Med/Psych Update

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Many endocrine disorders can manifest as depression, including relatively rare disorders such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (primary hyperaldosteronism) as well as common ones such as diabetes mellitus. Most clinicians do not routinely screen for adrenal disorders when evaluating depressed patients because the yield is low, but do screen for thyroid disease because these disorders often mimic depression. The following 3 cases from my practice illustrate some nuances of screening and treating depressed patients with suspected thyroid abnormalities.

CASE 1: Feeling ‘like an 80-year-old’

Ms. A, age 25, has a gastrointestinal stromal tumor (GIST) and states that she feels “like an 80-year-old woman.” She is sore all over with facial swelling, abdominal cramping, and fatigue. This feeling has worsened since she started chemotherapy with sunitinib for the GIST. Her Patient Health Questionnaire-9 (PHQ-9) score is 14 out of 27, indicating moderate depression. As part of a workup for her depression, what general laboratory tests would be most helpful?

Because Ms. A is of menstruating age, check hemoglobin/hematocrit levels to evaluate for anemia. Monitoring electrolytes would allow you to assess for hypernatremia/hyponatremia, hyperkalemia/hypokalemia, and impaired renal function, all of which could cause depressive symptoms. Depending on Ms. A’s habitus or risk of metabolic syndrome, a fasting blood glucose or hemoglobin A1C test to screen for diabetes mellitus might be valuable because depression may be associated with diabetes.¹ A1C is a preferred primary screening test for diabetes (≥6.5% constitutes a positive screen) based on revised clinical practice recommendations of the American Diabetes Association. A1C is available as an office-based test that requires just a drop of blood from a finger prick and does not require a fasting blood sample or a full laboratory analysis.

A popular test for a workup of depression is serum 25-hydroxyvitamin D [25(OH)D] (vitamin D), particularly for patients who live in areas with limited exposure to ultraviolet B radiation from sunlight.² In a study of older adults, vitamin D levels were 14% lower in patients with minor depression and 14% lower in patients with major depressive disorder compared with controls. This study suggests that depression severity is associated with decreased serum vitamin D levels,³ but the association between depression and vitamin D insufficiency and deficiency is unknown. Checking sex hormones also may be helpful depending on the patient’s symptoms, because testosterone deficiency in men and dehydroepiandrosterone deficiency in women can have a direct impact on a patient’s libido and overall sense of well-being. If repleted, improved levels of sex hormones can lead to a dramatic improvement in mood as well.

Because more than one-half of the estimated 27 million Americans with hyperthyroidism or hypothyroidism are undiagnosed, the American Thyroid Association recommends universal screening for thyroid dysfunction after age 35, with a recheck every 5 years.⁴ However, checking serum thyroid-stimulating hormone (TSH) levels this often may not be cost-effective. Typically, I do not follow this recommendation when assessing or treating asymptomatic individuals, but Ms. A has symptoms of hypothyroidism (Table 1) and is taking a medication—sunitinib—thought to be associated with hypothyroidism.⁵ Her serum TSH was very high (110 mIU/L; range 0.28 to 5.00) and her serum free T4 (FT4) was low (0.5 ng/dL; range 0.7 to 1.8). These values were consistent with overt hypothyroidism, defined as low FT4 and elevated TSH levels. This is in contrast to subclinical hypothyroidism (SH), which is defined as having an elevated serum TSH with normal thyroid hormone (T3 and T4) levels. SH presents in 5% of young patients (age <45) and increasingly is being diagnoses in older patients (age >55), who are most likely to suffer adverse effects in mood or cognition.⁶

Table 1

Hypothyroidism symptoms

CASE 1 CONTINUED: A classic case

Ms. A is started on a full levothyroxine replacement dose of 1.6 μg/kg/d. For hypothyroid patients who do not have cardiac symptoms, weight-based replacement is thought to be safe and more convenient than starting with a low dose and titrating up.⁷ Ms. A responds quickly. At 6-week follow-up—the recommended time interval for repeat thyroid lab testing after initiating thyroid replacement—her depressive symptoms are markedly improved and her PHQ-9 score is 6, indicating mild depression.

CASE 2: Chronic pain, low mood, and fatigue

Ms. B, age 62, has fibromyalgia and chronic back pain. She takes cyclobenzaprine, 5 mg 2 to 3 times daily, and oxycodone, 40 mg/d, and describes mild depressive symptoms when she presents for routine follow-up. Most of her complaints are related to chronic pain, but she has a history of low mood and fatigue. She says she was prescribed levothyroxine, but is unable to remember if she stopped taking it because of financial constraints or laboratory/clinical improvement. Her neurologist recently checked her serum TSH, which was elevated at 8.1 mIU/L. Is it best to restart thyroid replacement or wait 6 weeks and recheck her thyroid panel?

Mild SH typically is defined as TSH between 4.5 and 10 mIU/L. In contrast, TSH between 10 and 20 mIU/L is considered severe SH. Because Ms. B did not have prominent new symptoms, I felt it was reasonable to wait the recommended 6 weeks before rechecking her thyroid function. At follow-up, Ms. B’s TSH was 4.64 mIU/L and her FT4 was normal: 0.7 ng/dL. Thyroid replacement was not indicated because she did not have obvious symptoms and treating SH does not impact overall mood and cognition until TSH is ≥10 mIU/L.^8,9

CASE 2 CONTINUED: Prominent symptoms emerge

Ms. B returns several months later. Another clinician prescribed duloxetine, titrated from 30 mg to 60 mg, for worsening fibromyalgia. Her depressive symptoms are more prominent at this visit, and her PHQ-9 score has risen from 7 to 14, indicating moderate depression. She says previously she failed or poorly tolerated several antidepressants—fluoxetine, sertraline, and citalopram—but was hoping for a pharmacologic adjustment. Most evidence-based augmentation algorithms for treating major depression start with adding a second “traditional” antidepressant such as bupropion, then move to lithium, second-generation antipsychotics, or lamotrigine.¹⁰ But what about thyroid hormone augmentation?

Thyroid hormone often is on the lower rungs of depression treatment algorithms despite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial data. The data suggest triiodothyronine’s (T3) lower side effect burden and ease of use may offer an advantage over lithium augmentation for depressed patients who have failed several medication trials.¹¹ Liothyronine sodium (triiodothyronine) is a relatively benign medication with potential for augmentation when started at 25 to 50 mcg/d concurrently with antidepressants such as sertraline.¹² Unfortunately, most augmentation trials with T3 have been short-term—generally 4 to 8 weeks. In my practice, T3 has limited application; I use it mainly for patients with treatment-resistant depression who have failed several other treatments.

Lithium, the comparison medication to thyroid hormone in the third augmentation arm of the STAR*D trial, requires an annual check of thyroid function (TSH testing) to properly monitor for potential lithium-related hypothyroidism or thyroiditis. Hypothyroidism, for which thyroid replacement is required, with lithium therapy is common, affecting 8% to 27% of patients.¹³ Patients who rapidly gain weight at the beginning of lithium treatment seem to have a higher risk of developing hypothyroidism.¹³ However, the risk of developing lithium-induced hypothyroidism is tied to the length of treatment; the longer a patient has been treated with lithium, the greater the risk of developing lithium-induced hypothyroidism.

CASE 3: Unable to slow down

Mr. C, age 45, has a 20-year history of major depression controlled reasonably well with paroxetine, 40 mg. He presents with escalating anxiety, depression, and irritability. His wife is concerned about his overwhelming thoughts of death, especially because Mr. C’s father committed suicide 30 years ago under similar circumstances. Mr. C has been tremulous for the past month and has not been sleeping well. He feels like he is “in constant motion” and unable to slow down. He screens in the “highly likely” range for bipolar disorder on the Bipolar Spectrum Diagnostic Scale¹⁴ and is started on divalproex ER, 500 mg/d.

His thyroid function tests returns with a suppressed TSH of 0.03 mIU/L and an elevated FT4 of 3.26 ng/dL. Divalproex is discontinued and he is started on the beta blocker atenolol, 25 mg/d, to target his anxiety, tachycardia, and akathisia. TSH receptor antibody testing was positive, which, along with an abnormal radioactive iodine uptake scan, confirmed a diagnosis of Graves’ disease. He receives methimazole, 20 mg/d, as a temporizing measure. An endocrinologist completes a radioactive iodine (I-131) ablation procedure on Mr. C, which resolves his mood and anxiety symptoms.

Although hypothyroidism commonly is associated with depressive symptoms, hyperthyroidism also may present as depression. Most cases of overt hyperthyroidism are directly referred to an endocrinologist because when treating disorders such as Graves’ disease—the most common cause of hyperthyroidism, especially among women age 20 to 40—many nuclear medicine teams require the expert guidance of an endocrinologist before considering radioiodine ablation. Hyperthyroidism often is accompanied by psychiatric and somatic symptoms of an “overactive” nature (Table 2). However, older patients (age >65) with hyperthyroidism may develop apathetic hyperthyroidism, a subset that comprises approximately 10% to 15% of all hyperthyroidism cases in older adults.¹⁵ Rather than becoming nervous, jittery, and restless, patients with apathetic hyperthyroidism are depressed, lethargic, and weak, and may develop proximal myopathy or cardiomyopathy. It is essential to differentiate apathetic hyperthyroidism from typical hyperthyroidism because accurately diagnosing and treating apathetic hyperthyroidism will improve outcomes.¹⁵

Table 2

Hyperthyroidism symptoms

Using beta blockers to treat hyperthyroidism can help control tachycardia or palpitations, tremulousness, and anxiety that often are inherent in hyperthyroidism. But can beta blockers induce depressive symptoms? A 1-year prospective Dutch study of patients who had survived a myocardial infarction did not find evidence that beta blockers induced depressive symptoms.¹⁶ However, the long-term and high-dosage effects of beta blockers still are in question.¹⁶ In Mr. C’s case, beta blockers had only positive effects on his symptoms and did not exacerbate his depressive symptoms.

Related Resources

• National Women’s Health Resource Center, Inc. Thyroid disorders. www.healthywomen.org/condition/thyroid-disorders.
• American Thyroid Association. www.thyroid.org.
• American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/files/hypo-hyper.pdf.

Drug Brand Names

• Atenolol • Tenormin
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Cyclobenzaprine • Flexeril
• Divalproex ER • Depakote ER
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Levothyroxine • Levoxyl, Synthroid
• Liothyronine sodium • Cytomel, Triostat
• Lithium • Eskalith, Lithobid
• Methimazole • Tapazole
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sunitinib • Sutent

Disclosure

Dr. Raj is a speaker for AstraZeneca and Merck.

Discuss this article at www.facebook.com/CurrentPsychiatry

Many endocrine disorders can manifest as depression, including relatively rare disorders such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (primary hyperaldosteronism) as well as common ones such as diabetes mellitus. Most clinicians do not routinely screen for adrenal disorders when evaluating depressed patients because the yield is low, but do screen for thyroid disease because these disorders often mimic depression. The following 3 cases from my practice illustrate some nuances of screening and treating depressed patients with suspected thyroid abnormalities.

CASE 1: Feeling ‘like an 80-year-old’

Ms. A, age 25, has a gastrointestinal stromal tumor (GIST) and states that she feels “like an 80-year-old woman.” She is sore all over with facial swelling, abdominal cramping, and fatigue. This feeling has worsened since she started chemotherapy with sunitinib for the GIST. Her Patient Health Questionnaire-9 (PHQ-9) score is 14 out of 27, indicating moderate depression. As part of a workup for her depression, what general laboratory tests would be most helpful?

Because Ms. A is of menstruating age, check hemoglobin/hematocrit levels to evaluate for anemia. Monitoring electrolytes would allow you to assess for hypernatremia/hyponatremia, hyperkalemia/hypokalemia, and impaired renal function, all of which could cause depressive symptoms. Depending on Ms. A’s habitus or risk of metabolic syndrome, a fasting blood glucose or hemoglobin A1C test to screen for diabetes mellitus might be valuable because depression may be associated with diabetes.¹ A1C is a preferred primary screening test for diabetes (≥6.5% constitutes a positive screen) based on revised clinical practice recommendations of the American Diabetes Association. A1C is available as an office-based test that requires just a drop of blood from a finger prick and does not require a fasting blood sample or a full laboratory analysis.

A popular test for a workup of depression is serum 25-hydroxyvitamin D [25(OH)D] (vitamin D), particularly for patients who live in areas with limited exposure to ultraviolet B radiation from sunlight.² In a study of older adults, vitamin D levels were 14% lower in patients with minor depression and 14% lower in patients with major depressive disorder compared with controls. This study suggests that depression severity is associated with decreased serum vitamin D levels,³ but the association between depression and vitamin D insufficiency and deficiency is unknown. Checking sex hormones also may be helpful depending on the patient’s symptoms, because testosterone deficiency in men and dehydroepiandrosterone deficiency in women can have a direct impact on a patient’s libido and overall sense of well-being. If repleted, improved levels of sex hormones can lead to a dramatic improvement in mood as well.

Because more than one-half of the estimated 27 million Americans with hyperthyroidism or hypothyroidism are undiagnosed, the American Thyroid Association recommends universal screening for thyroid dysfunction after age 35, with a recheck every 5 years.⁴ However, checking serum thyroid-stimulating hormone (TSH) levels this often may not be cost-effective. Typically, I do not follow this recommendation when assessing or treating asymptomatic individuals, but Ms. A has symptoms of hypothyroidism (Table 1) and is taking a medication—sunitinib—thought to be associated with hypothyroidism.⁵ Her serum TSH was very high (110 mIU/L; range 0.28 to 5.00) and her serum free T4 (FT4) was low (0.5 ng/dL; range 0.7 to 1.8). These values were consistent with overt hypothyroidism, defined as low FT4 and elevated TSH levels. This is in contrast to subclinical hypothyroidism (SH), which is defined as having an elevated serum TSH with normal thyroid hormone (T3 and T4) levels. SH presents in 5% of young patients (age <45) and increasingly is being diagnoses in older patients (age >55), who are most likely to suffer adverse effects in mood or cognition.⁶

Table 1

Hypothyroidism symptoms

CASE 1 CONTINUED: A classic case

Ms. A is started on a full levothyroxine replacement dose of 1.6 μg/kg/d. For hypothyroid patients who do not have cardiac symptoms, weight-based replacement is thought to be safe and more convenient than starting with a low dose and titrating up.⁷ Ms. A responds quickly. At 6-week follow-up—the recommended time interval for repeat thyroid lab testing after initiating thyroid replacement—her depressive symptoms are markedly improved and her PHQ-9 score is 6, indicating mild depression.

CASE 2: Chronic pain, low mood, and fatigue

Ms. B, age 62, has fibromyalgia and chronic back pain. She takes cyclobenzaprine, 5 mg 2 to 3 times daily, and oxycodone, 40 mg/d, and describes mild depressive symptoms when she presents for routine follow-up. Most of her complaints are related to chronic pain, but she has a history of low mood and fatigue. She says she was prescribed levothyroxine, but is unable to remember if she stopped taking it because of financial constraints or laboratory/clinical improvement. Her neurologist recently checked her serum TSH, which was elevated at 8.1 mIU/L. Is it best to restart thyroid replacement or wait 6 weeks and recheck her thyroid panel?

Mild SH typically is defined as TSH between 4.5 and 10 mIU/L. In contrast, TSH between 10 and 20 mIU/L is considered severe SH. Because Ms. B did not have prominent new symptoms, I felt it was reasonable to wait the recommended 6 weeks before rechecking her thyroid function. At follow-up, Ms. B’s TSH was 4.64 mIU/L and her FT4 was normal: 0.7 ng/dL. Thyroid replacement was not indicated because she did not have obvious symptoms and treating SH does not impact overall mood and cognition until TSH is ≥10 mIU/L.^8,9

CASE 2 CONTINUED: Prominent symptoms emerge

Ms. B returns several months later. Another clinician prescribed duloxetine, titrated from 30 mg to 60 mg, for worsening fibromyalgia. Her depressive symptoms are more prominent at this visit, and her PHQ-9 score has risen from 7 to 14, indicating moderate depression. She says previously she failed or poorly tolerated several antidepressants—fluoxetine, sertraline, and citalopram—but was hoping for a pharmacologic adjustment. Most evidence-based augmentation algorithms for treating major depression start with adding a second “traditional” antidepressant such as bupropion, then move to lithium, second-generation antipsychotics, or lamotrigine.¹⁰ But what about thyroid hormone augmentation?

Thyroid hormone often is on the lower rungs of depression treatment algorithms despite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial data. The data suggest triiodothyronine’s (T3) lower side effect burden and ease of use may offer an advantage over lithium augmentation for depressed patients who have failed several medication trials.¹¹ Liothyronine sodium (triiodothyronine) is a relatively benign medication with potential for augmentation when started at 25 to 50 mcg/d concurrently with antidepressants such as sertraline.¹² Unfortunately, most augmentation trials with T3 have been short-term—generally 4 to 8 weeks. In my practice, T3 has limited application; I use it mainly for patients with treatment-resistant depression who have failed several other treatments.

Lithium, the comparison medication to thyroid hormone in the third augmentation arm of the STAR*D trial, requires an annual check of thyroid function (TSH testing) to properly monitor for potential lithium-related hypothyroidism or thyroiditis. Hypothyroidism, for which thyroid replacement is required, with lithium therapy is common, affecting 8% to 27% of patients.¹³ Patients who rapidly gain weight at the beginning of lithium treatment seem to have a higher risk of developing hypothyroidism.¹³ However, the risk of developing lithium-induced hypothyroidism is tied to the length of treatment; the longer a patient has been treated with lithium, the greater the risk of developing lithium-induced hypothyroidism.

CASE 3: Unable to slow down

Mr. C, age 45, has a 20-year history of major depression controlled reasonably well with paroxetine, 40 mg. He presents with escalating anxiety, depression, and irritability. His wife is concerned about his overwhelming thoughts of death, especially because Mr. C’s father committed suicide 30 years ago under similar circumstances. Mr. C has been tremulous for the past month and has not been sleeping well. He feels like he is “in constant motion” and unable to slow down. He screens in the “highly likely” range for bipolar disorder on the Bipolar Spectrum Diagnostic Scale¹⁴ and is started on divalproex ER, 500 mg/d.

His thyroid function tests returns with a suppressed TSH of 0.03 mIU/L and an elevated FT4 of 3.26 ng/dL. Divalproex is discontinued and he is started on the beta blocker atenolol, 25 mg/d, to target his anxiety, tachycardia, and akathisia. TSH receptor antibody testing was positive, which, along with an abnormal radioactive iodine uptake scan, confirmed a diagnosis of Graves’ disease. He receives methimazole, 20 mg/d, as a temporizing measure. An endocrinologist completes a radioactive iodine (I-131) ablation procedure on Mr. C, which resolves his mood and anxiety symptoms.

Although hypothyroidism commonly is associated with depressive symptoms, hyperthyroidism also may present as depression. Most cases of overt hyperthyroidism are directly referred to an endocrinologist because when treating disorders such as Graves’ disease—the most common cause of hyperthyroidism, especially among women age 20 to 40—many nuclear medicine teams require the expert guidance of an endocrinologist before considering radioiodine ablation. Hyperthyroidism often is accompanied by psychiatric and somatic symptoms of an “overactive” nature (Table 2). However, older patients (age >65) with hyperthyroidism may develop apathetic hyperthyroidism, a subset that comprises approximately 10% to 15% of all hyperthyroidism cases in older adults.¹⁵ Rather than becoming nervous, jittery, and restless, patients with apathetic hyperthyroidism are depressed, lethargic, and weak, and may develop proximal myopathy or cardiomyopathy. It is essential to differentiate apathetic hyperthyroidism from typical hyperthyroidism because accurately diagnosing and treating apathetic hyperthyroidism will improve outcomes.¹⁵

Table 2

Hyperthyroidism symptoms

Using beta blockers to treat hyperthyroidism can help control tachycardia or palpitations, tremulousness, and anxiety that often are inherent in hyperthyroidism. But can beta blockers induce depressive symptoms? A 1-year prospective Dutch study of patients who had survived a myocardial infarction did not find evidence that beta blockers induced depressive symptoms.¹⁶ However, the long-term and high-dosage effects of beta blockers still are in question.¹⁶ In Mr. C’s case, beta blockers had only positive effects on his symptoms and did not exacerbate his depressive symptoms.

Related Resources

• National Women’s Health Resource Center, Inc. Thyroid disorders. www.healthywomen.org/condition/thyroid-disorders.
• American Thyroid Association. www.thyroid.org.
• American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/files/hypo-hyper.pdf.

Drug Brand Names

• Atenolol • Tenormin
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Cyclobenzaprine • Flexeril
• Divalproex ER • Depakote ER
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Levothyroxine • Levoxyl, Synthroid
• Liothyronine sodium • Cytomel, Triostat
• Lithium • Eskalith, Lithobid
• Methimazole • Tapazole
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sunitinib • Sutent

Disclosure

Dr. Raj is a speaker for AstraZeneca and Merck.

Discuss this article at www.facebook.com/CurrentPsychiatry

Many endocrine disorders can manifest as depression, including relatively rare disorders such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (primary hyperaldosteronism) as well as common ones such as diabetes mellitus. Most clinicians do not routinely screen for adrenal disorders when evaluating depressed patients because the yield is low, but do screen for thyroid disease because these disorders often mimic depression. The following 3 cases from my practice illustrate some nuances of screening and treating depressed patients with suspected thyroid abnormalities.

CASE 1: Feeling ‘like an 80-year-old’

Ms. A, age 25, has a gastrointestinal stromal tumor (GIST) and states that she feels “like an 80-year-old woman.” She is sore all over with facial swelling, abdominal cramping, and fatigue. This feeling has worsened since she started chemotherapy with sunitinib for the GIST. Her Patient Health Questionnaire-9 (PHQ-9) score is 14 out of 27, indicating moderate depression. As part of a workup for her depression, what general laboratory tests would be most helpful?

Because Ms. A is of menstruating age, check hemoglobin/hematocrit levels to evaluate for anemia. Monitoring electrolytes would allow you to assess for hypernatremia/hyponatremia, hyperkalemia/hypokalemia, and impaired renal function, all of which could cause depressive symptoms. Depending on Ms. A’s habitus or risk of metabolic syndrome, a fasting blood glucose or hemoglobin A1C test to screen for diabetes mellitus might be valuable because depression may be associated with diabetes.¹ A1C is a preferred primary screening test for diabetes (≥6.5% constitutes a positive screen) based on revised clinical practice recommendations of the American Diabetes Association. A1C is available as an office-based test that requires just a drop of blood from a finger prick and does not require a fasting blood sample or a full laboratory analysis.

A popular test for a workup of depression is serum 25-hydroxyvitamin D [25(OH)D] (vitamin D), particularly for patients who live in areas with limited exposure to ultraviolet B radiation from sunlight.² In a study of older adults, vitamin D levels were 14% lower in patients with minor depression and 14% lower in patients with major depressive disorder compared with controls. This study suggests that depression severity is associated with decreased serum vitamin D levels,³ but the association between depression and vitamin D insufficiency and deficiency is unknown. Checking sex hormones also may be helpful depending on the patient’s symptoms, because testosterone deficiency in men and dehydroepiandrosterone deficiency in women can have a direct impact on a patient’s libido and overall sense of well-being. If repleted, improved levels of sex hormones can lead to a dramatic improvement in mood as well.

Because more than one-half of the estimated 27 million Americans with hyperthyroidism or hypothyroidism are undiagnosed, the American Thyroid Association recommends universal screening for thyroid dysfunction after age 35, with a recheck every 5 years.⁴ However, checking serum thyroid-stimulating hormone (TSH) levels this often may not be cost-effective. Typically, I do not follow this recommendation when assessing or treating asymptomatic individuals, but Ms. A has symptoms of hypothyroidism (Table 1) and is taking a medication—sunitinib—thought to be associated with hypothyroidism.⁵ Her serum TSH was very high (110 mIU/L; range 0.28 to 5.00) and her serum free T4 (FT4) was low (0.5 ng/dL; range 0.7 to 1.8). These values were consistent with overt hypothyroidism, defined as low FT4 and elevated TSH levels. This is in contrast to subclinical hypothyroidism (SH), which is defined as having an elevated serum TSH with normal thyroid hormone (T3 and T4) levels. SH presents in 5% of young patients (age <45) and increasingly is being diagnoses in older patients (age >55), who are most likely to suffer adverse effects in mood or cognition.⁶

Table 1

Hypothyroidism symptoms

CASE 1 CONTINUED: A classic case

Ms. A is started on a full levothyroxine replacement dose of 1.6 μg/kg/d. For hypothyroid patients who do not have cardiac symptoms, weight-based replacement is thought to be safe and more convenient than starting with a low dose and titrating up.⁷ Ms. A responds quickly. At 6-week follow-up—the recommended time interval for repeat thyroid lab testing after initiating thyroid replacement—her depressive symptoms are markedly improved and her PHQ-9 score is 6, indicating mild depression.

CASE 2: Chronic pain, low mood, and fatigue

Ms. B, age 62, has fibromyalgia and chronic back pain. She takes cyclobenzaprine, 5 mg 2 to 3 times daily, and oxycodone, 40 mg/d, and describes mild depressive symptoms when she presents for routine follow-up. Most of her complaints are related to chronic pain, but she has a history of low mood and fatigue. She says she was prescribed levothyroxine, but is unable to remember if she stopped taking it because of financial constraints or laboratory/clinical improvement. Her neurologist recently checked her serum TSH, which was elevated at 8.1 mIU/L. Is it best to restart thyroid replacement or wait 6 weeks and recheck her thyroid panel?

Mild SH typically is defined as TSH between 4.5 and 10 mIU/L. In contrast, TSH between 10 and 20 mIU/L is considered severe SH. Because Ms. B did not have prominent new symptoms, I felt it was reasonable to wait the recommended 6 weeks before rechecking her thyroid function. At follow-up, Ms. B’s TSH was 4.64 mIU/L and her FT4 was normal: 0.7 ng/dL. Thyroid replacement was not indicated because she did not have obvious symptoms and treating SH does not impact overall mood and cognition until TSH is ≥10 mIU/L.^8,9

CASE 2 CONTINUED: Prominent symptoms emerge

Ms. B returns several months later. Another clinician prescribed duloxetine, titrated from 30 mg to 60 mg, for worsening fibromyalgia. Her depressive symptoms are more prominent at this visit, and her PHQ-9 score has risen from 7 to 14, indicating moderate depression. She says previously she failed or poorly tolerated several antidepressants—fluoxetine, sertraline, and citalopram—but was hoping for a pharmacologic adjustment. Most evidence-based augmentation algorithms for treating major depression start with adding a second “traditional” antidepressant such as bupropion, then move to lithium, second-generation antipsychotics, or lamotrigine.¹⁰ But what about thyroid hormone augmentation?

Thyroid hormone often is on the lower rungs of depression treatment algorithms despite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial data. The data suggest triiodothyronine’s (T3) lower side effect burden and ease of use may offer an advantage over lithium augmentation for depressed patients who have failed several medication trials.¹¹ Liothyronine sodium (triiodothyronine) is a relatively benign medication with potential for augmentation when started at 25 to 50 mcg/d concurrently with antidepressants such as sertraline.¹² Unfortunately, most augmentation trials with T3 have been short-term—generally 4 to 8 weeks. In my practice, T3 has limited application; I use it mainly for patients with treatment-resistant depression who have failed several other treatments.

Lithium, the comparison medication to thyroid hormone in the third augmentation arm of the STAR*D trial, requires an annual check of thyroid function (TSH testing) to properly monitor for potential lithium-related hypothyroidism or thyroiditis. Hypothyroidism, for which thyroid replacement is required, with lithium therapy is common, affecting 8% to 27% of patients.¹³ Patients who rapidly gain weight at the beginning of lithium treatment seem to have a higher risk of developing hypothyroidism.¹³ However, the risk of developing lithium-induced hypothyroidism is tied to the length of treatment; the longer a patient has been treated with lithium, the greater the risk of developing lithium-induced hypothyroidism.

CASE 3: Unable to slow down

Mr. C, age 45, has a 20-year history of major depression controlled reasonably well with paroxetine, 40 mg. He presents with escalating anxiety, depression, and irritability. His wife is concerned about his overwhelming thoughts of death, especially because Mr. C’s father committed suicide 30 years ago under similar circumstances. Mr. C has been tremulous for the past month and has not been sleeping well. He feels like he is “in constant motion” and unable to slow down. He screens in the “highly likely” range for bipolar disorder on the Bipolar Spectrum Diagnostic Scale¹⁴ and is started on divalproex ER, 500 mg/d.

His thyroid function tests returns with a suppressed TSH of 0.03 mIU/L and an elevated FT4 of 3.26 ng/dL. Divalproex is discontinued and he is started on the beta blocker atenolol, 25 mg/d, to target his anxiety, tachycardia, and akathisia. TSH receptor antibody testing was positive, which, along with an abnormal radioactive iodine uptake scan, confirmed a diagnosis of Graves’ disease. He receives methimazole, 20 mg/d, as a temporizing measure. An endocrinologist completes a radioactive iodine (I-131) ablation procedure on Mr. C, which resolves his mood and anxiety symptoms.

Although hypothyroidism commonly is associated with depressive symptoms, hyperthyroidism also may present as depression. Most cases of overt hyperthyroidism are directly referred to an endocrinologist because when treating disorders such as Graves’ disease—the most common cause of hyperthyroidism, especially among women age 20 to 40—many nuclear medicine teams require the expert guidance of an endocrinologist before considering radioiodine ablation. Hyperthyroidism often is accompanied by psychiatric and somatic symptoms of an “overactive” nature (Table 2). However, older patients (age >65) with hyperthyroidism may develop apathetic hyperthyroidism, a subset that comprises approximately 10% to 15% of all hyperthyroidism cases in older adults.¹⁵ Rather than becoming nervous, jittery, and restless, patients with apathetic hyperthyroidism are depressed, lethargic, and weak, and may develop proximal myopathy or cardiomyopathy. It is essential to differentiate apathetic hyperthyroidism from typical hyperthyroidism because accurately diagnosing and treating apathetic hyperthyroidism will improve outcomes.¹⁵

Table 2

Hyperthyroidism symptoms

Using beta blockers to treat hyperthyroidism can help control tachycardia or palpitations, tremulousness, and anxiety that often are inherent in hyperthyroidism. But can beta blockers induce depressive symptoms? A 1-year prospective Dutch study of patients who had survived a myocardial infarction did not find evidence that beta blockers induced depressive symptoms.¹⁶ However, the long-term and high-dosage effects of beta blockers still are in question.¹⁶ In Mr. C’s case, beta blockers had only positive effects on his symptoms and did not exacerbate his depressive symptoms.

Related Resources

• National Women’s Health Resource Center, Inc. Thyroid disorders. www.healthywomen.org/condition/thyroid-disorders.
• American Thyroid Association. www.thyroid.org.
• American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/files/hypo-hyper.pdf.

Drug Brand Names

• Atenolol • Tenormin
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Cyclobenzaprine • Flexeril
• Divalproex ER • Depakote ER
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Levothyroxine • Levoxyl, Synthroid
• Liothyronine sodium • Cytomel, Triostat
• Lithium • Eskalith, Lithobid
• Methimazole • Tapazole
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sunitinib • Sutent

Disclosure

Dr. Raj is a speaker for AstraZeneca and Merck.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mrs. B, age 45, is referred by her primary care physician (PCP) for treatment of depressive symptoms that have worsened over the last 6 months. Her depressed mood is associated with worsening of multiple chronic, physical symptoms that began 4 years ago with several musculoskeletal complaints. Three years ago she developed recurrent abdominal discomfort and bloating, followed by recurrent chest pain. These symptoms have resulted in multiple trips to the hospital, several invasive procedures, and extensive medical consultation. After repeated workups, her symptoms are medically unexplained. These symptoms interfere with her ability to engage in and enjoy life.

Even after thorough investigation, up to one-third of patients’ physical symptoms remain unexplained.^1-3 Most patients with unexplained symptoms improve; however, a small proportion do not. Such patients often are referred for psychiatric consultation.

Workup may reveal psychiatric etiology of a patient’s medically unexplained physical symptoms (MUPS). Clinicians need to take a unique approach to caring for patients whose symptoms remain unexplained after workup because diagnostic features may emerge over time and a collaborative, unbiased, integrated approach eventually may reveal a treatable diagnosis. This type of approach also is important when no medical or psychiatric diagnosis can be reached.

This article reviews the prevalence, comorbidity, and treatment challenges of patients whose physical symptoms are medically unexplained, and recommends evidence-based treatment strategies.

Inconsistent terminology

The terms MUPS, medically unexplained symptoms, somatoform disorder, somatization, and the functional syndromes (eg, irritable bowel syndrome [IBS], fibromyalgia, interstitial cystitis, chronic fatigue, etc.) often are used interchangeably. This inconsistent nomenclature creates classification difficulties because several of these terms assume a different etiology for the patient’s physical symptoms (ie, medical vs psychiatric).

Physical symptoms typically are explained by:

• medical pathophysiology
• psychopathology, or
• unknown etiology (Figure).

MUPS typically are defined as physical or somatic symptoms without a known etiology after appropriate testing, workup, and referrals. Workup may be limited or extensive, may evolve over time (eg, diagnosis may be made 2 years after primary symptom onset), and often involves collaboration among several specialists.

The above definition does not specify severity, medical/psychiatric comorbidity, or number or duration of symptoms. A proposed classification, medically unexplained symptoms spectrum disorder, attempts to categorize patients with MUPS based on severity and duration of symptoms, as well as medical and/or psychiatric comorbidities (Table).⁴ MUPS may account for up to two-thirds of physical symptoms in specialty clinics; to read about the prevalence of MUPS, see the Box below.

Figure: Typical etiology of physical symptoms
NOS: Not otherwise specifiedTable

Medically unexplained symptoms spectrum disorder

CASE CONTINUED: Abuse and assault

Mrs. B has been married for 10 years and has 2 children. She denies using tobacco, alcohol, or illicit drugs. Both of her parents were in good physical health. As a child Mrs. B was physically and verbally abused by her father, and her parents divorced when she was 15. She was sexually assaulted while in college.

Mrs. B has had 1 previous depressive episode, which occurred shortly after the sexual assault. During that time she was hospitalized twice for attempting suicide by overdosing on prescription medications. She was stabilized on fluoxetine, 40 mg/d, which was tapered and discontinued after 2 years.

Factors linked to MUPS

Young women (age 16 to 25) are more likely to receive an MUPS diagnosis than men or older individuals. Employment, socioeconomic background, and educational level are not consistently associated with MUPS.⁵ Patients with MUPS have higher rates of physical and sexual abuse.⁶

Several studies have shown an association with childhood parental ill health and development of MUPS, but the exact nature of “ill health” was not clearly defined. Parental death was not associated with MUPS, which suggests that the association to parental ill health is related to non-threatening physical disease.⁶

Approximately 60% of patients with MUPS have a comorbid non-somatoform DSM-IV-TR diagnosis.^7-9 Symptoms and rates of depressive, anxiety, and panic disorders are higher in patients with MUPS than either healthy controls or patients with similar diseases of known organic pathology.^7,8

The estimated prevalence of somatoform disorder in patients with MUPS is approximately 4%, which is higher than in the general population (.2% to 2%).^7,8 On measures of mental and physical function, patients with MUPS who have somatoform disorders have been found to be more distressed than normal controls and patients with MUPS without somatoform disorders.⁸

Although few studies have directly examined the relationship between personality disorders and MUPS, there is evidence of an association between certain personality traits (eg, neuroticism, alexithymia, negative affect) and MUPS.^10,11

CASE CONTINUED: Rejected advice

Mrs. B has been worked up multiple times for acute coronary syndrome; been unsuccessfully treated for gastroesophageal reflux disease, lactose intolerance, and IBS; had a negative rheumatologic workup; and tried several medication regimens with no improvement in symptoms. Three years ago Mrs. B’s gastroenterologist implied her abdominal symptoms were caused by her history of sexual assault and suggested she seek psychiatric consultation. Offended, Mrs. B sought a second opinion and no longer sees her first gastroenterologist.

Barriers to treatment

Despite having high levels of psychosocial distress, health care utilization, and medical disability, patients with MUPS often are suboptimally treated. Factors that might contribute to this include:

• inadequate identification
• bias in diagnosis and treatment
• poor follow-up on referrals
• an absence of treatment guidelines.^7,12,13

Many clinicians are unaware of the high prevalence of MUPS, which often leads to repeated referral to specialty clinics, even when patients already have received an MUPS diagnosis.^12,14 Additionally, clinicians often are unaware of how individual biases influence their diagnostic thought process. A “difficult patient” may receive a MUPS diagnosis more readily than a “pleasant patient,” which could contribute to an incomplete workup. An epidemiologic study revealed that the strongest predictor of misdiagnosing MUPS is doctor dissatisfaction with the clinical encounter.¹⁵ Younger, unmarried, anxious patients receiving disability benefits are more likely to be incorrectly labeled as having MUPS, only to later receive a non-MUPS diagnosis.¹⁵

Bias in treatment and intervention also exists. Qualitative analysis of consultations suggests that physicians’ decisions to offer patients somatic treatments (eg, investigation, add/change medications, referral to specialists) are responses to patients’ extended and complex accounts of their symptoms.¹⁷ The likelihood of intervention was unrelated to patients’ request for treatment, and intervention became less likely when patients described psychosocial problems.¹⁶

Patients with MUPS and comorbid psychiatric disorders often are referred for psychosocial treatment, but 1 study found that as few as 10% of such patients follow up on a referral.¹⁷ In that study, 81% of MUPS patients were willing to receive psychosocial treatment in a primary care setting by their physician. Although there are many reasons patients with MUPS resist referral to mental health professionals, be aware that many of these individuals do not attribute their symptoms to psychosocial problems or experience their symptoms psychologically. To these patients, psychiatric referral may seem inappropriate or be perceived as belittling and minimizing their symptoms.

CASE CONTINUED: Frustration and guilt

Mrs. B’s depressive symptoms began 18 months ago with fatigue, poor sleep, and withdrawal from her children and husband. She struggles with hopelessness that her physical symptoms will not resolve and guilt because of the financial strain her medical care has placed on the family. She is extremely frustrated that her doctors are unable to find a medical diagnosis for her symptoms and fears that without a diagnosis she will be perceived as “crazy.” She is not certain if there is a medical explanation for her symptoms but vehemently believes they are not associated with her mood or psychosocial stress.

Treatment strategies

A collaborative, unbiased, integrated approach to treatment can address some of the challenges that arise when patients with MUPS confront the limitations of modern medicine. Integrated care involves ongoing communication among medical and psychiatric specialists, as well as collaboration with social workers, physical therapists, nutritionists, or pain management specialists when indicated.

Although the primary care provider often coordinates a MUPS patient’s medical treatment, a consulting psychiatrist plays an important educational, diagnostic, and therapeutic role. The therapeutic role is especially important because patients with MUPS frequently view their general practitioner as having a limited role in managing psychosocial problems.¹⁸

Because physical illness and psychosocial stress frequently coexist and compound each other, diagnostic efforts should focus on medical and psychiatric illness. Review the patient’s medical workup of the unexplained symptoms and, when indicated, request further testing. Evaluate the risks and benefits of additional testing and discuss them with the patient; additional testing carries a risk of iatrogenic harm, higher false-positive rates, and increased costs. Avoiding iatrogenic harm and unnecessary, overly aggressive testing is essential.

Identifying primary or comorbid psychiatric disease and psychosocial issues also is integral to managing patients with MUPS. This may be difficult because some patients might be hesitant to discuss psychosocial issues, whereas others may be unaware of psychiatric symptomatology or the connection between mental and physical illness. When possible, it may be useful to clarify symptomatology as:

• primarily somatic (expression of psychological illness through physical means)
• primarily psychiatric (psychiatric illness presenting with physical symptoms) or
• bordering between somatic and psychiatric.

CASE CONTINUED: Collaboration and improvement

You diagnose Mrs. B with major depressive disorder and prescribe fluoxetine, titrating her up to 40 mg/d. Mrs. B also begins weekly psychodynamic psychotherapy. In collaboration with her PCP, you decide to refer Mrs. B to physical therapy and direct psychotherapy toward coping strategies, with the hope of improving functionality. Although she continues to have musculoskeletal symptoms after completing physical therapy, Mrs. B notices moderate improvement and feels less distressed by these symptoms.

After 1 year of fluoxetine treatment, Mrs. B’s depressive symptoms improve. In psychotherapy, her fixation on physical symptoms and desire to establish a diagnosis gradually lessen. As her emotional trauma from childhood abuse unravels, psychotherapy shifts toward improving affect regulation. During this time Mrs. B experiences an increase in unexplained chest pain and shortness of breath, which later abate.

Continued follow-up with a gastroenterologist leads to a diagnosis of celiac disease. With treatment, her GI symptoms resolve.

What do patients want?

Begin MUPS treatment by developing a supportive, empathic relationship with the patient. Carefully listen to the patient’s description of his or her symptoms. Elucidating patients’ experience often is challenging because their narratives frequently are complex, nonlinear, and limited by time.¹⁸ Patients’ models for understanding their symptoms also may be complex.¹⁸ They may be reluctant to share their explanations, fearing they will be unable to communicate the complexity of their beliefs or their symptoms will be oversimplified.¹⁸

Focus on understanding what the patient seeks from the physician—emotional support vs diagnosis vs treatment. In a prospective naturalistic study, the content of MUPS patients’ narratives was correlated with what they sought from their physician.¹⁷ Patients who sought emotional support frequently discussed psychosocial problems, issues, and management. Patients who wanted an explanation for their symptoms often mentioned physical symptoms, explanations, and diseases. Those who were looking for additional testing or intervention often directly addressed this with the physician.¹⁷

Although many patients desire a diagnosis and somatic treatment, this is not always their primary agenda. Many MUPS patients seek emotional support or confirmation of their explanatory model.^17,18 Patients’ desires for emotional support, medical explanation, diagnosis, or somatic intervention often are neither clearly nor explicitly stated. Despite this, patients hope their physician understands the extent of their problems and value those who help them make sense of their narratives.¹⁸ Misunderstanding patients’ agendas can result in a mismatch of treatment expectations and fracture the patient-physician relationship. Developing mutual expectations is crucial to building rapport, improving collaborative care, and avoiding unnecessary, potentially harmful interventions.

Psychotherapic interventions

Psychopharmacologic treatment is indicated for MUPS patients who have comorbid psychiatric conditions.

Research of psychotherapy in MUPS has been plagued by methodologic problems and inconsistent results.³ Group therapy, short-term dynamic therapy, hypnotherapy, and cognitive-behavioral therapy (CBT) have been studied. In a trial of 140 MUPS patients who received 1 session of CBT, 71% experienced improvement in physical symptoms, 47% in functional status, and 38% in measures of psychological distress.¹⁹ A review of 34 randomized controlled trials involving 3,922 patients with somatoform disorders who received CBT found that some patients with MUPS responded after 5 to 6 sessions.³

Cognitive techniques focus on identifying and restructuring automatic, dysfunctional thoughts that may compound, perpetuate, or worsen somatic symptoms. Behavioral techniques include relaxation and efforts to increase motivation. A CBT treatment plan may involve establishing goals, addressing patients’ understanding of their symptoms, obtaining a commitment for treatment, and negotiating the details of the treatment plan.^8,12

Supportive techniques also are valuable in treating MUPS patients. Educate patients and treating physicians that there is a neurophysiologic basis for the patient’s physical symptoms and that symptoms may wax and wane. Reinforcement of functional improvement through concrete, practical solutions can help patients develop healthy, adaptive coping skills. Encouraging patients to move beyond somatic complaints to discuss social and personal difficulties can lead to more effective management of these problems.

Clearly communicate your initial impressions, diagnoses, and treatment plan to other members of the treatment team. A consultation letter from the psychiatrist to the PCP has been shown to decrease costs and slightly improve the patient’s functional status, symptoms, and quality of life.²⁰ When possible, educate the PCP and specialists about the dynamics, challenges, biases, and frustrations physicians commonly face when caring for MUPS patients.

Related Resources

• Burton C. Beyond somatization: a review of the understanding and treatment of medically unexplained physical symptoms. Brit J Gen Pract. 2003;53:233-239.
• Creed F. The outcome of medically unexplained symptoms—will DSM-V improve on DSM-IV somatoform disorders? J Psychosom Res. 2009;66:379-381.
• Katon W, Sullivan M, Walker E. Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits. Ann Intern Med. 2001;134(9 Pt 2):917-925.
• Sharpe M, Mayou R, Walker J. Bodily symptoms: new approaches to classification. J Psychosom Res. 2006;60: 353-356.

Drug Brand Names

• Fluoxetine • Prozac

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Box

Discuss this article at www.facebook.com/CurrentPsychiatry

Mrs. B, age 45, is referred by her primary care physician (PCP) for treatment of depressive symptoms that have worsened over the last 6 months. Her depressed mood is associated with worsening of multiple chronic, physical symptoms that began 4 years ago with several musculoskeletal complaints. Three years ago she developed recurrent abdominal discomfort and bloating, followed by recurrent chest pain. These symptoms have resulted in multiple trips to the hospital, several invasive procedures, and extensive medical consultation. After repeated workups, her symptoms are medically unexplained. These symptoms interfere with her ability to engage in and enjoy life.

Even after thorough investigation, up to one-third of patients’ physical symptoms remain unexplained.^1-3 Most patients with unexplained symptoms improve; however, a small proportion do not. Such patients often are referred for psychiatric consultation.

Workup may reveal psychiatric etiology of a patient’s medically unexplained physical symptoms (MUPS). Clinicians need to take a unique approach to caring for patients whose symptoms remain unexplained after workup because diagnostic features may emerge over time and a collaborative, unbiased, integrated approach eventually may reveal a treatable diagnosis. This type of approach also is important when no medical or psychiatric diagnosis can be reached.

This article reviews the prevalence, comorbidity, and treatment challenges of patients whose physical symptoms are medically unexplained, and recommends evidence-based treatment strategies.

Inconsistent terminology

The terms MUPS, medically unexplained symptoms, somatoform disorder, somatization, and the functional syndromes (eg, irritable bowel syndrome [IBS], fibromyalgia, interstitial cystitis, chronic fatigue, etc.) often are used interchangeably. This inconsistent nomenclature creates classification difficulties because several of these terms assume a different etiology for the patient’s physical symptoms (ie, medical vs psychiatric).

Physical symptoms typically are explained by:

• medical pathophysiology
• psychopathology, or
• unknown etiology (Figure).

MUPS typically are defined as physical or somatic symptoms without a known etiology after appropriate testing, workup, and referrals. Workup may be limited or extensive, may evolve over time (eg, diagnosis may be made 2 years after primary symptom onset), and often involves collaboration among several specialists.

The above definition does not specify severity, medical/psychiatric comorbidity, or number or duration of symptoms. A proposed classification, medically unexplained symptoms spectrum disorder, attempts to categorize patients with MUPS based on severity and duration of symptoms, as well as medical and/or psychiatric comorbidities (Table).⁴ MUPS may account for up to two-thirds of physical symptoms in specialty clinics; to read about the prevalence of MUPS, see the Box below.

Figure: Typical etiology of physical symptoms
NOS: Not otherwise specifiedTable

Medically unexplained symptoms spectrum disorder

CASE CONTINUED: Abuse and assault

Mrs. B has been married for 10 years and has 2 children. She denies using tobacco, alcohol, or illicit drugs. Both of her parents were in good physical health. As a child Mrs. B was physically and verbally abused by her father, and her parents divorced when she was 15. She was sexually assaulted while in college.

Mrs. B has had 1 previous depressive episode, which occurred shortly after the sexual assault. During that time she was hospitalized twice for attempting suicide by overdosing on prescription medications. She was stabilized on fluoxetine, 40 mg/d, which was tapered and discontinued after 2 years.

Factors linked to MUPS

Young women (age 16 to 25) are more likely to receive an MUPS diagnosis than men or older individuals. Employment, socioeconomic background, and educational level are not consistently associated with MUPS.⁵ Patients with MUPS have higher rates of physical and sexual abuse.⁶

Several studies have shown an association with childhood parental ill health and development of MUPS, but the exact nature of “ill health” was not clearly defined. Parental death was not associated with MUPS, which suggests that the association to parental ill health is related to non-threatening physical disease.⁶

Approximately 60% of patients with MUPS have a comorbid non-somatoform DSM-IV-TR diagnosis.^7-9 Symptoms and rates of depressive, anxiety, and panic disorders are higher in patients with MUPS than either healthy controls or patients with similar diseases of known organic pathology.^7,8

The estimated prevalence of somatoform disorder in patients with MUPS is approximately 4%, which is higher than in the general population (.2% to 2%).^7,8 On measures of mental and physical function, patients with MUPS who have somatoform disorders have been found to be more distressed than normal controls and patients with MUPS without somatoform disorders.⁸

Although few studies have directly examined the relationship between personality disorders and MUPS, there is evidence of an association between certain personality traits (eg, neuroticism, alexithymia, negative affect) and MUPS.^10,11

CASE CONTINUED: Rejected advice

Mrs. B has been worked up multiple times for acute coronary syndrome; been unsuccessfully treated for gastroesophageal reflux disease, lactose intolerance, and IBS; had a negative rheumatologic workup; and tried several medication regimens with no improvement in symptoms. Three years ago Mrs. B’s gastroenterologist implied her abdominal symptoms were caused by her history of sexual assault and suggested she seek psychiatric consultation. Offended, Mrs. B sought a second opinion and no longer sees her first gastroenterologist.

Barriers to treatment

Despite having high levels of psychosocial distress, health care utilization, and medical disability, patients with MUPS often are suboptimally treated. Factors that might contribute to this include:

• inadequate identification
• bias in diagnosis and treatment
• poor follow-up on referrals
• an absence of treatment guidelines.^7,12,13

Many clinicians are unaware of the high prevalence of MUPS, which often leads to repeated referral to specialty clinics, even when patients already have received an MUPS diagnosis.^12,14 Additionally, clinicians often are unaware of how individual biases influence their diagnostic thought process. A “difficult patient” may receive a MUPS diagnosis more readily than a “pleasant patient,” which could contribute to an incomplete workup. An epidemiologic study revealed that the strongest predictor of misdiagnosing MUPS is doctor dissatisfaction with the clinical encounter.¹⁵ Younger, unmarried, anxious patients receiving disability benefits are more likely to be incorrectly labeled as having MUPS, only to later receive a non-MUPS diagnosis.¹⁵

Bias in treatment and intervention also exists. Qualitative analysis of consultations suggests that physicians’ decisions to offer patients somatic treatments (eg, investigation, add/change medications, referral to specialists) are responses to patients’ extended and complex accounts of their symptoms.¹⁷ The likelihood of intervention was unrelated to patients’ request for treatment, and intervention became less likely when patients described psychosocial problems.¹⁶

Patients with MUPS and comorbid psychiatric disorders often are referred for psychosocial treatment, but 1 study found that as few as 10% of such patients follow up on a referral.¹⁷ In that study, 81% of MUPS patients were willing to receive psychosocial treatment in a primary care setting by their physician. Although there are many reasons patients with MUPS resist referral to mental health professionals, be aware that many of these individuals do not attribute their symptoms to psychosocial problems or experience their symptoms psychologically. To these patients, psychiatric referral may seem inappropriate or be perceived as belittling and minimizing their symptoms.

CASE CONTINUED: Frustration and guilt

Mrs. B’s depressive symptoms began 18 months ago with fatigue, poor sleep, and withdrawal from her children and husband. She struggles with hopelessness that her physical symptoms will not resolve and guilt because of the financial strain her medical care has placed on the family. She is extremely frustrated that her doctors are unable to find a medical diagnosis for her symptoms and fears that without a diagnosis she will be perceived as “crazy.” She is not certain if there is a medical explanation for her symptoms but vehemently believes they are not associated with her mood or psychosocial stress.

Treatment strategies

A collaborative, unbiased, integrated approach to treatment can address some of the challenges that arise when patients with MUPS confront the limitations of modern medicine. Integrated care involves ongoing communication among medical and psychiatric specialists, as well as collaboration with social workers, physical therapists, nutritionists, or pain management specialists when indicated.

Although the primary care provider often coordinates a MUPS patient’s medical treatment, a consulting psychiatrist plays an important educational, diagnostic, and therapeutic role. The therapeutic role is especially important because patients with MUPS frequently view their general practitioner as having a limited role in managing psychosocial problems.¹⁸

Because physical illness and psychosocial stress frequently coexist and compound each other, diagnostic efforts should focus on medical and psychiatric illness. Review the patient’s medical workup of the unexplained symptoms and, when indicated, request further testing. Evaluate the risks and benefits of additional testing and discuss them with the patient; additional testing carries a risk of iatrogenic harm, higher false-positive rates, and increased costs. Avoiding iatrogenic harm and unnecessary, overly aggressive testing is essential.

Identifying primary or comorbid psychiatric disease and psychosocial issues also is integral to managing patients with MUPS. This may be difficult because some patients might be hesitant to discuss psychosocial issues, whereas others may be unaware of psychiatric symptomatology or the connection between mental and physical illness. When possible, it may be useful to clarify symptomatology as:

• primarily somatic (expression of psychological illness through physical means)
• primarily psychiatric (psychiatric illness presenting with physical symptoms) or
• bordering between somatic and psychiatric.

CASE CONTINUED: Collaboration and improvement

You diagnose Mrs. B with major depressive disorder and prescribe fluoxetine, titrating her up to 40 mg/d. Mrs. B also begins weekly psychodynamic psychotherapy. In collaboration with her PCP, you decide to refer Mrs. B to physical therapy and direct psychotherapy toward coping strategies, with the hope of improving functionality. Although she continues to have musculoskeletal symptoms after completing physical therapy, Mrs. B notices moderate improvement and feels less distressed by these symptoms.

After 1 year of fluoxetine treatment, Mrs. B’s depressive symptoms improve. In psychotherapy, her fixation on physical symptoms and desire to establish a diagnosis gradually lessen. As her emotional trauma from childhood abuse unravels, psychotherapy shifts toward improving affect regulation. During this time Mrs. B experiences an increase in unexplained chest pain and shortness of breath, which later abate.

Continued follow-up with a gastroenterologist leads to a diagnosis of celiac disease. With treatment, her GI symptoms resolve.

What do patients want?

Begin MUPS treatment by developing a supportive, empathic relationship with the patient. Carefully listen to the patient’s description of his or her symptoms. Elucidating patients’ experience often is challenging because their narratives frequently are complex, nonlinear, and limited by time.¹⁸ Patients’ models for understanding their symptoms also may be complex.¹⁸ They may be reluctant to share their explanations, fearing they will be unable to communicate the complexity of their beliefs or their symptoms will be oversimplified.¹⁸

Focus on understanding what the patient seeks from the physician—emotional support vs diagnosis vs treatment. In a prospective naturalistic study, the content of MUPS patients’ narratives was correlated with what they sought from their physician.¹⁷ Patients who sought emotional support frequently discussed psychosocial problems, issues, and management. Patients who wanted an explanation for their symptoms often mentioned physical symptoms, explanations, and diseases. Those who were looking for additional testing or intervention often directly addressed this with the physician.¹⁷

Although many patients desire a diagnosis and somatic treatment, this is not always their primary agenda. Many MUPS patients seek emotional support or confirmation of their explanatory model.^17,18 Patients’ desires for emotional support, medical explanation, diagnosis, or somatic intervention often are neither clearly nor explicitly stated. Despite this, patients hope their physician understands the extent of their problems and value those who help them make sense of their narratives.¹⁸ Misunderstanding patients’ agendas can result in a mismatch of treatment expectations and fracture the patient-physician relationship. Developing mutual expectations is crucial to building rapport, improving collaborative care, and avoiding unnecessary, potentially harmful interventions.

Psychotherapic interventions

Psychopharmacologic treatment is indicated for MUPS patients who have comorbid psychiatric conditions.

Research of psychotherapy in MUPS has been plagued by methodologic problems and inconsistent results.³ Group therapy, short-term dynamic therapy, hypnotherapy, and cognitive-behavioral therapy (CBT) have been studied. In a trial of 140 MUPS patients who received 1 session of CBT, 71% experienced improvement in physical symptoms, 47% in functional status, and 38% in measures of psychological distress.¹⁹ A review of 34 randomized controlled trials involving 3,922 patients with somatoform disorders who received CBT found that some patients with MUPS responded after 5 to 6 sessions.³

Cognitive techniques focus on identifying and restructuring automatic, dysfunctional thoughts that may compound, perpetuate, or worsen somatic symptoms. Behavioral techniques include relaxation and efforts to increase motivation. A CBT treatment plan may involve establishing goals, addressing patients’ understanding of their symptoms, obtaining a commitment for treatment, and negotiating the details of the treatment plan.^8,12

Supportive techniques also are valuable in treating MUPS patients. Educate patients and treating physicians that there is a neurophysiologic basis for the patient’s physical symptoms and that symptoms may wax and wane. Reinforcement of functional improvement through concrete, practical solutions can help patients develop healthy, adaptive coping skills. Encouraging patients to move beyond somatic complaints to discuss social and personal difficulties can lead to more effective management of these problems.

Clearly communicate your initial impressions, diagnoses, and treatment plan to other members of the treatment team. A consultation letter from the psychiatrist to the PCP has been shown to decrease costs and slightly improve the patient’s functional status, symptoms, and quality of life.²⁰ When possible, educate the PCP and specialists about the dynamics, challenges, biases, and frustrations physicians commonly face when caring for MUPS patients.

Related Resources

• Burton C. Beyond somatization: a review of the understanding and treatment of medically unexplained physical symptoms. Brit J Gen Pract. 2003;53:233-239.
• Creed F. The outcome of medically unexplained symptoms—will DSM-V improve on DSM-IV somatoform disorders? J Psychosom Res. 2009;66:379-381.
• Katon W, Sullivan M, Walker E. Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits. Ann Intern Med. 2001;134(9 Pt 2):917-925.
• Sharpe M, Mayou R, Walker J. Bodily symptoms: new approaches to classification. J Psychosom Res. 2006;60: 353-356.

Drug Brand Names

• Fluoxetine • Prozac

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Box

Discuss this article at www.facebook.com/CurrentPsychiatry

Mrs. B, age 45, is referred by her primary care physician (PCP) for treatment of depressive symptoms that have worsened over the last 6 months. Her depressed mood is associated with worsening of multiple chronic, physical symptoms that began 4 years ago with several musculoskeletal complaints. Three years ago she developed recurrent abdominal discomfort and bloating, followed by recurrent chest pain. These symptoms have resulted in multiple trips to the hospital, several invasive procedures, and extensive medical consultation. After repeated workups, her symptoms are medically unexplained. These symptoms interfere with her ability to engage in and enjoy life.

Even after thorough investigation, up to one-third of patients’ physical symptoms remain unexplained.^1-3 Most patients with unexplained symptoms improve; however, a small proportion do not. Such patients often are referred for psychiatric consultation.

Workup may reveal psychiatric etiology of a patient’s medically unexplained physical symptoms (MUPS). Clinicians need to take a unique approach to caring for patients whose symptoms remain unexplained after workup because diagnostic features may emerge over time and a collaborative, unbiased, integrated approach eventually may reveal a treatable diagnosis. This type of approach also is important when no medical or psychiatric diagnosis can be reached.

This article reviews the prevalence, comorbidity, and treatment challenges of patients whose physical symptoms are medically unexplained, and recommends evidence-based treatment strategies.

Inconsistent terminology

The terms MUPS, medically unexplained symptoms, somatoform disorder, somatization, and the functional syndromes (eg, irritable bowel syndrome [IBS], fibromyalgia, interstitial cystitis, chronic fatigue, etc.) often are used interchangeably. This inconsistent nomenclature creates classification difficulties because several of these terms assume a different etiology for the patient’s physical symptoms (ie, medical vs psychiatric).

Physical symptoms typically are explained by:

• medical pathophysiology
• psychopathology, or
• unknown etiology (Figure).

MUPS typically are defined as physical or somatic symptoms without a known etiology after appropriate testing, workup, and referrals. Workup may be limited or extensive, may evolve over time (eg, diagnosis may be made 2 years after primary symptom onset), and often involves collaboration among several specialists.

The above definition does not specify severity, medical/psychiatric comorbidity, or number or duration of symptoms. A proposed classification, medically unexplained symptoms spectrum disorder, attempts to categorize patients with MUPS based on severity and duration of symptoms, as well as medical and/or psychiatric comorbidities (Table).⁴ MUPS may account for up to two-thirds of physical symptoms in specialty clinics; to read about the prevalence of MUPS, see the Box below.

Figure: Typical etiology of physical symptoms
NOS: Not otherwise specifiedTable

Medically unexplained symptoms spectrum disorder

CASE CONTINUED: Abuse and assault

Mrs. B has been married for 10 years and has 2 children. She denies using tobacco, alcohol, or illicit drugs. Both of her parents were in good physical health. As a child Mrs. B was physically and verbally abused by her father, and her parents divorced when she was 15. She was sexually assaulted while in college.

Mrs. B has had 1 previous depressive episode, which occurred shortly after the sexual assault. During that time she was hospitalized twice for attempting suicide by overdosing on prescription medications. She was stabilized on fluoxetine, 40 mg/d, which was tapered and discontinued after 2 years.

Factors linked to MUPS

Young women (age 16 to 25) are more likely to receive an MUPS diagnosis than men or older individuals. Employment, socioeconomic background, and educational level are not consistently associated with MUPS.⁵ Patients with MUPS have higher rates of physical and sexual abuse.⁶

Several studies have shown an association with childhood parental ill health and development of MUPS, but the exact nature of “ill health” was not clearly defined. Parental death was not associated with MUPS, which suggests that the association to parental ill health is related to non-threatening physical disease.⁶

Approximately 60% of patients with MUPS have a comorbid non-somatoform DSM-IV-TR diagnosis.^7-9 Symptoms and rates of depressive, anxiety, and panic disorders are higher in patients with MUPS than either healthy controls or patients with similar diseases of known organic pathology.^7,8

The estimated prevalence of somatoform disorder in patients with MUPS is approximately 4%, which is higher than in the general population (.2% to 2%).^7,8 On measures of mental and physical function, patients with MUPS who have somatoform disorders have been found to be more distressed than normal controls and patients with MUPS without somatoform disorders.⁸

Although few studies have directly examined the relationship between personality disorders and MUPS, there is evidence of an association between certain personality traits (eg, neuroticism, alexithymia, negative affect) and MUPS.^10,11

CASE CONTINUED: Rejected advice

Mrs. B has been worked up multiple times for acute coronary syndrome; been unsuccessfully treated for gastroesophageal reflux disease, lactose intolerance, and IBS; had a negative rheumatologic workup; and tried several medication regimens with no improvement in symptoms. Three years ago Mrs. B’s gastroenterologist implied her abdominal symptoms were caused by her history of sexual assault and suggested she seek psychiatric consultation. Offended, Mrs. B sought a second opinion and no longer sees her first gastroenterologist.

Barriers to treatment

Despite having high levels of psychosocial distress, health care utilization, and medical disability, patients with MUPS often are suboptimally treated. Factors that might contribute to this include:

• inadequate identification
• bias in diagnosis and treatment
• poor follow-up on referrals
• an absence of treatment guidelines.^7,12,13

Many clinicians are unaware of the high prevalence of MUPS, which often leads to repeated referral to specialty clinics, even when patients already have received an MUPS diagnosis.^12,14 Additionally, clinicians often are unaware of how individual biases influence their diagnostic thought process. A “difficult patient” may receive a MUPS diagnosis more readily than a “pleasant patient,” which could contribute to an incomplete workup. An epidemiologic study revealed that the strongest predictor of misdiagnosing MUPS is doctor dissatisfaction with the clinical encounter.¹⁵ Younger, unmarried, anxious patients receiving disability benefits are more likely to be incorrectly labeled as having MUPS, only to later receive a non-MUPS diagnosis.¹⁵

Bias in treatment and intervention also exists. Qualitative analysis of consultations suggests that physicians’ decisions to offer patients somatic treatments (eg, investigation, add/change medications, referral to specialists) are responses to patients’ extended and complex accounts of their symptoms.¹⁷ The likelihood of intervention was unrelated to patients’ request for treatment, and intervention became less likely when patients described psychosocial problems.¹⁶

Patients with MUPS and comorbid psychiatric disorders often are referred for psychosocial treatment, but 1 study found that as few as 10% of such patients follow up on a referral.¹⁷ In that study, 81% of MUPS patients were willing to receive psychosocial treatment in a primary care setting by their physician. Although there are many reasons patients with MUPS resist referral to mental health professionals, be aware that many of these individuals do not attribute their symptoms to psychosocial problems or experience their symptoms psychologically. To these patients, psychiatric referral may seem inappropriate or be perceived as belittling and minimizing their symptoms.

CASE CONTINUED: Frustration and guilt

Mrs. B’s depressive symptoms began 18 months ago with fatigue, poor sleep, and withdrawal from her children and husband. She struggles with hopelessness that her physical symptoms will not resolve and guilt because of the financial strain her medical care has placed on the family. She is extremely frustrated that her doctors are unable to find a medical diagnosis for her symptoms and fears that without a diagnosis she will be perceived as “crazy.” She is not certain if there is a medical explanation for her symptoms but vehemently believes they are not associated with her mood or psychosocial stress.

Treatment strategies

A collaborative, unbiased, integrated approach to treatment can address some of the challenges that arise when patients with MUPS confront the limitations of modern medicine. Integrated care involves ongoing communication among medical and psychiatric specialists, as well as collaboration with social workers, physical therapists, nutritionists, or pain management specialists when indicated.

Although the primary care provider often coordinates a MUPS patient’s medical treatment, a consulting psychiatrist plays an important educational, diagnostic, and therapeutic role. The therapeutic role is especially important because patients with MUPS frequently view their general practitioner as having a limited role in managing psychosocial problems.¹⁸

Because physical illness and psychosocial stress frequently coexist and compound each other, diagnostic efforts should focus on medical and psychiatric illness. Review the patient’s medical workup of the unexplained symptoms and, when indicated, request further testing. Evaluate the risks and benefits of additional testing and discuss them with the patient; additional testing carries a risk of iatrogenic harm, higher false-positive rates, and increased costs. Avoiding iatrogenic harm and unnecessary, overly aggressive testing is essential.

Identifying primary or comorbid psychiatric disease and psychosocial issues also is integral to managing patients with MUPS. This may be difficult because some patients might be hesitant to discuss psychosocial issues, whereas others may be unaware of psychiatric symptomatology or the connection between mental and physical illness. When possible, it may be useful to clarify symptomatology as:

• primarily somatic (expression of psychological illness through physical means)
• primarily psychiatric (psychiatric illness presenting with physical symptoms) or
• bordering between somatic and psychiatric.

CASE CONTINUED: Collaboration and improvement

You diagnose Mrs. B with major depressive disorder and prescribe fluoxetine, titrating her up to 40 mg/d. Mrs. B also begins weekly psychodynamic psychotherapy. In collaboration with her PCP, you decide to refer Mrs. B to physical therapy and direct psychotherapy toward coping strategies, with the hope of improving functionality. Although she continues to have musculoskeletal symptoms after completing physical therapy, Mrs. B notices moderate improvement and feels less distressed by these symptoms.

After 1 year of fluoxetine treatment, Mrs. B’s depressive symptoms improve. In psychotherapy, her fixation on physical symptoms and desire to establish a diagnosis gradually lessen. As her emotional trauma from childhood abuse unravels, psychotherapy shifts toward improving affect regulation. During this time Mrs. B experiences an increase in unexplained chest pain and shortness of breath, which later abate.

Continued follow-up with a gastroenterologist leads to a diagnosis of celiac disease. With treatment, her GI symptoms resolve.

What do patients want?

Begin MUPS treatment by developing a supportive, empathic relationship with the patient. Carefully listen to the patient’s description of his or her symptoms. Elucidating patients’ experience often is challenging because their narratives frequently are complex, nonlinear, and limited by time.¹⁸ Patients’ models for understanding their symptoms also may be complex.¹⁸ They may be reluctant to share their explanations, fearing they will be unable to communicate the complexity of their beliefs or their symptoms will be oversimplified.¹⁸

Focus on understanding what the patient seeks from the physician—emotional support vs diagnosis vs treatment. In a prospective naturalistic study, the content of MUPS patients’ narratives was correlated with what they sought from their physician.¹⁷ Patients who sought emotional support frequently discussed psychosocial problems, issues, and management. Patients who wanted an explanation for their symptoms often mentioned physical symptoms, explanations, and diseases. Those who were looking for additional testing or intervention often directly addressed this with the physician.¹⁷

Although many patients desire a diagnosis and somatic treatment, this is not always their primary agenda. Many MUPS patients seek emotional support or confirmation of their explanatory model.^17,18 Patients’ desires for emotional support, medical explanation, diagnosis, or somatic intervention often are neither clearly nor explicitly stated. Despite this, patients hope their physician understands the extent of their problems and value those who help them make sense of their narratives.¹⁸ Misunderstanding patients’ agendas can result in a mismatch of treatment expectations and fracture the patient-physician relationship. Developing mutual expectations is crucial to building rapport, improving collaborative care, and avoiding unnecessary, potentially harmful interventions.

Psychotherapic interventions

Psychopharmacologic treatment is indicated for MUPS patients who have comorbid psychiatric conditions.

Research of psychotherapy in MUPS has been plagued by methodologic problems and inconsistent results.³ Group therapy, short-term dynamic therapy, hypnotherapy, and cognitive-behavioral therapy (CBT) have been studied. In a trial of 140 MUPS patients who received 1 session of CBT, 71% experienced improvement in physical symptoms, 47% in functional status, and 38% in measures of psychological distress.¹⁹ A review of 34 randomized controlled trials involving 3,922 patients with somatoform disorders who received CBT found that some patients with MUPS responded after 5 to 6 sessions.³

Cognitive techniques focus on identifying and restructuring automatic, dysfunctional thoughts that may compound, perpetuate, or worsen somatic symptoms. Behavioral techniques include relaxation and efforts to increase motivation. A CBT treatment plan may involve establishing goals, addressing patients’ understanding of their symptoms, obtaining a commitment for treatment, and negotiating the details of the treatment plan.^8,12

Supportive techniques also are valuable in treating MUPS patients. Educate patients and treating physicians that there is a neurophysiologic basis for the patient’s physical symptoms and that symptoms may wax and wane. Reinforcement of functional improvement through concrete, practical solutions can help patients develop healthy, adaptive coping skills. Encouraging patients to move beyond somatic complaints to discuss social and personal difficulties can lead to more effective management of these problems.

Clearly communicate your initial impressions, diagnoses, and treatment plan to other members of the treatment team. A consultation letter from the psychiatrist to the PCP has been shown to decrease costs and slightly improve the patient’s functional status, symptoms, and quality of life.²⁰ When possible, educate the PCP and specialists about the dynamics, challenges, biases, and frustrations physicians commonly face when caring for MUPS patients.

Related Resources

• Burton C. Beyond somatization: a review of the understanding and treatment of medically unexplained physical symptoms. Brit J Gen Pract. 2003;53:233-239.
• Creed F. The outcome of medically unexplained symptoms—will DSM-V improve on DSM-IV somatoform disorders? J Psychosom Res. 2009;66:379-381.
• Katon W, Sullivan M, Walker E. Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits. Ann Intern Med. 2001;134(9 Pt 2):917-925.
• Sharpe M, Mayou R, Walker J. Bodily symptoms: new approaches to classification. J Psychosom Res. 2006;60: 353-356.

Drug Brand Names

• Fluoxetine • Prozac

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Box

Substance use and high-risk sexual behaviors are common among persons with severe mental illness and make them vulnerable to human immunodeficiency virus (HIV) infection.^1-3 The prevalence of HIV is 3 times higher among these patients compared with individuals who are not mentally ill. This article reviews risk factors for HIV transmission, HIV screening recommendations, and current testing options, including the fourth-generation HIV test.

According to the World Health Organization, in 2009:

• 33 million people were infected with HIV
• there were 2.6 million new infections
• 1.8 million people died from causes related to acquired immune deficiency syndrome (AIDS).⁴

In the United States, approximately 1 million people are living with HIV; 55, 000 new cases were diagnosed in North America in 2009.⁵ The demographics of those infected with HIV in the United States have changed substantially. Most newly infected individuals are African American, and younger adults have higher rates of new infections.⁶ With the introduction of standardized antiviral medication combinations and federal programs to provide universal access to medications in the mid 1990s, the number of AIDS cases and mortality dropped, but there have not been similar gains in the past decade.⁶

In countries With access to antiviral medications, medical advances in HIV treatment have transformed an infection with a high mortality rate into a chronic illness. However, the rate of new cases has not changed significantly in the past 10 years. Early detection and treatment initiation reduces high-risk behavior and subsequent transmission in patients with HIV. Evidence suggests that detecting HIV in the acute phase of the illness, when the viral load is high, reduces HIV transmission.^1,5,6

HIV screening

HIV screening should be part of routine psychiatric practice, especially in community and forensic settings. We recommend that all psychiatrists understand HIV screening guidelines from the Centers for Disease Control and Prevention (CDC)⁷ and the American College of Physicians (ACP).⁸ The CDC (2006)⁷ and ACP (2009)⁸ guidelines recommend HIV screening for:

• all patients age 13 to 64, unless the prevalence of undiagnosed HIV infection in your patients has been documented to be <0. 1%⁷
• all patients seeking treatment for sexually transmitted diseases, including each visit for a new complaint⁷
• all pregnant women⁷
• any patient who received a blood transfusion between 1978 and 1985.⁸

Rescreening frequency is determined on an individual basis, taking into consideration the patient’s risk of contracting HIV. The ACP guidelines recommend using rapid tests when available.⁸ Although the false positive rates are higher with rapid tests, the benefits of early detection and reducing transmission outweigh the cost of confirming positive tests.⁸

The fourth-generation test

The gold standard for HIV screening is the enzyme-linked immunosorbent assay antibody test followed by a western blot.⁸ This has a high sensitivity and specificity but there is a window of time between infection and detectable antibodies in serum during which patients have high virus levels (Figure).⁹ The combined antibody and antigen p24 test is a fourth-generation screening tool that detects HIV in the acute phase of the illness without requiring expensive ribonucleic acid viral tests.¹⁰ The fourth-generation test’s capacity to detect infection during the antibody-negative window when infectivity is highest may help decrease HIV transmission.¹¹

Figure When can HIV tests detect the virus?
EIA: enzyme immunoassay; HIV: human immunodeficiency virus; RNA: ribonucleic acid
Source: Adapted from reference 9

Psychiatrists’ role

Because psychiatrists routinely interact with patients who have an increased risk of HIV, they may be uniquely qualified to help these individuals. Psychiatrists often are comfortable discussing patients’ sexual and substance use history, which allows them to uncover and effectively address high-risk behaviors with appropriate testing and counseling. If testing confirms HIV infection, psychiatrists also can discuss altering high-risk behaviors (Table),^1,2 which has significant implications not only for patients, but also for public health.

Table

HIV transmission risk factors

Related Resource

• Centers for Disease Control and Prevention. HIV/AIDS. www.cdc.gov/hiv.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Substance use and high-risk sexual behaviors are common among persons with severe mental illness and make them vulnerable to human immunodeficiency virus (HIV) infection.^1-3 The prevalence of HIV is 3 times higher among these patients compared with individuals who are not mentally ill. This article reviews risk factors for HIV transmission, HIV screening recommendations, and current testing options, including the fourth-generation HIV test.

According to the World Health Organization, in 2009:

• 33 million people were infected with HIV
• there were 2.6 million new infections
• 1.8 million people died from causes related to acquired immune deficiency syndrome (AIDS).⁴

In the United States, approximately 1 million people are living with HIV; 55, 000 new cases were diagnosed in North America in 2009.⁵ The demographics of those infected with HIV in the United States have changed substantially. Most newly infected individuals are African American, and younger adults have higher rates of new infections.⁶ With the introduction of standardized antiviral medication combinations and federal programs to provide universal access to medications in the mid 1990s, the number of AIDS cases and mortality dropped, but there have not been similar gains in the past decade.⁶

In countries With access to antiviral medications, medical advances in HIV treatment have transformed an infection with a high mortality rate into a chronic illness. However, the rate of new cases has not changed significantly in the past 10 years. Early detection and treatment initiation reduces high-risk behavior and subsequent transmission in patients with HIV. Evidence suggests that detecting HIV in the acute phase of the illness, when the viral load is high, reduces HIV transmission.^1,5,6

HIV screening

HIV screening should be part of routine psychiatric practice, especially in community and forensic settings. We recommend that all psychiatrists understand HIV screening guidelines from the Centers for Disease Control and Prevention (CDC)⁷ and the American College of Physicians (ACP).⁸ The CDC (2006)⁷ and ACP (2009)⁸ guidelines recommend HIV screening for:

• all patients age 13 to 64, unless the prevalence of undiagnosed HIV infection in your patients has been documented to be <0. 1%⁷
• all patients seeking treatment for sexually transmitted diseases, including each visit for a new complaint⁷
• all pregnant women⁷
• any patient who received a blood transfusion between 1978 and 1985.⁸

Rescreening frequency is determined on an individual basis, taking into consideration the patient’s risk of contracting HIV. The ACP guidelines recommend using rapid tests when available.⁸ Although the false positive rates are higher with rapid tests, the benefits of early detection and reducing transmission outweigh the cost of confirming positive tests.⁸

The fourth-generation test

The gold standard for HIV screening is the enzyme-linked immunosorbent assay antibody test followed by a western blot.⁸ This has a high sensitivity and specificity but there is a window of time between infection and detectable antibodies in serum during which patients have high virus levels (Figure).⁹ The combined antibody and antigen p24 test is a fourth-generation screening tool that detects HIV in the acute phase of the illness without requiring expensive ribonucleic acid viral tests.¹⁰ The fourth-generation test’s capacity to detect infection during the antibody-negative window when infectivity is highest may help decrease HIV transmission.¹¹

Figure When can HIV tests detect the virus?
EIA: enzyme immunoassay; HIV: human immunodeficiency virus; RNA: ribonucleic acid
Source: Adapted from reference 9

Psychiatrists’ role

Because psychiatrists routinely interact with patients who have an increased risk of HIV, they may be uniquely qualified to help these individuals. Psychiatrists often are comfortable discussing patients’ sexual and substance use history, which allows them to uncover and effectively address high-risk behaviors with appropriate testing and counseling. If testing confirms HIV infection, psychiatrists also can discuss altering high-risk behaviors (Table),^1,2 which has significant implications not only for patients, but also for public health.

Table

HIV transmission risk factors

Related Resource

• Centers for Disease Control and Prevention. HIV/AIDS. www.cdc.gov/hiv.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Substance use and high-risk sexual behaviors are common among persons with severe mental illness and make them vulnerable to human immunodeficiency virus (HIV) infection.^1-3 The prevalence of HIV is 3 times higher among these patients compared with individuals who are not mentally ill. This article reviews risk factors for HIV transmission, HIV screening recommendations, and current testing options, including the fourth-generation HIV test.

According to the World Health Organization, in 2009:

• 33 million people were infected with HIV
• there were 2.6 million new infections
• 1.8 million people died from causes related to acquired immune deficiency syndrome (AIDS).⁴

In the United States, approximately 1 million people are living with HIV; 55, 000 new cases were diagnosed in North America in 2009.⁵ The demographics of those infected with HIV in the United States have changed substantially. Most newly infected individuals are African American, and younger adults have higher rates of new infections.⁶ With the introduction of standardized antiviral medication combinations and federal programs to provide universal access to medications in the mid 1990s, the number of AIDS cases and mortality dropped, but there have not been similar gains in the past decade.⁶

In countries With access to antiviral medications, medical advances in HIV treatment have transformed an infection with a high mortality rate into a chronic illness. However, the rate of new cases has not changed significantly in the past 10 years. Early detection and treatment initiation reduces high-risk behavior and subsequent transmission in patients with HIV. Evidence suggests that detecting HIV in the acute phase of the illness, when the viral load is high, reduces HIV transmission.^1,5,6

HIV screening

HIV screening should be part of routine psychiatric practice, especially in community and forensic settings. We recommend that all psychiatrists understand HIV screening guidelines from the Centers for Disease Control and Prevention (CDC)⁷ and the American College of Physicians (ACP).⁸ The CDC (2006)⁷ and ACP (2009)⁸ guidelines recommend HIV screening for:

• all patients age 13 to 64, unless the prevalence of undiagnosed HIV infection in your patients has been documented to be <0. 1%⁷
• all patients seeking treatment for sexually transmitted diseases, including each visit for a new complaint⁷
• all pregnant women⁷
• any patient who received a blood transfusion between 1978 and 1985.⁸

Rescreening frequency is determined on an individual basis, taking into consideration the patient’s risk of contracting HIV. The ACP guidelines recommend using rapid tests when available.⁸ Although the false positive rates are higher with rapid tests, the benefits of early detection and reducing transmission outweigh the cost of confirming positive tests.⁸

The fourth-generation test

The gold standard for HIV screening is the enzyme-linked immunosorbent assay antibody test followed by a western blot.⁸ This has a high sensitivity and specificity but there is a window of time between infection and detectable antibodies in serum during which patients have high virus levels (Figure).⁹ The combined antibody and antigen p24 test is a fourth-generation screening tool that detects HIV in the acute phase of the illness without requiring expensive ribonucleic acid viral tests.¹⁰ The fourth-generation test’s capacity to detect infection during the antibody-negative window when infectivity is highest may help decrease HIV transmission.¹¹

Figure When can HIV tests detect the virus?
EIA: enzyme immunoassay; HIV: human immunodeficiency virus; RNA: ribonucleic acid
Source: Adapted from reference 9

Psychiatrists’ role

Because psychiatrists routinely interact with patients who have an increased risk of HIV, they may be uniquely qualified to help these individuals. Psychiatrists often are comfortable discussing patients’ sexual and substance use history, which allows them to uncover and effectively address high-risk behaviors with appropriate testing and counseling. If testing confirms HIV infection, psychiatrists also can discuss altering high-risk behaviors (Table),^1,2 which has significant implications not only for patients, but also for public health.

Table

HIV transmission risk factors

Related Resource

• Centers for Disease Control and Prevention. HIV/AIDS. www.cdc.gov/hiv.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Consider this rare disorder in patients with rapid-onset neurologic symptoms

Ms. J, age 63, is admitted to Neurology with progressive dizziness and cognitive impairment. She had developed word-finding difficulties, weakness, memory problems, and an episode of arm shaking, which prompted referral for inpatient workup. Ms. J has a history of hypertension, palpitations, and diabetes mellitus.

Her neurologic examination is variable; some examiners find pronounced aphasia and right-sided weakness, whereas others document a nearly normal examination. Lumbar puncture (LP) shows normal cell count, glucose, protein, and negative Gram’s stain; MRI of the brain is normal. Enterovirus polymerase chain reaction, cryptococcal antigen, and Lyme antibody are negative. Electroencephalography (EEG) demonstrates diffuse slowing. The primary team requests psychiatric consultation to assess for conversion disorder.

Ms. J is cooperative with psychiatric evaluation. She denies current or past psychiatric symptomatology and does not meet criteria for major depression, dysthymia, adjustment disorder, anxiety disorder, psychosis, or mania. She denies personal or family history of suicidal or homicidal ideation, intent, or plan. Her youngest son died 5 years earlier; she is financially secure and her 40-year marriage is stable. Ms. J denies having a history of substance use, physical or sexual abuse, or trauma.

In the Cardiology clinic 2 months ago, Ms. J denied having neurologic symptoms and was noted to be doing well. Her neurologic symptoms began shortly after that visit and steadily progressed. She is unable to identify an inciting event or stressor. Ms. J worked until 2 weeks before this admission. Neurologic examination at the time of psychiatric consultation is notable for waxing and waning expressive aphasia, right homonymous hemianopsia, and mildly decreased strength in the left biceps and forearm.

Ms. J presented to her cardiologist reporting dizziness and blurred vision 6 weeks ago, and she was observed in the hospital 3 weeks earlier for further evaluation. Laboratory testing during that hospitalization included blood counts, basic metabolic panel, thyroid function studies, erythrocyte sedimentation rate, thiamine, folic acid and vitamin B12, rapid plasma reagin and human immunodeficiency virus antibody, and LP, all reported as within normal limits.

Thorough review of Ms. J’s medical records reveals abnormalities that would be difficult to ascribe to conversion disorder. Specifically, 6 weeks ago, MRI of the brain demonstrated restricted diffusion in the left occipital lobe, and cerebrospinal fluid (CSF) neuron-specific enolase was moderately elevated at 34 ng/mL. The psychiatric consultant discusses these findings and concern for possible rapidly progressive dementia or Creutzfeldt-Jakob disease (CJD) with the primary team, Ms. J, and her family.

Ms. J is discharged with testing for CSF protein 14-3-3 pending and medical follow-up in 10 days. At follow-up 1 week later, her symptoms are worse; she is completely aphasic and wheelchair-bound. Antithyroglobulin and antimicrosomal thyroid antibodies and paraneoplastic antibody panel return normal. CSF protein 14-3-3 ultimately returns positive, supporting a clinical diagnosis of CJD. Ms. J dies shortly after hospital follow-up, less than 4 months after her first complaint of neurologic symptoms. No autopsy is performed.

Patients with conversion disorder may present with neurologic symptoms such as blindness, seizures, paralysis, or sensory loss with no identifiable anatomical or medical explanation.¹ Conversion seizures—also known as pseudoseizures or nonepileptic seizures—may be clinically indistinguishable from generalized tonic-clonic seizures, but no EEG correlate can be identified.^1,2 Conversion disorder is conceptualized as an unconscious manifestation of psychological conflict or stress—patients are not aware they are producing symptoms—and has been associated with emotional, sexual, and physical trauma.^3,4

Conversion disorder is a diagnosis of exclusion and requires thorough evaluation to rule out neurologic or medical etiologies. The differential diagnosis for conversion disorder includes the broad medical differential diagnosis for the symptom, whether it be paralysis, seizures, sensory loss, or other presenting symptoms. Therefore, when evaluating patients for conversion disorder, be vigilant to the possibility of not only underlying psychological stress or trauma but also undiscovered medical or neurologic illness.

In Ms. J’s case, the primary team began to suspect there was no organic cause of her neurologic symptoms. However, psychiatric evaluation revealed that Ms. J had no history of stress or trauma that typically would be associated with conversion disorder, nor did she manifest other psychiatric symptoms, except waxing and waning mental status, which raised concerns for possible delirium or encephalopathy. Additionally, slowing on EEG was a nonspecific but abnormal finding that made conversion disorder unlikely. The consulting psychiatrist discussed this slowing, in conjunction with the abnormal MRI and elevated CSF neuron-specific enolase, with members of the referring Neurology service, who ordered additional testing of CSF for protein 14-3-3.

Creutzfeldt-Jakob disease

CJD is a rapidly progressive neurodegenerative disorder characterized by cognitive changes, behavioral changes, gait disturbances, akinetic mutism, and myoclonus.⁵ CJD results from the transition of prion proteins, which are present in the normal human brain, to disease-associated forms that aggregate and propagate and result in neurotoxicity with spongiform changes in neurons.⁶ The transition of normal prions to disease-associated prions may be hereditary, iatrogenic, infectious, or sporadic. Because the pathologic prion protein can be transmitted and normal sterilization procedures do not prevent the spread of CJD, special precautions should be taken to avoid contact with blood or CSF from patients suspected of having CJD.⁵

CJD most commonly occurs in the sporadic form, for which there are no identifiable risk factors, with an average age of onset between age 50 and 70. The disease affects women and men equally at a rate of 1 to 2 persons per million per year worldwide.^6,7 Most patients with CJD die within 12 months of diagnosis⁸; median survival is 4 to 5 months.^7,9 Although there is no approved or standard effective treatment for this uniformly fatal disease, research into the possibility of genetic or post-translational treatments is ongoing. One group reported inhibition of prion propagation by quinacrine and chlorpromazine in vitro.¹⁰ Clinical studies of quinacrine have demonstrated tolerability but no impact on the course of CJD.⁶

Clues to diagnosis. Although there is no treatment for CJD, early diagnosis can help patients and families understand the relentless progression of symptoms and also permits end-of-life planning and palliative care.¹¹ Diagnosing CJD requires a high level of suspicion and traditionally has required brain biopsy or autopsy for conclusive diagnosis, although in some cases rare EEG findings of periodic sharp wave complexes or generalized periodic epileptiform discharges (GPEDs) have suggested the diagnosis.^7,8,12 Recently, specific MRI findings have been described with fluid attenuated inversion recovery (FLAIR) and diffusion sequences.^9,13,14

Routine LP for CSF examination (including cell count, protein, and glucose) frequently is normal.⁸ Specific testing to assess for CJD is required. Elevated levels of CSF neuron-specific enolase (normal <30 ng/mL) and protein 14-3-3 (normal <8 ng/mL) are fairly sensitive and specific for CJD when assessed in patients with the proper clinical history, although normal levels of these proteins have been detected in patients later confirmed to have CJD.^7,15 A large multinational collaborative study of confirmed CJD cases that evaluated diagnostic test characteristics recommended that because each test has limitations and can be falsely negative—even in a case of later-confirmed CJD—a rational approach to diagnosis includes brain MRI with diffusion-weighted imaging, CSF analysis for protein 14-3-3, and EEG to assess for periodic sharp wave complexes or GPEDs.¹⁶

Because CJD presentation varies widely, most clinicians will not consider the diagnosis until the disease has progressed or the patient has died. Patients who present with psychological symptoms or predominant language disturbances and dysphagia may be referred to a psychiatrist or an ear, nose, and throat specialist before seeing a neurologist.⁹ Patients may be extensively evaluated and treated for conversion disorder when the correct diagnosis is CJD.¹⁷

Sporadic CJD traditionally is associated with neurologic presentations, whereas variant CJD is believed to present with psychiatric symptomatology. However, in a 25-year retrospective review of 126 patients with sporadic CJD, 80% of cases demonstrated psychiatric symptoms within the first 100 days of the disease course.¹⁸ Of these, nearly 25% showed psychiatric symptoms at presentation, including sleep disturbances, psychotic symptoms, agitation, and anxiety.

Psychiatrists should be aware of distinguishing features of rapidly progressive dementias and CJD, especially in the setting of psychiatric consultation, to rule out somatic etiologies of unexplained neurologic symptoms. It is important to obtain a history of baseline functioning, duration of decline, and psychiatric symptomatology to differentiate between organic and somatic causes. Differential diagnosis for rapidly progressive cognitive impairment is broad and includes delirium from diverse medical causes; rapidly progressive dementia such as accelerated Alzheimer’s disease, Lewy body disease, or frontotemporal dementia; and psychogenic causes, including conversion disorder (Table 1).^7,8,12Table 2 provides distinguishing features of CJD, Alzheimer’s disease, Lewy body disease, and frontotemporal dementia with motor neuron disease.^7,8,19

Table 1

Differential diagnosis of rapidly progressive dementia

Table 2

Distinguishing features of Creutzfeldt-Jakob disease

Related Resources

National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.

Centers for Disease Control and Prevention. About CJD. www.cdc.gov/ncidod/dvrd/cjd.

Drug Brand Names

Chlorpromazine • Thorazine, Largactil

Quinacine • Atabrine

Disclosure

Dr. Gagliardi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Consider this rare disorder in patients with rapid-onset neurologic symptoms

Ms. J, age 63, is admitted to Neurology with progressive dizziness and cognitive impairment. She had developed word-finding difficulties, weakness, memory problems, and an episode of arm shaking, which prompted referral for inpatient workup. Ms. J has a history of hypertension, palpitations, and diabetes mellitus.

Her neurologic examination is variable; some examiners find pronounced aphasia and right-sided weakness, whereas others document a nearly normal examination. Lumbar puncture (LP) shows normal cell count, glucose, protein, and negative Gram’s stain; MRI of the brain is normal. Enterovirus polymerase chain reaction, cryptococcal antigen, and Lyme antibody are negative. Electroencephalography (EEG) demonstrates diffuse slowing. The primary team requests psychiatric consultation to assess for conversion disorder.

Ms. J is cooperative with psychiatric evaluation. She denies current or past psychiatric symptomatology and does not meet criteria for major depression, dysthymia, adjustment disorder, anxiety disorder, psychosis, or mania. She denies personal or family history of suicidal or homicidal ideation, intent, or plan. Her youngest son died 5 years earlier; she is financially secure and her 40-year marriage is stable. Ms. J denies having a history of substance use, physical or sexual abuse, or trauma.

In the Cardiology clinic 2 months ago, Ms. J denied having neurologic symptoms and was noted to be doing well. Her neurologic symptoms began shortly after that visit and steadily progressed. She is unable to identify an inciting event or stressor. Ms. J worked until 2 weeks before this admission. Neurologic examination at the time of psychiatric consultation is notable for waxing and waning expressive aphasia, right homonymous hemianopsia, and mildly decreased strength in the left biceps and forearm.

Ms. J presented to her cardiologist reporting dizziness and blurred vision 6 weeks ago, and she was observed in the hospital 3 weeks earlier for further evaluation. Laboratory testing during that hospitalization included blood counts, basic metabolic panel, thyroid function studies, erythrocyte sedimentation rate, thiamine, folic acid and vitamin B12, rapid plasma reagin and human immunodeficiency virus antibody, and LP, all reported as within normal limits.

Thorough review of Ms. J’s medical records reveals abnormalities that would be difficult to ascribe to conversion disorder. Specifically, 6 weeks ago, MRI of the brain demonstrated restricted diffusion in the left occipital lobe, and cerebrospinal fluid (CSF) neuron-specific enolase was moderately elevated at 34 ng/mL. The psychiatric consultant discusses these findings and concern for possible rapidly progressive dementia or Creutzfeldt-Jakob disease (CJD) with the primary team, Ms. J, and her family.

Ms. J is discharged with testing for CSF protein 14-3-3 pending and medical follow-up in 10 days. At follow-up 1 week later, her symptoms are worse; she is completely aphasic and wheelchair-bound. Antithyroglobulin and antimicrosomal thyroid antibodies and paraneoplastic antibody panel return normal. CSF protein 14-3-3 ultimately returns positive, supporting a clinical diagnosis of CJD. Ms. J dies shortly after hospital follow-up, less than 4 months after her first complaint of neurologic symptoms. No autopsy is performed.

Patients with conversion disorder may present with neurologic symptoms such as blindness, seizures, paralysis, or sensory loss with no identifiable anatomical or medical explanation.¹ Conversion seizures—also known as pseudoseizures or nonepileptic seizures—may be clinically indistinguishable from generalized tonic-clonic seizures, but no EEG correlate can be identified.^1,2 Conversion disorder is conceptualized as an unconscious manifestation of psychological conflict or stress—patients are not aware they are producing symptoms—and has been associated with emotional, sexual, and physical trauma.^3,4

Conversion disorder is a diagnosis of exclusion and requires thorough evaluation to rule out neurologic or medical etiologies. The differential diagnosis for conversion disorder includes the broad medical differential diagnosis for the symptom, whether it be paralysis, seizures, sensory loss, or other presenting symptoms. Therefore, when evaluating patients for conversion disorder, be vigilant to the possibility of not only underlying psychological stress or trauma but also undiscovered medical or neurologic illness.

In Ms. J’s case, the primary team began to suspect there was no organic cause of her neurologic symptoms. However, psychiatric evaluation revealed that Ms. J had no history of stress or trauma that typically would be associated with conversion disorder, nor did she manifest other psychiatric symptoms, except waxing and waning mental status, which raised concerns for possible delirium or encephalopathy. Additionally, slowing on EEG was a nonspecific but abnormal finding that made conversion disorder unlikely. The consulting psychiatrist discussed this slowing, in conjunction with the abnormal MRI and elevated CSF neuron-specific enolase, with members of the referring Neurology service, who ordered additional testing of CSF for protein 14-3-3.

Creutzfeldt-Jakob disease

CJD is a rapidly progressive neurodegenerative disorder characterized by cognitive changes, behavioral changes, gait disturbances, akinetic mutism, and myoclonus.⁵ CJD results from the transition of prion proteins, which are present in the normal human brain, to disease-associated forms that aggregate and propagate and result in neurotoxicity with spongiform changes in neurons.⁶ The transition of normal prions to disease-associated prions may be hereditary, iatrogenic, infectious, or sporadic. Because the pathologic prion protein can be transmitted and normal sterilization procedures do not prevent the spread of CJD, special precautions should be taken to avoid contact with blood or CSF from patients suspected of having CJD.⁵

CJD most commonly occurs in the sporadic form, for which there are no identifiable risk factors, with an average age of onset between age 50 and 70. The disease affects women and men equally at a rate of 1 to 2 persons per million per year worldwide.^6,7 Most patients with CJD die within 12 months of diagnosis⁸; median survival is 4 to 5 months.^7,9 Although there is no approved or standard effective treatment for this uniformly fatal disease, research into the possibility of genetic or post-translational treatments is ongoing. One group reported inhibition of prion propagation by quinacrine and chlorpromazine in vitro.¹⁰ Clinical studies of quinacrine have demonstrated tolerability but no impact on the course of CJD.⁶

Clues to diagnosis. Although there is no treatment for CJD, early diagnosis can help patients and families understand the relentless progression of symptoms and also permits end-of-life planning and palliative care.¹¹ Diagnosing CJD requires a high level of suspicion and traditionally has required brain biopsy or autopsy for conclusive diagnosis, although in some cases rare EEG findings of periodic sharp wave complexes or generalized periodic epileptiform discharges (GPEDs) have suggested the diagnosis.^7,8,12 Recently, specific MRI findings have been described with fluid attenuated inversion recovery (FLAIR) and diffusion sequences.^9,13,14

Routine LP for CSF examination (including cell count, protein, and glucose) frequently is normal.⁸ Specific testing to assess for CJD is required. Elevated levels of CSF neuron-specific enolase (normal <30 ng/mL) and protein 14-3-3 (normal <8 ng/mL) are fairly sensitive and specific for CJD when assessed in patients with the proper clinical history, although normal levels of these proteins have been detected in patients later confirmed to have CJD.^7,15 A large multinational collaborative study of confirmed CJD cases that evaluated diagnostic test characteristics recommended that because each test has limitations and can be falsely negative—even in a case of later-confirmed CJD—a rational approach to diagnosis includes brain MRI with diffusion-weighted imaging, CSF analysis for protein 14-3-3, and EEG to assess for periodic sharp wave complexes or GPEDs.¹⁶

Because CJD presentation varies widely, most clinicians will not consider the diagnosis until the disease has progressed or the patient has died. Patients who present with psychological symptoms or predominant language disturbances and dysphagia may be referred to a psychiatrist or an ear, nose, and throat specialist before seeing a neurologist.⁹ Patients may be extensively evaluated and treated for conversion disorder when the correct diagnosis is CJD.¹⁷

Sporadic CJD traditionally is associated with neurologic presentations, whereas variant CJD is believed to present with psychiatric symptomatology. However, in a 25-year retrospective review of 126 patients with sporadic CJD, 80% of cases demonstrated psychiatric symptoms within the first 100 days of the disease course.¹⁸ Of these, nearly 25% showed psychiatric symptoms at presentation, including sleep disturbances, psychotic symptoms, agitation, and anxiety.

Psychiatrists should be aware of distinguishing features of rapidly progressive dementias and CJD, especially in the setting of psychiatric consultation, to rule out somatic etiologies of unexplained neurologic symptoms. It is important to obtain a history of baseline functioning, duration of decline, and psychiatric symptomatology to differentiate between organic and somatic causes. Differential diagnosis for rapidly progressive cognitive impairment is broad and includes delirium from diverse medical causes; rapidly progressive dementia such as accelerated Alzheimer’s disease, Lewy body disease, or frontotemporal dementia; and psychogenic causes, including conversion disorder (Table 1).^7,8,12Table 2 provides distinguishing features of CJD, Alzheimer’s disease, Lewy body disease, and frontotemporal dementia with motor neuron disease.^7,8,19

Table 1

Differential diagnosis of rapidly progressive dementia

Table 2

Distinguishing features of Creutzfeldt-Jakob disease

Related Resources

National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.

Centers for Disease Control and Prevention. About CJD. www.cdc.gov/ncidod/dvrd/cjd.

Drug Brand Names

Chlorpromazine • Thorazine, Largactil

Quinacine • Atabrine

Disclosure

Dr. Gagliardi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Consider this rare disorder in patients with rapid-onset neurologic symptoms

Ms. J, age 63, is admitted to Neurology with progressive dizziness and cognitive impairment. She had developed word-finding difficulties, weakness, memory problems, and an episode of arm shaking, which prompted referral for inpatient workup. Ms. J has a history of hypertension, palpitations, and diabetes mellitus.

Her neurologic examination is variable; some examiners find pronounced aphasia and right-sided weakness, whereas others document a nearly normal examination. Lumbar puncture (LP) shows normal cell count, glucose, protein, and negative Gram’s stain; MRI of the brain is normal. Enterovirus polymerase chain reaction, cryptococcal antigen, and Lyme antibody are negative. Electroencephalography (EEG) demonstrates diffuse slowing. The primary team requests psychiatric consultation to assess for conversion disorder.

Ms. J is cooperative with psychiatric evaluation. She denies current or past psychiatric symptomatology and does not meet criteria for major depression, dysthymia, adjustment disorder, anxiety disorder, psychosis, or mania. She denies personal or family history of suicidal or homicidal ideation, intent, or plan. Her youngest son died 5 years earlier; she is financially secure and her 40-year marriage is stable. Ms. J denies having a history of substance use, physical or sexual abuse, or trauma.

In the Cardiology clinic 2 months ago, Ms. J denied having neurologic symptoms and was noted to be doing well. Her neurologic symptoms began shortly after that visit and steadily progressed. She is unable to identify an inciting event or stressor. Ms. J worked until 2 weeks before this admission. Neurologic examination at the time of psychiatric consultation is notable for waxing and waning expressive aphasia, right homonymous hemianopsia, and mildly decreased strength in the left biceps and forearm.

Ms. J presented to her cardiologist reporting dizziness and blurred vision 6 weeks ago, and she was observed in the hospital 3 weeks earlier for further evaluation. Laboratory testing during that hospitalization included blood counts, basic metabolic panel, thyroid function studies, erythrocyte sedimentation rate, thiamine, folic acid and vitamin B12, rapid plasma reagin and human immunodeficiency virus antibody, and LP, all reported as within normal limits.

Thorough review of Ms. J’s medical records reveals abnormalities that would be difficult to ascribe to conversion disorder. Specifically, 6 weeks ago, MRI of the brain demonstrated restricted diffusion in the left occipital lobe, and cerebrospinal fluid (CSF) neuron-specific enolase was moderately elevated at 34 ng/mL. The psychiatric consultant discusses these findings and concern for possible rapidly progressive dementia or Creutzfeldt-Jakob disease (CJD) with the primary team, Ms. J, and her family.

Ms. J is discharged with testing for CSF protein 14-3-3 pending and medical follow-up in 10 days. At follow-up 1 week later, her symptoms are worse; she is completely aphasic and wheelchair-bound. Antithyroglobulin and antimicrosomal thyroid antibodies and paraneoplastic antibody panel return normal. CSF protein 14-3-3 ultimately returns positive, supporting a clinical diagnosis of CJD. Ms. J dies shortly after hospital follow-up, less than 4 months after her first complaint of neurologic symptoms. No autopsy is performed.

Patients with conversion disorder may present with neurologic symptoms such as blindness, seizures, paralysis, or sensory loss with no identifiable anatomical or medical explanation.¹ Conversion seizures—also known as pseudoseizures or nonepileptic seizures—may be clinically indistinguishable from generalized tonic-clonic seizures, but no EEG correlate can be identified.^1,2 Conversion disorder is conceptualized as an unconscious manifestation of psychological conflict or stress—patients are not aware they are producing symptoms—and has been associated with emotional, sexual, and physical trauma.^3,4

Conversion disorder is a diagnosis of exclusion and requires thorough evaluation to rule out neurologic or medical etiologies. The differential diagnosis for conversion disorder includes the broad medical differential diagnosis for the symptom, whether it be paralysis, seizures, sensory loss, or other presenting symptoms. Therefore, when evaluating patients for conversion disorder, be vigilant to the possibility of not only underlying psychological stress or trauma but also undiscovered medical or neurologic illness.

In Ms. J’s case, the primary team began to suspect there was no organic cause of her neurologic symptoms. However, psychiatric evaluation revealed that Ms. J had no history of stress or trauma that typically would be associated with conversion disorder, nor did she manifest other psychiatric symptoms, except waxing and waning mental status, which raised concerns for possible delirium or encephalopathy. Additionally, slowing on EEG was a nonspecific but abnormal finding that made conversion disorder unlikely. The consulting psychiatrist discussed this slowing, in conjunction with the abnormal MRI and elevated CSF neuron-specific enolase, with members of the referring Neurology service, who ordered additional testing of CSF for protein 14-3-3.

Creutzfeldt-Jakob disease