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. 2019 Jul 14;67(3):159–167. doi: 10.1080/20473869.2019.1638583

Second generation antipsychotic-induced weight gain in youth with autism spectrum disorders: a brief review of mechanisms, monitoring practices, and indicated treatments

Jeffrey Goltz 1,✉, Iliyan Ivanov 2, Timothy R Rice 2
PMCID: PMC8211136  PMID: 34188897

Abstract

The purpose of this review was to understand the impact of second generation antipsychotic (SGA)-induced weight gain on youth with autism spectrum disorders (ASDs), including the clinical evidence, mechanisms, monitoring guidelines, and treatments. To achieve this, multiple MEDLINE/PUBMED and Google database searches were performed and analyzed articles from January 2001 to April 2018. Existing evidences indicates youth with ASDs may be more prone to SGA-induced weight gain than youth with other psychiatric illnesses. The mechanism by which such weight gain occurs is unclear, but is likely multifactorial. Guidelines have been developed to monitor SGA-induced weight gain, though the existing guidelines have had limited adherence by clinicians. The available randomized control trials that have analyzed the benefit of metformin in youth suffering from SGA-induced weight gain have produced conflicting results, but the data looking specifically at youth with ASD have been positive. Increasing data on use of topiramate, melatonin, and zonisamide to treat SGA-induced weight gain in youth also exists and warrants further study. However, overall, the current understanding of the effect of SGA-induced weight gain on youth with ASD and the therapeutic use of medications like metformin is limited, but the existing literature provides useful guidelines for future research. The clinical algorithms for monitoring and managing SGA-induced weight gain have shown promise; however, their utility in routine clinical practice requires further investigation.

Keywords: second generation antipsychotic, youth, metformin, autism spectrum disorder, weight

Introduction

Second generation antipsychotics (SGAs) are increasingly used to treat aggressive behavior, self-injurious behavior, and irritability in youth with autism spectrum disorders (ASD) (Park 2016). However, both established and emerging evidence show that treatment with SGAs is associated with very significant weight gain (Maayan and Correll 2011). Youth are more vulnerable to the known metabolic adverse effects of SGAs than adult populations, including weight gain (Maayan and Correll 2011, Correll 2005, Martinez-Ortega et al. 2013). The increased rate of SGA prescriptions exacerbates the childhood obesity epidemic, creating longitudinal lasting detriments upon adult physical and mental health (Bean et al. 2008, Swallen et al. 2005). Accordingly, recommendations for baseline assessments, follow-up, and monitoring of weight and other metabolic measurements in general adult populations have been developed (American Diabetes Association et al. 2004). However, the presence of psychiatric disorders will affect issues of adherence and administration, capability to engage in psychosocial programming for exercise and nutritional counseling, and others. This is especially the case in youth populations where developmental disabilities, such as ASD, are present. Deviations from the parameters from which the guidelines for adult populations were created may be significant. This deviation may be very pronounced in youth populations with ASDs, where barriers including nonverbal status, poor social awareness of weight gain and obesity, and other factors will effect this population. Despite the reasons to believe that this population may be unique, there appears to be limited attention to the specific risks these medications have on youth with ASDs. This is concerning, as a recent study found that 13% of SGA prescriptions in children are for a primary diagnosis of developmental disorder, which is greater than the rate at which SGAs are given to children with bipolar disorders or schizophrenia (Olfson et al. 2012), and the presence of an ASD may be an independent risk factor in vulnerability to weight gain induced by SGAs (De Hert et al. 2011).

Hence, the purpose of this article is to discuss the known evidence of SGA-induced weight gain in youth with ASDs. We will review the proposed mechanisms of weight gain, clinical findings of SGA-induced weight gain in individuals with ASD, monitoring guidelines, and the evidence-based treatments for such weight gain in youth. We will discuss the use of metformin in this population as a possible beneficial intervention, as these individuals are often burdened with symptoms, family system needs, and service system structural deficits that impair the efficacy of some alternate interventions with efficacy in normotypically developing populations.

Method

Multiple searches from the National Library of Medicine (MEDLINE/Pubmed) and Google database were performed that included a combination of the following terms: antipsychotic, second generation, weight gain, treatment, metformin, autism, children, adolescents, topiramate, melatonin, and youth. The searches yielded articles from January 2001 to April 2018. Articles were selected based on their applicability to the topics under investigation. Articles reviewed included case reports, retrospective and prospective, uncontrolled trials, randomized controlled trials, systematic reviews, and meta-analyses. The information was synthesized, and integrated into our summary of the existing literature.

Results

SGA-induced weight gain: mechanisms

Despite the vast evidence supporting the notion of SGA-induced weight gain, the exact means by which this occurs remains currently unknown (Maayan and Correll 2010). Multiple mechanisms have been proposed regarding the various ways in which SGAs induce weight gain. There are substantial data to suggest that increased caloric intake contributes to SGA-induced weight gain in both adults and children (Roerig et al. 2011). A variety of theories have been suggested to explain this phenomenon. For example, the histamine H1 receptor in the hypothalamus, in particular the ventromedial hypothalamic (VMH) and paraventricular nuclei, are believed to play a role in appetite regulation. Evidence to support this notion includes a study performed by Magrani et al. (2004) where rats administered an H1 antagonist into the VMH demonstrated increased food and water intake, while H1 antagonists administered around the surrounding area produced no such effect. In addition, in human studies, a correlation has been demonstrated between increased H1 receptor affinity and weight gain (Kroeze et al. 2003).

Additional research has looked into the role of the serotonin 5HT-2A and 2C receptors. Multiple mice studies have been performed demonstrating that 5HT-2A antagonism has been linked to reduced satiety (Roerig et al. 2011). Human studies demonstrate that 5HT-2A antagonism reduces insulin receptor sensitivity (Giles et al. 2005). In regard to the 5HT-2C receptor, Hewitt et al. (2002) demonstrated that the use of 5HT-2C agonists in mice yielded decreased food intake. Other studies have demonstrated that knock-out 5HT-2C mice show resistance to the satiety effects of d-fenfluramine, a serotonin augmenting agent (Vickers et al. 1999).

Multiple other receptors, including muscarinic, dopamine D2, and adrenergic receptors, as well as receptors of peptides including leptin and ghrelin receptors have been studied (Roerig et al. 2011). Various genetic polymorphisms have been studied (Roerig et al. 2011). Some select variants show correlations with weight gain (Roerig et al. 2011).

Recent research has also looked at the effect of antipsychotics on the gastrointestinal tract’s microbiota profile and how this can influence SGA-induced weight gain (Skonieczna-Zydecka et al. 2018). For example, use of olanzapine in rats has been noted to increase the amount of intestinal Firmicutes and decrease Bacteroidetes, a microbiotic profile that has been found to be present in obesity (Davey et al. 2012, Skonieczna-Zydecka et al. 2018). A separate study noted a similar change in microbiome with use of risperidone in youth and also noted elevations in Clostridium, Lactobacillius, Ralstonia, and Erysipelotrichaceae family members in youth who had significant BMI increases while taking risperidone (Bahr et al. 2015). Such purported changes in gastrointestinal microbiota could be significant, as these microbiota are involved with nutrient breakdown and antipsychotic metabolism and alterations in those processes can potentially contribute to weight gain (Bahr et al. 2015).

Thus, the mechanism of SGA-induced weight gain likely involves multiple different neurotransmitters, receptors, and various substances and systems in the body. Additional research is needed to develop a more comprehensive theory and one which can clearly delineate the relative contributions and interactions of these various mechanisms. Future studies may explore any mechanisms specific to individuals with ASD.

SGA-induced weight gain: clinical data in youth with ASD

Aripiprazole and risperidone are the two SGAs approved for the treatment of irritability in ASD and are the most frequently used in these populations, often with weight gain considerations in mind. Still, both are problematic for youth in relation to metabolic risks. Multiple randomized controlled trials (RCTs) have demonstrated their efficacy in the treatment of irritability (Owen et al. 2009, Ichikawa et al. 2017, Marcus et al. 2009, McCracken et al. 2002) and, in light of this evidence, these metabolic concerns are highly relevant and in need of further delineation. Other SGAs remain less well studied: only one other RCT has been performed with a different SGA, olanzapine (Parikh et al. 2008, Kirino 2014).

Multiple trials demonstrate that SGAs are associated with a significantly greater increase in weight over placebo when treating irritability in youth with ASD. Most of these studies examine only risperidone or aripiprazole in relation to placebo (Owen et al. 2009, Shea et al. 2004, Hellings et al. 2001). To our knowledge, only two studies explore SGA-induced weight gain in individuals with ASD (Wink et al. 2014, Yoon et al. 2016).

Wink et al. (2014) performed a retrospective review comparing rates of weight gain of aripiprazole versus risperidone in youth with ASD ages 2–20 years in an outpatient treatment center. Results demonstrated no significant difference in rates of weight gain between the two SGAs. However, these results must be interpreted with caution, given the small sample size, lack of control group, and differences in prescribing practices among the various practitioners whose patients were analyzed.

Similar to Wink et al., Yoon et al. (2016) performed a retrospective analysis looking at 202 individuals with ASD aged 2.92–19.45 years who were treated with either olanzapine, aripiprazole, risperidone, quetiapine, and ziprasidone. The mean duration of treatment was 1.22 years. Changes in BMI (body mass index) z-score were evaluated. Olanzapine, aripiprazole, and risperidone showed a statistically significant increase in BMI z-score of 0.96 (CI 0.25–1.66), 0.19 (CI 0.00–0.38), and 0.35 (CI 0.03–0.68), respectively, whereas no significant increase was found with use of quetiapine and ziprasidone. Comparatively, olanzapine demonstrated a greater BMI z-score change than aripiprazole (0.39; CI 0.08–0.70) and risperidone (0.43; CI 0.12–0.74), as well as the other SGAs. No significant difference in BMI z-score was noted between aripiprazole and risperidone, similar to Wink et al.

These results too must be considered in the context of the studies’ weaknesses. For example, it was noted that there were fewer patients in the olanzapine group, comparatively, and olanzapine was generally prescribed to patients with a lower BMI z-score at baseline. Also, a difference in which SGA was prescribed based on age (risperidone was generally given to the younger age groups, whereas ziprasidone was more frequently given to the older age group) is a potential confounder. In addition, there was a lack of a control group and a lack of control for dosage in this retrospective study.

The findings from Yoon et al. and Wink et al. are nonetheless significant, as they contradict reviews analyzing the results of SGA-induced weight gain in other psychiatric conditions. In those studies, distinctions were noted among SGAs, including risperidone and aripiprazole (Maayan and Correll 2011). In addition, in a systematic review by De Hert et al. (2011), it was demonstrated that there was no difference between aripiprazole and placebo when analyzing data only from youth with schizophrenia or bipolar disorder (NNH 3.9; CI 0.2–5.4). When including data from youth with ASD, the result became significantly different (NNH 12; CI 8.3–16.8), which may suggest that youth with ASD may be more prone to weight gain on SGAs. We may hypothesize that many variables specific to youth with ASDs may mediate these sensitives, including more difficulties in controlling access to food related to various deficiencies in emotion regulation, communication, family system structures, and access to care.

The data presented suggests that youth with ASD may respond differently and may be more prone to weight gain from SGAs than youth with other mental illnesses, but the data to support this conclusion are sparse. Additional research comparing SGA weight gain among individuals of differing mental illnesses, especially ASD, is needed. Further studies would better clarify the differences between rates of weight gain amongst SGAs for youth of varying mental illnesses. These studies would significantly aid clinicians in treatment selection.

SGA-induced weight gain: monitoring

Monitoring the metabolic side effects of SGAs, including weight, is essential for recognizing the need to intervene. The most widely accepted guidelines are for adult populations and were published in 2004 by multiple medical associations, including the American Diabetic Association (ADA) and the American Psychiatric Association (American Diabetes Association et al. 2004, Maayan and Correll 2010). They recommend baseline weight gain monitoring followed by routine monitoring at 4, 8, and 12 weeks after starting or changing an SGA, followed by every 3 months thereafter. These guidelines also recommend considering switching the prescribed SGA if weight gain is more than 5% of a patient’s baseline. Correll & Carlson (2006) recommend even more stringent guidelines. For example, their work suggests that a measurement of height and weight is indicated at each office visit and also recommend follow up fasting blood work at three months from time of initiation and every six months thereafter. For additional details regarding these guidelines, see Table 1.

TABLE 1.

Guidelines for monitoring metabolic side effects in SGAs

Measurement ADA et al, 2004 Correll & Carlson, 2006
Baseline (prior to initiation of SGA) Height/Weight for BMI, Waist circumference, blood pressure, fasting plasma glucose, fasting lipid profile Height, weight, blood pressure, pulse, fasting blood work (full blood count with differential, serum electrolytes, glucose, lipids, liver and kidney function, thyroid-stimulating hormone), Prolactin
Follow Up-Assessments (all measurements can be done with increased frequency if clinically necessary) (all measurements can be done with increased frequency if clinically necessary)
Height, Weight At 4 weeks, 8 weeks, 12 weeks, every 3 months At each visit
Blood pressure, pulse At 12 weeks, annually thereafter Every 3 months
Fasting blood work Fasting glucose- at 12 weeks and annually thereafter. Fasting lipids- At 12 weeks and every 5 years thereafter At 3 months and then every 6 months
Prolactin No recommendations Only when symptomatic
Thyroid-stimulating hormone No recommendations At 1, 3, and 6 months from time of initiation. Annually, thereafter. (only if started on quetiapine)
Serum Calcium No recommendations At 1 months, 6 months, and annually thereafter
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BMI = Body mass idex.

Despite these guidelines, clinician’s adherence to them has been limited, especially in youth (Maayan and Correll 2010, Barnes et al. 2007, Morrato et al. 2010). Furthermore, when metabolic data exists, it may not influence clinician’s treatment decisions (Maayan and Correll 2010, Morrato et al. 2009). The development of improved treatment guidelines that enhance adherence and influence treatment decisions are needed to help guide the management of SGA side effects. Our review intends to promote that development.

SGA-induced weight gain: treatment in youth

As has been stated, SGA-induced weight gain leads to multiple medical comorbidities, is correlated with the development of a variety of psychiatric conditions, and is a known factor for antipsychotic discontinuation (Lieberman et al. 2005). For these and other reasons, means to limit weight gain are under active investigation. Lifestyle interventions have evidence showing efficacy in reducing rates of obesity (Caemmerer et al. 2012), but their utility may be limited. Many mental illnesses reduce compliance rates to these psychosocial programs (Klein et al. 2006). In addition, the only trial to make a direct comparison between lifestyle and pharmacologic interventions to treat antipsychotic weight gain demonstrated that pharmacologic approaches were superior to lifestyle changes (Wu et al. 2008).

In this setting, when we recognize the limitations of non-pharmacological interventions in youth, certain medications have been utilized to treat SGA-induced weight gain with great effect (Maayan and Correll 2010). To our knowledge, metformin is the best medicine studied in youth RCTs for the treatment of SGA-induced weight gain (Klein et al. 2006, Arman et al. 2008, Anagnostou et al. 2016, Goltz and Rice 2017). However, there remains to exist a valuable consensus regarding the role of metformin in attenuating youth weight gain while on SGAs (Mclellan et al. 2013). In the remainder of our current piece, we will discuss the existing evidence of the treatment of SGA-induced weight gain with metformin in youth and discuss the existing evidence of its use in youth with ASD.

SGA-induced weight gain: treatment with metformin in youth

In youth populations, several case reports, one retrospective review, and three uncontrolled trials have analyzed metformin’s efficacy for treating SGA-induced weight gain (Salau et al. 2015, Morrison et al. 2002, Weaver et al. 2010, Shin et al. 2009, Wink et al. 2017, Handen et al. 2017). Results have been mixed in the uncontrolled trials (Morrison et al. 2002, Shin et al. 2009, Handen et al. 2017), while the case reports and retrospective review detail a relatively small/modest benefit for metformin use, one of which investigated its use in ASD (Salau et al. 2015, Weaver et al. 2010, Wink et al. 2017).

To date, only three RCTs have been performed analyzing the efficacy of metformin for treating SGA-induced weight gain, one of which investigated its use in ASD. Klein et al. (2006) performed the first RCT analyzing the use of metformin for treating SGA-induced weight gain over a 16-week period. This study included 39 youth who were prescribed quetiapine, risperidone, or olanzapine. Participants were aged 10–17 and had a variety of psychiatric diagnoses. Participants were then treated with a lifestyle intervention by a registered dietician and given either metformin or placebo. The rate of weight gain was 0.31 kg/week (SD = 0.44) in the placebo group, corresponding to a BMI increase of 1.12 (SD 2.02). In the metformin group, weight gain was −0.03 kg/week (SD = 0.33), corresponding to a BMI decrease of 0.43 (SD = 1.07). After correcting for age-related changes, in the placebo group, the z-score for weight increased by 0.10 (SD = 0.29), but decreased by 0.14 (SD = 0.21), in the metformin group. These results obtained statistical significance. There was no difference in adverse events between groups.

Arman et al. (2008) conducted the second RCT. They conducted a 12-week study on 32 youth <20 years old who were diagnosed with schizophrenia and were being started on Risperdal (with doses ranging from 2 to 6 mg). Subjects were randomized to receive either metformin or placebo. The mean weight change between the beginning of the study and week 12 was 0.81 kg (SD = 0.33) in the metformin group and 2.2 kg (SD = 2.54) in the placebo group, a result indicating no statistical difference. A similar result was found for height and BMI changes. The main side effects of metformin in this trial were nausea, bloating, vomiting, diarrhea, and enuresis.

SGA-induced weight gain: treatment with metformin in youth with ASD

To date, only three known studies, including the third RCT of metformin’s use in youth with SGA-induced weight gain, have investigated the use of metformin in ASD (Klein et al. 2006, Arman et al. 2008, Anagnostou et al. 2016). In a retrospective review, Wink et al. (2017) investigated metformin’s use for the treatment of SGA induced weight gain. They analyzed data from 53 individuals with ASD ranges from ages 2 to 20 years of age. All individuals had been on an antipsychotic and treated with metformin, as their provider thought that their weight gain and/or increased appetite was due to their treatment. They obtained data on these individuals for an average of 2 years while on metformin treatment. The mean initial Z-BMI of participants was 1.86 (SD 0.6) and the final Z-BMI was 1.81 (SD 0.7), suggesting a stabilization of weight over time.

The RCT by Anagnostou et al. (2016) randomized 61 youth with ASD ages 6–17. All youth were on an SGA for at least one month (participants were on risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, or iloperidone), on a stable dose with no plans to change, and had a 7% or more increase in BMI within the last 12 months, or more than 5% if their baseline BMI was in the 85th percentile. On the metformin arm, youth ages 6–9 were placed on a metformin titration schedule ending at metformin 500 mg PO BID and youth ages 10–17 were titrated to a dose of 850 mg PO BID. The other group received placebo. Youth were observed over the course of 16 weeks and the primary outcome was a change in BMI z scores. Metformin was found to be superior to placebo in decreasing BMI z scores, with youth taking metformin experiencing a BMI z-score decrease of −0.08 (CI −0.13 to −0.04). Youth taking placebo showed no significant change in BMI z-scores (0.02, CI −0.03 to 0.06). Weight changes were also noted where, on average, youth taking metformin lost 2.7 kg more. However, the benefit of metformin was not seen until 8 weeks into the trial. The only statistically significant different side effect between metformin and placebo was abnormal feces, where individuals taking metformin reported a greater incidence than individuals taking placebo. Also, individuals taking metformin experienced gastrointestinal side effects on more days than individuals taking placebo.

In a 16-week open label extension of this trial, Handen et al. (2017) reported the results of youth receiving ongoing treatment with metformin and the results of youth switched from placebo to metformin. Metformin was retitrated for all youth using the same dosing strategy as the corresponding RCT. The primary outcome measured was change in BMI z-score. Fifty-two youth from the RCT participated (22 from the metformin group and 30 from the placebo group). In youth who took metformin in the RCT, there was no significant change in BMI z-score (0.03, CI −0.04 to 0.09) at the end of this trial from their BMIs at the end of the RCT. However, there was a significant change in youth who had been taking placebo when compared with their BMIs at the end of the RCT (−0.07, CI- −0.12 to −0.02). The authors report that individuals who took metformin in the RCT showed no statistically significant differences in reported adverse events in the following 16 weeks, though individuals who were switched to metformin only showed reduced rates of anger as an adverse event compared to individuals who took metformin in the RCT.

SGA-induced weight gain: treatment summary

Thus, existing evidence demonstrates mixed results regarding the benefits of metformin administration to treat SGA induced weight gain in youth, including those with ASD. However, the amount of data to support any conclusion regarding its use in youth, including those with ASD, is small. The results of the existing RCTs are summarized in Table 2. Additional and larger studies are needed to better establish its efficacy. In addition, the differences in design of the existing studies may influence the results and our knowledge of metformin’s efficacy. For example, different antipsychotics have been shown to cause varying rates of weight gain in youth, such as olanzapine vs quetiapine (Arango et al. 2009). In addition, there is evidence to suggest that some medications, like risperidone, increase the rate of weight gain in a dose dependent relationship (though some research indicates the contrary) (Haas et al. 2009a, 2009b). Also, it is unclear that the full benefit of metformin can be understood from these studies, as it has been shown that people can gain weight on antipsychotics for at least 3 years, an even longer period than these studies’ durations (Bushe et al. 2012). Additionally, though the duration of metformin’s lasting effects are unknown, adult trials lasting 6 months have shown that patients tend to continue losing weight over this period of time when taking metformin (de Silva et al. 2015).

TABLE 2.

RCTs examining metformin for treatment of SGA-induced weight gain in youth

Author Diagnosis N Age (yrs) Groups SGA used Duration (weeks) Weight Δ Between metformin and placebo
Klein et al. (2006) Most commonly, Bipolar disorder, Attentional disorders 39 10-17 Metformin 850mg PO qd/ placebo Olanzapine/risperidone/ quetiapine 16 −4.08kg (SD- 4.06)
Arman et al. (2008) Schizophrenia/ Schizoaffective disorder 32 <20 Metformin 500mg PO BID/ placebo Risperidone 12 No significant difference
Anagnostou et al. (2016) Autism Spectrum Disorder 61 6-17 Metformin 500mg PO BID/placebo Mostly risperidone/ aripiprazole 16 Metformin vs placebo- -2.73 kg (95% CI- -4.04- -1.43)
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SGA-induced weight gain: other treatments

To our knowledge, only two RCTs exist analyzing different pharmacotherapy for SGA-induced weight gain in youth. In a study designed to test the efficacy of topiramate as an adjunct to risperidone for treating irritability symptoms, Rezaei et al. (2010) performed an 8-week double-blind, placebo-controlled RCT with 40 children ages 4–12 with ASD. The dose of topiramate used was 100–200 mg per day, which was based on weight. In their secondary analysis of side effects, they found no significant difference in changes in weight between groups. In addition, Canitano’s (2005) open label trial of treating SGA-induced weight gain in 10 youth with ASD with topiramate demonstrated mixed results. However, its use in open label trials with other psychiatric illnesses have yielded more positive results (Tramontina et al. 2007, Wozniak et al. 2009). Also, a recent retrospective review looked at the results of using topiramate or zonisamide for the treatment of SGA-induced weight gain (Shapiro et al. 2015). It looked at 47 youth with a variety of psychiatric diagnoses (Major Depressive Disorder was most common). An average reduction of BMI from 1.3 to 4.1 per 6 months of treatment with use of topiramate or zonisamide was noted. However, there was no significant difference in weight loss noted between these two medications.

In addition, melatonin was recently investigated by Mostafavi et al. (2017) treating SGA-induced weight gain. The mechanism by which melatonin may inhibit weight gain is unclear. One proposed model is that melatonin may inhibit the suprachiasmatic nucleus of the hypothalamus, which, in turn, may inhibit the paraventricular nucleus, which, as described above, plays a role in regulating metabolism and appetite (Porfirio et al. 2017). In this RCT, data from 38 youth ages 11–17 with first episode bipolar disorder were analyzed over a period of 12 weeks. They received olanzapine and lithium for treatment of their bipolar disorder and were then randomized to receive melatonin 3 mg/day or placebo. However, the results failed to show a statistically significant difference in weight gain between the melatonin and placebo group. Thus, minimal data exist for use of other pharmacotherapies in youth. Additional research is required to further elucidate the possible benefit of other pharmacotherapies.

SGA-induced weight gain: evidence in adults

While the literature in youth is sparse, a little over 20 RCTs have been performed analyzing the utility of metformin for treating SGA-induced weight gain in adults. An understanding of the evidence for use of metformin in adults, for the time being, can help justify its use in children. Most of the RCTs in adults have demonstrated small/moderately positive results (Wu et al. 2008, Baptista et al. 2007, Carrizo et al. 2009, Chen et al. 2008, Jarskog et al. 2013, Rado and Cavanaugh 2016, Wang et al. 2012, Wu et al. 2008, Wu et al. 2012), though a negative trial (Baptista et al. 2006) also exists. In addition, multiple meta-analyses demonstrate a positive effect of metformin treating SGA-induced weight gain, with a recent meta-analysis demonstrating an average weight gain difference of –3.27 kg between subjects taking metformin versus placebo (de Silva et al. 2016). Subgroup analysis by de Silva et al. (2015) demonstrated a significantly greater effect for metformin used to treat weight gain when used with first episode patients, as opposed to chronic ones. However, Zheng et al. (2015) did not find a significant difference between these groups.

Thus, metformin appears to have a beneficial effect for treatment of SGA-induced weight gain in adults. However, it is unclear at this time how metformin’s efficacy in youth compared to adults may differ. The literature in youth is sparse and studies are fairly diverse in population and methodology.

Discussion

Existing data indicate that SGAs have a greater impact on weight in youth than in adults. This article prompts the need to clarify the differing effects SGAs have on children with differing psychiatric illnesses: preliminary data suggest that children with ASD may be affected by SGAs differently than children with other psychiatric illnesses. The treatment of SGA-induced weight gain with the use of metformin is of clinical relevance, as this agent could attenuate the potential long-term medical and psychiatric sequelae of weight gain. Clinical experience suggests that it may have significant benefit specific to youth with ASD; youth with ASD require tailored psychotherapeutic interventions (Hoffman and Rice 2012, Rice 2018), and it is reasonable to suggest that the unique clinical factors of this population would mediate pharmacotherapeutic interventions that interact with psychosocial variables as well. However, the literature investigating the treatment of SGA-induced weight gain with metformin is sparse and contains varying results, as well as differing methodologies. Larger and more longitudinal studies would better elucidate the benefit of metformin for treating SGA-induced weight gain and have the potential to better inform the clinician for its use in treatment. In the interim, perspectives supported by the available evidence are intended to inform clinicians and providers in the attempt to bridge the gap between recommendations and clinical practice.

Conflict of Interest

No potential conflict of interest was reported by the authors.

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