTable 7).
Effect of Changes in Appetite and Physical Activity During Treatment
Calculations were also made to assess the predictive power value of moderate or high (≥ 30 min/d) physical activity and of an appetite increase during the first month of treatment on long-term weight gain (Supplementary eTables 8 and 9). The AUC value indicated no predictive power for either parameter (AUC â‰ˆ 50).
Confirming previous studies in psychiatric patients,19,20 our study found a high prevalence of overweight status or obesity (39%) in the present cohort at baseline, which even increased after 1 year of treatment (50%). Notably, a higher (68%) prevalence of overweight status or obesity was measured in another Swiss cohort,20 which is probably explained by the longer treatment duration in the latter cohort (median = 2.3 years vs mean = 0.65 years). The increase of mean BMI after 1 year of treatment was dependent on age (decreasing with increasing age), which is in agreement with previous studies showing that being of young age is a risk factor for a stronger increase in BMI.21 Although weight gain in elderly patients is subject to controversial results,22,23 in the present study a moderate mean gain of 1 BMI unit was observed after 1 year in this age group, which is in agreement with the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATI-AD) study23 conclusion supporting the importance of metabolic monitoring also in elderly patients. Because of the small cohort size after stratification by the type of drugs prescribed, the frequent polymedication, and the previous history of past medications, it was not possible to differentiate the effects of each psychotropic drug separately.
An early weight gain of more than 5% was found to be the best predictor for a weight gain of ≥ 15% after 3 months and of ≥ 20% after 1 year. Of note, AUC values have also been calculated for the previously published threshold of 2 kg after 1 month.9-11 Similar results to the present analysis in terms of AUC values were found (data not shown). Because an absolute threshold expressed in kilograms does not take into account the large variability of baseline weight, a relative threshold expressed in percentage as presented in this study appears to be more relevant. The high negative predictive value indicates that this measure will correctly predict the future status of most patients (97% for 3 months, 93% for 12 months) who had a weight gain less than or equal to 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months, respectively. Over 1 year, these patients had a mean BMI increase of 1.2 kg/m2, which is significantly lower than the 3.1-kg/m2 increase observed in the high early weight-gain group. The low positive predictive value indicates that 71% and 70% of patients with an early weight gain > 5% will not reach the 15% and 20% threshold at 3 and 12 months. Although weight gain in this false-positive group at 3 months is still significantly higher than in the low weight-gain group, the difference was no longer significant at 12 months, indicating the necessity of long-term weight monitoring also in the group with low initial weight gain. Monitoring of metabolic parameters is performed in our department with advice to take into account significant changes of parameters by different means (discussion with the patients, diet and physical activity counseling, drug evaluation and changes). Because such possible interventions were not collected in this post hoc noninterventional study, it is not known if they could have contributed to part of the false-positive results.
These predictive parameters are in agreement and complete previous results obtained from clinical trials.9,10,24 Female gender, young age, low baseline BMI, and low triglyceride levels were proposed to predict antipsychotic-induced weight gain.3,20,25,26 In the present study, only BMI was found to be significantly different between both groups, being lower in the early weight-gain group at baseline. However, triglyceride values increased and HDL cholesterol values decreased with higher amplitude over 1 year, showing that these parameters are worsening faster in the early high weight-gain group, paralleling the faster increase of BMIs.
The threshold of more than 5% in the early phase of the treatment remained significant (Î² = 6.4%, Padjusted = .0001), even after adjusting for several confounders. These results indicate the robustness of this predictor and should motivate clinicians to monitor early weight changes more thoroughly for all patients and not only patients with known risk factors (ie, young patients, drug naive, and other factors). Although not formally demonstrated in the present study, the threshold of more than 5% weight gain after 1 month of treatment may also be used to detect some patients who could reach this threshold in a shorter period of time. Thus, very rapid and important weight gain should be evaluated by the treating physician and nurses independently of the usual time schedules for weight monitoring.
No significant influence of prescribed antipsychotics was found in the confirmatory analysis. This is in agreement with a previous study showing that an early weight gain of 2 kg is a good predictor for more weight gain during 24- to 28-week treatment with olanzapine and aripiprazole, 2 drugs with important differences in their potential to induce weight gain.9 These results suggest that, independently of the prescribed drugs (ie, atypical antipsychotics, mood stabilizers such as lithium or valproate, or sedative antidepressants such as mirtazapine), the 5% threshold should be used when monitoring weight gain during treatment.
To our knowledge, only 1 study27 previously investigated the role of appetite on long-term weight change, concluding that early weight gain was found to be a better predictor for further weight gain than appetite increase, which is in agreement with the present study. In addition, medium or high physical activity was also a poor predictor. However, the present results do not preclude the use of health promotion intervention, including physical activity or behavioral interventions that have shown some effect in psychiatric populations.28
Several limitations of the present study have to be mentioned. First, the majority of patients were not drug naive, and the observed weight gain was probably also the result of past treatments. However, such patients constitute the majority of psychiatric populations, which therefore might even strengthen the clinical validity of the present finding. Second, the follow-up period lasted only 1 year, but previous studies,29,30 as well as the present study, show that following drug introduction, most of the weight gain occurs during this period. Third, due to an insufficient number of observations, we could not determine an early weight-gain threshold specifically in young and elderly patients. However, the 5% threshold was significantly associated with important weight gain in these 2 age classes. Finally, the results concerning activity and appetite change have to be interpreted with caution because the evaluation was self-reported, used a nonvalidated scale, and may be not sensitive enough.
A strength of the present study is its longitudinal design with weight monitoring at regular time points during 1 year when patients started a weight-inducing psychotropic drug or switched the treatment. In addition, the use of therapeutic drug monitoring allowed us to assess the compliance of the patients, which is an important issue in psychiatric treatment.
In conclusion, this work underlines the importance of weight monitoring at the introduction and after a switch of antipsychotic drugs, mood stabilizers, or sedative antidepressants for all patients, independently of their gender, age, initial body weight, previous treatments, or illness duration. A weight gain of more than 5% during the first month of treatment should be used by the clinician as one of the early warning signs to consider those patients as being at higher risk of important weight gain during long-term treatment. A particular emphasis should be put on such patients by using all available strategies (ie, behavioral interventions or even replacing the causative weight gain-inducing drug if clinically possible, after a careful evaluation of the risk-benefit ratio of a drug switch), considering the major impact weight gain and its consequences have on quality of life and general health of patients.
Submitted: July 3, 2014; accepted November 11, 2014.
Drug names: aripiprazole (Abilify and others), clozapine (Clozaril, FazaClo, and others), lithium (Lithobid and others), mirtazapine (Remeron and others), olanzapine (Zyprexa and others), quetiapine (Seroquel and others), risperidone (Risperdal and others), ziprasidone (Geodon and others).
Author contributions: Drs Vandenberghe and Gholam-Rezaee contributed equally to the work. Dr Eap had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design was provided by Dr Eap. Acquisition of data was provided by Drs Vandenberghe, Saig×-Morgui, Choong, Solida-Tozzi, Kolly, Gallo, Thonney, Hedjal, Ambresin, von Gunten, and Conus and Ms Delacrétaz. Analysis and interpretation was provided by Drs Vandenberghe and Gholam-Rezaee. Drafting of the manuscript was provided by Drs Vandenberghe and Gholam-Rezaee. Critical revision of the manuscript for important intellectual content was provided by all authors. Statistical analysis was provided by Drs Gholam-Rezaee and Vandenberghe. Drs Eap and Conus obtained funding for the study. Administrative, technical, or material support was provided by Drs von Gunten, Ambresin, and Conus.
Potential conflicts of interest: Dr Eap received research support from Takeda and from the Roche Organ Transplantation Research Foundation (#152358701) in the previous 3 years. He received honoraria for conferences or teaching CME courses from Advisis, AstraZeneca, Essex Chemie, Lundbeck, Merck Sharp & Dohme, Sandoz, Servier, and Vifor-Pharma in the previous 3 years. Dr von Gunten received honoraria for a conference or a workshop participation from Vifor, Bayer Schering, and Schwabe in the previous 3 years. Drs Vanderberghe, Gholam-Rezaee, Saig×-Morgui, Choong, Solida-Tozzi, Kolly, Thonney, Gallo, Hedjal, Ambresin, and Conus and Ms Delacrétaz declare no conflict of interest in relation to the content of the article.
Funding/support: This work has been funded in part by the Swiss National Research Foundation (CBE and PC: 320030-120686 and 324730-144064).
Role of the sponsor: The funding sources had no role in the writing of the manuscript or in the decision to submit it for publication.
Previous presentation: Previously presented in part at the 22nd Annual European Congress of Psychiatry; March 1-4, 2014; Munich, Germany ▪ 168th Annual Meeting of the American Psychiatric Association; May 16-20, 2015; Toronto, Canada.
Acknowledgment: The authors are grateful to all participating psychiatrists and medical staff who were involved in the metabolic monitoring program.
Additional information: The original dataset is in possession of Dr Eap.
Supplementary material: See accompanying pages, which includes eTable 10 about comedication possibly inducing weight gain and additional eReferences.
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