The Importance of Second-Generation Antipsychotic-Related Weight Gain and Adherence Barriers in Youth with Bipolar Disorders: Patient,Parent,and Provider Perspectives

Abstract

Objectives:

The objective of this research was to understand physician, patient, and parent perspectives on barriers to second-generation antipsychotic (SGA) medication adherence in youth with bipolar spectrum disorders, and attitudes toward treatment of SGA-related weight gain.

Methods:

Patients diagnosed with bipolar disorder before age 18, parents of children diagnosed before 18, and clinicians with experience prescribing SGAs for these patients completed surveys regarding SGA-related side effects, adherence barriers, and acceptability of weight management strategies.

Results:

Patients (n = 225), parents (n = 128), and clinicians (n = 54) reported weight gain as the most concerning SGA-related side effect (45.6%, 38.9%, and 70.4%, respectively). Weight gain was also the top adherence barrier for patients (35.9%), but was ranked fourth (41.8%) by parents. Patients (61.5%) were more likely “definitely” willing to co-initiate another medication to manage weight gain upon SGA initiation than parents (20.1%) or clinicians (1.9%). Conversely, parents (54.9%) and clinicians (84.9%) were “definitely” willing to accept/prescribe a second medication aiming to reverse weight gain of ≥10 lbs., and patients (61.1%) were willing to add another medication to reverse any weight gain.

Conclusion:

SGA-related weight gain impairs medication adherence in young patients with bipolar disorder. Many young patients would start pharmacologic treatment to mitigate SGA-related weight gain at treatment initiation, parents and clinicians are more hesitant. This research informs patient-centered perspectives on SGA adherence barriers and strategies to minimize potential side effects, which may improve adherence in this vulnerable patient population.

Introduction

Bipolar disorders affect ∼2% of youth worldwide (Van Meter et al. 2011). Evidence-based pharmacological treatment strategies include the use of second-generation antipsychotics (SGAs) (Correll et al. 2010, 2011). Among youth with bipolar spectrum disorders, adherence rates vary from 44% to 65% depending on age, treatment-emergent side effects, time since diagnosis, and mono- versus poly-pharmacological interventions (Coletti et al. 2005; DelBello et al. 2007; Yazdi et al. 2008). Nonadherence to treatment is associated with higher risk of relapse, hospitalization, and comorbid psychiatric and medical illnesses (Clatworthy et al. 2007). According to a recent review of health care claims data, bipolar disorder is one of the most expensive behavioral health diagnoses to treat and medication nonadherence adds to the cost for adults with bipolar disorder (Lage and Hassan 2009). Svarstad et al. (2006) reported that among adults with bipolar disorder, patients who are nonadherent to their medications have a 73% rate of hospitalization, compared to 31% for those taking their medications as prescribed. In most cases, bipolar disorder can be better managed and outcomes improved if patients adhere to medication regimens. However, adherence remains a critical challenge for patients as well as clinicians (Lage and Hassan 2009).

While SGAs are effective in reducing symptoms of bipolar disorder, several side effects may negatively influence medication adherence, particularly among adolescents (Correll et al. 2011a; Goldstein et al. 2016). The results of a retrospective study (Jerrell and McIntyre 2008) compared incidence rates of adverse events of 4000 children and adolescents treated with first-generation antipsychotics or SGAs and a control cohort. The proportions of adverse events differed significantly as follows: obesity/weight gain (19.7% vs. 8.6%), type II diabetes mellitus (5.2% vs. 1.9%), dyslipidemia (4.2% vs. 10.8%), cardiovascular conditions (14.2% vs. 3.4%), neurological/nervous/sensory conditions (65.1% vs. 14.2%), and digestive/urogenital conditions (92.2% vs. 79.7%). These side effects, along with other predictors, may contribute to nonadherence and discontinuation of antipsychotic treatment among youth with bipolar disorder (Martinez-Ortega et al. 2013). Specifically, recent literature suggests patient and clinical factors, such as greater illness severity, substance use, and higher body mass index (BMI), were associated with poorer medication adherence (Goldstein et al. 2016; Edgcomb and Zima 2018). Despite the high rate of treatment nonadherence, there has been little research focusing on patient-centered perspectives of this phenomenon until recently.

Rosenblat et al. (2018) conducted an online survey through the Depression and Bipolar Support Alliance (DBSA) asking adults with bipolar and unipolar depression about their current treatments and reasons for wanting to change medications. The group with bipolar disorder side effects gave the most common reason for treatment discontinuation. In both groups, weight gain was the most common side effect leading to medication nonadherence. Similarly, in a study of 1300 adults with bipolar disorder, the most commonly reported adverse effect was weight gain (38%), ahead of sedation (29%) and concentration difficulties (24%) (McIntyre 2009). Importantly, 39% of the patients reported that weight gain had generated additional health problems. These results underscore the need to understand effective interventions to mitigate weight gain associated with psychotropic medications in adults and youth, as well as patient and parental acceptability of weight management strategies.

Nonpharmacologic interventions to mitigate weight gain in children and adolescents taking SGAs suggest that adopting a healthy lifestyle may be effective for some patients (Krill and Kumra 2014; Dayabandara et al. 2017). However, successful implementation of lifestyle strategies in populations with neuropsychiatric disorders may be challenging (Werneke et al. 2013). Findings from double-blind placebo-controlled studies suggest metformin (Zheng et al. 2015), including in youth (Anagnostou et al. 2016), is an effective pharmacologic alternative or adjunct to behavioral intervention for attenuating SGA-induced weight gain and, partly, for related metabolic side effects (Klein et al. 2006). This study aimed to examine patient, parent, and clinician perspectives on barriers to medication adherence among children and adolescents diagnosed with bipolar-spectrum disorders; attitudes toward SGA treatment-emergent side effects; the impact of SGA-induced weight gain; and thoughts regarding treatment of such weight gain. To our knowledge, this is the first study to examine younger patients' and their parents' preferences in addressing SGA-related adherence and adverse effects.

Methods

In preparation for a Patient-Centered Outcomes Research Institute-supported study (PCS-1406-19276), separate parent, patient, and clinician questionnaires were created using SurveyMonkey “Select.” Questions were vetted through parent, patient, and advocacy organization partners for content and clarity. The survey was completed by 497 patients diagnosed with bipolar disorder before age 18, 344 parents of a child diagnosed before age 18, and 54 clinicians with experience prescribing SGAs. Altogether, 287 parents had a child diagnosed with bipolar disorder before age 18 and 253 of these parents had a child prescribed an SGA before age 18. Among patient responders, 166 were diagnosed with bipolar disorder at age 18 or younger and 128 were prescribed an SGA before age 18. Therefore, 253 (50.9%) parents, 128 (37.4%) patients, and 54 (100%) clinicians met eligibility criteria.

The surveys were conducted in 2014. Since the survey was anonymous, the Institutional Review Board (IRB) determined this study was not human subjects' research and therefore, IRB approval was not needed, and no further action was necessary to publish the results.

Patient and parent questionnaires

The DBSA conducted an anonymous online survey for patients and parents through their website and Facebook page for 16 days (August 19, 2014–September 3, 2014). In addition, the National Alliance on Mental Illness distributed hard copies at their meetings to ensure a diverse sample that includes people without internet access. The patient survey contained nine items regarding SGA treatment history, side effect concern, reasons for nonadherence/discontinuation, potential approaches to weight management, and weight-related concerns (Supplementary Data). The parent survey included seven items assessing their child's SGA treatment history, level of concern regarding side effects, attitudes toward pharmacological and lifestyle weight management strategies, treatment discontinuation, and potential barriers to adherence (Supplementary Data). A member of the research team manually entered hand-written answers into SurveyMonkey.

Clinician questionnaires

Clinician surveys were distributed in 2014 to child and adolescent psychiatrists in the Cincinnati, Ohio; Dayton, Ohio; and Long Island, New York, regions. Questionnaires were also distributed to members of the Southwestern Ohio branch of the American Academy of Child and Adolescent Psychiatry listserv. The survey consisted of 10 items ranking concerns of potential SGA-related side effects, likelihood and timeline of initiating pharmacological weight management interventions, ease of tracking weight and weight gain, frequency of metabolic monitoring for patients on SGAs, and history/attitudes/comfort in prescribing metformin (Supplementary Data).

Results

Adherence

Thirty-four percent of patients reported taking their medication as prescribed <75% of the time. Altogether, 28.4% of parents responded that, to their knowledge, their child had stopped taking their medication on their own. Patients reported the barriers that always (vs. never or sometimes) get in the way of or cause them to stop taking their medications were weight gain (35.9%), trouble concentrating or remembering (26.4%), and excessive sleepiness (24.2%). Parents reported barriers to their child taking their medication were other side effects (46.9%), forgetting to take their medication (45.5%), not liking to be told to take medicine (44.8%), and weight gain (41.8%). The clinician survey did not include questions regarding potential causes of SGA treatment nonadherence.

Side effects

When asked to consider nine common treatment-emergent side effects, nearly half of patients (45.6%) ranked weight gain as most concerning, followed by feeling sleepy (17.2%) and difficulty concentrating (14.5%). Next, patients ranked a list of four common weight-related concerns from least to most important. Forty percent of patients reported low self-esteem to be their most important weight-related concern, followed by appearance (29.3%), and then current or long-term physical health (17.7% and 13.5%, respectively). Similarly, parents ranked weight gain as the most problematic side effect (38.9%), followed by tremors/stiffness/other movement-related problems (20.3%), and difficulty concentrating or remembering (10.9%). Among clinicians, 70.4% reported weight gain as the most concerning medication-related side effect. Less than 1% of clinicians ranked any other side effect, such as hyperglycemia or sedation, as most concerning (Table 1).

Table 1.

Parent, Patient, and Clinician Perspectives on the Most Concerning Second-Generation Antipsychotic Side Effect

	Parents (n = 221)	Patients (n = 103)	Clinicians (n = 54)
Most concerning SGA side effect, number (%)	Weight gain	Weight gain	Weight gain
Most concerning SGA side effect, number (%)	86 (38.9%)	47 (45.6%)	38 (70.4%)
Second most concerning SGA side effect, number (%)	Tremors, stiffness, or movement-related concerns	Feeling sleepy	Hyperglycemia
Second most concerning SGA side effect, number (%)	45 (20.4%)	18 (17.5%)	5 (9.3%)
Third most concerning SGA side effect, number (%)	Difficulty concentrating or remembering	Difficulty concentrating or remembering	Sedation
Third most concerning SGA side effect, number (%)	25 (11.3)	15 (14.6%)	4 (7.4%)

Responders ranked nine common SGA side effects from most concerning to least concerning. Data presented are only for the most concerning side effect reported.

SGA, second-generation antipsychotic.

Weight management attitudes

Patients were asked, “When you were a teenager, and started a medicine that typically causes weight gain, how willing would you have been to start a second medication to prevent this weight gain?” Well over half (61.5%) responded “definitely,” 27.1% replied “possibly,” and 11.5% said “not at all.” Similar attitudes emerged regarding adding a second medication if the patient had already gained weight, wherein 61.1% reported they would definitely be willing to add a second medication to either reduce or reverse the weight gain. In contrast, only 20.1% of parents said they would consider adding another medication at the start of treatment. However, more parents (54.9%) said they would consider adding another medication if their child gained ≥10 pounds, 49.1% would add another medication upon clinician request, and 48.8% would consider a second medication if their child complained about weight gain. When considering several viable options for weight management, a majority of parents felt that learning about a healthy lifestyle is a very acceptable approach (64.4%), whereas a majority of parents responded that medication is a somewhat acceptable approach (58.9%) to weight management. Only 27.4% of parents responded that medication is a very acceptable approach.

Among clinicians, 69.8% responded that they were not at all likely to prescribe medication at the initiation of SGA therapy. However, if a patient gained 10% of their BMI, 84.9% of clinicians would be extremely likely to add a concomitant medication; and 63.5% would be willing to add a second medication if the patient gained 10 or more pounds per inch of growth in height. Finally, 86.5% of clinicians responded they would be somewhat (59.6%) or extremely (26.9%) likely to add a medication if the patient complained about weight gain (Table 2).

Table 2.

Parent, Patient, and Clinician Willingness to Start a Second Medication to Prevent Second-Generation Antipsychotic-Induced Weight Gain

	Parents (n = 209)	Patients (n = 96)	Clinicians (n = 53)
No/not at all/not at all^a	113 (54.1%)	11 (11.5%)	37 (69.8%)
Maybe/possible/somewhat likely^a	54 (25.8%)	26 (27.1%)	15 (28.3%)
Yes/definitely/extremely likely^a	42 (20.1%)	59 (61.5%)	1 (1.9%)

Response choices were different across surveys; table entries are formatted parent choices/patient choices/clinician choices.

Clinician attitudes toward prescribing metformin

Most (74.1%) clinicians reported they had previously prescribed metformin to mitigate weight gain associated with SGAs, 61.1% were comfortable prescribing metformin for this indication, and 18.5% would feel comfortable prescribing with additional information and training. Among clinicians not comfortable prescribing metformin for weight gain, reasons included not being comfortable prescribing oral hypoglycemics (38.5%), the risk of side effects (38.5%), a lack of experience with metformin (23.1%), and not knowing the dosing (15.4%).

Discussion

SGA-related weight gain is one of the most concerning treatment-emergent side effects among patients, parents, and clinicians. Obesity and antipsychotic-related weight gain increase risks to short- and long-term physical health (Correll et al. 2011b) and have deleterious effects on quality-of-life indices for children and adolescents with psychiatric disorders (Martinez-Ortega et al. 2013). Patients diagnosed with bipolar disorder before age 18 report weight gain as the top barrier to SGA adherence, whereas parents ranked weight gain fourth, although still with a higher percentage than even patients. Although the clinician survey did not ask about potential adherence barriers, a majority of providers indicated that weight gain was the most troublesome SGA-related side effect. Not surprisingly, previous studies have demonstrated the impact of SGA-induced weight gain in terms of medication discontinuation and study dropout (McCloughen and Foster 2011). Patients report that diminished self-esteem due to weight gain had the greatest effect on their quality of life. It is unclear how often patients express these concerns to their parents and providers and whether increased communication would lead to early pharmacological intervention, increased medication adherence, and better quality of life.

Lifestyle changes alone may not be sufficient to moderate potential SGA-related weight gain and adverse metabolic effects (Caemmerer et al. 2012; Correll et al. 2020). Metformin has a well-documented safety profile and may be an efficacious pharmacologic option to mitigate weight gain (Zheng et al. 2015). Indeed, nearly 74% of clinicians previously prescribed metformin to treat SGA-induced weight gain and an additional 19% of clinicians indicated they would be comfortable prescribing metformin with additional information and training. The risk of potential metformin-related gastrointestinal side effects might be reduced with slow titration, dosing with meals, and utilizing extended-release formulations (Haupt et al. 1991; Nathan et al. 2009). Additional clinician training on appropriate dosing to achieve maximum efficacy and minimize side effects may be useful.

This study has a several limitations to note. First, results are based on self-report and are subject to recall bias. Second, the lack of demographic information limits analysis of correlates of the responses and examination of local differences in responses for clinicians surveyed in Ohio versus New York. In addition, patients were sampled nationally, while clinician responses represent only two regions. This, and convenience sampling, may limit generalizability of the findings. Third, in an attempt to simplify the survey, we did not ask for clinician perceptions for SGA nonadherence, omitted potential SGA-related side effects such as dry mouth, and did not include “perceived lack of effectiveness” as a reason clinicians might be uncomfortable prescribing metformin. However, to our knowledge, this is the first study to assess patient, caregiver, and clinician perspectives on the importance of weight gain in youth treated with antipsychotics and relevance for nonadherence, as well as on the readiness to employ strategies to prevent or mitigate antipsychotic-related weight gain. Future research may consider collecting objective adherence data and clinical prescribing habits. However, this research elucidates patient-centered factors important to SGA medication adherence.

The results of this survey suggest patients and parents view lifestyle and pharmacological intervention as viable treatments to reduce potential SGA-related weight gain. While parents and clinicians are more hesitant to initiate early pharmacological interventions to prevent, rather than teat antipsychotic-related, developmentally inappropriate weight gain than patients are, all agree on the need for effective strategies to manage weight gain after it has occurred. Our findings emphasize the importance of engaging youth and their families in early conversation about adherence and the potential side effects of SGAs. Future studies examining the comparative effectiveness of interventions to mitigate or reduce SGA-related side effects as well as the impact of such interventions on medication adherence, clinical outcomes, and overall patient quality of life are necessary.

Conclusion

SGA-related weight gain is a barrier to medication adherence in young patients with bipolar disorder. Many young patients are willing to initiate pharmacologic treatment to mitigate SGA-related weight gain at treatment initiation. However, parents and clinicians are much more hesitant to start a concomitant medication preventively at the start of treatment. Although clinicians and parents support healthy lifestyle interventions as an acceptable approach to weight gain, both would consider adding pharmacological treatment if the patient complained about gaining weight or if weight gain reached ≥10 lbs. Open communication among patients, their parents, and their clinicians regarding potential side effects of SGA treatment and possible strategies to minimize these side effects is crucial to maximize medication adherence and improve the physical and mental health of this vulnerable population.

Clinical Significance

Adherence to SGAs is an important issue for children and adolescents diagnosed with bipolar-spectrum disorders.

Patients, caregivers, and clinicians identified weight gain as the most concerning SGA-related side effect and major adherence barrier.

Management of clinically significant SGA-related weight gain with another medication was generally acceptable to all stakeholders.

Understanding barriers that lead to non-adherence and acceptable strategies to increase adherence has the potential to improve clinical and quality-of-life outcomes.

Footnotes

Acknowledgments

We would like to acknowledge Ms. Julia Small for her assistance in designing the survey. We also would like to acknowledge the memory of Dr. John Hutton who inspired us to design the survey.

Disclosures

C.U.C. has been a consultant and/or advisor to or has received honoraria from Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. M.P.D. receives research support from Acadia, Allergen, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion, and Supernus. She receives Consulting/Advisory Board/Honoraria from Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson and Johnson, Lundbeck, Neuronetics, Otsuka, Pfizer, Sunovion, and Supernus. L.P.D. receives research support from Acadia, Allergen, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion, and Supernus. The following authors have no disclosures to report: M.T.S., V.F., J.S., J.W., C.C.K., A.G.T., C.S., B.S., H.T., J.U., I.D., C.H., and T.B.

Supplementary Material

Supplementary Data

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