Introduction
Antipsychotic-induced weight gain has been recognized as a major health concern in children and adolescents [
1]. Although the magnitude of weight gain differs across type of antipsychotics and individuals, on average, 1 in 7 minors gains 7% or more weight within the first 6–8 weeks of treatment [
2]. This is not only highly stigmatizing, but also involves serious long-term health risks. Weight gain is associated with glucose and lipid abnormalities, thereby increasing the risk for diabetes and cardiovascular morbidity in children and adolescents using antipsychotics [
3,
4]. It has been suggested that this leads to higher rates of unexpected death in this population, even at young age [
5].
The observed weight gain in youths starting antipsychotic treatment is highly heterogeneous, with some youths gaining a lot of weight, while others do not [
6]. This heterogeneity suggests that certain patient-related factors underlie the risk for antipsychotic-induced weight gain. The identification of these risk factors is an important target in the prevention of obesity, as it can facilitate early recognition and interventions for children and adolescents at risk. Such interventions can include both behavioural and pharmacological interventions, which are proven to be effective at least to some extent in the management of antipsychotic-related weight gain in this population [
6,
7].
To date, literature is inconclusive about which children and adolescents are particularly at risk for weight gain during antipsychotic treatment. While it has been suggested that girls are at higher risk than boys [
4], other studies have found the opposite [
8], or did not find an influence of gender at all [
9]. Likewise, some studies showed that a young age is associated with more weight gain [
10,
11], while others found older age increases the risk for obesity [
4]. Data on clinical predictors are generally limited, although several studies found that a low baseline body mass index (BMI) is associated with more weight gain [
8,
12], and the concomitant use of stimulants would not be of significant influence [
12,
13].
It can be hypothesized that, amongst other factors, different follow-up durations might have contributed to these mixed findings. Weight gain in children and adolescents has been reported to be most pronounced during the first weeks of antipsychotic use and to stabilize during continued treatment, although long-term data are limited [
14,
15]. In these different phases of weight acceleration, several mechanisms that are involved in antipsychotic-related weight gain are likely to contribute differently. Although these mechanisms are only poorly understood, several neurotransmitter and endocrine systems, such as serotonergic, dopaminergic and histaminergic receptors and leptin, have been implicated [
16,
17]. As different patient-related factors, such as sex or comedication, might influence these mechanisms individually, the influence of risk factors might be time-dependent as well.
Therefore, the aim of this study is to describe risk factors for weight gain in children and adolescents using antipsychotic drugs with a short-, middle- and long-term duration of use.
Discussion
We found that antipsychotic-induced weight gain in children and adolescents was most pronounced during the first 15 weeks of use. A higher baseline BMI z score predicted a higher BMI z score during follow-up, while the use of stimulants was associated with lower BMI z scores after 15 weeks. Previous antipsychotic treatment was associated with less weight gain during the first 15 weeks of treatment.
Although significant weight gain in children and adolescents on antipsychotic treatment has been widely recognised, the time course of this weight gain is only poorly documented [
2]. A previous study has found that BMI
z score gain is most pronounced during the first month of treatment, while in our cohort, a longer period of accelerated weight gain of almost 4 months was found [
14]. Furthermore, although long-term data are generally lacking, several studies have described a slight decrease in BMI
z score after 6 months [
9,
14]. This plateauing was also observed in our study, but considerably later. Despite this, the BMI
z score generally does not return to the baseline value during long-term antipsychotic use. Limited data, however, have shown that after antipsychotic discontinuation, baseline BMI
z score values might recover [
24].
The mechanisms behind this course of antipsychotic-induced weight gain in youths are complex and only partly understood. Both increased appetite, increased food intake and an altered metabolism contribute to an imbalance between energy intake and energy expenditure, regulated by both neurotransmitter systems and hormonal changes. Within the neurotransmitter systems, the interaction of antipsychotic drugs with both dopamine, histamine and serotonin receptors has been suggested to moderate weight gain [
17]. These neurotransmitter–receptor interactions are expected to happen directly, as neurotransmitter-induced side effects like extrapyramidal symptoms and sedation can arise in several hours after initiation of antipsychotic treatment. As such, the weight-moderating effect too might start immediately. Conversely, the effects of dysregulation of the hormonal system are likely to take longer. Antipsychotic drugs affect leptin, also known as the satiety hormone [
16,
17]. As this hormone is secreted by adipose tissue, the effects on appetite might only become apparent after an increase in adipocytes, and thus might need more time. Although both mechanisms are likely to reach a new homeostasis after a while, the different time courses of the induction of these two mechanisms might partly explain the non-linear development of weight gain in children and adolescents using antipsychotics. Nevertheless, numerous other mechanisms, including gene–environment interactions and neuropeptides, play a role and have not yet been clarified, especially in children and adolescents.
This study found that patients with higher BMI
z score at baseline also had higher BMI
z scores during antipsychotic treatment. However, the interaction with time suggests a faster increase in bodyweight during the first 15 weeks of treatment in children with lower bodyweight. This resembles the findings from previous, mostly short-term studies, identifying lower baseline BMI as risk factor for weight gain in children and adolescents using antipsychotics [
8,
11,
12]. Nevertheless, this effect can be overestimated by the phenomenon of ‘regression to the mean’, indicating that extreme BMI values are naturally expected to grow closer to the population mean during follow-up [
25]. Also, a low baseline BMI as predictor is easily confounded by stage of illness, as younger and, thus, lighter children are likely to have less prior antipsychotic exposure [
16]. These children may gain more weight, as was found in our study.
Regardless of the change in weight, the finding that overweight children and adolescents are likely to remain overweight during antipsychotic treatment has important implications. Apart from the evident risk of lipid and glucose disturbances with obesity, an additional, distinct mechanism inducing metabolic abnormalities independently of weight gain is suggested for antipsychotic drugs [
17]. This results in an increased prevalence of metabolic abnormalities in overweight children using antipsychotics [
12], which calls for a close monitoring of overweight children at start of antipsychotic treatment. However, not all monitoring guidelines for children and adolescents on antipsychotic treatment provide such a standardized intensified monitoring schedule for overweight children [
1].
Most antipsychotic-induced side effects monitoring guidelines, developed as a result of the growing awareness of cardiometabolic adverse effects of antipsychotic drugs in children and adolescents, recommend a first visit at 3 months after start [
1,
26]. Given our findings that the most accelerated weight gain occurs in the first 15 weeks, it should be considered to bring this visit forward to 1 month after start of treatment. It has been shown previously that the weight gain at 1 month is predictive of problematic weight gain after 3 months in adolescents using antipsychotics, further confirming the added value of an early monitoring visit [
27]. In addition, bodyweight controlling strategies are expected to be most beneficial when offered at an early stage, as childhood obesity is likely to persist in adulthood [
28].
Stimulant use was associated with lower BMI
z scores from 15 weeks of follow-up. It is well-known that decreased appetite is a common side effect of stimulants [
29], thereby often leading to weight loss in children using this type of drugs. It seems obvious that concomitant stimulant use can attenuate antipsychotic-induced weight gain, although this has not been consistently demonstrated in previous studies [
12,
13]. Possibly, children in our study received higher dosages of stimulant drugs, but this could not be analysed. However, although concomitant stimulant use can possibly lower weight gain in children and adolescents using antipsychotic drugs, the risk for adverse cardiovascular adverse events remains unclear. While stimulants have been associated with an increased blood pressure and heart rate, and antipsychotics with cardiac arrhythmias, little is known about the combined cardiac risks in children and adolescents [
30,
31].
Children receiving a higher dose equivalent experienced more weight gain during the first weeks of use, although this finding did not remain significant in combination with other variables. A higher dosage has been described previously as a risk factor for short-term weight gain in children and adolescents using risperidone, although findings in adults have been conflicting [
10,
32,
33]. Furthermore, in this study, no difference in weight-inducing potency between different types of antipsychotic drugs was found. In randomized controlled settings, however, these differences have been clearly shown, with risperidone inducing more weight gain than aripiprazole [
34]. Although the relative weight-inducing properties of pipamperone have only been limitedly described, it is likely that this antipsychotic also contributes significantly to weight gain due to its strong anti-serotonergic properties. The differences between antipsychotics can diminish in an observational settings with limited sample sized like this study, as heavier children are more likely to start treatment with antipsychotics that are associated with less weight gain, such as aripiprazole. Similarly, another relatively small retrospective study performed in Dutch children and adolescents did not show a difference in weight gain between children using risperidone or aripiprazole, while based on the literature this could have been expected [
9].
The results of this study should be interpreted in the light of its limitations. First, due to the merely retrospective design, no causal relationship between patient-related factors and BMI z score gain could be established. Also, data were collected in a real-life, clinical setting, thereby allowing changes in antipsychotic regimens upon the physician’s discretion or patient preferences. This might have influenced the results, as dosages could be lowered or the antipsychotic drug could be stopped when a child gained too much weight or had other side effects. Moreover, drug adherence was not analysed. Lastly, the sample size of this study was relatively small and only a limited proportion of patients could be followed for several years, thereby possibly missing risk factors with a low-effect size.
However, this is the first study that describes risk factors for antipsychotic-induced weight gain in children and adolescents by distinguishing between short-, middle-, and long-term uses. Also, the follow-up duration in our cohort was considerably longer than in previous studies. Using advanced mixed-modelling techniques, we could use all weight assessments instead of only studying endpoint differences, which is especially important as weight gain was non-linear. The findings of this study can guide further, targeted monitoring of children at risk for antipsychotic-induced weight gain, thereby increasing safety of antipsychotic use in the young.