THE EVOLUTION OF MAN homo lethargicus gigantico

Transcription

1 THE EVOLUTION OF MAN homo lethargicus gigantico Weight Gain and Metabolic Abnormalities in Patients with Schizophrenia Leslie Citrome, MD, MPH Clinical Professor of Psychiatry and Behavioral Sciences New York Medical College Valhalla, New York Attending Physician Good Samaritan Hospital Suffern, New York Metabolic Syndrome (MetS) A public health concept What is Metabolic Syndrome (MetS)? MetS (also referred to as Syndrome X or Insulin Resistance Syndrome ) describes a cluster of CVD risk factors and metabolic alterations associated with excess fat weight Has been compared to cigarette smoking as an equal risk partner to premature CHD A starting point for clinical interventions known to reduce risk for obesity-related type 2 diabetes, CVD, and perhaps even cancer CVD = cardiovascular disease; CHD = coronary heart disease. NCEP ATP III. Circulation. 2002;106(25): Meigs JB. Diabetes Care. 2004;27(11): Ford ES, et al. Diabetes Care. 2003;26(3): How is This All Related? Complex Dyslipidemia TG, LDL HDL Endothelial Dysfunction Systemic Inflammation There are several competing definitions for MetS; these include: Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (ATP III) World Health Organization (WHO) Disordered Fibrinolysis Hypertension Insulin Resistance DM2/IGT/IFG Atherosclerosis Visceral Obesity TG = triglyceride; HDL = high-density lipoprotein; LDL = low-density lipoprotein; DM2 = type 2 diabetes mellitus; IGT = impaired glucose tolerance; IFG = impaired fasting glucose. Consensus Development Conference of the ADA. Diabetes Care. 1998;21(2): Adapted from Pradhan AD, et al. JAMA. 2001;286(3):

2 My Favorite MetS Definition 3 of the Following Risk Factors My Favorite MetS Definition 3 of the Following Risk Factors Risk Factor Abdominal obesity Triglycerides HDL-Cholesterol Blood pressure Fasting glucose Microalbuminuria Waist circumference: men > 102 cm (> 40 in); women > 88 cm (35 in) 150 mg/dl (1.695 mmol/l) Men < 40 mg/dl (1.036 mmol/l); women < 50 mg/dl (1.295 mmol/l) 130/85 mm Hg 100 mg/dl (5.5 mmol/l) Not included in this list, but found in other definitions Risk Factor Abdominal obesity Triglycerides HDL-Cholesterol Blood pressure Fasting glucose Microalbuminuria This requires a tape measure; we usually Waist circumference: measure body men weight > 102 as a cm proxy, (> 40 but in); keep in women mind > 88 cm that (35 muscle in) weighs more than fat. BMI > 30 kg/m 2 defines obesity. 150 mg/dl (1.695 mmol/l) Men < 40 mg/dl (1.036 mmol/l); women < 50 mg/dl (1.295 mmol/l) 130/85 mm Hg 100 mg/dl (5.5 mmol/l) Not included in this list, but found in other definitions NCEP ATP III. Circulation. 2002;106(25): See also Citrome L. J Psychopharmacol. 2005;19(6 Suppl): BMI = body mass index. NCEP ATP III. Circulation. 2002;106(25): See also Citrome L. J Psychopharmacol. 2005;19(6 Suppl): My Favorite MetS Definition 3 of the Following Risk Factors My Favorite MetS Definition 3 of the Following Risk Factors Risk Factor Abdominal obesity Triglycerides HDL-Cholesterol Blood pressure Fasting glucose Microalbuminuria Waist circumference: Elevation of triglycerides men > 102 can cm (> occur 40 in); before women substantial > 88 cm (35 weight in) gain has accumulated. 150 mg/dl (1.695 mmol/l) Men < 40 mg/dl (1.036 mmol/l); women < 50 mg/dl (1.295 mmol/l) 130/85 mm Hg 100 mg/dl (5.5 mmol/l) Not included in this list, but found in other definitions Risk Factor Abdominal obesity Triglycerides HDL-Cholesterol Blood pressure Fasting glucose Microalbuminuria Waist circumference: men > 102 cm (> 40 in); women It > has 88 cm never (35 been in) easier to measure blood pressure! Get one of these for less than $30: 150 mg/dl (1.695 mmol/l) Men < 40 mg/dl (1.036 mmol/l); women < 50 mg/dl (1.295 mmol/l) 130/85 mm Hg 100 mg/dl (5.5 mmol/l) Not included in this list, but found in other definitions NCEP ATP III. Circulation. 2002;106(25): See also Citrome L. J Psychopharmacol. 2005;19(6 Suppl): NCEP ATP III. Circulation. 2002;106(25): See also Citrome L. J Psychopharmacol. 2005;19(6 Suppl): My Favorite MetS Definition 3 of the Following Risk Factors Risk Factor Abdominal obesity Triglycerides HDL-Cholesterol Blood pressure Fasting glucose Microalbuminuria Waist circumference: men > 102 cm (> 40 in); women > 88 cm (35 in) 150 mg/dl (1.695 mmol/l) Men < 40 mg/dl (1.036 mmol/l); women < 50 mg/dl (1.295 Getting mmol/l) fasting bloods can be difficult. Screening for 130/85 diabetes mm mellitus Hg can now be done using HbA1c. 100 mg/dl (5.5 mmol/l) Not included in this list, but found in other definitions Cultural/Ethnic Issues BMI and waist circumference for Asians is generally lower Need a lower cutoff, eg, 90 cm in men (instead of 102 cm) or 80 cm in women (instead of 88 cm) In Japan, definition of obesity is BMI > 25 kg/m 2 (instead of 30 kg/m 2 ) HbA1c = hemoglobin A1c. NCEP ATP III. Circulation. 2002;106(25): See also Citrome L. J Psychopharmacol. 2005;19(6 Suppl): Tan CE, et al. Diabetes Care. 2004;27(5):

3 Overlap of Obesity, DM2, and MetS Prevalence of Obesity, DM2, and MetS among Persons with Schizophrenia (CATIE Study, USA) Obesity DM Obesity 42% (BMI > 30 kg/m 2 ) DM 12% MetS MetS 30% Citrome L, et al. South Med J. 2005;98(7): CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness. Stroup TS, et al. Schizophr Bull. 2003;29(1): MetS and Outpatients with Schizophrenia (United States) MetS in Schizophrenia (Meta-Analytic Rates) Kato MM, et al. Prim Care Companion J Clin Psychiatry. 2004;6(2): Cross-sectional study, N = 48 Prevalence of MetS was 63% In this study, patients with schizophrenia had a 3-fold greater risk to develop MetS than the general population Hispanic patients had a significantly greater prevalence of MetS than non-hispanic patients (P <.05) Increased waist circumference was the strongest clinical correlate with MetS Mitchell AJ, et al. Schizophr Bull. 2013;39(2): MetS 33% Waist 49% BP 39% TG 39% FPG % HDL 43% Smokers 54% Diabetes 11% You Can Be Metabolically Obese MetS in Normal-Weight Americans men B HW women Overall prevalence (SE) of the metabolic syndrome within each ethnicity, sex, and BMI category Consequences of MetS MetS is associated with a 4 relative risk of developing diabetes (in the general population) MetS is associated with a ~2-fold risk of CHD, stroke, and premature mortality (in the general population) MetS is significantly associated with cognitive impairment in schizophrenia and can potentially contribute to functional decline observed in some patients with schizophrenia throughout the course of illness BMI is an independent predictor of psychiatric rehospitalization St-Onge MP, et al. Diabetes Care. 2004;27(9): Alberti KG, et al. Circulation. 2009;120(6): Hanley AJ, et al. Circulation. 2005;112(24): Gami AS, et al. J Am Coll Cardiol. 2007;49(4): Bora E, et al. Psychol Med. 2017;47(6): Manu P, et al. J Clin Psychiatry. 2014;75(6):e573-e577.

4 How the Disease State of Schizophrenia Contributes to the Risk of Developing DM2 Why is the prevalence of diabetes 2- to 3-fold higher than in the general population? Glucose (mg/dl) Relative Function (%) Type 2 Diabetes Mellitus Natural History Postprandial Glucose Fasting Glucose Insulin Resistance At Risk for DM β Cell Failure Insulin Level Time (years) Obesity IFG* Diabetes Uncontrolled hyperglycemia Adapted by Angela R. Thompson, MSN, RN, FNP-C, CDE, BC-ADM, from Kendall DM, Bergenstal RM International Diabetes Center at Park Nicollet, Minneapolis, MN. Downloaded from Accessed July 12, Epidemiology High prevalence of undiagnosed diabetes, estimated to be up to 70% of all cases Prevalence of diabetes in SMI is 2- to 3-fold higher than in the general population Incidence of diabetes is higher and the onset of diabetes appears to be 10 to 20 years earlier than in the general population In a study of NY State hospitals, prevalence increased from 6.9% of 10,091 patients in 1997 to 14.5% of 7420 patients in 2004; incidence of newly treated diabetes increased from 0.9% in 1997 to 1.8% in 2004 As diabetes is uncommon in young healthy adults, the increased relative risk of diabetes is greatest in adolescents and young adults with SMI SMI = serious mental illness. Citrome L, et al. Psychiatr Serv. 2006;57(8): Epidemiology Prevalence of DM among All Unique Civil Adult Inpatients, New York State Office of Mental Health, vs General New York State Population Citrome L, et al. Psychiatr Serv. 2006;57(8): Mechanisms Genetics? Both schizophrenia and DM2 are highly heritable disorders Recent studies have identified at least 37 common genes that increase the risk of both diabetes and schizophrenia Approximately 11% and 14% of these risk genes for diabetes and schizophrenia, respectively, may account for the risk of the other disease In addition to affecting an individual s risk of diabetes directly, genetic polymorphisms in various genes, may also affect the risk of weight gain

5 Genetics? Genes that have been Linked to both Diabetes and Schizophrenia Gene Glycogen synthase kinase 3 (GSK3) Serine threonine protein kinase (AKT1) Dopamine D 2 receptor (DRD2) gene Tyrosine hydroxylase gene TCF7L2 gene Function Regulates both glucose metabolism and cognitive function Reduced expression in lymphocytes and the frontal cortex in schizophrenia. Mediates insulin signaling and glucose metabolism; reduced action leads to diminished phosphorylation of its substrates, including GSK3 Implicated in obesity and DM2, through alteration of insulin sensitivity and secretion. Affects risk of schizophrenia Associated with insulin resistance and schizophrenia Encodes for a transcription factor involved in Wnt/β-catenin signaling that has a role in pancreatic β cell function and is a susceptibility gene for DM2. Wnt signaling pathway plays a role in CNS development and is associated with schizophrenia CNS = central nervous system. Environment and Biological Effects of the Illness? Intra-uterine environmental factors: J-shaped relationship between birth weight and plasma glucose, insulin concentrations, and diabetes Childhood obesity Adult environment: diet and lifestyle, neighborhood environment, and poverty Inflammatory and neuroendocrine changes, including hypothalamic-pituitary adrenal (HPA) dysfunction (also observed in depression) Antipsychotic Medication? Caveat: SGAs Pharmacoepidemiologic database studies report that antipsychotics are associated with more diabetes than no treatment and treatment with an SGA is associated with a small 32% (15% 51%) increase in diabetes risk compared with FGAs FGA = first-generation antipsychotic; SGA = second-generation antipsychotic. Although the risk of diabetes for the newer SGAs is widely believed to be lower, this has not always been apparent in pharmaco-epidemiology studies For example, aripiprazole and ziprasidone were not associated with lower rates of diabetes than olanzapine, quetiapine, and risperidone in a pharmaceutical claims database Perhaps because of channeling bias whereby persons at higher risk for diabetes are prescribed antipsychotics that are perceived to be safer Bottom-line: Schizophrenia confers a high endogenous risk for diabetes, and the risk is further increased by both first-generation and second-generation antipsychotics Rajkumar AP, et al. Am J Psychiatry. 2017;174(7): Antipsychotic Medication Contribution of Weight Gain? Weight gain increases insulin resistance; this will eventually blossom into diabetes in vulnerable people with low pancreatic reserve Weight gain is likely the most common reason for developing DM2, especially for those with increased genetic risk and unhealthy lifestyle However, weight does not explain all the excess diabetes risk as some individuals develop diabetes without being overweight or gaining weight Furthermore, weight gain does not explain why some people develop diabetic ketoacidosis which occurs as a result of markedly impaired insulin secretion Antipsychotic Medication Glucose Homeostasis Through their interaction with multiple receptors, antipsychotics may affect insulin secretion by the β cells of the pancreas Central control of glucose homeostasis may also be affected by antipsychotics In addition to these pancreatic effects, in vitro work suggests that antipsychotics may directly impair insulin action by inhibiting insulin-mediated glucose uptake and glycogen synthesis

6 Antipsychotic Medication Pharmacologic Effects on β Cell Function? Summary: Schizophrenia and Diabetes Multiple mechanisms are involved in the association between SMI and diabetes Likely that the contributions of these risk factors operate differently between individuals Overall, it appears that an excess of traditional diabetes risk factors, such as obesity, poor diet, physical inactivity, and family history, convey a higher risk than treatment, but this does not discount the possibility that antipsychotics are the major contributor to the development of diabetes in certain individuals, particularly where the onset of diabetes is rapid after treatment initiation and other risk factors are absent SGA vs SGA SGA vs FGA Any Antipsychotic Medication Schizophrenia Antipsychotics and Weight Gain Traditional Risk Factors eg, family history, obesity, ethnicity, exercise, age Are There Differences? Can We Measure Them? Holt RI, et al. Diabetes Obes Metab. 2006;8(2): Antipsychotic-Related Weight Gain The heterogeneity of weight gain results from poorly understood drug-geneenvironment interactions Moderators include patient demographics, treatment setting, illness characteristics, past and baseline antipsychotic and comedication treatments, and baseline diet, activity and body composition Mediators include antipsychotic dose, comedications, medication side effects, and changes in diet and activity Correll CU, et al. Trends Mol Med. 2011;17(2): Antipsychotic-Related Weight Gain Almost all antipsychotics are associated with weight gain More pronounced in antipsychotic naïve patients Can occur over time Not clearly dose-dependent Antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets Nonetheless, there are differences that can be quantified when comparing groups of patients in clinical trials Your individual mileage may vary Bak M, et al. PLoS One. 2014;9(4):e Zhang JP, et al. Schizophr Bull. 2016;42(6):

7 NNH vs Placebo How many patients would you need to treat with a medication instead of placebo before you would encounter one additional adverse outcome? The smaller the NNH, it takes fewer patients to treat with a medication vs placebo before encountering an additional adverse outcome Thus, the higher the NNH, the less likely one would encounter that outcome NNH is a measure of clinical significance NNH does not measure statistical significance; it is not the same as a P-value NNH is an absolute effect size measure NNH is not a relative effect size measure such as the relative risk or odds ratio that are sometimes used to describe adverse outcomes NNH = number needed to harm. Citrome L, et al. Int J Clin Pract. 2013;67(5): NNT = number needed to treat. Citrome L. Curr Drug Saf. 2009;4(3): NNH vs Placebo Easy to Calculate What is the NNH for an outcome for Drug A vs placebo? f A = frequency of outcome for Drug A f B = frequency of outcome for placebo Attributable Risk Increase (ARI) = f A f B NNT = 1/AR, by convention, when not presenting fractions, we round up the NNT to the next higher whole number in order to avoid exaggerating a difference (lower NNH values = larger effect) For example, Drug A results in a headache 50% of the time, but placebo results in a headache 20% of the time: NNH = 1/[ ] = 1/0.30 = 3.33 Round up to 4 Citrome L. Curr Drug Saf. 2009;4(3): NNH vs Placebo Easy to Calculate What is the NNH for an outcome for Drug A vs placebo? f A = frequency of outcome for Drug A f B = frequency of outcome for placebo Attributable Risk Increase (ARI) = f A f B NNT = 1/AR, by convention, when not presenting fractions, we round up the NNT to the next higher whole number in order to avoid exaggerating a difference (lower NNH values = larger effect) NNH = 1/[ ] = 1/0.30 = 3.33 Round up to 4 For every 4 persons randomized to Drug A instead of placebo, you would encounter 1 additional person with a headache. What is an Acceptable NNH for Drug vs Placebo? NNH: < > 100 Adverse events that are mild or moderate, usually do not lead to discontinuation, and are usually temporary or cause no distress and do not pose a serious health risk eg, Mild nausea, or sedation during mania Adverse events that may lead to discontinuation but not associated with serious immediate health risks; alternatives do not have a better profile eg, Moderate weight gain Citrome L, et al. Int J Clin Pract. 2013;67(5): Adverse events that pose a significant health risk; for very severe adverse outcomes NNH values greater than 1000 may be more acceptable eg, Acute hemorrhage, serious rash NNH vs Placebo Easy to Find the Data and Figure it Out The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.8% for lurasidone-treated patients versus 3.3% for placebo-treated patients f A = f B = ARI = = NNT= 1/0.015 = 66.6 = 67 LATUDA (lurasidone hydrochloride) tablets, for oral use. Product Label Revised 2/ Accessed July 14, Weight Gain 7% of Baseline* Medication Schizophrenia Bipolar Mania *Among Adults on SGAs from Short-Term RCTs. Major Depressive Disorder Bipolar Depression Iloperidone Asenapine Lurasidone Brexpiprazole Cariprazine (to 6 mg/day) 34 No diff. - - Aripiprazole 21 No diff Olanzapine Paliperidone Quetiapine IR Quetiapine XR Risperidone (to 8 mg/day) Ziprasidone Citrome L. Int J Clin Pract. 2015;69(11): Citrome L. CNS Spectr. 2014;19(Suppl 1):4-11. Citrome L. Expert Opin Pharmacother. 2011;12(17):

8 Olanzapine Pattern of Weight Gain Olanzapine Early Weight Gainers Patients with higher baseline BMI (> 27.6) gained significantly less weight during treatment with olanzapine than their lighter counterparts The effect of olanzapine dose on weight was not significant In long-term ( 48 weeks) studies the proportions of patients who gained at least 7%, 15%, or 25% of their baseline weight were 64%, 32%, and 12%, respectively. Kinon BJ, et al. J Clin Psychiatry. 2001;62(2): Citrome L, et al. Clin Drug Invest. 2011;31(7): RWG = rapid weight gain group; NRWG = nonrapid weight gain group. Kinon BJ, et al. J Clin Psychopharmacol. 2005;25(3): % showed rapid increases in weight (RWG group) In the RWG group patients gained an average of 4% of their body weight (4 7 lb) within the first 2 weeks of treatment with olanzapine Patients in the RWG group were younger and had a lower baseline BMI Over the course of 52 weeks, patients in the RWG group gained significantly more weight and reached a higher plateau for mean weight increase at 38 weeks Olanzapine Early Weight Gainers 15% showed rapid increases in weight (RWG group) In the RWG group patients gained an average of 4% of their body weight (4 7 lb) within the first 2 weeks of treatment with olanzapine Similarly, in patients with bipolar mania or mixed mania, a Patients in the RWG group substantial amount of weight gain after were 30 younger weeks and was had a lower baseline BMI predicted by weight increases of 2 to 3 kg within the Over the course of 52 first 3 weeks of treatment. However, patients weeks, patients with in less the RWG pronounced early weight gain might still group be gained at risk significantly more weight and reached a if they have close to normal BMI at treatment higher plateau initiation. for mean weight increase at 38 weeks Lipkovich I, et al. J Clin Psychopharmacol. 2006;26(3): Interventions Kinon BJ, et al. J Clin Psychopharmacol. 2005;25(3): MetS Provides a Framework Eliminate or reduce modifiable risks Overweight or obese: diet/nutrition counseling Physically inactive: exercise 150 minutes/week minimum If pre-diabetic, begin measures to slow and/or prevent progression to diabetes Lifestyle and dietary modifications Regular screening Evaluate, monitor, and manage hypertension, atherogenic dyslipidemia, and other risk factors Refer to a primary care provider and/or specialist when necessary Grundy SM, et al. Circulation. 2005;112(17): MetS Provides a Framework (cont d) Weight loss 10 lb loss leads to a 30% decrease in risk for DM, a decrease in BP, and improvement in lipids Exercise Leads to decrease in weight, BP, and mortality Control of HbA1c Leads to a decrease in DM complication rate Control of BP Leads to a decrease in DM complication rate Grundy SM, et al. Circulation. 2005;112(17):

9 MetS: Incremental Improvements BMI by 1 point BP by 6 mm Hg (> 140 / 90) Decrease weight by 4 10 kg Chol. by 10% (TC: ) LDL-C by 30 mg/dl Healthy Weight Active Lifestyle Smoking (any LDL-C ) (BMI ) (> 20 min Walk) Cessation Prevention is Best: Especially Weight Young Adults CARDIA Study Men and women aged years (n = 4192) were followed for 15 years Risk for MetS increased 23% (20% 27%) per 4.5 kg (10 lb) of weight gained, whereas regular physical activity over time vs low activity was protective (RR 0.49 [ ]) Bottom line: BMI and weight gain are important risk factors for MetS; regular physical activity may counter this risk Correll CU. CNS Spectr. 2007;12(10 Suppl 17):12-20, 35. Carnethon MR, et al. Diabetes Care. 2004;27(11): Prevention is Best : Especially Weight Insulin Resistance Atherosclerosis Study (IRAS) 714 white, black, and Hispanic participants free of MetS at baseline 139 of these developed MetS in the subsequent 5 years Predictors of incident MetS were waist circumference (OR 1.7 [ ] per 11 cm), HDL cholesterol (0.6 [ ] per 15 mg/dl), and proinsulin (1.7 [ ] per 3.3 pmol/l) Signal detection analysis identified waist circumference (> 89 cm in women, > 102 cm in men) as the optimal predictor Bottom line: obesity may precede the development of other MetS components; interventions that address obesity and reduce waist circumference may reduce the incidence of MetS in nondiabetic adults Palaniappan L, et al. Diabetes Care. 2004;27(3): How Often Should We Check? Consensus Statement on Antipsychotic Drugs, Obesity, and Diabetes: Monitoring Protocol for Patients on SGAs Personal/ Family History Short-Term Baseline 4 wk 8 wk 12 wk Quarterly X Weight (BMI) X X X X X Long-Term Annually * X Waist X X Circumference Blood Pressure X X X Fasting Plasma X X X Glucose Every 5 yrs Fasting Lipid X X X [X] Profile *More frequent assessments may be warranted based on clinical status; consider also HbA1C. American Diabetes Association, et al. Diabetes Care. 2004;27(2): Barriers to Addressing CVD Risk in Patients with SMI Lifestyle and Habit Changes through Educational and Psychosocial Programs AAP = atypical antipsychotics. Druss BG. J Clin Psychiatry. 2007;68 Suppl 4: Lester H, et al. BMJ. 2005;330(7500):1122. Muir-Cochrane E. J Psychiatr Ment Health Nurs. 2006;13(4): De Hert M, et al. World Psychiatry. 2011;10(20):

10 Prevalence / Lack of Intervention (%) Call to Action: We Can Do Better CATIE: Rates of Pharmacologic Interventions for Abnormal Blood Pressure, Lipids, and Glucose n = 1488 n = 685 n = n = 481 n = 300 n = 75 n = 34 n = 471 n = 421 Hypertension Diabetes Dyslipidemia Cases Nasrallah HA, et al. Schizophr Res. 2006;86(1-3): Lack of Medical Intervention 68.3 Call to Action: We Can Do Better Self-Reported Lack of Medical Treatment in SMI Patients with Directly Assessed MetS and Self-Reported Hypertension, Lack of Medical Treatment (%) / 1359 Metabolic Syndrome Hypercholesterolemia, and Diabetes / 3608 Hypertension Correll CU, et al. Psychiatr Serv. 2010;61(9): / 3732 Elevated Cholesterol / 1754 Diabetes Medical Risk Management Strategies PREVENTION PRIMARY SECONDARY TERTIARY Treatment Initiation Healthy lifestyle counseling Healthy lifestyle intervention Start with lower-risk antipsychotic If Adverse Effect is Present Healthy lifestyle counseling/intervention Consider changing to lower-risk antipsychotic Consider weight loss intervention If Adverse Effect Progresses/Serious Healthy lifestyle counseling/intervention Considering changing to lower-risk antipsychotic Add targeted treatment for pathological values Consider referral to specialist Correll CU. CNS Spectr. 2007;12(10 Suppl 17):12-20, 35. Non-Pharmacologic Interventions for Antipsychotic-Associated Weight Gain Meta-analysis 17 studies (n = 810, mean age: 38.8 years, 52.7% male, 40.8% white, 85.6% with schizophrenia spectrum disorders) Significant reduction in weight ( 3.12 kg) and BMI ( 0.94 kg/m 2 ) compared with control groups Benefits extended to all secondary outcomes, except for HDL-C and systolic BP Subgroup analyses showed effects only in outpatient trials; effective treatments ranged from nutritional interventions to cognitive-behavioral therapy Caemmerer J, et al. Schizophr Res. 2012;140(1-3): See also Teasdale SB, et al. Br J Psychiatry. 2017;210(2): Pharmacologic Interventions for Antipsychotic-Associated Weight Gain Change in Bodyweight (kg) Favors Placebo Favors Intervention Meta-analysis 95% CI WMD More about Metformin Meta-analysis 21 RCTs (n = 1547) that tested metformin and placebo in patients taking antipsychotics Metformin was significantly superior to placebo in the primary outcome measures (body weight, BMI, fasting glucose, fasting insulin, triglycerides, and total cholesterol) Significantly higher frequencies of nausea/vomiting and diarrhea were found in the metformin group, but no differences were found in other adverse effects Adjunctive metformin is an effective, safe, and reasonable choice for antipsychotic-induced weight gain and metabolic abnormalities Maayan L, et al. Neuropsychopharmacology. 2010;35(7): Zheng W, et al. J Clin Psychopharmacol. 2015;35(5):

11 Using Metformin Early Using Metformin Safely The best weight outcomes are from preventing initial weight gain rather than attempting weight loss later in treatment Initiate metformin concomitantly with or soon after the initiation of antipsychotic medication use; particularly important for young, healthy patients who receive olanzapine or clozapine When combined with diet and lifestyle changes, metformin s effects appear more pronounced Start with 500 mg, twice a day, or 850 mg, once a day, with meals; dosage should be increased in increments of 500 mg/weekly or 850 mg, every 2 weeks, up to 2000 mg/day, given in divided doses Hendrick V, et al. Ann Clin Psychiatry. 2017;29(2): GI adverse effects are common with metformin: nausea, vomiting, abdominal discomfort, flatulence, and diarrhea Minimize by using gradual dose up-titration, administration of the drug with meals, and use of a time-release formulation Lactic acidosis is very rare with metformin Reduce risk by avoidance in patients with significantly impaired renal, liver, or cardiac functioning; check creatinine levels annually Metformin can impair vitamin B12 absorption: assess serum B12 levels annually GI = gastrointestinal. Andrade C. J Clin Psychiatry. 2016;77(11):e1491-e1494. Other Rx for Weight Loss Medications approved for weight loss have generally not been assessed in RCTs in persons with schizophrenia An exception is liraglutide (a GLP-1 receptor agonist) in patients with schizophrenia in stable treatment with clozapine or olanzapine, and who were overweight or obese, and had prediabetes; trial demonstrated efficacy Orlistat (a GI lipase inhibitor) added to clozapine or olanzapine did not show efficacy Topiramate (may also be helpful in decreasing symptoms of schizophrenia); watch for cognitive effects Adding aripiprazole to clozapine (or olanzapine) may be another option Larsen JR, et al. JAMA Psychiatry. 2017;74(7): Joffe G, et al. J Clin Psychiatry. 2008;69(5): Citrome L. Int J Clin Pract. 2014;68(12): Andrade C. J Clin Psychiatry. 2016:77(9):e1090-e1094. Conclusions People with schizophrenia/smi are at increased risk for MetS and related cardiovascular morbidity The risk for physical disorders in patients with SMI is conferred by mental illness, unhealthy lifestyle, and psychiatric treatments Medication-induced weight gain has predictable adverse cardiometabolic effects, and some antipsychotics alter glucose and lipid metabolism independent of changes in adiposity Educate and counsel about nutrition and exercise Regularly monitor weight, blood pressure, fasting glucose, or HbA1C and lipids Proactively manage physical illness in the SMI