Richard A. Bermudes, MD

At what point do the five risk factors that predict type 2 diabetes and cardiovascular disease (CVD) signal metabolic syndrome? When and how often should psychiatrists check for metabolic abnormalities? How can you manage metabolic problems caused by a psychotropic that controls the patient’s psychiatric symptoms?

This article answers those questions by addressing:

• clinical guidelines for diagnosing metabolic syndrome
• suggested intervals for monitoring at-risk patients
• strategies for managing metabolic abnormalities with lifestyle changes or medication.

CASE REPORT: 'FAT' AND FRUSTRATED

Ms. S, age 37, has had bipolar disorder for 10 years. She has tried numerous medications including mood stabilizers, antidepressants, and atypical antipsychotics. The combination of quetiapine, 200 mg bid, and lithium, 300 mg bid, has controlled her symptoms for the past 6 months.

Her weight has increased 40 lbs over the past decade; much of her weight gain has occurred since the birth of her two children, ages 4 and 6. At 5 feet, 3 inches and 170 lbs, she is frustrated over her weight gain, especially on the eve of her 20-year high school reunion. She is convinced that her medications have prevented weight loss.

Her waist, measured at the umbilicus, is 37 inches. Her body mass index (BMI) is 30—indicating clinical obesity—and her blood pressure is in the high normal range (134/80 mm Hg). She has not had gestational diabetes and has not seen a medical doctor since her last pregnancy, but her father has type 2 diabetes and hypertension. She drinks wine occasionally at social events and does not smoke.

The psychiatrist orders a fasting lipid panel and fasting glucose test to further assess her risk of heart disease. Total cholesterol and low-density lipoprotein (LDL) cholesterol are normal. Triglycerides are 125 mg/dL (normal) and her high-density lipoprotein (HDL) is 45 mg/dL—5 mg/dL below normal for a woman her age. Fasting glucose is 86 mg/dL (normal).

The psychiatrist schedules a visit the following month to assess her cardiac and diabetic risk and to discuss weight-loss interventions.

Discussion. In a busy clinical setting, the psychiatrist must accurately gauge Ms. S’ metabolic risk and devise a management strategy. Do her weight and low HDL suggest metabolic syndrome? Is she overeating or making unhealthy dietary choices, or are her psychotropics causing weight gain? Would switching psychotropics lead to bipolar relapse?

IMPLICATIONS OF METABOLIC SYNDROME

Patients with metabolic syndrome are at increased risk for:

• type 2 diabetes¹
• CVD²
• increased mortality from CVD and all causes.³

In a prospective study that followed 1,209 Finnish men over an average 11.4 years,⁴ men with metabolic syndrome were more likely than those with no metabolic problems to die from coronary heart disease, CVD, and any cause after adjustment for conventional cardiovascular risk factors. No one in either group had a baseline illness, suggesting that metabolic syndrome increases the risk of CVD or death regardless of whether underlying illness is present.

DEFINING METABOLIC SYNDROME

Metabolic syndrome is not a disease but a constellation of risk factors that provides a definable point of intervention before onset of type 2 diabetes or CVD.

According to the National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III), presence of three of these five criteria suggest metabolic syndrome:

• abdominal obesity
• insulin resistance
• high blood pressure
• elevated triglycerides
• below-normal HDL.

This definition offers a starting point for measuring risk factors in clinical practice and provides a definable target and parameters to avoid (Table 1).⁵ The guideline is also easy to follow: Waist circumference and blood pressure can be measured within seconds; blood glucose, HDL, and triglycerides can easily be measured before breakfast, after the patient has fasted for at least 6 hours.

Table 1

5 defined risk factors* for metabolic syndrome

MONITORING FREQUENCY

Although no empirical studies have addressed monitoring frequency for metabolic risk factors, several guidelines provide preliminary recommendations. Table 2 summarizes suggested intervals for monitoring weight, lipids, glucose, and waist circumference for patients taking atypical antipsychotics, based on recommendations from the 2004 American Diabetes Association (ADA) and American Psychiatric Association (APA) consensus development conference.⁶

Because atypicals are associated with serious metabolic risks, screen patients taking these agents for metabolic abnormalities at baseline and at regular intervals. Most guidelines recommend measuring blood pressure, BMI, waist circumference, fasting serum lipids (total, LDL, HDL, and triglycerides) and fasting glucose before starting or switching to an atypical and again 12 weeks later. Established risk for metabolic disturbances or dramatic metabolic changes (such as weight gain ≥7%, waist circumference ≥35 inches in women and ≥40 inches in men, or fasting blood sugars >110 mg/dL) demand more-frequent monitoring (ie, monitor high-risk patients quarterly).

Table 2

Suggested monitoring intervals for patients taking atypical antipsychotics*

MANAGING METABOLIC PROBLEMS

Managing metabolic abnormalities or metabolic syndrome is aimed at preventing type 2 diabetes and CVD. Levels of intervention include:

• weight management, weight control education, and promoting regular exercise and a healthy diet
• switching to a psychotropic that is less likely to cause weight gain, if clinically appropriate
• working with the patient’s primary care physician to manage dyslipidemia, hypertension, obesity, or hyperglycemia.

Weight management. Start by controlling weight and promoting regular exercise and healthy eating. Switching medications—often the first response—may not be the best option, particularly if the offending agent is relieving the patient’s psychiatric symptoms.

Losing weight, increasing exercise, and reducing fat and carbohydrate intake can reverse metabolic syndrome and delay onset of type 2 diabetes and CVD.⁷ Even a small weight loss, such as 10% of baseline body weight in persons who are overweight (BMI >25) or obese (BMI >30) can significantly reduce the risk of hypertension, hyperlipidemia, hyperglycemia, and death.⁷

Rather than promoting a single diet, tailor dietary advice to each patient’s metabolic abnormalities (Table 3). Although researchers disagree over whether a low-fat or low-carbohydrate diet produces better results, either diet will work as long as the patient consumes fewer calories than he or she expends. This is because weight loss alone reverses metabolic syndrome.

Likewise, exercise can reverse metabolic syndrome independent of diet change. Regular exercise at modest levels improves HDL,² triglycerides,¹⁷ blood pressure,¹⁸ and hyperglycemia.¹⁹

In one prospective study,²⁰ 621 subjects without chronic disease or injury underwent supervised aerobic training three times weekly for 20 weeks. Participants were told not to otherwise change their health and lifestyle habits.

Of the 105 persons in the cohort who had metabolic syndrome at baseline, 32 (30%) no longer had it after the aerobics program. Among these participants:

• 43% had lower triglycerides than at baseline
• 16% had higher HDL cholesterol
• 38% had lower blood pressure
• 9% had improved fasting glucose
• 28% reduced their waist circumference.

Table 3

Interventions for specific metabolic complications

Selling the benefits of exercise and weight loss to a mentally ill patient can be difficult. Attention, memory, and motivation deficits as well as smoking and substance abuse often get in the way.

By teaming up with clinicians with expertise in dieting such as nurses, dietitians, and recreational therapists, psychiatrists can more effectively promote long-term diet, exercise, and lifestyle changes.²¹

In a prospective 12-month trial,²² 20 patients who were taking atypical antipsychotics for schizophrenia or schizoaffective disorder completed a 52-week program that incorporated nutrition, exercise, and behavioral interventions. Twenty similar patients received treatment as usual. Patients in the program saw significant improvements in weight, blood pressure, exercise habits, nutrition, and hemoglobin A1c compared with the treatment-as-usual group.²²

Psychiatrists who treat privately insured patients should collaborate with the patient’s primary care physician. Many insurance plans will pay for 1 or 2 personal or group sessions with a dietitian, especially if the patient is diagnosed as being obese (BMI >30). Some large plans, such as Kaiser Permanente, will cover intensive multimodal treatment, especially for patients with a BMI >35. Calculating the patient’s BMI can help you document the need for antiobesity treatment (see Related resources).

Medication. If weight control and exercise do not reduce metabolic risk factors after 3 to 6 months, consider switching to an atypical antipsychotic with a lower propensity for causing metabolic effects.

Which agents most decrease metabolic risk has been debated. Preliminary evidence indicates that switching from other antipsychotics to aripiprazole or ziprasidone may reduce weight and improve cholesterol ratios.^23,24 These findings are consistent with the ADA/APA consensus guidelines, which indicate that metabolic risk varies among atypical antipsychotics (Table 4).⁶

Table 4

Atypical antipsychotics and their propensity for causing metabolic abnormalities

Targeted pharmacotherapy. Wait another 3 to 6 months to see if the medication change and weight loss/exercise interventions reduce metabolic risk factors. If they don’t, work with the patient’s primary care physician to manage hypertension, dyslipidemia, and obesity (Table 3).

Although no agents are approved for treating metabolic syndrome per se, medications targeted at individual symptoms are becoming the standard of care. Controlling blood pressure, HDL, and LDL in patients with metabolic syndrome can reduce risk for coronary heart disease by >50%.²⁵ Insulin-sensitizing agents and metformin in combination with lifestyle changes or used alone have been shown to delay onset of type 2 diabetes (Table 3).

CASE CONTINUED: 10 LBS IN 10 WEEKS

At her follow-up visit, Ms. S and her psychiatrist discuss her increased risk for diabetes and cardiovascular disease. She meets criteria for metabolic syndrome (low HDL, elevated blood pressure, and increased waist circumference).

Ms. S agrees to try a formal diet program with set menus, along with group support at her local community center. She also commits to walking 30 minutes three to four times a week with a target heart rate of 100 beats per minute. Although both quetiapine and lithium carry considerable risk of weight gain, she and her psychiatrist decide to wait at least 3 months before considering a medication change, as she is stable on this combination.

Ms. S schedules a follow-up visit with her primary care physician to ensure that she sticks to her weight loss and exercise programs. In the interim, the primary care physician and psychiatrist agree that her goal will be to lose 10 lbs over 10 weeks.

Related resources

• National Alliance for the Mentally Ill. Hearts and Minds Program, a booklet and program geared toward raising awareness regarding diabetes, diet, exercise, and smoking. Download at www.nami.org.
• Centers for Disease Control and Prevention: Body mass index formula for adults. http://www.cdc.gov/nccdphp/dnpa/bmi/bmi-adult-formula.htm.
• National Heart, Lung and Blood Institute body mass index calculator. http://www.nhlbisupport.com/bmi/bmicalc.htm.
• Keck PE Jr, Buse JB, Dagago-Jack S, et al. Managing metabolic concerns in patients with severe mental illness. A special report. Postgraduate Med 2003;1-92.

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Metformin • Glucophage
• Olanzapine • Zyprexa
• Orlistat • Xenical
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sibutramine • Meridia
• Ziprasidone • Geodon

Disclosure

Dr. Bermudes is a speaker for Bristol-Myers Squibb Co. and Pfizer Inc.

At what point do the five risk factors that predict type 2 diabetes and cardiovascular disease (CVD) signal metabolic syndrome? When and how often should psychiatrists check for metabolic abnormalities? How can you manage metabolic problems caused by a psychotropic that controls the patient’s psychiatric symptoms?

This article answers those questions by addressing:

• clinical guidelines for diagnosing metabolic syndrome
• suggested intervals for monitoring at-risk patients
• strategies for managing metabolic abnormalities with lifestyle changes or medication.

CASE REPORT: 'FAT' AND FRUSTRATED

Ms. S, age 37, has had bipolar disorder for 10 years. She has tried numerous medications including mood stabilizers, antidepressants, and atypical antipsychotics. The combination of quetiapine, 200 mg bid, and lithium, 300 mg bid, has controlled her symptoms for the past 6 months.

Her weight has increased 40 lbs over the past decade; much of her weight gain has occurred since the birth of her two children, ages 4 and 6. At 5 feet, 3 inches and 170 lbs, she is frustrated over her weight gain, especially on the eve of her 20-year high school reunion. She is convinced that her medications have prevented weight loss.

Her waist, measured at the umbilicus, is 37 inches. Her body mass index (BMI) is 30—indicating clinical obesity—and her blood pressure is in the high normal range (134/80 mm Hg). She has not had gestational diabetes and has not seen a medical doctor since her last pregnancy, but her father has type 2 diabetes and hypertension. She drinks wine occasionally at social events and does not smoke.

The psychiatrist orders a fasting lipid panel and fasting glucose test to further assess her risk of heart disease. Total cholesterol and low-density lipoprotein (LDL) cholesterol are normal. Triglycerides are 125 mg/dL (normal) and her high-density lipoprotein (HDL) is 45 mg/dL—5 mg/dL below normal for a woman her age. Fasting glucose is 86 mg/dL (normal).

The psychiatrist schedules a visit the following month to assess her cardiac and diabetic risk and to discuss weight-loss interventions.

Discussion. In a busy clinical setting, the psychiatrist must accurately gauge Ms. S’ metabolic risk and devise a management strategy. Do her weight and low HDL suggest metabolic syndrome? Is she overeating or making unhealthy dietary choices, or are her psychotropics causing weight gain? Would switching psychotropics lead to bipolar relapse?

IMPLICATIONS OF METABOLIC SYNDROME

Patients with metabolic syndrome are at increased risk for:

• type 2 diabetes¹
• CVD²
• increased mortality from CVD and all causes.³

In a prospective study that followed 1,209 Finnish men over an average 11.4 years,⁴ men with metabolic syndrome were more likely than those with no metabolic problems to die from coronary heart disease, CVD, and any cause after adjustment for conventional cardiovascular risk factors. No one in either group had a baseline illness, suggesting that metabolic syndrome increases the risk of CVD or death regardless of whether underlying illness is present.

DEFINING METABOLIC SYNDROME

Metabolic syndrome is not a disease but a constellation of risk factors that provides a definable point of intervention before onset of type 2 diabetes or CVD.

According to the National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III), presence of three of these five criteria suggest metabolic syndrome:

• abdominal obesity
• insulin resistance
• high blood pressure
• elevated triglycerides
• below-normal HDL.

This definition offers a starting point for measuring risk factors in clinical practice and provides a definable target and parameters to avoid (Table 1).⁵ The guideline is also easy to follow: Waist circumference and blood pressure can be measured within seconds; blood glucose, HDL, and triglycerides can easily be measured before breakfast, after the patient has fasted for at least 6 hours.

Table 1

5 defined risk factors* for metabolic syndrome

MONITORING FREQUENCY

Although no empirical studies have addressed monitoring frequency for metabolic risk factors, several guidelines provide preliminary recommendations. Table 2 summarizes suggested intervals for monitoring weight, lipids, glucose, and waist circumference for patients taking atypical antipsychotics, based on recommendations from the 2004 American Diabetes Association (ADA) and American Psychiatric Association (APA) consensus development conference.⁶

Because atypicals are associated with serious metabolic risks, screen patients taking these agents for metabolic abnormalities at baseline and at regular intervals. Most guidelines recommend measuring blood pressure, BMI, waist circumference, fasting serum lipids (total, LDL, HDL, and triglycerides) and fasting glucose before starting or switching to an atypical and again 12 weeks later. Established risk for metabolic disturbances or dramatic metabolic changes (such as weight gain ≥7%, waist circumference ≥35 inches in women and ≥40 inches in men, or fasting blood sugars >110 mg/dL) demand more-frequent monitoring (ie, monitor high-risk patients quarterly).

Table 2

Suggested monitoring intervals for patients taking atypical antipsychotics*

MANAGING METABOLIC PROBLEMS

Managing metabolic abnormalities or metabolic syndrome is aimed at preventing type 2 diabetes and CVD. Levels of intervention include:

• weight management, weight control education, and promoting regular exercise and a healthy diet
• switching to a psychotropic that is less likely to cause weight gain, if clinically appropriate
• working with the patient’s primary care physician to manage dyslipidemia, hypertension, obesity, or hyperglycemia.

Weight management. Start by controlling weight and promoting regular exercise and healthy eating. Switching medications—often the first response—may not be the best option, particularly if the offending agent is relieving the patient’s psychiatric symptoms.

Losing weight, increasing exercise, and reducing fat and carbohydrate intake can reverse metabolic syndrome and delay onset of type 2 diabetes and CVD.⁷ Even a small weight loss, such as 10% of baseline body weight in persons who are overweight (BMI >25) or obese (BMI >30) can significantly reduce the risk of hypertension, hyperlipidemia, hyperglycemia, and death.⁷

Rather than promoting a single diet, tailor dietary advice to each patient’s metabolic abnormalities (Table 3). Although researchers disagree over whether a low-fat or low-carbohydrate diet produces better results, either diet will work as long as the patient consumes fewer calories than he or she expends. This is because weight loss alone reverses metabolic syndrome.

Likewise, exercise can reverse metabolic syndrome independent of diet change. Regular exercise at modest levels improves HDL,² triglycerides,¹⁷ blood pressure,¹⁸ and hyperglycemia.¹⁹

In one prospective study,²⁰ 621 subjects without chronic disease or injury underwent supervised aerobic training three times weekly for 20 weeks. Participants were told not to otherwise change their health and lifestyle habits.

Of the 105 persons in the cohort who had metabolic syndrome at baseline, 32 (30%) no longer had it after the aerobics program. Among these participants:

• 43% had lower triglycerides than at baseline
• 16% had higher HDL cholesterol
• 38% had lower blood pressure
• 9% had improved fasting glucose
• 28% reduced their waist circumference.

Table 3

Interventions for specific metabolic complications

Selling the benefits of exercise and weight loss to a mentally ill patient can be difficult. Attention, memory, and motivation deficits as well as smoking and substance abuse often get in the way.

By teaming up with clinicians with expertise in dieting such as nurses, dietitians, and recreational therapists, psychiatrists can more effectively promote long-term diet, exercise, and lifestyle changes.²¹

In a prospective 12-month trial,²² 20 patients who were taking atypical antipsychotics for schizophrenia or schizoaffective disorder completed a 52-week program that incorporated nutrition, exercise, and behavioral interventions. Twenty similar patients received treatment as usual. Patients in the program saw significant improvements in weight, blood pressure, exercise habits, nutrition, and hemoglobin A1c compared with the treatment-as-usual group.²²

Psychiatrists who treat privately insured patients should collaborate with the patient’s primary care physician. Many insurance plans will pay for 1 or 2 personal or group sessions with a dietitian, especially if the patient is diagnosed as being obese (BMI >30). Some large plans, such as Kaiser Permanente, will cover intensive multimodal treatment, especially for patients with a BMI >35. Calculating the patient’s BMI can help you document the need for antiobesity treatment (see Related resources).

Medication. If weight control and exercise do not reduce metabolic risk factors after 3 to 6 months, consider switching to an atypical antipsychotic with a lower propensity for causing metabolic effects.

Which agents most decrease metabolic risk has been debated. Preliminary evidence indicates that switching from other antipsychotics to aripiprazole or ziprasidone may reduce weight and improve cholesterol ratios.^23,24 These findings are consistent with the ADA/APA consensus guidelines, which indicate that metabolic risk varies among atypical antipsychotics (Table 4).⁶

Table 4

Atypical antipsychotics and their propensity for causing metabolic abnormalities

Targeted pharmacotherapy. Wait another 3 to 6 months to see if the medication change and weight loss/exercise interventions reduce metabolic risk factors. If they don’t, work with the patient’s primary care physician to manage hypertension, dyslipidemia, and obesity (Table 3).

Although no agents are approved for treating metabolic syndrome per se, medications targeted at individual symptoms are becoming the standard of care. Controlling blood pressure, HDL, and LDL in patients with metabolic syndrome can reduce risk for coronary heart disease by >50%.²⁵ Insulin-sensitizing agents and metformin in combination with lifestyle changes or used alone have been shown to delay onset of type 2 diabetes (Table 3).

CASE CONTINUED: 10 LBS IN 10 WEEKS

At her follow-up visit, Ms. S and her psychiatrist discuss her increased risk for diabetes and cardiovascular disease. She meets criteria for metabolic syndrome (low HDL, elevated blood pressure, and increased waist circumference).

Ms. S agrees to try a formal diet program with set menus, along with group support at her local community center. She also commits to walking 30 minutes three to four times a week with a target heart rate of 100 beats per minute. Although both quetiapine and lithium carry considerable risk of weight gain, she and her psychiatrist decide to wait at least 3 months before considering a medication change, as she is stable on this combination.

Ms. S schedules a follow-up visit with her primary care physician to ensure that she sticks to her weight loss and exercise programs. In the interim, the primary care physician and psychiatrist agree that her goal will be to lose 10 lbs over 10 weeks.

Related resources

• National Alliance for the Mentally Ill. Hearts and Minds Program, a booklet and program geared toward raising awareness regarding diabetes, diet, exercise, and smoking. Download at www.nami.org.
• Centers for Disease Control and Prevention: Body mass index formula for adults. http://www.cdc.gov/nccdphp/dnpa/bmi/bmi-adult-formula.htm.
• National Heart, Lung and Blood Institute body mass index calculator. http://www.nhlbisupport.com/bmi/bmicalc.htm.
• Keck PE Jr, Buse JB, Dagago-Jack S, et al. Managing metabolic concerns in patients with severe mental illness. A special report. Postgraduate Med 2003;1-92.

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Metformin • Glucophage
• Olanzapine • Zyprexa
• Orlistat • Xenical
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sibutramine • Meridia
• Ziprasidone • Geodon

Disclosure

Dr. Bermudes is a speaker for Bristol-Myers Squibb Co. and Pfizer Inc.

At what point do the five risk factors that predict type 2 diabetes and cardiovascular disease (CVD) signal metabolic syndrome? When and how often should psychiatrists check for metabolic abnormalities? How can you manage metabolic problems caused by a psychotropic that controls the patient’s psychiatric symptoms?

This article answers those questions by addressing:

• clinical guidelines for diagnosing metabolic syndrome
• suggested intervals for monitoring at-risk patients
• strategies for managing metabolic abnormalities with lifestyle changes or medication.

CASE REPORT: 'FAT' AND FRUSTRATED

Ms. S, age 37, has had bipolar disorder for 10 years. She has tried numerous medications including mood stabilizers, antidepressants, and atypical antipsychotics. The combination of quetiapine, 200 mg bid, and lithium, 300 mg bid, has controlled her symptoms for the past 6 months.

Her weight has increased 40 lbs over the past decade; much of her weight gain has occurred since the birth of her two children, ages 4 and 6. At 5 feet, 3 inches and 170 lbs, she is frustrated over her weight gain, especially on the eve of her 20-year high school reunion. She is convinced that her medications have prevented weight loss.

Her waist, measured at the umbilicus, is 37 inches. Her body mass index (BMI) is 30—indicating clinical obesity—and her blood pressure is in the high normal range (134/80 mm Hg). She has not had gestational diabetes and has not seen a medical doctor since her last pregnancy, but her father has type 2 diabetes and hypertension. She drinks wine occasionally at social events and does not smoke.

The psychiatrist orders a fasting lipid panel and fasting glucose test to further assess her risk of heart disease. Total cholesterol and low-density lipoprotein (LDL) cholesterol are normal. Triglycerides are 125 mg/dL (normal) and her high-density lipoprotein (HDL) is 45 mg/dL—5 mg/dL below normal for a woman her age. Fasting glucose is 86 mg/dL (normal).

The psychiatrist schedules a visit the following month to assess her cardiac and diabetic risk and to discuss weight-loss interventions.

Discussion. In a busy clinical setting, the psychiatrist must accurately gauge Ms. S’ metabolic risk and devise a management strategy. Do her weight and low HDL suggest metabolic syndrome? Is she overeating or making unhealthy dietary choices, or are her psychotropics causing weight gain? Would switching psychotropics lead to bipolar relapse?

IMPLICATIONS OF METABOLIC SYNDROME

Patients with metabolic syndrome are at increased risk for:

• type 2 diabetes¹
• CVD²
• increased mortality from CVD and all causes.³

In a prospective study that followed 1,209 Finnish men over an average 11.4 years,⁴ men with metabolic syndrome were more likely than those with no metabolic problems to die from coronary heart disease, CVD, and any cause after adjustment for conventional cardiovascular risk factors. No one in either group had a baseline illness, suggesting that metabolic syndrome increases the risk of CVD or death regardless of whether underlying illness is present.

DEFINING METABOLIC SYNDROME

Metabolic syndrome is not a disease but a constellation of risk factors that provides a definable point of intervention before onset of type 2 diabetes or CVD.

According to the National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III), presence of three of these five criteria suggest metabolic syndrome:

• abdominal obesity
• insulin resistance
• high blood pressure
• elevated triglycerides
• below-normal HDL.

This definition offers a starting point for measuring risk factors in clinical practice and provides a definable target and parameters to avoid (Table 1).⁵ The guideline is also easy to follow: Waist circumference and blood pressure can be measured within seconds; blood glucose, HDL, and triglycerides can easily be measured before breakfast, after the patient has fasted for at least 6 hours.

Table 1

5 defined risk factors* for metabolic syndrome

MONITORING FREQUENCY

Although no empirical studies have addressed monitoring frequency for metabolic risk factors, several guidelines provide preliminary recommendations. Table 2 summarizes suggested intervals for monitoring weight, lipids, glucose, and waist circumference for patients taking atypical antipsychotics, based on recommendations from the 2004 American Diabetes Association (ADA) and American Psychiatric Association (APA) consensus development conference.⁶

Because atypicals are associated with serious metabolic risks, screen patients taking these agents for metabolic abnormalities at baseline and at regular intervals. Most guidelines recommend measuring blood pressure, BMI, waist circumference, fasting serum lipids (total, LDL, HDL, and triglycerides) and fasting glucose before starting or switching to an atypical and again 12 weeks later. Established risk for metabolic disturbances or dramatic metabolic changes (such as weight gain ≥7%, waist circumference ≥35 inches in women and ≥40 inches in men, or fasting blood sugars >110 mg/dL) demand more-frequent monitoring (ie, monitor high-risk patients quarterly).

Table 2

Suggested monitoring intervals for patients taking atypical antipsychotics*

MANAGING METABOLIC PROBLEMS

Managing metabolic abnormalities or metabolic syndrome is aimed at preventing type 2 diabetes and CVD. Levels of intervention include:

• weight management, weight control education, and promoting regular exercise and a healthy diet
• switching to a psychotropic that is less likely to cause weight gain, if clinically appropriate
• working with the patient’s primary care physician to manage dyslipidemia, hypertension, obesity, or hyperglycemia.

Weight management. Start by controlling weight and promoting regular exercise and healthy eating. Switching medications—often the first response—may not be the best option, particularly if the offending agent is relieving the patient’s psychiatric symptoms.

Losing weight, increasing exercise, and reducing fat and carbohydrate intake can reverse metabolic syndrome and delay onset of type 2 diabetes and CVD.⁷ Even a small weight loss, such as 10% of baseline body weight in persons who are overweight (BMI >25) or obese (BMI >30) can significantly reduce the risk of hypertension, hyperlipidemia, hyperglycemia, and death.⁷

Rather than promoting a single diet, tailor dietary advice to each patient’s metabolic abnormalities (Table 3). Although researchers disagree over whether a low-fat or low-carbohydrate diet produces better results, either diet will work as long as the patient consumes fewer calories than he or she expends. This is because weight loss alone reverses metabolic syndrome.

Likewise, exercise can reverse metabolic syndrome independent of diet change. Regular exercise at modest levels improves HDL,² triglycerides,¹⁷ blood pressure,¹⁸ and hyperglycemia.¹⁹

In one prospective study,²⁰ 621 subjects without chronic disease or injury underwent supervised aerobic training three times weekly for 20 weeks. Participants were told not to otherwise change their health and lifestyle habits.

Of the 105 persons in the cohort who had metabolic syndrome at baseline, 32 (30%) no longer had it after the aerobics program. Among these participants:

• 43% had lower triglycerides than at baseline
• 16% had higher HDL cholesterol
• 38% had lower blood pressure
• 9% had improved fasting glucose
• 28% reduced their waist circumference.

Table 3

Interventions for specific metabolic complications

Selling the benefits of exercise and weight loss to a mentally ill patient can be difficult. Attention, memory, and motivation deficits as well as smoking and substance abuse often get in the way.

By teaming up with clinicians with expertise in dieting such as nurses, dietitians, and recreational therapists, psychiatrists can more effectively promote long-term diet, exercise, and lifestyle changes.²¹

In a prospective 12-month trial,²² 20 patients who were taking atypical antipsychotics for schizophrenia or schizoaffective disorder completed a 52-week program that incorporated nutrition, exercise, and behavioral interventions. Twenty similar patients received treatment as usual. Patients in the program saw significant improvements in weight, blood pressure, exercise habits, nutrition, and hemoglobin A1c compared with the treatment-as-usual group.²²

Psychiatrists who treat privately insured patients should collaborate with the patient’s primary care physician. Many insurance plans will pay for 1 or 2 personal or group sessions with a dietitian, especially if the patient is diagnosed as being obese (BMI >30). Some large plans, such as Kaiser Permanente, will cover intensive multimodal treatment, especially for patients with a BMI >35. Calculating the patient’s BMI can help you document the need for antiobesity treatment (see Related resources).

Medication. If weight control and exercise do not reduce metabolic risk factors after 3 to 6 months, consider switching to an atypical antipsychotic with a lower propensity for causing metabolic effects.

Which agents most decrease metabolic risk has been debated. Preliminary evidence indicates that switching from other antipsychotics to aripiprazole or ziprasidone may reduce weight and improve cholesterol ratios.^23,24 These findings are consistent with the ADA/APA consensus guidelines, which indicate that metabolic risk varies among atypical antipsychotics (Table 4).⁶

Table 4

Atypical antipsychotics and their propensity for causing metabolic abnormalities

Targeted pharmacotherapy. Wait another 3 to 6 months to see if the medication change and weight loss/exercise interventions reduce metabolic risk factors. If they don’t, work with the patient’s primary care physician to manage hypertension, dyslipidemia, and obesity (Table 3).

Although no agents are approved for treating metabolic syndrome per se, medications targeted at individual symptoms are becoming the standard of care. Controlling blood pressure, HDL, and LDL in patients with metabolic syndrome can reduce risk for coronary heart disease by >50%.²⁵ Insulin-sensitizing agents and metformin in combination with lifestyle changes or used alone have been shown to delay onset of type 2 diabetes (Table 3).

CASE CONTINUED: 10 LBS IN 10 WEEKS

At her follow-up visit, Ms. S and her psychiatrist discuss her increased risk for diabetes and cardiovascular disease. She meets criteria for metabolic syndrome (low HDL, elevated blood pressure, and increased waist circumference).

Ms. S agrees to try a formal diet program with set menus, along with group support at her local community center. She also commits to walking 30 minutes three to four times a week with a target heart rate of 100 beats per minute. Although both quetiapine and lithium carry considerable risk of weight gain, she and her psychiatrist decide to wait at least 3 months before considering a medication change, as she is stable on this combination.

Ms. S schedules a follow-up visit with her primary care physician to ensure that she sticks to her weight loss and exercise programs. In the interim, the primary care physician and psychiatrist agree that her goal will be to lose 10 lbs over 10 weeks.

Related resources

• National Alliance for the Mentally Ill. Hearts and Minds Program, a booklet and program geared toward raising awareness regarding diabetes, diet, exercise, and smoking. Download at www.nami.org.
• Centers for Disease Control and Prevention: Body mass index formula for adults. http://www.cdc.gov/nccdphp/dnpa/bmi/bmi-adult-formula.htm.
• National Heart, Lung and Blood Institute body mass index calculator. http://www.nhlbisupport.com/bmi/bmicalc.htm.
• Keck PE Jr, Buse JB, Dagago-Jack S, et al. Managing metabolic concerns in patients with severe mental illness. A special report. Postgraduate Med 2003;1-92.

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Metformin • Glucophage
• Olanzapine • Zyprexa
• Orlistat • Xenical
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sibutramine • Meridia
• Ziprasidone • Geodon

Disclosure

Dr. Bermudes is a speaker for Bristol-Myers Squibb Co. and Pfizer Inc.

Psychiatrists commonly order thyroid testing and are often the first to confront abnormal thyroid test results. As thyroid testing has become more sophisticated and sensitive (Box 1), the interpretation and management of abnormal or slightly abnormal results has become increasingly complex. What’s more, older individuals, hospitalized patients, and those with psychiatric illness often present with subtle laboratory abnormalities.

Hyperthyroidism and hypothyroidism are highly prevalent disorders, especially in women and the elderly. Thyroid dysfunction is the second most common endocrine disorder after diabetes among elders. In the three cases that follow, some of the problems and solutions in dealing with thyroid testing are presented.

Case 1: Depression and thyroid abnormalities

J.R., 67, has a history of hypertension. She was referred for evaluation of depressive symptoms. She reports 3 months of increasing fatigue, lethargy, and poor motivation. Her weight has increased by 10 pounds over this period. Her physical exam, ECG, and chest x-ray are normal. She is well groomed and slightly overweight. Her medications have not changed recently and include hydrochlorothiazide 25 mg/d and an aspirin a day.

J.R. reports no history of treatment for psychiatric illness, denies current use of alcohol, tobacco, or illicit drugs, exhibits no abnormal movements or psychomotor changes, and her speech is articulate. Her mood is depressed, and her affect is restricted. She is not suicidal or homicidal, and her exam reveals no psychotic features.

Challenge Patients with thyroid abnormalities often present with psychiatric complaints. Classically, hypothyroidism can present like a depressive episode with similar symptoms of fatigue, anhedonia, weight gain, and sleep disturbance. Patients with hypothyroidism, however, may have physical complaints as well, which should alert the clinician to an underlying thyroid disorder. Typical physical complaints include hair loss, weight gain, dry skin, cold intolerance, constipation, muscle cramps, and joint pains. Women may also complain of menstrual disturbances such as menorrhagia, and may have trouble with fertility.

Box 1

What makes the diagnosis difficult and often missed is that some patients have hypothyroidism with minimal or no symptoms. This is especially true in elders because many of the signs and symptoms of hypothyroidism are attributed to “normal” aging. In one recent review of women older than 70 who were screened in an office-based setting, 2% were diagnosed with unsuspected overt hypothyroidism.¹ Because classical exam and laboratory findings associated with hypothyroidism tend to present later in the disorder, many patients with thyroid dysfunction have “normal” exams.

Exam findings associated with a hypo-functioning thyroid may include an enlarged thyroid gland (goiter) or nonpalpable gland, non-pitting edema (myxedema), sinus bradycardia, decrease in body temperature, and delayed relaxation of the deep tendon reflexes. Secondary laboratory abnormalities associated with hypothyroidism include normacytic anemia and elevated lipoproteins. Without specific thyroid testing, a “normal” physical does not rule out thyroid dysfunction.

Hyperthyroidism can also manifest as a depression in elders, known as “apathetic hyperthyroidism.” Patients report decreased cognition, depression, and fatigue, and often experience unexplained weight loss, muscle weakness, or atrial fibrillation. Therefore, elderly patients presenting with depression may have a hyper- or hypo-functioning thyroid.

Case 1 concluded The treating psychiatrist diagnosed the patient with major depression. In addition to treatment with an antidepressant, the patient underwent laboratory testing, including a complete blood count, metabolic panel, and TSH (thyroid stimulating hormone). Test results were normal except for a TSH of 64 mU/L, consistent with hypothyroidism. The patient was referred to her primary care physician to begin thyroid hormone replacement.

Comment Although psychiatric symptoms may be caused by clinically important thyroid dysfunction, thyroid function testing may uncover abnormalities of questionable clinical significance. The prevalence of abnormal thyroid hormone levels in hospitalized psychiatric patients ranges from 3% to 32%.² High thyroid levels (free T4 index and total T4) are associated with acutely psychotic patients such as those with schizophrenia, affective psychosis, and amphetamine abuses. Most studies show that these changes are transient and often normalize with correction of the psychiatric condition, usually within 10 days. Many researchers believe these findings are consistent with euthyroid sick syndrome (Box 2).³

Depressed patients and those with bipolar disorder often present with altered measures of the hypothalamic-pituitary-thyroid (HPT) axis. These abnormalities include mildly elevated or depressed T3, T4 and TSH levels and are not indicative of true thyroid dysfunction (Table 1). It has been debated whether these patients differ in prognosis from psychiatric patients without such abnormalities, although data in depressed patients suggest equivalent outcomes.⁴ Furthermore, there is no clear evidence that thyroid supplementation benefits depressed patients with mildly elevated TSH with normal T4 and T3 values.⁵

The prevalence of thyroid disorders in the general population depends largely on the age, sex, and iodine consumption of the population studied. Women in general face a greater risk of overt thyroid dysfunction than do men, and elders face a greater risk than do the young. High dietary iodine consumption is associated with autoimmune hypothyroidism, especially in the aged. Iodine deficiency facilitates the development of hyperthyroidism secondary to toxic nodular goiter.

Table 1

INTERPRETING TEST RESULTS

A number of other risk factors should also clue the clinician to thyroid dysfunction (Table 2).

Case 2: Subclinical thyroid abnormalities

S.J., 34, has a history of panic disorder that has been well controlled with a selective serotonin reuptake inhibitor (SSRI). He is referred to a primary care physician for an annual physical exam. His blood pressure is elevated as it has been on several occasions over the past year. His physical exam is otherwise normal. Laboratory and ECG test results are normal, except for an elevated TSH at 12 mU/L. Follow-up free T4 and free T3 tests are within normal limits. S.J. agrees to eat less salt to address his hypertension.

Challenge An elevated or decreased TSH with a normal thyroxine level (Table 1) is referred to as a “subclinical” thyroid disorder, which is more common than overt thyroid disorders. Women and elders are at greatest risk for subclinical hypothyroidism. In patients older than 60, the rate can be as high as 17% in women and 15% in men.⁶ The rate largely depends on the number of patients receiving exogenous thyroid hormone—16% in populations including individuals receiving exogenous thyroid hormone and as low as 0.6-1.1% in populations without such patients.¹ Chronic subclinical hypothyroidism or mild thyroid failure is the most common condition found in thyroid function screening.

Table 2

WHEN TO CONSIDER THYROID DYSFUNCTION

Although patients with subclinical abnormalities appear to be symptom-free, there are clinical implications for these patients. Subclinical hyperthyroidism in the elderly increases the risk for atrial fibrillation and osteoporosis. Postmenopausal women with chronically low TSH measures have lower bone density, especially in cortical bone (e.g., the forearm and hip). Subclinical hypothyroidism is associated with lipid abnormalities and progression to overt hypothyroidism. More recently it has become apparent that this “subclinical” syndrome is not as symptom-free as once assumed, with dry skin, cold intolerance, and easy fatigability more common than in euthyroid patients.⁷

Case 2 concluded Three months later, repeat testing reveals a negative thyroid antibody test, a TSH elevated to 9 mU/L, and a free T4 and fasting lipid profile within normal limits. S.J. and his physician discuss the pros and cons of thyroid replacement and decide to retest his thyroid function in 6 months with a repeat TSH.

Comment Should individuals with subclinical disorders be treated? How frequently should their thyroid function tests be monitored? The answers vary greatly among clinicians.

Some experts argue that treatment improves behavioral function and decreases lipid levels. Some clinicians take a “wait and see” approach because values can normalize in approximately 10% of patients.^6,8 Others treat based on presence of symptoms and risk of progression to overt thyroid failure (Table 2). If treatment is elected, only partial supplementation is usually needed. Most clinicians will start with a dose of 25 ug/d of T4 with adjustment every 6 to 8 weeks until the TSH is normalized.

Unless subclinical hyperthyroidism is secondary to over-replacement with exogenous thyroid hormone, this condtion can be more difficult to treat than subclinical hypothyroidism. Antithyroid therapy should be discussed with patients who have symptoms suggestive of hyperthyroidism, osteoporosis, recurrent atrial fibrillation, or thyroid gland nodules. Consultation with an endocrinologist can help clarify the risks and benefits and determine the specific antithyroid treatment appropriate for each patient.

Case 3: Medications and thyroid abnormalities

R.K., 56, has a long history of bipolar disorder. Upon presenting to his psychiatrist for routine follow-up, he reports a lack of energy but denies other symptoms of mania or depression. He periodically leaves work early or takes a short nap in his office to combat the fatigue. He feels that this may simply be part of “getting old.” He denies any new medical problems and has seen his family physician in the last year. He states that he has been compliant with his medications, lithium and olanzapine. He appears slightly withdrawn and blunted but otherwise there are no abnormal features.

His lithium level, thyroid function, or kidney function had not been checked for 7 months. Subsequent testing reveals an elevated TSH (50 mU/L), a normal kidney profile, and a lithium level in the therapeutic range.

Challenge In psychiatric settings, lithium carbonate is the drug most commonly associated with decreased thyroid function. Lithium interferes with both thyroid hormone synthesis and secretion. One-half of those taking lithium chronically develop goiter, and 40% develop subclinical or overt hypothyroidism.^9-11

Many patients treated with lithium test positive for antithyroid antibodies. It is unclear if this finding represents a chronic autoimmune thyroiditis or is secondary to lithium treatment itself. In any case, patients taking lithium face an increased risk of thyroid failure. Other risk factors for thyroid failure include female gender and duration of treatment. Lithium dosage does not seem to be related to risk.

Clinicians differ on the frequency of thyroid monitoring for patients taking lithium. For patients without a history of thyroid dysfunction, annual TSH testing is likely sufficient.

Other medications affecting thyroid hormone production include methimazole, propylthiouracil, and iodide-containing drugs and dyes. Methimazole and propylthiouracil are given to patients intentionally with overt hyperthyroidism and interfere with hormone synthesis. Patients receiving medications or dyes containing iodide may also be susceptible to hypothyroidism. These agents are partially deiodinated after they are given and therefore can cause transient or prolonged decreases in thyroid production.

Box 2

Some oral cholecystographic agents and the antiarrhythmic medication amiodarone are excreted slowly and can be associated with more prolonged decreases in thyroid hormone production. Iodide and medications containing iodide may precipitate a longer enduring hypothyroidism in patients with chronic autoimmune thyroiditis and in those with hyperthyroidism who have received radioactive iodine therapy or have undergone partial thyroidectomy.

The cholesterol-lowering bile acid sequestrants colestipol and cholestyramine can also inhibit thyroid reabsorption from the intestine, potentially leading to hypothyroidism. Patients dependent on exogenous T4 or who have an underlying decreased thyroid function may develop hypothyroidism.

Table 3

WHICH MEDICATIONS CAN CAUSE THYROID DYSFUNCTION?

Drugs that alter thyroid hormone metabolism can also be problematic. Although thyroid hormone is metabolized mostly by deiodination, it also undergoes glucuronidation and sulfation. Phenobarbital, rifampin, phenytoin, and carbamazepine all increase T4 and T3 metabolism by inducing these hepatic enzymes. In patients with no thyroid disease, phenytoin and carbamazepine can decrease circulating free T4 levels by 20% to 40%.¹² Patients receiving T4 replacement may need their dosage increased or risk hypothyroidism if placed on one of these medications (Table 3).

Several medications alter total T4 and T3 levels by increasing or decreasing thyroid-binding proteins. Examples include estrogens, androgens, anabolic steroids, methadone, and heroin. Most thyroid hormone circulates as bound, but it is the unbound form that is active in peripheral tissues. Patients thus can experience changes in the binding proteins, while the proportion of unbound (“free”) hormone at the tissue level remains unaffected.

Because this unbound form remains relatively unchanged, the patient with normal thyroid function remains euthyroid despite alterations in total thyroid levels. When patients with hypothyroidism start one of these medications, their replacement hormone dosage may need to be adjusted.

Related resources

• American Association of Clinical Endocrinologists. www.aace.com
• Clinical practice guidelines for evaluation and treatment of hypothyroidism and hyperthyroidism. Position statement on subclinical hypothyroidism and pregnancy
• Thyroid Federation International. www.thyroid-fed.org
• Online videos regarding thyroid disease (patient-directed). Patient handouts on thyroid disease
• Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill; 2001:2060-84

Drug brand names

• Amiodorone • Pacerone, Cordarone
• Colestipol • Colestid
• Methimazole • Tapazole
• Olanzapine • Zyprexa, Zyprexa Zydis
• Rifampin • Rifadin, Rimactane

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article.

Psychiatrists commonly order thyroid testing and are often the first to confront abnormal thyroid test results. As thyroid testing has become more sophisticated and sensitive (Box 1), the interpretation and management of abnormal or slightly abnormal results has become increasingly complex. What’s more, older individuals, hospitalized patients, and those with psychiatric illness often present with subtle laboratory abnormalities.

Hyperthyroidism and hypothyroidism are highly prevalent disorders, especially in women and the elderly. Thyroid dysfunction is the second most common endocrine disorder after diabetes among elders. In the three cases that follow, some of the problems and solutions in dealing with thyroid testing are presented.

Case 1: Depression and thyroid abnormalities

J.R., 67, has a history of hypertension. She was referred for evaluation of depressive symptoms. She reports 3 months of increasing fatigue, lethargy, and poor motivation. Her weight has increased by 10 pounds over this period. Her physical exam, ECG, and chest x-ray are normal. She is well groomed and slightly overweight. Her medications have not changed recently and include hydrochlorothiazide 25 mg/d and an aspirin a day.

J.R. reports no history of treatment for psychiatric illness, denies current use of alcohol, tobacco, or illicit drugs, exhibits no abnormal movements or psychomotor changes, and her speech is articulate. Her mood is depressed, and her affect is restricted. She is not suicidal or homicidal, and her exam reveals no psychotic features.

Challenge Patients with thyroid abnormalities often present with psychiatric complaints. Classically, hypothyroidism can present like a depressive episode with similar symptoms of fatigue, anhedonia, weight gain, and sleep disturbance. Patients with hypothyroidism, however, may have physical complaints as well, which should alert the clinician to an underlying thyroid disorder. Typical physical complaints include hair loss, weight gain, dry skin, cold intolerance, constipation, muscle cramps, and joint pains. Women may also complain of menstrual disturbances such as menorrhagia, and may have trouble with fertility.

Box 1

What makes the diagnosis difficult and often missed is that some patients have hypothyroidism with minimal or no symptoms. This is especially true in elders because many of the signs and symptoms of hypothyroidism are attributed to “normal” aging. In one recent review of women older than 70 who were screened in an office-based setting, 2% were diagnosed with unsuspected overt hypothyroidism.¹ Because classical exam and laboratory findings associated with hypothyroidism tend to present later in the disorder, many patients with thyroid dysfunction have “normal” exams.

Exam findings associated with a hypo-functioning thyroid may include an enlarged thyroid gland (goiter) or nonpalpable gland, non-pitting edema (myxedema), sinus bradycardia, decrease in body temperature, and delayed relaxation of the deep tendon reflexes. Secondary laboratory abnormalities associated with hypothyroidism include normacytic anemia and elevated lipoproteins. Without specific thyroid testing, a “normal” physical does not rule out thyroid dysfunction.

Hyperthyroidism can also manifest as a depression in elders, known as “apathetic hyperthyroidism.” Patients report decreased cognition, depression, and fatigue, and often experience unexplained weight loss, muscle weakness, or atrial fibrillation. Therefore, elderly patients presenting with depression may have a hyper- or hypo-functioning thyroid.

Case 1 concluded The treating psychiatrist diagnosed the patient with major depression. In addition to treatment with an antidepressant, the patient underwent laboratory testing, including a complete blood count, metabolic panel, and TSH (thyroid stimulating hormone). Test results were normal except for a TSH of 64 mU/L, consistent with hypothyroidism. The patient was referred to her primary care physician to begin thyroid hormone replacement.

Comment Although psychiatric symptoms may be caused by clinically important thyroid dysfunction, thyroid function testing may uncover abnormalities of questionable clinical significance. The prevalence of abnormal thyroid hormone levels in hospitalized psychiatric patients ranges from 3% to 32%.² High thyroid levels (free T4 index and total T4) are associated with acutely psychotic patients such as those with schizophrenia, affective psychosis, and amphetamine abuses. Most studies show that these changes are transient and often normalize with correction of the psychiatric condition, usually within 10 days. Many researchers believe these findings are consistent with euthyroid sick syndrome (Box 2).³

Depressed patients and those with bipolar disorder often present with altered measures of the hypothalamic-pituitary-thyroid (HPT) axis. These abnormalities include mildly elevated or depressed T3, T4 and TSH levels and are not indicative of true thyroid dysfunction (Table 1). It has been debated whether these patients differ in prognosis from psychiatric patients without such abnormalities, although data in depressed patients suggest equivalent outcomes.⁴ Furthermore, there is no clear evidence that thyroid supplementation benefits depressed patients with mildly elevated TSH with normal T4 and T3 values.⁵

The prevalence of thyroid disorders in the general population depends largely on the age, sex, and iodine consumption of the population studied. Women in general face a greater risk of overt thyroid dysfunction than do men, and elders face a greater risk than do the young. High dietary iodine consumption is associated with autoimmune hypothyroidism, especially in the aged. Iodine deficiency facilitates the development of hyperthyroidism secondary to toxic nodular goiter.

Table 1

INTERPRETING TEST RESULTS

A number of other risk factors should also clue the clinician to thyroid dysfunction (Table 2).

Case 2: Subclinical thyroid abnormalities

S.J., 34, has a history of panic disorder that has been well controlled with a selective serotonin reuptake inhibitor (SSRI). He is referred to a primary care physician for an annual physical exam. His blood pressure is elevated as it has been on several occasions over the past year. His physical exam is otherwise normal. Laboratory and ECG test results are normal, except for an elevated TSH at 12 mU/L. Follow-up free T4 and free T3 tests are within normal limits. S.J. agrees to eat less salt to address his hypertension.

Challenge An elevated or decreased TSH with a normal thyroxine level (Table 1) is referred to as a “subclinical” thyroid disorder, which is more common than overt thyroid disorders. Women and elders are at greatest risk for subclinical hypothyroidism. In patients older than 60, the rate can be as high as 17% in women and 15% in men.⁶ The rate largely depends on the number of patients receiving exogenous thyroid hormone—16% in populations including individuals receiving exogenous thyroid hormone and as low as 0.6-1.1% in populations without such patients.¹ Chronic subclinical hypothyroidism or mild thyroid failure is the most common condition found in thyroid function screening.

Table 2

WHEN TO CONSIDER THYROID DYSFUNCTION

Although patients with subclinical abnormalities appear to be symptom-free, there are clinical implications for these patients. Subclinical hyperthyroidism in the elderly increases the risk for atrial fibrillation and osteoporosis. Postmenopausal women with chronically low TSH measures have lower bone density, especially in cortical bone (e.g., the forearm and hip). Subclinical hypothyroidism is associated with lipid abnormalities and progression to overt hypothyroidism. More recently it has become apparent that this “subclinical” syndrome is not as symptom-free as once assumed, with dry skin, cold intolerance, and easy fatigability more common than in euthyroid patients.⁷

Case 2 concluded Three months later, repeat testing reveals a negative thyroid antibody test, a TSH elevated to 9 mU/L, and a free T4 and fasting lipid profile within normal limits. S.J. and his physician discuss the pros and cons of thyroid replacement and decide to retest his thyroid function in 6 months with a repeat TSH.

Comment Should individuals with subclinical disorders be treated? How frequently should their thyroid function tests be monitored? The answers vary greatly among clinicians.

Some experts argue that treatment improves behavioral function and decreases lipid levels. Some clinicians take a “wait and see” approach because values can normalize in approximately 10% of patients.^6,8 Others treat based on presence of symptoms and risk of progression to overt thyroid failure (Table 2). If treatment is elected, only partial supplementation is usually needed. Most clinicians will start with a dose of 25 ug/d of T4 with adjustment every 6 to 8 weeks until the TSH is normalized.

Unless subclinical hyperthyroidism is secondary to over-replacement with exogenous thyroid hormone, this condtion can be more difficult to treat than subclinical hypothyroidism. Antithyroid therapy should be discussed with patients who have symptoms suggestive of hyperthyroidism, osteoporosis, recurrent atrial fibrillation, or thyroid gland nodules. Consultation with an endocrinologist can help clarify the risks and benefits and determine the specific antithyroid treatment appropriate for each patient.

Case 3: Medications and thyroid abnormalities

R.K., 56, has a long history of bipolar disorder. Upon presenting to his psychiatrist for routine follow-up, he reports a lack of energy but denies other symptoms of mania or depression. He periodically leaves work early or takes a short nap in his office to combat the fatigue. He feels that this may simply be part of “getting old.” He denies any new medical problems and has seen his family physician in the last year. He states that he has been compliant with his medications, lithium and olanzapine. He appears slightly withdrawn and blunted but otherwise there are no abnormal features.

His lithium level, thyroid function, or kidney function had not been checked for 7 months. Subsequent testing reveals an elevated TSH (50 mU/L), a normal kidney profile, and a lithium level in the therapeutic range.

Challenge In psychiatric settings, lithium carbonate is the drug most commonly associated with decreased thyroid function. Lithium interferes with both thyroid hormone synthesis and secretion. One-half of those taking lithium chronically develop goiter, and 40% develop subclinical or overt hypothyroidism.^9-11

Many patients treated with lithium test positive for antithyroid antibodies. It is unclear if this finding represents a chronic autoimmune thyroiditis or is secondary to lithium treatment itself. In any case, patients taking lithium face an increased risk of thyroid failure. Other risk factors for thyroid failure include female gender and duration of treatment. Lithium dosage does not seem to be related to risk.

Clinicians differ on the frequency of thyroid monitoring for patients taking lithium. For patients without a history of thyroid dysfunction, annual TSH testing is likely sufficient.

Other medications affecting thyroid hormone production include methimazole, propylthiouracil, and iodide-containing drugs and dyes. Methimazole and propylthiouracil are given to patients intentionally with overt hyperthyroidism and interfere with hormone synthesis. Patients receiving medications or dyes containing iodide may also be susceptible to hypothyroidism. These agents are partially deiodinated after they are given and therefore can cause transient or prolonged decreases in thyroid production.

Box 2

Some oral cholecystographic agents and the antiarrhythmic medication amiodarone are excreted slowly and can be associated with more prolonged decreases in thyroid hormone production. Iodide and medications containing iodide may precipitate a longer enduring hypothyroidism in patients with chronic autoimmune thyroiditis and in those with hyperthyroidism who have received radioactive iodine therapy or have undergone partial thyroidectomy.

The cholesterol-lowering bile acid sequestrants colestipol and cholestyramine can also inhibit thyroid reabsorption from the intestine, potentially leading to hypothyroidism. Patients dependent on exogenous T4 or who have an underlying decreased thyroid function may develop hypothyroidism.

Table 3

WHICH MEDICATIONS CAN CAUSE THYROID DYSFUNCTION?

Drugs that alter thyroid hormone metabolism can also be problematic. Although thyroid hormone is metabolized mostly by deiodination, it also undergoes glucuronidation and sulfation. Phenobarbital, rifampin, phenytoin, and carbamazepine all increase T4 and T3 metabolism by inducing these hepatic enzymes. In patients with no thyroid disease, phenytoin and carbamazepine can decrease circulating free T4 levels by 20% to 40%.¹² Patients receiving T4 replacement may need their dosage increased or risk hypothyroidism if placed on one of these medications (Table 3).

Several medications alter total T4 and T3 levels by increasing or decreasing thyroid-binding proteins. Examples include estrogens, androgens, anabolic steroids, methadone, and heroin. Most thyroid hormone circulates as bound, but it is the unbound form that is active in peripheral tissues. Patients thus can experience changes in the binding proteins, while the proportion of unbound (“free”) hormone at the tissue level remains unaffected.

Because this unbound form remains relatively unchanged, the patient with normal thyroid function remains euthyroid despite alterations in total thyroid levels. When patients with hypothyroidism start one of these medications, their replacement hormone dosage may need to be adjusted.

Related resources

• American Association of Clinical Endocrinologists. www.aace.com
• Clinical practice guidelines for evaluation and treatment of hypothyroidism and hyperthyroidism. Position statement on subclinical hypothyroidism and pregnancy
• Thyroid Federation International. www.thyroid-fed.org
• Online videos regarding thyroid disease (patient-directed). Patient handouts on thyroid disease
• Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill; 2001:2060-84

Drug brand names

• Amiodorone • Pacerone, Cordarone
• Colestipol • Colestid
• Methimazole • Tapazole
• Olanzapine • Zyprexa, Zyprexa Zydis
• Rifampin • Rifadin, Rimactane

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article.

Psychiatrists commonly order thyroid testing and are often the first to confront abnormal thyroid test results. As thyroid testing has become more sophisticated and sensitive (Box 1), the interpretation and management of abnormal or slightly abnormal results has become increasingly complex. What’s more, older individuals, hospitalized patients, and those with psychiatric illness often present with subtle laboratory abnormalities.

Hyperthyroidism and hypothyroidism are highly prevalent disorders, especially in women and the elderly. Thyroid dysfunction is the second most common endocrine disorder after diabetes among elders. In the three cases that follow, some of the problems and solutions in dealing with thyroid testing are presented.

Case 1: Depression and thyroid abnormalities

J.R., 67, has a history of hypertension. She was referred for evaluation of depressive symptoms. She reports 3 months of increasing fatigue, lethargy, and poor motivation. Her weight has increased by 10 pounds over this period. Her physical exam, ECG, and chest x-ray are normal. She is well groomed and slightly overweight. Her medications have not changed recently and include hydrochlorothiazide 25 mg/d and an aspirin a day.

J.R. reports no history of treatment for psychiatric illness, denies current use of alcohol, tobacco, or illicit drugs, exhibits no abnormal movements or psychomotor changes, and her speech is articulate. Her mood is depressed, and her affect is restricted. She is not suicidal or homicidal, and her exam reveals no psychotic features.

Challenge Patients with thyroid abnormalities often present with psychiatric complaints. Classically, hypothyroidism can present like a depressive episode with similar symptoms of fatigue, anhedonia, weight gain, and sleep disturbance. Patients with hypothyroidism, however, may have physical complaints as well, which should alert the clinician to an underlying thyroid disorder. Typical physical complaints include hair loss, weight gain, dry skin, cold intolerance, constipation, muscle cramps, and joint pains. Women may also complain of menstrual disturbances such as menorrhagia, and may have trouble with fertility.

Box 1

What makes the diagnosis difficult and often missed is that some patients have hypothyroidism with minimal or no symptoms. This is especially true in elders because many of the signs and symptoms of hypothyroidism are attributed to “normal” aging. In one recent review of women older than 70 who were screened in an office-based setting, 2% were diagnosed with unsuspected overt hypothyroidism.¹ Because classical exam and laboratory findings associated with hypothyroidism tend to present later in the disorder, many patients with thyroid dysfunction have “normal” exams.

Exam findings associated with a hypo-functioning thyroid may include an enlarged thyroid gland (goiter) or nonpalpable gland, non-pitting edema (myxedema), sinus bradycardia, decrease in body temperature, and delayed relaxation of the deep tendon reflexes. Secondary laboratory abnormalities associated with hypothyroidism include normacytic anemia and elevated lipoproteins. Without specific thyroid testing, a “normal” physical does not rule out thyroid dysfunction.

Hyperthyroidism can also manifest as a depression in elders, known as “apathetic hyperthyroidism.” Patients report decreased cognition, depression, and fatigue, and often experience unexplained weight loss, muscle weakness, or atrial fibrillation. Therefore, elderly patients presenting with depression may have a hyper- or hypo-functioning thyroid.

Case 1 concluded The treating psychiatrist diagnosed the patient with major depression. In addition to treatment with an antidepressant, the patient underwent laboratory testing, including a complete blood count, metabolic panel, and TSH (thyroid stimulating hormone). Test results were normal except for a TSH of 64 mU/L, consistent with hypothyroidism. The patient was referred to her primary care physician to begin thyroid hormone replacement.

Comment Although psychiatric symptoms may be caused by clinically important thyroid dysfunction, thyroid function testing may uncover abnormalities of questionable clinical significance. The prevalence of abnormal thyroid hormone levels in hospitalized psychiatric patients ranges from 3% to 32%.² High thyroid levels (free T4 index and total T4) are associated with acutely psychotic patients such as those with schizophrenia, affective psychosis, and amphetamine abuses. Most studies show that these changes are transient and often normalize with correction of the psychiatric condition, usually within 10 days. Many researchers believe these findings are consistent with euthyroid sick syndrome (Box 2).³

Depressed patients and those with bipolar disorder often present with altered measures of the hypothalamic-pituitary-thyroid (HPT) axis. These abnormalities include mildly elevated or depressed T3, T4 and TSH levels and are not indicative of true thyroid dysfunction (Table 1). It has been debated whether these patients differ in prognosis from psychiatric patients without such abnormalities, although data in depressed patients suggest equivalent outcomes.⁴ Furthermore, there is no clear evidence that thyroid supplementation benefits depressed patients with mildly elevated TSH with normal T4 and T3 values.⁵

The prevalence of thyroid disorders in the general population depends largely on the age, sex, and iodine consumption of the population studied. Women in general face a greater risk of overt thyroid dysfunction than do men, and elders face a greater risk than do the young. High dietary iodine consumption is associated with autoimmune hypothyroidism, especially in the aged. Iodine deficiency facilitates the development of hyperthyroidism secondary to toxic nodular goiter.

Table 1

INTERPRETING TEST RESULTS

A number of other risk factors should also clue the clinician to thyroid dysfunction (Table 2).

Case 2: Subclinical thyroid abnormalities

S.J., 34, has a history of panic disorder that has been well controlled with a selective serotonin reuptake inhibitor (SSRI). He is referred to a primary care physician for an annual physical exam. His blood pressure is elevated as it has been on several occasions over the past year. His physical exam is otherwise normal. Laboratory and ECG test results are normal, except for an elevated TSH at 12 mU/L. Follow-up free T4 and free T3 tests are within normal limits. S.J. agrees to eat less salt to address his hypertension.

Challenge An elevated or decreased TSH with a normal thyroxine level (Table 1) is referred to as a “subclinical” thyroid disorder, which is more common than overt thyroid disorders. Women and elders are at greatest risk for subclinical hypothyroidism. In patients older than 60, the rate can be as high as 17% in women and 15% in men.⁶ The rate largely depends on the number of patients receiving exogenous thyroid hormone—16% in populations including individuals receiving exogenous thyroid hormone and as low as 0.6-1.1% in populations without such patients.¹ Chronic subclinical hypothyroidism or mild thyroid failure is the most common condition found in thyroid function screening.

Table 2

WHEN TO CONSIDER THYROID DYSFUNCTION

Although patients with subclinical abnormalities appear to be symptom-free, there are clinical implications for these patients. Subclinical hyperthyroidism in the elderly increases the risk for atrial fibrillation and osteoporosis. Postmenopausal women with chronically low TSH measures have lower bone density, especially in cortical bone (e.g., the forearm and hip). Subclinical hypothyroidism is associated with lipid abnormalities and progression to overt hypothyroidism. More recently it has become apparent that this “subclinical” syndrome is not as symptom-free as once assumed, with dry skin, cold intolerance, and easy fatigability more common than in euthyroid patients.⁷

Case 2 concluded Three months later, repeat testing reveals a negative thyroid antibody test, a TSH elevated to 9 mU/L, and a free T4 and fasting lipid profile within normal limits. S.J. and his physician discuss the pros and cons of thyroid replacement and decide to retest his thyroid function in 6 months with a repeat TSH.

Comment Should individuals with subclinical disorders be treated? How frequently should their thyroid function tests be monitored? The answers vary greatly among clinicians.

Some experts argue that treatment improves behavioral function and decreases lipid levels. Some clinicians take a “wait and see” approach because values can normalize in approximately 10% of patients.^6,8 Others treat based on presence of symptoms and risk of progression to overt thyroid failure (Table 2). If treatment is elected, only partial supplementation is usually needed. Most clinicians will start with a dose of 25 ug/d of T4 with adjustment every 6 to 8 weeks until the TSH is normalized.

Unless subclinical hyperthyroidism is secondary to over-replacement with exogenous thyroid hormone, this condtion can be more difficult to treat than subclinical hypothyroidism. Antithyroid therapy should be discussed with patients who have symptoms suggestive of hyperthyroidism, osteoporosis, recurrent atrial fibrillation, or thyroid gland nodules. Consultation with an endocrinologist can help clarify the risks and benefits and determine the specific antithyroid treatment appropriate for each patient.

Case 3: Medications and thyroid abnormalities

R.K., 56, has a long history of bipolar disorder. Upon presenting to his psychiatrist for routine follow-up, he reports a lack of energy but denies other symptoms of mania or depression. He periodically leaves work early or takes a short nap in his office to combat the fatigue. He feels that this may simply be part of “getting old.” He denies any new medical problems and has seen his family physician in the last year. He states that he has been compliant with his medications, lithium and olanzapine. He appears slightly withdrawn and blunted but otherwise there are no abnormal features.

His lithium level, thyroid function, or kidney function had not been checked for 7 months. Subsequent testing reveals an elevated TSH (50 mU/L), a normal kidney profile, and a lithium level in the therapeutic range.

Challenge In psychiatric settings, lithium carbonate is the drug most commonly associated with decreased thyroid function. Lithium interferes with both thyroid hormone synthesis and secretion. One-half of those taking lithium chronically develop goiter, and 40% develop subclinical or overt hypothyroidism.^9-11

Many patients treated with lithium test positive for antithyroid antibodies. It is unclear if this finding represents a chronic autoimmune thyroiditis or is secondary to lithium treatment itself. In any case, patients taking lithium face an increased risk of thyroid failure. Other risk factors for thyroid failure include female gender and duration of treatment. Lithium dosage does not seem to be related to risk.

Clinicians differ on the frequency of thyroid monitoring for patients taking lithium. For patients without a history of thyroid dysfunction, annual TSH testing is likely sufficient.

Other medications affecting thyroid hormone production include methimazole, propylthiouracil, and iodide-containing drugs and dyes. Methimazole and propylthiouracil are given to patients intentionally with overt hyperthyroidism and interfere with hormone synthesis. Patients receiving medications or dyes containing iodide may also be susceptible to hypothyroidism. These agents are partially deiodinated after they are given and therefore can cause transient or prolonged decreases in thyroid production.

Box 2

Some oral cholecystographic agents and the antiarrhythmic medication amiodarone are excreted slowly and can be associated with more prolonged decreases in thyroid hormone production. Iodide and medications containing iodide may precipitate a longer enduring hypothyroidism in patients with chronic autoimmune thyroiditis and in those with hyperthyroidism who have received radioactive iodine therapy or have undergone partial thyroidectomy.

The cholesterol-lowering bile acid sequestrants colestipol and cholestyramine can also inhibit thyroid reabsorption from the intestine, potentially leading to hypothyroidism. Patients dependent on exogenous T4 or who have an underlying decreased thyroid function may develop hypothyroidism.

Table 3

WHICH MEDICATIONS CAN CAUSE THYROID DYSFUNCTION?

Drugs that alter thyroid hormone metabolism can also be problematic. Although thyroid hormone is metabolized mostly by deiodination, it also undergoes glucuronidation and sulfation. Phenobarbital, rifampin, phenytoin, and carbamazepine all increase T4 and T3 metabolism by inducing these hepatic enzymes. In patients with no thyroid disease, phenytoin and carbamazepine can decrease circulating free T4 levels by 20% to 40%.¹² Patients receiving T4 replacement may need their dosage increased or risk hypothyroidism if placed on one of these medications (Table 3).

Several medications alter total T4 and T3 levels by increasing or decreasing thyroid-binding proteins. Examples include estrogens, androgens, anabolic steroids, methadone, and heroin. Most thyroid hormone circulates as bound, but it is the unbound form that is active in peripheral tissues. Patients thus can experience changes in the binding proteins, while the proportion of unbound (“free”) hormone at the tissue level remains unaffected.

Because this unbound form remains relatively unchanged, the patient with normal thyroid function remains euthyroid despite alterations in total thyroid levels. When patients with hypothyroidism start one of these medications, their replacement hormone dosage may need to be adjusted.

Related resources

• American Association of Clinical Endocrinologists. www.aace.com
• Clinical practice guidelines for evaluation and treatment of hypothyroidism and hyperthyroidism. Position statement on subclinical hypothyroidism and pregnancy
• Thyroid Federation International. www.thyroid-fed.org
• Online videos regarding thyroid disease (patient-directed). Patient handouts on thyroid disease
• Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill; 2001:2060-84

Drug brand names

• Amiodorone • Pacerone, Cordarone
• Colestipol • Colestid
• Methimazole • Tapazole
• Olanzapine • Zyprexa, Zyprexa Zydis
• Rifampin • Rifadin, Rimactane

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article.