A 50-year-old woman with hypertension   presents with a history of polyarticular small-joint pain for the last 3 months. Her pain is worse in the morning, and it affects her metacarpal, proximal, and distal phalangeal joints. She describes intermittent swelling of her hands and morning stiffness lasting 15 to 30 minutes.

See related article

Her physical examination is unremarkable, with no evidence of active inflammation (synovitis), joint tenderness, restrictions in movement, or deformity. Her description of her symptoms raises suspicion for an inflammatory arthritis, but her physical examination does not support this diagnosis.

Bedside musculoskeletal ultrasonography of her wrists reveals synovial hypertrophy, and power Doppler shows active inflammation, findings consistent with synovitis (Figure 1).
This scenario illustrates how musculoskeletal ultrasonography can prevent delayed diagnosis, thus directing the ordering of appropriate laboratory studies and allowing treatment for pain relief to be started promptly.

ULTRASONOGRAPHY HAS GAINED A SOLID ROLE

Ultrasonography has gained a solid role in the care of patients with musculoskeletal conditions.

Using obtained images, as well as power Doppler to assess inflammation, the clinician can visualize superficial anatomic structures, including the skin, muscles, joints, nerves, and the cortical layer of bone. Combining the dynamic assessment with the clinical history and findings of the physical examination makes musculoskeletal ultrasonography a powerful tool for diagnosis and management.¹

In this issue, Forney and Delzell² review the clinical use of ultrasonography of the muscles and bones and its advantages and disadvantages compared with other imaging methods. They describe its gain in popularity over the last decade and its incorporation into clinical care in multiple medical subspecialties.

Musculoskeletal ultrasonography is performed and interpreted by specially trained sonographers. It should be viewed as a complementary procedure, not as a replacement for a thorough and systematic clinical examination.³

ADVANTAGES ARE MANY

A major advantage of musculoskeletal ultrasonography over other imaging techniques is its capacity to dynamically assess joint and tendon movements⁴ and to immediately interpret them in real time.

In rheumatology, where it has made the biggest impact, it can help evaluate inflammatory and noninflammatory rheumatic diseases, assess treatment response, and guide joint injections.¹ It has been demonstrated to significantly improve timely diagnosis and management,⁵ decrease dependence on other imaging modalities, and reduce healthcare costs.⁶

With its easy portability, ultrasonography has also been integrated into orthopedics, podiatry, physical medicine and rehabilitation, sports medicine, and emergency medicine. Its role is expanding to include the assessment of the skin in systemic sclerosis, parotid and submandibular glands in Sjögren syndrome, nails in patients with psoriasis, and temporal arteries in giant cell arteritis.

A ROLE IN MEDICAL EDUCATION

Musculoskeletal ultrasonography has entered into medical education, with an increasing number of medical schools incorporating it into their curriculum over the last few years.⁷ It enhances student learning of anatomy, the physical examination, and pathologic findings of rheumatic diseases.^7,8 Some internal medicine residency programs have added ultrasonography to help identify anatomic structures for invasive procedures, increasing patient safety and reducing procedural complications.⁹

It has been incorporated into the core curriculum in many rheumatology fellowship training programs.¹⁰ Rheumatologists can now also take additional courses to enhance their skills and become certified sonographers.

Musculoskeletal ultrasonography has proven to be a useful adjunct to the physical examination. With its many advantages, it has gained acceptance and is now a mainstay in many subspecialties.

A 50-year-old woman with hypertension   presents with a history of polyarticular small-joint pain for the last 3 months. Her pain is worse in the morning, and it affects her metacarpal, proximal, and distal phalangeal joints. She describes intermittent swelling of her hands and morning stiffness lasting 15 to 30 minutes.

See related article

Her physical examination is unremarkable, with no evidence of active inflammation (synovitis), joint tenderness, restrictions in movement, or deformity. Her description of her symptoms raises suspicion for an inflammatory arthritis, but her physical examination does not support this diagnosis.

Bedside musculoskeletal ultrasonography of her wrists reveals synovial hypertrophy, and power Doppler shows active inflammation, findings consistent with synovitis (Figure 1).
This scenario illustrates how musculoskeletal ultrasonography can prevent delayed diagnosis, thus directing the ordering of appropriate laboratory studies and allowing treatment for pain relief to be started promptly.

ULTRASONOGRAPHY HAS GAINED A SOLID ROLE

Ultrasonography has gained a solid role in the care of patients with musculoskeletal conditions.

Using obtained images, as well as power Doppler to assess inflammation, the clinician can visualize superficial anatomic structures, including the skin, muscles, joints, nerves, and the cortical layer of bone. Combining the dynamic assessment with the clinical history and findings of the physical examination makes musculoskeletal ultrasonography a powerful tool for diagnosis and management.¹

In this issue, Forney and Delzell² review the clinical use of ultrasonography of the muscles and bones and its advantages and disadvantages compared with other imaging methods. They describe its gain in popularity over the last decade and its incorporation into clinical care in multiple medical subspecialties.

Musculoskeletal ultrasonography is performed and interpreted by specially trained sonographers. It should be viewed as a complementary procedure, not as a replacement for a thorough and systematic clinical examination.³

ADVANTAGES ARE MANY

A major advantage of musculoskeletal ultrasonography over other imaging techniques is its capacity to dynamically assess joint and tendon movements⁴ and to immediately interpret them in real time.

In rheumatology, where it has made the biggest impact, it can help evaluate inflammatory and noninflammatory rheumatic diseases, assess treatment response, and guide joint injections.¹ It has been demonstrated to significantly improve timely diagnosis and management,⁵ decrease dependence on other imaging modalities, and reduce healthcare costs.⁶

With its easy portability, ultrasonography has also been integrated into orthopedics, podiatry, physical medicine and rehabilitation, sports medicine, and emergency medicine. Its role is expanding to include the assessment of the skin in systemic sclerosis, parotid and submandibular glands in Sjögren syndrome, nails in patients with psoriasis, and temporal arteries in giant cell arteritis.

A ROLE IN MEDICAL EDUCATION

Musculoskeletal ultrasonography has entered into medical education, with an increasing number of medical schools incorporating it into their curriculum over the last few years.⁷ It enhances student learning of anatomy, the physical examination, and pathologic findings of rheumatic diseases.^7,8 Some internal medicine residency programs have added ultrasonography to help identify anatomic structures for invasive procedures, increasing patient safety and reducing procedural complications.⁹

It has been incorporated into the core curriculum in many rheumatology fellowship training programs.¹⁰ Rheumatologists can now also take additional courses to enhance their skills and become certified sonographers.

Musculoskeletal ultrasonography has proven to be a useful adjunct to the physical examination. With its many advantages, it has gained acceptance and is now a mainstay in many subspecialties.

A 50-year-old woman with hypertension   presents with a history of polyarticular small-joint pain for the last 3 months. Her pain is worse in the morning, and it affects her metacarpal, proximal, and distal phalangeal joints. She describes intermittent swelling of her hands and morning stiffness lasting 15 to 30 minutes.

See related article

Her physical examination is unremarkable, with no evidence of active inflammation (synovitis), joint tenderness, restrictions in movement, or deformity. Her description of her symptoms raises suspicion for an inflammatory arthritis, but her physical examination does not support this diagnosis.

Bedside musculoskeletal ultrasonography of her wrists reveals synovial hypertrophy, and power Doppler shows active inflammation, findings consistent with synovitis (Figure 1).
This scenario illustrates how musculoskeletal ultrasonography can prevent delayed diagnosis, thus directing the ordering of appropriate laboratory studies and allowing treatment for pain relief to be started promptly.

ULTRASONOGRAPHY HAS GAINED A SOLID ROLE

Ultrasonography has gained a solid role in the care of patients with musculoskeletal conditions.

Using obtained images, as well as power Doppler to assess inflammation, the clinician can visualize superficial anatomic structures, including the skin, muscles, joints, nerves, and the cortical layer of bone. Combining the dynamic assessment with the clinical history and findings of the physical examination makes musculoskeletal ultrasonography a powerful tool for diagnosis and management.¹

In this issue, Forney and Delzell² review the clinical use of ultrasonography of the muscles and bones and its advantages and disadvantages compared with other imaging methods. They describe its gain in popularity over the last decade and its incorporation into clinical care in multiple medical subspecialties.

Musculoskeletal ultrasonography is performed and interpreted by specially trained sonographers. It should be viewed as a complementary procedure, not as a replacement for a thorough and systematic clinical examination.³

ADVANTAGES ARE MANY

A major advantage of musculoskeletal ultrasonography over other imaging techniques is its capacity to dynamically assess joint and tendon movements⁴ and to immediately interpret them in real time.

In rheumatology, where it has made the biggest impact, it can help evaluate inflammatory and noninflammatory rheumatic diseases, assess treatment response, and guide joint injections.¹ It has been demonstrated to significantly improve timely diagnosis and management,⁵ decrease dependence on other imaging modalities, and reduce healthcare costs.⁶

With its easy portability, ultrasonography has also been integrated into orthopedics, podiatry, physical medicine and rehabilitation, sports medicine, and emergency medicine. Its role is expanding to include the assessment of the skin in systemic sclerosis, parotid and submandibular glands in Sjögren syndrome, nails in patients with psoriasis, and temporal arteries in giant cell arteritis.

A ROLE IN MEDICAL EDUCATION

Musculoskeletal ultrasonography has entered into medical education, with an increasing number of medical schools incorporating it into their curriculum over the last few years.⁷ It enhances student learning of anatomy, the physical examination, and pathologic findings of rheumatic diseases.^7,8 Some internal medicine residency programs have added ultrasonography to help identify anatomic structures for invasive procedures, increasing patient safety and reducing procedural complications.⁹

It has been incorporated into the core curriculum in many rheumatology fellowship training programs.¹⁰ Rheumatologists can now also take additional courses to enhance their skills and become certified sonographers.

Musculoskeletal ultrasonography has proven to be a useful adjunct to the physical examination. With its many advantages, it has gained acceptance and is now a mainstay in many subspecialties.

A 71-year-old woman is brought to the emergency department by her neighbor after complaining of fatigue and light-headedness for the last 8 hours. The patient lives alone and was feeling well when she woke up this morning, but then began to feel nauseated and vomited twice.

The patient appears drowsy and confused and cannot provide any further history. Her medical records show that she was seen in the cardiology clinic 6 months ago but has not kept her appointments since then.

Her medical history includes atrial fibrillation, hypertension, type 2 diabetes mellitus, and osteoarthritis. Her medications are daily warfarin, atenolol, aspirin, candesartan, and metformin, and she takes acetaminophen as needed. She is neither a smoker nor a drug user, but she drinks alcohol occasionally. Her family history is significant for her mother’s death from breast cancer at age 55.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Her neck veins are flat, and her chest is clear to auscultation with normal heart sounds. Abdominal palpation elicits discomfort in the middle segments, voluntary withdrawal, and abdominal wall rigidity. Her skin feels dry and cool, with decreased turgor.

Initial treatment

The patient is given 1 L of 0.9% saline intravenously over the first hour and then is transferred to the intensive care unit, where a norepinephrine drip is started to treat her ongoing hypotension. Normal saline is continued at a rate of 500 mL per hour for the next 4 hours.

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her blood pH is 7.34 (reference range 7.35–7.45), and her bicarbonate level is 18 mmol/L (22–26); a low pH and low bicarbonate together indicate metabolic acidosis. Her sodium level is 128 mmol/L (135–145), her chloride level is 100 mmol/L (97–107), and, as mentioned, her bicarbonate level is 18 mmol/L; therefore, her anion gap is 128 – (100 + 18) = 10 mmol/L, which is normal (≤ 10).¹

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

• Adrenal crisis
• Cardiogenic shock due to decreased cardiac contractility
• Intracranial hemorrhage
• Acute abdomen due to small bowel obstruction
• Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

The sudden onset and laboratory results that include hyperkalemia, hyponatremia, and normal anion gap metabolic acidosis raise suspicion of adrenal crisis resulting in acute mineralocorticoid and glucocorticoid insufficiency.¹

The patient’s elevated serum creatinine and high blood urea nitrogen-to-creatinine ratio of 26.9 (reference range 10–20) also suggest intravascular volume contraction. Her low hemoglobin level and supratherapeutic INR, possibly due to an interaction between warfarin and acetaminophen combined with poor medical follow-up, raise suspicion of acute bilateral adrenal necrosis due to hemorrhage.

Bilateral adrenal hemorrhage is one cause of adrenal crisis resulting in bilateral adrenal necrosis. Risk factors for adrenal hemorrhage include anticoagulation therapy, underlying coagulopathy, postoperative states, and certain infections such as meningococcemia and Haemophilus influenzae infection.^2–5 Nevertheless, in most cases the INR is in the therapeutic range and the patient has no bleeding elsewhere.⁴ Other causes of adrenal necrosis include emboli, sepsis, and blunt trauma.^6,7

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage can present with a decreased level of consciousness, but it is less likely to cause hypotension, as the cranial space is limited. If massive intracranial hemorrhage would occur, the increase in intracranial pressure would more likely cause hypertension by the Cushing reflex than hypotension.

Acute abdomen

Abdominal pain and rigidity along with fever can be presenting symptoms of both adrenal insufficiency and an acute abdomen due to intestinal obstruction.⁴ However, intestinal obstruction typically causes a high anion gap metabolic acidosis due to lactic acidosis, instead of the normal anion gap metabolic acidosis present in this patient.⁸ Moreover, her deranged electrolytes, supratherapeutic INR, and absence of previous gastroenterologic conditions make adrenal crisis a more likely diagnosis.

Septic shock

Septic shock would also cause fever and hypotension as bacterial toxins induce a pyrexic response and vasodilation. However, at such an early stage of sepsis, the patient would be expected to be warm and hyperemic, whereas this patient’s skin is cool and dry due to volume depletion secondary to adrenal insufficiency.⁹ Sepsis would also cause a high anion gap metabolic acidosis due to lactic acidosis, as opposed to this patient’s normal anion gap metabolic acidosis. These findings, along with the metabolic derangements and the absence of a focus of infection, make sepsis a less likely possibility.

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Blood is drawn for cultures and measurement of troponins and lactic acid, and urine samples are taken for culture and biochemical analysis. Chest radiography shows mild cardiomegaly. The patient is started empirically on vancomycin and cefepime, and her warfarin is discontinued.

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

• Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
• Perform abdominal computed tomography (CT) without contrast
• Perform transthoracic echocardiography
• Increase the norepinephrine infusion
• Immediately give fludrocortisone

First give fluids

The first step in managing a patient with suspected adrenal crisis is liberal intravenous fluid administration to replenish the depleted intravascular space. The amount and choice of fluid is empiric, but a recommendation is 1 L of normal saline or dextrose 5% in normal saline, infused quickly over the first hour and then titrated according to the patient’s fluid status.¹⁰

Measure cortisol and ACTH; start corticosteroids immediately

Immediate therapy with an appropriate stress dose of intravenous corticosteroids (eg, hydrocortisone 100 mg) is essential. However, this should be done after drawing blood for cortisol and ACTH measurements.¹⁰

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

In addition, in the early phase of evolving primary adrenal insufficiency, measurement of plasma renin and aldosterone levels may be beneficial, as mineralocorticoid deficiency may predominate.^10,12,13

One of the most important aims of early corticosteroid supplementation is to prevent further hyponatremia by reducing a reactive increase in antidiuretic hormone secretion caused by cortisol deficiency. Corticosteroids also help to restore normal blood pressure by increasing vascular tone, as glucocorticoid receptor activation potentiates the vasoconstrictor actions of norepinephrine, angiotensin II, and other vasoconstrictors.^14,15

Which corticosteroid to use?

Which corticosteroid to use in previously undiagnosed adrenal insufficiency is controversial. The Endocrine Society¹⁰ and Japan Endocrine Society¹⁶ clinical practice guidelines recommend hydrocortisone in a 100-mg intravenous bolus followed by 200 mg over 24 hours.

The choice of hydrocortisone is justified by its superior mineralocorticoid activity.^10,16 Further, hydrocortisone is preferred over dexamethasone if the patient is known to have primary adrenal insufficiency, or if the serum potassium level is higher than 6.0 mmol/L.

Some clinicians, on the other hand, recommend dexamethasone, given as a 4-mg intravenous bolus followed by 4-mg boluses every 12 hours. Their rationale is that dexamethasone, unlike hydrocortisone, does not interfere with subsequent serum cortisol assays if the patient later undergoes ACTH stimulation testing.¹⁷ Dexamethasone may also be preferred to minimize unwanted mineralocorticoid effects, such as in neurosurgical patients at risk of brain edema.

If hydrocortisone is used, ACTH stimulation testing can be done after withholding hydrocortisone for 24 hours once the patient is stable. (It should be restarted after the test if the results are abnormal.)

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

Echocardiography. Our patient is likely to have an element of cardiac failure, given her hypertension and cardiomegaly. However, decompensated heart failure is probably not the cause of her presentation. Thus, the first priority is to treat her adrenal crisis, and echocardiography should be deferred.

Increasing the norepinephrine infusion is unlikely to improve her blood pressure very much, as she is significantly volume-depleted. Further, low cortisol decreases the vascular response to norepinephrine.¹⁵

Mineralocorticoids such as fludrocortisone are used to treat primary adrenal insufficiency. However, they are not required during acute management of adrenal crisis, as 40 mg of hydrocortisone offers mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Thus, the high doses of hydrocortisone used to treat adrenal crisis provide adequate mineralocorticoid therapy.^10,18

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

The patient’s blood is drawn for serum cortisol and plasma ACTH measurements. A 100-mg intravenous bolus of hydrocortisone is given, followed by a 50-mg bolus every 6 hours until the patient stabilizes.

Twenty-four hours later, the patient states that she has more energy, and her appetite has improved. The norepinephrine infusion is stopped 48 hours after presentation, at which time her blood pressure is 120/70 mm Hg, heart rate 85 beats per minute and irregular, and temperature 36.7°C (98.1°F). Her current laboratory values include the following:

• Serum sodium 137 mmolL
• Serum potassium 4.3 mmol/L
• Hemoglobin 9.3 g/dL
• Serum cortisol (random) 7.2 μg/dL
• Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

• 7 am total serum cortisol measurement
• Random serum cortisol measurement
• 7 am salivary cortisol measurement
• 24-hour urinary free cortisol measurement
• ACTH stimulation test for cortisol
• Insulin tolerance test for cortisol

These tests also help determine the type of adrenal insufficiency (primary, secondary, or tertiary) and guide further management. Secondary adrenal insufficiency is caused by inadequate pituitary ACTH secretion and subsequent inadequate cortisol production, whereas tertiary adrenal insufficiency is caused by inadequate hypothalamic corticotropin-releasing hormone secretion and subsequent inadequate ACTH and cortisol production. The diagnosis of adrenal insufficiency relies first on demonstrating inappropriately low total serum cortisol production. Subsequently, serum ACTH helps to differentiate between primary (high ACTH) and secondary or tertiary (low or inappropriately normal ACTH) adrenal insufficiency.

Each test listed above may demonstrate a low cortisol level. However, in a nonacute setting, safety concerns (especially regarding insulin tolerance testing), poor diagnostic value, feasibility (ie, the difficulty of 24-hour tests), and poor sensitivity of 7 am cortisol make the ACTH stimulation test the most appropriate test in clinical practice to establish the diagnosis of adrenal insufficiency.

7 am serum cortisol measurement

Measuring the serum cortisol level early in the morning in the nonacute setting could be of diagnostic value, as an extremely low value (< 3–5 μg/dL) is almost 100% specific for adrenal insufficiency in the absence of concurrent exogenous steroid intake. However, the very low cutoff for this test causes poor sensitivity (about 33%), as many patients have partial adrenal insufficiency and hence have higher serum cortisol levels that may even be in the normal physiologic range.^19–22

Random serum cortisol measurements

Random serum cortisol measurements are not very useful in a nonacute setting, since cortisol levels are affected by factors such as stress and hydration status. Moreover, they fluctuate during the day in a circadian rhythm.

On the other hand, random serum cortisol is a very good test to evaluate for adrenal insufficiency in the acute setting. A random value higher than 15 to 18 μg/dL is almost always associated with adequate adrenal function and generally rules out adrenal insufficiency.^11,23,24

The same principle applies to early morning salivary cortisol. Only extremely low values (< 2.65 ng/mL) may distinguish patients with adrenal insufficiency from healthy individuals, with 97.1% sensitivity and 93.3% specificity.²⁵

Of note, early morning salivary cortisol is not routinely measured in most clinical practices for evaluation of adrenal function. Hence, morning serum and morning salivary cortisol are useful screening tools and have meaningful results when their values are in the extremes of the spectrum, but they are not reliable as a single test, as they may overlook patients with partial adrenal insufficiency.

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test involves an intramuscular or intravenous injection of cosyntropin (a synthetic analogue of ACTH fragment 1–24 that has the full activity of native ACTH) and measuring total serum cortisol at baseline, 30 minutes, and 60 minutes to assess the response of the adrenal glands.

The test can be done using a high or low dose of cosyntropin. The Endocrine Society’s 2016 guidelines recommend the high dose (250 μg) for most patients.¹⁰ The standard high-dose stimulation test can be done at any time during the day.²⁶ If the cosyntropin is injected intravenously, any value higher than 18 to 20 μg/dL indicates normal adrenal function and excludes adrenal insufficiency.^27,28 If intramuscular injection is used, any value higher than 16 to 18 μg/dL at 30 minutes post-consyntropin excludes adrenal insufficiency.²⁹

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

Insulin tolerance testing remains the gold standard for diagnosing adrenal insufficiency and assessing the integrity of the pituitary-adrenal axis. However, given its difficulty to perform, safety concerns, and the availability of other reliable tests, its use in clinical practice is limited. It is nonetheless useful in assessing patients with recent onset of ACTH deficiency.^30,31

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

She is started on oral hydrocortisone and fludrocortisone after intravenous hydrocortisone is discontinued. She is counseled about adhering to medications, wearing a medical alert bracelet, giving herself emergency cortisol injections, taking higher doses of hydrocortisone if she is ill, and monitoring her INR. She is discharged home after her symptoms resolve.

The patient does not keep her scheduled appointment and is lost to follow-up. She returns 2 years later complaining of fatigue and feeling unwell. She admits that she stopped taking hydrocortisone 1 year ago after reading an online article about corticosteroid side effects. She has continued to take fludrocortisone.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

• Intravascular volume depletion
• Hyponatremia
• Skin hyperpigmentation
• Normokalemia
• Elevated serum ACTH level

Intravascular volume depletion

Intravascular volume depletion is the least likely to be present. This is because intravascular volume depletion is mainly secondary to mineralocorticoid deficiency rather than corticosteroid deficiency, which is not present in this patient, as she is compliant with her mineralocorticoid replacement therapy.^32,33 However, even with sufficient mineralocorticoid replacement, mild hypotension may be present in this patient due to corticosteroid deficiency-induced loss of vascular tone.

Hyponatremia

Hyponatremia in adrenal insufficiency is not due only to mineralocorticoid deficiency. Patients with secondary or tertiary adrenal insufficiency may also exhibit hyponatremia.³⁴ ACTH deficiency in such patients is not expected to cause mineralocorticoid deficiency, as ACTH has only a minor role in aldosterone production.

It has been proposed that hyponatremia in secondary adrenal insufficiency is due to cortisol deficiency resulting in an increase of antidiuretic hormone secretion.^35,36 The mechanisms for increased antidiuretic hormone include cortisol deficiency resulting in an increased corticotropin-releasing hormone level, which acts as an antidiuretic hormone secretagogue,^37,38 and cortisol directly suppressing antidiuretic hormone secretion.³⁹

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation of the skin is present only in long-standing primary adrenal insufficiency. This is due to chronic cortisol deficiency causing an increased secretion of pro-opiomelanocortin, a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone, and other hormones. Melanocyte-stimulating hormone causes skin hyperpigmentation due to increased melanin synthesis.⁴⁰ The hyperpigmentation is seen in sun-exposed areas, pressure areas, palmar creases, nipples, and mucous membranes.

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

Mineralocorticoid deficiency results in hyperkalemia and metabolic acidosis by impairing renal excretion of potassium and acid.⁴¹ This patient is compliant with her mineralocorticoid replacement regimen; thus, potassium levels and pH are expected to be normal.

TAKE-HOME POINTS

• Suspect adrenal crisis in any patient who presents with shock.
• Acute abdomen or unexplained fever could be among the manifestations.
• Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
• Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
• In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
• Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

A 71-year-old woman is brought to the emergency department by her neighbor after complaining of fatigue and light-headedness for the last 8 hours. The patient lives alone and was feeling well when she woke up this morning, but then began to feel nauseated and vomited twice.

The patient appears drowsy and confused and cannot provide any further history. Her medical records show that she was seen in the cardiology clinic 6 months ago but has not kept her appointments since then.

Her medical history includes atrial fibrillation, hypertension, type 2 diabetes mellitus, and osteoarthritis. Her medications are daily warfarin, atenolol, aspirin, candesartan, and metformin, and she takes acetaminophen as needed. She is neither a smoker nor a drug user, but she drinks alcohol occasionally. Her family history is significant for her mother’s death from breast cancer at age 55.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Her neck veins are flat, and her chest is clear to auscultation with normal heart sounds. Abdominal palpation elicits discomfort in the middle segments, voluntary withdrawal, and abdominal wall rigidity. Her skin feels dry and cool, with decreased turgor.

Initial treatment

The patient is given 1 L of 0.9% saline intravenously over the first hour and then is transferred to the intensive care unit, where a norepinephrine drip is started to treat her ongoing hypotension. Normal saline is continued at a rate of 500 mL per hour for the next 4 hours.

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her blood pH is 7.34 (reference range 7.35–7.45), and her bicarbonate level is 18 mmol/L (22–26); a low pH and low bicarbonate together indicate metabolic acidosis. Her sodium level is 128 mmol/L (135–145), her chloride level is 100 mmol/L (97–107), and, as mentioned, her bicarbonate level is 18 mmol/L; therefore, her anion gap is 128 – (100 + 18) = 10 mmol/L, which is normal (≤ 10).¹

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

• Adrenal crisis
• Cardiogenic shock due to decreased cardiac contractility
• Intracranial hemorrhage
• Acute abdomen due to small bowel obstruction
• Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

The sudden onset and laboratory results that include hyperkalemia, hyponatremia, and normal anion gap metabolic acidosis raise suspicion of adrenal crisis resulting in acute mineralocorticoid and glucocorticoid insufficiency.¹

The patient’s elevated serum creatinine and high blood urea nitrogen-to-creatinine ratio of 26.9 (reference range 10–20) also suggest intravascular volume contraction. Her low hemoglobin level and supratherapeutic INR, possibly due to an interaction between warfarin and acetaminophen combined with poor medical follow-up, raise suspicion of acute bilateral adrenal necrosis due to hemorrhage.

Bilateral adrenal hemorrhage is one cause of adrenal crisis resulting in bilateral adrenal necrosis. Risk factors for adrenal hemorrhage include anticoagulation therapy, underlying coagulopathy, postoperative states, and certain infections such as meningococcemia and Haemophilus influenzae infection.^2–5 Nevertheless, in most cases the INR is in the therapeutic range and the patient has no bleeding elsewhere.⁴ Other causes of adrenal necrosis include emboli, sepsis, and blunt trauma.^6,7

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage can present with a decreased level of consciousness, but it is less likely to cause hypotension, as the cranial space is limited. If massive intracranial hemorrhage would occur, the increase in intracranial pressure would more likely cause hypertension by the Cushing reflex than hypotension.

Acute abdomen

Abdominal pain and rigidity along with fever can be presenting symptoms of both adrenal insufficiency and an acute abdomen due to intestinal obstruction.⁴ However, intestinal obstruction typically causes a high anion gap metabolic acidosis due to lactic acidosis, instead of the normal anion gap metabolic acidosis present in this patient.⁸ Moreover, her deranged electrolytes, supratherapeutic INR, and absence of previous gastroenterologic conditions make adrenal crisis a more likely diagnosis.

Septic shock

Septic shock would also cause fever and hypotension as bacterial toxins induce a pyrexic response and vasodilation. However, at such an early stage of sepsis, the patient would be expected to be warm and hyperemic, whereas this patient’s skin is cool and dry due to volume depletion secondary to adrenal insufficiency.⁹ Sepsis would also cause a high anion gap metabolic acidosis due to lactic acidosis, as opposed to this patient’s normal anion gap metabolic acidosis. These findings, along with the metabolic derangements and the absence of a focus of infection, make sepsis a less likely possibility.

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Blood is drawn for cultures and measurement of troponins and lactic acid, and urine samples are taken for culture and biochemical analysis. Chest radiography shows mild cardiomegaly. The patient is started empirically on vancomycin and cefepime, and her warfarin is discontinued.

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

• Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
• Perform abdominal computed tomography (CT) without contrast
• Perform transthoracic echocardiography
• Increase the norepinephrine infusion
• Immediately give fludrocortisone

First give fluids

The first step in managing a patient with suspected adrenal crisis is liberal intravenous fluid administration to replenish the depleted intravascular space. The amount and choice of fluid is empiric, but a recommendation is 1 L of normal saline or dextrose 5% in normal saline, infused quickly over the first hour and then titrated according to the patient’s fluid status.¹⁰

Measure cortisol and ACTH; start corticosteroids immediately

Immediate therapy with an appropriate stress dose of intravenous corticosteroids (eg, hydrocortisone 100 mg) is essential. However, this should be done after drawing blood for cortisol and ACTH measurements.¹⁰

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

In addition, in the early phase of evolving primary adrenal insufficiency, measurement of plasma renin and aldosterone levels may be beneficial, as mineralocorticoid deficiency may predominate.^10,12,13

One of the most important aims of early corticosteroid supplementation is to prevent further hyponatremia by reducing a reactive increase in antidiuretic hormone secretion caused by cortisol deficiency. Corticosteroids also help to restore normal blood pressure by increasing vascular tone, as glucocorticoid receptor activation potentiates the vasoconstrictor actions of norepinephrine, angiotensin II, and other vasoconstrictors.^14,15

Which corticosteroid to use?

Which corticosteroid to use in previously undiagnosed adrenal insufficiency is controversial. The Endocrine Society¹⁰ and Japan Endocrine Society¹⁶ clinical practice guidelines recommend hydrocortisone in a 100-mg intravenous bolus followed by 200 mg over 24 hours.

The choice of hydrocortisone is justified by its superior mineralocorticoid activity.^10,16 Further, hydrocortisone is preferred over dexamethasone if the patient is known to have primary adrenal insufficiency, or if the serum potassium level is higher than 6.0 mmol/L.

Some clinicians, on the other hand, recommend dexamethasone, given as a 4-mg intravenous bolus followed by 4-mg boluses every 12 hours. Their rationale is that dexamethasone, unlike hydrocortisone, does not interfere with subsequent serum cortisol assays if the patient later undergoes ACTH stimulation testing.¹⁷ Dexamethasone may also be preferred to minimize unwanted mineralocorticoid effects, such as in neurosurgical patients at risk of brain edema.

If hydrocortisone is used, ACTH stimulation testing can be done after withholding hydrocortisone for 24 hours once the patient is stable. (It should be restarted after the test if the results are abnormal.)

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

Echocardiography. Our patient is likely to have an element of cardiac failure, given her hypertension and cardiomegaly. However, decompensated heart failure is probably not the cause of her presentation. Thus, the first priority is to treat her adrenal crisis, and echocardiography should be deferred.

Increasing the norepinephrine infusion is unlikely to improve her blood pressure very much, as she is significantly volume-depleted. Further, low cortisol decreases the vascular response to norepinephrine.¹⁵

Mineralocorticoids such as fludrocortisone are used to treat primary adrenal insufficiency. However, they are not required during acute management of adrenal crisis, as 40 mg of hydrocortisone offers mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Thus, the high doses of hydrocortisone used to treat adrenal crisis provide adequate mineralocorticoid therapy.^10,18

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

The patient’s blood is drawn for serum cortisol and plasma ACTH measurements. A 100-mg intravenous bolus of hydrocortisone is given, followed by a 50-mg bolus every 6 hours until the patient stabilizes.

Twenty-four hours later, the patient states that she has more energy, and her appetite has improved. The norepinephrine infusion is stopped 48 hours after presentation, at which time her blood pressure is 120/70 mm Hg, heart rate 85 beats per minute and irregular, and temperature 36.7°C (98.1°F). Her current laboratory values include the following:

• Serum sodium 137 mmolL
• Serum potassium 4.3 mmol/L
• Hemoglobin 9.3 g/dL
• Serum cortisol (random) 7.2 μg/dL
• Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

• 7 am total serum cortisol measurement
• Random serum cortisol measurement
• 7 am salivary cortisol measurement
• 24-hour urinary free cortisol measurement
• ACTH stimulation test for cortisol
• Insulin tolerance test for cortisol

These tests also help determine the type of adrenal insufficiency (primary, secondary, or tertiary) and guide further management. Secondary adrenal insufficiency is caused by inadequate pituitary ACTH secretion and subsequent inadequate cortisol production, whereas tertiary adrenal insufficiency is caused by inadequate hypothalamic corticotropin-releasing hormone secretion and subsequent inadequate ACTH and cortisol production. The diagnosis of adrenal insufficiency relies first on demonstrating inappropriately low total serum cortisol production. Subsequently, serum ACTH helps to differentiate between primary (high ACTH) and secondary or tertiary (low or inappropriately normal ACTH) adrenal insufficiency.

Each test listed above may demonstrate a low cortisol level. However, in a nonacute setting, safety concerns (especially regarding insulin tolerance testing), poor diagnostic value, feasibility (ie, the difficulty of 24-hour tests), and poor sensitivity of 7 am cortisol make the ACTH stimulation test the most appropriate test in clinical practice to establish the diagnosis of adrenal insufficiency.

7 am serum cortisol measurement

Measuring the serum cortisol level early in the morning in the nonacute setting could be of diagnostic value, as an extremely low value (< 3–5 μg/dL) is almost 100% specific for adrenal insufficiency in the absence of concurrent exogenous steroid intake. However, the very low cutoff for this test causes poor sensitivity (about 33%), as many patients have partial adrenal insufficiency and hence have higher serum cortisol levels that may even be in the normal physiologic range.^19–22

Random serum cortisol measurements

Random serum cortisol measurements are not very useful in a nonacute setting, since cortisol levels are affected by factors such as stress and hydration status. Moreover, they fluctuate during the day in a circadian rhythm.

On the other hand, random serum cortisol is a very good test to evaluate for adrenal insufficiency in the acute setting. A random value higher than 15 to 18 μg/dL is almost always associated with adequate adrenal function and generally rules out adrenal insufficiency.^11,23,24

The same principle applies to early morning salivary cortisol. Only extremely low values (< 2.65 ng/mL) may distinguish patients with adrenal insufficiency from healthy individuals, with 97.1% sensitivity and 93.3% specificity.²⁵

Of note, early morning salivary cortisol is not routinely measured in most clinical practices for evaluation of adrenal function. Hence, morning serum and morning salivary cortisol are useful screening tools and have meaningful results when their values are in the extremes of the spectrum, but they are not reliable as a single test, as they may overlook patients with partial adrenal insufficiency.

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test involves an intramuscular or intravenous injection of cosyntropin (a synthetic analogue of ACTH fragment 1–24 that has the full activity of native ACTH) and measuring total serum cortisol at baseline, 30 minutes, and 60 minutes to assess the response of the adrenal glands.

The test can be done using a high or low dose of cosyntropin. The Endocrine Society’s 2016 guidelines recommend the high dose (250 μg) for most patients.¹⁰ The standard high-dose stimulation test can be done at any time during the day.²⁶ If the cosyntropin is injected intravenously, any value higher than 18 to 20 μg/dL indicates normal adrenal function and excludes adrenal insufficiency.^27,28 If intramuscular injection is used, any value higher than 16 to 18 μg/dL at 30 minutes post-consyntropin excludes adrenal insufficiency.²⁹

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

Insulin tolerance testing remains the gold standard for diagnosing adrenal insufficiency and assessing the integrity of the pituitary-adrenal axis. However, given its difficulty to perform, safety concerns, and the availability of other reliable tests, its use in clinical practice is limited. It is nonetheless useful in assessing patients with recent onset of ACTH deficiency.^30,31

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

She is started on oral hydrocortisone and fludrocortisone after intravenous hydrocortisone is discontinued. She is counseled about adhering to medications, wearing a medical alert bracelet, giving herself emergency cortisol injections, taking higher doses of hydrocortisone if she is ill, and monitoring her INR. She is discharged home after her symptoms resolve.

The patient does not keep her scheduled appointment and is lost to follow-up. She returns 2 years later complaining of fatigue and feeling unwell. She admits that she stopped taking hydrocortisone 1 year ago after reading an online article about corticosteroid side effects. She has continued to take fludrocortisone.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

• Intravascular volume depletion
• Hyponatremia
• Skin hyperpigmentation
• Normokalemia
• Elevated serum ACTH level

Intravascular volume depletion

Intravascular volume depletion is the least likely to be present. This is because intravascular volume depletion is mainly secondary to mineralocorticoid deficiency rather than corticosteroid deficiency, which is not present in this patient, as she is compliant with her mineralocorticoid replacement therapy.^32,33 However, even with sufficient mineralocorticoid replacement, mild hypotension may be present in this patient due to corticosteroid deficiency-induced loss of vascular tone.

Hyponatremia

Hyponatremia in adrenal insufficiency is not due only to mineralocorticoid deficiency. Patients with secondary or tertiary adrenal insufficiency may also exhibit hyponatremia.³⁴ ACTH deficiency in such patients is not expected to cause mineralocorticoid deficiency, as ACTH has only a minor role in aldosterone production.

It has been proposed that hyponatremia in secondary adrenal insufficiency is due to cortisol deficiency resulting in an increase of antidiuretic hormone secretion.^35,36 The mechanisms for increased antidiuretic hormone include cortisol deficiency resulting in an increased corticotropin-releasing hormone level, which acts as an antidiuretic hormone secretagogue,^37,38 and cortisol directly suppressing antidiuretic hormone secretion.³⁹

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation of the skin is present only in long-standing primary adrenal insufficiency. This is due to chronic cortisol deficiency causing an increased secretion of pro-opiomelanocortin, a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone, and other hormones. Melanocyte-stimulating hormone causes skin hyperpigmentation due to increased melanin synthesis.⁴⁰ The hyperpigmentation is seen in sun-exposed areas, pressure areas, palmar creases, nipples, and mucous membranes.

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

Mineralocorticoid deficiency results in hyperkalemia and metabolic acidosis by impairing renal excretion of potassium and acid.⁴¹ This patient is compliant with her mineralocorticoid replacement regimen; thus, potassium levels and pH are expected to be normal.

TAKE-HOME POINTS

• Suspect adrenal crisis in any patient who presents with shock.
• Acute abdomen or unexplained fever could be among the manifestations.
• Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
• Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
• In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
• Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

A 71-year-old woman is brought to the emergency department by her neighbor after complaining of fatigue and light-headedness for the last 8 hours. The patient lives alone and was feeling well when she woke up this morning, but then began to feel nauseated and vomited twice.

The patient appears drowsy and confused and cannot provide any further history. Her medical records show that she was seen in the cardiology clinic 6 months ago but has not kept her appointments since then.

Her medical history includes atrial fibrillation, hypertension, type 2 diabetes mellitus, and osteoarthritis. Her medications are daily warfarin, atenolol, aspirin, candesartan, and metformin, and she takes acetaminophen as needed. She is neither a smoker nor a drug user, but she drinks alcohol occasionally. Her family history is significant for her mother’s death from breast cancer at age 55.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Her neck veins are flat, and her chest is clear to auscultation with normal heart sounds. Abdominal palpation elicits discomfort in the middle segments, voluntary withdrawal, and abdominal wall rigidity. Her skin feels dry and cool, with decreased turgor.

Initial treatment

The patient is given 1 L of 0.9% saline intravenously over the first hour and then is transferred to the intensive care unit, where a norepinephrine drip is started to treat her ongoing hypotension. Normal saline is continued at a rate of 500 mL per hour for the next 4 hours.

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her blood pH is 7.34 (reference range 7.35–7.45), and her bicarbonate level is 18 mmol/L (22–26); a low pH and low bicarbonate together indicate metabolic acidosis. Her sodium level is 128 mmol/L (135–145), her chloride level is 100 mmol/L (97–107), and, as mentioned, her bicarbonate level is 18 mmol/L; therefore, her anion gap is 128 – (100 + 18) = 10 mmol/L, which is normal (≤ 10).¹

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

• Adrenal crisis
• Cardiogenic shock due to decreased cardiac contractility
• Intracranial hemorrhage
• Acute abdomen due to small bowel obstruction
• Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

The sudden onset and laboratory results that include hyperkalemia, hyponatremia, and normal anion gap metabolic acidosis raise suspicion of adrenal crisis resulting in acute mineralocorticoid and glucocorticoid insufficiency.¹

The patient’s elevated serum creatinine and high blood urea nitrogen-to-creatinine ratio of 26.9 (reference range 10–20) also suggest intravascular volume contraction. Her low hemoglobin level and supratherapeutic INR, possibly due to an interaction between warfarin and acetaminophen combined with poor medical follow-up, raise suspicion of acute bilateral adrenal necrosis due to hemorrhage.

Bilateral adrenal hemorrhage is one cause of adrenal crisis resulting in bilateral adrenal necrosis. Risk factors for adrenal hemorrhage include anticoagulation therapy, underlying coagulopathy, postoperative states, and certain infections such as meningococcemia and Haemophilus influenzae infection.^2–5 Nevertheless, in most cases the INR is in the therapeutic range and the patient has no bleeding elsewhere.⁴ Other causes of adrenal necrosis include emboli, sepsis, and blunt trauma.^6,7

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage can present with a decreased level of consciousness, but it is less likely to cause hypotension, as the cranial space is limited. If massive intracranial hemorrhage would occur, the increase in intracranial pressure would more likely cause hypertension by the Cushing reflex than hypotension.

Acute abdomen

Abdominal pain and rigidity along with fever can be presenting symptoms of both adrenal insufficiency and an acute abdomen due to intestinal obstruction.⁴ However, intestinal obstruction typically causes a high anion gap metabolic acidosis due to lactic acidosis, instead of the normal anion gap metabolic acidosis present in this patient.⁸ Moreover, her deranged electrolytes, supratherapeutic INR, and absence of previous gastroenterologic conditions make adrenal crisis a more likely diagnosis.

Septic shock

Septic shock would also cause fever and hypotension as bacterial toxins induce a pyrexic response and vasodilation. However, at such an early stage of sepsis, the patient would be expected to be warm and hyperemic, whereas this patient’s skin is cool and dry due to volume depletion secondary to adrenal insufficiency.⁹ Sepsis would also cause a high anion gap metabolic acidosis due to lactic acidosis, as opposed to this patient’s normal anion gap metabolic acidosis. These findings, along with the metabolic derangements and the absence of a focus of infection, make sepsis a less likely possibility.

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Blood is drawn for cultures and measurement of troponins and lactic acid, and urine samples are taken for culture and biochemical analysis. Chest radiography shows mild cardiomegaly. The patient is started empirically on vancomycin and cefepime, and her warfarin is discontinued.

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

• Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
• Perform abdominal computed tomography (CT) without contrast
• Perform transthoracic echocardiography
• Increase the norepinephrine infusion
• Immediately give fludrocortisone

First give fluids

The first step in managing a patient with suspected adrenal crisis is liberal intravenous fluid administration to replenish the depleted intravascular space. The amount and choice of fluid is empiric, but a recommendation is 1 L of normal saline or dextrose 5% in normal saline, infused quickly over the first hour and then titrated according to the patient’s fluid status.¹⁰

Measure cortisol and ACTH; start corticosteroids immediately

Immediate therapy with an appropriate stress dose of intravenous corticosteroids (eg, hydrocortisone 100 mg) is essential. However, this should be done after drawing blood for cortisol and ACTH measurements.¹⁰

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

In addition, in the early phase of evolving primary adrenal insufficiency, measurement of plasma renin and aldosterone levels may be beneficial, as mineralocorticoid deficiency may predominate.^10,12,13

One of the most important aims of early corticosteroid supplementation is to prevent further hyponatremia by reducing a reactive increase in antidiuretic hormone secretion caused by cortisol deficiency. Corticosteroids also help to restore normal blood pressure by increasing vascular tone, as glucocorticoid receptor activation potentiates the vasoconstrictor actions of norepinephrine, angiotensin II, and other vasoconstrictors.^14,15

Which corticosteroid to use?

Which corticosteroid to use in previously undiagnosed adrenal insufficiency is controversial. The Endocrine Society¹⁰ and Japan Endocrine Society¹⁶ clinical practice guidelines recommend hydrocortisone in a 100-mg intravenous bolus followed by 200 mg over 24 hours.

The choice of hydrocortisone is justified by its superior mineralocorticoid activity.^10,16 Further, hydrocortisone is preferred over dexamethasone if the patient is known to have primary adrenal insufficiency, or if the serum potassium level is higher than 6.0 mmol/L.

Some clinicians, on the other hand, recommend dexamethasone, given as a 4-mg intravenous bolus followed by 4-mg boluses every 12 hours. Their rationale is that dexamethasone, unlike hydrocortisone, does not interfere with subsequent serum cortisol assays if the patient later undergoes ACTH stimulation testing.¹⁷ Dexamethasone may also be preferred to minimize unwanted mineralocorticoid effects, such as in neurosurgical patients at risk of brain edema.

If hydrocortisone is used, ACTH stimulation testing can be done after withholding hydrocortisone for 24 hours once the patient is stable. (It should be restarted after the test if the results are abnormal.)

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

Echocardiography. Our patient is likely to have an element of cardiac failure, given her hypertension and cardiomegaly. However, decompensated heart failure is probably not the cause of her presentation. Thus, the first priority is to treat her adrenal crisis, and echocardiography should be deferred.

Increasing the norepinephrine infusion is unlikely to improve her blood pressure very much, as she is significantly volume-depleted. Further, low cortisol decreases the vascular response to norepinephrine.¹⁵

Mineralocorticoids such as fludrocortisone are used to treat primary adrenal insufficiency. However, they are not required during acute management of adrenal crisis, as 40 mg of hydrocortisone offers mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Thus, the high doses of hydrocortisone used to treat adrenal crisis provide adequate mineralocorticoid therapy.^10,18

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

The patient’s blood is drawn for serum cortisol and plasma ACTH measurements. A 100-mg intravenous bolus of hydrocortisone is given, followed by a 50-mg bolus every 6 hours until the patient stabilizes.

Twenty-four hours later, the patient states that she has more energy, and her appetite has improved. The norepinephrine infusion is stopped 48 hours after presentation, at which time her blood pressure is 120/70 mm Hg, heart rate 85 beats per minute and irregular, and temperature 36.7°C (98.1°F). Her current laboratory values include the following:

• Serum sodium 137 mmolL
• Serum potassium 4.3 mmol/L
• Hemoglobin 9.3 g/dL
• Serum cortisol (random) 7.2 μg/dL
• Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

• 7 am total serum cortisol measurement
• Random serum cortisol measurement
• 7 am salivary cortisol measurement
• 24-hour urinary free cortisol measurement
• ACTH stimulation test for cortisol
• Insulin tolerance test for cortisol

These tests also help determine the type of adrenal insufficiency (primary, secondary, or tertiary) and guide further management. Secondary adrenal insufficiency is caused by inadequate pituitary ACTH secretion and subsequent inadequate cortisol production, whereas tertiary adrenal insufficiency is caused by inadequate hypothalamic corticotropin-releasing hormone secretion and subsequent inadequate ACTH and cortisol production. The diagnosis of adrenal insufficiency relies first on demonstrating inappropriately low total serum cortisol production. Subsequently, serum ACTH helps to differentiate between primary (high ACTH) and secondary or tertiary (low or inappropriately normal ACTH) adrenal insufficiency.

Each test listed above may demonstrate a low cortisol level. However, in a nonacute setting, safety concerns (especially regarding insulin tolerance testing), poor diagnostic value, feasibility (ie, the difficulty of 24-hour tests), and poor sensitivity of 7 am cortisol make the ACTH stimulation test the most appropriate test in clinical practice to establish the diagnosis of adrenal insufficiency.

7 am serum cortisol measurement

Measuring the serum cortisol level early in the morning in the nonacute setting could be of diagnostic value, as an extremely low value (< 3–5 μg/dL) is almost 100% specific for adrenal insufficiency in the absence of concurrent exogenous steroid intake. However, the very low cutoff for this test causes poor sensitivity (about 33%), as many patients have partial adrenal insufficiency and hence have higher serum cortisol levels that may even be in the normal physiologic range.^19–22

Random serum cortisol measurements

Random serum cortisol measurements are not very useful in a nonacute setting, since cortisol levels are affected by factors such as stress and hydration status. Moreover, they fluctuate during the day in a circadian rhythm.

On the other hand, random serum cortisol is a very good test to evaluate for adrenal insufficiency in the acute setting. A random value higher than 15 to 18 μg/dL is almost always associated with adequate adrenal function and generally rules out adrenal insufficiency.^11,23,24

The same principle applies to early morning salivary cortisol. Only extremely low values (< 2.65 ng/mL) may distinguish patients with adrenal insufficiency from healthy individuals, with 97.1% sensitivity and 93.3% specificity.²⁵

Of note, early morning salivary cortisol is not routinely measured in most clinical practices for evaluation of adrenal function. Hence, morning serum and morning salivary cortisol are useful screening tools and have meaningful results when their values are in the extremes of the spectrum, but they are not reliable as a single test, as they may overlook patients with partial adrenal insufficiency.

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test involves an intramuscular or intravenous injection of cosyntropin (a synthetic analogue of ACTH fragment 1–24 that has the full activity of native ACTH) and measuring total serum cortisol at baseline, 30 minutes, and 60 minutes to assess the response of the adrenal glands.

The test can be done using a high or low dose of cosyntropin. The Endocrine Society’s 2016 guidelines recommend the high dose (250 μg) for most patients.¹⁰ The standard high-dose stimulation test can be done at any time during the day.²⁶ If the cosyntropin is injected intravenously, any value higher than 18 to 20 μg/dL indicates normal adrenal function and excludes adrenal insufficiency.^27,28 If intramuscular injection is used, any value higher than 16 to 18 μg/dL at 30 minutes post-consyntropin excludes adrenal insufficiency.²⁹

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

Insulin tolerance testing remains the gold standard for diagnosing adrenal insufficiency and assessing the integrity of the pituitary-adrenal axis. However, given its difficulty to perform, safety concerns, and the availability of other reliable tests, its use in clinical practice is limited. It is nonetheless useful in assessing patients with recent onset of ACTH deficiency.^30,31

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

She is started on oral hydrocortisone and fludrocortisone after intravenous hydrocortisone is discontinued. She is counseled about adhering to medications, wearing a medical alert bracelet, giving herself emergency cortisol injections, taking higher doses of hydrocortisone if she is ill, and monitoring her INR. She is discharged home after her symptoms resolve.

The patient does not keep her scheduled appointment and is lost to follow-up. She returns 2 years later complaining of fatigue and feeling unwell. She admits that she stopped taking hydrocortisone 1 year ago after reading an online article about corticosteroid side effects. She has continued to take fludrocortisone.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

• Intravascular volume depletion
• Hyponatremia
• Skin hyperpigmentation
• Normokalemia
• Elevated serum ACTH level

Intravascular volume depletion

Intravascular volume depletion is the least likely to be present. This is because intravascular volume depletion is mainly secondary to mineralocorticoid deficiency rather than corticosteroid deficiency, which is not present in this patient, as she is compliant with her mineralocorticoid replacement therapy.^32,33 However, even with sufficient mineralocorticoid replacement, mild hypotension may be present in this patient due to corticosteroid deficiency-induced loss of vascular tone.

Hyponatremia

Hyponatremia in adrenal insufficiency is not due only to mineralocorticoid deficiency. Patients with secondary or tertiary adrenal insufficiency may also exhibit hyponatremia.³⁴ ACTH deficiency in such patients is not expected to cause mineralocorticoid deficiency, as ACTH has only a minor role in aldosterone production.

It has been proposed that hyponatremia in secondary adrenal insufficiency is due to cortisol deficiency resulting in an increase of antidiuretic hormone secretion.^35,36 The mechanisms for increased antidiuretic hormone include cortisol deficiency resulting in an increased corticotropin-releasing hormone level, which acts as an antidiuretic hormone secretagogue,^37,38 and cortisol directly suppressing antidiuretic hormone secretion.³⁹

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation of the skin is present only in long-standing primary adrenal insufficiency. This is due to chronic cortisol deficiency causing an increased secretion of pro-opiomelanocortin, a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone, and other hormones. Melanocyte-stimulating hormone causes skin hyperpigmentation due to increased melanin synthesis.⁴⁰ The hyperpigmentation is seen in sun-exposed areas, pressure areas, palmar creases, nipples, and mucous membranes.

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

Mineralocorticoid deficiency results in hyperkalemia and metabolic acidosis by impairing renal excretion of potassium and acid.⁴¹ This patient is compliant with her mineralocorticoid replacement regimen; thus, potassium levels and pH are expected to be normal.

TAKE-HOME POINTS

• Suspect adrenal crisis in any patient who presents with shock.
• Acute abdomen or unexplained fever could be among the manifestations.
• Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
• Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
• In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
• Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

To the Editor: We read with great interest the article by Munyon et al¹ addressing recent developments in perioperative medicine. We would like to comment on the perioperative interruption of dual antiplatelet therapy, a common clinical problem.

Several registry analyses have shown that, with second-generation drug-eluting stents, interruption of 1 antiplatelet agent after the first month is safe.^2,3 These registries included a substantial proportion of patients whose index stenting procedure was performed for acute coronary syndrome (up to 60%).² On average, antiplatelet therapy interruption was brief (about 6 to 7 days).

Additional registry analyses have shown that surgery may be safely performed beyond the first month after drug-eluting stent placement.^4,5 Specifically, a large Danish analysis of patients with a drug-eluting stent who underwent noncardiac surgery, matched to control patients without ischemic heart disease, showed that the risk of perioperative myocardial infarction and death was not increased beyond the first month after drug-eluting stent implantation. Specifically, the risk was not increased at the 1- to 2-month and 2- to 12-month postimplantation intervals. Acute coronary syndrome was the indication for stenting in 56% of the patients.

Therefore, while surgery is preferably delayed 6 months after drug-eluting stent implantation (class I recommendation in the European Society of Cardiology guidelines), surgery may be selectively performed 1 to 6 months after drug-eluting stent implantation with an acceptable risk. This is particularly so if the index stenting was performed in the setting of stable coronary arterial disease (class IIa recommendation if stenting was performed in the setting of stable coronary arterial disease without complex procedural features; class IIb recommendation if stenting was performed in the setting of acute coronary syndrome or complex procedural features).⁶ After drug-eluting stent implantation, the earliest cutpoint for considering surgery is 1 month rather than 3 months.

When surgery is performed within this 1- to 6-month interval, thienopyridine interruption should be kept brief and dual antiplatelet therapy reinitiated as soon as possible postoperatively. In fact, when thienopyridine therapy is interrupted 1 to 6 months after drug-eluting stent implantation, stent thrombosis typically occurs more than 6 or 7 days after interruption.⁷

To the Editor: We read with great interest the article by Munyon et al¹ addressing recent developments in perioperative medicine. We would like to comment on the perioperative interruption of dual antiplatelet therapy, a common clinical problem.

Several registry analyses have shown that, with second-generation drug-eluting stents, interruption of 1 antiplatelet agent after the first month is safe.^2,3 These registries included a substantial proportion of patients whose index stenting procedure was performed for acute coronary syndrome (up to 60%).² On average, antiplatelet therapy interruption was brief (about 6 to 7 days).

Additional registry analyses have shown that surgery may be safely performed beyond the first month after drug-eluting stent placement.^4,5 Specifically, a large Danish analysis of patients with a drug-eluting stent who underwent noncardiac surgery, matched to control patients without ischemic heart disease, showed that the risk of perioperative myocardial infarction and death was not increased beyond the first month after drug-eluting stent implantation. Specifically, the risk was not increased at the 1- to 2-month and 2- to 12-month postimplantation intervals. Acute coronary syndrome was the indication for stenting in 56% of the patients.

Therefore, while surgery is preferably delayed 6 months after drug-eluting stent implantation (class I recommendation in the European Society of Cardiology guidelines), surgery may be selectively performed 1 to 6 months after drug-eluting stent implantation with an acceptable risk. This is particularly so if the index stenting was performed in the setting of stable coronary arterial disease (class IIa recommendation if stenting was performed in the setting of stable coronary arterial disease without complex procedural features; class IIb recommendation if stenting was performed in the setting of acute coronary syndrome or complex procedural features).⁶ After drug-eluting stent implantation, the earliest cutpoint for considering surgery is 1 month rather than 3 months.

When surgery is performed within this 1- to 6-month interval, thienopyridine interruption should be kept brief and dual antiplatelet therapy reinitiated as soon as possible postoperatively. In fact, when thienopyridine therapy is interrupted 1 to 6 months after drug-eluting stent implantation, stent thrombosis typically occurs more than 6 or 7 days after interruption.⁷

To the Editor: We read with great interest the article by Munyon et al¹ addressing recent developments in perioperative medicine. We would like to comment on the perioperative interruption of dual antiplatelet therapy, a common clinical problem.

Several registry analyses have shown that, with second-generation drug-eluting stents, interruption of 1 antiplatelet agent after the first month is safe.^2,3 These registries included a substantial proportion of patients whose index stenting procedure was performed for acute coronary syndrome (up to 60%).² On average, antiplatelet therapy interruption was brief (about 6 to 7 days).

Additional registry analyses have shown that surgery may be safely performed beyond the first month after drug-eluting stent placement.^4,5 Specifically, a large Danish analysis of patients with a drug-eluting stent who underwent noncardiac surgery, matched to control patients without ischemic heart disease, showed that the risk of perioperative myocardial infarction and death was not increased beyond the first month after drug-eluting stent implantation. Specifically, the risk was not increased at the 1- to 2-month and 2- to 12-month postimplantation intervals. Acute coronary syndrome was the indication for stenting in 56% of the patients.

Therefore, while surgery is preferably delayed 6 months after drug-eluting stent implantation (class I recommendation in the European Society of Cardiology guidelines), surgery may be selectively performed 1 to 6 months after drug-eluting stent implantation with an acceptable risk. This is particularly so if the index stenting was performed in the setting of stable coronary arterial disease (class IIa recommendation if stenting was performed in the setting of stable coronary arterial disease without complex procedural features; class IIb recommendation if stenting was performed in the setting of acute coronary syndrome or complex procedural features).⁶ After drug-eluting stent implantation, the earliest cutpoint for considering surgery is 1 month rather than 3 months.

When surgery is performed within this 1- to 6-month interval, thienopyridine interruption should be kept brief and dual antiplatelet therapy reinitiated as soon as possible postoperatively. In fact, when thienopyridine therapy is interrupted 1 to 6 months after drug-eluting stent implantation, stent thrombosis typically occurs more than 6 or 7 days after interruption.⁷

In Reply: We reported on publications from 2016–2017 and, unfortunately, at the time we were writing our paper, the European Society of Cardiology (ESC) update on dual antiplatelet therapy¹ had not yet been published. We presented the recommendations from the American College of Cardiology (ACC) and American Heart Association (AHA),² which differ from the recently published ESC guidelines. The ESC suggests that the minimum waiting period after drug-eluting stent placement before noncardiac surgery should be 1 month rather than 3 months but acknowledges that in the setting of complex stenting or recent acute coronary syndrome, 6 months is preferred. The recommendation in this latter scenario is a class IIb C recommendation—essentially expert consensus opinion.

Further, in the study by Egholm et al,³ the event rates in patients undergoing noncardiac surgery in the 1- to 2-month period were numerically higher than in the control group, and no adjusted odds ratios were given. The numbers of events were very low, and a change of only 1 or 2 events in the other direction in the groups would likely make it statistically significant.

All of these recommendations are based on observational studies and registry data, as there are no randomized controlled trials to address this issue. There are many complexities to be accounted for including the type of stent, timing, circumstances surrounding stenting, anatomy, number of stents, patient comorbidities (particularly age, diabetes mellitus, cardiac disease), type of surgery and anesthesia, and perioperative management of antiplatelet therapy. While we acknowledge the ESC recommendation, we would urge caution in the recommendation to wait only 1 month, and in the United States most would prefer to wait 3 months if possible.

In Reply: We reported on publications from 2016–2017 and, unfortunately, at the time we were writing our paper, the European Society of Cardiology (ESC) update on dual antiplatelet therapy¹ had not yet been published. We presented the recommendations from the American College of Cardiology (ACC) and American Heart Association (AHA),² which differ from the recently published ESC guidelines. The ESC suggests that the minimum waiting period after drug-eluting stent placement before noncardiac surgery should be 1 month rather than 3 months but acknowledges that in the setting of complex stenting or recent acute coronary syndrome, 6 months is preferred. The recommendation in this latter scenario is a class IIb C recommendation—essentially expert consensus opinion.

Further, in the study by Egholm et al,³ the event rates in patients undergoing noncardiac surgery in the 1- to 2-month period were numerically higher than in the control group, and no adjusted odds ratios were given. The numbers of events were very low, and a change of only 1 or 2 events in the other direction in the groups would likely make it statistically significant.

All of these recommendations are based on observational studies and registry data, as there are no randomized controlled trials to address this issue. There are many complexities to be accounted for including the type of stent, timing, circumstances surrounding stenting, anatomy, number of stents, patient comorbidities (particularly age, diabetes mellitus, cardiac disease), type of surgery and anesthesia, and perioperative management of antiplatelet therapy. While we acknowledge the ESC recommendation, we would urge caution in the recommendation to wait only 1 month, and in the United States most would prefer to wait 3 months if possible.

In Reply: We reported on publications from 2016–2017 and, unfortunately, at the time we were writing our paper, the European Society of Cardiology (ESC) update on dual antiplatelet therapy¹ had not yet been published. We presented the recommendations from the American College of Cardiology (ACC) and American Heart Association (AHA),² which differ from the recently published ESC guidelines. The ESC suggests that the minimum waiting period after drug-eluting stent placement before noncardiac surgery should be 1 month rather than 3 months but acknowledges that in the setting of complex stenting or recent acute coronary syndrome, 6 months is preferred. The recommendation in this latter scenario is a class IIb C recommendation—essentially expert consensus opinion.

Further, in the study by Egholm et al,³ the event rates in patients undergoing noncardiac surgery in the 1- to 2-month period were numerically higher than in the control group, and no adjusted odds ratios were given. The numbers of events were very low, and a change of only 1 or 2 events in the other direction in the groups would likely make it statistically significant.

All of these recommendations are based on observational studies and registry data, as there are no randomized controlled trials to address this issue. There are many complexities to be accounted for including the type of stent, timing, circumstances surrounding stenting, anatomy, number of stents, patient comorbidities (particularly age, diabetes mellitus, cardiac disease), type of surgery and anesthesia, and perioperative management of antiplatelet therapy. While we acknowledge the ESC recommendation, we would urge caution in the recommendation to wait only 1 month, and in the United States most would prefer to wait 3 months if possible.

In the article “Gas under the right diaphragm” (Matsuura H, Hata H. Cleve Clin J Med 2018; 85[2]:98–100), Figure 2 appeared upside down. It should have appeared as follows:

This correction has been made to the online version.

In the article “Gas under the right diaphragm” (Matsuura H, Hata H. Cleve Clin J Med 2018; 85[2]:98–100), Figure 2 appeared upside down. It should have appeared as follows:

This correction has been made to the online version.

In the article “Gas under the right diaphragm” (Matsuura H, Hata H. Cleve Clin J Med 2018; 85[2]:98–100), Figure 2 appeared upside down. It should have appeared as follows:

This correction has been made to the online version.

On page 949 of the article “Diagnostic value of the physical examination in patients with dyspnea” (Shellenberger RA, Balakrishnan B, Avula S, Ebel A, Shaik S. Cleve Clin J Med 2017; 84[12]:943–950), the terms “abdominojugular reflex” and “hepatojugular reflex” should have been “abdominojugular reflux” and “hepatojugular reflux.” This error also occurred in Table 5 on that page.

On page 949 of the article “Diagnostic value of the physical examination in patients with dyspnea” (Shellenberger RA, Balakrishnan B, Avula S, Ebel A, Shaik S. Cleve Clin J Med 2017; 84[12]:943–950), the terms “abdominojugular reflex” and “hepatojugular reflex” should have been “abdominojugular reflux” and “hepatojugular reflux.” This error also occurred in Table 5 on that page.

On page 949 of the article “Diagnostic value of the physical examination in patients with dyspnea” (Shellenberger RA, Balakrishnan B, Avula S, Ebel A, Shaik S. Cleve Clin J Med 2017; 84[12]:943–950), the terms “abdominojugular reflex” and “hepatojugular reflex” should have been “abdominojugular reflux” and “hepatojugular reflux.” This error also occurred in Table 5 on that page.

Could European data privacy rules cost you big? Synthetic opioids drive increases in overdose deaths. Robocalls increase diabetic retinopathy screenings in low-income patients. And a new ranking points physicians toward practice-friendly South Dakota.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Could European data privacy rules cost you big? Synthetic opioids drive increases in overdose deaths. Robocalls increase diabetic retinopathy screenings in low-income patients. And a new ranking points physicians toward practice-friendly South Dakota.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Could European data privacy rules cost you big? Synthetic opioids drive increases in overdose deaths. Robocalls increase diabetic retinopathy screenings in low-income patients. And a new ranking points physicians toward practice-friendly South Dakota.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

High preconception blood pressure is associated with a greater risk of pregnancy loss, according to analysis of data from a randomized clinical trial of aspirin and pregnancy outcomes.

Researchers in the EAGeR (Effects of Aspirin on Gestational and Reproduction) trial analyzed data from 1,228 women attempting pregnancy with a history of pregnancy loss. After researchers adjusted for treatment assignment, body mass index (BMI), race, marital status, smoking, parity, and time from last pregnancy loss, an increase in all blood pressure measures was associated with a 17% increase in the risk of pregnancy loss (Hypertension. doi: 10.1161/hypertensionaha.117.10705).

thodonal/Thinkstock

cardnews@mdedge.com

SOURCE: Nobles CJ et al. Hypertension. 2018 Apr 2;71. doi: 10.1161/hypertensionaha.117.10705.

High preconception blood pressure is associated with a greater risk of pregnancy loss, according to analysis of data from a randomized clinical trial of aspirin and pregnancy outcomes.

Researchers in the EAGeR (Effects of Aspirin on Gestational and Reproduction) trial analyzed data from 1,228 women attempting pregnancy with a history of pregnancy loss. After researchers adjusted for treatment assignment, body mass index (BMI), race, marital status, smoking, parity, and time from last pregnancy loss, an increase in all blood pressure measures was associated with a 17% increase in the risk of pregnancy loss (Hypertension. doi: 10.1161/hypertensionaha.117.10705).

thodonal/Thinkstock

cardnews@mdedge.com

SOURCE: Nobles CJ et al. Hypertension. 2018 Apr 2;71. doi: 10.1161/hypertensionaha.117.10705.

High preconception blood pressure is associated with a greater risk of pregnancy loss, according to analysis of data from a randomized clinical trial of aspirin and pregnancy outcomes.

Researchers in the EAGeR (Effects of Aspirin on Gestational and Reproduction) trial analyzed data from 1,228 women attempting pregnancy with a history of pregnancy loss. After researchers adjusted for treatment assignment, body mass index (BMI), race, marital status, smoking, parity, and time from last pregnancy loss, an increase in all blood pressure measures was associated with a 17% increase in the risk of pregnancy loss (Hypertension. doi: 10.1161/hypertensionaha.117.10705).

thodonal/Thinkstock

cardnews@mdedge.com

SOURCE: Nobles CJ et al. Hypertension. 2018 Apr 2;71. doi: 10.1161/hypertensionaha.117.10705.

As many as one-third of workers in some sectors of health care and social service may have hearing loss, according to the researchers at the National Institute for Occupational Safety and Health (NIOSH) who studied audiograms from hundreds of US companies. Theirs is the first known study to estimate and compare the prevalence of noise-exposed worker hearing loss by subsector within the Health Care and Social Assistance (HSA) sector.

Some subsectors had higher than expected prevalence of hearing loss for an industry that has had assumed “low exposure” to noise, NIOSH says. Most of the HSA subsector prevalence estimates ranged from 14% to 18%, but the Medical and Diagnostic Laboratories subsector had 31% prevalence, the Offices of All Other Miscellaneous Health Practitioners had 24% prevalence, and Child Day Care Services had a 52% higher risk compared with that of the reference industry.

NIOSH says successful noise reduction measures have been documented in hospital settings. Exposure to chemotherapy drugs can be better prevented and laboratories can be modified to reduce the level of noise. When noise can’t be removed or reduced to safe levels, NIOSH recommends implementing an effective hearing conservation program.

Hearing loss is the third most common chronic physical condition in the US, NIOSH says. But Elizabeth Masterson, PhD, epidemiologist and lead author of the study, says, “Occupational hearing loss is entirely preventable.”

As many as one-third of workers in some sectors of health care and social service may have hearing loss, according to the researchers at the National Institute for Occupational Safety and Health (NIOSH) who studied audiograms from hundreds of US companies. Theirs is the first known study to estimate and compare the prevalence of noise-exposed worker hearing loss by subsector within the Health Care and Social Assistance (HSA) sector.

Some subsectors had higher than expected prevalence of hearing loss for an industry that has had assumed “low exposure” to noise, NIOSH says. Most of the HSA subsector prevalence estimates ranged from 14% to 18%, but the Medical and Diagnostic Laboratories subsector had 31% prevalence, the Offices of All Other Miscellaneous Health Practitioners had 24% prevalence, and Child Day Care Services had a 52% higher risk compared with that of the reference industry.

NIOSH says successful noise reduction measures have been documented in hospital settings. Exposure to chemotherapy drugs can be better prevented and laboratories can be modified to reduce the level of noise. When noise can’t be removed or reduced to safe levels, NIOSH recommends implementing an effective hearing conservation program.

Hearing loss is the third most common chronic physical condition in the US, NIOSH says. But Elizabeth Masterson, PhD, epidemiologist and lead author of the study, says, “Occupational hearing loss is entirely preventable.”

As many as one-third of workers in some sectors of health care and social service may have hearing loss, according to the researchers at the National Institute for Occupational Safety and Health (NIOSH) who studied audiograms from hundreds of US companies. Theirs is the first known study to estimate and compare the prevalence of noise-exposed worker hearing loss by subsector within the Health Care and Social Assistance (HSA) sector.

Some subsectors had higher than expected prevalence of hearing loss for an industry that has had assumed “low exposure” to noise, NIOSH says. Most of the HSA subsector prevalence estimates ranged from 14% to 18%, but the Medical and Diagnostic Laboratories subsector had 31% prevalence, the Offices of All Other Miscellaneous Health Practitioners had 24% prevalence, and Child Day Care Services had a 52% higher risk compared with that of the reference industry.

NIOSH says successful noise reduction measures have been documented in hospital settings. Exposure to chemotherapy drugs can be better prevented and laboratories can be modified to reduce the level of noise. When noise can’t be removed or reduced to safe levels, NIOSH recommends implementing an effective hearing conservation program.

Hearing loss is the third most common chronic physical condition in the US, NIOSH says. But Elizabeth Masterson, PhD, epidemiologist and lead author of the study, says, “Occupational hearing loss is entirely preventable.”

Aripiprazole, brexpiprazole, and cariprazine are dopamine receptor partial agonists, and on the surface, they appear similar. However, there are key differences in terms of available indications, formulations, pharmacodynamics, pharmacokinetics, dosing, drug interactions, tolerability, and other factors related to successful use.¹ This review will cover the main points that the knowledgeable clinician will need to be mindful of when prescribing these agents.

Aripiprazole

Aripiprazole was launched in the United States in 2002² as the first dopamine receptor partial agonist approved for the treatment of schizophrenia; it later received additional indications for adults with manic or mixed episodes associated with bipolar I disorder and the maintenance treatment of bipolar I disorder, as well as for the adjunctive treatment of major depressive disorder (MDD). Pediatric indications include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, irritability associated with autistic disorder, and Tourette’s disorder.

Several formulations also became available, including a short-acting injection indicated for agitation associated with schizophrenia or bipolar mania, and oral disintegrating tablets and an oral solution that could substitute for the regular tablet. Presently the medication has gone “generic,” and not all formulations are being manufactured. The long-acting formulations of aripiprazole (aripiprazole monohydrate and aripiprazole lauroxil) are considered different products, each with its own product insert, with indications that are more limited in scope than for the oral forms.^3,4

Although dopamine D2 receptor partial agonism is a relevant mechanism of action, partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors also play a role.² Actions at receptors other than dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A may explain some of the other clinical effects of aripiprazole. In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34 nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) receptors.

Dosage recommendations for adults with schizophrenia suggest a starting and maintenance dose of 10 to 15 mg/d.² Although the maximum dose is 30 mg/d, there is no evidence that doses >15 mg/d are superior to lower doses.⁵ In adolescents with schizophrenia, the product label recommends a starting dose of 2 mg/d, a maintenance dose of 10 mg/d, and a maximum dose of 30 mg/d. Recommendations for dosing in bipolar mania are similar. Dosing for the other indications is lower.

Efficacy in schizophrenia can be quantified using number needed to treat (NNT) for response vs placebo. The NNT answers the question “How many patients need to be randomized to aripiprazole vs placebo before expecting to encounter one additional responder?”⁶ From the 4 positive pivotal short-term acute schizophrenia trials for aripiprazole in adults,^7-10 using the definition of response as a ≥30% decrease in the Positive and Negative Syndrome Scale (PANSS) total score or a Clinical Global Impressions–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved), and pooling the data for aripiprazole doses 10 to 30 mg/d, response rates were 38% for aripiprazole vs 24% for placebo, resulting in a NNT of 8 (95% confidence interval [CI] 6 to 13).

From the 4 positive pivotal short-term acute bipolar mania trials for aripiprazole monotherapy in adults^11-14 using the definition of response as a ≥50% decrease in the Young Mania Rating Scale (YMRS) total score, and pooling the data for aripiprazole doses 15 to 30 mg/d, response rates were 47% for aripiprazole vs 31% for placebo, resulting in a NNT of 7 (95% CI 5 to 11).¹ Similar results were observed in the adjunctive aripiprazole acute bipolar mania trial¹⁵ where the NNT for response was also 7.¹

Continue to: From the 2 positive pivotal short-term...

From the 2 positive pivotal short-term acute MDD trials for aripiprazole,^16,17 using the definition of response as a ≥50% decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and pooling the data (aripiprazole flexibly dosed 2 to 20 mg/d, with a median dose of 10 mg/d), response rates were 33% for aripiprazole vs 20% for placebo, resulting in a NNT of 8 (95% CI 6 to 17). After including a third trial not described in product labeling,¹⁸ the NNT became a more robust 7 (95% CI 5 to 11).¹

The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) in the pivotal trials were akathisia (schizophrenia); akathisia, sedation, restlessness, tremor, and extrapyramidal disorder (bipolar mania, monotherapy); akathisia, insomnia, and extrapyramidal disorder (bipolar mania, adjunctive therapy); akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision (MDD); and nausea (short-acting IM formulation). Table 1¹ summarizes the tolerability information regarding rate of discontinuation due to adverse events (an overall indicator of tolerability), and the incidence of the most common adverse event, together with the calculated number needed to harm (NNH). Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability; for the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability for these indications.

Brexpiprazole

Brexpiprazole was launched in the United States in 2015 for 2 indications: schizophrenia and the adjunctive treatment of MDD, both in adults.¹⁹ In terms of binding, brexpiprazole has very high binding affinities to serotonin 5-HT1A (0.12 nM), adrenergic α1B (0.17 nM), dopamine D2 (0.30 nM), serotonin 5-HT2A (0.47 nM), and adrenergic α2C (0.59 nM) receptors, and high binding affinities to dopamine D3 (1.1 nM), serotonin 5-HT2B (1.9 nM), adrenergic α1D (2.6 nM), serotonin 5-HT7 (3.7 nM), and adrenergic α1A (3.8 nM) receptors.

The 1-mg/d starting dose for brexpiprazole is lower than the recommended dose range of 2 to 4 mg/d for schizophrenia or the recommended dose of 2 mg/d for MDD.¹⁹ Thus brexpiprazole requires titration. The recommended rate of titration depends on the disease state being treated. For schizophrenia, the recommended titration schedule is to increase the dose to 2 mg/d on Day 5 through Day 7, then to 4 mg/d (the maximum recommended dose) on Day 8 based on the patient’s clinical response and tolerability. For MDD, there is the option of starting at 0.5 mg/d and the titration process is slower, with dosage increases occurring at weekly intervals, and with a maximum dose of 3 mg/d.

Using the identical definition of response in persons with schizophrenia as for the aripiprazole data described above, pooling together all the available data for the recommended target dose of brexpiprazole for schizophrenia (2 to 4 mg/d) from the 2 studies listed in the product label,^20,21 the percentage of responders was 46%, compared with 31% for the pooled placebo groups, yielding a NNT of 7 (95% CI 5 to 12).²²

Continue to: For MDD...

For MDD, using the definition of response as a ≥50% decrease in MADRS total score, and pooling the results for brexpiprazole 1, 2, and 3 mg/d from the 2 pivotal trials,^23,24 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI 8 to 26).²² Including the 1.5-mg/d dose arm and the placebo arm from the phase II study for which results are also available but not included in product labelling, the NNT becomes a slightly more robust 11 (95% CI 8 to 20).²² Although the magnitude of the NNT effect size is stronger for aripiprazole than for brexpiprazole, the 95% CIs do overlap.

The most commonly encountered adverse event in the short-term trials in schizophrenia (incidence ≥4% and at least twice the rate of placebo) was increased weight. The most commonly encountered adverse events in the short-term trials in MDD (incidence ≥5% and at least twice the rate of placebo) were increased weight and akathisia. Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability, and for MDD the NNH vs placebo on discontinuation because of an adverse event was 50, representing reasonable overall tolerability for this indication as well (Table 1¹).

Cariprazine

Cariprazine was launched in the United States in 2015 for 2 indications: schizophrenia, and the acute treatment of manic or mixed episodes associated with bipolar I disorder, both in adults.²⁵ In terms of binding, cariprazine has very high binding affinities to dopamine D3 (0.085 nM), dopamine D2L (0.49 nM), serotonin 5-HT2B (0.58 nM), and dopamine D2S (0.69 nM) receptors, and high binding affinity to serotonin 5-HT1A (2.6 nM) receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine and didesmethyl cariprazine, that have in vitro receptor binding profiles similar to the parent drug. This latter metabolite, didesmethyl cariprazine, has a half-life of 1 to 3 weeks, and is the active moiety responsible for the majority of cariprazine’s effect when in steady state. Thus, following discontinuation of cariprazine, the decline in plasma concentrations of active drug will be slow.

The starting dose for cariprazine for schizophrenia, 1.5 mg/d, can be therapeutic. The dosage can be increased to 3 mg/d on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments to a maximum dose of 6 mg/d. For the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d; this can be done on Day 2. Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.²⁵

A more conservative definition of response was used in the reporting of the cariprazine acute schizophrenia studies. This was simply a ≥30% decrease in the PANSS total score, and did not include the option of including patients who scored a 1 or 2 on the CGI-I. For pooled doses of cariprazine 1.5 to 6 mg/d,^26-28 the percentage of responders was 31%, compared with 21% for the pooled placebo groups, yielding a NNT of 10 (95% CI 7 to 18).¹ Although the magnitude of the NNT effect size is weaker for cariprazine than the other dopamine receptor partial agonists, the 95% CI overlaps with that of aripiprazole and brexpiprazole. An appropriately designed head-to-head trial would be necessary to directly test noninferiority.

Continue to: Pooling the data...

Pooling the data from the 3 pivotal short-term acute bipolar mania trials for cariprazine monotherapy in adults^29-31 and using the definition of response as a ≥50% decrease in the YMRS total score for the recommended target dose of 3 to 6 mg/d, the percentage of responders was 57%, compared with 36% for the pooled placebo groups, yielding a NNT of 5 (95% CI 4 to 8).¹ The magnitude of the NNT effect size is stronger for cariprazine than for aripiprazole, but the 95% CIs overlap.

The most commonly encountered adverse events in the short-term trials (incidence ≥5% and at least twice the rate of placebo) were extrapyramidal symptoms and akathisia (schizophrenia); and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness (bipolar mania). In the schizophrenia studies, rates of discontinuation because of an adverse event were not higher for active medication vs placebo, suggesting excellent overall tolerability, and for bipolar disorder the NNH vs placebo on discontinuation because of an adverse event was 20, representing reasonable overall tolerability for this indication as well (Table 1).

Differences to consider

Indications. Although all 3 medications are approved for the treatment of schizophrenia, both aripiprazole and brexpiprazole are also approved for adjunctive treatment of MDD, and both aripiprazole and cariprazine are also approved for acute treatment of manic or mixed episodes associated with bipolar I disorder. In addition, aripiprazole is approved for a number of different disease states in pediatric patients. Aripiprazole has also been approved in a number of different formulations (oral and IM), but brexpiprazole and cariprazine are presently available only as oral pills (tablets for brexpiprazole, capsules for cariprazine).

Contraindications. All 3 agents are contraindicated in patients with a known hypersensitivity reaction to the product. All 3 also have a “black-box” warning for increased mortality in geriatric patients with dementia-related psychosis, a warning that is found in all antipsychotic medication labels. Additional black-box warnings are included regarding suicidality in the product labels of aripiprazole and brexpiprazole by virtue of their approval for the treatment of MDD.

Pharmacodynamics. All 3 agents describe a similar mechanism of action in their respective product labels: “efficacy … could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.”^2,19,25

Continue to: However, binding affinities differ...

However, binding affinities differ substantially among the agents (for example, cariprazine has only moderate binding affinity at serotonin 5-HT2A receptors [18.8 nM]), and differences also exist in terms of intrinsic activity at the receptors where partial agonism is operative. Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia), and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.^32,33 When cariprazine was compared with aripiprazole in functional assays for dopamine D2 and D3 receptors, similar D2 and higher D3 antagonist-partial agonist affinity and a 3- to 10-fold greater D3 vs D2 selectivity was observed for cariprazine.³⁴ Whether specifically targeting the dopamine D3 receptor over the dopamine D2 receptor is clinically advantageous remains unknown, but in preclinical studies, dopamine D3–preferring agents may exert pro-cognitive effects.^35-37 All 3 agents have only moderate binding affinities to histamine H1 receptors, thus sedation should not be prominent for any of them. None of the 3 agents have appreciable binding at muscarinic receptors, thus adverse effects related to antimuscarinic activity should not be present as well.

Schizophrenia is a heterogenous disorder. We know from clinical practice that patients respond differently to specific antipsychotics. Having different pharmacodynamic “fingerprints” to choose from allows for flexibility in treatment. Moreover, dopamine receptor partial agonists provide an alternative to the array of dopamine receptor antagonists, such as the other second-generation antipsychotics and all first-generation antipsychotics.

Dosing. Although all 3 agents are dosed once daily, only for aripiprazole is the recommended starting dose the same as the recommended maintenance dose in adults with schizophrenia or bipolar mania. Although the starting dose for cariprazine for schizophrenia can be therapeutic (1.5 mg/d), for the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d.

Half-life. Aripiprazole and brexpiprazole share a similar elimination half-life: approximately 75 hours and 94 hours for aripiprazole and its active metabolite dehydro-aripiprazole, respectively, and 91 hours and 86 hours for brexpiprazole and its major metabolite, DM-3411 (inactive), respectively. Cariprazine is strikingly different, with an elimination half-life of 2 to 4 days, and approximately 1 to 3 weeks for its active metabolite didesmethyl cariprazine.

Drug interactions. Both aripiprazole and brexpiprazole are metabolized via cytochrome P450 (CYP) 2D6 and CYP3A4, and thus the dose may need to be adjusted in the presence of CYP2D6 inhibitors or CYP3A4 inhibitors/inducers; with inhibitors, the dose is decreased by half or more, and with inducers, the dose is doubled. In contrast, cariprazine is primarily metabolized by CYP3A4 and thus potential drug–drug interactions are primarily focused on CYP3A4 inhibitors (decrease cariprazine dose by half) and inducers (co-prescribing of cariprazine with a CYP3A4 inducer is not recommended).

Continue to: Tolerability

Tolerability. For all 3 agents, rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability.^2,19,25 For the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability. For the most commonly encountered adverse event for each medication, the NNH values ranged from 5 (akathisia for aripiprazole for adjunctive use in MDD) to 50 (increased weight for brexpiprazole for schizophrenia). Of special interest are the adverse events of weight gain ≥7% from baseline, somnolence adverse events, and akathisia adverse events; the NNH values vs placebo for these are listed in Table 2¹. Pragmatically, NNH values <10 are likely to be more clinically relevant. For aripiprazole, brexpiprazole, and cariprazine for the treatment of schizophrenia, none of the NNH values for weight gain, somnolence, or akathisia were <10; however, this was not the case for the mood disorders, where in general, akathisia was more frequently observed for each of the agents. For the indication of schizophrenia, the rank order for propensity for weight gain appears to be brexpiprazole > aripiprazole > cariprazine, the propensity for somnolence aripiprazole > brexpiprazole > cariprazine, and the propensity for akathisia cariprazine > aripiprazole > brexpiprazole; however, this is by indirect comparison, and appropriately designed head-to-head clinical trials will be necessary in order to accurately assess these potential differences.

Because of the partial agonist activity at the dopamine D2 receptor, aripiprazole, brexpiprazole, and cariprazine are less likely to cause hyperprolactinemia than other first-line first- or second-generation antipsychotics. Other differentiating features of the dopamine receptor partial agonists compared with other choices include a relative lack of effect on the QT interval.³⁸ In general, as predicted by their relatively lower binding affinities to histamine H1 receptors, the dopamine receptor partial agonists are not especially sedating.³⁹

Likelihood to be helped or harmed

The concept of likelihood to be helped or harmed (LHH) can be useful to assess benefit vs risk, provided you select a relevant harm to contrast with the expected benefit.⁴⁰ Table 3¹ provides the NNT for response, NNH for discontinuation because of an adverse event (where applicable), the NNHs for weight gain ≥7%, somnolence adverse events, and akathisia adverse events, together with the calculated LHH (where applicable). With the exception of aripiprazole for the treatment of MDD when comparing response vs akathisia, all LHH values are >1.0, and thus the benefit (response) would be encountered more often than the harm. When LHH values are ≥10, this can be interpreted that one would encounter a response at least 10 times more often than the adverse event of interest. This was observed for brexpiprazole for the treatment of schizophrenia when comparing response vs akathisia, for cariprazine for schizophrenia when comparing response vs somnolence, for aripiprazole for bipolar mania when comparing response vs discontinuation because of an adverse event, and for cariprazine for bipolar mania when comparing response vs somnolence.

Beyond acute studies

When treating patients with schizophrenia, delaying time to relapse is a main goal. In placebo-controlled randomized withdrawal studies of oral aripiprazole, brexpiprazole, and cariprazine in patients with schizophrenia, observed relapse rates vs placebo were reported, allowing the calculation of NNT vs placebo for the avoidance of relapse.^41-44 These NNT values were similar and ranged from 4 to 5. For aripiprazole, relapse rates vs placebo in the 26-week study were 34% vs 57%, resulting in a NNT of 5 (95% CI 3 to 9); brexpiprazole, 52-week study, 13.5% vs 38.5%, NNT of 4 (95% CI 3 to 8); and cariprazine, 72-week study, 25% vs 47.5%, NNT of 5 (95% CI 3 to 11). In addition, cariprazine, 4.5 mg/d, has been directly compared with risperidone, 4 mg/d, in a 26-week double-blind study in non-geriatric adult patients with schizophrenia and predominant negative symptoms for at least 6 months.⁴⁵ Cariprazine was superior to risperidone on the PANSS–Negative Factor Score, and response to treatment (decrease ≥20% in PANSS–Negative Factor Score) was achieved by more patients treated with cariprazine by 26 weeks than those treated with risperidone (69% vs 58%, NNT 9 [95% CI 5 to 44]).

Caveats

The harms discussed in this article are primarily from acute studies and do not reflect effects that can take time to develop, such as tardive dyskinesia, the long-term accumulation of body weight, and the development of insulin resistance/type 2 diabetes mellitus.⁴⁰ The data presented are from carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from those encountered in routine clinical practice. Keep in mind that adverse events may differ in terms of impact and may not be clinically relevant if the adverse event is mild, time-limited, or easily managed. Moreover, different patients carry different propensities to experience different adverse events or to achieve a therapeutic response.

Continue to: Bottom Line

Although aripiprazole, brexpiprazole, and cariprazine are all dopamine receptor partial agonists with demonstrated efficacy in psychiatric disorders, they differ in terms of available formulations, indications, pharmacodynamics, pharmacokinetics, titration requirements, and tolerability. Careful consideration of these factors can increase the likelihood of successful treatment.

Related Resources

• Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013;27(11):879-911.
• Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67(5):407-411.
• U.S. Food & Drug Administration. Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Abilify Maintena
Brexpiprazole • Rexulti
Cariprazine • Vraylar

Aripiprazole, brexpiprazole, and cariprazine are dopamine receptor partial agonists, and on the surface, they appear similar. However, there are key differences in terms of available indications, formulations, pharmacodynamics, pharmacokinetics, dosing, drug interactions, tolerability, and other factors related to successful use.¹ This review will cover the main points that the knowledgeable clinician will need to be mindful of when prescribing these agents.

Aripiprazole

Aripiprazole was launched in the United States in 2002² as the first dopamine receptor partial agonist approved for the treatment of schizophrenia; it later received additional indications for adults with manic or mixed episodes associated with bipolar I disorder and the maintenance treatment of bipolar I disorder, as well as for the adjunctive treatment of major depressive disorder (MDD). Pediatric indications include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, irritability associated with autistic disorder, and Tourette’s disorder.

Several formulations also became available, including a short-acting injection indicated for agitation associated with schizophrenia or bipolar mania, and oral disintegrating tablets and an oral solution that could substitute for the regular tablet. Presently the medication has gone “generic,” and not all formulations are being manufactured. The long-acting formulations of aripiprazole (aripiprazole monohydrate and aripiprazole lauroxil) are considered different products, each with its own product insert, with indications that are more limited in scope than for the oral forms.^3,4

Although dopamine D2 receptor partial agonism is a relevant mechanism of action, partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors also play a role.² Actions at receptors other than dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A may explain some of the other clinical effects of aripiprazole. In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34 nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) receptors.

Dosage recommendations for adults with schizophrenia suggest a starting and maintenance dose of 10 to 15 mg/d.² Although the maximum dose is 30 mg/d, there is no evidence that doses >15 mg/d are superior to lower doses.⁵ In adolescents with schizophrenia, the product label recommends a starting dose of 2 mg/d, a maintenance dose of 10 mg/d, and a maximum dose of 30 mg/d. Recommendations for dosing in bipolar mania are similar. Dosing for the other indications is lower.

Efficacy in schizophrenia can be quantified using number needed to treat (NNT) for response vs placebo. The NNT answers the question “How many patients need to be randomized to aripiprazole vs placebo before expecting to encounter one additional responder?”⁶ From the 4 positive pivotal short-term acute schizophrenia trials for aripiprazole in adults,^7-10 using the definition of response as a ≥30% decrease in the Positive and Negative Syndrome Scale (PANSS) total score or a Clinical Global Impressions–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved), and pooling the data for aripiprazole doses 10 to 30 mg/d, response rates were 38% for aripiprazole vs 24% for placebo, resulting in a NNT of 8 (95% confidence interval [CI] 6 to 13).

From the 4 positive pivotal short-term acute bipolar mania trials for aripiprazole monotherapy in adults^11-14 using the definition of response as a ≥50% decrease in the Young Mania Rating Scale (YMRS) total score, and pooling the data for aripiprazole doses 15 to 30 mg/d, response rates were 47% for aripiprazole vs 31% for placebo, resulting in a NNT of 7 (95% CI 5 to 11).¹ Similar results were observed in the adjunctive aripiprazole acute bipolar mania trial¹⁵ where the NNT for response was also 7.¹

Continue to: From the 2 positive pivotal short-term...

From the 2 positive pivotal short-term acute MDD trials for aripiprazole,^16,17 using the definition of response as a ≥50% decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and pooling the data (aripiprazole flexibly dosed 2 to 20 mg/d, with a median dose of 10 mg/d), response rates were 33% for aripiprazole vs 20% for placebo, resulting in a NNT of 8 (95% CI 6 to 17). After including a third trial not described in product labeling,¹⁸ the NNT became a more robust 7 (95% CI 5 to 11).¹

The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) in the pivotal trials were akathisia (schizophrenia); akathisia, sedation, restlessness, tremor, and extrapyramidal disorder (bipolar mania, monotherapy); akathisia, insomnia, and extrapyramidal disorder (bipolar mania, adjunctive therapy); akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision (MDD); and nausea (short-acting IM formulation). Table 1¹ summarizes the tolerability information regarding rate of discontinuation due to adverse events (an overall indicator of tolerability), and the incidence of the most common adverse event, together with the calculated number needed to harm (NNH). Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability; for the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability for these indications.

Brexpiprazole

Brexpiprazole was launched in the United States in 2015 for 2 indications: schizophrenia and the adjunctive treatment of MDD, both in adults.¹⁹ In terms of binding, brexpiprazole has very high binding affinities to serotonin 5-HT1A (0.12 nM), adrenergic α1B (0.17 nM), dopamine D2 (0.30 nM), serotonin 5-HT2A (0.47 nM), and adrenergic α2C (0.59 nM) receptors, and high binding affinities to dopamine D3 (1.1 nM), serotonin 5-HT2B (1.9 nM), adrenergic α1D (2.6 nM), serotonin 5-HT7 (3.7 nM), and adrenergic α1A (3.8 nM) receptors.

The 1-mg/d starting dose for brexpiprazole is lower than the recommended dose range of 2 to 4 mg/d for schizophrenia or the recommended dose of 2 mg/d for MDD.¹⁹ Thus brexpiprazole requires titration. The recommended rate of titration depends on the disease state being treated. For schizophrenia, the recommended titration schedule is to increase the dose to 2 mg/d on Day 5 through Day 7, then to 4 mg/d (the maximum recommended dose) on Day 8 based on the patient’s clinical response and tolerability. For MDD, there is the option of starting at 0.5 mg/d and the titration process is slower, with dosage increases occurring at weekly intervals, and with a maximum dose of 3 mg/d.

Using the identical definition of response in persons with schizophrenia as for the aripiprazole data described above, pooling together all the available data for the recommended target dose of brexpiprazole for schizophrenia (2 to 4 mg/d) from the 2 studies listed in the product label,^20,21 the percentage of responders was 46%, compared with 31% for the pooled placebo groups, yielding a NNT of 7 (95% CI 5 to 12).²²

Continue to: For MDD...

For MDD, using the definition of response as a ≥50% decrease in MADRS total score, and pooling the results for brexpiprazole 1, 2, and 3 mg/d from the 2 pivotal trials,^23,24 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI 8 to 26).²² Including the 1.5-mg/d dose arm and the placebo arm from the phase II study for which results are also available but not included in product labelling, the NNT becomes a slightly more robust 11 (95% CI 8 to 20).²² Although the magnitude of the NNT effect size is stronger for aripiprazole than for brexpiprazole, the 95% CIs do overlap.

The most commonly encountered adverse event in the short-term trials in schizophrenia (incidence ≥4% and at least twice the rate of placebo) was increased weight. The most commonly encountered adverse events in the short-term trials in MDD (incidence ≥5% and at least twice the rate of placebo) were increased weight and akathisia. Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability, and for MDD the NNH vs placebo on discontinuation because of an adverse event was 50, representing reasonable overall tolerability for this indication as well (Table 1¹).

Cariprazine

Cariprazine was launched in the United States in 2015 for 2 indications: schizophrenia, and the acute treatment of manic or mixed episodes associated with bipolar I disorder, both in adults.²⁵ In terms of binding, cariprazine has very high binding affinities to dopamine D3 (0.085 nM), dopamine D2L (0.49 nM), serotonin 5-HT2B (0.58 nM), and dopamine D2S (0.69 nM) receptors, and high binding affinity to serotonin 5-HT1A (2.6 nM) receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine and didesmethyl cariprazine, that have in vitro receptor binding profiles similar to the parent drug. This latter metabolite, didesmethyl cariprazine, has a half-life of 1 to 3 weeks, and is the active moiety responsible for the majority of cariprazine’s effect when in steady state. Thus, following discontinuation of cariprazine, the decline in plasma concentrations of active drug will be slow.

The starting dose for cariprazine for schizophrenia, 1.5 mg/d, can be therapeutic. The dosage can be increased to 3 mg/d on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments to a maximum dose of 6 mg/d. For the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d; this can be done on Day 2. Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.²⁵

A more conservative definition of response was used in the reporting of the cariprazine acute schizophrenia studies. This was simply a ≥30% decrease in the PANSS total score, and did not include the option of including patients who scored a 1 or 2 on the CGI-I. For pooled doses of cariprazine 1.5 to 6 mg/d,^26-28 the percentage of responders was 31%, compared with 21% for the pooled placebo groups, yielding a NNT of 10 (95% CI 7 to 18).¹ Although the magnitude of the NNT effect size is weaker for cariprazine than the other dopamine receptor partial agonists, the 95% CI overlaps with that of aripiprazole and brexpiprazole. An appropriately designed head-to-head trial would be necessary to directly test noninferiority.

Continue to: Pooling the data...

Pooling the data from the 3 pivotal short-term acute bipolar mania trials for cariprazine monotherapy in adults^29-31 and using the definition of response as a ≥50% decrease in the YMRS total score for the recommended target dose of 3 to 6 mg/d, the percentage of responders was 57%, compared with 36% for the pooled placebo groups, yielding a NNT of 5 (95% CI 4 to 8).¹ The magnitude of the NNT effect size is stronger for cariprazine than for aripiprazole, but the 95% CIs overlap.

The most commonly encountered adverse events in the short-term trials (incidence ≥5% and at least twice the rate of placebo) were extrapyramidal symptoms and akathisia (schizophrenia); and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness (bipolar mania). In the schizophrenia studies, rates of discontinuation because of an adverse event were not higher for active medication vs placebo, suggesting excellent overall tolerability, and for bipolar disorder the NNH vs placebo on discontinuation because of an adverse event was 20, representing reasonable overall tolerability for this indication as well (Table 1).

Differences to consider

Indications. Although all 3 medications are approved for the treatment of schizophrenia, both aripiprazole and brexpiprazole are also approved for adjunctive treatment of MDD, and both aripiprazole and cariprazine are also approved for acute treatment of manic or mixed episodes associated with bipolar I disorder. In addition, aripiprazole is approved for a number of different disease states in pediatric patients. Aripiprazole has also been approved in a number of different formulations (oral and IM), but brexpiprazole and cariprazine are presently available only as oral pills (tablets for brexpiprazole, capsules for cariprazine).

Contraindications. All 3 agents are contraindicated in patients with a known hypersensitivity reaction to the product. All 3 also have a “black-box” warning for increased mortality in geriatric patients with dementia-related psychosis, a warning that is found in all antipsychotic medication labels. Additional black-box warnings are included regarding suicidality in the product labels of aripiprazole and brexpiprazole by virtue of their approval for the treatment of MDD.

Pharmacodynamics. All 3 agents describe a similar mechanism of action in their respective product labels: “efficacy … could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.”^2,19,25

Continue to: However, binding affinities differ...

However, binding affinities differ substantially among the agents (for example, cariprazine has only moderate binding affinity at serotonin 5-HT2A receptors [18.8 nM]), and differences also exist in terms of intrinsic activity at the receptors where partial agonism is operative. Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia), and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.^32,33 When cariprazine was compared with aripiprazole in functional assays for dopamine D2 and D3 receptors, similar D2 and higher D3 antagonist-partial agonist affinity and a 3- to 10-fold greater D3 vs D2 selectivity was observed for cariprazine.³⁴ Whether specifically targeting the dopamine D3 receptor over the dopamine D2 receptor is clinically advantageous remains unknown, but in preclinical studies, dopamine D3–preferring agents may exert pro-cognitive effects.^35-37 All 3 agents have only moderate binding affinities to histamine H1 receptors, thus sedation should not be prominent for any of them. None of the 3 agents have appreciable binding at muscarinic receptors, thus adverse effects related to antimuscarinic activity should not be present as well.

Schizophrenia is a heterogenous disorder. We know from clinical practice that patients respond differently to specific antipsychotics. Having different pharmacodynamic “fingerprints” to choose from allows for flexibility in treatment. Moreover, dopamine receptor partial agonists provide an alternative to the array of dopamine receptor antagonists, such as the other second-generation antipsychotics and all first-generation antipsychotics.

Dosing. Although all 3 agents are dosed once daily, only for aripiprazole is the recommended starting dose the same as the recommended maintenance dose in adults with schizophrenia or bipolar mania. Although the starting dose for cariprazine for schizophrenia can be therapeutic (1.5 mg/d), for the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d.

Half-life. Aripiprazole and brexpiprazole share a similar elimination half-life: approximately 75 hours and 94 hours for aripiprazole and its active metabolite dehydro-aripiprazole, respectively, and 91 hours and 86 hours for brexpiprazole and its major metabolite, DM-3411 (inactive), respectively. Cariprazine is strikingly different, with an elimination half-life of 2 to 4 days, and approximately 1 to 3 weeks for its active metabolite didesmethyl cariprazine.

Drug interactions. Both aripiprazole and brexpiprazole are metabolized via cytochrome P450 (CYP) 2D6 and CYP3A4, and thus the dose may need to be adjusted in the presence of CYP2D6 inhibitors or CYP3A4 inhibitors/inducers; with inhibitors, the dose is decreased by half or more, and with inducers, the dose is doubled. In contrast, cariprazine is primarily metabolized by CYP3A4 and thus potential drug–drug interactions are primarily focused on CYP3A4 inhibitors (decrease cariprazine dose by half) and inducers (co-prescribing of cariprazine with a CYP3A4 inducer is not recommended).

Continue to: Tolerability

Tolerability. For all 3 agents, rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability.^2,19,25 For the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability. For the most commonly encountered adverse event for each medication, the NNH values ranged from 5 (akathisia for aripiprazole for adjunctive use in MDD) to 50 (increased weight for brexpiprazole for schizophrenia). Of special interest are the adverse events of weight gain ≥7% from baseline, somnolence adverse events, and akathisia adverse events; the NNH values vs placebo for these are listed in Table 2¹. Pragmatically, NNH values <10 are likely to be more clinically relevant. For aripiprazole, brexpiprazole, and cariprazine for the treatment of schizophrenia, none of the NNH values for weight gain, somnolence, or akathisia were <10; however, this was not the case for the mood disorders, where in general, akathisia was more frequently observed for each of the agents. For the indication of schizophrenia, the rank order for propensity for weight gain appears to be brexpiprazole > aripiprazole > cariprazine, the propensity for somnolence aripiprazole > brexpiprazole > cariprazine, and the propensity for akathisia cariprazine > aripiprazole > brexpiprazole; however, this is by indirect comparison, and appropriately designed head-to-head clinical trials will be necessary in order to accurately assess these potential differences.

Because of the partial agonist activity at the dopamine D2 receptor, aripiprazole, brexpiprazole, and cariprazine are less likely to cause hyperprolactinemia than other first-line first- or second-generation antipsychotics. Other differentiating features of the dopamine receptor partial agonists compared with other choices include a relative lack of effect on the QT interval.³⁸ In general, as predicted by their relatively lower binding affinities to histamine H1 receptors, the dopamine receptor partial agonists are not especially sedating.³⁹

Likelihood to be helped or harmed

The concept of likelihood to be helped or harmed (LHH) can be useful to assess benefit vs risk, provided you select a relevant harm to contrast with the expected benefit.⁴⁰ Table 3¹ provides the NNT for response, NNH for discontinuation because of an adverse event (where applicable), the NNHs for weight gain ≥7%, somnolence adverse events, and akathisia adverse events, together with the calculated LHH (where applicable). With the exception of aripiprazole for the treatment of MDD when comparing response vs akathisia, all LHH values are >1.0, and thus the benefit (response) would be encountered more often than the harm. When LHH values are ≥10, this can be interpreted that one would encounter a response at least 10 times more often than the adverse event of interest. This was observed for brexpiprazole for the treatment of schizophrenia when comparing response vs akathisia, for cariprazine for schizophrenia when comparing response vs somnolence, for aripiprazole for bipolar mania when comparing response vs discontinuation because of an adverse event, and for cariprazine for bipolar mania when comparing response vs somnolence.

Beyond acute studies

When treating patients with schizophrenia, delaying time to relapse is a main goal. In placebo-controlled randomized withdrawal studies of oral aripiprazole, brexpiprazole, and cariprazine in patients with schizophrenia, observed relapse rates vs placebo were reported, allowing the calculation of NNT vs placebo for the avoidance of relapse.^41-44 These NNT values were similar and ranged from 4 to 5. For aripiprazole, relapse rates vs placebo in the 26-week study were 34% vs 57%, resulting in a NNT of 5 (95% CI 3 to 9); brexpiprazole, 52-week study, 13.5% vs 38.5%, NNT of 4 (95% CI 3 to 8); and cariprazine, 72-week study, 25% vs 47.5%, NNT of 5 (95% CI 3 to 11). In addition, cariprazine, 4.5 mg/d, has been directly compared with risperidone, 4 mg/d, in a 26-week double-blind study in non-geriatric adult patients with schizophrenia and predominant negative symptoms for at least 6 months.⁴⁵ Cariprazine was superior to risperidone on the PANSS–Negative Factor Score, and response to treatment (decrease ≥20% in PANSS–Negative Factor Score) was achieved by more patients treated with cariprazine by 26 weeks than those treated with risperidone (69% vs 58%, NNT 9 [95% CI 5 to 44]).

Caveats

The harms discussed in this article are primarily from acute studies and do not reflect effects that can take time to develop, such as tardive dyskinesia, the long-term accumulation of body weight, and the development of insulin resistance/type 2 diabetes mellitus.⁴⁰ The data presented are from carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from those encountered in routine clinical practice. Keep in mind that adverse events may differ in terms of impact and may not be clinically relevant if the adverse event is mild, time-limited, or easily managed. Moreover, different patients carry different propensities to experience different adverse events or to achieve a therapeutic response.

Continue to: Bottom Line

Although aripiprazole, brexpiprazole, and cariprazine are all dopamine receptor partial agonists with demonstrated efficacy in psychiatric disorders, they differ in terms of available formulations, indications, pharmacodynamics, pharmacokinetics, titration requirements, and tolerability. Careful consideration of these factors can increase the likelihood of successful treatment.

Related Resources

• Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013;27(11):879-911.
• Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67(5):407-411.
• U.S. Food & Drug Administration. Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Abilify Maintena
Brexpiprazole • Rexulti
Cariprazine • Vraylar

Aripiprazole, brexpiprazole, and cariprazine are dopamine receptor partial agonists, and on the surface, they appear similar. However, there are key differences in terms of available indications, formulations, pharmacodynamics, pharmacokinetics, dosing, drug interactions, tolerability, and other factors related to successful use.¹ This review will cover the main points that the knowledgeable clinician will need to be mindful of when prescribing these agents.

Aripiprazole

Aripiprazole was launched in the United States in 2002² as the first dopamine receptor partial agonist approved for the treatment of schizophrenia; it later received additional indications for adults with manic or mixed episodes associated with bipolar I disorder and the maintenance treatment of bipolar I disorder, as well as for the adjunctive treatment of major depressive disorder (MDD). Pediatric indications include schizophrenia, acute treatment of manic or mixed episodes associated with bipolar I disorder, irritability associated with autistic disorder, and Tourette’s disorder.

Several formulations also became available, including a short-acting injection indicated for agitation associated with schizophrenia or bipolar mania, and oral disintegrating tablets and an oral solution that could substitute for the regular tablet. Presently the medication has gone “generic,” and not all formulations are being manufactured. The long-acting formulations of aripiprazole (aripiprazole monohydrate and aripiprazole lauroxil) are considered different products, each with its own product insert, with indications that are more limited in scope than for the oral forms.^3,4

Although dopamine D2 receptor partial agonism is a relevant mechanism of action, partial agonist activity at serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors also play a role.² Actions at receptors other than dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A may explain some of the other clinical effects of aripiprazole. In terms of binding, aripiprazole has very high binding affinities (Ki) to dopamine D2 (0.34 nM), dopamine D3 (0.8 nM), and serotonin 5-HT2B (0.36 nM) receptors, and high binding affinities to serotonin 5-HT1A (1.7 nM) and serotonin 5-HT2A (3.4 nM) receptors.

Dosage recommendations for adults with schizophrenia suggest a starting and maintenance dose of 10 to 15 mg/d.² Although the maximum dose is 30 mg/d, there is no evidence that doses >15 mg/d are superior to lower doses.⁵ In adolescents with schizophrenia, the product label recommends a starting dose of 2 mg/d, a maintenance dose of 10 mg/d, and a maximum dose of 30 mg/d. Recommendations for dosing in bipolar mania are similar. Dosing for the other indications is lower.

Efficacy in schizophrenia can be quantified using number needed to treat (NNT) for response vs placebo. The NNT answers the question “How many patients need to be randomized to aripiprazole vs placebo before expecting to encounter one additional responder?”⁶ From the 4 positive pivotal short-term acute schizophrenia trials for aripiprazole in adults,^7-10 using the definition of response as a ≥30% decrease in the Positive and Negative Syndrome Scale (PANSS) total score or a Clinical Global Impressions–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved), and pooling the data for aripiprazole doses 10 to 30 mg/d, response rates were 38% for aripiprazole vs 24% for placebo, resulting in a NNT of 8 (95% confidence interval [CI] 6 to 13).

From the 4 positive pivotal short-term acute bipolar mania trials for aripiprazole monotherapy in adults^11-14 using the definition of response as a ≥50% decrease in the Young Mania Rating Scale (YMRS) total score, and pooling the data for aripiprazole doses 15 to 30 mg/d, response rates were 47% for aripiprazole vs 31% for placebo, resulting in a NNT of 7 (95% CI 5 to 11).¹ Similar results were observed in the adjunctive aripiprazole acute bipolar mania trial¹⁵ where the NNT for response was also 7.¹

Continue to: From the 2 positive pivotal short-term...

From the 2 positive pivotal short-term acute MDD trials for aripiprazole,^16,17 using the definition of response as a ≥50% decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and pooling the data (aripiprazole flexibly dosed 2 to 20 mg/d, with a median dose of 10 mg/d), response rates were 33% for aripiprazole vs 20% for placebo, resulting in a NNT of 8 (95% CI 6 to 17). After including a third trial not described in product labeling,¹⁸ the NNT became a more robust 7 (95% CI 5 to 11).¹

The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) in the pivotal trials were akathisia (schizophrenia); akathisia, sedation, restlessness, tremor, and extrapyramidal disorder (bipolar mania, monotherapy); akathisia, insomnia, and extrapyramidal disorder (bipolar mania, adjunctive therapy); akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision (MDD); and nausea (short-acting IM formulation). Table 1¹ summarizes the tolerability information regarding rate of discontinuation due to adverse events (an overall indicator of tolerability), and the incidence of the most common adverse event, together with the calculated number needed to harm (NNH). Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability; for the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability for these indications.

Brexpiprazole

Brexpiprazole was launched in the United States in 2015 for 2 indications: schizophrenia and the adjunctive treatment of MDD, both in adults.¹⁹ In terms of binding, brexpiprazole has very high binding affinities to serotonin 5-HT1A (0.12 nM), adrenergic α1B (0.17 nM), dopamine D2 (0.30 nM), serotonin 5-HT2A (0.47 nM), and adrenergic α2C (0.59 nM) receptors, and high binding affinities to dopamine D3 (1.1 nM), serotonin 5-HT2B (1.9 nM), adrenergic α1D (2.6 nM), serotonin 5-HT7 (3.7 nM), and adrenergic α1A (3.8 nM) receptors.

The 1-mg/d starting dose for brexpiprazole is lower than the recommended dose range of 2 to 4 mg/d for schizophrenia or the recommended dose of 2 mg/d for MDD.¹⁹ Thus brexpiprazole requires titration. The recommended rate of titration depends on the disease state being treated. For schizophrenia, the recommended titration schedule is to increase the dose to 2 mg/d on Day 5 through Day 7, then to 4 mg/d (the maximum recommended dose) on Day 8 based on the patient’s clinical response and tolerability. For MDD, there is the option of starting at 0.5 mg/d and the titration process is slower, with dosage increases occurring at weekly intervals, and with a maximum dose of 3 mg/d.

Using the identical definition of response in persons with schizophrenia as for the aripiprazole data described above, pooling together all the available data for the recommended target dose of brexpiprazole for schizophrenia (2 to 4 mg/d) from the 2 studies listed in the product label,^20,21 the percentage of responders was 46%, compared with 31% for the pooled placebo groups, yielding a NNT of 7 (95% CI 5 to 12).²²

Continue to: For MDD...

For MDD, using the definition of response as a ≥50% decrease in MADRS total score, and pooling the results for brexpiprazole 1, 2, and 3 mg/d from the 2 pivotal trials,^23,24 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI 8 to 26).²² Including the 1.5-mg/d dose arm and the placebo arm from the phase II study for which results are also available but not included in product labelling, the NNT becomes a slightly more robust 11 (95% CI 8 to 20).²² Although the magnitude of the NNT effect size is stronger for aripiprazole than for brexpiprazole, the 95% CIs do overlap.

The most commonly encountered adverse event in the short-term trials in schizophrenia (incidence ≥4% and at least twice the rate of placebo) was increased weight. The most commonly encountered adverse events in the short-term trials in MDD (incidence ≥5% and at least twice the rate of placebo) were increased weight and akathisia. Rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability, and for MDD the NNH vs placebo on discontinuation because of an adverse event was 50, representing reasonable overall tolerability for this indication as well (Table 1¹).

Cariprazine

Cariprazine was launched in the United States in 2015 for 2 indications: schizophrenia, and the acute treatment of manic or mixed episodes associated with bipolar I disorder, both in adults.²⁵ In terms of binding, cariprazine has very high binding affinities to dopamine D3 (0.085 nM), dopamine D2L (0.49 nM), serotonin 5-HT2B (0.58 nM), and dopamine D2S (0.69 nM) receptors, and high binding affinity to serotonin 5-HT1A (2.6 nM) receptors. Cariprazine forms 2 major metabolites, desmethyl cariprazine and didesmethyl cariprazine, that have in vitro receptor binding profiles similar to the parent drug. This latter metabolite, didesmethyl cariprazine, has a half-life of 1 to 3 weeks, and is the active moiety responsible for the majority of cariprazine’s effect when in steady state. Thus, following discontinuation of cariprazine, the decline in plasma concentrations of active drug will be slow.

The starting dose for cariprazine for schizophrenia, 1.5 mg/d, can be therapeutic. The dosage can be increased to 3 mg/d on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5-mg or 3-mg increments to a maximum dose of 6 mg/d. For the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d; this can be done on Day 2. Cariprazine has been tested in clinical trials at higher doses; however, doses that exceed 6 mg/d did not confer significant additional benefit.²⁵

A more conservative definition of response was used in the reporting of the cariprazine acute schizophrenia studies. This was simply a ≥30% decrease in the PANSS total score, and did not include the option of including patients who scored a 1 or 2 on the CGI-I. For pooled doses of cariprazine 1.5 to 6 mg/d,^26-28 the percentage of responders was 31%, compared with 21% for the pooled placebo groups, yielding a NNT of 10 (95% CI 7 to 18).¹ Although the magnitude of the NNT effect size is weaker for cariprazine than the other dopamine receptor partial agonists, the 95% CI overlaps with that of aripiprazole and brexpiprazole. An appropriately designed head-to-head trial would be necessary to directly test noninferiority.

Continue to: Pooling the data...

Pooling the data from the 3 pivotal short-term acute bipolar mania trials for cariprazine monotherapy in adults^29-31 and using the definition of response as a ≥50% decrease in the YMRS total score for the recommended target dose of 3 to 6 mg/d, the percentage of responders was 57%, compared with 36% for the pooled placebo groups, yielding a NNT of 5 (95% CI 4 to 8).¹ The magnitude of the NNT effect size is stronger for cariprazine than for aripiprazole, but the 95% CIs overlap.

The most commonly encountered adverse events in the short-term trials (incidence ≥5% and at least twice the rate of placebo) were extrapyramidal symptoms and akathisia (schizophrenia); and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness (bipolar mania). In the schizophrenia studies, rates of discontinuation because of an adverse event were not higher for active medication vs placebo, suggesting excellent overall tolerability, and for bipolar disorder the NNH vs placebo on discontinuation because of an adverse event was 20, representing reasonable overall tolerability for this indication as well (Table 1).

Differences to consider

Indications. Although all 3 medications are approved for the treatment of schizophrenia, both aripiprazole and brexpiprazole are also approved for adjunctive treatment of MDD, and both aripiprazole and cariprazine are also approved for acute treatment of manic or mixed episodes associated with bipolar I disorder. In addition, aripiprazole is approved for a number of different disease states in pediatric patients. Aripiprazole has also been approved in a number of different formulations (oral and IM), but brexpiprazole and cariprazine are presently available only as oral pills (tablets for brexpiprazole, capsules for cariprazine).

Contraindications. All 3 agents are contraindicated in patients with a known hypersensitivity reaction to the product. All 3 also have a “black-box” warning for increased mortality in geriatric patients with dementia-related psychosis, a warning that is found in all antipsychotic medication labels. Additional black-box warnings are included regarding suicidality in the product labels of aripiprazole and brexpiprazole by virtue of their approval for the treatment of MDD.

Pharmacodynamics. All 3 agents describe a similar mechanism of action in their respective product labels: “efficacy … could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.”^2,19,25

Continue to: However, binding affinities differ...

However, binding affinities differ substantially among the agents (for example, cariprazine has only moderate binding affinity at serotonin 5-HT2A receptors [18.8 nM]), and differences also exist in terms of intrinsic activity at the receptors where partial agonism is operative. Compared with aripiprazole, brexpiprazole has lower intrinsic activity at the dopamine D2 receptor (and thus is expected to cause less akathisia), and has an approximately 10-fold higher affinity for serotonin 5-HT1A and 5-HT2A receptors, also potentially enhancing tolerability and perhaps anxiolytic activity.^32,33 When cariprazine was compared with aripiprazole in functional assays for dopamine D2 and D3 receptors, similar D2 and higher D3 antagonist-partial agonist affinity and a 3- to 10-fold greater D3 vs D2 selectivity was observed for cariprazine.³⁴ Whether specifically targeting the dopamine D3 receptor over the dopamine D2 receptor is clinically advantageous remains unknown, but in preclinical studies, dopamine D3–preferring agents may exert pro-cognitive effects.^35-37 All 3 agents have only moderate binding affinities to histamine H1 receptors, thus sedation should not be prominent for any of them. None of the 3 agents have appreciable binding at muscarinic receptors, thus adverse effects related to antimuscarinic activity should not be present as well.

Schizophrenia is a heterogenous disorder. We know from clinical practice that patients respond differently to specific antipsychotics. Having different pharmacodynamic “fingerprints” to choose from allows for flexibility in treatment. Moreover, dopamine receptor partial agonists provide an alternative to the array of dopamine receptor antagonists, such as the other second-generation antipsychotics and all first-generation antipsychotics.

Dosing. Although all 3 agents are dosed once daily, only for aripiprazole is the recommended starting dose the same as the recommended maintenance dose in adults with schizophrenia or bipolar mania. Although the starting dose for cariprazine for schizophrenia can be therapeutic (1.5 mg/d), for the treatment of bipolar mania, cariprazine will need to be titrated from the starting dose of 1.5 mg/d to the recommended target dose range of 3 to 6 mg/d.

Half-life. Aripiprazole and brexpiprazole share a similar elimination half-life: approximately 75 hours and 94 hours for aripiprazole and its active metabolite dehydro-aripiprazole, respectively, and 91 hours and 86 hours for brexpiprazole and its major metabolite, DM-3411 (inactive), respectively. Cariprazine is strikingly different, with an elimination half-life of 2 to 4 days, and approximately 1 to 3 weeks for its active metabolite didesmethyl cariprazine.

Drug interactions. Both aripiprazole and brexpiprazole are metabolized via cytochrome P450 (CYP) 2D6 and CYP3A4, and thus the dose may need to be adjusted in the presence of CYP2D6 inhibitors or CYP3A4 inhibitors/inducers; with inhibitors, the dose is decreased by half or more, and with inducers, the dose is doubled. In contrast, cariprazine is primarily metabolized by CYP3A4 and thus potential drug–drug interactions are primarily focused on CYP3A4 inhibitors (decrease cariprazine dose by half) and inducers (co-prescribing of cariprazine with a CYP3A4 inducer is not recommended).

Continue to: Tolerability

Tolerability. For all 3 agents, rates of discontinuation because of an adverse event were not higher for active medication vs placebo for the schizophrenia studies, suggesting excellent overall tolerability.^2,19,25 For the other disease states, NNH values ranged from 17 (adjunctive use of aripiprazole for bipolar mania) to 100 (aripiprazole monotherapy for bipolar mania), representing reasonable overall tolerability. For the most commonly encountered adverse event for each medication, the NNH values ranged from 5 (akathisia for aripiprazole for adjunctive use in MDD) to 50 (increased weight for brexpiprazole for schizophrenia). Of special interest are the adverse events of weight gain ≥7% from baseline, somnolence adverse events, and akathisia adverse events; the NNH values vs placebo for these are listed in Table 2¹. Pragmatically, NNH values <10 are likely to be more clinically relevant. For aripiprazole, brexpiprazole, and cariprazine for the treatment of schizophrenia, none of the NNH values for weight gain, somnolence, or akathisia were <10; however, this was not the case for the mood disorders, where in general, akathisia was more frequently observed for each of the agents. For the indication of schizophrenia, the rank order for propensity for weight gain appears to be brexpiprazole > aripiprazole > cariprazine, the propensity for somnolence aripiprazole > brexpiprazole > cariprazine, and the propensity for akathisia cariprazine > aripiprazole > brexpiprazole; however, this is by indirect comparison, and appropriately designed head-to-head clinical trials will be necessary in order to accurately assess these potential differences.

Because of the partial agonist activity at the dopamine D2 receptor, aripiprazole, brexpiprazole, and cariprazine are less likely to cause hyperprolactinemia than other first-line first- or second-generation antipsychotics. Other differentiating features of the dopamine receptor partial agonists compared with other choices include a relative lack of effect on the QT interval.³⁸ In general, as predicted by their relatively lower binding affinities to histamine H1 receptors, the dopamine receptor partial agonists are not especially sedating.³⁹

Likelihood to be helped or harmed

The concept of likelihood to be helped or harmed (LHH) can be useful to assess benefit vs risk, provided you select a relevant harm to contrast with the expected benefit.⁴⁰ Table 3¹ provides the NNT for response, NNH for discontinuation because of an adverse event (where applicable), the NNHs for weight gain ≥7%, somnolence adverse events, and akathisia adverse events, together with the calculated LHH (where applicable). With the exception of aripiprazole for the treatment of MDD when comparing response vs akathisia, all LHH values are >1.0, and thus the benefit (response) would be encountered more often than the harm. When LHH values are ≥10, this can be interpreted that one would encounter a response at least 10 times more often than the adverse event of interest. This was observed for brexpiprazole for the treatment of schizophrenia when comparing response vs akathisia, for cariprazine for schizophrenia when comparing response vs somnolence, for aripiprazole for bipolar mania when comparing response vs discontinuation because of an adverse event, and for cariprazine for bipolar mania when comparing response vs somnolence.

Beyond acute studies

When treating patients with schizophrenia, delaying time to relapse is a main goal. In placebo-controlled randomized withdrawal studies of oral aripiprazole, brexpiprazole, and cariprazine in patients with schizophrenia, observed relapse rates vs placebo were reported, allowing the calculation of NNT vs placebo for the avoidance of relapse.^41-44 These NNT values were similar and ranged from 4 to 5. For aripiprazole, relapse rates vs placebo in the 26-week study were 34% vs 57%, resulting in a NNT of 5 (95% CI 3 to 9); brexpiprazole, 52-week study, 13.5% vs 38.5%, NNT of 4 (95% CI 3 to 8); and cariprazine, 72-week study, 25% vs 47.5%, NNT of 5 (95% CI 3 to 11). In addition, cariprazine, 4.5 mg/d, has been directly compared with risperidone, 4 mg/d, in a 26-week double-blind study in non-geriatric adult patients with schizophrenia and predominant negative symptoms for at least 6 months.⁴⁵ Cariprazine was superior to risperidone on the PANSS–Negative Factor Score, and response to treatment (decrease ≥20% in PANSS–Negative Factor Score) was achieved by more patients treated with cariprazine by 26 weeks than those treated with risperidone (69% vs 58%, NNT 9 [95% CI 5 to 44]).

Caveats

The harms discussed in this article are primarily from acute studies and do not reflect effects that can take time to develop, such as tardive dyskinesia, the long-term accumulation of body weight, and the development of insulin resistance/type 2 diabetes mellitus.⁴⁰ The data presented are from carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from those encountered in routine clinical practice. Keep in mind that adverse events may differ in terms of impact and may not be clinically relevant if the adverse event is mild, time-limited, or easily managed. Moreover, different patients carry different propensities to experience different adverse events or to achieve a therapeutic response.

Continue to: Bottom Line

Although aripiprazole, brexpiprazole, and cariprazine are all dopamine receptor partial agonists with demonstrated efficacy in psychiatric disorders, they differ in terms of available formulations, indications, pharmacodynamics, pharmacokinetics, titration requirements, and tolerability. Careful consideration of these factors can increase the likelihood of successful treatment.

Related Resources

• Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013;27(11):879-911.
• Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67(5):407-411.
• U.S. Food & Drug Administration. Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Abilify Maintena
Brexpiprazole • Rexulti
Cariprazine • Vraylar