Running head: ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 1

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1 Running head: ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 1 Antipsychotic Medication-Associated Weight Gain: Development of an Evidence-Based Management Algorithm and Practice Guideline for Primary Care Providers Tracy E. Thornett University of Hawaii at Hilo-School of Nursing June 11, 2015 Committee Chair: Alice Davis Committee Member: Cecilia Mukai

2 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 2 Abstract Obesity is a growing public health concern. Although people from all walks of life are affected by obesity, rates of this chronic disease are especially high among individuals with mental illness. Of particular concern are patients who take antipsychotic medications, as weight gain is a well-established side effect of many of these drugs. This practice inquiry project investigated the problem of antipsychotic medication-associated weight gain by applying the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to develop a preliminary evidence-based practice guideline and algorithm for use by primary care providers. As part of the project, an interdisciplinary panel of key stakeholders evaluated the proposed guideline for both quality and applicability. The results of this evaluation are discussed with future revision and expansion of the guideline in mind. Additionally, implications for advanced nursing practice are examined and strategies for promoting safe, effective, patientcentered, and equitable health care are suggested.

3 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 3 Table of Contents Chapter Problem Statement Support for the Problem..7 Project Purpose...8 Objectives and Aims Chapter 2.10 Review of Literature Theoretical and Conceptual Foundation Chapter Project Design...31 Facilities and Resources.31 Study Population and Setting Key Questions Interventions.. 32 Comparison...33 Outcomes...33 Evidence Search Strategy.33 Data Extraction and Quality Assessment..34 Data Synthesis and Analysis 34 Evaluation..35 Human Subjects and Ethics...36 Chapter Part 1: Systematic Review and Clinical Practice Guideline.37

4 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 4 Part 2: Guideline Evaluation Chapter Purpose, Aims, and Objectives..44 The Guideline. 45 Project Facilitators.46 Project Barriers..46 Project Limitations Plan for Revision...48 Chapter Relevance to Advanced Nursing Practice..49 Contributions to Practice Future Projects...53 References 54 Appendices 87 Appendix A: List of Second-Generation Antipsychotics Appendix B: Summary of GRADE Approach to Rating Importance of Outcomes...88 Appendix C: Summary of GRADE Approach to Rating Quality. 89 Appendix D: Risk of Bias Summaries..90 Appendix E: Forest Plots According to Interventions and Outcomes.. 92 Appendix F: Summary of the Determinants of Strength of Recommendations...96 Appendix G: Summary of AGREE II Instrument Questions Appendix H: Consent Form for Guideline Evaluators...98 Appendix I: Institutional Review Board Approval Letter....99

5 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 5 Appendix J: Summary of Database Findings..100 Appendix K: Characteristics of Excluded Studies..103 Appendix L: Characteristics of Included Studies Appendix M: Summary of AGREE II Evaluation Data.126 Appendix N: Permissions to Reproduce Copyrighted Materials Appendix O: Clinical Practice Guideline...146

6 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 6 Chapter 1: Statement of the Problem Obesity is a growing social and public health concern in the United States and globally. The Centers for Disease Control and Prevention (CDC) report that as of 2010, more than onethird (35.7%) of U.S. adults were obese and this rate has increased since 1988 in adults of all income and education levels. Furthermore, it is reported that in the same year 17% of children between the ages of 2 and 19 years were obese, which is triple the rate observed in 1980 (CDC, 2013). These findings suggest that the rates of obesity will continue to increase. As such, the rising prevalence of obesity has prompted calls from researchers, journalists, policy makers, corporations, healthcare professionals, and independent organizations to advocate for increased efforts to both manage and prevent obesity. Although there is significant concern about the prevalence of obesity in the general population, obesity rates are alarmingly high among individuals diagnosed with a mental illness. For example, the prevalence rate of obesity in patients with schizophrenia is estimated to be 1.5 to 4 times higher than that of the general population (Mukundan, Faulkner, Cohn, & Remington, 2010; Reynolds & Kirk, 2010). Similarly, the prevalence of metabolic syndrome (a combination of risk factors including central adiposity, elevated triglycerides, decreased HDL cholesterol, hypertension, and glucose intolerance) among schizophrenics is approximately 40%, or twice that of the general population (Maayan & Correll, 2010; Reynolds & Kirk, 2010). Of particular concern is a subpopulation of adults who take antipsychotic medications. In fact, weight gain is an established, predictable side effect of second-generation antipsychotic (SGA) medications (Usher, Park, & Foster, 2013), with as many as three-quarters of patients receiving an antipsychotic medication experiencing a baseline weight increase of more than 7% (Wu et al., 2008). Weight gain, as a side effect, poses a special problem in this population, not only in

7 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 7 regard to medication adherence, but also because obesity is associated with numerous medical, psychological, social, and economic consequences. Given the increased prevalence of obesity among individuals diagnosed with mental illness, along with their elevated vulnerability to medication-induced weight gain, one important area of inquiry for successful weight management in this population is the identification of effective interventions which are specific to antipsychotic-associated weight gain. This project investigated antipsychotic-associated weight gain within the context of the obesity epidemic and examined potential solutions for preventing and/or intervening to reduce this side effect. Effective solutions for antipsychotic-associated weight gain will help to promote medication adherence among the mentally ill, prevent relapse, improve physical health and related quality of life, and ultimately, improve treatment outcomes for this vulnerable population. Problem Statement Growing concerns about the prevalence and consequences of obesity require clinicians to tailor obesity prevention and treatment strategies to known causes of weight gain. SGAs have weight gain as an established common side effect. This medication side effect poses a special problem for patients with mental illness, who already experience significant health disparities and substantial barriers to medication adherence. Support for the Problem Adults diagnosed with severe mental illness (SMI) experience substantial health disparities compared to the overall population. For example, up to 60% of patients with SMI are obese (White, Elmore, Luthin, & Cates, 2013), compared to approximately 36% of the overall U.S. population (CDC, 2013). Additionally, adults with SMI have higher rates of conditions such as dyslipidemias, metabolic syndrome, hypertension, and type 2 diabetes mellitus, which

8 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 8 ultimately result in shorter life spans and increased mortality (White, et al., 2013). Unfortunately, many of the medications used to treat SMI (particularly SGAs) have adverse effects that include problematic metabolic changes and associated weight gain. These medication effects compound the already significant health disparities experienced by individuals with SMI. Given these challenges, there is a need for clear guidelines that help to address the physical consequences of antipsychotic therapy, particularly those related to weight gain. Project Purpose The purpose of this project was to develop evidence-based practice recommendations for the management of antipsychotic-associated weight gain in adults. In order to develop such practice recommendations, research questions were designed that focus on the elements of the clinical problem that are of the greatest interest and concern. A standard method was used to design effective research questions, namely, the PICO approach. PICO stands for Population, Intervention, Comparison, and Outcomes. Additionally, a time element (Time) may be added to the question by the researcher to add greater precision (Moran, 2014). The following PICO questions were used to guide the literature review in order to generate practice recommendations based upon the best possible evidence: 1. In adults taking second-generation antipsychotic medication (P), how does medication switching (I) compare to standard care (C) for decreasing weight (O)? 2. In adults taking second-generation antipsychotic medication (P), how do pharmacological interventions (I) compare to standard care (C) for decreasing weight (O)?

9 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 9 3. In adults taking second-generation antipsychotic medication (P), how do behavioral interventions (I) compare to standard care (C) for decreasing weight (O)? Objectives and Aims There were two primary aims of this project. The first aim was to improve the care and treatment of adults with SMI by effectively addressing population-specific physical health concerns by developing evidence-based recommendations that will assist primary care providers in the management of antipsychotic-associated weight gain. Objectives for achieving this aim included: 1. Conduct a structured literature review investigating interventions for managing antipsychotic-associated weight gain. 2. Analyze the literature to both grade and compare interventions. 3. Determine best practice recommendations for the management of weight gain in adults taking antipsychotic medications. The second aim of the project was to promote the translation of new knowledge into health care practice by achieving the following objectives: 4. Synthesize findings into an evidence-based algorithm and guideline for managing antipsychotic-associated weight gain in the primary care setting. 5. Discuss the relevance of medication-associated weight gain to advanced nursing practice. 6. Suggest strategies for advanced nursing practice that promote the Institute of Medicine s (IOM) aims for quality care, specifically those relating to the safe, effective, and equitable care of patients.

10 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 10 Chapter 2: Project Description Review of Literature The review of literature begins with a general overview of obesity and a synopsis of the current state of knowledge regarding the causes of obesity. It then follows with an overview of antipsychotics, a discussion of the current knowledge surrounding antipsychotic-associated weight gain and proposed mechanisms of action, a review of the consequences of weight gain, and a summary of recent trends in antipsychotic prescribing. Finally, the section concludes with a description of the current interventions used in the management of antipsychotic-associated weight gain, along with specific examples to illustrate each intervention strategy. Prevalence and Costs of Overweight and Obesity The CDC reports that as of 2010, more than one-third (35.7%) of U.S. adults were obese and that this rate has increased since 1988 in adults of all income and education levels. Furthermore, they report that 17% of children between the ages of 2 and 19 years were obese and that this is triple the rate observed in 1980 (CDC, 2013). Medical expenditures related to obesity were estimated to be $75 billion in 2003 (Donohoe, 2008). Others have suggested that obesity accounts for 6 to 7 percent of overall healthcare expenditures and costs as much as $100 billion annually in the United States (Tai- Seale & Chandler, 2003). More recently, the CDC estimated the cost of obesity in the U.S in 2008 was $147 billion. Furthermore, the CDC determined that medical costs for obese individuals were $1,429 higher than for people of normal weight (CDC, 2013). Obesity Knowledge Obesity is defined by a standard medical text as a state of excess adipose tissue mass, (Flier & Maratos-Flier, 2008, p. 462). While this is often equated with increased body weight,

11 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 11 there are clear problems with this approach, as evidenced by muscular athletes who may weigh more, but are also very lean. Furthermore, because human weights exist on a continuum, the authors of the same text concede that designating a line between lean or obese is somewhat arbitrary, (p. 462). The authors point out that the Body Mass Index (BMI), which is equal to weight divided by height squared in kg/m 2, is the most commonly used method to define obesity. They admit, however, that BMI is still not a direct measure of adiposity and further acknowledge that while obesity is associated with a number of clinically relevant problems (such as insulin resistance, diabetes, hypertension, and hyperlipidemia), the underlying mechanism for this association has still not been identified. Despite these limitations, BMI is still the most ubiquitous measure of obesity in the research literature, and as such, discussion about obesity must be confined to this primary parameter. Within these guidelines, overweight is medically defined as a BMI between 25 and 30, while obesity is defined as a BMI greater than 30 (Flier & Maratos-Flier, 2008). Obesity causes. The causes of obesity are complex and multifactorial. Generally, obesity is attributed to an overall positive energy balance, with individuals consuming too much food (increased caloric intake) and engaging in too little physical exercise (decreased caloric expenditure). In other words, too many calories in, plus too few calories out, equals weight gain. While there is little doubt about the physics of this energy balance axiom, several mechanisms contribute both to the behaviors that promote obesity, and to the biological mechanisms that affect the storage and metabolism of fat. Factors known to affect the behaviors associated with obesity include chronic stress (McEwen, 2008), mental illness (Taylor et al., 2012), low socioeconomic status (Ernsberger & Koletsky, 1999), low educational attainment (Befort, Nazir, & Perri, 2012; Braveman, Cubbin,

12 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 12 Egerter, Williams & Pamuk, 2010; Roskam, et al., 2010), social and cultural norms (Williams, Crockett, Harrison, & Thomas, 2012), the built environment, such as sidewalks and neighborhood parks (Wen & Kowaleski-Jones, 2012), geographic residency, such as urban or rural location (Befort et al., 2012; Tai-Seale & Chandler, 2003), food marketing (Williams et al., 2012), food availability (Larson, Story, & Nelson, 2009), food insecurity (Pan, Sherry, Njai, & Blanck, 2012), and lifestyle preferences. Factors known to affect the biological storage and metabolism of fat include chronic stress (McEwen, 2008), genetics and epigenetics (Speakman & O'Rahilly, 2012), the environment in utero (Lillycrop & Burdge, 2011), medical disorders (CDC, 2013), injury (Selassie, Snipe, Focht & Welldaregay, 2013), gut microbes (Jumpertz et al., 2011; Ley, Turnbaugh, Klein, & Gordon, 2006; Lomangino, 2006; Ridaura, et al., 2013), environmental chemicals (Grün & Blumberg, 2009; Thayer, Heindel, Bucher & Gallo, 2012), and medications (Grün & Blumberg, 2009). In particular, numerous studies have demonstrated that antipsychotic medications promote significant weight gain leading to obesity (Maayan & Correll, 2010; Mukundan et al., 2010; Reynolds & Kirk, 2010). Overview of Antipsychotics Introduced in the 1950 s, chlorpromazine was recognized as being the first medication to effectively treat the psychotic symptoms of schizophrenia, such as hallucinations and delusions. Numerous antipsychotics were subsequently developed which have similar mechanisms of action, however, all of these medications were (and still are) commonly associated with the adverse effects of elevated prolactin and extrapyramidal symptoms (EPS) such as Parkinsonism and tardive dyskinesia. Additionally, these first-generation medications were limited in their efficacy for treating the full range of symptoms in schizophrenia. In the 1970 s, clozapine was

13 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 13 developed as the first atypical antipsychotic, otherwise known a second-generation antipsychotic (SGA). These SGAs showed greater efficacy in reducing psychotic symptoms and markedly reduced risk for neurological side effects. Unfortunately, most of these SGAs have their own adverse effects, including metabolic changes such as glucose intolerance and hyperlipidemia, as well as substantial medication-induced weight gain (Ballon, Pajvani, Freyberg, Leibel, & Lieberman, 2014; Lett et al., 2011). Despite these effects, SGAs are now considered the standard-of-care in schizophrenia, due to their improved tolerability over first-generation antipsychotics. Additionally, SGAs are now increasingly being used as adjunctive therapies for mood disorders such as depression and bipolar disorder (Ballon et al., 2014; Maayan & Correll, 2010). Antipsychotics and Weight gain As noted previously, SGAs are currently the primary treatment for schizophrenia (Mukundan et al., 2010) and are often used as an adjunct treatment in many other psychiatric disorders (Maayan & Correll, 2010). Unfortunately, this class of drugs also has well-known side effects that include weight gain and metabolic disturbance (Maayan & Correll, 2010; Mukundan et al., 2010; Reynolds & Kirk, 2010). It appears, however, that the magnitude of weight gain varies according to specific drugs, with some medications having greater risk potential than others (De Hert, 2012; Maayan & Correll, 2010; Mukundan et al., 2010; Usher, Park, Foster, & Buettner, 2012). For example, one recent meta-analysis concluded that nearly every antipsychotic had some degree of associated weight gain after only 10 weeks of treatment. The greatest weight increase was seen with olanzapine and clozapine, which increased body weight by 9 to 10 lbs (4-4.5 kg) on average after only 10 weeks of treatment (Mukundan et al., 2010). Another study demonstrated that there are relative differences in antipsychotic-associated weight

14 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 14 gain in the first 10 weeks of treatment for SGAs with the following findings: Clozapine, 4.45 kg; Olanzapine, 4.15 kg; Risperidone, 2.10 kg; and Ziprasidone, 0.04 kg (Usher et al., 2012). Furthermore, this adverse effect is quite common, with one study demonstrating marked weight gain of at least 7% body weight after one year of treatment in 86% of patients taking olanzapine, 65% of patients taking quetiapine, and 63% of patients taking amisulpride (Maayan & Correll, 2010). Another study demonstrated that this effect is even greater in adolescents, with 90.5% of patients gaining >7% of their baseline body weight after taking olanzapine for only 12 weeks (Maayan & Correll, 2010). Overall, weight gain is estimated to affect between 15%-72% of patients taking antipsychotics (De Hert, 2012). In addition to concerns about weight gain, one study reported that patients taking antipsychotics had a quadrupled incidence of diabetes and a doubled incidence of hypertension compared to those in control groups (Lett et al., 2011). Both of these conditions are known to be associated with obesity, and it is not entirely clear whether this increased incidence is due to obesity, the stress associated with having a severe mental illness, or to the use of the antipsychotic medications themselves. Finally, another recent meta-analysis investigating newer antipsychotic agents (including asenapine, iloperidone, lurasidone, and paliperidone) was unable to reach any strong conclusions regarding the metabolic effects of these newer medications, but results suggest that lurasidone has the lowest weight gain potential of the group (De Hert, 2012). These newer SGAs have yet to be integrated into the current knowledge of antipsychoticassociated weight gain. Mechanisms of Antipsychotic-Associated Weight Gain In contrast to first generation antipsychotics which are more specific to and have greater affinity for D2 receptors, SGAs have a strong affinity for 5-HT2 receptors as well as affinities for

15 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 15 dopaminergic, muscarinic, histaminergic, and adrenergic receptors. In particular, increased risk of metabolic abnormalities has been associated with the 5-HT2c- and H1 blocking activity of second-generation antipsychotics (Lett et al., 2011; Reynolds & Kirk, 2010). Despite these associations, the physiologic mechanism of antipsychotic-induced weight gain is not well understood and is most likely due to a myriad of factors including appetite stimulation, direct impairment of metabolic regulation, alteration of insulin sensitivity, and sedation leading to decreased physical activity (Maayan & Correll, 2010; Wu et al., 2008). In addition, genetics may be one of the strongest risk factors influencing antipsychotic-associated weight gain, as demonstrated by recent twin and sibling studies. These studies conclude that 60-80% of antipsychotic-induced weight gain is contributed by genetic factors (Gebhardt et al., 2010; Lett et al., 2011). Lett et al. (2011) note, however, that heritable causes of antipsychotic-associated weight gain are likely to be polygenic, with approximately 60 important genes related to antipsychotic-induced weight gain currently being investigated, especially the genes HTR2C and DRD2. Gene variants with susceptibility to antipsychotic influence include pathways involving intracellular signaling via G-protein coupled receptors, intercellular synaptic signaling, appetite regulators (such as leptin, neuropeptide Y, pro-melanin-concentrating hormone, ghrelin, and endocannabinoids), lipid metabolism, and proinflammatory cytokines (such as tumor necrosis factor alpha). These are among the many mechanisms being investigated with the potential to explain the pathophysiology of antipsychotic-associated weight gain. Finally, it has also been hypothesized that since most SGAs are metabolized by CYP450 enzymes, gene polymorphisms resulting in poor CYP450 activity may also be a mechanism for associated weight gain (Lett et al., 2011; Reynolds & Kirk, 2010). Lett et al. (2011) concede, however, that there remains a paucity of evidence to support these various theories at this time, and assert that antipsychotic-

16 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 16 associated weight gain is likely due to the combined contribution of several risk alleles as well as other environmental, behavioral, and epigenetic factors traditionally associated with obesity. Obesity-Associated Complications & Diseases Obesity has been linked with overall increased morbidity and mortality. Many studies report that obesity is associated with 2 times the risk of all-cause mortality, coronary heart disease, stroke, type II diabetes, and metabolic syndrome (Lett et al., 2011; Mukundan et al., 2010). Furthermore, it is associated with an increased risk of some cancers, musculoskeletal problems, and negative psychological consequences (Mukundan et al., 2010). These health risks are compounded by the observation from several studies that people with severe mental illness die up to 25 to 30 years sooner than the general population, with cardiovascular disease cited as the leading cause of death (Maayan & Correll, 2010; Wu et al., 2008). Ultimately, the risk of mortality in patients with schizophrenia is estimated to be 2.5 times higher than age-matched people in the general population (Maayan & Correll, 2010). With obesity as a major risk factor for additional morbidity and mortality, weight gain associated with the treatment of psychosis is emerging as a significant clinical, social, and economic concern. Ultimately, both the health and cost concerns associated with obesity compel clinicians to carefully consider the seriousness of antipsychotic-associated weight gain. Stigma of Obesity Stigma is defined as the negative attitudes, beliefs, perceptions, and behaviors associated with a mark of disgrace related to a particular circumstance, quality, or person (Abate, 2001). In the current sociocultural environment, the stigma of obesity induces significant mental health effects such as chronic stress, low self-esteem, and negative self concept (Xiao, Baker, & Oyewumi, 2012). Furthermore, obesity-related stigma often results in obese individuals having

17 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 17 reduced access to social resources known to promote health such as positive interpersonal relationships, education, gainful employment, and access to healthcare (Puhl & Heuer, 2009). Finally, the stigmatization of weight gain and obesity is considered a major factor in patient nonadherence to their medication regimen, especially among the mentally ill (Lett et al, 2011). Ultimately, the stigma-related effects of obesity add to the burden of health disparities already experienced by individuals with mental illness. Weight Gain and Treatment Non-adherence Medication-associated weight gain is not only associated with increased health risks, but is also linked with decreased quality of life and poor treatment adherence in individuals diagnosed with mental illness (Correll, Lencz, & Malhotra, 2011). For example, one study reported a significant association between subjective distress from weight gain and medication non-adherence in people with schizophrenia (Weiden, Mackell, & McDonnell, 2004). Furthermore, Lett et al. (2011) assert that weight gain is a leading factor in patient noncompliance with their prescribed medication regimen, particularly in response to the social stigmatization of weight gain and obesity. Trends in Antipsychotic Prescribing Although SGAs have well-established metabolic side effects, such as weight gain, their use continues to increase. In fact, antipsychotics are now among the most commonly prescribed, and most costly, medications being used in the United States today (Olfson, Blanco, Liu, Wang, & Correll, 2012). In recent years, the percentage of visits to primary care providers that included a prescription for antipsychotics increased significantly faster than the corresponding percentage of visits to psychiatrists (Olfson, Kroenke, Wang, & Blanco, 2014). According to Olfson et al. (2012), among antipsychotic medication visits for adults, the most commonly prescribed drugs

18 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 18 were quetiapine (32.6%) followed by risperidone (16.9%), olanzapine (15.2%), and aripiprazole (13.8%). More recently, aripiprazole was recently listed as the 14 th most prescribed medication (ahead of all other SGAs) in the United States and had the highest sales of any prescription medication, at $7.2 billion during the period between July 2013 and June 2014 (Brooks, 2014). Although SGAs were initially approved for schizophrenia, they are now used for several other conditions including psychoses, bipolar disorder, delirium, depression, personality disorders, dementia, and autism (Alexander, Gallagher, Mascola, Moloney, & Stafford, 2011). Many of these conditions are treated with SGAs as off-label, meaning that they have not yet been approved by the Federal Drug Administration for such purposes. Management Approaches to Antipsychotic-Associated Weight Gain Various strategies have previously been identified to address antipsychotic-associated weight gain. Mayaan and Correll (2010), in an article reviewing research related to antipsychotic-related weight gain, have described three primary approaches for management: switching medication, pharmacological augmentation, and behavioral intervention. Additionally, other researchers have suggested that the initial selection of medication with the lowest weightgain potential is prudent (White et al., 2013). The following section provides additional information about each of these management options. Medication selection. Selecting the appropriate medication at the start of treatment is an important initial strategy in preventing weight gain. For patients who are already overweight or obese, or who have expressed concerns about the possibility of gaining weight, the provider must choose a medication with the lowest potential for medication-associated weight gain (White, et al., 2013). As described previously, the greatest weight increases have been observed with olanzapine and clozapine (Mukundan et al., 2010), while ziprasidone and aripiprazole are

19 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 19 associated with the least weight gain (Lett et al., 2008). Additionally, there is some evidence that ziprasidone and aripiprazole may provide protection against weight gain (Reynolds & Kirk, 2010). Evidence regarding newer SGAs (such as asenapine, iloperidone, lurasidone, and paliperidone) is still limited, however, recent findings suggest that lurasidone may have the lowest weight-gain potential of these (De Hert, 2012). Switching medications. Studies have shown that switching between atypical antipsychotics can result in significant weight changes. For example, one study reports that patients switched to olanzapine gained weight, while those who switched to risperidone lost weight (Mukundan et al., 2010). When using the switching strategy to manage weight gain, however, it is important for the provider to first establish a clear connection between the antipsychotic exposure and the weight gain (White, et al., 2013). A consensus statement on this issue recommends that if a stable patient on a second-generation antipsychotic gains 5% of his or her initial weight at any time during therapy, one should consider switching the medication, (Mukundan et al., 2010, p. 6). Other considerations for switching medications include whether there is: a new onset of another health risk condition (hyperlipidemia, diabetes, etc.), nonadherence to the medication regimen due to weight gain, and/or abuse of other medications in order to offset the weight gain (White, et al., 2013). When a decision is made to switch antipsychotic medications because of the weight effects, several methods have been suggested for making the transition (Mukundan et al., 2010): 1. Cross-tapering gradually titrating up the new medication while tapering off the older medication. 2. Starting the new medication at the therapeutic dose while tapering off the older one. 3. Stopping the older medication abruptly while gradually increasing the new one.

20 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN Starting the new drug at therapeutic dose and stopping the old one abruptly. Slow cross-tapering is generally considered the safest approach to medication switching at this time (Maayan & Correll, 2010; Mukundan et al., 2010). Additionally, rapid switching may worsen outcomes (such as early termination of treatment), particularly when switching to aripiprazole or risperdone (Maayan & Correll, 2010). Although related reviews are limited by a relatively small number of studies on this topic, findings indicate that switching medications to an antipsychotic with the least potential for weight gain is both a pragmatic and effective approach to addressing this problem. It is cautioned, however, that medication switching be implemented with careful consideration, particularly in regard to concerns about psychiatric symptom exacerbation leading to relapse and an increased risk of discontinuing treatment (Mukundan et al., 2010). Pharmacologic augmentation. Studies investigating pharmacologic interventions to mitigate antipsychotic-associated weight gain report promising results for the use of adjunct medications. It is generally recommended, however, that adjunctive medications be started only after non-pharmacological strategies such a lifestyle changes and other behavioral interventions have failed to produce sustained weight loss (White, et al., 2013). Medications currently showing promise for mitigating the effects of antipsychotic-associated weight gain include amantadine, metformin, nizatidine, and topiramate (Maayan, Vakhrusheva, & Correll, 2010; White, et al., 2013). Other medications with positive findings include reboxetine, sibutramine, and dexfenfluramine, however, these are not available in the United States at this time (White, et al., 2013). Of all the adjunctive medications identified, metformin and topiramate show the most promise for reducing antipsychotic-associated weight gain (White, et al., 2013). According to

21 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 21 one related meta-analysis, patients experienced an average weight change of kg versus placebo over a mean time period of 3 weeks using various adjunct medications. In particular, metformin was identified as the most superior to placebo with an average decrease of 2.94 kg. Other agents superior to placebo included fenfluramine (-2.60 kg), sibutramine (-2.56 kg), topiramate (-2.52 kg), and reboxetine (-1.90 kg). In a major limitation to the findings of the review, however, the results of the studies were found to be rather heterogeneous. This suggests that there were likely significant differences across the various studies and individual agents. Furthermore, even in the studies demonstrating the most profound weight loss, subjects lost only part (and not all) of the weight they had gained during treatment. Additionally, as previously mentioned, reboxetine, sibutramine, and dexfenfluramine are not currently available in the United States. Finally, although metformin outperformed other agents, there is still not enough evidence to support its regular use as an adjunctive medication to prevent weight gain in patients taking antipsychotic medications (Maayan, Vakhrusheva, & Correll, 2010) and the use of topiramate is associated with several other adverse effects and risks including sedation, memory problems, acute myopia, metabolic acidosis, nephrolithiasis, paresthesias, and increased suicidality (White, et al., 2013). At this time, there may be too few randomized controlled trials testing adjunct medications for antipsychotic-associated weight gain to support clinical practice guidelines. Furthermore, there are no head-to-head studies of these pharmacologic interventions to demonstrate clear superiority of certain medications over others (Faulkner, Cohn, & Remington, 2007; Maayan & Correll, 2010; Maayan et al., 2010). Finally, current studies conflict about whether pharmacological intervention is superior to behavioral intervention in preventing and treating antipsychotic-associated weight gain (Maayan & Correll, 2010).

22 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 22 Behavioral interventions. Behavioral intervention is often considered the first line treatment in non-medication-related weight gain. In a meta-analysis of behavioral interventions designed to reduce antipsychotic-associated weight gain, the authors report that nutritional counseling was as effective as cognitive behavioral therapy, and both were superior to treatment as usual (Maayan et al., 2010, p. 1521). Furthermore, similar studies have found no significant difference in prevention versus intervention, and individual versus group interventions (Maayan & Correll, 2010). In contrast, not all studies demonstrate the effectiveness of behavioral interventions for preventing weight gain. For example, one randomized controlled trial of nurseled weight management and exercise intervention for people taking second-generation antipsychotics showed no significant difference between the intervention group compared to those in the control group (Usher et al., 2012). Combination approach. As yet, only a single study has examined the effectiveness of a combined approach to antipsychotic-associated weight gain (Maayan & Correll, 2010). This study investigated the efficacy of metformin and found that the use of this drug in conjunction with lifestyle interventions was more effective than either metformin or lifestyle intervention used alone (Wu, et al., 2008). Since then, multiple trials are currently underway to test this approach further (Maayan & Correll, 2010). In general, however, most obesity management programs assume that a combination approach will yield better results than single interventions alone. Need for Guideline A recent search of clinical practice guideline resources, such as the Agency for Healthcare Research and Quality (AHRQ) National Guideline Clearinghouse and UpToDate (an evidence-based clinical decision support system), reveals that no formal guidelines exists to

23 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 23 specifically address antipsychotic-associated weight gain. Although there are several review articles summarizing the evidence for interventions to manage antipsychotic-associated weight gain, none provide a simple, clear format for clinicians to use in everyday practice. Final Summary of Literature Review Obesity is a growing social and public health concern, with raising rates of obesity across all ages and demographics. The increasing prevalence of obesity means that healthcare providers will be caring for a greater proportion of obese individuals. At the same time that obesity prevalence is rising, so too is the use of antipsychotics which have been linked with significant metabolic changes and weight gain. Medication-associated weight gain in the treatment of mental illness, particularly in regard to the use of SGAs, is a serious concern for a multitude of reasons including medical, psychological, social, and economic. In addition, adherence to medication regimens is threatened by this very common side effect, putting psychiatric patients at serious risk for relapse. While research investigating ways to manage SGA-associated weight gain is ongoing, no clear guideline yet exists that reflects the current state of knowledge regarding this issue. Theoretical and Conceptual Foundation The development of clinical practice recommendations begins with a clear concept and explicit framework for translating research into evidence-based practice. This section provides a summary of the concepts and theoretical framework used to inform the project s design and implementation. The ACE Star Model of Knowledge Transformation (Stevens, 2013) is used to link concepts for translation of evidence into practice. The GRADE theoretical framework will be used to both inform project design and as a method to analyze and synthesize the evidence regarding the effectiveness of interventions designed to manage SGA-associated weight gain.

24 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 24 Concepts Map and Definitions The ACE Star Model of Knowledge Transformation was developed as a conceptual model to simplify the approach of translating health care research into evidence-based clinical practice. The model is a five-point star (Figure 1) that depicts the critical steps for moving research findings into practice interventions (Stevens, 2013). Stevens (2013) asserts that it is inefficient for clinicians to search through volumes of research articles in order to make safe and effective practice decisions while caring for patients. Rather, clinical decision-making is best supported by evidence-based recommendations, which are summarized in the form of clinical practice guidelines. The five points of the star are further described below. Figure 1. The ACE Star Model of Knowledge Transformation, copyrighted material (Stevens, 2012). Reproduced with expressed permission. Discovery research. According to Stevens (2004), discovery research is the knowledge generating stage. This represents the traditional field of scientific inquiry, using defined research methodologies to understand and describe natural and social phenomena. The products of this

25 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 25 stage may be referred to as primary research studies and includes the full spectrum of research designs, from randomized control trials to qualitative studies. Evidence summary. Stevens (2004) describes evidence summary as the synthesis of research knowledge into a single statement that meaningfully conveys the state of science regarding a topic. Evidence summaries are also part of knowledge generation, as they create new knowledge from the combination of studies. Stevens identifies several advantages to evidence summaries such as the reduction of large volumes of information into a manageable form, enhanced generalizability, identification of consistencies and inconsistencies across studies, increased statistical power for assessing cause and effect, reduction in bias, integration of existing information, increased efficiency in time between research findings and clinical practice implementation, and establishment of a basis for continuous update with new evidence as it emerges. Translation into guidelines. According to the ACE Star Model, the translation of evidence into guidelines requires two stages: translation of evidence into practice recommendations and integration into practice. The goal of translation is to produce a useful summary of evidence in the form of recommendations that address time, cost, and care standards (Stevens, 2004). Practice integration. The step of practice integration involves changing both individual and organizational practices to reflect the most current evidence. This change can be achieved through both formal and informal processes, and involves the factors that address rate of adoption and the sustainability of the changes (Stevens, 2004). Process, outcome evaluation. The final stage in the ACE Star Model is the evaluation of the impact evidence-based practice has upon various outcomes including patient health,

26 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 26 patient and provider satisfaction, efficacy, efficiency, cost, and health status impact (Stevens, 2004). Related Terms Guidelines. Guidelines are described by the World Health Organization (WHO, 2012) as recommendations intended to assist providers and recipients of health care and other stakeholders to make informed decisions, (p. 1). Additionally, these recommendations must be generated by a process that is objective, comprehensive, free of bias, meets a public health need, and is clear enough for others to see how the recommendation has been developed, by whom, and on what basis. Stevens (2004) states that well-developed clinical practice guidelines describe the benefits, harms, and costs of various decision options. Furthermore, strong guidelines are developed systematically using a process that is described explicitly and can, therefore, be reproduced. Finally, evidence-based clinical practice guidelines clearly identify the strength of the evidence in relation to each practice recommendation (Stevens, 2004). Evidence-based practice. Many definitions of evidence-based practice exist, however, all include themes of applying the most current research to clinical practice decisions. The website for the Agency for Healthcare Research and Quality (AHRQ, n.d.) defines evidencebased practice as: Applying the best available research results (evidence) when making decisions about health care. Health care professionals who perform evidence-based practice use research evidence along with clinical expertise and patient preferences. Systematic reviews (summaries of health care research results) provide information that aids in the process of evidence-based practice.

27 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 27 Hierarchy of evidence. When reviewing evidence to make practice recommendations, researchers and clinicians rank evidence to reflect the type of studies that can provide the best findings for clinical practice. In general, these hierarchies are presented as pyramids depicting the best types of evidence at the peak. Systematic reviews and meta-analyses are considered the gold standard of evidence, with Cochrane Systematic Reviews among the most widely recognized and respected (Fitzpatrick, 2007). Figure 2 depicts a suggested evidence hierarchy based upon these premises (University of Washington, 2011). Figure 2. Hierarchy of evidence. The highest levels on the pyramid are considered the best evidence for clinical practice (University of Washington, 2011). Reproduced with permission. Theoretical Framework The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system is a framework used in the development of guidelines in healthcare. It was created and refined by an international working group of health professionals, researchers, and guideline

28 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 28 developers with the purpose of designing an optimal system for rating quality of evidence and determining the strength of recommendations for clinical practice guidelines (Guyatt, 2011). GRADE is now used by many health-related organizations including the WHO, CDC, AHRQ, American College of Physicians, Cochrane Collaboration, UpToDate, and over 60 other major organizations (Schunemann, Ahmed, & Morgan, 2011). Researchers promoting the use of GRADE have identified how the methodology itself is embedded in a larger theoretical framework (Figure 3) that outlines an ideal process for guideline development. Figure 3 depicts the relationships between the formulation of PICO questions, the creation of evidence profiles for quality assessment, and the translation of these findings into practice recommendations for clinical guidelines (Schunemann, et al., 2011).

29 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 29 Figure 3: The GRADE framework for guideline development (Schunemann, et al., 2011). Reproduced with permission. The Insitute for Clinical Systems Improvement (2015) identifies several advantages of using the GRADE framework and quality assessment methodology including: Provides explicit and comprehensive criteria for downgrading and upgrading quality of evidence ratings Clearly separates quality of evidence and strength of recommendations with a transparent process of moving from evidence evaluation to recommendation Provides clear, pragmatic interpretations of strong versus weak recommendations for use by clinicians, patients, and policy-makers

30 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 30 Includes an explicit acknowledgement of values and preferences In the GRADE process, evidence is gathered according to the PICO question, with systematic reviews utilized first. Additional literature may be reviewed (using randomized control trials, observational studies, etc.) and included to enhance the overall quality of evidence.

31 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 31 Chapter 3: Project Design and Evaluation Plan The purpose of this project was to develop evidence-based practice recommendations for the management of antipsychotic-associated weight gain in adults. The following section describes the overall design of the project, the implementation of the project, and the method for evaluation upon completion of the evidence-based algorithm and guideline for managing antipsychotic-associated weight gain in the primary care setting. Project Design The project design was informed by the GRADE approach to guideline development. Key elements of the GRADE approach include the formulation of PICO questions, the creation of evidence profiles for quality assessment, and the translation of these findings into practice recommendations (Schunemann, et al., 2011). Additionally, project evaluation is an important component of the project, with evaluation measures also informing the overall project design. Facilities and Resources Minimal facilities and resources were needed for project implementation, as this project relied primarily upon electronic sources of data. Furthermore, management and analysis of data was conducted using free and/or already available software. These software programs included EndNote for storing and managing articles, ReviewManager5 (RevMan5) for meta-analysis of study data and generation of risk of bias summaries, and GRADEpro (McMaster University, 2014) for data analysis, synthesis, and display. Additional materials (in the form of paper, pens, staples, etc.) were also needed for both project implementation and evaluation, however, such expenses were minimal and the cost of these were borne entirely by the researcher.

32 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 32 Study Population and Setting The population studied in this project included adults between the ages of 18 and 65 years who were receiving treatment with SGAs (see Appendix A for a list of SGAs). Trials included were those conducted in settings generalizable to the U.S. primary care system, feasible for conducting in the primary care setting, eligible for referral from primary care, or conducted in commercial settings (e.g., Weight Watchers). Trials conducted in hospitals, institutionalized settings, school-based programs, occupational settings, churches, and other settings deemed not generalizable to the primary care setting were excluded. Key Questions 1. In adults taking second-generation antipsychotic medication (P), how does medication switching (I) compare to standard care (C) for decreasing weight (O)? 2. In adults taking second-generation antipsychotic medication (P), how do pharmacological interventions (I) compare to standard care (C) for decreasing weight (O)? 3. In adults taking second-generation antipsychotic medication (P), how do behavioral interventions (I) compare to standard care (C) for decreasing weight (O)? Interventions Only interventions that focused upon weight loss were included and these were further limited to the following intervention strategies: switching medications between SGAs, pharmacotherapies used as adjunctive medications, and behavioral interventions. Combination interventions (such as pharmacotherapy plus behavioral interventions) were excluded with the assumption that combination therapies are generally considered more effective than single

33 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 33 interventions alone. Interventions that did not focus primarily on weight or that did not report weight-related outcomes were also be excluded. Comparison All interventions were compared to standard care. In this project, standard care refers to patients who continue their usual antipsychotic medication without any other specific interventions to reduce weight gain. Outcomes The primary outcome for consideration was weight loss as measured by standard instruments such as standing scales. Secondary outcomes included global state, adverse effects, serious adverse effects, and discontinuation of treatment. Serious adverse effects included serious treatment-related harms such as death, medical issue requiring hospitalization, and psychiatric issue requiring hospitalization. Outcomes reported more than 12 months after the start of the intervention were included when available. Outcomes related to treatment-related harms had no minimum follow up requirement. Outcomes were prioritized according to the GRADE method (Appendix B) prior to initiation of the study. Evidence Search Strategy The evidence search was conducted using relevant electronic databases such as the Cochrane Database of Systematic Reviews, MEDLINE (PubMed), CINAHL, and Web of Science. Additionally, websites hosting clinical practice guidelines (such as AHRQ) were searched for any updates related to antipsychotic medications and weight gain. Searches were supplemented by reviewing reference lists from other relevant publications. Search terms included antipsychotic*, obes*, switching, intervention*, topiramate, metformin, behav*, and systematic review. Only studies conducted between February 28, 2005 and February 28, 2015

34 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 34 were considered. Additionally, only studies available in English and obtainable as full-text using the University of Hawaii at Hilo journal subscriptions were used. Only interventions focused upon weight loss were considered and limited to the following intervention strategies: switching medications, adjunct medications, and behavioral interventions. Combination interventions (such as adjunct medication plus behavioral intervention) were excluded with the assumption that combination therapies are generally considered more effective than single interventions alone. Interventions that did not focus primarily upon weight or did not report weight-related outcomes were excluded. Interventions focused upon dietary and physical activity changes were also excluded, as these are considered standard care for weight management. Studies of child, adolescent, and inpatient populations were excluded as the guideline was focused upon adults in the outpatient setting. Data Extraction and Quality Assessment Potentially relevant studies were identified for each review question and search result titles and abstracts were screened according to the inclusion and exclusion criteria. Those papers identified for inclusion were then obtained in full text and further reviewed against the inclusion and exclusion criteria. The studies were then classified according to a hierarchy of evidence, utilizing systematic reviews first and then high-quality randomized-controlled trials. Evidence quality was assessed according to the GRADE criteria (Appendix C). Data Synthesis and Analysis Evidence for medication switching, pharmacological augmentation, and behavioral interventions were separately synthesized and displayed as evidence summaries using the GRADEpro software. Data from randomized controlled trials were entered into the RevMan5 software according to the outcomes of interest. Furthermore, the individual studies were

35 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 35 evaluated for risk of bias and a risk of bias summary was generated for each of the interventions (Appendix D). Pooled data was then depicted in forest plots for each intervention and according to the outcomes of interest (Appendix E). This pooled data was then exported to the GRADEpro software to generate evidence tables (Appendix O, pp ) and summary of findings tables (Appendix O, pp ). These summaries included GRADE ratings for each intervention described, according to the quality assessment domains included in the GRADEpro software. Recommendations for clinical practice were then developed according to the GRADE standards (Appendix F) and utilizing the Guideline Development Tables included in the GRADEpro software. Evidence-to-decision tables generated by the GRADEpro software are displayed in Appendix O (pp ). Recommendations were then organized in the form of a guideline (Appendix O), along with a proposed management algorithm (Appendix O, p. 181) that reflects the study findings and other sources of evidence-based practice. Evaluation The final product of the project (the practice guideline) was evaluated by a small panel of interdisciplinary experts and stakeholders. Invited participants included experts from academia, behavioral health, primary care, and family members of patients affected by antipsychoticassociated weight gain. Participants were recruited via networking by the researcher through personal and professional contacts. The AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument was used by panel members to evaluate the practice guideline produced by the project. The AGREE II instrument is a standardized method to assess the quality of guidelines. It is a generic instrument that can be applied to guidelines in any disease and any step in the healthcare continuum (i.e. prevention, management, public health). Key domains measured by the AGREE II instrument include: scope and purpose, stakeholder

36 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 36 involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Additionally, the AGREE II instrument includes a rating of the overall quality of the guideline and whether the guideline would be recommended for use in practice. The statements used for assessments in each domain are listed in Appendix G. Finally, the AGREE II developers recommend that an evaluation panel contain no less than 2 people and preferably greater than 4 evaluators to increase the reliability of the assessment (AGREE Next Steps Consortium, 2009). For this project, invitations were sent to 11 prospective participant evaluators. For those that returned consents, a digital or paper copy of the guideline was distributed to the evaluators and a link to an on-line survey containing the AGREE II questions was sent via . Once the AGREE II evaluations were collected, descriptive statistics were generated summarizing the ratings (by domain, question, and overall score). Additionally, the written comments offered by the evaluators were summarized by describing the major themes identified. Ethics and Human Subjects Protection The research project proposal was submitted to the Institutional Review Board (IRB) of the University of Hawaii as an exempt application, as the project did not involve experimentation with human participants. For evaluators of the guideline, a consent form (Appendix H) was used to ensure their rights and responsibilities as participants in a research project. This consent, along with the project application was approved by the IRB on March 5, 2015 (Appendix I). Copies of the consents have been kept on a digital file by the author. The identities of the participants were not required for submission of the evaluation responses.

37 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 37 Chapter 4: Results The following section describes the objective results of the project in two parts. The first part refers to the results of the systematic review and the final synthesis of the evidence, the clinical practice guideline. The second part of this section describes the feedback from the evaluators of the guideline, using both descriptive statistics and summaries of the comments according to the major themes identified. Part 1: Systematic Review and Clinical Practice Guideline As described in the project design, a systematic search was conducted using 4 electronic databases using series of key search terms for each intervention. After applying the inclusion and exclusion criteria, 21 articles were included in the evidence review, including 12 systematic reviews and 9 high-quality randomized controlled trials. Appendix O (pp ) provides flow diagrams of the article selection according to each review question. Note that the number of systematic reviews cited in the flow diagrams is greater than the 21 articles stated here. This discrepancy results from systematic reviews that included more than one intervention type in their analysis, and were therefore, listed more than once in the article selection process. Tables of database findings are included in Appendix J and tables of excluded studies are included in Appendix K. Initially, it was hoped that data from the systematic reviews could be used to generate summary of findings tables and evidence summaries directly. Given the narrow scope of the PICO questions, however, randomized controlled trials were extracted from these systematic reviews and the data were collected for meta-analyses according to each intervention. Pooled data was summarized using forest plots (Appendix E) according to the following outcomes of interest:

38 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN Weight change 2. Global state 3. Adverse effects 4. Serious adverse effects 5. Discontinuation of treatment The findings were then validated by comparing pooled data to the outcomes of similar meta-analyses reported in the systematic reviews identified in the evidence search. Additionally, each study included in the meta-analyses and summary of findings tables were critically appraised using a risk of bias tool embedded in the RevMan5 software. A summary of the risk of bias assessments for each of the included studied can be found in Appendix D and a description of all included studies can be found in Appendix L. Once the studies were appraised and the data were pooled, the results were exported to the GRADEpro software. This software includes another quality of evidence rating tool, which allows the reviewer to grade evidence according to the outcomes of interest. Additionally, outcomes were rated according to the GRADE methodology outlined in Appendix B. Evidence tables were then generated for each intervention (Appendix O, pp ) following the GRADE criteria embedded in the software. Furthermore, these evidence tables were then used to generate summary of findings tables (Appendix O, pp ), a recommended format for presenting the findings of systematic reviews. Synthesis of the evidence into a clinical practice guideline was facilitated by the GRADEpro software s evidence-to-decision guideline development template. Key questions were addressed by reviewing the evidence from the systematic review and by referencing additional articles related to patient preferences, medication side-effects, resource utilization,

39 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 39 incremental costs, and feasibility of implementing recommendations. From these evidence-todecision tables (Appendix O, pp ), a guideline was written following the web-based format utilized by AHRQ s National Guideline Clearinghouse (AHRQ, 2015). Additionally, an algorithm (Appendix O, p. 181) was developed to synthesize the recommendations included in the guideline. The full guideline, along with supporting documentation, is found in Appendix O. Part 2: Guideline Evaluation As described in the project design, participants were recruited to evaluate the clinical practice guideline in Appendix O. Eleven potential evaluators were identified and a recruitment flyer and consent were sent by to each prospective participant by . In response, nine people returned signed consents to the principle investigator. For those consenting to participate, either a digital or paper copy of the guideline was provided according to evaluator preference. Additionally, each evaluator received an with a hyperlink to a web-based survey containing the AGREE II questions. Included with each question in the web-based survey were AGREE II user manual instructions to provide clarity. For each survey question/statement, participants were asked to rate their answer on a 7-point Likert scale (1-strongly disagree to 7 strongly agree). Additionally, a comment box was provided for each question to allow for optional evaluator feedback. Of the nine participants, seven completed the on-line survey. Data was collected on May 5, 2015 for the evaluator responses and a summary is provided in Appendix M. The following section provides a description of the evaluators, along with a summary of the responses from each of the six domains from AGREE II survey, and a final summary of the overall evaluation of the guideline according to the responses of the participants.

40 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 40 Evaluators. Seven people participated in the guideline evaluation. Among these were two academics/professors (one specializing in pharmacy and the other in neuroscience), one advance practice nurse, two physicians (one primary care physician and one psychiatrist), one psychologist, and one family member of a patient affected by antipsychotic-associated weight gain. Additionally, the family member is also a registered nurse working in acute behavioral health. Of the these stakeholders, two identified their clinical specialty as academic/research, four as behavioral/mental health, one as primary care, two as pharmacology, and one as other. Scope and purpose. In general, the majority of evaluators (85.7%) rated the guideline 6 or higher in the various aspects of this domain. Strengths identified in the comments include that the objectives were clear and concise, and the health questions were straight-forward and relevant. Limitations identified by evaluators included a need to address the health risks associated with obesity such as metabolic dysfunction, diabetes, and cardiovascular disease. Additionally, some evaluators noted that the target population was too generalized and the diagnoses were not specific enough. Stakeholder involvement. The results for this domain were mixed, with evaluators somewhat divided in two of the three questions/statements. For example, only 66.7% of evaluators agreed or strongly agreed (rated 5 or higher) that the views and preferences of the target population (patients, public, etc.) had been sought. The remaining participants (33.3%) rated this question as a 4 or neutral. Evaluators commented that more information regarding patient perspectives should be provided, particularly in regard to what patients believe is (or is not) effective in weight management. Likewise, only 57.1% of participants strongly agreed that the guideline development group (i.e. evaluators) included individuals from all relevant professional groups. Suggestions for professionals to involve in the guideline evaluation

41 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 41 included registered dieticians, social workers, and staff in forensic settings such as prisons and probation offices. Evaluators were more unified, however, in their response to the AGREE II statement regarding the target users of the guideline, with 85.7% of participants strongly agreeing that target users were clearly defined. Comments from this section indicate, however, that the target user group could have been expanded, such as to patients in the long-term care setting. Rigor of development. Responses in this domain were mostly favorable, with one major exception: a procedure for updating the guideline. Reviewers were mixed in their response to this statement, noting that they could not find information to answer the question. Indeed, the only mention of an update for the guideline, was in reference to modifications that might be made after feedback from the evaluations. In other areas, however, the majority of evaluators agreed or strongly agreed that systematic methods were used to search for evidence (71.4%), that the criteria for selecting the evidence was clearly described (85.7%), that the strengths and limitations of the body of evidence were clearly described (100%), that the methods for formulating the recommendations were clearly described (100%), that the health benefits, side effects, and risks have been considered in formulating the recommendations (71.5%), that there was an explicit link between the recommendations and the supporting evidence (100%), and that the guideline has been externally reviewed by experts prior to its publication (100%). Strengths identified in the comments include that the review was thorough, with excellent data sources and categorization. Limitations offered in the comments included a lack of explanation for the exclusion of FDA approved obesity management medications, the lack of adequate long-term follow up in the included studies, concern about whether sufficient attention was given to the side-effects of adjunct medications, a need for further discussion of co-morbidities, and the need

42 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 42 for additional information regarding the emerging knowledge of the role of genetics in the development of obesity. Clarity of presentation. The reviewers were unified in their reporting regarding the clarity of the guideline presentation. On all questions/statements for this domain, evaluators agreed or strongly agreed that the recommendations were specific and unambiguous (100%), that the different management options were clearly presented (100%), and that key recommendations were easily identifiable (100%). Limitations offered in the comments included the need for specific dosages, the need for guidance with managing complications and co-morbidities, and the concern about the limited scope of the guideline (which only targets weight gain). Applicability. The evaluators were largely unified in their response regarding the applicability of the guideline. The majority (83.3%) agreed or strongly agreed that the guideline described facilitators and barriers to its application, however, the comments indicated that this area could have been expanded with extra attention given to patient acceptance of the risks involved, patient adherence to recommendations, and reimbursement issues related to off label use of medications and referral to specialists. Additionally, 100% of respondents agreed or strongly agreed that the guideline provided advice and/or tools on how the recommendations could be put into practice. In particular, comments noted that the algorithm was easy to follow and put into practice. One commenter suggested, however, that an additional test (Hemoglobin A1c) be included in the assessment and monitoring. In regard to resource implications for applying the recommendations, the majority (83.3%) agreed or strongly agreed that these had been considered in the guideline. Commenters noted, however, that this section could have been expanded to include reimbursement issues and availability of specialists. Finally, 100% of

43 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 43 evaluators agreed or strongly agreed that the guideline presented monitoring and/or auditing criteria. Editorial independence. Questions in this domain were difficult for respondents to answer, as issues regarding editorial independence (such as funding and competing interests) were not explicitly addressed in the guideline. For the current draft of the guideline, no funding was provided to the author and the competing interests of the guideline evaluators were not surveyed. Overall guideline assessment. The guideline received favorable overall ratings, with 14.3% of evaluators rating it as a 5, 57.1% of evaluators rating it as a 6, and 28.6% of evaluators rating it as a 7. Additionally, 50% of respondents would recommend the guideline for use without any modifications and 50% would recommend it with some modifications. One evaluator did not answer this question. Evaluators who offered comments in this section noted a desire for more literature regarding the use of metformin before supporting the recommendations and suggested that perhaps cognitive-behavioral therapy should play a more dominant role in the algorithm. Other comments were consistent with those offered in the previous domains.

44 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 44 Chapter 5: Recommendations and Conclusions The following section describes how the results of the project are linked with project s purpose and how the aims and objectives were achieved. Furthermore, the guideline developed from the project is discussed from the author s perspective, in light of the evaluation results. Additionally, facilitators and barriers to the project are reviewed and limitations to the project are discussed. Purpose, Aims, and Objectives The purpose of this project was to develop evidence-based practice recommendations for the management of antipsychotic-associated weight gain in adults. This was accomplished by using a structured methodology to develop a clinical practice guideline targeting this problem. The purpose of the project was supported by two primary aims. The first aim was to improve the care and treatment of adults with SMI by effectively addressing their population-specific physical health concerns through the development of evidence-based recommendations designed to assist primary care providers in the management of antipsychotic-associated weight gain. Objectives for achieving this aim included: 1. Conduct a structured literature review investigating interventions for managing antipsychotic-associated weight gain. 2. Analyze the literature to both grade and compare interventions. 3. Determine best practice recommendations for the management of weight gain in adults taking antipsychotic medications. Each of the above objectives were achieved using the methods described in chapter 3. Briefly, these methods included: a systematic review of the literature according to the PICO questions created, identification of studies meeting the inclusion and exclusion criteria, meta-

45 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 45 analysis of the data from the highest quality evidence available for each intervention strategy and according to the identified outcomes, quality assessment of the included studies, prioritization of the outcomes, quality assessment of the evidence according to the outcomes, synthesis of the evidence in summary of findings tables, analysis and comparison of the interventions according to the quality of the evidence, and formulation of recommendations using a structured evidenceto-decision framework. The second aim of the project was to promote the translation of new knowledge into health care practice by achieving the following objectives: 4. Synthesize findings into an evidence-based algorithm and guideline for managing antipsychotic-associated weight gain in the primary care setting. 5. Discuss the relevance of medication-associated weight gain to advanced nursing practice. 6. Suggest strategies for advanced nursing practice that promote the IOM s aims for quality care, specifically those relating to the safe, effective, and equitable care of patients. Only one of the above objectives has thus far been addressed, which is the synthesis of the project findings into an evidence-based algorithm and guideline. The product of this objective is included in Appendix O. As for the objectives numbered five and six, these are discussed in the last chapter of this manuscript. The Guideline The product of this project, the clinical practice guideline (Appendix O), was favorably received by a diverse panel of stakeholders with clinical expertise in family practice, advanced nursing practice, psychiatry, psychology, pharmacology, and neuroscience. Although some of

46 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 46 the domains measured by the AGREE II instrument were more weakly rated than others, the guideline currently provides a sound foundation for establishing best-practices in the management of antipsychotic-associated weight gain in adults. Previously, peer-reviewed articles have offered clinical practice advice for this problem (Alvarez-Jimenez, Hetrick, Gonzalez-Blanch, Gleeson, & McGorry, 2008; Bonfioli, Berti, Goss, Muraro, & Burti, 2012; Buckley & Correll, 2008; Fiedorowicz, Miller, Bishop, Calarge, Ellingrod, & Hayes, 2012; Hasnain, Vieweg, & Hollett, 2012; Maayan & Correll, 2010; Mizuno, et al., 2014), but to date, none has offered a comprehensive guideline for providers. This guideline developed during this project helps to fill this need. Additionally, the external review of the guideline using a structured evaluation completed by key stakeholders, helps to strengthen its validity for future use in practice. Project Facilitators The successful completion of this project was facilitated by: Free access to an extensive body of evidence made easily available through electronic databases and the internet Availability of free software for analyzing and synthesizing data Availability of free web-based tutorials for using the software and applying the GRADE methodology Easy dissemination of guideline and evaluation instrument using and webbased surveys Willingness of stakeholders to take the time to evaluate the guideline Project Barriers Barriers to the successful completion of this project included:

47 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 47 Time constraints An overwhelming body of evidence that required the scope of inquiry to be substantially narrowed Lack of technical skill required for using related software and appropriately applying the GRADE methodology Lack of a guideline development group at the outset Lack of cost-analysis data for the interventions recommended in the guideline Project Limitations There were several limitations to this project, but most important among them, was the fact that the guideline was developed with only one researcher/author. In nearly all systematic reviews, articles are critiqued against inclusion and exclusion criteria by at least two authors. This helps to reduce both the risk of bias and error in article selection. The same is true with evaluating the quality of studies included in the evidence summaries. Although the GRADE approach offers structured, specific guidance for assessing risk of bias and the quality of evidence, ultimately, these decisions remain part of the subjective purview of the assessors. Likewise, according to the GRADE methodology, guidelines panels (comprised of multiple individuals with diverse expertise) should be involved in formulating the guideline recommendations before development. Recommendations are typically negotiated among panel members through discussion, reflection, and debate that considers the quality of evidence, the balance of benefits and harms, the values and preferences of stakeholders (including patients), and the anticipated resources needed (costs). Although some of these elements were addressed by having the guideline externally reviewed and evaluated, multiple people should have been involved in all phases of the guideline development; from formulating the PICO questions to

48 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 48 conducting the systematic review, and from assessing the quality of evidence to making recommendations. Other limitations of the project include the narrow scope of the guideline, the lack of long-term follow up for the interventions, the limited number of studies included in the metaanalyses, and the lack of data regarding patient preferences and cost-effectiveness of interventions. There are many reasons for these limitation, but most significantly, is the fact the project was conducted by a sole individual. Sole authorship required a narrow scope, to make the project manageable. This narrow scope then limited the number of studies for meta-analysis, again, to make the project more manageable. As for the lack of long-term follow up for interventions, this gap in the literature is a concern of many authors of systematic reviews examining the problem of antipsychotic-associated weight gain and calls have been made for longer term studies. Likewise, the lack of studies examining patient preferences and the costeffectiveness of proposed interventions represent significant gaps in the literature. Further studies examining these issues will help with the development of a more comprehensive and patient-centered guideline in the future. Plan for Revision Given the limitations of this project, a prudent plan for revision of the guideline includes additional inquiry into patient perspectives regarding antipsychotic medications, medicationassociated weight gain, barriers to treatment adherence, and prioritization of treatment outcomes. Additionally, the guideline would clearly benefit from greater participation by key stakeholders and a more explicit explanation for the exclusion of medications and treatments targeting at obesity in the general population. These changes must be implemented before the guideline can be submitted for dissemination to providers and patients.

49 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 49 Chapter 6: Implications for Practice The following section provides a discussion regarding the project s contributions to practice and identifies research possibilities for future projects. Furthermore, objectives five and six of the project are addressed by describing the project s relevance of antipsychotic medication-associated weight gain to advanced nursing practice and suggesting strategies for promoting the Institute of Medicine s aims for quality care, specifically those relating to safe, effective, patient-centered, and equitable care. Relevance to Advanced Nursing Practice The use of SGAs for a wide spectrum of conditions continues to increase (Alexander, et al., 2011; Olfson, et al., 2014). As these medications become more commonly prescribed, it is prudent for advance practice nurses to be aware of the significant metabolic effects SGAs can have upon the patients taking them. Likewise, the advance practice nurse must be familiar with the recommended metabolic monitoring parameters for patients receiving SGAs, as well as informed about the most effective interventions for addressing adverse effects such as glucose dysregulation, insulin resistance, dyslipidemia, and weight gain. Additionally, as obesity rates continue to increase, advanced practice nurses must learn to tailor weight loss interventions to probable causes that are specific to the individual patient, such as the weight-gain effect associated with many psychotropic medications. Contributions to Practice The major contribution to practice achieved by this project is the establishment of a clinical practice guideline for managing antipsychotic-associated weight gain. As noted previously, although several articles exist that provide clinical practice advice for this problem, to date, none have comprehensively summarized the evidence-based interventions into a single

50 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 50 guideline. The development of this guideline provides clinicians with evidence-based tools that are specifically targeted at this known, predictable cause of obesity. These tools are meant to both complement and support more universal approaches to weight management, and are explicitly designed to address the population-specific health concerns of individuals with mental illness, particularly those taking antipsychotic medications. Furthermore, the guideline is designed to promote the IOM quality care aims for safety, effectiveness, patient-centeredness, and equity. Safety. The IOM calls upon the healthcare system, and related professionals, to provide treatment that does not result in additional harm or injury to patients (Berwick, 2002). In the case of SGAs, while these medications have a positive impact upon a wide range of psychiatric symptoms, they are also associated with significant metabolic changes that can have long-lasting negative physical and social effects upon patients. This project helps to both raise awareness of the adverse effects of SGAs and provide needed tools for clinicians to intervene early, ideally limiting the negative impact these medications may have upon patients. Additionally, the project s use of the GRADE methodology helps to promote greater recognition of evidence summaries, which clinicians can use to more efficiently translate the latest scientific knowledge into everyday clinical practice. Such evidence summaries provide a standardized format to assist clinicians with quickly evaluating the safety outcomes of treatment interventions across multiple studies. To advance the IOM s quality care aim of safety, healthcare professionals should use evidence summaries regularly to assess key outcomes, particularly when weighing the risks and benefits of treatment options with patients. Effectiveness. The IOM asserts that the healthcare system should only provide services and interventions that are based upon scientific knowledge (Berwick, 2002). In the context of

51 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 51 obesity, interventions must be targeted at the underlying cause of weight gain in order to be effective. This project identified evidence-based strategies for managing weight gain caused by antipsychotic medications by creating evidence summaries using the GRADE methodology. This GRADE approach was specifically designed to translate scientific knowledge into clinical practice, by providing researchers and clinicians with a standardized system for both rating the quality of evidence and determining the strength of clinical practice recommendations. To advance the IOM s quality care aim of effectiveness, healthcare professionals should use evidence summaries to assess the outcomes of interventions. Likewise, researchers and guideline developers should use the GRADE methodology to ensure high-quality, transparent, and evidence-based clinical practice recommendations. Patient-centeredness. In a paradigm shift for understanding the patient-provider relationship, the IOM calls on healthcare professionals to honor and respect a patient s culture, social context, specific needs, and individual choices (Berwick, 2002). In regard to SGAs and weight gain, this project addressed the social and physical impact of this medication side effect by seeking out evidence-based interventions to address the problem. Too often, patients are blamed for weight gain and obesity, resulting in stigmatization and poorer quality of care (Puhl & Heuer, 2009). This project helps clinicians focus upon the specific needs of patients, by raising awareness about the problem of medication-associated weight gain and providing evidence-based solutions. Furthermore, the unique health challenges of individuals with mental illness are targeted, namely, the much higher rates of obesity in this population. Likewise, medication adherence is a known problem for individuals diagnosed with mental illness, with weight gain identified as a significant reason for not taking the prescribed psychotropic medications (Correll, et al., 2011; Lett, et al., 2011; Mukundan et al., 2010; Weiden, et al., 2004).

52 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 52 In order to meet the IOM quality care aim of effectiveness, providers should consider patient concerns about weight gain when selecting medications. Likewise, developers of clinical practice guidelines should seek out patient values and preferences at the outset (and throughout) the guideline development process, while also encouraging greater patient participation in guideline development. Equity. The IOM, recognizing the problem of growing health disparities, calls upon healthcare professionals to provide care that does not vary in quality due to personal characteristics and tasks the healthcare system with closing gaps in health status experienced by vulnerable populations (Berwick, 2002). This project focused upon reducing the health disparities experienced by individuals with mental illness by developing a guideline targeted at population-specific health care needs. The aims and objectives of this project were driven by the observation that obesity rates among individuals with mental illness are markedly higher than the general population (De Hert, et al., 2011). By providing evidence-based solutions for antipsychotic-associated weight gain, this project helps to promote medication adherence, improve physical health and related quality of life, and ultimately, reduce morbidity and mortality for patients with mental illness. Healthcare professionals can support the IOM quality care aim of equity by learning more about health disparities and seeking out ways to uncover, challenge, and change the implicit and explicit biases (we all have) that are associated with the physical and social characteristics of vulnerable populations. For researchers, healthcare policy makers, and guideline developers, consider health disparities as a starting point for clinical practice problems.

53 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 53 Future Projects There are many future research possibilities related to this project. In particular, additional research is needed regarding the long-term impact of antipsychotic-associated weight gain upon the overall quality of life, physical health, and treatment adherence patterns of patients affected by this problem. Likewise, additional studies comparing the various interventions for managing antipsychotic-associated weight gain (particularly studies with long-term follow up) are needed to help clarify the safest and most effective treatments. Finally, there is a paucity of costanalysis research for interventions targeted at managing antipsychotic-associated weight gain. Such information would be valuable to both practitioners and policy-makers as organizations strive for greater efficiency in healthcare spending. Additional research in all of these areas will help healthcare professionals promote the IOM s aims for patient care that is safe, effective, patient-centered, and equitable.

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87 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 87 Appendix A List of Second-Generation Antipsychotics Aripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone

88 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 88 Appendix B Summary of GRADE method for rating importance of study outcomes (Guyatt, et al., 2011). Reproduced with permission.

89 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 89 Appendix C Summary of the GRADE approach to rating quality of evidence (Balshem et al., 2011). Initial Rating of Quality of Evidence HIGH Randomized Trials LOW Observational Studies Criteria for Rating Evidence HIGHER Large Effect +1 Large +2 Very large Dose Response +1 Evidence of a gradient Residual Confounding +1 Would reduce demonstrated effect +1 Would suggest a spurious effect if no effect was observed Criteria for Rating Evidence LOWER Risk of Bias -1 Serious -2 Very serious Inconsistency -1 Serious -2 Very serious Indirectness -1 Serious -2 Very serious Imprecision -1 Serious -2 Very serious Publication Bias -1 Likely -2 Very likely Significance of Overall Quality of Evidence Quality Level Symbol Definition HIGH We are very confident that the true effect lies close to that of the estimate of the effect MODERATE We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different LOW Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect VERY LOW We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

90 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 90 Appendix D Risk of Bias Summaries Figure D1: Risk of bias summary for medication switching studies.

91 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 91 Figure D2: Risk of bias summary for adjunct medication studies. Figure D3: Risk of bias summary for cognitive behavioral studies.

92 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 92 Appendix E Forest Plots According to Intervention and Outcomes Figure E1: Forest plot comparison: Medication switching, outcome weight loss. Figure E2: Forest plot comparison: Medication switching, outcome global state. Figure E3: Forest plot comparison: Medication switching, outcome any adverse effect. Figure E4: Forest plot comparison: Medication switching, outcome serious adverse effect. Figure E5: Forest plot comparison: Medication switching, outcome discontinuation of treatment.

93 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 93 Figure E6: Forest plot comparison: Adjunct medication, outcome weight loss. Figure E7: Forest plot comparison: Adjunct medication, outcome global state. Figure E8: Forest plot comparison: Adjunct medication, outcome adverse effects (no data).

94 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 94 Figure E9: Forest plot comparison: Adjunct medication, outcome serious adverse effects. Figure E10: Forest plot comparison: Adjunct medication, outcome discontinuation of treatment. Figure E11: Forest plot comparison: Cognitive behavioral therapy, outcome weight loss.

95 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 95 Figure E11: Forest plot comparison: Cognitive behavioral therapy, outcome discontinuation of treatment.

96 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 96 Appendix F Summary of the Determinants of the Strength of Recommendations Based Upon the GRADE Approach (Andrews, et al., 2013). Determinants Quality of Evidence Balance of Benefits & Harms Values and Preferences Resource Allocation (Costs) Explanation Higher quality evidence supports a strong recommendation, lower quality evidence more likely to warrant a weak recommendation Greater benefit than harm supports a strong recommendation, while smaller or more uncertain benefit more likely to warrant a weak recommendation Greater variability in values and preferences more likely to warrant a weak recommendation Higher cost of intervention more likely to warrant a weak recommendation

97 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 97 Appendix G AGREE II Instrument Questions

98 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 98 Appendix H Consent Form for Guideline Evaluators.

99 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 99 Appendix I Institutional Review Board Approval Letter

100 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 100 Appendix J Summary of Database Findings Table J1: Database Findings Medication Switching Database Key Words Results Cochrane Library Antipsychotic* 148 Search limits: -Cochrane reviews -Between MEDLINE (EBSCO) Search limits: -Full text -Between All adult -English language CINAHL (EBSCO) Search limits: -Full text -Between All adult -English language Web of Science Search limits: -Between English language Antipsychotic* AND weight* Antipsychotic* AND weight* AND switching Antipsychotic* Antipsychotic* AND weight* Antipsychotic* AND weight* AND switching Antipsychotic* Antipsychotic* AND weight* Antipsychotic* AND weight* AND switching Antipsychotic* Antipsychotic* AND weight* Antipsychotic* AND weight* AND switching Refine: Science & technology only Refine: Review Refine: English Refine: Web of Science Core Collection (Excludes MEDLINE and Biological Abstracts) , ,454 7,

101 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 101 Table J2: Database Findings Adjunct Medications Database Key Words Results Cochrane Library Antipsychotic* 170 Search limits: -Reviews -Between MEDLINE (EBSCO) Search limits: -Full text -Between All adult 19+ years -English language CINAHL (EBSCO) Search limits: -Full text -Between All adult -English language Web of Science Search limits: -Between English language Antipsychotic* AND obes* Antipsychotic* Antipsychotic* AND obes* Antipsychotic* AND obes* AND intervention* Antipsychotic* AND obes* AND metformin Antipsychotic* AND obes* AND topiramate Antipsychotic* Antipsychotic* AND obes* Antipsychotic* AND obes* AND intervention* Antipsychotic* Antipsychotic* AND obes* Antipsychotic* AND obes* AND intervention* Antipsychotic* AND obes* AND intervention* AND systematic review 5 2, ,592 1,

102 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 102 Table J3: Database Findings Behavioral Interventions Database Key Words Results Cochrane Library Antipsychotic* 170 Search limits: -Reviews -Between MEDLINE (EBSCO) Search limits: -Full text -Between All adult 19+ years -English language CINAHL (EBSCO) Search limits: -Full text -Between All adult -English language Web of Science Search limits: -Between English language Antipsychotic* AND obes* Antipsychotic* Antipsychotic* AND obes* Antipsychotic* AND obes* AND intervention* Antipsychotic* AND obes* AND intervention* AND behav* Antipsychotic* Antipsychotic* AND obes* Antipsychotic* AND obes* AND intervention* Antipsychotic* Antipsychotic* AND obes* Antipsychotic* AND obes* AND intervention* Antipsychotic* AND obes* AND intervention* AND behav* Antipsychotic* AND obes* AND intervention* AND behav* AND systematic review 5 2, ,656 1,

103 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 103 Appendix K Characteristics of Excluded Studies Table K1: Characteristics of Excluded Studies Medication Switching Study Characteristics Reason for exclusion Aguis 2010 Type: Review Sample: 5 major studies involving antipsychotics No mention of weight in relation to medication switching Andersen 2005 Arnoldy 2013 Type: pilot study, non-randomized Sample: 6 adults with schizophrenia spectrum diagnoses who had experienced significant weight gain after long-term treatment with olanzapine and/or risperidone Intervention: Switch to perphenazine plus buspirone Type: case study Sample: 56 year-old male with schizophrenia Intervention: switched from clozapine to aripiprazole Non-randomized; Very small sample; Switch to conventional antipsychotic plus a non-antipsychotic medication; Average 10 kg weight loss Lowest level of evidence Berner 2007 Type: Systematic Review No mention of switching to reduce weight gain Bhuvaneswar 2009 Bobo 2010 Buchanan 2010 Type: Narrative review Topic: Adverse endocrine and metabolic effects of psychotropic drugs Type: Review Intervention: olanzapine-fluoxetine combination (Symbyax) Type: Expert consensus statement Topic: Treatment recommendations for schizophrenia No usable data; Saved for general overview Focus on adding antipsychotic to antidepressants for treatment resistant depression No usable data; Saved for general overview Buckley 2008 Pending ILLiad request No full text available Buckley 2008 Type: Narrative review Topic: Strategies for switching antipsychotics No usable data; Some references extracted for further review Cassano 2007 Type: Review Topic: Aripiprazole in schizophrenia No specific data regarding weight change when switching to aripiprazole

104 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 104 Chawla 2008 Type: Prospective, non-controlled cohort study Sample: 26 patients taking standard oral olanzapine Intervention: switch to orally disintegrating tablets No control group; Olanzapine known cause of weight gain Citrome 2007 ILLiad request submitted No full text available Citrome 2008 ILLiad request submitted No full text available Citrome 2009 Type: Article Intervention: Switch to ziprasidone No specific numbers provided regarding weight loss and switch to ziprasidone Citrome 2012 Type: Narrative Review Limited data on weight loss as a result of switching Citrome 2012 Citrome 2014 Citrome 2014 Cohn 2007 Type: Review article Topic: lurasidone Type: systematic review Sample: 22 articles Intervention: aripiprazole Type: Systematic Review of observational/naturalistic studies and open-label studies Topic: effects of aripiprazole on weight and metabolic outcomes Type: Review Topic: Metabolic monitoring in patients taking antipsychotics No usable data; No switching studies included No medication switching mentioned Observational, openlabel, noncontrolled; No usable data; Selected citations reviewed for further use Mostly focused on monitoring, not intervention; Saved for overview Correll 2010 No abstract available No full text available Cousins 2007 Type: Review No mention of Topic: Treatments for bipolar disorder switching to reduce Croxtall 2008 De Fazio 2010 Type: review Sample: Adults with schizophrenia Intervention: taking or switched to aripiprazole Type: Review article Topic: aripiprazole weight gain Only includes one study of medication switching to aripiprazole and effect on weight (Newcomer, 2008); Newcomer 2008 already included in Cochrane Review (Mukundan, 2010) No usable data; No mention of switching to reduce weight gain

105 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 105 Dell Osso 2013 Dold 2012 Edlinger 2005 Edwards 2008 Essock 2006 Fabiolini 2013 Faulkner 2006 Gallego 2012 Ganguli 2008 Type: Review Sample: Unknown Type: systematic review Sample: 34 studies with 2657 participants Intervention: randomized controlled trials comparing benzodiazepines (as monotherapy or as adjunctive agent) with antipsychotic drugs or placebo for the pharmacological management of schizophrenia and/or schizophrenia-like psychoses Type: Review article Topic: Switching second-generation antipsychotics Type: Review of clinical trials Topic: Clinical outcomes and cost analysis Type: Secondary analysis of randomized controlled trial Sample: Data from Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) Intervention: switching versus staying on antipsychotic monotherapies Type: Review Sample: Unknown Type: Narrative review Topic: Strategies for management of weight gain in patients taking antipsychotic medication Type: Systematic Review Topic: Safety of antipsychotic polypharmacy Type: randomized, open-label Sample: 123 adult patients taking olanzapine Intervention: switch to risperidone No mention of medication switching Does not specifically address weight loss; Does not switch between antipsychotics No usable data; All studies referenced older than 2005; None of the studies have weight as a primary outcome No mention of switching to reduce weight gain No outcome measures regarding weight change No full text available; Switching and weight loss not mentioned as inquiry for the review No usable data; Saved for general overview No mention of medication switching; No usable data Studied effect of switching method, therefore short duration, only 6 weeks; No significant weight change observed Gierisch 2014 ILLiad request submitted No full text available

106 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 106 Godleski 2005 Type: Open-label, nonrandomized Sample: 13 patients taking depot antipsychotic Intervention: switched to oral olanzapine No mention of switching to reduce weight gain; Olanzapine known cause of weight gain Gopal 2010 Type: Expert Review of clinical trials Focus only on longacting injectable paliperidone; no mention of weight Greenberg 2007 Type: Review No full text available Topic: ziprasidone Hasnain 2011 Type: Narrative Review Focused on adjunct medications; Saved for adjunct evidence summary Hasnain 2012 Type: Literature review Topic: weight gain and antipsychotics and antidepressants No usable data; Used for overview of problem Hasnain 2013 ILLiad request submitted No full text available Hawley 2010 Type: open-label, non-randomized Sample: 182 adults taking antipsychotics Intervention: switch to long-acting injectable risperidone Non-randomized; Majority of patients switching from conventional antipsychotic to atypical antipsychotic Hester 2005 ILLiad request submitted No full text available Hong 2012 Ishitobi 2013 Kantrowitz 2008 Karagianis 2008 Type: Observational study Sample: 17,000 outpatients with schizophrenia taking olanzapine or risperidone Intervention: switch to olanzapine or risperidone Type: prospective, open-label Sample: 9 male patients with autism spectrum disorders Type: Review Topic: Efficacy and safety of olanzapine Type: Narrative Review of case series Topic: Olanzapine standard tablets versus orally disintegrating tablets Observational; Olanzapine known cause of weight gain Includes children and adolescents No mention of switching to reduce weight gain; Olanzapine known cause of weight gain No usable data; Olanzapine known cause of weight gain

107 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 107 Kim 2009 Type: open-label, non-randomized Sample: 36 adults with schizophrenia taking conventional antipsychotics Intervention: switch to long-acting injectable risperidone Non-randomized; Patients switched from conventional antipsychotic to atypical antipsychotic; Significant weight gain after switch Kim 2010 ILLiad request submitted No full text available Lee 2013 Type: Prospective, open-label, noncontrolled Sample: 56 patients with bipolar disorder taking olanzapine Intervention: switch to ziprasidone No control group Liauw 2010 ILLiad request submitted No full text available Lin 2009 Type: prospective cohort study, nonrandomized Sample: 46 inpatient adults with schizophrenia, taking an SGA, with BMI >27 kg/m 2 Intervention: switch to amisulpride Not randomized, inpatient setting Lu 2007 Type: Prospective, observational Sample: 1267 outpatients with schizophrenia taking conventional antipsychotics Intervention: switch to olanzapine Switch from conventional antipsychotics; Olanzapine known cause of weight gain Martinez-Ortega 2013 Type: Review Sample: 127 reports Includes children and adolescents Medved 2009 Type: Article Focused on diabetes and psychiatric disorders; No mention of medication switching Meyer 2005 Montes 2007 Newcomer 2013 Type: Post-hoc analysis, open-label, non-randomized Sample: 121 patients with metabolic syndrome taking olanzapine Intervention: switch to risperidone Type: Observational, open-label Sample: 84 outpatients with schizophrenia or schizoaffective disorder experiencing some type of metabolic disturbance related to antipsychotic use Intervention: switch to ziprasidone Type: Literature review Topic: Switching antipsychotic medication Post-hoc, nonrandomized, no control group Observational No usable data; Some references extracted for further review

108 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 108 Nyhuis 2010 Type: post-hoc analysis of RCT Sample: 664 adults taking antipsychotics Intervention: Open-label switching between first generation antipsychotic, olanzapine, and risperidone Type: Randomized, open-label trial Sample: 175 patients (inpatient and outpatient) with schizophrenia considering switch due to inefficacy or intolerability Intervention: switch to aripiprazole using one of three different switching approaches Reports predictors of medication switching, not outcomes from switching Pae 2009 Outcome measures include BMI but not weight specifically; No usable data; No control group; Designed to test tolerability of switching method rather than switch effect upon weight Pani 2008 Type: Review article No usable data; No Topic: amisulpride reference to studies using switch to reduce weight gain Rege 2008 Type: Narrative review No usable data; Saved Topic: mechanisms and management of for general overview; antipsychotic induced weight gain Many duplicate studies in references Ried 2006 ILLiad request submitted No full text available Roffeei 2014 Rosa 2012 Rosenheck 2009 Type: Head-to-head controlled comparison Sample: 115 patients with schizophrenia with 1 year of metabolic abnormalities associated with antipsychotic use Intervention: switch to ziprasidone or aripiprazole Type: Prospective, non-randomized trial Sample: 96 adults with non-acute psychotic disorders taking olanzapine Intervention: switch to long-acting injectable risperidone Type: Secondary analysis of randomized controlled trial Sample: Data from Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) Intervention: switching versus staying on antipsychotic monotherapies No control group; Useful for comparing effects of ziprasidone or aripiprazole, but because no control, low quality evidence for switching strategy in general Non-random, no control group Outcome measures regarding weight do not include usable data; Switching was not explicitly intended to address weight gain

109 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 109 Rossi 2009 Type: open-label, non-randomized Sample: 347 adults with schizophrenia or schizoaffective disorder taking antipsychotics Intervention: switch to long-acting injectable risperidone Non-randomized; No information about type of antipsychotics taken prior to switch; No significant weight gain after switch Samtani 2011 Type: Narrative Review No mention of weight in regard to medication switching Schorr 2008 Suttajit 2014 Suzuki 2012 Takeuchi 2010 Tanaka 2008 Verma 2010 Type: Non-controlled cohort study Sample: 53 overweight patients with schizophrenia taking antipsychotics Intervention: switch to aripiprazole Type: Systematic review Sample: 11 RCTs Type: case study Sample: 19 year-old female with schizophrenia Intervention: switched from blonanserin to quetiapine Type: Observational Sample: 32 patients with schizophrenia taking antipsychotics Intervention: switch to aripiprazole Type: Clinical trail Topic: Metabolic effects of olanzapine Type: open-label trial Sample: 25 adults with schizophrenia spectrum disorders taking antipsychotics Intervention: switch to long-acting injectable risperidone No control group Includes children and adolescents; No switching mentioned Lowest level of evidence; blonanserin not available in the United States Observational study, no control group, no randomization No mention of switching to reduce weight gain; Olanzapine known cause of weight gain Weight loss was not the purpose of switching; Weight gain a significant outcome; Half of participants dropped out Wang 2014 Type: Review of three studies? Unclear Abstract does not mention switching; No full text available Weber 2009 Type: fictional case study Fictional case study Wehmeier 2007 Type: Prospective study Topic: Quality of life for outpatients with schizophrenia taking antipsychotics No mention of switching to reduce weight gain Weiden 2007 ILLiad request submitted No full text available

110 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 110 Weiden 2008 Ye 2012 Type: randomized cross-titration methods, no control group Sample: 185 outpatient adults taking risperidone, olanzapine, or conventional antipsychotic Intervention: switch to ziprasidone using varying cross-tapering methods Type: Naturalistic/observational study Sample: 258 patients with schizophrenia taking risperidone Intervention: switch to olanzapine No control group Observational; Olanzapine known cause of weight gain Table K2: Characteristics of Excluded Studies Adjunct Medication Study Characteristics Reason for exclusion Attux 2013 Type: RCT Sample: 160 adults taking SGAs Intervention: Lifestyle interventions No mention of medication for weight loss Baker 2011 Baptista 2006 Barnes 2008 Blouin 2009 Bonfioli 2012 Brown 2012 Type: Study protocol Sample: Adults with severe mental illness taking antipsychotic medication and current smoker Intervention: Lifestyle intervention Type: RCT Sample: 40 adults taking olanzapine Intervention: Metformin Type: quality improvement study Sample: adults taking antipsychotics Intervention: screening for metabolic syndrome Type: nonrandomized pilot study Sample: 16 adults taking SGAs Intervention: Lifestyle (diet & exercise) Type: Systematic Review Topic: Non-pharmacological interventions for weight management in psychosis Type: Retrospective study Sample: 95 adults with schizophrenia No intervention Study protocol; Focused on lifestyle interventions; No mention of medication for weight loss Reported in later review Focus on quality improvement screening program Focus on lifestyle interventions; No mention of medication for weight loss Focus on lifestyle interventions; No mention of medication for weight loss Focus on predictors of death from natural causes; No mention of medication for weight loss Involves children Brufani 2001 Type: Review article Topic: metformin in children Chen 2009 Type: Nonrandomized clinical Focus on lifestyle

111 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 111 Cimo 2012 Correll 2010 intervention study Sample: 33 adults taking SGAs with BMI >25 Intervention: Lifestyle mixed with behavioral Type: Systematic Review Topic: Lifestyle interventions to improve type II diabetes in patients with schizophrenia or schizoaffective disorder Type: Comparative review Topic: mood stabilizers and antipsychotics interventions; No mention of medication for weight loss Focus on lifestyle interventions; No mention of medication for weight loss Includes pediatric patients Curtis 2012 Type: Discussion paper Opinion piece DeHert 2011 Type: Evaluation of guidelines Topic: Screening and monitoring of cardiometabolic risk in schizophrenia Evans 2005 Fernandez 2014 Ha 2006 Type: RCT Sample: 51 adults taking olanzapine Intervention: nutritional Type: Systematic Review Topic: Lifestyle interventions to reduce cardiovascular risk in patients with severe mental disorders Type: Article Topic: Mechanism of action for topiramate on body weight Type: Systematic Review Topic: Male fertility and psychiatric considerations Focus on screening and monitoring; No mention of medication for weight loss Focus on nutritional interventions; No mention of medication for weight loss Focus on lifestyle interventions; No mention of medication for weight loss No new clinical data regarding efficacy for reducing body weight Hall 2012 Not relevant; No mention of medication for weight loss Haw 2012 Study of adolescents Includes adolescents Hellerstein 2007 Hjorth 2014 Johnstone 2009 Lin 2005 Type: Observational study Sample: charts of 105 adults at a community mental health center Type: Systematic Review Topic: Interventions to reduce overweight and obesity in schizophrenia Type: Qualitative study Topic: Barriers to physical activity in schizophrenia Type: case series Topic: 3 adults taking SGAs No intervention Medication interventions excluded; Saved for behavioral search Qualitative study; No intervention; No mention of medication for weight loss Case series; low level of evidence

112 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 112 McElroy 2007 McIntyre 2012 Ohlsen 2005 Pearsall 2014 Porsdal 2010 Intervention: topiramate Type: Comparative study, RCT Sample: 46 outpatients with bipolar taking antipsychotics or mood stabilizers Intervention: topiramate vs. sibutramine Type: Literature Review Topic: Evidence-Based Practice Recommendations for management of mood disorders with comorbid metabolic disorders Type: Nonrandomized Sample: adults with severe mental illness taking antipsychotics Intervention: lifestyle intervention Type: Systematic Review Topic: Exercise for patients with mental illness Type: Observational study Sample: 363 adults attending psychiatric clinics Intervention: Lifestyle intervention Includes mood stabilizers Does not specifically address antipsychotic medications and weight gain Focus on lifestyle interventions; No mention of medication for weight loss Focus on lifestyle interventions; No mention of medication for weight loss Focus on lifestyle interventions; No mention of medication for weight loss Roberts 2011 Type: Narrative Review Focus on lifestyle interventions; No mention of medication for weight loss Seeman 2008 Shin 2008 Usher 2013 Vandyk 2012 Verhaeghe 2011 Type: Perspective article Intervention: Preventative services for women with schizophrenia Type: Review article Topic: obesity in children taking SGAs Type: RCT Sample: 101 adults taking SGAs Intervention: Lifestyle interventions Type: Qualitative study Sample: 18 patients with schizophrenia and medication-induced weight gain No intervention Type: Systematic Review Topic: Lifestyle interventions in persons with severe mental disorders Focus on preventative health interventions; No mention of medication for weight loss Involves children No mention of medication for weight loss Qualitative study; No intervention; No mention of medication for weight loss Focus on lifestyle interventions; No mention of medication

113 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 113 Vieweg 2005 Yarborough 2013 Yearwood 2001 Type: review Sample: 21 articles Intervention: antipsychotic medications in children and adolescents Type: Study protocol Sample: Adults taking antipsychotic medication Intervention: Lifestyle interventions Type: Practice article Topic: Prader-Willli Syndrome for weight loss Limited to children and adolescents; No mention of medication for weight loss Study protocol; Focused on lifestyle interventions; No mention of medication for weight loss Not relevant; No mention of medication for weight loss

114 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 114 Appendix L Characteristics of Included Studies Characteristics of Included Studies Medication Switching Table L1: Characteristics of Included Study by Newcomer (2008) Methods Allocation: Randomized Blindness: Double Duration: 16 weeks Setting: Multi-site, multinational, outpatient Participants Diagnosis: Schizophrenia or schizoaffective disorder N = 173 Age: Between years, mean~39 years (SD 10) BMI: >27kg/m 2 Sex: 111 males and 62 females History: mg olanzapine 1-24 months prior to screening, clinically stable, weight gain prior to olanzapine verified Excluded: other axis 1 disorder, Type I or II diabetes mellitus, women who were pregnant, breastfeeding, or unwilling/unable to use acceptable form of contraception during the entire study period, any clinically significant neurological abnormality (i.e. epilepsy, Parkinson s disease), stroke, TIA, increased risk of suicide, psychoactive substance or alcohol dependence (except for caffeine and nicotine), increase in symptoms requiring hospitalization or change in antipsychotic therapy, weight loss >10% of total body weight 3 months before screening, received ECT 3 months prior, received aripiprazole or other investigational agent 4 weeks prior, previously failed a course of aripiprazole 10 mg per day for 4 weeks, abnormal vital signs, ECG, or laboratory tests Interventions 1. Switch to aripiprazole monotherapy (mean dose 16 mg per day), N = Continue olanzapine monotherapy (mean dose 15.9 mg per day), N = 85 Outcomes Weight (kg), BMI, waist circumference, fasting lipid levels, fasting plasma glucose, fasting insulin, fasting C-peptide, Clinical Global Impressions- Severity of Illness (CGI-S) scores, adverse effects, and significant adverse effects Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection Unclear Risk bias) Quote: evenly randomly assigned Comment: May indicate alternate allocation (considered quasi-random and insufficient) or could simply refer to even distribution of participants (88 received intervention, 85 in control group)

115 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 115 Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Unclear Risk Low Risk Low Risk Low Risk Low Risk Not described Quote: double-blind study Comments: Methods not described, but unlikely to impact outcomes such as weight, physiologic measures Quote: double-blind study Comments: Methods not described, but unlikely to impact outcomes such as weight, physiologic measures Reports rates of attrition and gives reasons (i.e. due to adverse effects) when able; Attrition rates due to adverse effects similar between groups; Intervention group with higher number of attrition overall, but consistent with studies showing that switching groups discontinue treatment earlier than those continuing medication Baseline measures reflective of outcome measures; Data sufficient for metaanalysis Other bias Unclear Risk Some authors employed by interested pharmaceutical company Table L2: Characteristics of Included Study by Stroup (2011) Methods Allocation: Random Blindness: Double Duration: 24 weeks Setting: Multi-site, outpatient, United States Participants Diagnosis: Schizophrenia or schizoaffective disorder N = 215 Age: Mean~41 years (SD 11.1) BMI: >27kg/m 2 Sex: 137 males and 78 females History: Patients clinically stable on olanzapine, quetiapine, or risperidone and who were at increased risk of cardiovascular disease as evidenced by BMI 27 and dyslipidemia. Patients on qualifying medication for at least 3 months prior to enrollment and had desire to improve their metabolic risk profile Interventions 1. Titrated switch to aripiprazole (between 5-30 mg daily), N = Continue current therapy: olanzapine (5-20 mg daily), quetiapine ( mg daily), or risperidone (1-16 mg daily), N = 106 Outcomes Weight, lipids, global state, adverse effects, serious adverse effects,

116 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 116 discontinuation of treatment Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) High Risk Quote: randomly assigned on a 1:1 basis Comment: Indicate alternate allocation (considered quasi-random and insufficient) Unclear Risk High Risk Low Risk Low Risk Low Risk Not described Quote: "Participants and their physicians were aware of the medication assignment Comment: Unlikely to impact physiologic outcomes such as weight Raters of outcomes were "blinded to treatment" Reports rates of attrition and gives reasons (i.e. due to adverse effects) when able; Attrition rates due to adverse effects similar between groups; Intervention group with higher number of attrition overall, but consistent with studies showing that switching groups discontinue treatment earlier than those continuing medication Baseline measures reflective of outcome measures; Data sufficient for metaanalysis Other bias Low Risk The study appears to be free of other sources of bias Characteristics of Included Studies Adjunct Medication Table L3: Characteristics of Included Study by Afshar (2009) Methods Allocation: randomized Blindness: double-blind, placebo-controlled Duration: 8 weeks Setting: outpatient, Iran Participants Diagnosis: schizophrenia N = 32 Age: Between years, mean~38 years (SD±5.1) Sex: 20 males and 12 females History: Patients who had poor clinical outcome in spite of long-term

117 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 117 Interventions Outcomes treatment with several types of antipsychotics who were currently receiving treatment with clozapine at a maximum dose of 100 mg/day for the previous 2 months. No significant difference in baseline measurements between treatment and control groups. 3. Addition of topiramate starting at 25 mg/day and increasing to 300 mg/day by titrating up 25 mg/day every 3 to 4 days according to individual tolerability, N = Continue clozapine monotherapy plus placebo, N = 16 Weight (kg), BMI, Positive and Negative Syndrome Scale (PANSS), tolerability of treatment, adverse effects, and significant adverse effects Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Low risk Low risk Low risk Low risk Low risk Quote: "Patients were randomly assigned to one of two groups using random number generator software." Quote: "The researcher who allocated patients to one of the two group had no role in the treatment plan or filling the questionnaires, and the psychiatrist responsible for the treatment of patients and filling PANSS was not informed about patients' medication. Follow-up was conducted using patient's code." Quote: "Placebo tablets were made...with the same appearance as topiramate Quote: "The psychiatrist responsible for the treatment of patients and filling PANSS was not informed about patients' medication."tablets." All patients completed the study; Outcome data reflects baseline measurement data, but not all outcomes had specific information included in the article, rather these were listed and described as "had insignificant differences in two groups at the beginning and end of the study." Selective reporting (reporting bias) Unclear risk Not all outcomes had specific information included in the article, rather these were listed and described as "had insignificant differences in two groups at the beginning and end of the study." Other bias Low risk No evidence of other bias detected

118 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 118 Table L4: Characteristics of Included Study by Baptista (2007) Methods Allocation: Random Blindness: Double Duration: 12 weeks Setting: Multi-site, inpatient and outpatient, Venezuela Participants Diagnosis: Schizophrenia or bipolar disorder, taking olanzapine N = 80 Age: Reported by sex and group type, means between 42.4 years and 46.2 years, with varying SDs by group BMI in placebo group: ~26.18 kg/m 2 (SD 5.7) BMI in experimental group: ~25.0 kg/m 2 (SD 4.9) Sex: 42 males and 30 females History: Patients older than 18 years, free of hormone replacement therapy, no chronic disease besides mental disorder, and with normal physical and laboratory tests (liver, kidney, thyroid, and fasting glucose) before starting olanzapine. Olanzapine treatment for at least 4 months and with desire to lose weight or prevent weight gain. Interventions 3. Continue current therapy plus metformin, N = Continue current therapy plus placebo, N = 36 Outcomes Weight, waist circumference, fasting glucose, HbA1c, insulin, lipids, leptin, c-reactive protein, fibrinogen, cortisol, growth hormone, global state, adverse effects, serious adverse effects, discontinuation of treatment Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection Low Risk bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Low Risk Low Risk Low Risk Low Risk Quote: "Subjects were randomly assigned through a computer-based program." Quote: "The study coordinator was the only team's member to know the individual treatment." Quote: "The study coordinator was the only team's member to know the individual treatment." Quote: "identical placebo pills" Quote: "The study coordinator was the only team's member to know the individual treatment." Quote: "Seven subjects abandoned the study by change in residence and one patient relapsed and required combined antipsychotic treatment." Selective reporting Low Risk Outcome data reflective of baseline data (reporting bias) collected and intent of the study Other bias Low Risk No evidence of other bias detected

119 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 119 Table L5: Study by Carrizo (2009) Methods Allocation: Random Blindness: Double Duration: 14 weeks Setting: Single site, outpatient, Venezuela Participants Diagnosis: Schizophrenia, receiving clozapine > 3 months N = 61 Age in placebo group: Mean~39.6 years (SD 9.7) Age in experimental group: Mean~38.3 years (SD 9.7) BMI in placebo group: >27.4 kg/m 2 (SD 5.7) BMI in experimental group: >28.7 kg/m 2 (SD 5.3) Sex: Not reported History: Patients primarily with schizophrenia receiving treatment with clozapine for >3 consecutive months, older than 18 years, free of hormone replacement therapy, and with normal physical and laboratory test (kidney, thyroid, and liver). Also, no symptoms of type II diabetes. No significant differences between groups at baseline. Interventions 1. Add extended release metformin mg PO daily, N = Continue current therapy, N = 30 Outcomes Weight, lipids, insulin, glucose, leptin, cortisol, blood pressure, waist circumference, HbA1c, global state, adverse effects, serious adverse effects, discontinuation of treatment Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Low Risk Quote: "Patients were randomly assigned by a computer program" Allocation concealment Low Risk Quote: "Only the study coordinator (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Low Risk Low Risk Unclear Risk knew the treatment assignment" Quote: "Metformin or placebo in identical pills. Both treatments were daily provided with the last meal in a double-blined protocol. Only the study coordinator knew the treatment assignment." Quote: "Only the study coordinator knew the treatment assignment." One psychiatrist conducted both initial and follow-up assessments. Quote: "All the placebo subjects completed the study. Seven out of 31 metformin-treated patients abandoned the protocol before the first follow-up

120 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 120 visit at week 7. One woman became pregnant, and the other dropouts had a severe mental disorder at baseline and manifested vague and unstable side effects that even the caregivers could not explain. None of these patients complained of gastrointestinal discomfort." Selective reporting (reporting bias) Low Risk Outcome data reflective of baseline data collected and intent of the study Other bias Low Risk No evidence of other bias detected Table L5: Characteristics of Included Study by Narula (2010) Methods Allocation: Random Blindness: Double Duration: 12 weeks Setting: Single site, majority outpatient, India Participants Diagnosis: Schizophrenia, first episode, drug naïve N = 77 (72 randomly assigned) Age in placebo group: Mean~31 years (SD 10.1) Age in experimental group: Mean~31.2 years (SD 9.7) BMI in placebo group: ~20.2 kg/m 2 (SD 3.92) BMI in experimental group: ~20.56 kg/m 2 (SD 3.85) Sex: 44 males and 23 females History: Patients attending psychiatry clinic at tertiary care hospital in New Delhi, India with first-episode schizophrenia. Drug naïve and between the ages of years. Excluded if any other neuropsychiatric illness, on any other medications known to influence weight, any substance abuse diagnosis in the past 3 months, pregnancy, lactation, or not using adequate contraception. Interventions 1. Olanzapine 5-20 mg PO daily, N = Olanzapine 5-20 mg PO daily plus topiramate mg PO daily:, N = 33 Outcomes Weight, lipids, fasting glucose, insulin, insulin resistance, leptin, blood pressure, global state, adverse effects, serious adverse effects, discontinuation of treatment Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Unclear Risk Unclear Risk Low Risk Randomization method not described Allocation concealment not described Described as "double-blind" but blinding methods are not explicitly described

121 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 121 Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Low Risk Low Risk Described as "double-blind" but blinding methods are not explicitly described Exclusion and attrition information provided for all participants not included in study Selective reporting (reporting bias) Low Risk Outcome data reflective of baseline data collected and intent of the study Other bias Low Risk No evidence of other bias detected Table L6: Characteristics of Included Study by Wu (2008) Methods Allocation: Random Blindness: Double Duration: 12 weeks Setting: Single site, outpatient, China Participants Diagnosis: Schizophrenia, first episode N = 128 Age: Mean~26.3 years (SD 0.8) BMI: ~24.5 kg/m 2 Sex: 64 males and 64 females History: Patients aged 18 to 45 years with first psychotic episode of schizophrenia taking only 1 antipsychotic medication of clozapine, olanzapine, risperidone, or sulpiride for over 3 months with no more than a 25% increase in dosage. Also have gained more than 10% of pre-drug body weight within the first year of treatment and have been seen in the outpatient clinic at least once in previous 12 months. Excluded if liver or renal dysfunction, cardiovascular disease, diabetes mellitus, pregnant or lactating, physical condition limiting ability to perform lifestyle modifications, other psychiatric diagnosis, or history of substance abuse. Interventions 1. Continue current therapy plus placebo, N = Continue current therapy plus placebo plus lifestyle intervention, N = Continue current therapy plus metformin 750 mg PO daily (divided into 3 doses, with meals), N = Continue current therapy plus metformin 750 mg PO daily (divided into 3 doses, with meals) plus lifestyle intervention, N = 32 Outcomes Weight, waist circumference, fasting glucose, insulin, global state, adverse effects, serious adverse effects, discontinuation of treatment Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Low Risk Quote: "Participants were randomized through a computergenerated table in blocks of 8 to

122 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 122 ensure approximately equal numbers of participants in each group." Allocation concealment (selection bias) Low Risk Quote: "To ensure concealment of the treatment assignment, randomization was conducted independently of the investigators by a research pharmacist at a separate facility and medication was provided in coded containers of identical-appearing capsules of metformin or placebo supplied by the manufacturer." Blinding of participants and personnel (performance bias) Low Risk Quote: "To ensure concealment of the treatment assignment, randomization was conducted independently of the investigators by a research pharmacist at a separate facility and medication was provided in coded containers of identical-appearing capsules of metformin or placebo supplied by the manufacturer." Blinding of outcome assessment (detection bias) Low Risk Quote: "The research nurses who performed all assessments were blinded to the treatments that the patients were receiving and were not involved in implementing any aspects of the intervention." Incomplete outcome data (attrition bias) Low Risk Exclusion and attrition information provided for all participants not included in study Selective reporting (reporting bias) Low Risk Outcome data reflective of baseline data collected and intent of the study Other bias Low Risk No evidence of other bias detected Characteristics of Included Studies Behavioral Interventions Table L7: Characteristics of Included Study by Attux (2013) Methods Allocation: Random Blindness: Single Duration: 12 weeks Setting: Multi-site, outpatient, Brazil Participants Diagnosis: Schizophrenia, being treated with antipsychotic N = 160 Age in standard care group: Mean~38.3 years (SD 10.7) Age in intervention group: Mean~36.2 years (SD 9.9) BMI in standard care group: ~29.9 kg/m 2 (SD 5.2)

123 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 123 Interventions Outcomes BMI in intervention group: ~29.1 kg/m 2 (SD 4.7) Sex: 96 males and 64 females History: Patients between 18 to 65 years old, with schizophrenia, using any antipsychotic in the past 3 months, and clinically stable. Also had motivation to lose weight or had concern about weight gain. Excluded if presence of diabetes mellitus, history of eating disorder or substance abuse, and taking or planning to take any weightreducing medications. 3. Standard care (i.e. regular visits to psychiatrist and psychosocial interventions), N = Lifestyle Wellness Program (one hour weekly sessions combining behavioral interventions and psychoeducation), N = 81 Weight, waist circumference, blood pressure, glucose, lipids, insulin, global state, multiple secondary outcomes, discontinuation of treatment Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Unclear Risk Unclear Risk Low Risk Low Risk Low Risk Quote: "Randomly allocated" No description of randomization method Quote: "Randomly allocated" No description of allocation concealment Quote: "Blind investigators applied the following instruments..." Unable to blind participants to intervention Quote: "Blind investigators applied the following instruments..." All exclusions and attrition data provided for first 3 months, no attrition information provided for 6-month follow-up, but data for this group was not included Selective reporting Unclear Risk 6-month outcome data not reported, but (reporting bias) explained by authors Other bias Low Risk No evidence of other bias detected Table L8: Characteristics of Included Study by Khazaal (2007) Methods Allocation: Random Blindness: Unclear Duration: 12 weeks of intervention, 24 week follow up Setting: Single site, outpatient, Switzerland Participants Diagnosis: Taking an antipsychotic

124 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 124 N = 61 Age in standard care group: Mean~38.3 years (SD 10.4) Age in intervention group: Mean~43 years (SD 9.8) BMI in standard care group: ~28.7 kg/m 2 (SD 4.3) BMI in intervention group: ~32.4 kg/m 2 (SD 5.0) Sex: 28 males and 33 females History: Patients between 18 to 65 years, taking an antipsychotic for at least 2 months, and with a reported weight gain of >2 kg over 6 months of antipsychotic treatment. Excluded if diagnosis of anorexia, bulimia nervosa, opiate, alcohol, or cocaine dependence, mental retardation, or diabetes mellitus. Interventions 1. Standard care (Brief Nutritional Education), N = Cognitive-behavioral therapy on eating and weightrelated cognitions, N = 31 Outcomes Weight, eating and weight-related cognitions, binge eating symptomatology Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Unclear Risk Quote: "Eligible patients were randomly allocated to one of the two treatments" No description of randomization method Allocation concealment (selection bias) Unclear Risk No description of allocation concealment Blinding of participants and personnel (performance Unclear Risk No description of blinding of participants or personnel bias) Blinding of outcome assessment (detection bias) Unclear Risk No description of blinding of outcome assessment Incomplete outcome data (attrition bias) Unclear Risk Attrition rates reported but not explained Selective reporting (reporting bias) Low Risk Outcome data reflects baseline data and intent of study Other bias Low Risk No evidence of other bias detected Table L9: Characteristics of Included Study by Weber (2006) Methods Allocation: Random Blindness: Unclear Duration: 16 weeks Setting: Single site, outpatient, United States Participants Diagnosis: Schizophrenia or schizoaffective disorder N = 17 Age: Between 18 and 65 years old, no mean reported BMI: 25 kg/m 2, Mean = 33 kg/m 2

125 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 125 Interventions Outcomes Sex: 5 males and 12 females History: Patients taking only one oral atypical antipsychotic and with a BMI 25 kg/m 2. Excluded if acutely psychotic, in need of immediate detoxification, or alcohol dependent. 1. Treatment as usual (scheduled appointments at public mental health clinic), N = 7 2. Cognitive/behavioral intervention (1-hour structured group sessions once per week), N = 8 Weight, weight-to-hip ratio, fasting glucose, discontinuation of treatment Notes Risk of Bias Assessment Bias Author s judgment Support for judgment Randomization (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Unclear Risk Unclear Risk Unclear Risk Low Risk Quote: "were randomized" No description of randomization method No description of allocation concealment Quote: "Placebo controlled," Control group "continued to receive care as usual at the clinic." Not exactly clear how this is a "placebo," an unrelated group intervention would have been more appropriate. Quote: "All measurements were completed by one Graduate Research Assistant who was blind to the randomization." Incomplete outcome data (attrition bias) Low Risk Attrition rates reported with explanations given Selective reporting (reporting bias) Low Risk Outcome data reflects baseline data and intent of study Other bias Low Risk No evidence of other bias detected

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142 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 142 Appendix N Permissions to Reproduce Copyrighted Materials Figure N1: Permission to reproduce ACE Star Model of Evidence-Based Practice image (Stevens, 2012).

143 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 143 Figure N2: Permission to reproduce Hierarchy of Evidence image (University of Washington, 2011).

144 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 144 Figure N3: Permission to reproduce the GRADE framework for guideline development (Schunemann, et al., 2011).

145 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 145 Figure N4: Permission to reproduce the Summary of GRADE method for rating importance of study outcomes (Guyatt, et al., 2011).

146 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 146 Guideline Title Appendix O Clinical Practice Guideline Guideline Information Management of medication-associated weight gain in adults taking antipsychotics. Bibliographic Source N/A Guideline Status This is a provisional release of the guideline. It is still under development while pending review by experts and revision according to feedback. FDA Warning/Regulatory Alert Adjunct medications suggested for the management of antipsychotic-associated weight gain have not been approved by the FDA for this purpose. Disease/Condition(s) Scope Weight gain caused by antipsychotic medication Guideline Category Evaluation Management Prevention Treatment Clinical Specialty Family Practice General Practice Mental Health Care Primary Care Psychiatry Intended Users

147 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 147 Advance Practice Nurses Health Care Providers Hospitals Nurses Patients Pharmacists Physician Assistants Physicians Psychologists/Non-physician Behavioral Health Clinicians Guideline Objective(s) To offer evidence-based practice advice on the management of weight gain in adults taking antipsychotic medications. Target Population Adults taking atypical antipsychotic medications who are concerned about weight gain or who have experienced >5% increase in body weight since starting antipsychotic therapy. Interventions and Practices Considered 1. Screening and evaluation of individuals for antipsychotic-associated weight gain 2. Management and prevention options for antipsychotic-associate weight gain in adults Major Outcomes Considered Change in weight (primary outcome) Global state Adverse events Serious adverse events Discontinuation of treatment Methods Used to Collect/Select the Evidence Methodology Hand-searches of Published Literature (Primary and Secondary Sources) Searches of Electronic Databases Description of Methods Used to Collect/Select the Evidence

148 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 148 Review questions were developed using a PICO framework (patient, intervention, comparison, and outcome). A total of 3 review questions were identified: 1. In adults taking antipsychotic medication (P), how does medication switching (I) compare to standard care (C) for decreasing weight (O)? 2. In adults taking antipsychotic medication (P), how do pharmacological interventions (I) compare to standard care (C) for decreasing weight (O)? 3. In adults taking antipsychotic medication (P), how do behavioral interventions (I) compare to standard care (C) for decreasing weight (O)? The evidence search was conducted using electronic databases such as the Cochrane Database of Systematic Reviews, MEDLINE (PubMed), CINAHL, and Web of Science. Additionally, websites hosting clinical practice guidelines were searched for any updates related to antipsychotic medications and weight gain. Searches were supplemented by reviewing the reference lists from other relevant publications. Search terms included antipsychotic*, obes*, switching, intervention*, topiramate, metformin, behav*, and systematic review. Only studies conducted between February 28, 2005 and February 28, 2015 were considered. Additionally, only studies available in English and obtainable as full-text using the University of Hawaii at Hilo journal subscriptions were used. Only interventions focused upon weight loss were considered and limited to the following intervention strategies: switching medications, adjunct medications, and behavioral interventions. Combination interventions (such as adjunct medication plus behavioral intervention) were excluded with the assumption that combination therapies are generally considered more effective than single interventions alone. Interventions that did not focus primarily upon weight or did not report weight-related outcomes were excluded. Interventions focused upon dietary and physical activity changes were also excluded, as these are considered standard care for weight management. Studies of child, adolescent, and inpatient populations were excluded as this guideline is focused upon adults in the outpatient setting. Potentially relevant studies were identified for each review question and search result titles and abstracts were screened according to the inclusion and exclusion criteria. Those papers identified for inclusion were then obtained in full text and further reviewed against the inclusion and exclusion criteria. The studies were then classified according to a hierarchy of evidence, utilizing systematic reviews first and then high-quality randomized-controlled trials. Number of Source Documents 21 articles were included in the evidence review, including 12 systematic reviews and 9 high quality randomized controlled trials. Refer to Appendix A for a flow diagram of article selection according to each review question. Note that the number of systematic reviews cited in the flow diagrams is greater than the number listed here. This discrepancy is a result of systematic reviews that included more than one intervention type in their analysis, and were therefore, listed more than once in the article selection process.

149 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 149 Methods Used to Assess the Quality and Strength of the Evidence The quality and strength of included studies were rated according to the Grading of Recommendations Assessment, Development, and Evaluation criteria (see scheme given below). Rating Scheme for the Strength of the Evidence Overall Quality of Outcome Evidence according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Level High quality Moderate quality Low quality Very low quality Description We are very confident that the true effect lies close to that of the estimate of the effect We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Methods Used to Analyze the Evidence Meta-Analysis Review of Published Meta-Analyses Systematic Review with Evidence Tables Description of the Methods Used to Analyze the Evidence Included studies were critically appraised using the GRADE risk of bias assessment criteria. Key information was then extracted regarding each study s methods, PICO factors, and results. Where possible, meta-analyses were conducted to combine the results of the studies for each review question according to the outcomes of interest. This was done using Cochrane Review Manager (RevMan5) software. Pooled risk ratios were calculated for binary outcomes. Pooled measures of central tendency (means) and variation (standard deviation) were calculated for continuous outcomes. For interpretation of binary outcome results, differences in the absolute event rate were calculated using software developed by the GRADE working group (GRADEpro) using data reported in the control group of included studies. For interpretation of continuous data, mean ranges for control groups were manually entered and the anticipated absolute effects for each intervention were calculated by GRADEpro according to the data from the meta-analyses. The quality of evidence for each outcome in each intervention was assessed using the GRADE quality assessment criteria. Evidence profiles were then generated for each review question (see Appendix B) and summaries of findings were created (see Appendix C). The GRADE Guideline Development Tool (GDT) was then

150 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 150 used to make specific recommendations regarding each review question, using an evidence-to-decision table (see Appendix D). Methods Used to Formulate Recommendations Author determination GRADE evidence-to-decision tables (Appendix D) Description of Methods Used to Formulate the Recommendation Recommendations were formulated using the GRADE Guideline Development Tool after reviewing: -The evidence summaries for each review question -Findings from similar systematic reviews -Expert consensus statements regarding antipsychotic medications and obesity. -Cost-analyses of interventions (when available) -Studies of patient outcome and intervention preferences (when available) Rating Scheme for the Strength of the Recommendation The wording of recommendations conforms to the standards set by the GRADE Guideline Development Tool, whereby a strong recommendation uses the words we recommend and a weak recommendation uses the words we suggest. Cost Analysis The literature was searched for economic data regarding each of the interventions reviewed. Unfortunately, there was limited evidence available for determining the costeffectiveness of the interventions included. When possible, cost information was included the guideline development tables (Appendix D). Method of Guideline Validation External Peer Review Description of Method of Guideline Validation A draft of the guideline was reviewed by an interdisciplinary panel of key stakeholders including: -Advance Practice Nurses -Family members of patients affected -Family Practice Physicians -Other Healthcare Professionals/Experts -Primary Care Providers -Psychiatrists Participating reviewers used the AGREE II (Appraisal of Guidelines for Research and

151 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 151 Evaluation II) instrument to assess the quality and applicability of the guideline. Major Recommendations Generic Principles of Care Recommendations All adults taking antipsychotic medication should have their weight routinely checked at the start of therapy and at regular intervals thereafter. Weight should be evaluated in relation to height by calculating the patient s Body Mass Index (BMI) to screen for overweight or obesity. Define the degree of overweight or obesity in adults according to the following table: Classification BMI (kg/m 2 ) Healthy weight Overweight Obesity I Obesity II Obesity III 40 or more Interpret BMI with caution by considering individual differences in muscularity, fitness level, age, gender, racial/ethnic group, and comorbidities. Offer lifestyle interventions for weight management according to the patient s risk and preferences, following standard obesity management guidelines for the general adult population. Specific Principles of Care Weight gain and associated metabolic dysfunction are now recognized as significant problems primarily associated with the newer (second-generation or atypical) antipsychotic medications (Leucht et al., 2013). Prevalence rates of antipsychotic-associated weight gain are between 15% to 72% (De Hert et al., 2011), with some medications having much greater weight-gain liability than others (Leucht et al., 2013). Additionally, several studies report that psychotropic medication-associated weight gain is distressing to patients (McCloughen & Foster, 2011) and may represent an important barrier to medication adherence (DiBonaventura, Gabriel, Dupclay, Gupta, & Kim, 2012; Weiden, Mackell, & McDonnell, 2004). Furthermore, individuals with severe mental illness experience significant physical health disparities, with markedly higher rates of obesity, as well as increased morbidity and mortality overall (De Hert et al., 2011). Recommendation #1: Medication Switching

152 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 152 We recommend switching antipsychotic medication for patients who have experienced >5% body weight increase since the initiation of therapy, if the patient is willing to consider switching and has a relapse prevention and safety plan in place. Justification Systematic reviews report that an elective switch from antipsychotics with high weightgain liability to those with low weight-gain potential can improve weight outcomes with minimal risk of psychiatric deterioration (Grande et al., 2014; John W. Newcomer, Weiden, & Buchanan, 2013). With any medication switch, however, the potential for relapse exists and patients, in collaboration with the healthcare team, should have plan in place to ensure safety. Subgroup Considerations A systematic review of medication adherence in schizophrenia reports that lack of insight, medication beliefs, and substance abuse are key drivers of medication nonadherence (Higashi et al., 2013). These factors require careful assessment by the treatment team for patients considering medication switching. Risks of medication nonadherence include increased risk of relapse, hospitalization, and suicide (Higashi et al., 2013). Additionally, expert authors assert that patients with long-term (several years) exposure to an antipsychotic with high weight-gain liability are less likely to benefit from medication switching, whereas patients with relatively short-term exposure are more likely to benefit (Hasnain, Vieweg, & Hollett, 2012). Implementation Consideration Systematic reviews do not report any significant differences in outcomes associated with the medication switching strategy (i.e. abrupt stop/start versus cross-tapering) in patients taking antipsychotics (Mukundan, Faulkner, Cohn, & Remington, 2010; John W. Newcomer et al., 2013). In general, however, a cross-tapering strategy (where the current medication is gradually reduced while a new medication is gradually increased) is believed by many to reduce the risk of adverse effects and discontinuation of treatment (Buckley & Correll, 2008; John W. Newcomer et al., 2013). Medication should be switched from those with high weight-gain liability to those with lower weight-gain potential. The following list of antipsychotics (including both first- and secondgeneration antipsychotics) is ordered from highest weight-gain potential (olanzapine) to lowest weight potential (haloperidol) according to a recent meta-analysis (Leucht et al., 2013): olanzipine (highest weight-gain potential) zotepine clozapine iloperidone

153 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 153 Definitions chlorpromazine sertindole quetiapine risperidone paliperidone asenapine amisulpride aripiprazole lurasidone ziprasidone haloperidol (lowest weight-gain potential) Relapse prevention and safety plan There are many forms that a relapse prevention plan can take, but in general, they are written statements that include collaboratively identified warning signs of relapse (i.e. difficulty sleeping, decreased tolerability of auditory hallucinations) and are specific to the individual client. For each symptom, coping skills are identified that have been helpful to the patient in the past. In addition to coping skills, an action plan is included that usually involves contacting the prescriber for urgent follow-up. A safety plan should also be included, in case of further escalation of symptoms. A safety plan includes written instructions that direct the patient toward a mental health telephone crisis line and/or the nearest emergency department, should he or she begin to experience suicidal and/or homicidal thoughts, or other thoughts of self-harm. Recommendation #2: Adjunct Medications We suggest offering adjunct medications (metformin or topiramate) for patients taking antipsychotics who have experienced >5% body weight increase since initiation of therapy, particularly those patients who are reluctant to switch to an antipsychotic with lower weight-gain potential and for whom lifestyle interventions have been (or are likely to be) unsuccessful. Adjunct medication should be offered in conjunction with lifestyle modification for maximum weight loss benefit. Justification Antipsychotic-associated weight gain is most pronounced during the first 12 weeks of treatment and early intervention has been shown to substantially reduce and/or reverse weight gain while also preventing related metabolic effects (Newall et al., 2012). Systematic reviews evaluating the efficacy of metformin for antipsychoticassociated weight gain consistently report clinically significant weight loss with low rates of adverse effects (Fiedorowicz et al., 2012; Hasnain, Fredrickson, & Vieweg, 2011;

154 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 154 Mizuno et al., 2014; Newall et al., 2012). Systematic reviews regarding topiramate also report significant weight loss, however, there is much greater variability in the incidence and severity of adverse effects (Generali & Cada, 2014; Mahmood, Booker, Huang, & Coleman, 2013). Appendix A provides a summary of findings for the outcomes related to using adjunct medications for this problem. Additionally, studies consistently report that adjunct medications for managing antipsychotic-associated weight gain show the most benefit when combined with lifestyle interventions (Hasnain et al., 2011). Subgroup Considerations Studies assessing adjunct pharmacotherapy in antipsychotic-associated weight gain include patients primarily taking olanzapine and clozapine (Mizuno et al., 2014). This finding suggests greater effect for patients taking these medications, and lesser effect for patients taking antipsychotics with lower weight-gain liability. Additionally, older patients with long-term exposure to antipsychotic-induced weight gain benefit less from metformin, than younger newly-exposed patients (Hasnain et al., 2012). This finding suggests that the best candidates for metformin adjunct therapy are those that are younger and have a shorter history of antipsychotic use. In terms of adverse effects, metformin is associated with the rare occurrence of lactic acidosis, primarily in patients with renal insufficiency and has also been recently associated with the generation of amyloid-beta proteins, involved in the development of Alzheimer's disease. These findings suggest that metformin should be used cautiously in elderly patients and those with renal impairment and/or cognitive decline (Björkhem-Bergman, Asplund, & Lindh, 2011). In studies of topiramate, reduction in general psychopathologic symptoms were reported in patient's with schizophrenia (Mahmood et al., 2013). This suggests that patients with schizophrenia may achieve additional benefit from topiramate, beyond the medication's weight loss effect. Implementation Considerations The FDA has not yet approved metformin for medication-associated weight gain. The use of metformin for this purpose would be considered "off-label." The FDA has approved topiramate (in combination with phentermine, under the brand name Qsymia) for general weight loss. For metformin, gastrointestinal symptoms (nausea, diarrhea, and bloating) are the most common side effects (up to 30%). These symptoms can be avoided with gradual dose increases and administration with food. Additionally, metformin is not reported to have any significant drug-drug interactions, including with antipsychotic medications (Newall et al., 2012). Topiramate is associated with a number of side effects including paresthesia, hypoesthesia, changes in taste, cognitive impairment, and acute glaucoma (rare). These side effects must be discussed with patients considering topiramate as an adjunctive therapy (Ellinger, Ipema, & Stachnik, 2010; Kramer et al., 2011). The incidence of side effects is reported as greater at higher doses, although these appear to diminish over the course of treatment (Ko, Joe, Jung, & Kim, 2005). In regard to its weight loss effect, studies of topiramate report that longer duration of treatment and higher doses are associated with greater weight loss (Ko et al., 2005; Kramer et al., 2011).

155 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 155 Recommendation #3: Cognitive-Behavioral Therapy We suggest offering cognitive-behavioral therapy to all patients taking antipsychotic medications who may be concerned about weight gain as a side effect, have more than 1 risk factor for obesity, or have already experienced weight gain. Justification Systematic reviews of behavioral interventions for reducing antipsychotic-associated weight gain report that these interventions, in combination with lifestyle changes, produce modest weight reduction (Alvarez-Jimenez, Hetrick, Gonzalez-Blanch, Gleeson, & McGorry, 2008; Faulkner, Cohn, & Remington, 2007). Additionally, behavioral interventions appear to help patients prevent weight gain when initiated early in the course of antipsychotic therapy (Alvarez-Jimenez et al., 2008; Gabriele, Dubbert, & Reeves, 2009). The cost-effectiveness of this approach, however, is not certain, nor is it's relative superiority compared to more traditional educational interventions for nutrition and physical activity (Alvarez-Jimenez et al., 2008). Subgroup Considerations There were no significant subgroup differences noted in the literature. One systematic review reports that there were similar effects between groups with chronic illness and first-episode psychosis (Bonfioli, Berti, Goss, Muraro, & Burti, 2012). Implementation Considerations Group interventions appear to be as effective as individual interventions for preventing weight gain and promoting weight loss (Alvarez-Jimenez et al., 2008), providing a more cost-effective option for patients and payers. Longer length of intervention and followup appears to produce greater weight loss (Gabriele et al., 2009). Monitoring and Evaluation A consensus statement on antipsychotic drugs and obesity recommends weight monitoring at 4, 8, and 12 weeks after initiating or changing antipsychotic therapy, and every 3 months thereafter (American Diabetes Association, 2004). Clinical Algorithm See Appendix E for larger image.

156 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 156 Figure 1: Clinical algorithm for the management of antipsychotic-associated weight gain. Refer to Appendices C and D. Potential Benefits Evidence Supporting the Recommendations Benefits/Harms of Implementing Guideline Recommendations Appropriate identification, assessment, and management of antipsychotic-associated weight gain. Refer to in Appendix D for further information regarding the balance of benefits and harms for each intervention. Potential Harms Risk of relapse, hospitalization, and suicide with medication switching. Side effects of adjunct medications used.

157 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 157 Unclear cost-effectiveness of cognitive-behavioral therapy for weight loss. Qualifying Statements This guideline represents the views of one author after careful evaluation of the evidence for interventions to manage antipsychotic-associated weight gain. The recommendations reflect the best evidence at the time of publication and continued research may result in new knowledge that generates different recommendations. The guideline does not replace the individual responsibility of healthcare professionals to make clinical decisions based upon the circumstances of the individual patient, the context of care, and the product information for any of the medications suggested. Implementation of this guideline is at the sole discretion of the healthcare professional, in collaboration with the patient and the treatment team. Treatment and care should be tailored to the individual needs and preferences of patients. Decisions about treatment should be patient-directed with supportive guidance from the healthcare professional. Appropriate information must be provided to the patient regarding the potential benefits and harms of each intervention option, before treatment decisions are made. The guideline recommends some medications for indications that have not been approved by the FDA, but only if there was good evidence to support their use. The decision to use such medications is the sole responsibility of the medication prescriber. Description of the Implementation Strategy Implementation of the Guideline An implementation strategy is pending external peer review. Implementation Tools Clinical Algorithm Mobile Device Resources Institute of Medicine (IOM) National Healthcare Quality Report Categories IOM Care Need Getting Better Living with Illness

158 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 158 IOM Domain Staying Healthy Effectiveness Equity Patient-centeredness Safety Identifying Information and Availability Pending peer review and evaluation of the guideline.

159 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 159 Appendix A: Summary of Article Selection Summary of Article Selection Medication Switching Figure 2: Stages of article selection for systematic review of medication switching. Summary of Article Selection Adjunct Medication Figure 3: Stages of article selection for systematic review of adjunct medication.

160 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 160 Summary of Article Selection Cognitive-Behavioral Therapy Figure 4: Stages of article selection for systematic review of cognitive-behavioral therapy.

161 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 161 Evidence Profile Medication Switching Appendix B: Evidence Profile Tables Included studies: John W Newcomer et al. (2008), Stroup et al. (2011)

162 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 162 Evidence Profile Adjunct Medication Included studies: Afshar et al. (2009), Baptista et al. (2007), Carrizo et al. (2009), Narula, Rehan, Unni, and Gupta (2010), Wu, Zhao, Jin, and et al. (2008)

163 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 163 Evidence Profile Cognitive-Behavioral Therapy Included studies: Attux et al. (2013), Khazaal et al. (2007), Weber and Wyne (2006)

164 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 164 Appendix C: Summary of Findings Summary of Findings Medication Switching Included studies: John W Newcomer et al. (2008), Stroup et al. (2011)

165 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 165 Summary of Findings Adjunct Medication Included studies: Afshar et al. (2009), Baptista et al. (2007), Carrizo et al. (2009), Narula et al. (2010), Wu et al. (2008)

166 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 166 Summary of Findings Cognitive-Behavioral Therapy Included studies: Attux et al. (2013), Khazaal et al. (2007), Weber and Wyne (2006)

167 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 167 Appendix D: Evidence to Decision Tables Evidence to Decision Table Medication Switching

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171 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 171 Evidence to Decision Table Adjunct Medication

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176 ANTIPSYCHOTIC MEDICATION-ASSOCIATED WEIGHT GAIN 176 Evidence to Decision Table Cognitive-Behavioral Therapy

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