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CME Released: 12/10/2002; Valid for credit through 12/10/2003

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This activity is intended for psychiatrists, primary care physicians, psychiatric nurses, and other health care professionals.

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As novel treatment options for the management of psychosis continue to become available, clinicians must be updated ontheir potential risks and associated comorbidities, including type 2 diabetes mellitus. This activity will update psychiatrists,primary care physicians, and psychiatric nurses on novel treatment options for psychosis, and the possible associated risksfor developing type 2 diabetes mellitus.

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Upon completion of this program, participants should be able to:

Describe the relationship between obesity, insulin resistance, and type 2 diabetes mellitus.1.Review the newer antipsychotic medications and their ability to improve overall outcomes in schizophrenia.2.Discuss how specific pharmacologic treatments contribute to weight gain.3.Describe abnormalities in glucose and lipid metabolism and weight regulation associated with antipsychoticmedications.

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All other healthcare professionals completing continuing education credit for this activity will be issued a certificate ofparticipation.

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This activity has been planned and produced in accordance with the Essential Areas and Policies of the Accreditation Councilfor Continuing Medical Education (ACCME). The Center for Health Care Education, Inc, is accredited by the ACCME toprovide continuing medical education for physicians.

The CHCE designates this educational activity for a maximum of 1.0 hour in category 1 credit toward the AMA Physician'sRecognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

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New Insights in Diabetes and Psychiatric Illness: Integrating Management ... http://www.medscape.org/viewarticle/442813_print

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President, Professor of Medicine, Morehouse School of Medicine; Chairman, National Diabetes Education Program, Atlanta,Georgia.

Disclosure: Is a member of the Speakers Bureau and a consultant for Aventis Pharmaceuticals Inc., Bayer Corporation,Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck & Co., Inc., Novartis AG, Pfizer Inc., TakedaPharmaceuticals North America, Inc.

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Associate Professor of Psychiatry, Washington University School of Medicine, St. Louis, MO

Disclosure: Receives grant support from NARSAD and National Institutes of Health, AstraZeneca, Eli Lilly and Company,

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. Fortechnical assistance, contact [email protected]

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Janssen Pharmaceuticals, and Pfizer Inc.Is a lecturer and a consultant to AstraZeneca, Eli Lilly and Company, JanssenPharmaceuticals, and Pfizer Inc.

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Professor of Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY;Chief, Division of Endocrinology, Diabetes, and Nutrition, St. Luke's-Roosevelt Hospital Center, New York, NY.

Disclosure: Receives honoraria, grants and/or research support, and is a consultant to GlaxoSmithKline, Schering-PloughCorporation, and Takeda Pharmaceuticals North America, Inc.

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Director, Schizophrenia Research Program; Professor of Psychiatry, SUNY Health Sciences Center at Brooklyn, Brooklyn,New York.

Disclosure: Receives grants and/or research support, and is a member of the Speakers Bureau and a consultant toAstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Novartis AG, and Pfizer Inc.

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Welcome and Introduction

New Insights in Diabetes and Psychiatric Illness: IntegratingManagementFaculty: James R. Gavin III, MD, PhD; Peter J.Weiden, MD; F. Xavier Pi-Sunyer, MD; John W. Newcomer, MD

Posted: 10/10/2002


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Leading Causes of Disability

Those of us in the diabetes field tend to focus sharply on the explosive epidemic confronting us, and we seldom stop to thinkabout the degree to which there are other causes of chronic disability.

When you look at the leading causes of disability between both sexes, number 4 among them is schizophrenia. Among males,it is number 5. And among females, the second leading cause of disability in the age group 15 to 44 years is schizophrenia.

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Leading Causes of Disability

In general, the burden of psychiatric conditions has been heavily underestimated. Of the 10 leading causes of disabilityworldwide in 1990, 5 of them were, in fact, psychiatric.


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What we're doing in this program is looking at the interface between the major disability of psychiatric illness and the placewhere it meets another major disabling disease, type 2 diabetes. There is indeed an interrelationship, in part driven by the newemergent treatments used to control psychiatric diseases.

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Diabetes Mellitus in the United States: Increasing Prevalence of Diagnosed Cases

What you're seeing here is the extent to which diabetes is a major problem in this society. Over the time from 1958 through themid-1990s, there has been a 5-fold increase in this disease. And in recent years, it shows no signs of slacking off.

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Annual Healthcare Costs for Diabetes Patients: 1992

Not only are the numbers increasing at an enormous rate, but more importantly, we are spending a lot of money in support of


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diabetes-related healthcare costs. We're spending over $100 billion and, in fact, figures comparable with this are being spentin support of psychiatric illnesses.

One might wonder how are these conditions coupled? Where do they meet? At what place is there an interface? We'regaining a new appreciation for the degree to which the management of psychiatric illness, and many of the consequences oftreatment, promote the development of type 2 diabetes.

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Type 2 Diabetes Mellitus

For example, you don't get type 2 diabetes unless you have the combination of insulin resistance and diminished beta-cellfunction. By the end of this program, you will see that the emerging developments in the management of many psychiatricillnesses do, in fact, heavily influence this particular problem, and what we're beginning to be concerned about is the extent towhich the management of psychiatric illness will be driving the development of more insulin resistance and indeed more type 2diabetes in the future. And there are implications for all of us in that.

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Epidemiology of Obesity and Weight Gain: The Impact on Diabetes

My talk is about the epidemiology of obesity and weight gain and its impact on diabetes.

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Classification of Overweight and Obesity by BMI

I want to begin with a classification of overweight and obesity by body mass index (BMI) that has been approved by theNational Institutes of Health and the World Health Organization. Underweight is a BMI of less than 18.5 kg/m2. The normalrange is 18.5 to 24.9. Overweight is 25 to 29.9, and obesity is greater than 30 -- divided into 3 groups, 30 to 35, 35 to 40, andgreater than 40. Body mass index is kilograms per meters squared -- kilograms of weight divided by meters in height squared.


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Prevalence of Obesity in the United States: 1960-1991

This figure is the prevalence of obesity in the United States taken from the National Health and Nutrition Examination Surveys(NHANES) that were initiated in 1960, 1971, 1976, and 1988. It is clear that the percentage overweight in the population wasrelatively steady in both men and women between 1960 and 1980 with about a quarter of the population being overweight.

On the other hand, in the NHANES of 1988 to 1991, the percentage overweight increased to about one third of the population,31.7% in men and 34.9% in women. This 8% jump in a decade is an extraordinary increase in a population group, and weknow because of other surveys that the rate is increasing 1% per year.

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Obesity Distribution in the United States Population (NHANES)


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We're not only obese in this country, but we are very obese; and this is the obesity distribution in the United States populationas taken from the NHANES of 1988 to 1991. Only 41.3% of the population has a BMI of 25 or less (normal range or below).Sixteen percent are between 25 and 27, 18.6% between 27 and 30, 16.1% between 30 and 35, an astounding 5.1% at 35 to40, and 2.9% above 40. So we have a very large shoulder to the right of the population with an increase in overweight and inobesity that is extremely large.

This is true in the United States, but it is also becoming true in other industrialized countries of the world, particularly in Europe,Australia, South Africa, New Zealand, and parts of Asia.

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Prevalence of Overweight and Obesity Among Adults Age 20 to 80+ Years, by Gender, Race/Ethnicity, and Age: UnitedStates, 1960-1994

The prevalence of overweight and obesity among adults age 20 to 80+ years is shown in this figure. You can see the data forboth white men and women, and minority groups in this country, including black men and women, and Mexican American menand women. On the left are the data for combined overweight and obesity, and on the right, the data for obesity.

It is clear that the minority women, black, non-Hispanic, and Mexican American, have levels that are much higher than their mencounterparts -- 65.8% of black women are overweight, 65.9% of Mexican American women. But even white women are 49.2%.And when you get to obesity, it's 23.5% for white women, 36.7% for black, non-Hispanic women, and 33.3% for MexicanAmerican women.


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Prevalence of Obesity Among US Adults: BRFSS, 1991

On this map of the United States is the prevalence of obesity among US adults from data gathered by the Centers for DiseaseControl. In light blue, you have a prevalence of less than 10% of the population; in somewhat darker blue, 10% to 15%; and invery dark blue, greater than 15%. Only 5 states have a prevalence in 1991 of greater than 15%.

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Prevalence of Obesity Among US Adults: BRFSS, 1998

But if you go to the data for 1998, there are no states that have a prevalence under 10%. A significant number have 10% to15%, and the greatest number has greater than 15%. So we have essentially a galloping epidemic of obesity/overweight in thepopulation of the United States.


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Components of the Metabolic Syndrome

Why are public health authorities worried about this increasing prevalence of obesity in the United States and around theworld? It's because obesity is related to insulin resistance, and this leads to the metabolic syndrome, or so-called syndromeX, with a number of components that lead to disease that causes a great deal of morbidity and mortality in the country.

Insulin resistance is associated with hyperinsulinemia, and this is abetted by central obesity. The hyperinsulinemia and insulinresistance tends to enhance the likelihood of an individual having hypertension, glucose intolerance, abnormal blood lipidscharacterized primarily by an increased serum very low density lipoprotein (VLDL) triglyceride, a decreased serumhigh-density lipoprotein (HDL) cholesterol, and hyperuricemia. The combination of all those factors leads to a very increasedrisk of macrovascular disease.


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Insulin Sensitivity in Relation to BMI

In this study by Campbell and Gerich, you can see the relation of insulin sensitivity to BMI. If you look at the areas between aBMI of 19 and a BMI of 25, the insulin sensitivity is normal and flat. But beginning at a BMI of about 25 or 26, there is adecrease in insulin sensitivity -- an increase in insulin resistance. And the insulin resistance tends to get worse as the BMI, oras the overweight/obesity increases.

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Insulin vs Clock Time

Insulin resistance is characterized by hyperinsulinemia, as shown in this figure from Polonsky at Washington University. Thefigure shows the insulin levels in the bloodstream over 24 hours in a group of normal individuals (in yellow) and a group ofobese individuals (in red). You can see the fluctuations for the 3 meals that were given to these individuals: one at 7:00 AM,


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one at 1:00 PM, and one at 6:00 PM. It's clear that insulin is elevated not only postprandially but also in the fasting state so thatif you take an area under the curve -- an integrated curve of the secretion of insulin -- over a 24-hour period, the obeseindividuals have a 4- to 6-fold greater need of insulin than do normal-weight individuals.

These are obese individuals who do not yet have diabetes. The inability of insulin to do its job appropriately in getting glucoseinto the cell and getting glucose utilized, oxidized, and stored, means that the beta cell of the pancreas is putting out 5- to6-fold more insulin per day in these individuals.

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The insulin resistance and hyperinsulinism that occurs with weight gain leads to these conditions, which lead to a great deal ofmorbidity and mortality in this country: type 2 diabetes, hypertension, dyslipidemia, and a hypercoagulable state that tends tolead to myocardial infarction and cardiovascular disease.

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Risk of Type 2 Diabetes Mellitus Using BMI

The risk of type 2 diabetes developing in an individual is clearly seen in this slide from the Nurses Study. The Nurses Study isfollowing 116,000 nurses in the northeast United States, and this is a report of a 16-year follow-up. As one goes from a BMIbelow 22 to a BMI of 35, there is a gradually increasing relative risk for developing diabetes. A BMI less than 22 is set at 1,and you can see that at 35+, one has a 90- to 95-fold risk of developing diabetes over 16 years. Even within the normal range,there is a significant increase as one moves from a BMI of 22 to a BMI of 25.

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Weight Gain and Diabetes Risk

It's not only the amount of weight that one is carrying that is important, but it's where one started. This is seen in this study byChan, et al that was published in 1994 showing a weight change since age 21 years of less than 5 kg, 5 to 10 kg, or greaterthan 10 kg in the population divided by those who started at age 21 with a BMI under 22, a BMI of 22 to 23, or a BMI of 24 andhigher. While there's an increased risk as the weight gain increases from less than 5 kg to greater than 10 kg, it's clear that inthose individuals who started at a BMI of 24, gaining the same amount of weight increased their risk significantly. Your BMI asyou enter your adult years is as important as the weight that you put on over the next 10 or 15 years.


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Weight Gain and Diabetes Risk

It's not only the amount of weight that one is carrying that is important, but it's where one started. This is seen in this study byChan, et al that was published in 1994 showing a weight change since age 21 years of less than 5 kg, 5 to 10 kg, or greaterthan 10 kg in the population divided by those who started at age 21 with a BMI under 22, a BMI of 22 to 23, or a BMI of 24 andhigher. While there's an increased risk as the weight gain increases from less than 5 kg to greater than 10 kg, it's clear that inthose individuals who started at a BMI of 24, gaining the same amount of weight increased their risk significantly. Your BMI asyou enter your adult years is as important as the weight that you put on over the next 10 or 15 years.

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Patterns of Body Fat Distribution

The patterns of fat distribution are important. Abdominal or android fat distribution -- fat distribution in the central or upper body


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-- has been found in both cross-sectional and longitudinal studies to be significantly more risky for health than gluteal femoralor lower body or gynoid obesity.

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Probability of Developing Diabetes: BMI and WHR

In this study done in Goteborg, Sweden, you can see the percentage probability of developing diabetes during 13.5 years offollow-up in relation to tertiles of the initial BMI and waist-to-hip ratio -- with BMI being a measure of total fat burden and waist-to-hip ratio being a measure of whether the fat is centrally distributed, or gluteal femorally, or peripherally distributed.

On the left in the pyramid are the BMI tertiles for the population. Number I would be the tertile with the lowest weight, numberIII the highest weight. On the right are the waist-to-hip tertiles. Number I would be the one with the least abdominal or centralobesity, and number III the highest.

It's clear that you can be in the third tertile for weight or fatness and if you're still in the first tertile for waist-to-hip ratio, that isyour fatness is peripheral rather than central, your risk for diabetes does not increase.

On the other hand, you could be in the lowest tertile for BMI and if you have central obesity, your risk goes up 6-fold from .5 to2.9. If you're in the third tertile for both fatness or fat load and central obesity, your risk goes up 30-fold, from .5 to 15.2. Sothere is an independent risk for fat burden, and there's also an independent and synergistic risk from fat distribution.


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Relationship Between Visceral Adipose Tissue and Predisposition to Diabetes in Male Subjects

Fat distribution also increases the amount of insulin that is circulating. In this study by Pouliot and colleagues from LavalUniversity, a group of individuals were compared after being given a 75-g oral glucose tolerance test. The light blue curve islean individuals who were age-matched to obese individuals. The red individuals have low central or visceral adipose tissue(low intra-abdominal adipose tissue) and the green individuals are weight-matched for the reds but have high intra-abdominalor central adipose tissue.

You can see on the right that those individuals who have high levels of intra-abdominal visceral fat have a much higher level ofinsulin circulating in response to a glucose stimulus. They're at more insulin resistance and require more insulin, and becausewith fatness and intra-abdominal fat and fat in the liver, less insulin is degraded by the insulin as it passes through the liver andmore of it can get out into the peripheral circulation.

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Obesity and Hypertension Risk

Obesity is also related to hypertension risk. There are numerous studies, both cross-sectional and longitudinal, that show therelationship between increased weight or increased fatness and hypertension. This is one from the Canadian Guidelines forHealthy Weights taken from the Canadian surveys of the representative groups in the population.

Men are in green, and women are in blue, and what is shown is the percentage of those individuals in the population who arehypertensive, who have a systolic blood pressure greater than 140 mm Hg. As the weight or the total fat burden increases,hypertension in the population increases accordingly. This is true in both men and women; and in those individuals with a BMIof 31 and above, about a third of the population is hypertensive.

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The High TG/Low HDL Cholesterol Dyslipidemic Phenotype and Dense LDL Cholesterol


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With insulin resistance and obesity, there is a characteristic dyslipidemia, which is abnormal blood lipids. It is called the hightriglyceride/low HDL cholesterol phenotype. And that is characterized also by dense low-density lipoprotein (LDL) cholesterolparticles.

So what you have in obese individuals, and particularly in individuals who have central or abdominal obesity, is a hightriglyceride, a low HDL cholesterol, and increased number of dense LDL particles that are small but very atherogenic. And thecombination of those 3 components greatly increases the risk for coronary heart disease in these individuals.

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Risk of Ischemic Heart Disease During 5-Year Follow-Up Period According to Quartiles of Fasting Glucose Concentrations

You can see the effect of hyperinsulinemia on cardiovascular risk in this study reported by Despres in 1996. This is the risk ofischemic heart disease over 5-year follow-up according to quartiles of fasting insulin concentration in a representativepopulation of people from Quebec. On the left is the lowest fasting insulin quartile, which means the group with the lowestinsulin resistance or the greatest insulin sensitivity. On the right is the quartile with the greatest insulin resistance or least insulinsensitivity. The red bars include the epidemiological analysis including all the confounders, and the white bars, it is controllingfor the confounders, such as lipids.

Whether you control for the confounders or not, there is a clear ascendancy in risk of ischemic heart disease over just 5 years.So as one goes from the lowest quartile to the highest quartile, the risk increases 8-fold.


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Hypercoagulability in Insulin Resistance

Part of the reason for this increased cardiovascular risk with insulin resistance is due to the hypercoagulability that occurs inthis condition. There is increased plasminogen activator inhibitor-1 (PAI-1) circulation. PAI-1 is important in clearing clots fromthe circulation. Increased fibrinogen is important in enhancing clotting, as is the case with increased von Willebrand factor,increased factor X, and increased platelet aggregation, which occurs in this condition. All of these components tend toenhance clotting in individuals who have insulin resistance.

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Weight and Depression


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Another component of weight and weight gain that has not been focused on very much previously, but which certainly occurs,is the relationship of weight gain to depression. Depression causes either a diminished or an increased appetite in differentindividuals. So it can cause subsequent weight loss or subsequent weight gain.

Successful antidepressant treatment can reverse such changes over the short term, but sometimes some antidepressantscan cause weight gain that does not normalize the weight or the appetite. The rates of weight-related adverse events may varyacross antidepressant classes and within classes.

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Possible Mechanisms of Antidepressant-Induced Weight Gain

There are a number of possible mechanisms for antidepressant-induced weight gain. There could be central nervous systemeffect on specific receptors, such as histamine receptors or serotonin receptors, leading to change in appetite regulation.There could be increased food intake related to decreased satiety. There could be sedative effects of the antidepressantmedication leading to decreased physical activity and caloric expenditure. There could be shifts in food preferences, andthere could be, as a side effect, dry mouth and throat leading to increased intake of caloric beverages.

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Antipsychotic-Induced Weight Gain: Long-Term Considerations

Antipsychotic weight gain is a growing problem. With long-term treatment, weight gain can accumulate in an individual overmany months. After a time, weight gain usually plateaus but remains elevated.

Once the weight gain has occurred, it is very difficult to lose. And with the weight gain comes the medical consequences thatI've been speaking about. There is also a very important detrimental effect on self-esteem and on compliance withantidepressant medication.

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Antipsychotics and Weight Gain: Meta-Analysis of Short-Term (10 Weeks) Treatment

I'd like to conclude by showing you this meta-analysis of antipsychotic drugs and weight gain. This shows the effect of


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short-term, 10-week treatment with a variety of agents. It is clear that weight change will vary with the agent -- some causingessentially no weight gain, some very little, and some a great deal.

I think it is important for primary care physicians and for psychiatrists who are using antipsychotic medication on patients to beaware of differential adverse effects of different drugs on weight gain, and try to include in the treatment of these patients aneffort to prevent weight gain as antipsychotic treatment is continued.

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Pathophysiology of Insulin Resistance

The principal purpose of my presentation is to highlight how we tie all these issues together, and to point out that interface thatwill have the psychiatrists and the endocrinologists and the diabetes healthcare professional having more conversations andworking to common purpose.


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Diabetes Trends in the United States: 1990-1998

By now, you know that it is more than just the weight problem. Dr. Pi-Sunyer has told you about what was happening with weighttrends in the United States. This is also happening in the case of diabetes. In these national trends, the blue colored statesrepresent those states with the highest incidence of diabetes. The yellow colored states are those with intermediate levels ofdiabetes. And the salmon colored states represent those with the lowest incidence.

What we see is that between 1990 and 1998, a large number of states have turned blue. We are developing a lot of diabetesin parallel with all of that obesity.

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Regulation of Blood Glucose


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What is happening at the tissue level? What is the physiological explanation for much of what you have heard about and thatwe are going to be increasingly worried about as we begin to see more schizophrenics being treated, more insulin resistancebeing precipitated, more type 2 diabetes developing, and all of us having to participate in their clinical care?

The central character in all of what we know of glucose regulation is insulin. It stimulates glucose uptake in muscle. Itdepresses glucose production in liver. And while there are other tissues that are indifferent to the effects of insulin, such as thebrain, fat is very sensitive to insulin.

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Dynamic Interaction Between Insulin Secretion and Insulin Sensitivity

All that we are talking about is a dynamic interaction between insulin secretion and insulin sensitivity, which is what glucosehomeostasis is really about.


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Dynamic Interaction Between Insulin Secretion and Insulin Sensitivity

When defects occur in that relationship, they occur over time. This is a longitudinal study over 20 years in total duration.

People who did not have any genetic risk for diabetes are pictured in yellow. People who were genetically at risk, that is theyhad a positive family history for type 2 diabetes, are depicted in orange. And all of these persons were studied by using aglucose tolerance test in which they had their glucose and their insulin level measured simultaneously.

At the start of the study, nobody had diabetes. All of these are normal glucoses. There were some people who simply had arisk compared with those who had no risk. And those who had some risk had somewhat higher insulins at a time when theirglucoses, although normal, were still a bit higher than they should have been given the amount of insulin available.

These people already had the stigmata of a condition that subsequently became more apparent at mid-life, namely, they wereproducing a lot of insulin in response to the same glucose challenge, but their serum glucoses were not good at all. This is thesine qua non of clinical insulin resistance.

And the insulin resistance problem didn't go away. It was simply joined by the problem of pancreatic deficiency. The insulinresponse to the same glucose challenge is gone. These people go on to develop frank diabetes.


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Insulin Resistance

The principal organs that we know are affected in that sort of progression of glucose abnormalities are usually cited as liver,which is guilty of increased production of glucose; and muscle, which is cited for its inability to respond appropriately to insulinand, therefore, you get diminished glucose uptake.

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Measuring Insulin Sensitivity: Euglycemic Insulin Clamp

When we look at the methodologies that we have to actually quantify the insulin sensitivity, the gold standard is theeuglycemic/hyperinsulinemic insulin clamp. In order to maintain a glucose level that is fixed at a normal threshold, what onedoes in a subject is to ramp up the insulin concentration and then clamp the insulin using a computerized algorithm in anartificial pancreas at a hyperinsulinemic level, and then see how much glucose you have to infuse to maintain the glucose at


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this predetermined level with this much insulin coming in. The more resistant to insulin you are, the less glucose you need tohave infused to maintain this predetermined glucose level. There are all kinds of other methods that can be used, but theycome out with the same bottom line.

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Peripheral Insulin Resistance: Changes in Peripheral Glucose Uptake

This is work from Groop, who shows that, as a function of increasing plasma insulin, when you look at glucose metabolism inpeople with type 2 diabetes, they do not get up to the same level of glucose metabolism as controls, or nondiabetics, nomatter how high you push the insulin because of their insulin resistance.

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Insulin Sensitivity in Various Clinical States


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The bottom line here is that when you apply those techniques and you look across a spectrum of clinical conditions, what doyou find? Compared with controls, you find reduced insulin sensitivity, or insulin resistance, in a variety of settings, certainlytype 2 diabetes. But one could argue that the most common clinical condition in which we find insulin resistance is actuallyobesity.

Essential hypertension is also such a condition.

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Obesity and Insulin Resistance

Obesity has now become, because of its huge prevalence in this society, a major chronic disease player. It has assumed itscentral role in the pathogenesis of clinical insulin resistance largely by the growing realization of the metabolic contributions offat tissue to glucose homeostasis in a wide variety of body tissues.


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Visceral Fat Distribution: Normal vs Type 2 Diabetes Mellitus

People who are at high risk for developing type 2 diabetes have visceral accumulations of fat, and you can see this with thesecomputed tomography (CT) scans. These slices show that there is a significant accumulation of visceral fat in the person withtype 2 diabetes compared with the person without diabetes.

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FFAs: A Link Between Obesity and Insulin Resistance

It turns out that fat is not a passive tissue. This adipose tissue is metabolically active. It is resistant to insulin and, therefore, it isundergoing accelerated lipolysis, generating free fatty acids. And those free fatty acids do exactly the opposite of what insulinwould do at the tissue level.


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So instead of muscle tissue being stimulated to take up glucose, it is inhibited. Instead of glucose production being inhibitedby insulin in the liver, free fatty acids stimulate it. And what happens is that you now have this contribution to insulin resistanceby this active fat tissue.

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The same thing can happen even when you look at muscle. This is an extremity of a lean person, and you see what happens.You see all of this rich, dense skeletal muscle. Somebody who is not as vigorous may not look like this.

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In this picture there is this huge interdigitation of fat with muscle tissue. This is more than marbling. I don't know exactly whatthe word for this should be. What you have in close proximity to this muscle tissue is all of this metabolically active fat, andthere is an enormous metabolic price to be paid for that kind of juxtaposition.


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Glucose Metabolism During Euglycemic Insulin Clamp

When we look at the metabolism of muscle in people with type 2 diabetes, what we see is that under insulin-stimulatedconditions, not the basal rates, there is a significant decrease in glucose metabolism. That is where the insulin resistancemanifests itself.

This excessive lipolysis from this rich fat store that we see under conditions of obesity certainly has a significant deleteriouseffect in muscle.

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The liver isn't spared. The increased free fatty acid oxidation, the augmentation of gluconeogenesis as a result of exposure ofthe liver to those increased free fatty acid levels, results in hepatic glucose output being augmented, and this is precisely whatdrives up fasting plasma glucose levels.

�� 5:&

Insulin Resistance and Beta-Cell Dysfunction Produce Hyperglycemia in Type 2 Diabetes Mellitus

So we begin to see how all of these things then tie together in this sort of comprehensive picture. We see that a metabolicallyactive excess adipose-tissue depot drives a lot of changes that can worsen the insulin resistance. And we have seen otherexamples that suggest that there may be deleterious effects from metabolically active fat depots on beta-cell function as well.What we would submit here is that anything that drives the accumulation of additional adipose tissue, excessive fat, hassignificant health consequences that derive from all of the consequences of the insulin resistant state and the insulinresistance syndrome.

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�� 5;&

Weight and Mortality

People with insulin resistance syndrome die from cardiovascular complications. And when you look at the relationship withweight, the milieu in which you see so much of this insulin resistance, you see the relationship between that weight andmortality.

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Prevalence of Obesity (BMI Greater Than 30) in Adults Aged 20-80 Years by Gender and Ethnicity

It is not good to be fat for a long, long time.

And for certain high-risk minority groups, this is an even bigger problem. You have heard already about the degree to whichAfrican Americans and some Latino populations have excess prevalence of obesity. These issues begin to compound, and


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this is the consequence that we are most directly concerned with in our discussions during this presentation.

�� 4=&

The Diabetes Explosion: Diagnosed Cases Over the Past 4 Decades

Over time, there has been an explosion of type 2 diabetes, and that explosion has been driven principally by the explosion inobesity.

�� 45&

Insulin Resistance: An Underlying Cause of Type 2 Diabetes Mellitus

That brings us back to our paradigm. What is driving this interaction is the psychiatrists trying to take better care ofschizophrenics with these atypical agents that are powerful in terms of what they can do for the psychiatric illnesses. They arealso powerful in terms of their potential and what they can do to insulin resistance.


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What you see is that there are certain things that drive insulin resistance and obesity is one of them. There are otherconsequences of insulin resistance, including type 2 diabetes.

There are also medications that are important contributors to insulin resistance and, therefore, these are medications that canmake contributions to the sequelae that we worry so much about.

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�� 44&

Weight Responses to Olanzapine and Ziprasidone

Ziprasidone is one of those weight-neutral drugs. Olanzapine is one of those blue drugs down at the other end of thespectrum.

Let's look at what happens when you do this direct comparison. At the start of this particular study and at the end of the 6weeks of treatment, they did measurements at baseline and at endpoint. Median weights with ziprasidone did not reallychange, but with olanzapine there was a robust increase in median weight.


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�� 46&

Fasting Insulin Responses to Olanzapine and Ziprasidone

What about the insulin levels? For ziprasidone, they were not really different. With olanzapine, a robust increase in insulinlevels occurred. There was hyperinsulinemia. And what you will see is that this hyperinsulinemia that occurs with this drugoccurred without a change in glucose.

�� 47&

Fasting HOMA IR Responses to Olanzapine and Ziprasidone

Any time you have no glucose change and you look at a homeostasis model assessment, what you see when you look forinsulin resistance parameters is that with ziprasidone, over this period of treatment, there was no change in insulin resistance.But with olanzapine, by using the same kind of approach, there was an increase in insulin resistance, and this is entirelyconsistent with the fact that despite the increase in insulin levels, when you look at median glucoses, the glucose didn't change


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in either setting.

�� 48&

Fasting Glucose Responses to Olanzapine and Ziprasidone

The only way you sustain similar glucoses in the face of much higher insulin levels is by this agent driving a higher degree ofinsulin resistance.

�� 49&

Fasting LDL Responses to Olanzapine and Ziprasidone

What is consistent with that? All of the things that you have heard about that track with the insulin resistance syndrome areconsistent with that. You would expect for the lipids to start getting abnormal, and they do. For example, with olanzapinetreatment, the low-density lipoprotein (LDL) levels go up. They don't change with ziprasidone. If anything, they trend downward.


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�� 4:&

Fasting Triglyceride Responses to Olanzapine and Ziprasidone

The triglycerides do not change with ziprasidone, but with olanzapine there is a significant increase, reflecting all of thestigmata that you would worry about in a setting where you have the potential for the insulin resistance syndrome.

�� 4;&

Insulin Resistance: An Underlying Cause of Type 2 Diabetes Mellitus

So what we are beginning to see with the emergence of these atypical agents for the management of schizophrenia is theemergence of more insulin resistance in the setting of certain kinds of medications.

And what are the consequences of that? The consequences are that we are beginning to see more stigmata of the insulinresistance syndrome. And because of that, we are likely to see more type 2 diabetes.


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We worry that there will be more accelerated atherosclerosis in this population. And in our attempts to actually improve life forthem, we may be making them feel better psychiatrically, but negatively affecting what is likely to happen to them metabolicallyover a period of time.

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�� 5&

Health Outcomes: Overall Metabolic Health

�� 4&

Obesity and Mortality Risk

A key health issue for all of us is that increases in adiposity or fatness are related to increases in overall mortality risk. When


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we reach 25 kg/m2 body mass index, the World Health Organization says that we are overweight because this is where webegin to see steady increases in mortality risk or mortality ratio.

When we reach 30 kg/m2, the World Health Organization designates us as obese because we are now on the linear part ofthe curve, increasing mortality risk with increasing levels of adiposity. The majority of the increase in mortality with increasingadiposity comes from increases in cardiovascular disease and diabetes mellitus.

�� 6&

Antipsychotic-Induced Weight Gain

The problem for patients taking antipsychotic medications is that antipsychotic medications can increase weight and increaselevels of adiposity. We just mentioned that increasing adiposity increases your risk of type 2 diabetes and hyperglycemia, andthis occurs via increases in insulin resistance. In addition to the risk of cardiovascular disease in general, rates of hypertensionand the risk of dyslipidemias also increase.

Most antipsychotic medications can cause weight gain, with some medications, particularly clozapine and olanzapine,associated with the highest levels of weight gain.


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�� 7&

Primary Effects of Insulin on Blood Glucose

To understand more about the risk of diabetes mellitus, we need to understand that diabetes mellitus is actually a group ofmetabolic disorders. The common theme is hyperglycemia, but this can occur due to defects in insulin secretion, insulinaction, or both. Insulin is secreted from the pancreas, targeting skeletal muscle to turn on glucose uptake or transport fromcirculation into muscle tissue; and insulin also targets the liver to shut off hepatic glucose production.

When you have decreases in sensitivity to insulin action, termed insulin resistance, you see an increasing need for insulin to besecreted from the pancreas. When the pancreas cannot meet that increasing need, you see patients go into type 2 diabetes,with insulin resistance and a defect in insulin secretion.

�� 8&

Adjusted Log-Odds of Diabetes in Relation to Baseline BMI by Sex and Race


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One of the major factors that increases insulin resistance is increases in abdominal adiposity. This slide indicates that withincreasing Body mass index, there is a log-linear increase in the risk for developing diabetes mellitus. This increase is not dueto just any adiposity. It's not arm or leg adiposity. This is due to abdominal adiposity, in particular, visceral or in-the-belly fat.

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�� 9&

Neuropsychiatric Conditions and Glucose Regulation

When we turn to psychiatric patients and try to understand some of the special issues for this population, we first need tounderstand that all of the major neuropsychiatric conditions have been associated with an elevated risk of diabetes mellitusand disturbances in glucose regulation, primarily a type 2 diabetes picture.

Major depressive disorder and minor depressive disorders have been associated with an up to 2-fold increase in the risk ofdiabetes mellitus. We're focusing, however, on psychiatric disorders such as schizophrenia that are a primary target forantipsychotic therapy. Papers going back to 1914, and a series of papers in the 1940s, describe an association betweenschizophrenia and an elevated risk of type 2 diabetes mellitus.


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�� :&

Conventional Antipsychotics: Effects on Glucose Regulation and Diabetes

When antipsychotic medications were first introduced with chlorpromazine in 1954, we saw a series of reports describing howthis low-potency phenothiazine could aggravate existing diabetes mellitus, and could produce new onset cases of type 2diabetes. For example, the introduction of chlorpromazine increased prevalence in one clinical setting from approximately 4%to approximately 17%. Various groups reported these abnormalities in glucose control, including the National Diabetes DataGroup, which added phenothiazines to the "bad" list, a list of medications that could disturb glucose metabolism. They addedphenothiazines in the 1970s. The point I'm trying to make is that this is not a new story. This is actually an old story that weforgot to some degree.

The reason that we forgot this is not just bad memory. This is in part due to the fact that not all antipsychotic medicationsproduce this association to the same degree. Some medications, for example high-potency drugs such as haloperidol, seemnot to do this as much as low-potency phenothiazines. This helped us to forget this clinical problem in part as more and morehaloperidol was used around the world. In addition, this was an early demonstration that not all drugs are created equal withregard to this particular adverse event.


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�� ;&

Published Case Reports: Summary

With the introduction of newer antipsychotic medications, beginning with clozapine, we saw a resurgence of clinical reportsdescribing this problem of new onset diabetes mellitus, exacerbations of existing diabetes, impaired glucose tolerance, andcomplications such as diabetic ketoacidosis (DKA).

This is a summary of the published case reports from a Medline search conducted in March 2001, and what you see is anuneven frequency of distribution of reports across the different medications; and this is not explained by shear numbers ofprescriptions or when medications came onto the market.

For example olanzapine, on the market some years after risperidone, has had a higher frequency of reports of these adverseevents. We also can see from this that there is going to be the potential perhaps to see this adverse event with anymedication. Again, it's a question of frequency whether this will be a common event or a rare or infrequent event.

The problem with DKA is that this has some potential mortality associated with it. In the MedWatch, which is the Food andDrug Administration (FDA) postmarketing surveillance database, in 1999 there were already something like 8 deaths that hadbeen reported due to DKA. There is 1 death listed here, published in the German literature, during a DKA episode in a patientreceiving olanzapine treatment.


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Incidence of Clinically Significant Laboratory Abnormalities in Ziprasidone Phase 2/3

This shows the clinical trial database, which contained random glucoses for different antipsychotic medications: ziprasidone,placebo, haloperidol, and risperidone.

The threshold or the criteria being used to track hyperglycemia is a random glucose value. This is not the most sensitiveindicator, but using this criterion of 1.2 times the upper limit of normal, approximately 15% of the patients taking ziprasidone,approximately 15% of the patients taking risperidone, approximately 16% of those on haloperidol, and about 12% of those onplacebo achieved this threshold criteria for hyperglycemia when they did not have it at the beginning of the trial.

The point is that ziprasidone, a newer medication, looks to be in the same ballpark as risperidone and haloperidol in terms ofproducing relatively little hyperglycemia in comparison with the higher rates we've seen for some other medications.


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�� 5=&

Diabetic Ketoacidosis

DKA we need to understand, because this is a severe metabolic disorder characterized by hyperglycemia, ketonemia, andacidosis. This has a rapid and unpredictable onset.

The real problem for DKA is it has a mortality rate that we have not been able to entirely eliminate even in the best hospitals inthe world. In those ideal settings we cannot get the mortality rate below about 2%, meaning that 2 out of every 100 patients thatwalk into the emergency room in this metabolic state may not walk out.

Mortality goes up as a function of age, intercurrent illness, and how long it takes you to get to the emergency room and startyour insulin therapy. In geriatric populations, published mortality goes up to 20%; and in general, clinicians in the field ofpsychiatry are very worried that patients taking antipsychotic medications may not beat the average. They may, in fact, doworse than average in terms of how long it takes them to get to the emergency room and start that potentially lifesaving therapywith insulin.

We're going to have to be watchful for signs and symptoms of DKA, including polyuria (excess urination) and polydipsia(excess drinking). These are signs of out of control blood sugar and warrant a glucose check today.

When you add abdominal symptoms such as nausea, vomiting, pain, and central nervous system depression (the patient issedated and you did not increase the dose of anything), these are really cardinal features that begin to look like DKA. DKAoften happens in the setting of intercurrent infection and fever, and in the severe presentations has a characteristichyperventilation syndrome.

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�� 55&

Newer Antipsychotics: Effects on Glucose Regulation and Diabetes

Thankfully most patients are not going to go into DKA. This remains a rare to infrequent event. Most patients taking mosttreatments are going to instead develop some small increase in glucose levels much more commonly than large increases.And the "$10,000 question" becomes: Does a small increase in plasma glucose matter from a clinical standpoint?


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And I want to make the case that this does matter. This is based on a well-developed literature in the diabetology andcardiology fields describing how increases in glucose levels, even below the threshold for defining diabetes mellitus orimpaired glucose control, increase long-term cardiovascular risk.

�� 54&

Hyperglycemia: Impaired Glucose Regulation to Diabetes Mellitus

This illustrates how rising glucose levels eventually cross diagnostic thresholds for diabetes mellitus with fasting levels greaterthan 126 mg/dL, and an impaired or intermediate range of glucose control is defined as between a fasting level of 110 and126 mg/dL.

When you have diabetes mellitus, or even impaired glucose tolerance or impaired fasting glucose, you are at increased riskfor both micro- and macrovascular disease. Microvascular disease is what we hear the most about. This is the risk ofretinopathy, nephropathy, and neuropathies. Macrovascular disease is atherosclerosis. This is the risk of myocardial infarctionand stroke.

The good news is that your microvascular disease risk may not increase significantly until you get up into the glucose levelsassociated with diabetes mellitus or impaired control. The bad news is that macrovascular disease, the risk of myocardialinfarction and stroke, may be elevated even with glucose levels in the technically normoglycemic range. The left-hand tip of thearrow in the normoglycemic range, let's say, is an ideal fasting glucose of 75 mg/dL, and hopefully we all wake up with thatlevel. But you could be as high as 109 mg/dL, and you would still technically be normoglycemic.

You don't want to be 109 mg/dL. The difference between 75 and 109 mg/dL, both technically normoglycemic, is a big jump incardiovascular risk.


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�� 56&

Relationship of Hyperglycemia to Cardiovascular Disease

The story is that macrovascular disease risk, the risk of myocardial infarction and stroke, increases progressively andcontinuously with increasing glucose levels. There is no clear threshold for microvascular disease. This progressiverelationship between glucose levels and cardiovascular risk has been well described in nondiabetic and diabetic populations,with papers going back to 1980.

�� 57&

Odds Ratio of MI as a Function of Fasting Blood Glucose (FBG)

There are 3 types of studies in general that have been used to establish this point. The most common type is a case-controldesign. This illustrates a case control study by Gerstein and colleagues indicating that as fasting glucose levels rise, the risk ofmyocardial infarction rises. Remember that 110 mg/dL defines the threshold for impaired fasting glucose. So you can achieve


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greater than 3 times the chance of a myocardial infarction while still having fasting glucoses below the impaired threshold.

In this study, when they excluded patients with diabetes mellitus and impaired control, looking only at those individuals withnormoglycemia, controlling for smoking, adiposity, and triglyceride levels, still a 21 mg/dL increase in postprandial glucoseindependently increased your odds of myocardial infarction 1.6 times.

�� 58&

Carotid Intima-Media Thickness as a Function of FPG

This is another type of study, which is a bit more extensive. These are carotid ultrasounds looking at carotid intima-media wallthickness. There is a measure of atherosclerotic plaque wall thickness on the vertical axis. Across the horizontal axis areincreasing levels of fasting plasma glucose, with the first 4 bars in the normoglycemic range and the final right-hand bar in theelevated/impaired fasting glucose range.

As fasting glucose rises, the thickness of the atherosclerotic plaque in the carotid artery is measurably increasing. This is,unfortunately, the plaque that, if we are very unlucky, becomes thick enough so that in well advanced age we have themisfortune of turning our head sharply one day and having a piece of this plaque break off and go to middle cerebral arteryterritory where you can get your classic motor or sensory strip infarct.


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�� 59&

Progressive Relationship Between Glucose and Cardiovascular Risk

Illustrating the relationship between rising glucose levels and cardiovascular risk, this is a study of about 95,700 subjects in ameta-analysis, where the mean follow-up period was 12.4 years. Fasting glucoses are on the left, 2-hour postload glucoses onthe right, and the risk for both figures is the relative risk of developing a myocardial infarction, stroke, or sudden death.Confidence intervals are on the outside, and the odds ratio is up the middle. Moving up from a more or less ideal plasmaglucose level of 62 mg/dL or 4 mmol/L, you're seeing progressively and continuously rising risk of these cardiovascularevents. There is no clear threshold. There is not a point below which your risk is zero until you get down to levels such as 62mg/dL, which most of us do not see.

�� 5:&

Methods of Quantifying Glucoregulatory Status in Humans


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This illustrates the methods that can be used to quantify glucose metabolism in humans, moving from the least sensitiverandom glucoses up to the gold standard measures.

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�� 5;&

Medication-Related Abnormalities in Glucose Regulation in Schizophrenia

This study used modified oral glucose tolerance tests. This study was funded by the National Institute of Mental Health and theNational Alliance for Research in Schizophrenia and Depression (NARSD); and the results are currently in press at theArchives of General Psychiatry.

This study used nondiabetic patients with schizophrenia who were receiving treatment with either typical antipsychotics(primarily haloperidol and fluphenazine), risperidone, olanzapine, or clozapine. We also had healthy control subjects.

All groups in this study were matched for adiposity. All groups were matched for age and balanced for ethnicity. The reason it'simportant to match for factors such as adiposity is that increasing abdominal adiposity would increase insulin resistance andpotentially produce a much worse picture of glucose metabolism. The question we're asking in this study is: When the levelsof adiposity are the same, can you still see differences in the level of glucose control across different medication treatments?

In this study, we see plasma glucose levels on the left, plasma insulin levels on the right, and a fasting baseline followed by anoral glucose tolerance challenge with 50 g of dextrose.

On the left, at every time point, it matters what group you're in. At every time point, olanzapine-treated subjects had highermean glucose levels than patients taking typical antipsychotics.

Clozapine-treated subjects at the fasting and final time point had higher mean glucose levels than the patients taking typicalantipsychotics. And both clozapine- and olanzapine-treated subjects at all those same time points had elevated plasmaglucose levels in comparison with the healthy control subjects. It's relatively easy to be higher than healthy controls becausethey don't have psychiatric disease or any medications on board.

Risperidone-treated subjects did not have a perfect picture. At 3 time points, risperidone-treated subjects had elevatedglucose levels in comparison with the untreated healthy controls only. At no time point in this study were the risperidone-treatedsubjects' plasma glucose levels higher than the patients taking typical antipsychotics.


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Three points I'd like to make. Notice on the right, plasma insulin levels are still rising at the final time point in the clozapine- andolanzapine-treated subjects. This is a picture of the pancreas working overtime, if you will, to put out more insulin, to try to getthose higher glucose levels to come down. It's just not working very well, and this is a picture consistent with insulin resistance.

Notice also that, on the glucose side, at the highest final plasma glucose mean level, olanzapine-treated subjects are about 50mg/dL higher than the healthy control mean. We said that 21 mg/dL increases in postprandial glucose are independentlyassociated with a 1.6 times elevated chance of myocardial infarction. The point that we wanted to make with this study is thatthese results seem to be potentially clinically, as well as statistically, significant.

And the final point that I'd make is that all subjects were matched for adiposity or fatness. But in my clinic, patients are notnecessarily matched for adiposity. Some patients are gaining more weight than others. They're developing higher levels ofadiposity than others, and in those circumstances we would expect to see even more insulin resistance than in this kind ofcomparison where the groups all have equivalent levels of adiposity.

�� 5<&

HOMA Insulin Resistance in Treated Patients With Schizophrenia

This analysis is from that same data set looking at a calculation of insulin resistance in these matched groups of patients andcontrols showing, again, olanzapine-treated subjects having higher levels of insulin resistance than patients taking typicalantipsychotics.


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�� 4=&

HOMA Insulin Resistance Responses to Olanzapine and Ziprasidone

This is a study that was funded by Pfizer and presented in a preliminary form at the American Psychiatric Association in 2001.This shows the results of a prospective, randomized treatment assignment to either ziprasidone or olanzapine with a 6-weekfollow-up. What you see in the olanzapine-treated subjects is an approximate doubling of insulin resistance using thiscalculation, with a small increase in insulin resistance on ziprasidone.

In this case at that final time point, the olanzapine-treated subjects have gained more weight than the ziprasidone-treatedsubjects. So this study offers the advantages of both the randomization and the real-world weight gain.

�� 45&

IVGTT With Minimal Model Analysis: Antipsychotic-Associated Differences in Insulin Sensitivity


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These are the results of a preliminary analysis by Henderson and colleagues from Harvard University using yet anothertechnique. This is an intravenous glucose-tolerance test with another mathematical model to analyze the results -- coming upwith a measure of insulin sensitivity, serum insulin (SI), where higher levels are better. This analysis shows risperidone-treatedsubjects having higher insulin sensitivity in comparison with clozapine- and olanzapine-treated subjects. Again, subjects werematched for adiposity, and in the real world, if we let some of these groups gain more weight and develop more adiposity thanothers, the results could potentially be exaggerated.

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�� 44&

Need for Early Detection of Impaired Glucose Regulation

The American Diabetes Association has emphasized for all Americans that undiagnosed type 2 diabetes is common. In theUnited States we've been missing up to half the cases. We know that retinopathy begins early, and we know that there is anincreased risk for macrovascular disease, especially beginning below the threshold for diagnosis. All of this leads up to anemphasis on the need for early detection and treatment.


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�� 46&

Cardiovascular Mortality in Schizophrenia

Are patients with schizophrenia dying more often of cardiovascular disease? These 2 studies indicate yes; and, in fact, it lookslike they have an approximately overall 2-fold increase in cardiovascular mortality, with cardiovascular disease being thenumber one cause of excess deaths in females. This is not all due to increases in glucose, of course. This is due to multiplefactors, including glucose, dyslipidemia, smoking, obesity, sedentary lifestyle, and perhaps a lower level of medical care.

�� 47&

Consequences of Weight Gain on Mortality

Fontaine and colleagues conducted a provocative analysis using Framingham Heart Study data. This is the community inMassachusetts that was followed for many years. And from those data we know that a particular amount of weight gain can beassociated with a specific increase in the incidence of death, impaired glucose tolerance, and hypertension over a fixed period


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of time. So using Framingham Heart Study data and knowing how much weight gain can be expected on an antipsychotic suchas clozapine, the authors calculated that one would see an approximate increase of 400+ additional deaths secondary toweight gain during clozapine treatment, but speculated that this might be offset by the number of lives that would be savedduring clozapine treatment by preventing suicide.

The prevention of suicide on clozapine was a point supported by some earlier papers. In fact, Rosenheck from Yale recentlywas unable to replicate that prevention in the Archives of General Psychiatry 2001.

The paper here suggests that at best we may be losing as many individuals as we are saving but from different causes ofmortality. And I think the point of the paper was to try to emphasize to psychiatrists that we need to move beyond a focus onlyon purely psychiatric causes of mortality to understand all causes of mortality, including cardiovascular risks.

�� 48&

Conclusions

In conclusion, antipsychotic treatment-induced weight gain can increase risk for hyperglycemia and type 2 diabetes, andincrease risk for hypertension, dyslipidemias, and cardiovascular disease. We also know that antipsychotic treatment isassociated with changes in glucose regulation, and this is potentially interacting with disease and lifestyle-relatedabnormalities.

Glucose dysregulation can lead to short-term and long-term complications, including the risk of DKA. While DKA is notcommon, and hopefully it will continue to be infrequent to rare, we do want to be watchful for this, as well as an increased riskof cardiovascular events in the long run.


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�� 49&

Conclusions

These problems are going to require that we increase our vigilance and our level of monitoring for hyperglycemia,dyslipidemia, and weight gain. We're going to have to do education with patients and with care providers to reduce the risk ofDKA. This is going to be required in addition to monitoring.

And we're going to have to choose good collaborators. We need to choose an interested family practice physician, or aninternist -- it does not necessarily have to be an endocrinologist -- someone who can work with us on managing theseproblems in patients with psychiatric disease.

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Conclusions


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I don't think there is going to be a single approach, a single "one size fits all." We're going to need to individualize treatmentdecisions considering risk factors: for example, preexisting obesity, preexisting increases in weight, smoking, hypertension,and certain ethnic risk factors for diabetes mellitus. Anyone who's African American, Asian American, a Pacific Islander,Hispanic American, and most indigenous people have an elevated risk of diabetes mellitus relative to Caucasian populations.

We're going to have to consider family history and preexisting hyperglycemia as we make treatment decisions about whatantipsychotics to use, and treatment decisions about how intensively to monitor individual patients.

Finally, we're going to need more research in this area to help us with these treatment decisions and to optimize long-termoutcomes.

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�� 5&

Antipsychotics and Obesity

I'll be talking about the relationship between antipsychotics and obesity, and give you some clinical management tips and newinformation about what's happening in the field.


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�� 4&

Antipsychotic Therapy: Historical Perspective in the United States

When we take a historical perspective of antipsychotics, there are really 2 waves of antipsychotics. The first series ofbreakthroughs started in the 1950s with chlorpromazine (Thorazine) and ended with the high-potency conventionalantipsychotics. And then there was the development and rapid introduction of the newer or so-called atypical antipsychoticsover the last 10 years between clozapine and ziprasidone. So we have 2 classes of agents, the older conventionals and thenewer atypicals.

�� 6&

Older Antipsychotics

As a general rule, the older antipsychotics that were introduced between the 1950s and the 1970s were breakthroughs in thesense that they were the first drugs to control positive symptoms and help patients leave the hospital and try to reintegrate in


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the community, the positive symptoms being hallucinations, delusions, etc.

It's also important to tell our patients that the older medicines were not very effective for the other symptoms of schizophrenia,which include the withdrawal states such as negative symptoms, cognitive problems, and depression. If we had to give thesedrugs a report card, they might get a B+ for positive symptoms, but at best a C- for the negative symptoms and cognitivesymptoms.

The terrible problem with the older medicines were the extrapyramidal symptoms (EPS), the Parkinsonism that these drugsgave to the vast majority of patients which were disabling, distressing, wreaked havoc in patients' lives, and certainly erodedcompliance. And this was a terrible price to pay for having to take a medicine to help keep you well.

The older medicines had a wide range of effects on weight gain, some causing no weight gain, in particular molindone(Moban), and others causing a tremendous amount of weight gain, such as thioridazine (Mellaril). But most had moderateeffects on weight gain.

�� 7&

Newer Atypical Antipsychotics

This is the list of the newer atypical antipsychotics that have come with clozapine and after clozapine. I like to think of thesemedicines as a family. And like your family or my family, families share certain similarities and differences. Families may sharea physical resemblance or certain characteristics, and these drugs share a certain resemblance or characteristics.

In particular, what cuts across all of these medicines, from clozapine to the latest, ziprasidone, is lower or no EPS. So whilethese medicines can still cause some EPS, it's much less than the older medicines. One way these families are unique is thatthey have different levels of weight gain among them.

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�� 8&

Understanding of Drug Toxicity Changes Over Time

For those of you who have trained in the 1990s, it's hard for me to describe what a dramatic change the atypicals have had inour understanding of how antipsychotics work and the burden of antipsychotics on patients. This talks about another drug,cigarettes, to make the point that if you look way back, how our understanding of drug toxicity changes over time.

Here you have an ad that sells Camels, and in the 1950s, they didn't find one single case of throat irritation due to smokingCamels. That was then, now is now, and we now know differently.

�� 9&

Early Theory That EPS Needed for Therapeutic Response

In the old days with the conventional antipsychotics, it was thought that EPS or Parkinsonism was needed in order to get the


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patient better.

This is from a textbook in 1955 saying that "We have a great proportion of Parkinsonism as a result of deliberately pushing thechlorpromazine to the point of achieving a Parkinson's response." These doctors had the best of intentions, but the theory waswrong.

What does this have to do with today? Today we often hear that weight gain is associated with good clinical response toantipsychotics. That's a big theory. Well, that theory is not true. It's not proven, and in my opinion will be proven to be as falseas the old theory that you needed to have EPS in order to get better. Be very careful about associating a toxic side effect witha therapeutic response because in many ways, that justifies what we do. And let's not have the same legacy of what we did inthe past, which was to deliberately cause EPS with the misguided hope of having patients get better.

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Essence of "Atypicality" Is Less Severe and Fewer EPS

Going back to less EPS, the major benefit of the atypicals is that less EPS is a wonderful thing for the patient and translates tomany other benefits, as shown.


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Understanding of Drug Toxicity Changes Over Time

Let's go back to that Camel ad and revisit that question. Remember that in the 1950s, this Camel ad said that noted throatdoctors did not find a single case of throat irritation. What does this have to do with today? Today our understanding of thetoxicity and side effects of the medications is changing again. And once we have solved the EPS problem in our patients,which remains the biggest side effect problem with the older medicines, we have to take a serious look at other problems andother side effects and confront those head-on.

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Impact of Antipsychotic Medications on Obesity and Cardiac Risk Factors


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Since most of this talk is going to be on the side effects of antipsychotics causing obesity, I'd like to show that obesity was aproblem in patients with schizophrenia before the atypicals came out.

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BMI Distributions for General Population and for Those With Schizophrenia

This looks at the rates of obesity, or the rates of body mass index (BMI) distributions, comparing the general population withthose with schizophrenia. Those with schizophrenia are in pink, and on the right there's a shift towards higher BMI. And on theright above 30 kg/m2 are BMIs that cause medical problems. You can see higher pink bars than blue bars, meaning obesitywas more of a problem in schizophrenia before the atypicals, and other medical problems as well, such as diabetes orpremature cardiovascular death.

So when we consider the role of atypical antipsychotics on obesity and health, we're not talking about these drugs necessarilycausing all of the health problems among patients with schizophrenia. We are considering whether these drugs exacerbate orincrease the likelihood of health problems over and above their already poor medical health.


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Weight Gain and Antipsychotics

The newer medicines in general cause more weight gain than the older medicines, either in terms of the likelihood of any givenpatient gaining weight or the average weight gained per patient.

Until ziprasidone came out, this was a class effect; you had weight problems over and above the high-potency conventionalswith the class of atypical antipsychotics. Now we have an exception in that class, and that exception is ziprasidone.

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Estimated Mean Weight Gain at 10 Weeks With Antipsychotics

This is a meta-analysis done by Allison and colleagues looking at estimated weight gain at 10 weeks of treatment. On the Yaxis is weight gain in kg estimated at 10 weeks. It looks like a staircase, so there are different estimated weight gains


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depending on the medication used.

On the right are the drugs that cause the most weight gain on average, and on the left are the drugs that cause the least weightgain.

On the right of this graph you'll see more drugs in blue. Blue are the medicines that are newer atypical antipsychotics, andwhite are the older, conventional antipsychotics, and you see more white on the left.

There are some exceptions to this, but in general, the take-home message is that the class of atypical antipsychotics causemore weight gain than the class of high-potency conventionals.

However, there's a big exception to this in terms of the atypicals, and that is ziprasidone, which is towards the left. You can'teven see the bar because it does not cause weight gain or weight loss on average after 10 weeks of treatment.

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Atypical Antipsychotic-Induced Weight Gain

This shows long-term weight gain over a year for all the first-line atypical antipsychotics. These are different studies that aremerged together, but it will give you a sense that these are long-term issues as well as short-term issues.

Olanzapine causes the most weight gain on average, with at least 6 kg after a year. Risperidone and quetiapine areintermediary. Newer studies with quetiapine show that there may be some weight loss and resumption of weight neutralityaround a year, and that is not shown here.

The only medicine that does not cause any average weight gain or weight loss, it is weight-neutral, is the one on the bottom indashes, and that is ziprasidone.

I want to caution you about this. These are averages, so if you take the one that causes the most weight gain, olanzapine, thatdoesn't mean that everyone gains weight. There are some people who will stay thin on olanzapine.

Some patients will gain weight on ziprasidone. But for every patient that gains weight on ziprasidone, there will be a patient wholoses weight. Again, these are averages; on average we're talking about weight neutrality.

The clinical take-home point I'd like to make is that weight gain is an early side effect occurring, as you can see in thesegraphs, in the first 6 to 8 weeks of treatment. Those people who gain weight, you'll see it early on. And it is usually sustained


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through a year, although the data are not totally clear. There may be a renormalization on quetiapine.

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In Which Areas Are Patients Least Satisfied?

Let's look at whether this is a problem from many different points of view. Let's first ask the patient if this is a problem. Thislooks at self-reported life problems; where are you dissatisfied? It doesn't ask the patient whether it is related to medicine ornot, but just areas in life. And surprise, numbers 1, 2, and 3 are sex, weight, and money.

There are gender differences in this; women are more concerned about weight and men are more concerned about sex.

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Frequency of Adverse Effects Distress

When we ask patients if they are distressed about side effects and we focus on weight gain, patients taking atypicals are muchmore distressed about weight effects or weight problems than those taking conventionals. It's about a 2:1 ratio in terms ofproportion of patients distressed.

They are concerned about weight in general and they're blaming weight problems -- right or wrong, we can't tell -- on theirmedication. And that is more likely to happen for patients on atypicals. This survey was done before ziprasidone came out.

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Noncompliance and BMI Status

We're running into behavioral problems related to weight. Here in a study that I analyzed, we're looking at self-reportednoncompliance according to the weight status. And you have a linear relationship, with noncompliance being higher as you gainweight, and the mediating factor, which is not shown here, is distress attributed to weight gain related to the antipsychotics.

These data suggest a strong relationship between weight gain and noncompliance, at least in this cohort of patients who filledout the self-report instrument, and we couldn't find any better explanation for this.

So we're already moving towards weight gain being a predictor of noncompliance, which presumably then would be a predictorof relapse and having the patient get into trouble with schizophrenia.

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Schizophrenia: Cardiovascular Mortality in Stockholm County

The irony is that we now have better medicines that can help patients recover to degrees that we have not seen before, but weare seeing excess mortality in the same patients.

This shows cardiovascular mortality in patients with schizophrenia, and these are not compared with healthy controls. We knowthat patients with schizophrenia die earlier. These mortality figures are comparing patients to other patients in different timeperiods. And the mortality of having schizophrenia and dying from a premature cardiac death is rising over time, and it is morecommon now than it was even 10 years ago.

This certainly is consistent with my clinical practice where I see patients who've done a lot better in terms of everything else intheir lives, go on to have heart attacks, fractured hips, and all sorts of medical complications related to health problems. Myimpression is that the atypical antipsychotics don't help the patients lose weight. They don't help the patient deal with theirother medical problems and may, in fact, make them worse.


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Clinical Issues With Weight Gain and Atypical Antipsychotics

What are the clinical take-home messages? What do we know about weight gain and atypical antipsychotics? Not everyonegains weight, and we do not have good predictors for who we put on what medicine; who's going to gain a lot of weight andwho won't.

We can't tell ahead of time who's going to be gaining a lot of weight and become a problem. It is not just the underweightpatients who gain weight. The risk of gaining weight cuts across underweight, normal weight, and overweight patients. Themechanism of action is not well understood. It is almost surely related to appetite, not metabolism. These patients will eat outthe kitchen.

An important clinical message is that weight gain is not a dose-related side effect. You will see the same amount of weight gainacross a therapeutic dose range of the atypical antipsychotics, so don't lower the dose because of weight gain. You eitherneed to deal with it or switch the medicine. But it is not a dose-sensitive side effect.

One thing that is helpful for those patients who gain weight is that they're going to gain it right away, within the first few weeks,certainly within the first 6 weeks. So that's a critical time to get the patient's baseline weight for follow-up. If you see weightgain, it's going to be early, it's going to be fast. If you don't see it in the first 6 weeks, it probably won't happen.

Weight gain will eventually plateau, depending on the drug, and usually levels off between 3 months and 1 year, the exceptionbeing clozapine, where patients probably continue to gain weight on average throughout their clozapine treatment.


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Managing Obesity in Schizophrenia

How do we manage obesity? We should make weight a routine part of the evaluation just as we did 20 years ago with theAmes Scale in tardive dyskinesia (TD) once we learned that TD was a big problem. We need to obtain weight, and get thepatient's height as well. You only need to do that once. And then you can do your BMI calculations.

Put obesity and weight control in your treatment plan. Depending on the patient, depending on their medical problems,depending on how well they do, and so on, you may put weight management high up in the treatment plan or it may be lower inthe treatment plan.

I would still say issues of compliance, substance abuse, and control of positive symptoms are more important than weight. If Ihave a patient for whom I cannot control their symptoms or who is drinking and drugging, I'm going to deal with that first beforeI put them on a diet.

On the other hand, when patients are stabilized and doing well, or their compliance depends on weight, then it goes up on thepriority list. Also we need to consider how we're going to manage obesity and, like all treatments, there are psychosocialinterventions and pharmacologic interventions.

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Ziprasidone Switch Studies

Now we have a pharmacologic intervention that really works with patients who have weight problems on atypical antipsychotics.A series of studies looked at the impact of switching to ziprasidone on a variety of symptoms, including weight, other sideeffects, and metabolic parameters. These were stable outpatients who were doing okay but not great on a previous medicine,and 3 studies looked at this. One study looked at patients on conventional antipsychotics. Another study looked at patients onrisperidone, and another study looked at patients on olanzapine. All of these were switched to ziprasidone and followed for 6weeks.

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Switching to Ziprasidone: Weight Changes After 6 Weeks

Let's look at the results of this study. We have the 3 studies, depending on what the patients were switched from. On the left,


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you see the weight change from patients switched from conventionals to ziprasidone, and you see slight weight gainnumerically, although not statistically significant. I think it's fair to say that switching from a high-potency conventional toziprasidone is kind of a wash after 6 weeks. Certainly you don't get the kind of weight gain you see switching from aconventional to other atypicals after 6 weeks.

Patients who are switched from risperidone are shown in the middle column, and here you have some weight loss that is juststatistically significant. So after 6 weeks, patients who switch from risperidone to ziprasidone will lose some weight.

And on the right, you have patients switched from olanzapine to ziprasidone. Here you have quite dramatic weight loss,especially when you consider this is a 6-week switch study: almost 2 kg in 6 weeks, quite something for a specificpharmacologic intervention.

The bottom shows the baseline BMIs in all these switch groups, and these were not svelte patients. These were overweightpatients who really did need to lose weight.

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This is a patient who is a dramatic success story from one of these switch studies. This is Nellie, who had a dramatic clinicalbenefit from switching to ziprasidone from risperidone, and who also lost 100 lb in the course of the year. This is a photo ofNellie about a year after she switched to ziprasidone, and she lost about 100 lb switching to ziprasidone from risperidone. Shealso showed some negative symptom improvement, cognitive improvement, and looks terrific. This clearly does not happenwith everyone, but shows you what can happen if the patient is lucky enough to both get superior clinical response toziprasidone and also achieve the weight benefits. These are sustained weight losses that I saw in my clinical trials withziprasidone.


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Should You Switch?

These are some of the issues you need to consider in terms of the pros and cons of switching someone just for weight. Youneed to do a risk/benefit assessment. What are the benefits of the current antipsychotic? The general rule is that the more thebenefits of that current antipsychotic, the more you'd be nervous about switching. What are the risks of switching in terms ofefficacy? And how much of a weight problem is there? Have you considered other options, pharmacologic and psychosocial?

A few tips on pharmacologic options. Remember that it is not a dose phenomenon, so when you do a pharmacologicintervention, lowering the dose should not be one of your treatments. I carefully review the chart and the patient's regimen tosee if they're on any other medicines besides the antipsychotic that cause weight gain. In particular, some mood stabilizerssuch as lithium or valproate can cause weight gain. If I can get them off that, maybe I can solve the problem.

I'm generally very reluctant to add weight loss medicines, especially stimulants - methylphenidate (Ritalin), amphetamines,and so on -- which may exacerbate the psychosis. I'm very reluctant to prescribe topiramate because of its side effects.Sibutramine (Meridia) certainly can lead to some weight loss. I'm doing a trial in that and it seems to be safe.

Has the patient been given a psychosocial intervention - Weight Watchers, reviewing the diet, going over to a residentialtreatment staff nutritionist? Has that been tried and has that failed? If not, you might want to try that prior to switching.

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Efficacy of Ziprasidone vs Olanzapine for Acute Treatment of Schizophrenia

Another way to deal with the problem of weight gain associated with the atypical antipsychotics is to start with a weight-neutralantipsychotic. Here is a study of acute psychotic patients relapsing who were randomized to either olanzapine or ziprasidone.And here is the response curve; in terms of acute efficacy, these drugs are equivalent. In terms of likelihood of response andmean symptom reduction, both are very effective antipsychotics.

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Ziprasidone vs Olanzapine: Weight Changes in Study Completers

However, this shows the weight gain and the weight change after 6 weeks of treatment. On the right, you have about a 10-lbweight gain associated with olanzapine. And on the left, you have minimal weight gain associated with ziprasidone. Even after 6weeks of initiating treatment, there are marked differences in weight profile.


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Conclusions

In conclusion, obesity is a problem and probably will be more of a problem in the years to come. We're going to see more andmore medical complications, and this is particularly sad for patients who do well in other domains of their illness. They'regetting their lives back, but then getting sick from heart disease, diabetes, and so on.

The management of obesity needs to be modified for the limitations posed by schizophrenia. It's unrealistic to stopantipsychotics, and it's unrealistic to push the patient as hard as we might push obese patients in psychosocial programswithout schizophrenia.

The good news is that there are clinically relevant differences in the weight profiles among the newer antipsychoticmedications. It's no longer a class effect and perhaps we can use this to the patient's advantage.

Contents of New Insights in Diabetes and Psychiatric Illness: Integrating Management[/viewprogram/2049]

New Insights in Diabetes and Psychiatric Illness: Integrating Management[/viewarticle/442813]

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