Acute and maintenance effects of non-pharmacologic interventions for antipsychotic associated weight gain and metabolic abnormalities: A meta-analytic comparison of randomized controlled trials
Introduction
Antipsychotic efficacy for psychotic disorders (Leucht et al., 2009), bipolar disorder (Correll et al., 2010), major depressive disorders (Nelson and Papakostas, 2009) and irritability/aggression associated with autism (Correll et al., 2011a), as well as off-label use in other psychiatric conditions (Maher et al., 2011) is counterbalanced by significant weight gain and cardiometabolic risk (Allison et al., 1999, American Diabetes Association et al., 2004, Lieberman et al., 2005, Kahn et al., 2008, De Hert et al., 2012). This weight gain is problematic as it may adversely affect adherence, quality of life (Allison et al., 2003), and especially, cardiovascular morbidity and mortality (Newcomer, 2005, Correll et al., 2011b, De Hert et al., 2011).
Pharmacologic interventions to ameliorate antipsychotic weight gain have had moderate success. Out of 15 agents examined in a recent meta-analysis, only five showed significant benefit versus placebo, and three were already taken off the market due to adverse effects (fenfluramine, sibutramine, reboxetine). Metformin and topiramate reduced antipsychotic-related weight gain compared to placebo by 2.5–3 kg after 8–12 weeks of treatment (Maayan et al., 2010). Pharmacologic interventions can cause additional side effects (Maayan and Correll, 2010). Metformin carries a risk of lactic acidosis, particularly in the elderly and in those with compromised renal function, and its use can be limited by nausea, vomiting and diarrhea. Topiramate has been associated with cognitive blunting (Narula et al., 2010).
Conversely, non-pharmacological interventions do not have such side effects and have shown promise. In a meta-analysis of 10 randomized controlled (RCTs) (n = 482) Alvarez-Jimenez et al. (2008) reported that non-pharmacological interventions led to 2.56 kg less weight gain and 0.91 kg/m2 less BMI increase than the control condition and that nutritional counseling was equivalent to cognitive behavioral therapy (CBT). While this meta-analysis provided support for non-pharmacological interventions, the small number of studies precluded secondary analyses regarding metabolic outcomes, and the mediating impact of treatment duration. A more recent, systematic review included the same 10 RCTs plus 6 additional, but non-randomized studies (Gabriele et al., 2009), reporting similar results.
The current study expands upon the prior publications (Alvarez-Jimenez et al., 2008, Gabriele et al., 2009) by (1) including additional RCTs , and (2) analyzing effects on insulin, glucose, high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, triglycerides, and systolic blood pressure. In addition we also aimed to assess maintenance effects after the behavioral interventions ended.
Section snippets
Search
A literature search was conducted in PsycInfo, Medline, PubMed, CINAHL, and the Cochrane Library using the following search terms: ‘weight,’ ‘antipsychotic,’ and ‘intervention’ plus ‘behavioral,’ ‘psychoeducation,’ ‘exercise,’ or ‘cognitive’. Reference lists of relevant articles were searched for additional studies. When required data was missing, first/corresponding authors were contacted for additional information.
Included in this meta-analysis were RCTs of non-pharmacological interventions
Results
We identified 17 RCTs, including 810 participants, that had a comparison group (Table 1). Data were extracted from an 18th publication (Alvarez-Jimenez et al., 2010) for follow-up information on an active treatment study (Alvarez-Jimenez et al., 2006). Treatment duration ranged from 8 to 72 weeks (8 studies (47%) with > 12 week duration, mean: 19.6 weeks). Treatment involved CBT (N = 7, 41%) and nutritional and/or exercise interventions (N = 10, 59%). Participants' mean age was 38.1 years in the
Discussion
In this largest to date meta-analysis of 17 studies, including 810 participants, non-pharmacologic interventions were significantly more effective than the respective control condition regarding the reduction in weight and all metabolic parameters, except for HDL-cholesterol and systolic blood pressure. The interventions resulted in 3.12 kg less weight gain and a 0.94 kg/m2 lower BMI unit increase compared to the control conditions. In addition, at least regarding body weight, beneficial effects
Role of funding source
Supported in parts by The Zucker Hillside Hospital National Institute of Mental Health (NIMH) Advanced Center for Intervention and Services Research for the Study of Schizophrenia (MH MH090590) and by the Stanley Medical Research Institute Award 07TGF-1112. The NIMH and Stanley Medical Research Institute had no further role in study design, collection, analysis, interpretation of data, writing of the report, and in the decision to submit the paper for publication.
Contributors
Mrs. Caemmerer undertook the literature search, statistical analysis, and wrote the first draft of the manuscript. Drs. Correll and Maayan designed the meta-analysis, provided intellectual guidance and contributed to the procurement of studies to be included in the meta-analysis and to later drafts of the manuscript. All authors contributed significantly to and have approved the final manuscript.
Conflict of interest
Mrs. Caemmerer has nothing to disclose.
Dr. Maayan has received research support from Eli Lilly and Pfizer.
Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Actelion, Alexza; AstraZeneca, Biotis, Bristol-Myers Squibb, Cephalon, Desitin, Eli Lilly, GSK, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, Novartis, Ortho-McNeill/Janssen/J&J, Otsuka, Pfizer, ProPhase, and Sunovion. He has received grant support from BMS, Feinstein Institute for Medical
Acknowledgments
The authors wish to thank Allison Larr of the Nathan Kline Institute and Constance Moussouris of the Columbia University Postbaccalaureate Premedical Program for their assistance with the preparation of this manuscript.
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