Behavioral Weight Loss Treatment in Antipsychotic Treated Youth

Abstract

Background

Antipsychotic-treated youth have increased risk for the development of obesity and type 2 diabetes. Behavioral weight loss treatments show promise in reducing obesity and diabetes risk in antipsychotic treated adults, but have received no study in antipsychotic treated youth.

Objective

We describe a rationale for behavioral weight loss interventions in high-weight antipsychotic treated youth, and report behavioral, anthropomorphic, and metabolic findings from a case series of obese antipsychotic-treated adolescents participating in a short-term, family-based behavioral weight loss intervention.

Methods

We adapted the Traffic Light Plan, a 16-week family-based weight loss intervention that promotes healthy energy balance using the colors of the traffic light to categorize the nutritional value of foods and intensity of physical activity, adapting a social ecological framework to address health behavior change in multiple social contexts. The intervention was administered to three obese adolescents with long-term antipsychotic medication exposure. Efficacy of the intervention was evaluated with a battery of anthropomorphic and metabolic assessments including weight, body mass index percentile, whole body adiposity, liver fat content, and fasting plasma glucose and lipids. Participants and their parents also filled out a treatment satisfaction questionnaire upon study completion.

Results

Two males and 1 female (all aged 14 years) participated. All 3 participants attended all 16 sessions, and experienced beneficial changes in adiposity, fasting lipids and liver fat content associated with weight stabilization or weight loss. Adolescents and their parents all reported a high level of satisfaction with the treatment.

Conclusions

Family-based behavioral weight loss treatment can be feasibly delivered and is acceptable to antipsychotic-treated youth and their families. Randomized controlled trials are needed to fully evaluate the effectiveness and acceptability of behavioral weight loss interventions in antipsychotic treated youth and their families.

Introduction

Pediatric obesity is a rising public health concern and is associated with early onset of cardiovascular disease risk conditions such as fatty liver and diabetes. (1–3) Children with psychiatric conditions may be particularly vulnerable to the development of obesity and related adverse health conditions. (4) The increased risk for obesity in psychiatric populations is exacerbated by use of second-generation antipsychotics (hereafter referred to as antipsychotics), which increase risk for weight gain and related adverse changes in lipid and glucose metabolism. (5, 6) Youth treated with antipsychotic agents are more than twice as likely as children in the general population to develop obesity-related cardiometabolic risk conditions like diabetes, hypertension and hyperlipidemia. (7–9) In populations where obesity is secondary to medical treatments, first-line treatment strategies include discontinuation of agents that cause or contribute to weight gain, or substitution with a lower-risk agent if one is available. (10) Although antipsychotic discontinuation in youth is associated with weight loss, it may come at the price of psychiatric symptom recurrence, including aggressive or self-injurious behavior. (11–13) Therefore, it is imperative to identify strategies to mitigate weight gain when chronic antipsychotic treatment is necessary.

The putative mechanisms of antipsychotic-induced weight gain are related to the medications’ combination of dopamine blockade at the D2 receptor, antagonism or inverse agonism at 5HT2C serotonin receptors, antagonism at 5HT2A serotonin receptors, antagonism at alpha (1A) adrenergic receptors and especially antagonism at histamine (1) receptors. (14) Blocking activity of dopamine, particularly in subcortical, limbic and striatal areas of the brain, leads to an up-regulation of post-synaptic receptors as well as increased dopamine within the synaptic cleft, which may create a “reward deficiency” syndrome that prevents satiety. (15) Serotonin receptor inverse agonism or antagonism may lead to decreased satiety and hyperphagia. (16–19) Finally, weight gain has long been associated with centrally active drugs that have high affinity for the histamine (1) receptor, and H1 antagonism is known to increase feeding (18, 19) and sedation, with predictable reductions in caloric expenditure. (14) While pharmacologically driven, treatment-related weight gain could potentially be addressed by behavioral strategies that address decreased satiety, increased food seeking and sedentary behavior (See Table 1). Core principles of behavioral weight loss that may impact satiety and activity level typically involve food and activity substitutions, with progressive goal setting and reinforcement to reach the identified terminal health behavior targets and to change food and activity preferences.

Table 1.

Proposed Mechanisms of Antipsychotic-induced Weight Gain and Suggested Behavioral Strategies to Restore Energy Balance

Receptor and CNS Location	Antipsychotic Action	Resultant Behaviors leading to Positive Energy Balance	Behavioral Weight Loss Approach to Normalize Energy Balance
5-HT2A/5-HT2C1 lateral hypothalamus, arcuate nucleus	Inverse Agonism (5HT2A) or antagonism (5HT2C), paradoxical down regulation of receptors	satiety, hyperphagia leading to increased caloric intake	Identify palatable, high volume foods with lower caloric density to substitute for high energy density foods
H12 Posterior hypothalamus Peripheral SNS	Antagonism, disruption of leptin-mediated signaling, lipolysis & thermoregulation	food intake sympathetic NS activity Sedation and physical activity leading to decreased caloric expenditure	Food substitution, increase energy expenditure with short, simple activities throughout the day
D2/D33 Cortex, subcortical areas, limbic system, striatum	Antagonism, post-synaptic up regulation of receptors, increased synaptic dopamine	“Reward deficiency” leading to preference for and intake of energy dense foods	Food substitution, particular focus on taste preference; selectively incorporate small amounts of energy dense foods to avoid sense of deprivation
α-14 Ventro-medial hypothalamus	Antagonism	satiety leading to food intake	Food subsitution with particular focus on volume to promote satiety

¹5-HT = 5-hydroxytryptamine receptors, type 2A and 2C

²Histamine type 1 receptor

³Dopamine type 2 and 3 receptors

⁴Alpha type 1 adrenoreceptor

Intensive behavioral weight loss and lifestyle modification programs have been successfully adapted for use in antipsychotic-treated adults with psychotic disorders and other severe mental illnesses. (20–22) One particularly successful weight loss intervention has incorporated psychosocial and cognitive rehabilitation strategies into a health education framework located within a setting where patients received mental health care and social support. (23) Social ecological approaches to health behavior change in psychiatric populations consider the adjustment, coping and adaptive functioning of the individual within a social and cultural context. (23) This focus on facilitating the individual’s involvement in and impact on the environment as an agent of change is thought to enhance the likelihood of sustained improvement in health behaviors. Social ecological models of pediatric health behavior change include the family as an integral part of the child’s immediate environment, and promote the development of parent-facilitated social networks that support health behavior change and address social barriers to engaging in health behavior change. (24, 25) Weight loss treatments utilizing a social ecological approach to health behavior change may be ideally suited to promoting health behavior change in this population, considering psychosocial barriers to participation may be more pronounced compared to non-psychiatrically ill individuals. Family is part of the first and perhaps most important layer of social ecology in the lives of children, and thus social ecological approaches that focus on the involvement of social supports, including family, may be of primary importance in individuals facing psychiatric illnesses as barriers to health behavior change.

Family-based behavioral weight loss treatment (FBT) is considered first-line for the management of pediatric obesity. (26, 27) Published meta-analyses document that such interventions lead to improved weight outcomes among children and adolescents. (28, 29) However, these reports also highlight the need for studies that evaluate treatment-related changes in metabolic parameters and that test strategies for enhancing real-world intervention delivery, particularly in at-risk populations such as individuals with psychiatric illness who are treated with antipsychotic medications. (30) To our knowledge, two studies including behavioral weight loss as part of the study design have been conducted in overweight or obese youth treated with antipsychotics. (31, 32) However, we are aware of no published studies evaluating the feasibility and efficacy of family-based behavioral weight loss interventions in this population, nor of any studies that measure the impact of such interventions on metabolic health outcomes.

The present report describes a modified FBT approach to weight loss in antipsychotic treated youth and reports on the first three participants in a randomized controlled trial to evaluate the efficacy of FBT for weight loss in antipsychotic treated youth ages 6–18. The design of this study involves delivering weekly FBT to antipsychotic-treated youth with psychiatric illnesses compared to otherwise healthy but overweight or obese youth, with a monthly standard of care antipsychotic-treated reference group. The primary outcomes of this study include gold-standard measures of body composition and metabolism, including change in total percent body fat and liver fat, measured respectively via dual energy X-ray absorptiometry (DEXA) and magnetic resonance spectroscopy (MRS), as well as common clinical measures such as body mass index (BMI), BMI percentile, vital signs and fasting plasma lipid and glucose values. We hypothesize that individuals treated with antipsychotic agents can successfully participate in behavioral weight loss treatment without adverse weight or metabolic outcomes. Here, we describe the weekly FBT program adapted for use in antipsychotic treated youth to incorporate a social ecological approach, and report changes in weight and other measures of metabolic health in the initial three antipsychotic treated obese youth who completed the weight loss treatment.

Methods

Participants

Three adolescent participants were recruited from the Washington University School of Medicine Child & Adolescent Psychiatry Outpatient Clinic. In all cases, the participant’s pediatrician or primary care provider was notified of study participation and provided medical assent for participation. Outpatient weights and heights collected in the year prior to study enrollment were obtained for all participants from their primary care provider or treating psychiatrist. Inclusion criteria for the overall study include: i) overweight (BMI percentile ≥85) or obese (BMI percentile ≥95) youth aged 6–18; ii) any DSM-IV-TR diagnosis iii) at least 6 continuous months of antipsychotic treatment iv) documented weight gain greater than expected (eg crossing percentile line on BMI growth chart) v) evidence of psychiatric stability (no inpatient hospitalizations in the previous 6 months, no changes in psychotropic medication doses for 4 weeks); vi) consenting adult caregiver willing to participate in the study vii) ability to provide assent for participation as evidenced by documented or clinically estimated IQ of 70 or higher. Exclusion criteria include: i) youth who were not overweight or obese by BMI percentile; ii) age outside specified range of 6–18 years; iii) no presence of DSM-IV-TR diagnosis; iv) <6 months of antipsychotic treatment; v) active suicidality or substance use disorders; v) not psychiatrically stable and/or antipsychotic treatment deemed inappropriate; vi) no consenting adult caregiver able to participate in the study; vii) estimated or documented IQ <70. Concurrent treatment with selective serotonin reuptake inhibitors (SSRIs) and attention deficit-hyperactivity disorder (ADHD) medications (including stimulants, atomoxetine or alpha agonist agents below a total daily dose of 2 mg/kg methylphenidate equivalent) was permitted to increase generalizability of results. A large portion of antipsychotic treated youth are concurrently treated with SSRI’s, stimulants and other psychotropic medications; (33) more specifically, an increasingly common use of antipsychotic medication is in treatment resistant ADHD. (34)

Study Assessments

Participants were youth ages 6–18 enrolled in the NIMH-funded “Measurement of Cardiometabolic Risk in Antipsychotic Treated Youth” study, which is a randomized controlled trial to evaluate metabolic changes in overweight or obese youth treated with antipsychotic medications during behavioral weight loss treatment, compared with obese or overweight but otherwise healthy controls undergoing the same behavioral weight loss treatment. All participants underwent a clinical evaluation by a study psychiatrist to ensure psychiatric stability and appropriateness of continued antipsychotic treatment during study participation. Diagnoses were based on DSM-IV-TR criteria and corroborated with records of previous psychiatric treatment. A consensus study diagnosis was based on the preponderance of clinical and study data. Baseline assessments were conducted within 1 month of study enrollment and endpoint assessments were conducted within 2 weeks of completing the 16-week weight loss treatment. All study assessments were performed at the Washington University Pediatric Research Unit (PRU), Center for Clinical Imaging in Research (CCIR) and Nutrition Obesity Research Center (NORC) and included: height and weight performed on a calibrated stadiometer (Seca® 240 Wall-Mounted Stadiometer) and scale, (Seca® 684 Digital Multifunctional Scale) respectively, by a trained research nurse; whole body percent fat measured using Dual Energy X-Ray Absorptiometry (DEXA) (Delphi W densitometer equipped with version 12.4 software; Hologic, Waltham, MA); intra-hepatic triglyceride content (IHTG) determined at baseline and study endpoint by proton magnetic resonance spectroscopy with a 1.5T scanner (MAGNETOM Sonata; Seimens, Erlangen, Germany) with all frequencies (i.e. chemical shifts) measured relative to the principal water ¹H resonance; fasting plasma lipids (total cholesterol, low density lipoprotein or LDL cholesterol, high density lipoprotein or HDL cholesterol and triglyceride) and glucose. Weekly treatment weights were measured on a digital office-based scale (Health o meter, Sunbeam Products, Inc., 2010). BMI, BMI percentile, and BMI z-score were calculated from medical records for each subject at 12 and 6 months prior to study enrollment, as well as at baseline and endpoint study assessments. The Washington University in St. Louis Institutional Review Board approved this study.

Treatment Description

Family-based behavioral weight loss treatment (FBT) is an evidence-based intervention consisting of weekly sessions over 12–24 weeks including individual family weigh-ins and meetings with a trained interventionist as well as separate parent and child groups. (35) FBT targets family support and restructuring the home environment to enable healthier behaviors, while establishing self-regulatory behaviors to promote weight management. A weight loss goal range of 0.5–2 lbs per week is set for both child and participating adult, a range that is in line with evidence-based childhood obesity treatment (36) and recommendations for healthy child development and weight management. (26, 37) Expected annual weight gain during normal growth and development varies based on age and gender, and can range from 2–3 lbs in pre- and post-pubertal youth to 8–12 lbs per year during pre-pubertal and pubertal growth stages, with weight gain higher in pr-pubertal females than in males, and higher weight gain in males during puberty. (38, 39) For individuals who are already high weight, the range of 0.5 to 2 lbs per week is a safe weight loss range for all ages and stages of growth. Core components of behavioral weight loss strategies include education on energy balance, shaping behaviors to promote stimulus control and self-monitoring. The Traffic Light Plan is used as a framework to help families shift their energy intake and expenditure using a classification system in which the nutritional value of foods and the intensity value of activities are coded as RED for “stop and think” to indicate the least healthy options, YELLOW for “caution” to indicate moderately healthy options, and GREEN for “go” to indicate the healthiest options. (40–43) Both the participating parent and youth are asked to self-monitor daily food intake and physical activity. Youth and their participating parent are asked to select from a list of behavioral rewards (which exclude options related to food or sedentary behavior) for accumulating points when weekly goals are met. Child and parent weights are measured at each in-person session.

In the present case series, modifications were made to the existing FBT framework in order to facilitate delivery in an outpatient psychiatric treatment setting. First, we removed the weekly group meeting and increased contact with the treatment team through a mid-week phone check-in, while incorporating the group content and skills practice into the individual family sessions. This was done to reduce the total time spent in person per week by families and interventionists, while allowing interventionists to provide support and reminders to engage in self-monitoring and health behavior changes throughout the week. We also employed a simplified, one-page food and activity log composed of visual cues for RED and GREEN foods and activities. This was done to simplify food logging in youth who had learning disabilities or other cognitive challenges. We created and used a “taste log” to incentivize trying new GREEN and YELLOW foods and promote serial desensitization for youth with food aversions or sensory integration difficulties. In addition, we included an ecological-based social facilitation component to each session to encourage the consolidation of health behavior changes across environmental contexts, taking into account developmental stage of the participating youth and encouraging parents to facilitate the development and use of peer and community networks to support health behavior change. Weekly treatment goals were divided into energy balance, weight loss and social facilitation domains, and target ranges for scaled goal attainment were created within each domain. This allowed the interventionist to individualize weekly goals based on child- and family-level characteristics and needs.

Results

Table 2 presents each of the three cases in detail. Quantitative cardiometabolic outcomes are presented in Table 3. Beneficial changes in fasting total cholesterol, LDL cholesterol, adiposity and liver fat content were documented in Participant 1 and Participant 3, who both experienced the greater changes in BMI percentile or z-score than Participant 2. All participants experienced a slowing of weight gain compared to pre-treatment weight trajectory (Figure 1). No clinically significant changes in fasting glucose and triglyceride values. Participating parents and youth reported that they were either “very satisfied” (n=2) or “somewhat satisfied” (n=1) with the treatment program at study completion. Two parents reported that they would not suggest any changes to the treatment; one parent suggested the use of a computer or mobile device application for homework and self-monitoring.

Table 2.

Participant Characteristics and Case Description

Participant 1 was a 14-year-old Caucasian male diagnosed with PDD-NOS1 and ADHD,2 combined type, and Learning Disorder (Reading and Written Expression). He had received psychiatric treatment since age 5, and at study enrollment was taking atomoxetine (Strattera) 100 mg daily, paroxetine (Paxil) 10 mg daily and risperidone (Risperdal) 3 mg daily. Medical comorbidities related to obesity included impaired fasting glucose.4 Prior to study participation, food limits being set in the home resulted in aggressive behavioral outbursts. Treatment was tailored as follows: To address parent modeling of responsive and assertive communication skills, the therapist worked with parents on how to identify and anticipate behavioral triggers prior to setting limits and boundaries. To address difficulties with recording foods related to learning disorder, daily family check-ins allowed the participant to narrate or dictate food intake to the participating parent, while the youth utilized Traffic Light Plan materials to identify nutrition data for each food item.

Participant 2 was a 14-year-old Caucasian female diagnosed with Mood Disorder Not Otherwise Specified and GAD.3 She had received psychiatric treatment since age 7, and at study enrollment was taking quetiapine (Seroquel) 100 mg twice daily and 200 mg at bedtime; sertraline (Zoloft) 150 mg daily. Medical comorbidity related to obesity included hypercholesterolemia.5 Parental health problems, including limited mobility and mild cognitive impairment impacted the ability to perform key parenting skills (e.g., regular grocery shopping, help with completing self-monitoring logs, facilitation of conversations to promote healthy behaviors at home and with peers). Treatment was tailored as follows: To reduce cognitive load, handouts incorporating visual cues and simplified messages regarding the primary message in each meeting were utilized to reinforce session content, and the one-page food and activity log was introduced to simplify self-monitoring. To address parental difficulties and communication challenges, the therapists modeled adaptive communication strategies and provided cues for collaborative problem solving.

Participant 3 was a 14-year-old Caucasian male diagnosed with PDD-NOS1 and ADHD,2 combined type. He had received psychiatric treatment since age 3, and at study enrollment was taking osmotic-release oral system (OROS)-methylphenidate (Concerta) 54 mg daily, quetiapine (Seroquel) 150 mg twice daily and 100 mg at bedtime and paroxetine (Paxil) 15 mg daily. Medical comorbidity related to obesity included dyslipidemia.5 This youth began treatment with a significant preference for RED foods, and taste aversion to most GREEN foods. Parents reported weight had gradually become a problem over time because their child had limited taste preferences and became severely agitated when new foods were introduced. Treatment was tailored as follows: To address distress about trying new foods related to sensory aversion, the interventionist worked with the family on communication strategies and provided support and education about distress tolerance for parents and youth. To engage the youth both during the session and during the week at home and school, a focus of therapy became rewarding attempts to try new GREEN foods using the taste log.

¹Pervasive Developmental Disorder Not Otherwise Specified

²Attention Deficit-Hyperactivity Disorder

³Generalized Anxiety Disorder

⁴Defined by American Diabetes Association Criteria (33)

⁵Defined by NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents (34)

Table 3.

Changes in Metabolic Health During Study Participation

	Participant 1		Participant 2		Participant 3		Mean Change
	Baseline	Endpoint	Baseline	Endpoint	Baseline	Endpoint
Weight (lbs)	165.6	153.7	270.1	268.7	141.8	141.5	−4.53
BMI %ile	91.13	80.94	99.48	99.41	96.16	92.69	−4.58
BMI z-score	1.35	0.88	2.56	2.52	1.77	1.45	−0.28
Fasting Glucose (mg/dL)	103	93	87	86	97	97	−3.67
Fasting Total Cholesterol (mg/dL)	166	145	209	239	160	139	−4.00
Fasting HDL Cholesterol (mg/dL)	57	62	56	60	41	38	2
Fasting Triglycerides (mg/dL)	59	63	93	106	128	70	−13.67
Fasting LDL Cholesterol (mg/dL)	97	70	134	158	93	87	−3
DEXA Total Percent Fat	28.4	24.2	46.9	48.4	35.6	28.6	−3.23
Percent Liver Fat	2.08	0.62	1.92	2.76	3.54	1.31	−0.95

Figure 1.

Participant Weight Trajectories, 1 year Pre-Treatment and During Treatment

Conclusions

Children with mental health conditions, especially those who are treated with antipsychotics, are vulnerable to developing obesity and related health problems. Little research has been conducted on weight loss interventions in this population. Family-based behavioral weight loss interventions are low-risk and are considered first-line treatments for pediatric obesity with evidence for long-term sustainability. (35) The preliminary results reported here represent, to our knowledge, the first behavioral weight loss intervention adapted for use in youth treated with antipsychotic medications.

The primary goal of this pilot study was to demonstrate the feasibility of delivering a behavioral weight loss treatment to families of youth with psychiatric conditions. All participants experienced a beneficial change in or stabilization of BMI percentile and z-score from pre-treatment conditions, and these changes are similar to previous FBT studies. (24) Although greater weight loss was associated with greater change in metabolic parameters, it is notable that small reductions in weight were associated with measurable improvements in portions of the lipid panel and in liver fat content. Finally, each of the three cases involved a parenting component that challenged the family’s ability to maintain healthy weight, suggesting that a family-based approach may be useful in this population to support parents in helping their children make health behavior changes.

There are important limitations to note. As a case series, the sample of participants reported here was small and warrants continued evaluation, as results may not be representative of the general population of children with psychiatric conditions who are overweight or obese. Moreover, these participants were adolescents, and our larger trial addresses both children and adolescents (ages 6–18y). Estimates of children’s height growth patterns can be used to anticipate weight-for-height changes needed to achieve normal weight status and guide weight loss targets, based on youth’s age- and sex-specific BMI percentiles. (44, 45) It is important to note that our presented cases are adolescents with BMIs above the 99^th percentile for age and gender at entry, and children who are younger and closer to the 85^th BMI percentile need to lose less weight to normalize BMI percentile than youth who are older and have a higher severity of obesity. (45) Thus, expansion of our sample to younger children across BMI percentiles in the overweight and obese ranges may provide additional information about treatment response and may indicate whether treatment for this population that is at risk for continued weight gain warrants additional adaptations (e.g., whether weight maintenance is appropriate, rather than weight loss, in younger children on antipsychotic medication with a BMI that is closer to the 85^th percentile). (26, 37, 45) Additionally, there may be important differences in response to interventions based on gender, ethnicity, age and socio-demographic variables that are not represented by the individuals reported on in this case series.

Of note, selection bias can confound results in studies of behavior change, as individuals who participate in research studies may be more motivated than those in the general population to make health behavior changes. Participant 1 is an example of this and may be quite representative of individuals with mild autism who also have ADHD symptoms; commonly these individuals are treated with a combination of stimulant and antipsychotic therapy. While it could be argued that Participant 1 lost weight prior to starting FBT due to concurrent stimulant therapy, which has a known anorectic effect, stimulants have not been associated with significant weight loss in antipsychotic treated individuals. (46, 47) A more likely cause of weight loss prior to beginning treatment is the latter described motivational force for behavioral change. Following observation of the pre-treatment weight trajectory for Participant 1, we modified our study timeline to allow only 2 weeks between baseline testing and beginning FBT. Finally, although the potential mechanism or mechanisms of antipsychotic-related weight gain can be surmised from receptor binding profiles, future studies should evaluate neurobiological changes associated with antipsychotic treatment as well as with weight loss treatment in order to develop more effective and individualized weight loss treatments.

Clinical Significance

The present report demonstrates that a minimally modified, family-based weight loss intervention can be feasibly delivered to youth with psychiatric disorders, and could be disseminable in clinical settings where weekly encounters with a behavioral health provider are feasible, such as in community mental health centers. While beneficial changes were noted in liver fat, whole body adiposity, and in fasting total and LDL cholesterol, definitive conclusions regarding the effectiveness of this intervention cannot be made based on the first three participants’ results. Further study is needed to more definitively determine treatment effectiveness, as well as to clearly identify population- and diagnosis-specific challenges to weight loss, and to determine the most effective strategies for personalizing treatment and mobilizing family members and supports to promote weight loss success.