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 Oct 18 2006, 09:42 PM
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Admin Team
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QUOTE From Medscape Psychiatry & Mental Health
Expert Interview
The Urgent Challenge of Health and Nutrition Issues in Psychiatric Patients: Strategies for Assessment and Collaboration: An Expert Interview With David J. Hellerstein, MD
Posted 08/10/2006
Editor's Note:
The metabolic side effects of atypical antipsychotics often create major problems for patients. In this interview, Elizabeth Saenger, PhD, Editorial Director for Medscape Psychiatry & Mental Health, interviewed David J. Hellerstein, MD, to find out how psychiatrists and allied health professionals might "First, do no harm" with patients who are taking medications associated with high rates of obesity, hypertension, hyperglycemia, hyperlipidemia, and cardiac death. Dr. Hellerstein is Associate Professor of Clinical Psychiatry, Columbia University, New York, NY, and Research Psychiatrist, New York State Psychiatric Institute, New York, NY.
Medscape: You gave a talk at the American Psychiatric Association on a study you did with colleagues at the New York State Psychiatric Institute on assessing health and nutrition status of urban psychiatric outpatients. What was the purpose of your study?
David J. Hellerstein, MD: It was to assess the health status of chronically mentally ill outpatients who were treated in our Washington Heights Community Service. It is particularly relevant to mental health practitioners -- because I think everyone is concerned about the results of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) -- in understanding the side effects of the newer atypical antipsychotic medicines and the interactions of those side effects in obesity and metabolic syndrome.
We wanted to assess those problems in our own population -- among patients in our local community who are treated with these medications.
The second purpose of our study was to look at what kinds of administrative and clinical issues come up when you try to assess health status in a local clinical setting -- and then to generalize our findings to other practitioners.
Medscape: How did you conduct the study?
Dr. Hellerstein: As part of a quality improvement project, we looked at the patients in a day treatment program in one of our two outpatient clinics in Washington Heights, a largely Hispanic community in upper Manhattan. We did a chart review for medical diagnoses and for laboratory tests such as lipids and glucose levels. We interviewed patients about the availability of medical care and their nutritional habits. And we had a nurse obtain measurements such as body mass index (BMI) and blood pressure.
Medscape: What did you find?
Dr. Hellerstein: What we found was really quite disturbing. We found a very high rate of obesity -- particularly central obesity, which means that patients had very large abdominal circumference, which is related to a number of adverse health outcomes including mortality from cardiovascular disease. Central obesity was particularly common among female patients. A significant number of patients had elevated random or fasting glucose levels, but did not have clinical diagnoses of diabetes-related problems. We found that only about a quarter of the patients had normal blood pressures. Also, lipids were modestly elevated among most patients. Often, these pieces of information were not available in the chart in a way that would enable clinicians to incorporate health status into clinical decision-making -- for instance, deciding which atypical antipsychotic to use.
This overall picture of health status for these Hispanic outpatients was very consistent with the mortality data in our Washington Heights clinics over the previous 5-year period. Mortality statistics showed that a large number of patients had died unexpectedly. Generally, their deaths were attributed to cardiovascular or diabetes-related causes. These patients were usually in their mid 50s, and many did not have diagnoses of acute medical illness.
Basically, what we found in our cross-sectional assessment of this patient sample were high rates of obesity, hypertension, hyperglycemia, and hyperlipidemia, which would consistently put these people at high risk for adverse outcomes, including premature death.
Medscape: Do you think these patient health statistics were due to a psychotropic medication, or do you think that if you had a control group, you would have equally bad statistics?
Dr. Hellerstein: It is difficult to know, because obesity rates have been reported to be high among various groups of Hispanic origin in the United States. For the patients in our study, we suspect that their family members may have high levels of obesity as well -- but these chronic patients are probably at greater risk than unaffected family members because of mental illness, smoking, and antipsychotic treatment. Within our day treatment sample, it appeared that some patients were at higher risk than others. There was a correlation between overweight -- which is BMI of 25 or greater -- and being on an atypical psychotic medication. And there was a high correlation between obesity -- which is defined as a BMI of 30 or greater -- and being on an atypical agent. So, among this sample, being on atypical antipsychotics did seem to be associated with higher risk.
In this particular clinic, most patients are Hispanic. They're urban dwellers. Many of them are immigrants. And many of them are poor. So they have several risk factors that make these increased rates of obesity and metabolic syndrome of even greater concern, once you add atypical antipsychotics and mood stabilizers to the picture.
Medscape: Were you able to do anything to minimize patient risks?
Dr. Hellerstein: We're in the midst of assessing that. We have found that about two thirds of the whole sample have seen their primary care doctor in the past year. These patients are pretty well cared for from a medical point of view. But that's not enough.
The second thing is that patients have a high degree of access to grocery stores. They don't have to buy all their food in a corner store or bodega. Many of them cook for themselves or live with a relative who cooks for them.
So these patients have the opportunity to get healthcare already. They probably have the opportunity to get better nutrition. These things give us hints in terms of what we could do to try to improve the situation, which would also include encouraging patients to devise a health and nutrition education program for themselves.
We clearly need better health assessments in the psychiatric record. We're working on how to meet the Marder criteria[1] for monitoring BMI among patients treated with antipsychotic medication. It is not an easy thing to do. So we are trying to find simplified ways to do health monitoring and to provide health education in the clinic setting.
Medscape: Can you tell me a little bit more about the Marder criteria?
Dr. Hellerstein: The Marder criteria recommend that BMI be measured at baseline and every month for 6 months after initiating or changing second-generation antipsychotics. The BMI should be measured every 3 months after that, and more frequently for overweight patients.
Assessment for diabetes at baseline would include a fasting glucose or hemoglobin A1c. With patients at normal risk, this would be rechecked before a new antipsychotic is started and then yearly. In the high-risk patients, ie, those with diabetes or weight gain, these would need to be monitored before a new antipsychotic is added, after 4 months of treatment, and then yearly.
Lipids monitoring would include a baseline lipids assessment of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. For normal-risk individuals, those with LDL of 130 or less, this would be repeated every 2 years, and for high-risk patients with an LDL greater than 130, it would be done every 6 months.
It seems fairly simple, but in a busy outpatient setting that doesn't already have primary care doctors on staff and where the staff is very busy with clinical management, implementing these standards into routine care is not easy to do. One possible measure would just be to hire an internist or nurse practitioner to manage these issues. It would be costly, at least in the short term, though it may save money in the long term. There is often not a budget line for these staff members, though. For psychiatric outpatient settings that are trying to implement these criteria without having internal medicine physicians on staff, there may be ways to simplify things.
Medscape: How could you simplify them?
Dr. Hellerstein: To assess weight, I think every psychiatrist should have a scale in his or her office. You can get a fairly accurate digital scale for less than fifty dollars. We are getting a digital scale for every psychiatrist's office. Physicians also need a ruler on the wall that shows height. Then they can easily calculate their BMI.
It may be hard to remember to measure BMI every month, but most clinicians will do this if it is required as part of the quarterly treatment plan. You may incorporate BMI and other measures that are in the treatment plan into a template that has to be filled out regularly.
In assessing lipids or glucose levels, it's the same thing. The question is: How do you get the information into the chart? And how do you bring it to the attention of clinicians?
Administrators need to find ways to have good flow-sheets in paper charts. For electronic medical records systems, we need the kind of prompts and pop-ups and so on that make it easy for clinicians to know what is required. With regard to nutrition and health aids for education, depending on the specific population, a wide range of materials are available. For instance, for Hispanic patients like ours, there are Spanish-language nutrition brochures and handouts, posters, bingo games, and all kinds of other nutritional materials. You can have materials in the waiting room.
Another thing is that programming in clinical settings can be adapted to include health monitoring and health improvement issues. Group therapy sessions can include measuring BMI and abdominal girth, as well as discussions about health and nutrition and medication side effects and exercise. Nutrition education can include food preparation exercises and education about portion sizes. Programs can also review what kinds of foods and beverages are provided for day-program patients. Schedules can include a walk in the park or around the block and stretching and relaxation exercises -- thus incorporating physical activity into the program. Each of these things may have a modest effect, it's true, but they all do convey the message.
Medscape: Yes. How willing do you think physicians and institutions will be to convey this message? In other words, do you think some cultural change will be necessary?
Dr. Hellerstein: I've just been talking about the practical side. And I think that there's a kind of cultural and institutional or even psychological side to it, which is that these kinds of standards -- like the Marder recommendations -- have created an unfunded mandate for clinicians. There's already a huge list of mandates that clinicians are responsible for: assessment of safety, substance abuse issues, family issues, sexual abuse, and violence. Now, added to that list, is a new mandate: you need to monitor your patients' health status and do it in a fairly intensive way.
The real difficulty for clinicians is not following these recommendations, but rather, "What do you do about it?" That's actually the biggest problem at this point: the clinician may find various abnormalities -- weight gain, glucose intolerance. You have a patient who is finally relatively stable on an atypical antipsychotic, say olanzapine, that causes weight gain. The clinician may be afraid to rock the boat.
Medscape: Right.
Dr. Hellerstein: The clinician wonders, "What interventions can I perform to decrease these risk factors?" – instead of closing his or her eyes and continuing the olanzapine, and hoping that nothing bad happens.
The biggest problem is that we don't have good intervention programs to reverse weight gain for these patients. That's the conundrum for using antipsychotics for the treatment of psychosis: how to minimize these risks related to medications that are frequently very effective.
There are behavioral interventions, education interventions, and pharmacologic interventions -- but none of them is tremendously effective, and none of them is particularly well studied, especially among subpopulations like urban Hispanic outpatients. There is a whole range of things we might be able to do. But once you start to think about this problem, it creates some complications. It creates an urgent new research agenda. It increases the administrative and clinical agenda. And it's clearly very difficult to address these issues on the day-to-day level in a particular clinic or program.
Medscape: Yes, these side effects create complications that are difficult to solve. Is there anything you would like to add?
Dr. Hellerstein: I'd like to add 2 things. First, the issues we talked about should be incorporated into the education of physicians, particularly the training of doctors who are interested in going into primary care, because they will need to know about psychiatry. And psychiatrists definitely need to know more about health monitoring for chronically ill patients, so it has to be built into psychiatric residency curricula.
Second, I think collaboration between internists and psychiatrists is crucial, both on the clinical and research levels. For example, there are some really interesting opportunities for researchers in diabetes, hypertension, stroke, and other medical specialties to collaborate with psychiatrists to work on what is often an iatrogenically induced problem. There's an opportunity to have physicians collaborate in a productive way across disciplines to address these very significant public health issues.
References:-
1. Marder, SR, Essock, SM, Miller, AL, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry. 2004;161:1334-1349.
Related Links
Online CME Articles
Metabolic Issues in the Management of Bipolar Disorder: Focus on Weight Gain
Interviewee Affiliation: David J. Hellerstein, MD, Associate Professor of Clinical Psychiatry, Columbia University, New York, NY; Research Psychiatrist, New York State Psychiatric Institute, New York, NY
Disclosure for Interviewer: Elizabeth Saenger, PhD, has disclosed no relevant financial relationships
Disclosure for Interviewee: David Hellerstein, MD, has disclosed that he has received grants for clinical research from Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Pfizer, and Wyeth. Dr. Hellerstein has also disclosed that he has served as an advisor or consultant to Bristol-Myers Squibb.
Medscape Psychiatry & Mental Health. 2006;11(2) ©2006 Medscape
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Oct 18 2006, 09:48 PM
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Admin Team
Group: Super Administrators
Posts: 10,700
Joined: 15-June 04
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Member No.: 4
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QUOTE Metabolic Issues in the Management of Bipolar Disorder: Focus on Weight Gain
Introduction
Treatment options for bipolar disorder have been expanding rapidly. Clinicians are now able to target the different phases of the illness with a broad variety of mood stabilizers, antidepressants, and atypical antipsychotic agents. Despite therapeutic optimism, it has become increasingly clear that the many efficacious medications have potentially serious side effects. Thus, even as more extensive treatment options evolve, the treatment decision process becomes more complex.
Metabolic factors in particular have become a major focus of concern. Health issues related to obesity, glucose dysregulation, and dyslipidemia are becoming epidemic in the general population and are even more prevalent among the chronically mentally ill. Since many psychotropic agents negatively impact on these factors, serious health consequences may worsen for individuals facing lifetime treatment. This article will review the nature of these multiple health risks of major concern to patients and clinicians, as well as discuss the many issues involved in selecting appropriate pharmacologic interventions.
The Metabolic Syndrome
Defining the Metabolic Syndrome
In 1988, Dr. Gerald Reaven delineated a cluster of physiological disturbances that he hypothesized were related to the risk of chronic heart disease (CHD).[1] He called the cluster Syndrome X, a construct that is now more widely known as the metabolic syndrome. The concept of the metabolic syndrome was developed in part to counter the narrow viewpoint that evolved from long-term naturalistic studies such as the Framingham Study. Based on these data, it was proposed that increased cholesterol and hypertension were the primary factors increasing cardiovascular risk.[2,3]
As outlined by the National Cholesterol Education Program (NCEP) Expert Panel, one of several groups that has proposed criteria for metabolic syndrome, there are 5 primary components of the metabolic syndrome: (1) obesity, (2) insulin resistance and hyperinsulinemia, (3) impairments in glucose tolerance and type 2 diabetes, (4) dyslipidemia, and (5) hypertension (Table 1).[4]
Table 1. Components of the Metabolic Syndrome
Metabolic Feature Components Guidelines
(Rx made with 3 or more of the following 5 risk factors)
Obesity Includes excess total body fat, fat distribution, and increased visceral fat Waist circumference
Men > 102 cm (40 in)
Women >88 cm (>35 in)
Insulin resistance and hyperinsulinemia
Impaired glucose tolerance and type 2 diabetes Fasting glucose >/= 110 mg/dL
Dyslipidemia Includes hypertriglyceridemia, decreased HDL cholesterol, and increased LDL cholesterol
1. Triglycerides >/= 150
2. HDL
* Men < 40 mg/dL
* Women < 50 mg/dL
Hypertension BP >/= 130/85 mm Hg
HDL = high-density lipoprotein; LDL = low-density lipoprotein; BP = blood pressure
Health Risks and the Metabolic Syndrome
In a survey of 8814 individuals conducted between 1988 and 1994 as part of the Third National Health and Nutrition Examination Survey, 21.8% of the men and 23.7% of the women manifested the metabolic syndrome.[5] Prevalence increased with age: 6.7% of subjects aged 20 to 29 years old manifested, which increased to approximately 42% to 43% in those aged 60 to 69 years old. There was significant ethnic and gender variability: Mexican Americans manifested a 31.9% higher rate and the rate in Mexican American women was 26% higher than in men. African American women reported a 57% higher rate compared with African American men. The syndrome was present in 4.6% of normal weight individuals, 22.4% of overweight subjects, and 59.6% of obese men.[6] Older age, postmenopausal status, current smoking, low household income, high carbohydrate intake, no alcohol intake, and lack of physical activity were associated with the presence of the syndrome.
There is a strong association between elements of the metabolic syndrome and risk factors associated with cardiac disease. Alexander and colleagues[7] classified adults according to the presence or absence of the syndrome and further stratified their sample into individuals with or without diabetes. Individuals over 50 years of age who did not have the metabolic syndrome had the lowest incidence of CHD, even if diabetes was present (8.7% did not have diabetes and 7.5% did). In individuals with metabolic syndrome without diabetes, the rate of CHD was 13.9%; those with the metabolic syndrome and diabetes had the highest prevalence rate of CHD at 19.2%. In the Women's Ischemia Syndrome Evaluation (WISE) Study, 780 subjects underwent coronary angiography to evaluate suspected myocardial ischemia.[8] The metabolic syndrome but not the body mass index (BMI) was strongly associated with coronary artery changes.
In a Finnish study, 1209 men aged 42 to 60 years were assessed according to 4 different sets of criteria for the metabolic syndrome for a follow-up period of approximately 11.4 years.[9] Depending on the criteria, the prevalence ranged from 8.8% to 14.3%. Men with the metabolic syndrome as defined by the NCEP were 2.9 to 4.2 times more likely to suffer from CHD compared with those without the syndrome.
In a study of patients with schizoaffective disorder, bipolar subtype patients were assessed for the presence of the metabolic syndrome prior to entry into the study.[10] Of the 33 subjects evaluated, 42.4% met the criteria, a rate higher than that reported in the general population.
Multivariable risk factor analyses such as the metabolic syndrome complex have consistently proven to be a more useful approach compared with treating each variable in isolation. Approximately half of CHD risk occurs in individuals with multiple marginal risk factors.[11]
The Obesity Epidemic
Obesity in the United States has been rising dramatically throughout the last several decades and continues to escalate.[12] In a survey of 4115 men and women, it was found that the percentage of the US population who are overweight (defined as a BMI >/= 25 kg/m2) increased from 55.9% in 1988-1994 to 64.5% in 1999-2000.[13] The rate of obesity (defined as a BMI >/= 30 kg/m2) increased from 22.9% to 30.5% over that same period. Black women aged 40 years or older were the most overweight; in 1999-2000 more than 50% of black females were obese and more than 80% overweight.
A Centers for Disease Control and Prevention telephone survey of US adults aged 18 years or older showed that the prevalence of obesity increased from 12.0% in 1991 to 17.9% in 1998, and occurred in all states, in both males and females, in all age groups, and at all educational levels. The largest increase was noted in the 18- to 29-year-old group, which showed an increase from 7.1% to 12.1%. Higher increases were also noted in individuals with some college education (10.6% to 17.8%) and in Hispanics (7.1% to 12.1%). There were also significant regional differences: an increase of 31.9% occurred in the mid-Atlantic states compared with an increase of 67.2% in the south Atlantic region. Delaware had the lowest increase (11.3%) while Georgia had the highest (101.8%).[14]
Mokdad and colleagues[15] conducted a survey of 195,005 adults in 2001 and found the prevalence of obesity to be 20.9% and self-reported diabetes to be 7.9%. All of these rates had increased from a similar survey conducted just 1 year previously.[16] Increases in body weight were associated with a broad variety of diseases and health risks, including diabetes, high blood pressure, increased cholesterol, asthma, arthritis, as well as general poor health status.
The location of body fat distribution may be an important predisposing factor to the metabolic syndrome. Visceral or abdominal obesity may be a more reliable indicator of risk as opposed to obesity per se, and this may be due to altered plasma lipid transport patterns.[17] A CAT scan can be used to obtain an accurate assessment of the nature and extent of fat distribution.[18]
Diabetes
Diabetes is becoming increasingly prevalent in this county and is associated with the increase in obesity rates. Abdominal obesity, in particular, has been associated with insulin resistance.[19] Approximately 16 million people in the United States have diabetes, and it has been estimated that the worldwide prevalence will double by the year 2025.[20] Individuals without frank diabetes but with elevated baseline glucose (> 110 mg/dL to < 126 mg/dL) or increased postload levels after a glucose tolerance test challenge (2-hour postload >140 mg/dL to < 200 mg/dL) are at higher risk for future development of frank diabetes. The risk of developing the disorder in this group is 5% to 10% per year.[20]
The presence of diabetes greatly increases the risk of developing other diseases. Over a 7-year period, 20.2% of individuals with diabetes and no prior myocardial infarction (MI) suffered an MI compared with 3.5% in matched controls. A diabetes patient with a history of an MI had a 45% risk of another MI compared with 18.8% in controls.[21]
Lipid Disorders
Lipid Metabolism
Lipids circulate in the plasma as cholesterol and cholesterol esters, phospholipids, and triglycerides.[22] Since lipids are not soluble in aqueous solution, they must be processed in order to be suspended in plasma. They are initially packaged as chylomicrons. Subsequently, after processing by the liver, they are made into smaller, denser lipoproteins, which then circulate through the body. Lipoproteins (Figure 1) are composed of a fatty core, surrounded by an outer membrane of phospholipids interspersed with cholesterol and apolipoproteins. The fatty core consists of cholesterol, cholesterol esters, triglycerides, as well as free fatty acids. Low-density lipoproteins (LDL) contain apolipoprotein B, while high- density lipoproteins (HDL) contain apolipoprotein A.
Figure 1. Structure of a lipoprotein. From: Davidson MH, Jacobson TH. How Statins Work: The Development of Cardiovascular Disease and Its Treatment With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors. Medscape Clinical Update. 2001. Available at: http://www.medscape.com/viewprogram/608. Accessed August 23, 2005.
The different lipoproteins vary in size and density, and the lipid particle nomenclature is based on these differences (Figure 2).
Figure 2. Classification of lipoproteins. From: Davidson MH, Jacobson TH. How Statins Work: The Development of Cardiovascular Disease and Its Treatment With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors. Medscape Clinical Update. 2001. Available at: http://www.medscape.com/viewprogram/608. Accessed August 23, 2005.
Key: cholesterol (red stars), apolipoprotein B (keys), apolipoprotein A (y shapes), and membrane proteins (gray dots).
Fat is a concentrated source of energy and is used as fuel by body tissues. All cell membranes include lipids. Several hormones, including androgens, estrogens, and corticosteroids, are derived from lipids. However, if excess lipids are present, they are deposited as fatty tissue and predispose an individual to CHD as well as other diseases.
Lipoproteins may either promote or protect against atherosclerosis and heart disease. High levels of LDL cholesterol are a well-known risk factor for CHD. The Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults defined fasting levels of < 100 mg/dL as optimal.[23] For high-risk individuals with multiple risk factors, a goal of < 70 mg/dL may be advisable.[24] In contrast, HDL cholesterol has been shown to be protective of cardiovascular disease.[25] Levels of < 40 mg/dL in men and < 50 mg/dL in women have been noted to be a risk factor even in the presence of normal total cholesterol.[26]
Elevated triglycerides are also an independent risk factor for CHD and serve to reduce the size of the LDL complex. Familial forms of hypertriglyceridemia have been shown to lead to increased risk of CHD.[27] In a meta-analysis of 17 prospective population-based studies that included 46,000 men with an average of 8 years of follow-up and 11,000 women with an average 11-year follow-up, the relative risk of increased triglycerides in men was 1.32 and in women was 1.76. Some of the studies included HDL levels, and when these levels were factored in, the risk fell to 1.14 in men and 1.37 in women. Although this lowered the risk factor, it still remained significant, which indicates that triglycerides are a risk factor independent of HDL cholesterol levels.[28]
The lipid profile makeup may also influence glucose metabolism. In a study of 1549 subjects participating in the Insulin Resistance Atherosclerosis Study, LDL size was related to several parameters associated with insulin resistance.[29] The relationship was independent of BMI, triglyceride, as well as HDL cholesterol levels, and was more pronounced in men than women. These findings point out the complex interrelationship of various factors and components involved in the metabolic syndrome.
Fat Distribution Patterns
The distribution of fat may be related to the development of the metabolic syndrome. In a 7-year follow-up study of 721 Mexican Americans, waist circumference was found to be the best predictor of development of noninsulin-dependent diabetes mellitus vs BMI, waist/hip ratio, or other measures.[30] Diabetes risk in the highest quartile of waist circumference was 11 times that in the lowest quartile. Although there was an association between BMI and waist/hip ratio and subsequent diabetes development, their predictive value appeared to be related primarily to waist circumference.
However, Rexrode and colleagues[31] found that the relationship between waist circumference and the development of CHD in a cohort of 16,164 men was modest. Men in the highest quintile had a relative risk of 1.6 compared with men in the lowest quintile. Waist circumference did not remain an independent predictor after BMI was taken into account.[31] In an 8-year prospective study of 44,702 female nurses between the ages of 40 and 65 years, Rexrode and colleagues[32] found that waist circumference was significantly associated with the risk of future cardiac events after adjustment for BMI. The relative risk of women with a waist circumference of 96.5 cm (38 in) was 3.06 compared with nonoverweight subjects. Obesity was also a risk for eventual development of diabetes in this cohort.[33] Therefore, fat distribution patterns appear to be a risk factor for obesity and other health issues, although factors such as sex and ethnicity may affect the outcome.
Additive Risk Factor Models
As the number of risk factors increases, the probability of morbidity and mortality increases. It is the additive value of multiple risks inherent in the metabolic syndrome that makes this construct a more powerful predictor than any one variable in isolation. In an analysis of the Framingham Study data, it was found that obesity accounted for 47% of the risk in a high-risk population for developing coronary artery disease.[34] Of this, 31% of the risk could be attributed to smoking, physical inactivity, low income, and low educational levels. All these factors are increased in the chronically mentally ill population. Approximately half the risk of CHD in the general populations occurs in individuals with multiple marginal risk factors.[11]
Morbidity and Mortality Associated With Mental Illness
Overall Morbidity and Mortality
Patients with chronic psychiatric disorders are at increased risk for morbidity and mortality resulting from a variety of medical diseases, including respiratory illnesses, infectious diseases, obesity, diabetes mellitus, and cardiovascular disease.[35] Even prior to the introduction of modern psychotropic agents in the 1950s, there was evidence that the chronically mentally ill suffered from higher rates of medical disorders. As early as the 1920s, for example, there were reports that patients with schizophrenia and manic depression manifested abnormal glucose metabolism.[36,37]
In patients with schizophrenia and affective disorders, the prevalence of risk factors for cardiovascular disease (CVD) is approximately 1.5 to 2.0 times higher than the rate in the general population.[2] In a meta-analysis of 18 studies of patients with schizophrenia, all studies except one noted an increase in mortality.[38] Approximately 41% of excess deaths were related to suicide or accidents, while 59% were attributed to natural causes. CVD was the most common cause of death in patients, accounting for 34% of deaths in males and 31% in females.
A Swedish study assessed all individuals with a hospital diagnosis of bipolar disorder (n = 15,386) or unipolar disorder (n = 39,182) between the years of 1973 and 1995.[39] For all natural causes of death, the Standardized Mortality Ratio (SMR) was 1.9 for males and 2.1 for females in the bipolar cohort. In those with unipolar disorder, the SMR was 1.5 for males and 1.6 for females.
In a long-term prospective follow-up study of 406 patients with affective disorders lasting up to 38 years, 99% of the cohort was assessed for mortality statistics.[40] Patients were followed for at least 22 years; 76% had died by the time of final assessment. Deaths from suicide as well as circulatory diseases were elevated in both men and women. Patients with unipolar depression had higher suicide rates than did individuals with either bipolar I or II disorder.
Mood Disorders and Obesity
Mood disorders have been associated with obesity. In a sample of 59 middle-aged men with increased waist-hip ratio, significantly higher depression and anxiety scores were noted.[41] Insulin and glucose levels were significantly related to the Hamilton Depression Scale scores. Morning cortisol levels were negatively correlated with the Beck Depression Inventory and the Montgomery-Asberg Depression Rating Scale.
It has been postulated that glucocorticoids play a central role in the pathogenesis of the metabolic syndrome.[42] Mood disorders have also been associated with hypothalamic-pituitary-adrenal axis dysregulation,[43] which may be a link to metabolic morbidities in bipolar disorder.
In a survey of 644 outpatients with bipolar disorder, 58% were noted to be overweight, 21% obese, and 5% extremely obese.[44] American patients had significantly higher rates of obesity compared with European counterparts. Obesity was positively correlated with age, comorbid binge-eating disorders, hypertension, arthritis, diabetes mellitus, exercise habits, and consumption of coffee.
In a retrospective study of 50 patients with bipolar disorder, 68% were either overweight or obese.[45] Weight gain was noted during acute treatment but not during the maintenance phase of the study. Increases in BMI were positively related to depression scores and negatively related to mania scores.
In a study of 175 patients with bipolar I disorder receiving maintenance treatment, obese individuals experienced poorer outcomes and had an increased number of depressive episodes with a significantly shorter time to recurrence.[46] Weight control interventions may be a way to improve overall outcomes in this patient population.
Treated bipolar patients in euthymic state were found to be more obese compared with controls.[47] Patients on antipsychotic drugs were significantly more obese compared with those not treated with these agents. There were several factors that distinguished these patients from controls -- an increased intake of daily total sucrose with more energy derived from carbohydrates, an elevated total intake of sweetened drinks, and a lower level of exercise.[48]
Diabetes and Mood Disorders
In a retrospective study of 243 inpatients aged 50 to 74 years, patients with schizophrenia as well as major depression, bipolar I disorder, and schizoaffective disorder manifested increased rates of type 2 diabetes mellitus.[49]
Patients with schizophrenia appear to have problems with glucose regulation at baseline. In a study of drug-naive first-episode patients, 15% of individuals with schizophrenia showed evidence of impaired glucose tolerance compared with 0% of controls.[50] The patient cohort also manifested higher fasting glucose levels, insulin levels, and cortisol levels.
In a study of hospitalized adults, the rate of those taking both antipsychotic medications as well as medications for diabetes was 9.5% for men and 14.7% for women, higher than the approximate 6% prevalence of individuals diagnosed with diabetes in the general population.[51] In a comparison of atypical agents utilized in the treatment of mood disorders, the risk of developing diabetes in patients treated with either risperidone or a high potency typical antipsychotic was equal to the rate in untreated controls as indicated by claims data from 2 large health plans.[52] In contrast, the odds ratio (OR) with olanzapine and low potency agents was significantly higher compared with controls (OR = 4289 and 4972, respectively).
In a sample of 345 hospitalized patients with manic or mixed subtype bipolar disorder, the rate of diabetes was 9.9%, greater than the 3.4% rate expected from national norms.[53] The author's own studies in a VA population showed a high proportion of bipolar patients with diabetes (26%).[54] Individuals with comorbid diabetes mellitus had more lifetime psychiatric hospitalizations than the nondiabetic subjects. Several reasons were posited to explain this comorbid association, including a common genetic relationship, the presence of hypercortisolemia that induces diabetes, diabetic vascular lesions that contribute to a manic presentation an overlapping central nervous system abnormality that results in metabolic and mood disturbances, or the effect of psychotropic medications.
Lifestyle Factors
Lifestyle clearly plays a role in the pathogenesis of the metabolic syndrome and subsequent negative health risks. Despite the widely known positive effects associated with regular exercise and adequate diet, a survey of the general population found that 27% of respondents did not engage in any physical activity and 28.2% were not regularly active.[15] Only 24.4% consumed at least 5 portions of fruits or vegetables daily.
Sedentary behavior has been associated with the risk of diabetes and obesity. A 6-year Nurses' Health Study found that each 2-hour/day increase in television viewing was associated with an approximate 23% increase in obesity and 14% increase in diabetes.[55] Age, smoking, exercise levels, and dietary factors were controlled. Each 2-hour/day increment in sitting at work was associated with a 5% increase in levels of obesity and a 7% increase in diabetes. Each 1-hour/day of brisk walking was related to a 24% decrease in obesity and a 34% decrease in diabetes. The chronically mentally ill tend to engage in more unhealthy habits and are more likely to have lifestyles with potentially negative health consequences. The rate of cigarette smoking is higher among patients with schizophrenia as well as bipolar disorder. In one study, the rate of smoking was found to be 57.5% in patients with schizophrenia, 55.1% in patients with bipolar disorder, and 47.3% in controls.[56] In a study of state hospital patients, the prevalence rates of either a history of smoking or current smoking was found to be 92% and 83%, respectively, for patients with schizophrenia; 78% and 65% for patients with mood disorders; and 47% and 26% for community controls.[57] Other negative lifestyle factors among the chronically mentally ill include sedentary behavior, poor nutrition, as well as avoidance of medical professionals. Furthermore, the healthcare system is often ill equipped to handle the behavioral and emotional problems of the chronically mentally ill. Each of these factors tends to exacerbate underlying health problems of the chronically mentally ill.
Managing Weight Gain
There are several ways to manage weight gain and other metabolic issues in the patient with bipolar disorder. Patients at highest risk for health problems should identified, although it is good clinical practice to stress healthy lifestyles to all patients with chronic mental illness.
Psychoeducational counseling should focus on the importance of attending to weight and associated issues and introduce practical ways of changing unhealthy lifestyles. Changes in diet should involve avoidance of high caloric, nutritionally poor foods such as fast foods or unhealthy snacks. Introduction of balanced healthy alternatives including fresh fruits and vegetables, lean meats, and fish should be stressed. It is often helpful to have a scale available to monitor the effect of the interventions and call attention to the importance of losing weight.
As in the general population, modest exercise appears to have multiple positive effects in the chronically mentally ill.[58] A 16-week walking program in patients with schizophrenia resulted in decreases in BMI and improvements in psychological symptoms compared with nonactive controls.
The importance of appropriate psychopharmacologic interventions is essential to minimizing risk. Individuals with a personal or family history of predisposing health difficulties should be treated most cautiously. Medication combinations with potentially additive negative side effects should be avoided if possible. For example, in bipolar patients, olanzapine should not be coprescribed with valproate unless necessary. Each agent's high weight gain potential may result in a synergistic effect and greatly increase the risk of weight gain. Some agents such as topiramate[59] and zonisamide[60] which are awaiting approval by the FDA, may induce some weight loss. However, alternatives such as dietary and lifestyle interventions, switching to pharmacologic agents with lower weight gain profiles, or combination therapy with lower doses of potentially weight-inducing agents should be attempted prior to introduction of these agents.
Metabolic Profiles of Pharmacologic Agents
Mood Stabilizers
Lithium. Lithium, the oldest available mood stabilizer, causes weight gain in 30% to 65% of patients.[61-63]
Valproate.Valproate frequently may cause significant weight gain, an effect that may be mediated in part by the tendency to increase insulin and thereby stimulate appetite.[64] A review of weight gain with valproate shows that up to 71% of patients with epilepsy gained weight with valproate.[65] Polycystic ovarian syndrome has been associated with valproate in some but not all studies, and weight gain along with androgen excess has been posited as a mechanism for this disorder.[66] In an analysis of food intake compared with energy expenditure of patients treated with valproate, those with weight gain manifested a lower metabolic rate rather than caloric intake.[67]
Carbamazepine. There is substantial literature on carbamazepine due to its use in epilepsy for about 3 decades, like valproate. Although carbamazepine has been used off-label for mania since the late 1970s, an extended-release form (Equetro™) was only recently approved by the FDA.
In recent FDA bipolar disorder studies with extended-release carbamazepine, the mean weight gain was 1.0 kg vs 0.1 kg with placebo in a 3-week trial.[68] The mean weight gain in a 6-month extension study[69] was a low 0.7% (equivalent to 0.5 kg in a 70-kg man), suggesting that weight gain in bipolar patients is minimal during long-term treatment with extended-release carbamazepine. Studies suggest a low rate of weight gain with carbamazepine in 2.5% to 14% of epilepsy patients.[65]
Lamotrigine. Lamotrigine is an anticonvulsant indicated only for maintenance treatment of bipolar disorder; it shows no efficacy in acute mania. Like carbamazepine, it causes little if any weight gain. In a survey of 32 studies including 463 patients, the mean change in body weight was 0.5 (± 5) kg.[70]
Topiramate. Topiramate, which is indicated for epilepsy, is not approved for bipolar disorder due to failed clinical trials. However, it has been noted to induce weight loss and is sometimes utilized (off-label) to counteract the weight gain induced by other agents.[59,63,71]
Zonisamide. Zonisamide, approved as an anticonvulsant but not as a mood stabilizer, is also associated with weight loss.[60]
Antidepressants
Antidepressants vary widely in inducing weight gain.[72] The tricyclic antidepressants tend to produce more weight gain than the selective serotonin reuptake inhibitors (SSRIs). Paroxetine appears to be more likely to induce weight gain compared with the other SSRIs.[73] Bupropion is generally considered to be weight neutral,[74] while the dual-acting serotonergic and noradrenergic agent mirtazapine has a high tendency to induce weight gain.[75]
In general, the use of unopposed antidepressants in the treatment of bipolar depression should be avoided due to the increased risks of switching to mania, mixed mania, or to rapid-cycling. Thus, a mood stabilizer should be combined with an antidepressant in individuals who present with bipolar depression, and the selection of a mood stabilizer with a low weight-gain profile can help avoid the additive effects of weight gain that may occur in combination therapy.
Antipsychotics
Despite the equal efficacy of all of the atypical antipsychotic agents in schizophrenia and bipolar disorder, each agent possesses a markedly different side effect profile. Choice of the appropriate intervention often hinges on minimizing risk to the patient while maximizing the therapeutic response.[76]
Despite the need for caution in the use of these agents as a class, clozapine and olanzapine have consistently been found to have the largest metabolic side effect burden. Ziprasidone and aripiprazole are the least likely to cause metabolic disturbances, while quetiapine and risperidone are intermediate in effect.
Antipsychotics and Weight Gain
In a comparison of several atypical agents in patients with schizophrenia,[77] olanzapine was associated with the greatest weight gain (74.5% of the cohort). Risperidone resulted in weight gain in 53.4%, and haloperidol in 40.0%. The proportion of patients with "clinically relevant" weight gain (defined as >/= 7% of the initial body weight) was highest with olanzapine (45.7%) compared with risperidone (30.6%) and haloperidol (22.4%). Five patients (13.5%) treated with quetiapine manifested some weight gain, but none showed a weight gain of >/= 7%. This may have been due to the relatively shorter duration of treatment with this agent.
In a seminal review of the literature, Allison and colleagues[78] examined the short-term weight gain with old and new antipsychotics in 81 clinical trials and found that olanzapine with a weight gain average of 4.15 kg and clozapine with 4.45 kg were associated with the highest weight gain after 10 weeks of treatment. Risperidone was associated with an average weight gain of 2.10 kg and ziprasidone produced a negligible increase of 0.04 kg. The worst of the conventional antipsychotics was thioridazine, which produced a weight gain of 3.4 kg in 10 weeks. Neither aripiprazole nor quetiapine were included due to the lack of published data at the time. Subsequent studies of mean weight gain at the end of 1 year showed that olanzapine was associated with the highest degree of mean weight gain (12.3 kg), risperidone and quetiapine with a moderate amount (2.4 kg), and aripiprazole and ziprasidone with the lowest amount (0.5 kg to 1 kg).[79]
Fontaine and associates[80] used data from the Framingham Study to assess clozapine's impact on weight gain, which was then compared with its impact on decreasing suicide.[81] The estimated 492 suicide deaths per 100,000 patients that could be saved over 10 years was nearly offset by the calculated increase in mortality from obesity-related health risks of 416 per 100,000. These negative effects were calculated to be most serious in individuals with higher baseline BMIs, more so in men more than women, and increased with age.
Abnormal glucose metabolism can be observed in patients taking atypical antipsychotics even in the absence of weight changes. Henderson and colleagues[82] studied nonobese subjects stabilized on clozapine, olanzapine, or risperidone. Patients treated with clozapine or olanzapine manifested significantly larger increases in serum insulin concentrations as well as decreased insulin sensitivity compared with patients treated with risperidone. Using data from FDA MedWatch, Koller and Doraiswamy,[83] showed that fatal cases of diabetic ketoacidosis can occur early in the course of treatment with olanzapine, even before any weight gain occurs; this suggests that weight gain is not necessary for severe cases of diabetes to occur with some atypical antipsychotics.
Antipsychotic-Associated Hyperlipidemia
Analogous to the findings about weight gain, clozapine and olanzapine place the patient at greatest risk compared with the other agents. In a retrospective study, Wirshing and colleagues[84] found that patients treated with clozapine or olanzapine had statistically significant increases in triglyceride as well as glucose levels. Atmaca and associates[85] conducted a comparison of quetiapine, olanzapine, risperidone, and clozapine in patients with schizophrenia and measured triglyceride as well as leptin levels. Leptin, a protein hormone primarily secreted by adipocytes, is involved in weight regulation through its action at the hypothalamus. The comparative study showed that increases in triglyceride, weight, and leptin were greatest in olanzapine and clozapine patients, modest in the quetiapine group, and minimal in the risperidone-treated group. Newcomer[86] conducted a comprehensive review of the differential metabolic effects of atypical antipsychotics, including weight gain, dyslipidemia, and diabetes. It subsequently became evident that the atypical agents could induce glucose dysregulation to varying degrees, at times resulting in serious consequences such as ketoacidosis and death.
Antipsychotics and Diabetes Mellitus
Shortly after the phenothiazine antipsychotic chlorpromazine was introduced in the 1950s, there was evidence of glucose dysregulation accompanying the use of these agents.[87] It has subsequently become evident that atypical agents can induce glucose dysregulation to varying degrees, at times resulting in serious consequences such as ketoacidosis.[86]
Koller and Doraiswamy[83] documented 237 cases of olanzapine-associated hyperglycemia, of which 188 were new-onset diabetes and most (73%) occurred within 6 months of the initiation of therapy. Glucose levels were greater than 1000 mg/dL in 41 patients; 23 patients died. Discontinuation of the medication or dosage reduction resulted in improvement in 78% of patients. When patients were rechallenged with olanzapine, hyperglycemia recurred in 80% of cases.
Newcomer and colleagues[88] administered modified glucose tolerance tests to nondiabetic patients with schizophrenia receiving either clozapine, olanzapine, risperidone, or typical antipsychotics vs normal controls. Olanzapine- and clozapine-treated patients had the most pronounced elevations of glucose. Koro and associates[89] compared 19,637 patients with schizophrenia drawn from a general practice research database vs 2696 controls. Individuals treated with olanzapine had a markedly higher risk of developing diabetes compared with both normal controls (OR = 5.8) and patients on typical agents (OR = 4.2). Risperidone-treated patients had an elevated risk, although the increase was not significant (OR = 2.2). The OR for patients treated with conventional agents was 1.6.
Consensus Statement on Antipsychotic Therapy
In order to address concerns about the metabolic side effects of atypical antipsychotic agents, a consensus statement, developed by 4 societies -- the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity[90] -- reached some conclusions:
* The most clear-cut data supporting an association between diabetes and the atypical agents is for clozapine and olanzapine (Table 2). The risk in patients taking risperidone or quetiapine is considered to be unclear due to the lack of definitive studies, although there have been some published case reports. The data for aripiprazole and ziprasidone are limited due to the recent introduction of these agents; however, no increased risk had been demonstrated at the time of the consensus statement.
* Clozapine and olanzapine are associated with the greatest increase in lipids, including total cholesterol, LDL cholesterol, and triglycerides. These agents also are the most likely to decrease protective HDL cholesterol. Aripiprazole and ziprasidone are not associated with a worsening lipid profile, while risperidone and quetiapine are intermediate in effect.
* Atypical effects on weight gain are similar to the other parameters, with olanzapine and clozapine being the most likely to induce significant degrees of weight gain. Risperidone and quetiapine are intermediate in effect and aripiprazole and ziprasidone are the least likely.
Table 2. ADA, APA, AACE, and NAASO Consensus on Antipsychotic Drugs and Obesity and Diabetes
Antipsychotic Weight Gain Diabetes Risk Dyslipidemia
Clozapine +++ + +
Olanzapine +++ + +
Risperidone ++ 0 0
Quetiapine ++ 0 0
Aripiprazole ± - -
Ziprasidone ± - -
+ = increased effect
- = no effect
0 = discrepant results
Table adapted from: American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65:267-272.
The panel made several recommendations to minimize the risks of these agents (Table 3):
* BMI and waist circumference should be monitored throughout therapy in all patients on atypical agents.
* Personal and family history of obesity, dyslipidemia, diabetes, hypertension, and/or cardiovascular risk should be reviewed.
* Baseline blood pressure, fasting glucose, and lipids should be obtained and monitored.
Table 3. Monitoring Protocol for Patients on Atypical Antipsychotics*
Baseline 4 Weeks 8 Weeks 12 Weeks Quarterly Annually Every 5 Years
Personal/
family history X X
Weight (BMI) X X X X X
Waist circumference X X
Blood pressure X X X
Fasting plasma glucose X X X
Fasting lipid profile X X X
* More frequent assessments may be warranted based on clinical status.
Reprinted with permission. From: American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65:267-272.
Conclusion
The number of pharmacotherapeutic options available for the treatment of bipolar disorder has increased substantially over the past decade. This has resulted in great optimism that this severe, recurrent, and hard-to-treat psychiatric brain disorder may be more effectively managed. However, the health risks associated with some agents can be significant. The clinician must therefore be continuously vigilant to ensure minimal weight gain and avoid obesity-associated metabolic complications by matching each bipolar patient with the safest agent(s), especially since these patients may often require combination pharmacotherapy. Only by balancing physical and psychiatric health management to minimize morbidity and mortality can good clinical and functional outcomes be achieved.
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Authors and Disclosures
As an organization accredited by the ACCME, Medscape requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as "financial relationships in any amount, occurring within the past 12 months, that create a conflict of interest."
Medscape encourages Authors to identify investigational products or off-label uses of products regulated by the U.S. Food and Drug Administration, at first mention and where appropriate in the content.
Author
Henry A. Nasrallah, MD
Professor of Psychiatry, Neurology and Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio; Director, Schizophrenia Research Program, University of Cincinnati Medical Center, Cincinnati, Ohio
Disclosure: Henry A. Nasrallah, MD, has disclosed that he has received grants for clinical research and/or educational activities from AstraZeneca, Janssen, Pfizer, Abbott, Shire, Lilly, and Forest. Dr. Nasrallah has also disclosed that he serves as an advisor to Abbott, AstraZeneca, and Shire.
Martin L. Korn, MD
Psychiatrist, Department of Psychiatry, The Mount Vernon Hospital, Mount Vernon, New York
Disclosure: Martin L. Korn, MD, has disclosed that he has received grants for educational activities from AstraZeneca and Bristol-Myers Squibb.
Editor
Elizabeth Saenger, PhD
Editorial Director, Medscape Psychiatry & Mental Health
Disclosure: Elizabeth Saenger, PhD, has disclosed no relevant financial relationships.
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