Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Three myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are associated with an abnormal somatic mutation of the JAK2 gene. Essential thrombocythemia is considered when there is a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow. The manifestations of PV, ET, and PMF all typically occur within the sixth or seventh decade of life. A patient may present with an abnormal blood count but be asymptomatic at the time. Over the course and progression of the disease, increases in hematocrit or platelet counts along with symptoms such as headaches, blurred vision, and plethora may occur.¹ The JAK2 V617F mutation is responsible for the production of the JAK2 protein, which is continuously activated, promoting the growth and division of cells such as erythrocytes, granulocytes, and platelets. It has been reported that there is a nearly 100% incidence of the JAK2 mutation in patients with polycythemia vera, and a 50% incidence in patients with essential thrombocythemia and primary myelofibrosis.²

The discovery of the JAK2 mutation in PV, ET, and PMF was an important advancement in helping distinguish these disorders from other MPNs, including chronic myelogenous leukemia, but its presence does not explain why some individuals develop ET and others, PV or PMF.³ Although there have been familial cases proven of ET, the somatic JAK2 mutation is acquired and not inherited. In this report, we describe the unusual circumstance of JAK2 V617F mutation in a brother and a sister who were both diagnosed with essential thrombocythemia.

Case presentations and summaries

RS, a 69-year-old white man, was referred to our service in 2006 for continued care of previously diagnosed essential thrombocythemia. At the time of his initial visit to our clinic, his complete blood count was normal, the platelet count being adequately controlled by anagrelide at a daily dose of 4.0 mg. He complained of palpitations and peripheral neuropathy. A bone marrow biopsy was performed, revealing moderate hypercellularity, atypical megakaryocytosis, and a negative BCR-ABL mutation but a positive JAK2 V617F mutation. The patient is now treated with hydroxyurea 1,000 mg daily in divided doses, which better controls his counts and does not have the side effects of anagrelide.

SW, a 73-year-old woman, and brother of RS (they share the same biological mother and father), was noted to have a mild thrombocytosis in 2008. In 2013, her platelet count rose to 865,000 cells/uL (normal, 150,000-450,000 cells/uL, age and sex adjusted) and she was referred to our clinic. A bone marrow biopsy was performed, revealing borderline hypercellularity with atypical megakaryocytosis and the presence of a JAK2 V617F mutation. As with her brother, the BCR-ABL mutation was not present. She has also responded to treatment with hydroxyurea, but at a reduced dosage of 500 mg daily.

A third sibling, AS, again of the same biological mother and father, had died of multiple veno-occlusive cerebral vascular events long before the diagnoses on his younger siblings had been made. The suggestion of any underling hematologic pathology would be interesting, but speculative. Nothing is known about the parents’ medical history. None of the three siblings had children.

Discussion

Much research has been done to understand the pathogenesis of and find a cure for myeloproliferative disorders, but despite some progress, a cure remains elusive. However, there have been some advances that have contributed to partial cures for MPNs. One of the major breakthroughs in MPN research, about 50 years ago, was related to the “sporadic vs familial debate” around the Philadelphia chromosome.4 It led to the discovery of the reciprocal translocation between chromosomes 9 and 22, known as the BCR-ABL mutation, which is found in many CML patients. This discovery allowed researchers to focus their attention on other tyrosine kinase domains, such as the JAK2 V617F mutation, which is presented in the three other MPNs; PV, ET, and PMF. Both the JAK2 V617F and BCR-ABL mutations are active in signaling transcription, more commonly growth of cells.⁴

Since the discovery of the JAK2 V617F mutation in early 2005, it has become a leading diagnostic criteria for myeloproliferative diseases. The presence of the JAK2 V617F mutation and the measurement of its allele burden can be assessed by examination of either peripheral blood or bone marrow samples.⁵

The JAK2 V617F mutation is a result of a single change in the DNA nucleotide base pair that causes a substitution of a valine amino acid for a phenylalanine amino acid at the 617 position on exon 14 within the JAK2 kinase regulatory domain. This point mutation disrupts the regular control of the JAK2 by removing its ability to turn off, leading to uncontrolled blood cell growth.⁶ When the JAK2 V617F mutation cannot be demonstrated in a patient with the hallmarks of an MPN, the detection of other JAK2 and MPL proto-oncogene, thrombopoietin receptor mutations may be used as a diagnostic procedure for other MPNs.⁷

Other mutations incorporated in JAK2 domain can be detected in the coding portions of the DNA known as exons. One such mutation is the JAK2 exon 12, which is involved in JAK2 V617F-negative PV patients. This mutation is not detected in patients with ET or PMF and is 2%-5% present in patients with PV. There are other somatic mutations in the thrombopoietin receptors that work in accordance with thrombopoietin: MPL W515L and MPL W515K, which are found at chromosome 1p34, are identified in about 5% of PMF and 1% of ET patients, but are not present in PV patients.^8.9

Pikman and colleagues reported in 2009 that the JAK2 V617F mutation is not acquired randomly.⁹ Their findings showed that, only in white populations, does the JAK2 V617F mutation arise preferentially on a specific constitutional JAK2 46/1 haplotype. According to the authors, the preconceived notion a of randomly acquired JAK2 V617F mutation does not account for familial MPN’s. Familial MPNs are thought to be produced by sporadic and extremely penetrant substitutions in genes that still are not identified and the 46/1 haplotype does not explain for the phenotypic diversity correlated with the JAK2 V617F gene. The 46/1 haplotype, however, correlates more frequently with different MPN subtypes. There are two hypotheses that try to explain how an acquired mutation as prevailing as the JAK2 V617F mutation can be associated with certain inherited backgrounds. The first hypothesis asserts the V617F accumulates at a faster rate than other genes because of the fundamentally unstable genetics of the 46/1 haplotype. The second theory is that all the mutated genes, including the V617F, arise at equal rates, but 46/1 may grant a selective advantage to the V617F-positive clone or interacts in some way to increase the likelihood of abnormal blood counts. A study that examined both these hypotheses concluded that the 46/1 haplotype was present more frequently in patients with myeloproliferative disorders than in their control groups and even more so in cases that were proven to be V617F-positive.10

There are very few cases that have reported familial MPN’s, especially as the pedigrees of the familial MPN’s illustrate that inheritance patterns are notably heterogeneous, indicating that there may be a range of different germline mutations driving the susceptibility. With recent data, the JAK2 V617F mutation in tandem with MPL W515L/K and inactivating TET2 mutations still continue to be the most frequently acquired mutations involved in both familial and sporadic MPN. As far as we know, there have been no cases to prove that JAK2 V617F and MPL W515L/K mutations are inherited through the germline, but there are other alleles that may pass through the germline that can be associated with hereditary thrombocytosis.¹¹ Further cytogenetic studies will clarify the pathogenesis of these disorders and possibly lead to effective targeted therapies.

Tonsillar carcinoma is the most common of the oropharyngeal malignancies of the head and neck region after thyroid and laryngeal carcinoma. Squamous cell carcinoma is the most frequent histologic type of these tumors.¹ Tonsillar tumors may originate in the oral cavity, oropharynx, hypopharynx, or larynx. In the United States, more than 5,000 new cases of oropharynx cancer are diagnosed annually.² Men are affected three to four times more often than are women, and the rate of incidence increases after the 4th decade of life.³ Surveillance, Epidemiology, and End Results data from 1975-2004 show that tonsillar squamous cell carcinoma has had one of the largest increases in the male-to-female incidence rate ratios.⁴ The overall incidence of tonsillar carcinoma is increasing, especially in the younger population, and this may be attributed to increasing rates of human papilloma virus.^5,6

Squamous cell carcinoma in the head and neck originate from subsites within the oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.⁷ Traditionally, alcohol consumption and tobacco use were considered the most significant risk factors for the development of tonsillar cancer.⁸ More recently, however, the high-risk oncogenic human papilloma virus has emerged as a clinical entity in the pathogenesis of squamous cell carcinoma in the head and neck. Other risk factors include poor oral hygiene, mechanical irritation, chewing of betel quid preparations, and a lack of vegetables and fruits in the diet.^9-11 Squamous cell carcinoma of the oropharynx often presents late with lymph node involvement at the time of diagnosis. Nonspecific symptoms such as a sore throat and dysphagia can allow head and neck cancer to evade early detection. Many patients with tonsillar carcinoma present with advanced disease because early lesions are generally asymptomatic when small. This absence of symptoms is responsible for 67%-77% of patients presenting with tumors larger than 2.0 cm and often with regional nodal metastasis. At presentation, 45% of anterior tonsillar pillar lesions and 76% of tonsillar fossa lesions have clinically positive necks.¹²

Despite significant treatment advances, the management of advanced squamous cell carcinoma of the tonsil remains challenging. Historically, surgery was considered the standard of care for patients with tonsillar carcinoma with or without postoperative adjuvant radiotherapy. In locally advanced tonsillar carcinoma, extensive surgery with major tissue reconstruction was necessary, leading to speech dysfunction, cosmetic deformities, and difficulties in swallowing, all of which are detrimental to patient quality of life.¹³ Given the critical role of the oropharynx in speech and swallowing, nonsurgical therapy with organ-preserving chemoradiation has gained a greater role in the treatment of tonsil carcinoma.¹³ Over the past decade, innovations in radiation therapy techniques have led to the introduction of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) for the treatment of various cancers including tonsillar carcinoma.^14,15 IMRT is an advanced mode of conformal high-precision radiotherapy that uses computer-controlled multiple small radiation beams of varying intensities to deliver precise radiation doses to the target tissues while sparing adjacent healthy tissues.¹⁴ By incorporating three-dimensional computed-tomography (CT) or positron-emission–tomography (PET) imaging technology, IMRT allows the radiation dose to conform more precisely to the three-dimensional shape of the tumor while modulating the intensity of the radiation beam and minimizing its dose to those adjacent sensitive and unaffected organs. IGRT uses a range of two-, three-, and four-dimensional imaging techniques that improve the precision and accuracy of the delivery of the radiation dose to the targeted tumor tissue while minimizing the dose to the surrounding normal tissue during the course of radiation therapy (Figure 1). In this report, we present challenging cases of advanced tonsillar carcinoma and describe our experience in managing the disease using a hyperfractionated IMRT-IGRT based three-dimensional conformal radiation therapy protocol with concurrent chemotherapy.

Case presentations and summaries

Case 1

A 52-year-old white, nonsmoking man who worked in a research chemical laboratory, presented with complaints of throat pain and difficulty in swallowing. The patient had a history of asthma and allergies and had been seen by an ear, nose, and throat (ENT) specialist prior to his visit to our oncology center. A biopsy was performed on a right tonsillar mass measuring 2.7 x 3.6 cm. A computed-tomography (CT) scan showed 2 enlarged inhomogeneous lymph nodes measuring 2.9 cm and 1.7 cm. The nodes were well defined with no soft tissue edema. Neoplasm was favored as a diagnosis and biopsy of the mass was carried out. A biopsy specimen measuring 1.0 x 0.4 x 0.3 cm revealed a moderately differentiated infiltrating squamous cell carcinoma, which extended to the edge of the biopsy specimen. The patient’s Karnofsky performance status was 90% (ie, able to carry on normal activity; minor signs or symptoms of disease).

A CT scan of the chest was clear with no evidence of malignant involvement. A subsequent CT scan of the neck revealed a primary neoplasm of the right faucial tonsil measuring 3.3 x 3.0 cm and associated with right level II, level III, and level IV pathological lymphadenopathy. Positron-emission tomography (PET) imaging of the neck revealed a right tonsillar lesion of 2.7 x 3.0 cm involving the right parapharyngeal space (Figure 2, Case 1). The standardized uptake value (SUV) of the PET scan of the primary lesion was measured at 7.3. A cluster of right level II cervical nodes measuring 3.2 x 2.5 cm had an SUV of 3.5. A 1.0-cm right level III jugular node was also seen with an SUV of 1.6, and a right level IV lymph node measuring 1.5 x 1.0 cm was seen with an SUV of 1.8. No other lesions were noted. The tumor stage was T2N2bM0, a stage IVa disease.

Case 2

A 49-year-old black male presented with throat pain and a mass seen initially by his family physician. The patient had a history of tobacco use (at least 1 cigar a day) periodically for about 10 years and had quit cigar smoking 15 years prior to developing his disease. An initial evaluation indicated that the patient had a hypopharyngeal mass in the left inferior pole of his tonsil with near occlusion of the hypopharyngeal airway. His larynx could not be visualized because of the obstructive mass. A neck lymph node measuring 3.0 cm in the left jugulodigastric region was also noted. The patient’s Karnofsky performance status was 90%. Subsequently, the patient underwent excision of the right tonsil and left tonsillar region.

The pathology of the right tonsil was found to be benign. Histology of the left tonsil revealed invasive squamous cell carcinoma. The resected tumor size measured 3.7 x 2.7 x 2.5 cm. The tumor was moderately differentiated involving the deep surgical margins. No lymphovascular invasion was seen. A PET scan revealed a mass arising from the left tonsillar pillar measuring 3.6 x 2.6 x 3.3 cm with deviation of the epiglottis posteriorly nearing the left vallecula. In addition, multiple large cervical nodal lesions in the left level II nodal chain were seen, with the largest measuring 3.1 x 3.0 x 4.5 cm with an SUV of 3.4. Displacement of the left submandibular gland with several further enlarged level II lymph nodes was observed. In the region of left vallecula, there was soft tissue thickening with increased activity measuring 2.7 x 1.5 cm, likely crossing the midline with an SUV of 5.5. The rest of the neck was negative for metastatic involvement (Figure 2, Case 2). The tumor stage was T3N2Mx, a stage IVa disease.

The patient had a Port-A-Cath placed, which caused a hemothorax after placement of the port and delayed initiating his treatment. A pretreatment MRI scan of the neck revealed multiple conglomerate hypodense peripherally enhancing nodular areas in the left neck posterior to the left submandibular gland deep to the parotid tail worrisome for necrotic lymphadenopathy. The patient underwent a course of hyperfractionated IMRT-IGRT in 67 fractions of 120 cGy twice daily for a total dose of 8,040 cGy to the primary tumor site.¹⁶ The patient had a port and PEG tube prior to initiating his radiation therapy. He received IMRT-IGRT with concurrent chemotherapy that was selected based on the recommendation of his genomic testing.^17,18 The chemotherapy regimen used included carboplatin (300 mg weekly) and docetaxel (400 mg weekly). The patient had a treatment break because he was hospitalized for anemia and pancytopenia from his chemotherapy and he received supportive cancer care with epoetin alfa.A post therapy PET scan was negative for evidence of hypermetabolic malignancy; however, a 3.3 x 2.7 cm calcified lesion representing likely level III jugular lymph node exhibited no measurable activity at that time. The follow-up after 40 months indicated that the patient had no reported recurrence of the disease (Figure 2, Case 2). The patient’s demographics, tumor characteristics, and the treatment details are summarized in the Table.
 

Case 3

A 53-year-old white man, who had no smoking or tobacco history but who was exposed to chemicals including sulfuric acid, hydrogen chloride gas, and glycols at work, presented initially with a sore throat that became more painful over time. His ENT specialist referred him for a CT scan of the neck, which revealed a left-sided neck mass measuring 2.5 cm in diameter posterior to the submandibular gland and lateral to carotid sheath and anterior to the triangle (Figure 2, Case 3). The mass appeared to be encapsulated. There was a lobulated spherical mass in the left supraglottic area with formation of the airway of the pyriform sinus and additional anterior vascular involvement was noted. The mass measured 3.6 cm in transverse diameter.

A left tonsillar biopsy specimen measuring 1.4 x 0.6 x 0.2 cm was obtained, and its pathology revealed that the patient had a metastatic squamous cell carcinoma. The left neck lymph node mass aspiration also revealed the presence of squamous cell carcinoma. A PET-CT scan staging showed a dominant tonsillar fossa mass extending from the soft palate down to the pyriform sinus measuring 4.2 x 3.8 cm, with an SUV uptake of 7.3. There was a dominant left level II necrotic lymph node presence measuring 5.0 x 3.7 cm, with an SUV of 3.0. The patient’s Karnofsky performance status was 90%. The tumor stage was T4N2M0, a stage IVa disease. The patient received a course of conformal hyperfractionated IMRT-IGRT delivered to the primary tumor in 67 fractions at 120 cGy twice daily for a total dose of 8,040 cGy¹⁶ and concurrent carboplatin chemotherapy at a weekly dose of 200 mg.

After completion of his radiation therapy, chemotherapy was changed based on genomic testing from single agent to doublet with carboplatin (area under the curve (AUC) dose of 2 or 200 mg, weekly) plus docetaxel (25 mg/m² weekly for 3 weeks and 1 week off ).^17,18 A PET scan after chemoradiation therapy revealed a marked anatomical improvement in the primary neoplastic disease seen in the faucial tonsil. The tonsillar mass noted previously had almost completely resolved over the interval, with only a mild persistent asymmetrical thickening of around 1.5 cm, with a peak SUV of 2.0. A lymph node of 2.8 x 2.0 cm was present anterior to the left sternocleidomastoid muscle exhibiting SUV of only 1.8. No other abnormal lesions were noted (Figure 2, Case 3). The patient continues to do extremely well without local recurrence of the disease 46 months after radiation therapy (see Table for patient demographics, tumor characteristics, and therapy details.)
 

Discussion

The management of patients with primary squamous cell carcinoma of the oropharyngeal remains controversial. Traditionally, early-stage tonsillar squamous cell carcinoma was managed by a single modality treatment, either by surgery or radiation therapy, each showing similar efficacy and outcomes.¹⁹ For late-stage disease, a combined approach using surgery and radiation therapy was found to be superior to single modality treatment. However, surgery in conjugation with radiation therapy has been associated with significant toxicities compared with the radiation therapy alone.¹³Therefore, the use of radiation therapy without surgery is becoming more common with increasingly sophisticated radiation therapy techniques and organ preservation approach in patients with squamous cell carcinoma of the tonsil.

Findings from several studies have shown that in stage I or II oropharyngeal cancer, single modality treatment with radiation therapy achieves 80%-90% of local control of the disease, but poorer outcomes are reported for locally advanced stages III/IV with a local control rate of 63%-74%.²⁰ These findings and others have led to a shift to evaluate the clinical benefits of radiation therapy given with concurrent chemotherapy for the primary treatment of advanced stage oropharyngeal squamous cell carcinoma.^20,21 Findings from a number of studies have since reported comparable efficacy and toxicity outcomes using this regimen with concurrent chemotherapy in patients with locally advanced head and neck squamous cell cancer.^22-24 Synchronous carboplatin chemotherapy was used effectively as an alternative to cisplatin with fewer potential adverse effects in the good prognosis group of patients with oropharyngeal squamous cell carcinoma.^25,26 For our 3 patients, we used carboplatin-based chemotherapy with concurrent advanced hyperfractionated radiation therapy techniques to successfully manage tonsillar squamous cell carcinoma and reduce renal toxicity and neuropathy.

Advanced radiation therapy techniques such as IMRT-IGRT are used routinely at the University Cancer and Diagnostic Centers in Houston, Texas, to manage a range of malignant cancers.²⁷ These innovative techniques have the potential to deliver highly conformal dose-intense radiation to targeted regions of disease, while sparing adjacent critical nonmalignant tissue. The improved shaping of high-dose distributions with IMRT-IGRT could mitigate treatment-related toxicities. For example, the use of advanced radiation therapy techniques has been associated with increased preservation of parotid salivary flow.^28-30 The use of advanced radiation therapy techniques in head and neck squamous cell carcinoma is growing, and early evidence confirms its ability to secure excellent local and regional disease control.^31,32 In this study, we have demonstrated that by using hyperfractionated conformal three-dimensional IMRT-IGRT we were able not only to manage advanced tonsillar squamous cell carcinoma and treat the malignant metastasis, but also spare adjacent critical organs that were not involved in the disease, thus reducing many of the detrimental side effects associated with hyperfractionated chemoradiation.

All 3 patients were followed for between 40 and 46 months. They continue to do extremely well without local recurrence of their disease, indicating a 100% disease control and overall survival rate. The disease control and survival outcomes for our patients with stage IVA disease compare favorably to other published reports in the literature.^33,34 Findings from a study by Prestwich and colleagues³³ of 41 patients with stage IV tonsillar carcinoma showed that the radiation therapy with concurrent chemotherapy achieved local and regional disease control in 91% of complete responders and an overall survival rate of 66% at 3 years. Similarly, Setton and colleagues³⁴ reported on 442 patients – 50% with tonsillar cancer, 46% with base-of-tongue cancer – who underwent IMRT and concurrent chemotherapy and who achieved a 3-year overall survival of 84.9%. Our study findings demonstrate that hyperfractionated conformal three-dimensional IMRT-IGRT with concurrent chemotherapy can be delivered safely and effectively to patients with advanced tonsillar squamous cell carcinoma.
 

Acknowledgment

The authors thank Ms June Lyliston, LVN, for editing and proofreading the manuscript.

Tonsillar carcinoma is the most common of the oropharyngeal malignancies of the head and neck region after thyroid and laryngeal carcinoma. Squamous cell carcinoma is the most frequent histologic type of these tumors.¹ Tonsillar tumors may originate in the oral cavity, oropharynx, hypopharynx, or larynx. In the United States, more than 5,000 new cases of oropharynx cancer are diagnosed annually.² Men are affected three to four times more often than are women, and the rate of incidence increases after the 4th decade of life.³ Surveillance, Epidemiology, and End Results data from 1975-2004 show that tonsillar squamous cell carcinoma has had one of the largest increases in the male-to-female incidence rate ratios.⁴ The overall incidence of tonsillar carcinoma is increasing, especially in the younger population, and this may be attributed to increasing rates of human papilloma virus.^5,6

Squamous cell carcinoma in the head and neck originate from subsites within the oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.⁷ Traditionally, alcohol consumption and tobacco use were considered the most significant risk factors for the development of tonsillar cancer.⁸ More recently, however, the high-risk oncogenic human papilloma virus has emerged as a clinical entity in the pathogenesis of squamous cell carcinoma in the head and neck. Other risk factors include poor oral hygiene, mechanical irritation, chewing of betel quid preparations, and a lack of vegetables and fruits in the diet.^9-11 Squamous cell carcinoma of the oropharynx often presents late with lymph node involvement at the time of diagnosis. Nonspecific symptoms such as a sore throat and dysphagia can allow head and neck cancer to evade early detection. Many patients with tonsillar carcinoma present with advanced disease because early lesions are generally asymptomatic when small. This absence of symptoms is responsible for 67%-77% of patients presenting with tumors larger than 2.0 cm and often with regional nodal metastasis. At presentation, 45% of anterior tonsillar pillar lesions and 76% of tonsillar fossa lesions have clinically positive necks.¹²

Despite significant treatment advances, the management of advanced squamous cell carcinoma of the tonsil remains challenging. Historically, surgery was considered the standard of care for patients with tonsillar carcinoma with or without postoperative adjuvant radiotherapy. In locally advanced tonsillar carcinoma, extensive surgery with major tissue reconstruction was necessary, leading to speech dysfunction, cosmetic deformities, and difficulties in swallowing, all of which are detrimental to patient quality of life.¹³ Given the critical role of the oropharynx in speech and swallowing, nonsurgical therapy with organ-preserving chemoradiation has gained a greater role in the treatment of tonsil carcinoma.¹³ Over the past decade, innovations in radiation therapy techniques have led to the introduction of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) for the treatment of various cancers including tonsillar carcinoma.^14,15 IMRT is an advanced mode of conformal high-precision radiotherapy that uses computer-controlled multiple small radiation beams of varying intensities to deliver precise radiation doses to the target tissues while sparing adjacent healthy tissues.¹⁴ By incorporating three-dimensional computed-tomography (CT) or positron-emission–tomography (PET) imaging technology, IMRT allows the radiation dose to conform more precisely to the three-dimensional shape of the tumor while modulating the intensity of the radiation beam and minimizing its dose to those adjacent sensitive and unaffected organs. IGRT uses a range of two-, three-, and four-dimensional imaging techniques that improve the precision and accuracy of the delivery of the radiation dose to the targeted tumor tissue while minimizing the dose to the surrounding normal tissue during the course of radiation therapy (Figure 1). In this report, we present challenging cases of advanced tonsillar carcinoma and describe our experience in managing the disease using a hyperfractionated IMRT-IGRT based three-dimensional conformal radiation therapy protocol with concurrent chemotherapy.

Case presentations and summaries

Case 1

A 52-year-old white, nonsmoking man who worked in a research chemical laboratory, presented with complaints of throat pain and difficulty in swallowing. The patient had a history of asthma and allergies and had been seen by an ear, nose, and throat (ENT) specialist prior to his visit to our oncology center. A biopsy was performed on a right tonsillar mass measuring 2.7 x 3.6 cm. A computed-tomography (CT) scan showed 2 enlarged inhomogeneous lymph nodes measuring 2.9 cm and 1.7 cm. The nodes were well defined with no soft tissue edema. Neoplasm was favored as a diagnosis and biopsy of the mass was carried out. A biopsy specimen measuring 1.0 x 0.4 x 0.3 cm revealed a moderately differentiated infiltrating squamous cell carcinoma, which extended to the edge of the biopsy specimen. The patient’s Karnofsky performance status was 90% (ie, able to carry on normal activity; minor signs or symptoms of disease).

A CT scan of the chest was clear with no evidence of malignant involvement. A subsequent CT scan of the neck revealed a primary neoplasm of the right faucial tonsil measuring 3.3 x 3.0 cm and associated with right level II, level III, and level IV pathological lymphadenopathy. Positron-emission tomography (PET) imaging of the neck revealed a right tonsillar lesion of 2.7 x 3.0 cm involving the right parapharyngeal space (Figure 2, Case 1). The standardized uptake value (SUV) of the PET scan of the primary lesion was measured at 7.3. A cluster of right level II cervical nodes measuring 3.2 x 2.5 cm had an SUV of 3.5. A 1.0-cm right level III jugular node was also seen with an SUV of 1.6, and a right level IV lymph node measuring 1.5 x 1.0 cm was seen with an SUV of 1.8. No other lesions were noted. The tumor stage was T2N2bM0, a stage IVa disease.

Case 2

A 49-year-old black male presented with throat pain and a mass seen initially by his family physician. The patient had a history of tobacco use (at least 1 cigar a day) periodically for about 10 years and had quit cigar smoking 15 years prior to developing his disease. An initial evaluation indicated that the patient had a hypopharyngeal mass in the left inferior pole of his tonsil with near occlusion of the hypopharyngeal airway. His larynx could not be visualized because of the obstructive mass. A neck lymph node measuring 3.0 cm in the left jugulodigastric region was also noted. The patient’s Karnofsky performance status was 90%. Subsequently, the patient underwent excision of the right tonsil and left tonsillar region.

The pathology of the right tonsil was found to be benign. Histology of the left tonsil revealed invasive squamous cell carcinoma. The resected tumor size measured 3.7 x 2.7 x 2.5 cm. The tumor was moderately differentiated involving the deep surgical margins. No lymphovascular invasion was seen. A PET scan revealed a mass arising from the left tonsillar pillar measuring 3.6 x 2.6 x 3.3 cm with deviation of the epiglottis posteriorly nearing the left vallecula. In addition, multiple large cervical nodal lesions in the left level II nodal chain were seen, with the largest measuring 3.1 x 3.0 x 4.5 cm with an SUV of 3.4. Displacement of the left submandibular gland with several further enlarged level II lymph nodes was observed. In the region of left vallecula, there was soft tissue thickening with increased activity measuring 2.7 x 1.5 cm, likely crossing the midline with an SUV of 5.5. The rest of the neck was negative for metastatic involvement (Figure 2, Case 2). The tumor stage was T3N2Mx, a stage IVa disease.

The patient had a Port-A-Cath placed, which caused a hemothorax after placement of the port and delayed initiating his treatment. A pretreatment MRI scan of the neck revealed multiple conglomerate hypodense peripherally enhancing nodular areas in the left neck posterior to the left submandibular gland deep to the parotid tail worrisome for necrotic lymphadenopathy. The patient underwent a course of hyperfractionated IMRT-IGRT in 67 fractions of 120 cGy twice daily for a total dose of 8,040 cGy to the primary tumor site.¹⁶ The patient had a port and PEG tube prior to initiating his radiation therapy. He received IMRT-IGRT with concurrent chemotherapy that was selected based on the recommendation of his genomic testing.^17,18 The chemotherapy regimen used included carboplatin (300 mg weekly) and docetaxel (400 mg weekly). The patient had a treatment break because he was hospitalized for anemia and pancytopenia from his chemotherapy and he received supportive cancer care with epoetin alfa.A post therapy PET scan was negative for evidence of hypermetabolic malignancy; however, a 3.3 x 2.7 cm calcified lesion representing likely level III jugular lymph node exhibited no measurable activity at that time. The follow-up after 40 months indicated that the patient had no reported recurrence of the disease (Figure 2, Case 2). The patient’s demographics, tumor characteristics, and the treatment details are summarized in the Table.
 

Case 3

A 53-year-old white man, who had no smoking or tobacco history but who was exposed to chemicals including sulfuric acid, hydrogen chloride gas, and glycols at work, presented initially with a sore throat that became more painful over time. His ENT specialist referred him for a CT scan of the neck, which revealed a left-sided neck mass measuring 2.5 cm in diameter posterior to the submandibular gland and lateral to carotid sheath and anterior to the triangle (Figure 2, Case 3). The mass appeared to be encapsulated. There was a lobulated spherical mass in the left supraglottic area with formation of the airway of the pyriform sinus and additional anterior vascular involvement was noted. The mass measured 3.6 cm in transverse diameter.

A left tonsillar biopsy specimen measuring 1.4 x 0.6 x 0.2 cm was obtained, and its pathology revealed that the patient had a metastatic squamous cell carcinoma. The left neck lymph node mass aspiration also revealed the presence of squamous cell carcinoma. A PET-CT scan staging showed a dominant tonsillar fossa mass extending from the soft palate down to the pyriform sinus measuring 4.2 x 3.8 cm, with an SUV uptake of 7.3. There was a dominant left level II necrotic lymph node presence measuring 5.0 x 3.7 cm, with an SUV of 3.0. The patient’s Karnofsky performance status was 90%. The tumor stage was T4N2M0, a stage IVa disease. The patient received a course of conformal hyperfractionated IMRT-IGRT delivered to the primary tumor in 67 fractions at 120 cGy twice daily for a total dose of 8,040 cGy¹⁶ and concurrent carboplatin chemotherapy at a weekly dose of 200 mg.

After completion of his radiation therapy, chemotherapy was changed based on genomic testing from single agent to doublet with carboplatin (area under the curve (AUC) dose of 2 or 200 mg, weekly) plus docetaxel (25 mg/m² weekly for 3 weeks and 1 week off ).^17,18 A PET scan after chemoradiation therapy revealed a marked anatomical improvement in the primary neoplastic disease seen in the faucial tonsil. The tonsillar mass noted previously had almost completely resolved over the interval, with only a mild persistent asymmetrical thickening of around 1.5 cm, with a peak SUV of 2.0. A lymph node of 2.8 x 2.0 cm was present anterior to the left sternocleidomastoid muscle exhibiting SUV of only 1.8. No other abnormal lesions were noted (Figure 2, Case 3). The patient continues to do extremely well without local recurrence of the disease 46 months after radiation therapy (see Table for patient demographics, tumor characteristics, and therapy details.)
 

Discussion

The management of patients with primary squamous cell carcinoma of the oropharyngeal remains controversial. Traditionally, early-stage tonsillar squamous cell carcinoma was managed by a single modality treatment, either by surgery or radiation therapy, each showing similar efficacy and outcomes.¹⁹ For late-stage disease, a combined approach using surgery and radiation therapy was found to be superior to single modality treatment. However, surgery in conjugation with radiation therapy has been associated with significant toxicities compared with the radiation therapy alone.¹³Therefore, the use of radiation therapy without surgery is becoming more common with increasingly sophisticated radiation therapy techniques and organ preservation approach in patients with squamous cell carcinoma of the tonsil.

Findings from several studies have shown that in stage I or II oropharyngeal cancer, single modality treatment with radiation therapy achieves 80%-90% of local control of the disease, but poorer outcomes are reported for locally advanced stages III/IV with a local control rate of 63%-74%.²⁰ These findings and others have led to a shift to evaluate the clinical benefits of radiation therapy given with concurrent chemotherapy for the primary treatment of advanced stage oropharyngeal squamous cell carcinoma.^20,21 Findings from a number of studies have since reported comparable efficacy and toxicity outcomes using this regimen with concurrent chemotherapy in patients with locally advanced head and neck squamous cell cancer.^22-24 Synchronous carboplatin chemotherapy was used effectively as an alternative to cisplatin with fewer potential adverse effects in the good prognosis group of patients with oropharyngeal squamous cell carcinoma.^25,26 For our 3 patients, we used carboplatin-based chemotherapy with concurrent advanced hyperfractionated radiation therapy techniques to successfully manage tonsillar squamous cell carcinoma and reduce renal toxicity and neuropathy.

Advanced radiation therapy techniques such as IMRT-IGRT are used routinely at the University Cancer and Diagnostic Centers in Houston, Texas, to manage a range of malignant cancers.²⁷ These innovative techniques have the potential to deliver highly conformal dose-intense radiation to targeted regions of disease, while sparing adjacent critical nonmalignant tissue. The improved shaping of high-dose distributions with IMRT-IGRT could mitigate treatment-related toxicities. For example, the use of advanced radiation therapy techniques has been associated with increased preservation of parotid salivary flow.^28-30 The use of advanced radiation therapy techniques in head and neck squamous cell carcinoma is growing, and early evidence confirms its ability to secure excellent local and regional disease control.^31,32 In this study, we have demonstrated that by using hyperfractionated conformal three-dimensional IMRT-IGRT we were able not only to manage advanced tonsillar squamous cell carcinoma and treat the malignant metastasis, but also spare adjacent critical organs that were not involved in the disease, thus reducing many of the detrimental side effects associated with hyperfractionated chemoradiation.

All 3 patients were followed for between 40 and 46 months. They continue to do extremely well without local recurrence of their disease, indicating a 100% disease control and overall survival rate. The disease control and survival outcomes for our patients with stage IVA disease compare favorably to other published reports in the literature.^33,34 Findings from a study by Prestwich and colleagues³³ of 41 patients with stage IV tonsillar carcinoma showed that the radiation therapy with concurrent chemotherapy achieved local and regional disease control in 91% of complete responders and an overall survival rate of 66% at 3 years. Similarly, Setton and colleagues³⁴ reported on 442 patients – 50% with tonsillar cancer, 46% with base-of-tongue cancer – who underwent IMRT and concurrent chemotherapy and who achieved a 3-year overall survival of 84.9%. Our study findings demonstrate that hyperfractionated conformal three-dimensional IMRT-IGRT with concurrent chemotherapy can be delivered safely and effectively to patients with advanced tonsillar squamous cell carcinoma.
 

Acknowledgment

The authors thank Ms June Lyliston, LVN, for editing and proofreading the manuscript.

Tonsillar carcinoma is the most common of the oropharyngeal malignancies of the head and neck region after thyroid and laryngeal carcinoma. Squamous cell carcinoma is the most frequent histologic type of these tumors.¹ Tonsillar tumors may originate in the oral cavity, oropharynx, hypopharynx, or larynx. In the United States, more than 5,000 new cases of oropharynx cancer are diagnosed annually.² Men are affected three to four times more often than are women, and the rate of incidence increases after the 4th decade of life.³ Surveillance, Epidemiology, and End Results data from 1975-2004 show that tonsillar squamous cell carcinoma has had one of the largest increases in the male-to-female incidence rate ratios.⁴ The overall incidence of tonsillar carcinoma is increasing, especially in the younger population, and this may be attributed to increasing rates of human papilloma virus.^5,6

Squamous cell carcinoma in the head and neck originate from subsites within the oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.⁷ Traditionally, alcohol consumption and tobacco use were considered the most significant risk factors for the development of tonsillar cancer.⁸ More recently, however, the high-risk oncogenic human papilloma virus has emerged as a clinical entity in the pathogenesis of squamous cell carcinoma in the head and neck. Other risk factors include poor oral hygiene, mechanical irritation, chewing of betel quid preparations, and a lack of vegetables and fruits in the diet.^9-11 Squamous cell carcinoma of the oropharynx often presents late with lymph node involvement at the time of diagnosis. Nonspecific symptoms such as a sore throat and dysphagia can allow head and neck cancer to evade early detection. Many patients with tonsillar carcinoma present with advanced disease because early lesions are generally asymptomatic when small. This absence of symptoms is responsible for 67%-77% of patients presenting with tumors larger than 2.0 cm and often with regional nodal metastasis. At presentation, 45% of anterior tonsillar pillar lesions and 76% of tonsillar fossa lesions have clinically positive necks.¹²

Despite significant treatment advances, the management of advanced squamous cell carcinoma of the tonsil remains challenging. Historically, surgery was considered the standard of care for patients with tonsillar carcinoma with or without postoperative adjuvant radiotherapy. In locally advanced tonsillar carcinoma, extensive surgery with major tissue reconstruction was necessary, leading to speech dysfunction, cosmetic deformities, and difficulties in swallowing, all of which are detrimental to patient quality of life.¹³ Given the critical role of the oropharynx in speech and swallowing, nonsurgical therapy with organ-preserving chemoradiation has gained a greater role in the treatment of tonsil carcinoma.¹³ Over the past decade, innovations in radiation therapy techniques have led to the introduction of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) for the treatment of various cancers including tonsillar carcinoma.^14,15 IMRT is an advanced mode of conformal high-precision radiotherapy that uses computer-controlled multiple small radiation beams of varying intensities to deliver precise radiation doses to the target tissues while sparing adjacent healthy tissues.¹⁴ By incorporating three-dimensional computed-tomography (CT) or positron-emission–tomography (PET) imaging technology, IMRT allows the radiation dose to conform more precisely to the three-dimensional shape of the tumor while modulating the intensity of the radiation beam and minimizing its dose to those adjacent sensitive and unaffected organs. IGRT uses a range of two-, three-, and four-dimensional imaging techniques that improve the precision and accuracy of the delivery of the radiation dose to the targeted tumor tissue while minimizing the dose to the surrounding normal tissue during the course of radiation therapy (Figure 1). In this report, we present challenging cases of advanced tonsillar carcinoma and describe our experience in managing the disease using a hyperfractionated IMRT-IGRT based three-dimensional conformal radiation therapy protocol with concurrent chemotherapy.

Case presentations and summaries

Case 1

A 52-year-old white, nonsmoking man who worked in a research chemical laboratory, presented with complaints of throat pain and difficulty in swallowing. The patient had a history of asthma and allergies and had been seen by an ear, nose, and throat (ENT) specialist prior to his visit to our oncology center. A biopsy was performed on a right tonsillar mass measuring 2.7 x 3.6 cm. A computed-tomography (CT) scan showed 2 enlarged inhomogeneous lymph nodes measuring 2.9 cm and 1.7 cm. The nodes were well defined with no soft tissue edema. Neoplasm was favored as a diagnosis and biopsy of the mass was carried out. A biopsy specimen measuring 1.0 x 0.4 x 0.3 cm revealed a moderately differentiated infiltrating squamous cell carcinoma, which extended to the edge of the biopsy specimen. The patient’s Karnofsky performance status was 90% (ie, able to carry on normal activity; minor signs or symptoms of disease).

A CT scan of the chest was clear with no evidence of malignant involvement. A subsequent CT scan of the neck revealed a primary neoplasm of the right faucial tonsil measuring 3.3 x 3.0 cm and associated with right level II, level III, and level IV pathological lymphadenopathy. Positron-emission tomography (PET) imaging of the neck revealed a right tonsillar lesion of 2.7 x 3.0 cm involving the right parapharyngeal space (Figure 2, Case 1). The standardized uptake value (SUV) of the PET scan of the primary lesion was measured at 7.3. A cluster of right level II cervical nodes measuring 3.2 x 2.5 cm had an SUV of 3.5. A 1.0-cm right level III jugular node was also seen with an SUV of 1.6, and a right level IV lymph node measuring 1.5 x 1.0 cm was seen with an SUV of 1.8. No other lesions were noted. The tumor stage was T2N2bM0, a stage IVa disease.

Case 2

A 49-year-old black male presented with throat pain and a mass seen initially by his family physician. The patient had a history of tobacco use (at least 1 cigar a day) periodically for about 10 years and had quit cigar smoking 15 years prior to developing his disease. An initial evaluation indicated that the patient had a hypopharyngeal mass in the left inferior pole of his tonsil with near occlusion of the hypopharyngeal airway. His larynx could not be visualized because of the obstructive mass. A neck lymph node measuring 3.0 cm in the left jugulodigastric region was also noted. The patient’s Karnofsky performance status was 90%. Subsequently, the patient underwent excision of the right tonsil and left tonsillar region.

The pathology of the right tonsil was found to be benign. Histology of the left tonsil revealed invasive squamous cell carcinoma. The resected tumor size measured 3.7 x 2.7 x 2.5 cm. The tumor was moderately differentiated involving the deep surgical margins. No lymphovascular invasion was seen. A PET scan revealed a mass arising from the left tonsillar pillar measuring 3.6 x 2.6 x 3.3 cm with deviation of the epiglottis posteriorly nearing the left vallecula. In addition, multiple large cervical nodal lesions in the left level II nodal chain were seen, with the largest measuring 3.1 x 3.0 x 4.5 cm with an SUV of 3.4. Displacement of the left submandibular gland with several further enlarged level II lymph nodes was observed. In the region of left vallecula, there was soft tissue thickening with increased activity measuring 2.7 x 1.5 cm, likely crossing the midline with an SUV of 5.5. The rest of the neck was negative for metastatic involvement (Figure 2, Case 2). The tumor stage was T3N2Mx, a stage IVa disease.

The patient had a Port-A-Cath placed, which caused a hemothorax after placement of the port and delayed initiating his treatment. A pretreatment MRI scan of the neck revealed multiple conglomerate hypodense peripherally enhancing nodular areas in the left neck posterior to the left submandibular gland deep to the parotid tail worrisome for necrotic lymphadenopathy. The patient underwent a course of hyperfractionated IMRT-IGRT in 67 fractions of 120 cGy twice daily for a total dose of 8,040 cGy to the primary tumor site.¹⁶ The patient had a port and PEG tube prior to initiating his radiation therapy. He received IMRT-IGRT with concurrent chemotherapy that was selected based on the recommendation of his genomic testing.^17,18 The chemotherapy regimen used included carboplatin (300 mg weekly) and docetaxel (400 mg weekly). The patient had a treatment break because he was hospitalized for anemia and pancytopenia from his chemotherapy and he received supportive cancer care with epoetin alfa.A post therapy PET scan was negative for evidence of hypermetabolic malignancy; however, a 3.3 x 2.7 cm calcified lesion representing likely level III jugular lymph node exhibited no measurable activity at that time. The follow-up after 40 months indicated that the patient had no reported recurrence of the disease (Figure 2, Case 2). The patient’s demographics, tumor characteristics, and the treatment details are summarized in the Table.
 

Case 3

A 53-year-old white man, who had no smoking or tobacco history but who was exposed to chemicals including sulfuric acid, hydrogen chloride gas, and glycols at work, presented initially with a sore throat that became more painful over time. His ENT specialist referred him for a CT scan of the neck, which revealed a left-sided neck mass measuring 2.5 cm in diameter posterior to the submandibular gland and lateral to carotid sheath and anterior to the triangle (Figure 2, Case 3). The mass appeared to be encapsulated. There was a lobulated spherical mass in the left supraglottic area with formation of the airway of the pyriform sinus and additional anterior vascular involvement was noted. The mass measured 3.6 cm in transverse diameter.

A left tonsillar biopsy specimen measuring 1.4 x 0.6 x 0.2 cm was obtained, and its pathology revealed that the patient had a metastatic squamous cell carcinoma. The left neck lymph node mass aspiration also revealed the presence of squamous cell carcinoma. A PET-CT scan staging showed a dominant tonsillar fossa mass extending from the soft palate down to the pyriform sinus measuring 4.2 x 3.8 cm, with an SUV uptake of 7.3. There was a dominant left level II necrotic lymph node presence measuring 5.0 x 3.7 cm, with an SUV of 3.0. The patient’s Karnofsky performance status was 90%. The tumor stage was T4N2M0, a stage IVa disease. The patient received a course of conformal hyperfractionated IMRT-IGRT delivered to the primary tumor in 67 fractions at 120 cGy twice daily for a total dose of 8,040 cGy¹⁶ and concurrent carboplatin chemotherapy at a weekly dose of 200 mg.

After completion of his radiation therapy, chemotherapy was changed based on genomic testing from single agent to doublet with carboplatin (area under the curve (AUC) dose of 2 or 200 mg, weekly) plus docetaxel (25 mg/m² weekly for 3 weeks and 1 week off ).^17,18 A PET scan after chemoradiation therapy revealed a marked anatomical improvement in the primary neoplastic disease seen in the faucial tonsil. The tonsillar mass noted previously had almost completely resolved over the interval, with only a mild persistent asymmetrical thickening of around 1.5 cm, with a peak SUV of 2.0. A lymph node of 2.8 x 2.0 cm was present anterior to the left sternocleidomastoid muscle exhibiting SUV of only 1.8. No other abnormal lesions were noted (Figure 2, Case 3). The patient continues to do extremely well without local recurrence of the disease 46 months after radiation therapy (see Table for patient demographics, tumor characteristics, and therapy details.)
 

Discussion

The management of patients with primary squamous cell carcinoma of the oropharyngeal remains controversial. Traditionally, early-stage tonsillar squamous cell carcinoma was managed by a single modality treatment, either by surgery or radiation therapy, each showing similar efficacy and outcomes.¹⁹ For late-stage disease, a combined approach using surgery and radiation therapy was found to be superior to single modality treatment. However, surgery in conjugation with radiation therapy has been associated with significant toxicities compared with the radiation therapy alone.¹³Therefore, the use of radiation therapy without surgery is becoming more common with increasingly sophisticated radiation therapy techniques and organ preservation approach in patients with squamous cell carcinoma of the tonsil.

Findings from several studies have shown that in stage I or II oropharyngeal cancer, single modality treatment with radiation therapy achieves 80%-90% of local control of the disease, but poorer outcomes are reported for locally advanced stages III/IV with a local control rate of 63%-74%.²⁰ These findings and others have led to a shift to evaluate the clinical benefits of radiation therapy given with concurrent chemotherapy for the primary treatment of advanced stage oropharyngeal squamous cell carcinoma.^20,21 Findings from a number of studies have since reported comparable efficacy and toxicity outcomes using this regimen with concurrent chemotherapy in patients with locally advanced head and neck squamous cell cancer.^22-24 Synchronous carboplatin chemotherapy was used effectively as an alternative to cisplatin with fewer potential adverse effects in the good prognosis group of patients with oropharyngeal squamous cell carcinoma.^25,26 For our 3 patients, we used carboplatin-based chemotherapy with concurrent advanced hyperfractionated radiation therapy techniques to successfully manage tonsillar squamous cell carcinoma and reduce renal toxicity and neuropathy.

Advanced radiation therapy techniques such as IMRT-IGRT are used routinely at the University Cancer and Diagnostic Centers in Houston, Texas, to manage a range of malignant cancers.²⁷ These innovative techniques have the potential to deliver highly conformal dose-intense radiation to targeted regions of disease, while sparing adjacent critical nonmalignant tissue. The improved shaping of high-dose distributions with IMRT-IGRT could mitigate treatment-related toxicities. For example, the use of advanced radiation therapy techniques has been associated with increased preservation of parotid salivary flow.^28-30 The use of advanced radiation therapy techniques in head and neck squamous cell carcinoma is growing, and early evidence confirms its ability to secure excellent local and regional disease control.^31,32 In this study, we have demonstrated that by using hyperfractionated conformal three-dimensional IMRT-IGRT we were able not only to manage advanced tonsillar squamous cell carcinoma and treat the malignant metastasis, but also spare adjacent critical organs that were not involved in the disease, thus reducing many of the detrimental side effects associated with hyperfractionated chemoradiation.

All 3 patients were followed for between 40 and 46 months. They continue to do extremely well without local recurrence of their disease, indicating a 100% disease control and overall survival rate. The disease control and survival outcomes for our patients with stage IVA disease compare favorably to other published reports in the literature.^33,34 Findings from a study by Prestwich and colleagues³³ of 41 patients with stage IV tonsillar carcinoma showed that the radiation therapy with concurrent chemotherapy achieved local and regional disease control in 91% of complete responders and an overall survival rate of 66% at 3 years. Similarly, Setton and colleagues³⁴ reported on 442 patients – 50% with tonsillar cancer, 46% with base-of-tongue cancer – who underwent IMRT and concurrent chemotherapy and who achieved a 3-year overall survival of 84.9%. Our study findings demonstrate that hyperfractionated conformal three-dimensional IMRT-IGRT with concurrent chemotherapy can be delivered safely and effectively to patients with advanced tonsillar squamous cell carcinoma.
 

Acknowledgment

The authors thank Ms June Lyliston, LVN, for editing and proofreading the manuscript.

About 25% of patients with fecal incontinence benefit from conservative treatments, which merit a “rigorous trial” before considering surgery, experts write in a Clinical Practice Update in the December issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.08.023).

“A stepwise approach should be followed for management of fecal incontinence. In our experience, many incontinent patients who are considered refractory to conservative therapy have not received an optimal trial of conservative therapy,” states Adil E. Bharucha, MBBS, MD, of the Mayo Clinic and the Mayo Foundation in Rochester, Minn., and his associates.

Fecal incontinence affects 7%-15% of individuals and has potentially “devastating” implications for quality of life, the experts note. They recommend starting treatment by meticulously documenting bowel habits, triggers of incontinence, and treatment history. For fecal incontinence with diarrhea, they suggest eliminating caffeine and poorly absorbed dietary sugars, such as sorbitol and fructose, and adding loperamide, starting with one 2-mg tablet taken 30 minutes before breakfast and titrating up to a maximum of 16 mg per day. Other conservative therapeutic options for diarrhea include fiber supplementation, scheduled toileting, a bowel retraining program, anticholinergic agents, clonidine, and cholestyramine or colesevelam to correct bile salt malabsorption. Patients whose fecal incontinence involves constipation should start with laxatives and anorectal testing for evacuation disorders. Rectal cleansing with a small enema or tap water can help prevent stool leakage, the experts write.

If these conservative measures fail to improve fecal incontinence, they recommend anorectal manometry to test for anal weakness, reduced or increased rectal sensation, and impaired rectal balloon expulsion, all of which can improve with biofeedback therapy to retrain the pelvic floor. If biofeedback fails, consider perianal bulking agents, such as intra-anal injection of dextranomer, the experts suggest. Sacral nerve stimulation might be indicated if moderate or severe fecal incontinence does not respond to at least 3 months of conservative treatment. However, the experts do not recommend percutaneous tibial nerve stimulation, which failed to outperform sham stimulation in a 12-week, double-blind, multicenter trial (Lancet. 2015;386:1640-8). Surgery is indicated for fecal incontinence associated with major anatomic defects, such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity. Additionally, sphincteroplasty is an option for postpartum women with fecal incontinence, patients with recent sphincter injuries, and patients with sphincter damage and fecal incontinence fecal incontinence that fails to improve with conservative and biofeedback therapy, perianal bulking injection, and sacral nerve stimulation, according to the clinical practice update.

Barrier devices should be offered if fecal incontinence fails conservative treatments and surgery, or if surgery is not an option. Most anal plugs are “poorly tolerated,” with two exceptions – a Food and Drug Administration–approved device from Renew Medical and a vaginal insert and pressure-regulated pump from Pelvalon. Colostomy might be indicated if patients with severe fecal incontinence fail conservative treatment and or are not candidates for barrier devices, minimally invasive surgeries, and sphincteroplasty.

If severe fecal incontinence that is refractory to or contraindicated for all these interventions, the experts suggest considering artificial anal sphincter repair by dynamic graciloplasty. Surgery also is indicated to repair major anatomic defects such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity, they noted. A magnetic anal sphincter device is a possibility for patients with medically refractory severe fecal incontinence who have failed or are not candidates for barrier devices, perianal bulking injection, sacral nerve stimulation, sphincteroplasty, or a colostomy. However, the study that led to FDA approval of a magnetic anal sphincter device included only 35 patients, and 7 (20%) had the device removed because of infection, erosion, or inefficacy. Another patient required a stoma in order to be able to defecate, and a total of 40% had moderate or severe complications when pain and bleeding were also considered, the experts noted.

Biofeedback is the preferred treatment for defecatory disorders – that is, chronic constipation or constipation-predominant irritable bowel syndrome with impaired rectal evacuation, according to the clinical practice update. The experts recommend against sacral nerve stimulation, anteretrograde colonic enemas, and stapled transanal rectal resection for patients with defecatory disorders. Surgical treatment typically is reserved for the small minority of patients with considerable pelvic organ or rectal prolapse, they note.

The National Institutes of Health Sciences provided funding. The authors reported having no conflicts of interest.

imnews@frontlinemedcom.com

About 25% of patients with fecal incontinence benefit from conservative treatments, which merit a “rigorous trial” before considering surgery, experts write in a Clinical Practice Update in the December issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.08.023).

“A stepwise approach should be followed for management of fecal incontinence. In our experience, many incontinent patients who are considered refractory to conservative therapy have not received an optimal trial of conservative therapy,” states Adil E. Bharucha, MBBS, MD, of the Mayo Clinic and the Mayo Foundation in Rochester, Minn., and his associates.

Fecal incontinence affects 7%-15% of individuals and has potentially “devastating” implications for quality of life, the experts note. They recommend starting treatment by meticulously documenting bowel habits, triggers of incontinence, and treatment history. For fecal incontinence with diarrhea, they suggest eliminating caffeine and poorly absorbed dietary sugars, such as sorbitol and fructose, and adding loperamide, starting with one 2-mg tablet taken 30 minutes before breakfast and titrating up to a maximum of 16 mg per day. Other conservative therapeutic options for diarrhea include fiber supplementation, scheduled toileting, a bowel retraining program, anticholinergic agents, clonidine, and cholestyramine or colesevelam to correct bile salt malabsorption. Patients whose fecal incontinence involves constipation should start with laxatives and anorectal testing for evacuation disorders. Rectal cleansing with a small enema or tap water can help prevent stool leakage, the experts write.

If these conservative measures fail to improve fecal incontinence, they recommend anorectal manometry to test for anal weakness, reduced or increased rectal sensation, and impaired rectal balloon expulsion, all of which can improve with biofeedback therapy to retrain the pelvic floor. If biofeedback fails, consider perianal bulking agents, such as intra-anal injection of dextranomer, the experts suggest. Sacral nerve stimulation might be indicated if moderate or severe fecal incontinence does not respond to at least 3 months of conservative treatment. However, the experts do not recommend percutaneous tibial nerve stimulation, which failed to outperform sham stimulation in a 12-week, double-blind, multicenter trial (Lancet. 2015;386:1640-8). Surgery is indicated for fecal incontinence associated with major anatomic defects, such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity. Additionally, sphincteroplasty is an option for postpartum women with fecal incontinence, patients with recent sphincter injuries, and patients with sphincter damage and fecal incontinence fecal incontinence that fails to improve with conservative and biofeedback therapy, perianal bulking injection, and sacral nerve stimulation, according to the clinical practice update.

Barrier devices should be offered if fecal incontinence fails conservative treatments and surgery, or if surgery is not an option. Most anal plugs are “poorly tolerated,” with two exceptions – a Food and Drug Administration–approved device from Renew Medical and a vaginal insert and pressure-regulated pump from Pelvalon. Colostomy might be indicated if patients with severe fecal incontinence fail conservative treatment and or are not candidates for barrier devices, minimally invasive surgeries, and sphincteroplasty.

If severe fecal incontinence that is refractory to or contraindicated for all these interventions, the experts suggest considering artificial anal sphincter repair by dynamic graciloplasty. Surgery also is indicated to repair major anatomic defects such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity, they noted. A magnetic anal sphincter device is a possibility for patients with medically refractory severe fecal incontinence who have failed or are not candidates for barrier devices, perianal bulking injection, sacral nerve stimulation, sphincteroplasty, or a colostomy. However, the study that led to FDA approval of a magnetic anal sphincter device included only 35 patients, and 7 (20%) had the device removed because of infection, erosion, or inefficacy. Another patient required a stoma in order to be able to defecate, and a total of 40% had moderate or severe complications when pain and bleeding were also considered, the experts noted.

Biofeedback is the preferred treatment for defecatory disorders – that is, chronic constipation or constipation-predominant irritable bowel syndrome with impaired rectal evacuation, according to the clinical practice update. The experts recommend against sacral nerve stimulation, anteretrograde colonic enemas, and stapled transanal rectal resection for patients with defecatory disorders. Surgical treatment typically is reserved for the small minority of patients with considerable pelvic organ or rectal prolapse, they note.

The National Institutes of Health Sciences provided funding. The authors reported having no conflicts of interest.

imnews@frontlinemedcom.com

About 25% of patients with fecal incontinence benefit from conservative treatments, which merit a “rigorous trial” before considering surgery, experts write in a Clinical Practice Update in the December issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.08.023).

“A stepwise approach should be followed for management of fecal incontinence. In our experience, many incontinent patients who are considered refractory to conservative therapy have not received an optimal trial of conservative therapy,” states Adil E. Bharucha, MBBS, MD, of the Mayo Clinic and the Mayo Foundation in Rochester, Minn., and his associates.

Fecal incontinence affects 7%-15% of individuals and has potentially “devastating” implications for quality of life, the experts note. They recommend starting treatment by meticulously documenting bowel habits, triggers of incontinence, and treatment history. For fecal incontinence with diarrhea, they suggest eliminating caffeine and poorly absorbed dietary sugars, such as sorbitol and fructose, and adding loperamide, starting with one 2-mg tablet taken 30 minutes before breakfast and titrating up to a maximum of 16 mg per day. Other conservative therapeutic options for diarrhea include fiber supplementation, scheduled toileting, a bowel retraining program, anticholinergic agents, clonidine, and cholestyramine or colesevelam to correct bile salt malabsorption. Patients whose fecal incontinence involves constipation should start with laxatives and anorectal testing for evacuation disorders. Rectal cleansing with a small enema or tap water can help prevent stool leakage, the experts write.

If these conservative measures fail to improve fecal incontinence, they recommend anorectal manometry to test for anal weakness, reduced or increased rectal sensation, and impaired rectal balloon expulsion, all of which can improve with biofeedback therapy to retrain the pelvic floor. If biofeedback fails, consider perianal bulking agents, such as intra-anal injection of dextranomer, the experts suggest. Sacral nerve stimulation might be indicated if moderate or severe fecal incontinence does not respond to at least 3 months of conservative treatment. However, the experts do not recommend percutaneous tibial nerve stimulation, which failed to outperform sham stimulation in a 12-week, double-blind, multicenter trial (Lancet. 2015;386:1640-8). Surgery is indicated for fecal incontinence associated with major anatomic defects, such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity. Additionally, sphincteroplasty is an option for postpartum women with fecal incontinence, patients with recent sphincter injuries, and patients with sphincter damage and fecal incontinence fecal incontinence that fails to improve with conservative and biofeedback therapy, perianal bulking injection, and sacral nerve stimulation, according to the clinical practice update.

Barrier devices should be offered if fecal incontinence fails conservative treatments and surgery, or if surgery is not an option. Most anal plugs are “poorly tolerated,” with two exceptions – a Food and Drug Administration–approved device from Renew Medical and a vaginal insert and pressure-regulated pump from Pelvalon. Colostomy might be indicated if patients with severe fecal incontinence fail conservative treatment and or are not candidates for barrier devices, minimally invasive surgeries, and sphincteroplasty.

If severe fecal incontinence that is refractory to or contraindicated for all these interventions, the experts suggest considering artificial anal sphincter repair by dynamic graciloplasty. Surgery also is indicated to repair major anatomic defects such as rectovaginal fistula, full-thickness rectal prolapse, fistula in ano, or cloaca-like deformity, they noted. A magnetic anal sphincter device is a possibility for patients with medically refractory severe fecal incontinence who have failed or are not candidates for barrier devices, perianal bulking injection, sacral nerve stimulation, sphincteroplasty, or a colostomy. However, the study that led to FDA approval of a magnetic anal sphincter device included only 35 patients, and 7 (20%) had the device removed because of infection, erosion, or inefficacy. Another patient required a stoma in order to be able to defecate, and a total of 40% had moderate or severe complications when pain and bleeding were also considered, the experts noted.

Biofeedback is the preferred treatment for defecatory disorders – that is, chronic constipation or constipation-predominant irritable bowel syndrome with impaired rectal evacuation, according to the clinical practice update. The experts recommend against sacral nerve stimulation, anteretrograde colonic enemas, and stapled transanal rectal resection for patients with defecatory disorders. Surgical treatment typically is reserved for the small minority of patients with considerable pelvic organ or rectal prolapse, they note.

The National Institutes of Health Sciences provided funding. The authors reported having no conflicts of interest.

imnews@frontlinemedcom.com

Despite an abundance of evidenced-based literature supporting monoamine oxidase inhibitors (MAOIs) as an effective treatment for depression, use of these agents has decreased drastically in the past 3 decades. A lack of industry support and the ease of use of other agents are contributing factors, but the biggest impediments to routine use of MAOIs are unfamiliarity with their efficacy advantages and concerns about adverse effects, particularly the risk of hypertensive crises and serotonin syndrome. Many misconceptions regarding these medications are based on outdated data and studies that are no longer reliable.

The goal of this 2-part review is to provide clinicians with updated information regarding MAOIs. Part 1 provides a brief description of:

• the pharmacology of nonselective irreversible MAOIs
• the mechanism by which tyramine induces hypertension
• sources of clinically significant tyramine exposure
• what to tell patients about dietary restrictions and MAOIs.

Part 2 of this guide will cover the risk of serotonin syndrome when MAOIs are combined with inhibitors of serotonin reuptake, how to initiate MAOI therapy, and augmenting MAOIs with other agents.

The pharmacology of MAOIs

First used clinically in the 1950s to treat tuberculosis, MAOIs have a long and interesting history (see the Box “A brief history of monoamine oxidase inhibitors”). Table 1¹ lists MAOIs currently available in the United States, including the MAO-B–specific agent rasagiline, which is used for Parkinson’s disease.

Manipulation of the monoamines serotonin, norepinephrine, and dopamine is fundamental to managing major depressive disorder (MDD), yet only nonselective MAOIs directly promote neurotransmission of all 3 by inhibiting MAO-A and MAO-B.² The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study demonstrated that <50% of MDD patients achieve remission in monotherapy trials of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, mirtazapine, or bupropion, necessitating consideration of antidepressant combinations, augmentation options, and eventually irreversible, nonselective MAOIs such as phenelzine, tranylcypromine, or isocarboxazid.^3,4 Nonselective MAOIs thus offer a therapeutic opportunity for patients who do not respond to single or dual-mechanism strategies; moreover, nonselective MAOIs have compelling effectiveness data for other conditions, including panic disorder and social phobia.⁵ Although MAOIs are among the most effective pharmacologic agents for MDD,⁶ they are underutilized because of an inadequate understanding of risk mechanisms and resultant fear of catastrophic outcomes. Because of the difficulties encountered in achieving clinical remission for MDD, the nonselective MAOIs deserve a second look.
 

Differentiation of MAO-A from MAO-B. It is essential to understand the mechanism of action of MAOIs, specifically the impact of MAO-A inhibition. Although the enzyme MAO was known in the 1950s, it wasn’t until 1968 that Johnston⁷ postulated the existence of >1 form. In 1971, Goridis and Neff⁸ used clorgyline to examine the deamination rate by MAO of tyramine and norepinephrine. They found that tyramine appeared to be a substrate of both MAO isoforms, but only 1 of the MAO types was sensitive to the inhibitory effects of clorgyline. They also discerned that norepinephrine was only a substrate for MAO-A, and that this form of MAO was sensitive to clorgyline inhibition. Thus, the forms of MAO were characterized by their preferred substrates (Table 2^9,10), and then later by their tissue distribution. Phenylethylamine is a naturally occurring compound found in foods, such as chocolate, and has an in vitro pharmacology similar to amphetamine but with 1 important difference: it has a short half-life of 5 to 10 minutes after oral ingestion, and therefore no appreciable CNS impact.

Within the CNS, norepinephrine and dopamine neurons possess both MAO forms, with the MAO-A content greater than MAO-B. Serotonergic neurons only contain MAO-B.¹¹ Outside of the CNS, MAO-A predominates, with only platelets and lymphocytes possessing MAO-B activity.¹¹ The overall relative tissue proportions of MAO-A to MAO-B activity are: brain, 25% MAO-A, 75% MAO-B; liver, 50% MAO-A, 50% MAO-B; intestine, 80% MAO-A, 20% MAO-B; and peripheral adrenergic neurons, 90% MAO-A, 10% MAO-B.

Because of its specificity for serotonin and norepinephrine, CNS MAO-A inhibition is necessary for antidepressant effects. MAO-B inhibition by itself does not appear to raise CNS dopamine levels unless exogenous dopamine is supplied.¹¹ All MAOIs used in the United States to treat depression are irreversible, nonselective inhibitors of MAO-A and MAO-B.

Selegiline in oral form generates low plasma levels and primarily inhibits MAO-B. The transdermal form of selegiline achieves significantly greater systemic exposure, and at these higher plasma levels selegiline is a nonselective, irreversible MAOI effective for MDD (Figure 1¹²). Administering selegiline systemically via a transdermal patch avoids clinically significant MAOI effects in the gut, so no dietary warnings exist for the lowest dose (6 mg/24 hours), although there are warnings for the higher dosages (9 mg/24 hours and 12 mg/24 hours).

MAOIs and tyramine: Dietary requirements

Clinicians who are familiar with MAOIs recognize that there are dietary restrictions to minimize patients’ exposure to tyramine. As most clinicians know, significant tyramine ingestion may cause an increase in blood pressure (BP) in patients taking an MAOI, but many overestimate the prevalence of foods high in tyramine content since the original reports emerged in the early 1960s.¹⁸ In a recent monograph, one of the leading experts on MAOIs, Professor Ken Gillman, stated:

Very few foods now contain problematically high tyramine levels, that is a result of great changes in international food production methods and hygiene regulations. Cheese is the only food that, in the past, has been associated with documented fatalities resulting from hypertension. Nowadays most cheeses are quite safe, and even ‘matured’ cheeses are usually safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still required.¹⁹

What is tyramine? Tyramine is a biogenic amine that is virtually absent in fresh animal protein sources but is enriched after decay or fermentation.²⁰ Modern food processing and handling methods have significantly limited the tyramine content in processed foods, with the exception of certain cheeses and sauces, as discussed below. Moreover, modern assaying techniques using high-performance liquid chromatography have generated extremely accurate assessments of the tyramine content of specific foods.²¹ Data published prior to 2000 are not reliable, because many of these publications employed outdated methods.¹⁷

When ingested, tyramine is metabolized by gut MAO-A, with doses up to 400 mg causing no known effects, although most people rarely ingest >25 mg during a meal.²² In addition to being a substrate for MAO-A, tyramine is also a substrate for the dopamine transporter, norepinephrine transporter (NET), the vesicular monoamine transporter 2, and TAAR1.²³ Tyramine enters the cell via NET, where it interacts with TAAR1, a G protein-coupled receptor that is responsive to trace amines, such as tyramine, as well as amphetamines.²⁰ The agonist properties at TAAR1 are the presumed site of action for the BP effects of tyramine, because binding results in potent release of norepinephrine.^20,24 When tyramine is supplied to an animal in which MAO-A is inhibited, the decreased peripheral catabolism of tyramine results in markedly increased norepinephrine release by peripheral adrenergic neurons. Moreover, the absence of MAO-A activity in those neurons prevents any norepinephrine breakdown, resulting in robust synaptic norepinephrine delivery and peripheral effects.

All orally administered irreversible MAOIs potently inhibit gut and systemic MAO-A, and are susceptible to the impact of significant tyramine ingestion. The exception is selegiline transdermal (Figure 1¹²), as appreciable gut MAO-A inhibition does not occur until doses >6 mg/24 hours are reached.²² No significant pressor response was seen in participants taking selegiline transdermal, 6 mg/24 hours for 13 days, who consumed a meal that provided 400 mg of tyramine.²² Conversely, for oral agents that produce gut MAO-A inhibition, tyramine doses as low as 8 to 10 mg (when administered as tyramine capsules) may increase systolic pressure by 30 mm Hg.²⁵ The dietary warnings do not apply to rasagiline, which is a selective MAO-B inhibitor, although rasagiline may have an impact on resting BP; the prescribing information for rasagiline includes warnings about hypotension and hypertension.²⁶

What to tell patients about tyramine. Although administering pure tyramine capsules can induce a measurable change in systolic BP, when ingested as food, tyramine doses <50 mg are unlikely to cause an increase in BP sufficient to warrant clinical intervention, although some individuals can be sensitive to 10 to 25 mg.¹⁹ When discussing with patients safety issues related to diet, there are a few important concepts to remember¹⁹:

• In an era when the tyramine content of foods was much higher (1960 to 1964) and MAOI users received no dietary guidance, only 14 deaths were reported among an estimated 1.5 million patients who took MAOIs.
• MAOIs do not raise BP, and their use is associated with orthostasis in some patients.
• Routine exercise or other vigorous activities (eg, weightlifting) can raise systolic pressure well above 200 mm Hg, and routine baseline systolic pressures, ranging from 180 to 220 mm Hg, do not increase the risk of subarachnoid hemorrhage.
• Hospital evaluation is needed only if a substantial amount of tyramine is ingested (eg, estimated ≥100 mg), and self-monitoring shows a systolic BP ≥220 mm Hg over a prolonged period (eg, 2 hours). Ingestion of 100 mg of tyramine would almost certainly have to be intentional, as it would require one to consume 3.5 oz of the most highly tyramine-laden cheeses.
   

Emphasize to patients that only a small number of highly aged cheeses, foods, and sauces contain high quantities of tyramine, and that even these foods can be enjoyed in small amounts. All patients who are prescribed an MAOI also should purchase a portable BP cuff for those rare instances when a dietary indiscretion may have occurred and the person experiences a headache within 1 to 2 hours after tyramine ingestion. Most reactions are self-limited and resolve over 2 to 4 hours.

Patients who ingest ≥100 mg of tyramine should be evaluated by a physician. Under no circumstances should a patient be given a prescription for nifedipine or other medications that can abruptly lower BP, because this may result in complications, including myocardial infarction.^27,28 Counsel patients to remain calm. Some clinicians endorse the use of low doses of benzodiazepines (the equivalent of alprazolam 0.5 mg) to facilitate this, because anxiety elevates BP. A recent emergency room study of patients with an initial systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg without end organ damage demonstrated that alprazolam, 0.5 mg, was as effective as captopril, 25 mg, in lowering BP.²⁹

Also, tell patients that if a food is unfamiliar and highly aged or fermented, they should avoid it until they can further inquire about it. In a review, Gillman¹⁹ provides the tyramine content of an exhaustive list of cheeses, aged meats, and sauces (see Related Resources). For other products, patients often can obtain information directly from the manufacturer. In many parts of the world, assays for tyramine content are required as a demonstration of adequate product safety procedures. Even the most highly aged cheeses with a tyramine content of 1,000 g/kg can be enjoyed in small amounts (<1 oz), and most products would require heroic intake to achieve clinically significant tyramine ingestion (Table 3¹⁹).

Improved education can clarify the risks

Medications such as lithium, clozapine, and MAOIs have a proven record of efficacy, yet often are underused due to fears engendered by lack of systematic training. A recent initiative in New York thus aimed to increase rates of clozapine prescribing by providing clinicians with an education consultation center.³⁰ Similarly, enhanced education regarding MAOIs could increase the use of these highly effective medications. With a better understanding of MAOIs, clinicians can become adept at using these medications, and therefore expand the armamentarium of agents available to patients with MDD, as well as to those with panic disorder and social phobia.
 

Despite an abundance of evidenced-based literature supporting monoamine oxidase inhibitors (MAOIs) as an effective treatment for depression, use of these agents has decreased drastically in the past 3 decades. A lack of industry support and the ease of use of other agents are contributing factors, but the biggest impediments to routine use of MAOIs are unfamiliarity with their efficacy advantages and concerns about adverse effects, particularly the risk of hypertensive crises and serotonin syndrome. Many misconceptions regarding these medications are based on outdated data and studies that are no longer reliable.

The goal of this 2-part review is to provide clinicians with updated information regarding MAOIs. Part 1 provides a brief description of:

• the pharmacology of nonselective irreversible MAOIs
• the mechanism by which tyramine induces hypertension
• sources of clinically significant tyramine exposure
• what to tell patients about dietary restrictions and MAOIs.

Part 2 of this guide will cover the risk of serotonin syndrome when MAOIs are combined with inhibitors of serotonin reuptake, how to initiate MAOI therapy, and augmenting MAOIs with other agents.

The pharmacology of MAOIs

First used clinically in the 1950s to treat tuberculosis, MAOIs have a long and interesting history (see the Box “A brief history of monoamine oxidase inhibitors”). Table 1¹ lists MAOIs currently available in the United States, including the MAO-B–specific agent rasagiline, which is used for Parkinson’s disease.

Manipulation of the monoamines serotonin, norepinephrine, and dopamine is fundamental to managing major depressive disorder (MDD), yet only nonselective MAOIs directly promote neurotransmission of all 3 by inhibiting MAO-A and MAO-B.² The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study demonstrated that <50% of MDD patients achieve remission in monotherapy trials of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, mirtazapine, or bupropion, necessitating consideration of antidepressant combinations, augmentation options, and eventually irreversible, nonselective MAOIs such as phenelzine, tranylcypromine, or isocarboxazid.^3,4 Nonselective MAOIs thus offer a therapeutic opportunity for patients who do not respond to single or dual-mechanism strategies; moreover, nonselective MAOIs have compelling effectiveness data for other conditions, including panic disorder and social phobia.⁵ Although MAOIs are among the most effective pharmacologic agents for MDD,⁶ they are underutilized because of an inadequate understanding of risk mechanisms and resultant fear of catastrophic outcomes. Because of the difficulties encountered in achieving clinical remission for MDD, the nonselective MAOIs deserve a second look.
 

Differentiation of MAO-A from MAO-B. It is essential to understand the mechanism of action of MAOIs, specifically the impact of MAO-A inhibition. Although the enzyme MAO was known in the 1950s, it wasn’t until 1968 that Johnston⁷ postulated the existence of >1 form. In 1971, Goridis and Neff⁸ used clorgyline to examine the deamination rate by MAO of tyramine and norepinephrine. They found that tyramine appeared to be a substrate of both MAO isoforms, but only 1 of the MAO types was sensitive to the inhibitory effects of clorgyline. They also discerned that norepinephrine was only a substrate for MAO-A, and that this form of MAO was sensitive to clorgyline inhibition. Thus, the forms of MAO were characterized by their preferred substrates (Table 2^9,10), and then later by their tissue distribution. Phenylethylamine is a naturally occurring compound found in foods, such as chocolate, and has an in vitro pharmacology similar to amphetamine but with 1 important difference: it has a short half-life of 5 to 10 minutes after oral ingestion, and therefore no appreciable CNS impact.

Within the CNS, norepinephrine and dopamine neurons possess both MAO forms, with the MAO-A content greater than MAO-B. Serotonergic neurons only contain MAO-B.¹¹ Outside of the CNS, MAO-A predominates, with only platelets and lymphocytes possessing MAO-B activity.¹¹ The overall relative tissue proportions of MAO-A to MAO-B activity are: brain, 25% MAO-A, 75% MAO-B; liver, 50% MAO-A, 50% MAO-B; intestine, 80% MAO-A, 20% MAO-B; and peripheral adrenergic neurons, 90% MAO-A, 10% MAO-B.

Because of its specificity for serotonin and norepinephrine, CNS MAO-A inhibition is necessary for antidepressant effects. MAO-B inhibition by itself does not appear to raise CNS dopamine levels unless exogenous dopamine is supplied.¹¹ All MAOIs used in the United States to treat depression are irreversible, nonselective inhibitors of MAO-A and MAO-B.

Selegiline in oral form generates low plasma levels and primarily inhibits MAO-B. The transdermal form of selegiline achieves significantly greater systemic exposure, and at these higher plasma levels selegiline is a nonselective, irreversible MAOI effective for MDD (Figure 1¹²). Administering selegiline systemically via a transdermal patch avoids clinically significant MAOI effects in the gut, so no dietary warnings exist for the lowest dose (6 mg/24 hours), although there are warnings for the higher dosages (9 mg/24 hours and 12 mg/24 hours).

MAOIs and tyramine: Dietary requirements

Clinicians who are familiar with MAOIs recognize that there are dietary restrictions to minimize patients’ exposure to tyramine. As most clinicians know, significant tyramine ingestion may cause an increase in blood pressure (BP) in patients taking an MAOI, but many overestimate the prevalence of foods high in tyramine content since the original reports emerged in the early 1960s.¹⁸ In a recent monograph, one of the leading experts on MAOIs, Professor Ken Gillman, stated:

Very few foods now contain problematically high tyramine levels, that is a result of great changes in international food production methods and hygiene regulations. Cheese is the only food that, in the past, has been associated with documented fatalities resulting from hypertension. Nowadays most cheeses are quite safe, and even ‘matured’ cheeses are usually safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still required.¹⁹

What is tyramine? Tyramine is a biogenic amine that is virtually absent in fresh animal protein sources but is enriched after decay or fermentation.²⁰ Modern food processing and handling methods have significantly limited the tyramine content in processed foods, with the exception of certain cheeses and sauces, as discussed below. Moreover, modern assaying techniques using high-performance liquid chromatography have generated extremely accurate assessments of the tyramine content of specific foods.²¹ Data published prior to 2000 are not reliable, because many of these publications employed outdated methods.¹⁷

When ingested, tyramine is metabolized by gut MAO-A, with doses up to 400 mg causing no known effects, although most people rarely ingest >25 mg during a meal.²² In addition to being a substrate for MAO-A, tyramine is also a substrate for the dopamine transporter, norepinephrine transporter (NET), the vesicular monoamine transporter 2, and TAAR1.²³ Tyramine enters the cell via NET, where it interacts with TAAR1, a G protein-coupled receptor that is responsive to trace amines, such as tyramine, as well as amphetamines.²⁰ The agonist properties at TAAR1 are the presumed site of action for the BP effects of tyramine, because binding results in potent release of norepinephrine.^20,24 When tyramine is supplied to an animal in which MAO-A is inhibited, the decreased peripheral catabolism of tyramine results in markedly increased norepinephrine release by peripheral adrenergic neurons. Moreover, the absence of MAO-A activity in those neurons prevents any norepinephrine breakdown, resulting in robust synaptic norepinephrine delivery and peripheral effects.

All orally administered irreversible MAOIs potently inhibit gut and systemic MAO-A, and are susceptible to the impact of significant tyramine ingestion. The exception is selegiline transdermal (Figure 1¹²), as appreciable gut MAO-A inhibition does not occur until doses >6 mg/24 hours are reached.²² No significant pressor response was seen in participants taking selegiline transdermal, 6 mg/24 hours for 13 days, who consumed a meal that provided 400 mg of tyramine.²² Conversely, for oral agents that produce gut MAO-A inhibition, tyramine doses as low as 8 to 10 mg (when administered as tyramine capsules) may increase systolic pressure by 30 mm Hg.²⁵ The dietary warnings do not apply to rasagiline, which is a selective MAO-B inhibitor, although rasagiline may have an impact on resting BP; the prescribing information for rasagiline includes warnings about hypotension and hypertension.²⁶

What to tell patients about tyramine. Although administering pure tyramine capsules can induce a measurable change in systolic BP, when ingested as food, tyramine doses <50 mg are unlikely to cause an increase in BP sufficient to warrant clinical intervention, although some individuals can be sensitive to 10 to 25 mg.¹⁹ When discussing with patients safety issues related to diet, there are a few important concepts to remember¹⁹:

• In an era when the tyramine content of foods was much higher (1960 to 1964) and MAOI users received no dietary guidance, only 14 deaths were reported among an estimated 1.5 million patients who took MAOIs.
• MAOIs do not raise BP, and their use is associated with orthostasis in some patients.
• Routine exercise or other vigorous activities (eg, weightlifting) can raise systolic pressure well above 200 mm Hg, and routine baseline systolic pressures, ranging from 180 to 220 mm Hg, do not increase the risk of subarachnoid hemorrhage.
• Hospital evaluation is needed only if a substantial amount of tyramine is ingested (eg, estimated ≥100 mg), and self-monitoring shows a systolic BP ≥220 mm Hg over a prolonged period (eg, 2 hours). Ingestion of 100 mg of tyramine would almost certainly have to be intentional, as it would require one to consume 3.5 oz of the most highly tyramine-laden cheeses.
   

Emphasize to patients that only a small number of highly aged cheeses, foods, and sauces contain high quantities of tyramine, and that even these foods can be enjoyed in small amounts. All patients who are prescribed an MAOI also should purchase a portable BP cuff for those rare instances when a dietary indiscretion may have occurred and the person experiences a headache within 1 to 2 hours after tyramine ingestion. Most reactions are self-limited and resolve over 2 to 4 hours.

Patients who ingest ≥100 mg of tyramine should be evaluated by a physician. Under no circumstances should a patient be given a prescription for nifedipine or other medications that can abruptly lower BP, because this may result in complications, including myocardial infarction.^27,28 Counsel patients to remain calm. Some clinicians endorse the use of low doses of benzodiazepines (the equivalent of alprazolam 0.5 mg) to facilitate this, because anxiety elevates BP. A recent emergency room study of patients with an initial systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg without end organ damage demonstrated that alprazolam, 0.5 mg, was as effective as captopril, 25 mg, in lowering BP.²⁹

Also, tell patients that if a food is unfamiliar and highly aged or fermented, they should avoid it until they can further inquire about it. In a review, Gillman¹⁹ provides the tyramine content of an exhaustive list of cheeses, aged meats, and sauces (see Related Resources). For other products, patients often can obtain information directly from the manufacturer. In many parts of the world, assays for tyramine content are required as a demonstration of adequate product safety procedures. Even the most highly aged cheeses with a tyramine content of 1,000 g/kg can be enjoyed in small amounts (<1 oz), and most products would require heroic intake to achieve clinically significant tyramine ingestion (Table 3¹⁹).

Improved education can clarify the risks

Medications such as lithium, clozapine, and MAOIs have a proven record of efficacy, yet often are underused due to fears engendered by lack of systematic training. A recent initiative in New York thus aimed to increase rates of clozapine prescribing by providing clinicians with an education consultation center.³⁰ Similarly, enhanced education regarding MAOIs could increase the use of these highly effective medications. With a better understanding of MAOIs, clinicians can become adept at using these medications, and therefore expand the armamentarium of agents available to patients with MDD, as well as to those with panic disorder and social phobia.
 

Despite an abundance of evidenced-based literature supporting monoamine oxidase inhibitors (MAOIs) as an effective treatment for depression, use of these agents has decreased drastically in the past 3 decades. A lack of industry support and the ease of use of other agents are contributing factors, but the biggest impediments to routine use of MAOIs are unfamiliarity with their efficacy advantages and concerns about adverse effects, particularly the risk of hypertensive crises and serotonin syndrome. Many misconceptions regarding these medications are based on outdated data and studies that are no longer reliable.

The goal of this 2-part review is to provide clinicians with updated information regarding MAOIs. Part 1 provides a brief description of:

• the pharmacology of nonselective irreversible MAOIs
• the mechanism by which tyramine induces hypertension
• sources of clinically significant tyramine exposure
• what to tell patients about dietary restrictions and MAOIs.

Part 2 of this guide will cover the risk of serotonin syndrome when MAOIs are combined with inhibitors of serotonin reuptake, how to initiate MAOI therapy, and augmenting MAOIs with other agents.

The pharmacology of MAOIs

First used clinically in the 1950s to treat tuberculosis, MAOIs have a long and interesting history (see the Box “A brief history of monoamine oxidase inhibitors”). Table 1¹ lists MAOIs currently available in the United States, including the MAO-B–specific agent rasagiline, which is used for Parkinson’s disease.

Manipulation of the monoamines serotonin, norepinephrine, and dopamine is fundamental to managing major depressive disorder (MDD), yet only nonselective MAOIs directly promote neurotransmission of all 3 by inhibiting MAO-A and MAO-B.² The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study demonstrated that <50% of MDD patients achieve remission in monotherapy trials of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, mirtazapine, or bupropion, necessitating consideration of antidepressant combinations, augmentation options, and eventually irreversible, nonselective MAOIs such as phenelzine, tranylcypromine, or isocarboxazid.^3,4 Nonselective MAOIs thus offer a therapeutic opportunity for patients who do not respond to single or dual-mechanism strategies; moreover, nonselective MAOIs have compelling effectiveness data for other conditions, including panic disorder and social phobia.⁵ Although MAOIs are among the most effective pharmacologic agents for MDD,⁶ they are underutilized because of an inadequate understanding of risk mechanisms and resultant fear of catastrophic outcomes. Because of the difficulties encountered in achieving clinical remission for MDD, the nonselective MAOIs deserve a second look.
 

Differentiation of MAO-A from MAO-B. It is essential to understand the mechanism of action of MAOIs, specifically the impact of MAO-A inhibition. Although the enzyme MAO was known in the 1950s, it wasn’t until 1968 that Johnston⁷ postulated the existence of >1 form. In 1971, Goridis and Neff⁸ used clorgyline to examine the deamination rate by MAO of tyramine and norepinephrine. They found that tyramine appeared to be a substrate of both MAO isoforms, but only 1 of the MAO types was sensitive to the inhibitory effects of clorgyline. They also discerned that norepinephrine was only a substrate for MAO-A, and that this form of MAO was sensitive to clorgyline inhibition. Thus, the forms of MAO were characterized by their preferred substrates (Table 2^9,10), and then later by their tissue distribution. Phenylethylamine is a naturally occurring compound found in foods, such as chocolate, and has an in vitro pharmacology similar to amphetamine but with 1 important difference: it has a short half-life of 5 to 10 minutes after oral ingestion, and therefore no appreciable CNS impact.

Within the CNS, norepinephrine and dopamine neurons possess both MAO forms, with the MAO-A content greater than MAO-B. Serotonergic neurons only contain MAO-B.¹¹ Outside of the CNS, MAO-A predominates, with only platelets and lymphocytes possessing MAO-B activity.¹¹ The overall relative tissue proportions of MAO-A to MAO-B activity are: brain, 25% MAO-A, 75% MAO-B; liver, 50% MAO-A, 50% MAO-B; intestine, 80% MAO-A, 20% MAO-B; and peripheral adrenergic neurons, 90% MAO-A, 10% MAO-B.

Because of its specificity for serotonin and norepinephrine, CNS MAO-A inhibition is necessary for antidepressant effects. MAO-B inhibition by itself does not appear to raise CNS dopamine levels unless exogenous dopamine is supplied.¹¹ All MAOIs used in the United States to treat depression are irreversible, nonselective inhibitors of MAO-A and MAO-B.

Selegiline in oral form generates low plasma levels and primarily inhibits MAO-B. The transdermal form of selegiline achieves significantly greater systemic exposure, and at these higher plasma levels selegiline is a nonselective, irreversible MAOI effective for MDD (Figure 1¹²). Administering selegiline systemically via a transdermal patch avoids clinically significant MAOI effects in the gut, so no dietary warnings exist for the lowest dose (6 mg/24 hours), although there are warnings for the higher dosages (9 mg/24 hours and 12 mg/24 hours).

MAOIs and tyramine: Dietary requirements

Clinicians who are familiar with MAOIs recognize that there are dietary restrictions to minimize patients’ exposure to tyramine. As most clinicians know, significant tyramine ingestion may cause an increase in blood pressure (BP) in patients taking an MAOI, but many overestimate the prevalence of foods high in tyramine content since the original reports emerged in the early 1960s.¹⁸ In a recent monograph, one of the leading experts on MAOIs, Professor Ken Gillman, stated:

Very few foods now contain problematically high tyramine levels, that is a result of great changes in international food production methods and hygiene regulations. Cheese is the only food that, in the past, has been associated with documented fatalities resulting from hypertension. Nowadays most cheeses are quite safe, and even ‘matured’ cheeses are usually safe in healthy-sized portions. The variability of sensitivity to tyramine between individuals, and the sometimes unpredictable amount of tyramine content in foods, means a little knowledge and care are still required.¹⁹

What is tyramine? Tyramine is a biogenic amine that is virtually absent in fresh animal protein sources but is enriched after decay or fermentation.²⁰ Modern food processing and handling methods have significantly limited the tyramine content in processed foods, with the exception of certain cheeses and sauces, as discussed below. Moreover, modern assaying techniques using high-performance liquid chromatography have generated extremely accurate assessments of the tyramine content of specific foods.²¹ Data published prior to 2000 are not reliable, because many of these publications employed outdated methods.¹⁷

When ingested, tyramine is metabolized by gut MAO-A, with doses up to 400 mg causing no known effects, although most people rarely ingest >25 mg during a meal.²² In addition to being a substrate for MAO-A, tyramine is also a substrate for the dopamine transporter, norepinephrine transporter (NET), the vesicular monoamine transporter 2, and TAAR1.²³ Tyramine enters the cell via NET, where it interacts with TAAR1, a G protein-coupled receptor that is responsive to trace amines, such as tyramine, as well as amphetamines.²⁰ The agonist properties at TAAR1 are the presumed site of action for the BP effects of tyramine, because binding results in potent release of norepinephrine.^20,24 When tyramine is supplied to an animal in which MAO-A is inhibited, the decreased peripheral catabolism of tyramine results in markedly increased norepinephrine release by peripheral adrenergic neurons. Moreover, the absence of MAO-A activity in those neurons prevents any norepinephrine breakdown, resulting in robust synaptic norepinephrine delivery and peripheral effects.

All orally administered irreversible MAOIs potently inhibit gut and systemic MAO-A, and are susceptible to the impact of significant tyramine ingestion. The exception is selegiline transdermal (Figure 1¹²), as appreciable gut MAO-A inhibition does not occur until doses >6 mg/24 hours are reached.²² No significant pressor response was seen in participants taking selegiline transdermal, 6 mg/24 hours for 13 days, who consumed a meal that provided 400 mg of tyramine.²² Conversely, for oral agents that produce gut MAO-A inhibition, tyramine doses as low as 8 to 10 mg (when administered as tyramine capsules) may increase systolic pressure by 30 mm Hg.²⁵ The dietary warnings do not apply to rasagiline, which is a selective MAO-B inhibitor, although rasagiline may have an impact on resting BP; the prescribing information for rasagiline includes warnings about hypotension and hypertension.²⁶

What to tell patients about tyramine. Although administering pure tyramine capsules can induce a measurable change in systolic BP, when ingested as food, tyramine doses <50 mg are unlikely to cause an increase in BP sufficient to warrant clinical intervention, although some individuals can be sensitive to 10 to 25 mg.¹⁹ When discussing with patients safety issues related to diet, there are a few important concepts to remember¹⁹:

• In an era when the tyramine content of foods was much higher (1960 to 1964) and MAOI users received no dietary guidance, only 14 deaths were reported among an estimated 1.5 million patients who took MAOIs.
• MAOIs do not raise BP, and their use is associated with orthostasis in some patients.
• Routine exercise or other vigorous activities (eg, weightlifting) can raise systolic pressure well above 200 mm Hg, and routine baseline systolic pressures, ranging from 180 to 220 mm Hg, do not increase the risk of subarachnoid hemorrhage.
• Hospital evaluation is needed only if a substantial amount of tyramine is ingested (eg, estimated ≥100 mg), and self-monitoring shows a systolic BP ≥220 mm Hg over a prolonged period (eg, 2 hours). Ingestion of 100 mg of tyramine would almost certainly have to be intentional, as it would require one to consume 3.5 oz of the most highly tyramine-laden cheeses.
   

Emphasize to patients that only a small number of highly aged cheeses, foods, and sauces contain high quantities of tyramine, and that even these foods can be enjoyed in small amounts. All patients who are prescribed an MAOI also should purchase a portable BP cuff for those rare instances when a dietary indiscretion may have occurred and the person experiences a headache within 1 to 2 hours after tyramine ingestion. Most reactions are self-limited and resolve over 2 to 4 hours.

Patients who ingest ≥100 mg of tyramine should be evaluated by a physician. Under no circumstances should a patient be given a prescription for nifedipine or other medications that can abruptly lower BP, because this may result in complications, including myocardial infarction.^27,28 Counsel patients to remain calm. Some clinicians endorse the use of low doses of benzodiazepines (the equivalent of alprazolam 0.5 mg) to facilitate this, because anxiety elevates BP. A recent emergency room study of patients with an initial systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg without end organ damage demonstrated that alprazolam, 0.5 mg, was as effective as captopril, 25 mg, in lowering BP.²⁹

Also, tell patients that if a food is unfamiliar and highly aged or fermented, they should avoid it until they can further inquire about it. In a review, Gillman¹⁹ provides the tyramine content of an exhaustive list of cheeses, aged meats, and sauces (see Related Resources). For other products, patients often can obtain information directly from the manufacturer. In many parts of the world, assays for tyramine content are required as a demonstration of adequate product safety procedures. Even the most highly aged cheeses with a tyramine content of 1,000 g/kg can be enjoyed in small amounts (<1 oz), and most products would require heroic intake to achieve clinically significant tyramine ingestion (Table 3¹⁹).

Improved education can clarify the risks

Medications such as lithium, clozapine, and MAOIs have a proven record of efficacy, yet often are underused due to fears engendered by lack of systematic training. A recent initiative in New York thus aimed to increase rates of clozapine prescribing by providing clinicians with an education consultation center.³⁰ Similarly, enhanced education regarding MAOIs could increase the use of these highly effective medications. With a better understanding of MAOIs, clinicians can become adept at using these medications, and therefore expand the armamentarium of agents available to patients with MDD, as well as to those with panic disorder and social phobia.
 

According to the U.S. Department of Health and Human Services, in 2007, 88% of 1.4 million Medicare claims for second-generation antipsychotics (SGAs) in older adult nursing home residents were associated with a dementia diagnosis. Similar trends have been observed in Canada and Europe.^1-4 In a retrospective analysis of medication data from older residents with dementia in 6 care homes in England, long-term (ie, >1 month) use of antipsychotics was the most frequent potentially inappropriate prescribing practice.³ In another study in 7 European countries and Israel, the overall prevalence of antipsychotic use among long-term care residents with dementia was 33%.¹ Similarly, a recent literature review⁵ found that 22% to 86% of antipsychotic prescriptions to older individuals were off-label; this practice was particularly common for individuals with agitation.

Because of the aging population and widespread prescription of antipsychotics to older patients, clinicians need information on the relative risks of using these medications in this population. In the United States, all antipsychotics carry a FDA “black-box” warning of the increased risk of death in older adults with dementia. In addition, the risk of death is increased when prescribing antipsychotics to older adults with other conditions, such as Parkinson’s disease,⁶ and other safety and tolerability concerns, including falls and fractures, sedation, metabolic abnormalities, and extrapyramidal effects, are highly relevant to geriatric patients.

This 3-part review summarizes findings and recommendations on prescribing antipsychotics to older individuals with schizophrenia, bipolar disorder, depression, and dementia. This third and final installment:

• briefly summarizes the major studies and analyses relevant to prescribing antipsychotics to older patients with dementia
• provides a summative opinion on safety and tolerability issues in these older patients
• highlights the gaps in the evidence base and areas that need additional research.

Summary of benefits, place in treatment armamentarium

Behavioral and psychological symptoms of dementia (BPSD) include agitation, delusional beliefs, repetitive questioning, hallucinations, aggression, wandering, and various socially inappropriate behaviors.⁷ These occur almost universally in all types and stages of dementia.⁷ BPSD are among the most complex, stressful, and costly aspects of dementia care, and lead to a myriad of poor health outcomes, including excess morbidity, mortality, hospital stays, and early nursing home placement.^8-11 Because BPSD usually occur across all types and stages of dementia,^7,12-16 the prevalence of BPSD mirrors the overall prevalence of dementia.

Although all expert organizations, including the American Psychiatric Association,¹⁷ recommend nonpharmacologic strategies as first-line treatment for BPSD, for the most part, these recommendations have not been translated into standard clinical management or routine care.¹⁸ Because of a perceived lack of other options, the current mainstay of treatment is the off-label use of psychotropics such as antipsy­chotics. Of all the agents currently used for BPSD, SGAs have the strongest evidence base, although benefits are modest at best (standardized effect size 0.13 to 0.16).^19,20 In terms of individual SGAs, only risperidone is indicated for aggression in Canada and in Europe (not in the United States); risperidone has the best evidence for efficacy, with a meta-analysis of 5 published randomized controlled trials (RCTs) reporting that risperidone is superior to other SGAs for aggression in dementia.^21,22 As a class, first-generation antipsychotics (FGAs) have no clear evidence for BPSD as defined broadly; however, there may be slight benefit for haloperidol for aggression.^23,24

Clinical Trials

Adverse effects. A meta-analysis of RCTs of SGAs found that, compared with placebo, SGAs have increased rates of several adverse effects. These include somnolence (17% drug vs 7% placebo; odds ratio [OR], 2.84; 95% confidence interval [CI], 2.25 to 3.58; P < .00001); extrapyramidal symptoms (13% drug vs 8% placebo; OR, 1.51; 95% CI, 1.20 to 1.91; P = .0005; primarily attributable to risperidone); abnormal gait (10% drug vs 2% placebo; OR, 3.42; 95% CI, 1.78 to 6.56; P = .0002; attributable to olanzapine and risperidone); edema (9% drug vs 4% placebo; OR, 1.99; 95% CI, 1.20 to 3.30; P = .008; attributable to olanzapine and risperidone); urinary tract infections/incontinence (16% drug vs 12% placebo; OR, 1.28; 95% CI, 1.02 to 1.61; P = .04); cognitive impairment measured as difference in Mini-Mental State Examination score (95% CI, 0.38 to 1.09; P < .0001)²⁵; and stroke (1.9% drug vs 0.9% placebo, OR, 2.13; 95% CI, 1.20 to 3.75; P = .009).^21,26

In the 42-site Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer’s disease RCT, 421 outpatients with Alzheimer’s disease and BPSD were randomized to an SGA (risperidone, olanzapine, or quetiapine) or placebo. Compared with placebo, SGAs had a higher rate of parkinsonism or extrapyramidal signs (olanzapine and risperidone groups); sedation; confusion/changes in mental status (olanzapine and risperidone); psychotic symptoms (olanzapine); and increase in body weight and body mass index.²⁶

In the 2005 FDA black-box warning, pneumonia and cardiac adverse effects were cited as primary causes of death for patients with dementia taking SGAs. A subsequent observational study confirmed that use of either FGAs or SGAs in geriatric patients was associated with an increased risk of pneumonia, in a dose-dependent manner.²⁷ Although there is limited data on cardiac adverse effects in older adults, especially those with dementia taking antipsychotics,²⁸ 1 observational study of nursing home residents²⁹ found that those taking FGAs had a significantly higher risk of hospitalization for ventricular arrhythmia or cardiac arrest compared with those who were not taking FGAs. In contrast, there was no increased risk with SGAs.

Mortality.
 In 2005, the FDA announced that based on a reanalysis of 17 placebo-controlled trials (many of which were unpublished) that SGAs were associated with a 1.7-fold increase in mortality compared with placebo.³⁰ As a result, the FDA issued a black-box warning for using SGAs in patients with dementia. The overall OR in a published meta-analysis of mortality with SGAs was 1.54 (1.06 to 2.23; z = 2.28; P = .02), with pooled events of 3.5% mortality vs 2.3% (drug vs placebo).²¹ This meta-analysis²¹ also included ad hoc analyses of haloperidol; using combined data from 2 contrasts of haloperidol (with risperidone and quetiapine; 243 patients receiving haloperidol and 239 receiving placebo) they also found 15 deaths (6.2%) with haloperidol and 9 (3.8%) with placebo, resulting in an OR of 1.68.

Other clinical data

Observational studies. Most observational studies have confirmed concerns regarding increased mortality in patients with BPSD who take antipsychotics, with FGAs having a higher risk than SGAs^18,31 and SGAs having a higher risk compared with most other psychotropics.³² Three studies that found no increase in mortality with antipsychotics in patients with dementia had methodological issues, including examining prevalence as opposed to new users,^33,34 not controlling for exposure,^10,33,34 power issues,^10,34 not controlling for other psychiatric medications,¹⁰ and varying lengths of follow-up.¹⁰ An FDA black-box warning for FGAs was announced in 2008³⁰ based on 2 observational studies that showed an increased risk of mortality in older adults taking FGAs vs SGAs.^35,36

In terms of specific SGAs, Kales et al³⁷ examined the mortality risk associated with individual antipsychotics using various methods to control for confounding. Among a national sample of >33,000 older veterans with dementia newly started on haloperidol, risperidone, olanzapine, quetiapine, or valproic acid and derivatives (as a nonantipsychotic comparator), the highest mortality across all analyses (intent to treat, exposure, propensity-adjusted) was associated with haloperidol, followed by risperidone and olanzapine, valproic acid, and quetiapine.

Most recently, a retrospective case-control study (90,786 patients age ≥65 with dementia) examined the number needed to harm (NNH; ie, number of patients needed to receive treatment that would result in 1 death) over 180 days following initiation of an FGA or SGA.³⁸ This study found the following NNHs: haloperidol, 26 (95% CI, 15 to 99); risperidone, 27 (95% CI, 19 to 46); olanzapine, 40 (95% CI, 21 to 312); and quetiapine, 50 (95% CI, 30 to 150).³⁸ These results are congruent with a review of observational studies that found the highest risk of mortality was associated with haloperidol and chlorpromazine, and the lowest risk with olanzapine, quetiapine, and ziprasidone.²⁸

Patterns of antipsychotic use in older dementia patients

There are high rates of antipsychotic use in patients with dementia. Before the FDA issued the black-box warning, the Aging Demographics and Memory study found that the rate of antipsychotic use in community (outpatient) older adults with dementia was approximately 19% between 2002 and 2004 in a representative sample of 307 older adults.³⁹ Another study examining trends in community antipsychotic use in the U.S. Department of Veterans Affairs (VA) found that in the 1990s, SGA use was increasing; approximately 18% of outpatients with dementia were taking these agents.⁴⁰ Use of SGAs began to decline in 2003, ahead of the 2005 black-box warning, in tandem with other advisories (eg, diabetes, metabolic syndrome,⁴¹ and stroke risk).^42,43 Olanzapine and risperidone showed declining rates between 2003 and 2005, whereas quetiapine use significantly increased during this period. All 3 SGAs declined after the black-box warning. However, by the end of 2007, the use of SGAs had leveled off to approximately 12% of VA patients with dementia. A recent U.S. Government Accountability Office (GAO) report found that in 2012, 14% of older adult Medicare Part D enrollees with dementia living in the community were prescribed an antipsychotic.⁴⁴

Use in nursing home residents. Because BPSD are one of the main reasons people with dementia are placed in nursing homes, it is not surprising that rates of antipsychotic use are higher in these settings than in the community. Prior to the black-box warning, studies found that 24% to 32% of nursing home residents were treated with antipsychotics.^45-47 A study examining VA nursing homes (n = 133 facilities, n = 3,692 veterans) found that approximately 26% of residents were prescribed antipsychotics in 2004 to 2005.⁴⁸ The Center for Medicare and Medicaid Services (CMS) National Partnership to Improve Dementia Care in Nursing Homes has appeared to lower antipsychotic medication use in nursing homes; the rate decreased from 24% in long-stay nursing home residents nationwide in 2011 to 19% by the end of 2014. Specific to dementia, a 2010 CMS report⁴⁹ indicated that approximately 40% of nursing home residents with cognitive impairment and behavioral issues, without psychosis, received antipsychotics. The GAO data indicated that approximately 33% of older Medicare Part D enrollees with dementia who spent >100 days in a nursing home were prescribed an antipsychotic in 2012.⁴⁴ A recent Canadian study using drug claims data found that overall psychotropic use in patients with dementia remains high, finding that three-fourths of all patients with dementia in long-term care are given at least 1 psychotropic, and up to one-third are prescribed SGAs.⁵⁰ European data similarly show that antipsychotics continue to be prescribed to up to one-third of long-term care residents with dementia, with 7 out of 10 receiving an SGA.¹

Conclusions

The Table provides a summary of the evidence regarding the use of antipsychotics in patients with dementia. Expert consensus is that among BPSD, aggression and psychosis are the primary indications for using antipsychotics.⁵¹ Based on multiple RCTs and meta-analyses, the evidence for using SGAs to treat these symptoms is moderate at best. However, in real-world practice settings, SGAs are widely used for symptoms, such as wandering, inappropriate behaviors, resistance to care, etc., for which there is no evidence for efficacy other than sedation. Furthermore, even when there is a potential for benefit, this must be balanced against the risk of adverse effects, including somnolence, worsened cognition, extra­pyramidal symptoms, stroke, and mortality.
 

Clinicians who care for older adults with BPSD should strive to increase the use of first-line nonpharmacologic strategies, by using structured approaches such as DICE (Describe, Investigate, Create, Evaluate) described in the Box.⁵¹ Antipsychotics should be reserved for situations in which nonpharmacologic approaches are unsuccessful, or there is concern for serious or imminent risk to the patient or others.

In the future, observational studies using biomarkers, such as neuroimaging markers, of brain health in older patients taking antipsychotics for various durations may give us a better understanding of long-term antipsychotic safety and tolerability and the monitoring required to assess long-term burden of specific antipsychotics in real-world samples.⁵² However, because of various biases, observational data may not provide answers to all questions,⁵³ and a major challenge is that the number of published RCTs specific to geriatric patients is not growing substantially. Pharmacotherapy evidence is not keeping up with demographic trends. Key developments in RCTs will be the inclusion of biomarkers via neuroimaging, drug serum or brain levels, and genetic profiling. Because of the modest findings of benefits of antipsychotics in dementia and safety concerns addressing brain health in preclinical or early stages, identification of effective non-drug interventions and identifying true disease-modifying agents will be the next challenges of dementia research.
 

According to the U.S. Department of Health and Human Services, in 2007, 88% of 1.4 million Medicare claims for second-generation antipsychotics (SGAs) in older adult nursing home residents were associated with a dementia diagnosis. Similar trends have been observed in Canada and Europe.^1-4 In a retrospective analysis of medication data from older residents with dementia in 6 care homes in England, long-term (ie, >1 month) use of antipsychotics was the most frequent potentially inappropriate prescribing practice.³ In another study in 7 European countries and Israel, the overall prevalence of antipsychotic use among long-term care residents with dementia was 33%.¹ Similarly, a recent literature review⁵ found that 22% to 86% of antipsychotic prescriptions to older individuals were off-label; this practice was particularly common for individuals with agitation.

Because of the aging population and widespread prescription of antipsychotics to older patients, clinicians need information on the relative risks of using these medications in this population. In the United States, all antipsychotics carry a FDA “black-box” warning of the increased risk of death in older adults with dementia. In addition, the risk of death is increased when prescribing antipsychotics to older adults with other conditions, such as Parkinson’s disease,⁶ and other safety and tolerability concerns, including falls and fractures, sedation, metabolic abnormalities, and extrapyramidal effects, are highly relevant to geriatric patients.

This 3-part review summarizes findings and recommendations on prescribing antipsychotics to older individuals with schizophrenia, bipolar disorder, depression, and dementia. This third and final installment:

• briefly summarizes the major studies and analyses relevant to prescribing antipsychotics to older patients with dementia
• provides a summative opinion on safety and tolerability issues in these older patients
• highlights the gaps in the evidence base and areas that need additional research.

Summary of benefits, place in treatment armamentarium

Behavioral and psychological symptoms of dementia (BPSD) include agitation, delusional beliefs, repetitive questioning, hallucinations, aggression, wandering, and various socially inappropriate behaviors.⁷ These occur almost universally in all types and stages of dementia.⁷ BPSD are among the most complex, stressful, and costly aspects of dementia care, and lead to a myriad of poor health outcomes, including excess morbidity, mortality, hospital stays, and early nursing home placement.^8-11 Because BPSD usually occur across all types and stages of dementia,^7,12-16 the prevalence of BPSD mirrors the overall prevalence of dementia.

Although all expert organizations, including the American Psychiatric Association,¹⁷ recommend nonpharmacologic strategies as first-line treatment for BPSD, for the most part, these recommendations have not been translated into standard clinical management or routine care.¹⁸ Because of a perceived lack of other options, the current mainstay of treatment is the off-label use of psychotropics such as antipsy­chotics. Of all the agents currently used for BPSD, SGAs have the strongest evidence base, although benefits are modest at best (standardized effect size 0.13 to 0.16).^19,20 In terms of individual SGAs, only risperidone is indicated for aggression in Canada and in Europe (not in the United States); risperidone has the best evidence for efficacy, with a meta-analysis of 5 published randomized controlled trials (RCTs) reporting that risperidone is superior to other SGAs for aggression in dementia.^21,22 As a class, first-generation antipsychotics (FGAs) have no clear evidence for BPSD as defined broadly; however, there may be slight benefit for haloperidol for aggression.^23,24

Clinical Trials

Adverse effects. A meta-analysis of RCTs of SGAs found that, compared with placebo, SGAs have increased rates of several adverse effects. These include somnolence (17% drug vs 7% placebo; odds ratio [OR], 2.84; 95% confidence interval [CI], 2.25 to 3.58; P < .00001); extrapyramidal symptoms (13% drug vs 8% placebo; OR, 1.51; 95% CI, 1.20 to 1.91; P = .0005; primarily attributable to risperidone); abnormal gait (10% drug vs 2% placebo; OR, 3.42; 95% CI, 1.78 to 6.56; P = .0002; attributable to olanzapine and risperidone); edema (9% drug vs 4% placebo; OR, 1.99; 95% CI, 1.20 to 3.30; P = .008; attributable to olanzapine and risperidone); urinary tract infections/incontinence (16% drug vs 12% placebo; OR, 1.28; 95% CI, 1.02 to 1.61; P = .04); cognitive impairment measured as difference in Mini-Mental State Examination score (95% CI, 0.38 to 1.09; P < .0001)²⁵; and stroke (1.9% drug vs 0.9% placebo, OR, 2.13; 95% CI, 1.20 to 3.75; P = .009).^21,26

In the 42-site Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer’s disease RCT, 421 outpatients with Alzheimer’s disease and BPSD were randomized to an SGA (risperidone, olanzapine, or quetiapine) or placebo. Compared with placebo, SGAs had a higher rate of parkinsonism or extrapyramidal signs (olanzapine and risperidone groups); sedation; confusion/changes in mental status (olanzapine and risperidone); psychotic symptoms (olanzapine); and increase in body weight and body mass index.²⁶

In the 2005 FDA black-box warning, pneumonia and cardiac adverse effects were cited as primary causes of death for patients with dementia taking SGAs. A subsequent observational study confirmed that use of either FGAs or SGAs in geriatric patients was associated with an increased risk of pneumonia, in a dose-dependent manner.²⁷ Although there is limited data on cardiac adverse effects in older adults, especially those with dementia taking antipsychotics,²⁸ 1 observational study of nursing home residents²⁹ found that those taking FGAs had a significantly higher risk of hospitalization for ventricular arrhythmia or cardiac arrest compared with those who were not taking FGAs. In contrast, there was no increased risk with SGAs.

Mortality.
 In 2005, the FDA announced that based on a reanalysis of 17 placebo-controlled trials (many of which were unpublished) that SGAs were associated with a 1.7-fold increase in mortality compared with placebo.³⁰ As a result, the FDA issued a black-box warning for using SGAs in patients with dementia. The overall OR in a published meta-analysis of mortality with SGAs was 1.54 (1.06 to 2.23; z = 2.28; P = .02), with pooled events of 3.5% mortality vs 2.3% (drug vs placebo).²¹ This meta-analysis²¹ also included ad hoc analyses of haloperidol; using combined data from 2 contrasts of haloperidol (with risperidone and quetiapine; 243 patients receiving haloperidol and 239 receiving placebo) they also found 15 deaths (6.2%) with haloperidol and 9 (3.8%) with placebo, resulting in an OR of 1.68.

Other clinical data

Observational studies. Most observational studies have confirmed concerns regarding increased mortality in patients with BPSD who take antipsychotics, with FGAs having a higher risk than SGAs^18,31 and SGAs having a higher risk compared with most other psychotropics.³² Three studies that found no increase in mortality with antipsychotics in patients with dementia had methodological issues, including examining prevalence as opposed to new users,^33,34 not controlling for exposure,^10,33,34 power issues,^10,34 not controlling for other psychiatric medications,¹⁰ and varying lengths of follow-up.¹⁰ An FDA black-box warning for FGAs was announced in 2008³⁰ based on 2 observational studies that showed an increased risk of mortality in older adults taking FGAs vs SGAs.^35,36

In terms of specific SGAs, Kales et al³⁷ examined the mortality risk associated with individual antipsychotics using various methods to control for confounding. Among a national sample of >33,000 older veterans with dementia newly started on haloperidol, risperidone, olanzapine, quetiapine, or valproic acid and derivatives (as a nonantipsychotic comparator), the highest mortality across all analyses (intent to treat, exposure, propensity-adjusted) was associated with haloperidol, followed by risperidone and olanzapine, valproic acid, and quetiapine.

Most recently, a retrospective case-control study (90,786 patients age ≥65 with dementia) examined the number needed to harm (NNH; ie, number of patients needed to receive treatment that would result in 1 death) over 180 days following initiation of an FGA or SGA.³⁸ This study found the following NNHs: haloperidol, 26 (95% CI, 15 to 99); risperidone, 27 (95% CI, 19 to 46); olanzapine, 40 (95% CI, 21 to 312); and quetiapine, 50 (95% CI, 30 to 150).³⁸ These results are congruent with a review of observational studies that found the highest risk of mortality was associated with haloperidol and chlorpromazine, and the lowest risk with olanzapine, quetiapine, and ziprasidone.²⁸

Patterns of antipsychotic use in older dementia patients

There are high rates of antipsychotic use in patients with dementia. Before the FDA issued the black-box warning, the Aging Demographics and Memory study found that the rate of antipsychotic use in community (outpatient) older adults with dementia was approximately 19% between 2002 and 2004 in a representative sample of 307 older adults.³⁹ Another study examining trends in community antipsychotic use in the U.S. Department of Veterans Affairs (VA) found that in the 1990s, SGA use was increasing; approximately 18% of outpatients with dementia were taking these agents.⁴⁰ Use of SGAs began to decline in 2003, ahead of the 2005 black-box warning, in tandem with other advisories (eg, diabetes, metabolic syndrome,⁴¹ and stroke risk).^42,43 Olanzapine and risperidone showed declining rates between 2003 and 2005, whereas quetiapine use significantly increased during this period. All 3 SGAs declined after the black-box warning. However, by the end of 2007, the use of SGAs had leveled off to approximately 12% of VA patients with dementia. A recent U.S. Government Accountability Office (GAO) report found that in 2012, 14% of older adult Medicare Part D enrollees with dementia living in the community were prescribed an antipsychotic.⁴⁴

Use in nursing home residents. Because BPSD are one of the main reasons people with dementia are placed in nursing homes, it is not surprising that rates of antipsychotic use are higher in these settings than in the community. Prior to the black-box warning, studies found that 24% to 32% of nursing home residents were treated with antipsychotics.^45-47 A study examining VA nursing homes (n = 133 facilities, n = 3,692 veterans) found that approximately 26% of residents were prescribed antipsychotics in 2004 to 2005.⁴⁸ The Center for Medicare and Medicaid Services (CMS) National Partnership to Improve Dementia Care in Nursing Homes has appeared to lower antipsychotic medication use in nursing homes; the rate decreased from 24% in long-stay nursing home residents nationwide in 2011 to 19% by the end of 2014. Specific to dementia, a 2010 CMS report⁴⁹ indicated that approximately 40% of nursing home residents with cognitive impairment and behavioral issues, without psychosis, received antipsychotics. The GAO data indicated that approximately 33% of older Medicare Part D enrollees with dementia who spent >100 days in a nursing home were prescribed an antipsychotic in 2012.⁴⁴ A recent Canadian study using drug claims data found that overall psychotropic use in patients with dementia remains high, finding that three-fourths of all patients with dementia in long-term care are given at least 1 psychotropic, and up to one-third are prescribed SGAs.⁵⁰ European data similarly show that antipsychotics continue to be prescribed to up to one-third of long-term care residents with dementia, with 7 out of 10 receiving an SGA.¹

Conclusions

The Table provides a summary of the evidence regarding the use of antipsychotics in patients with dementia. Expert consensus is that among BPSD, aggression and psychosis are the primary indications for using antipsychotics.⁵¹ Based on multiple RCTs and meta-analyses, the evidence for using SGAs to treat these symptoms is moderate at best. However, in real-world practice settings, SGAs are widely used for symptoms, such as wandering, inappropriate behaviors, resistance to care, etc., for which there is no evidence for efficacy other than sedation. Furthermore, even when there is a potential for benefit, this must be balanced against the risk of adverse effects, including somnolence, worsened cognition, extra­pyramidal symptoms, stroke, and mortality.
 

Clinicians who care for older adults with BPSD should strive to increase the use of first-line nonpharmacologic strategies, by using structured approaches such as DICE (Describe, Investigate, Create, Evaluate) described in the Box.⁵¹ Antipsychotics should be reserved for situations in which nonpharmacologic approaches are unsuccessful, or there is concern for serious or imminent risk to the patient or others.

In the future, observational studies using biomarkers, such as neuroimaging markers, of brain health in older patients taking antipsychotics for various durations may give us a better understanding of long-term antipsychotic safety and tolerability and the monitoring required to assess long-term burden of specific antipsychotics in real-world samples.⁵² However, because of various biases, observational data may not provide answers to all questions,⁵³ and a major challenge is that the number of published RCTs specific to geriatric patients is not growing substantially. Pharmacotherapy evidence is not keeping up with demographic trends. Key developments in RCTs will be the inclusion of biomarkers via neuroimaging, drug serum or brain levels, and genetic profiling. Because of the modest findings of benefits of antipsychotics in dementia and safety concerns addressing brain health in preclinical or early stages, identification of effective non-drug interventions and identifying true disease-modifying agents will be the next challenges of dementia research.
 

According to the U.S. Department of Health and Human Services, in 2007, 88% of 1.4 million Medicare claims for second-generation antipsychotics (SGAs) in older adult nursing home residents were associated with a dementia diagnosis. Similar trends have been observed in Canada and Europe.^1-4 In a retrospective analysis of medication data from older residents with dementia in 6 care homes in England, long-term (ie, >1 month) use of antipsychotics was the most frequent potentially inappropriate prescribing practice.³ In another study in 7 European countries and Israel, the overall prevalence of antipsychotic use among long-term care residents with dementia was 33%.¹ Similarly, a recent literature review⁵ found that 22% to 86% of antipsychotic prescriptions to older individuals were off-label; this practice was particularly common for individuals with agitation.

Because of the aging population and widespread prescription of antipsychotics to older patients, clinicians need information on the relative risks of using these medications in this population. In the United States, all antipsychotics carry a FDA “black-box” warning of the increased risk of death in older adults with dementia. In addition, the risk of death is increased when prescribing antipsychotics to older adults with other conditions, such as Parkinson’s disease,⁶ and other safety and tolerability concerns, including falls and fractures, sedation, metabolic abnormalities, and extrapyramidal effects, are highly relevant to geriatric patients.

This 3-part review summarizes findings and recommendations on prescribing antipsychotics to older individuals with schizophrenia, bipolar disorder, depression, and dementia. This third and final installment:

• briefly summarizes the major studies and analyses relevant to prescribing antipsychotics to older patients with dementia
• provides a summative opinion on safety and tolerability issues in these older patients
• highlights the gaps in the evidence base and areas that need additional research.

Summary of benefits, place in treatment armamentarium

Behavioral and psychological symptoms of dementia (BPSD) include agitation, delusional beliefs, repetitive questioning, hallucinations, aggression, wandering, and various socially inappropriate behaviors.⁷ These occur almost universally in all types and stages of dementia.⁷ BPSD are among the most complex, stressful, and costly aspects of dementia care, and lead to a myriad of poor health outcomes, including excess morbidity, mortality, hospital stays, and early nursing home placement.^8-11 Because BPSD usually occur across all types and stages of dementia,^7,12-16 the prevalence of BPSD mirrors the overall prevalence of dementia.

Although all expert organizations, including the American Psychiatric Association,¹⁷ recommend nonpharmacologic strategies as first-line treatment for BPSD, for the most part, these recommendations have not been translated into standard clinical management or routine care.¹⁸ Because of a perceived lack of other options, the current mainstay of treatment is the off-label use of psychotropics such as antipsy­chotics. Of all the agents currently used for BPSD, SGAs have the strongest evidence base, although benefits are modest at best (standardized effect size 0.13 to 0.16).^19,20 In terms of individual SGAs, only risperidone is indicated for aggression in Canada and in Europe (not in the United States); risperidone has the best evidence for efficacy, with a meta-analysis of 5 published randomized controlled trials (RCTs) reporting that risperidone is superior to other SGAs for aggression in dementia.^21,22 As a class, first-generation antipsychotics (FGAs) have no clear evidence for BPSD as defined broadly; however, there may be slight benefit for haloperidol for aggression.^23,24

Clinical Trials

Adverse effects. A meta-analysis of RCTs of SGAs found that, compared with placebo, SGAs have increased rates of several adverse effects. These include somnolence (17% drug vs 7% placebo; odds ratio [OR], 2.84; 95% confidence interval [CI], 2.25 to 3.58; P < .00001); extrapyramidal symptoms (13% drug vs 8% placebo; OR, 1.51; 95% CI, 1.20 to 1.91; P = .0005; primarily attributable to risperidone); abnormal gait (10% drug vs 2% placebo; OR, 3.42; 95% CI, 1.78 to 6.56; P = .0002; attributable to olanzapine and risperidone); edema (9% drug vs 4% placebo; OR, 1.99; 95% CI, 1.20 to 3.30; P = .008; attributable to olanzapine and risperidone); urinary tract infections/incontinence (16% drug vs 12% placebo; OR, 1.28; 95% CI, 1.02 to 1.61; P = .04); cognitive impairment measured as difference in Mini-Mental State Examination score (95% CI, 0.38 to 1.09; P < .0001)²⁵; and stroke (1.9% drug vs 0.9% placebo, OR, 2.13; 95% CI, 1.20 to 3.75; P = .009).^21,26

In the 42-site Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer’s disease RCT, 421 outpatients with Alzheimer’s disease and BPSD were randomized to an SGA (risperidone, olanzapine, or quetiapine) or placebo. Compared with placebo, SGAs had a higher rate of parkinsonism or extrapyramidal signs (olanzapine and risperidone groups); sedation; confusion/changes in mental status (olanzapine and risperidone); psychotic symptoms (olanzapine); and increase in body weight and body mass index.²⁶

In the 2005 FDA black-box warning, pneumonia and cardiac adverse effects were cited as primary causes of death for patients with dementia taking SGAs. A subsequent observational study confirmed that use of either FGAs or SGAs in geriatric patients was associated with an increased risk of pneumonia, in a dose-dependent manner.²⁷ Although there is limited data on cardiac adverse effects in older adults, especially those with dementia taking antipsychotics,²⁸ 1 observational study of nursing home residents²⁹ found that those taking FGAs had a significantly higher risk of hospitalization for ventricular arrhythmia or cardiac arrest compared with those who were not taking FGAs. In contrast, there was no increased risk with SGAs.

Mortality.
 In 2005, the FDA announced that based on a reanalysis of 17 placebo-controlled trials (many of which were unpublished) that SGAs were associated with a 1.7-fold increase in mortality compared with placebo.³⁰ As a result, the FDA issued a black-box warning for using SGAs in patients with dementia. The overall OR in a published meta-analysis of mortality with SGAs was 1.54 (1.06 to 2.23; z = 2.28; P = .02), with pooled events of 3.5% mortality vs 2.3% (drug vs placebo).²¹ This meta-analysis²¹ also included ad hoc analyses of haloperidol; using combined data from 2 contrasts of haloperidol (with risperidone and quetiapine; 243 patients receiving haloperidol and 239 receiving placebo) they also found 15 deaths (6.2%) with haloperidol and 9 (3.8%) with placebo, resulting in an OR of 1.68.

Other clinical data

Observational studies. Most observational studies have confirmed concerns regarding increased mortality in patients with BPSD who take antipsychotics, with FGAs having a higher risk than SGAs^18,31 and SGAs having a higher risk compared with most other psychotropics.³² Three studies that found no increase in mortality with antipsychotics in patients with dementia had methodological issues, including examining prevalence as opposed to new users,^33,34 not controlling for exposure,^10,33,34 power issues,^10,34 not controlling for other psychiatric medications,¹⁰ and varying lengths of follow-up.¹⁰ An FDA black-box warning for FGAs was announced in 2008³⁰ based on 2 observational studies that showed an increased risk of mortality in older adults taking FGAs vs SGAs.^35,36

In terms of specific SGAs, Kales et al³⁷ examined the mortality risk associated with individual antipsychotics using various methods to control for confounding. Among a national sample of >33,000 older veterans with dementia newly started on haloperidol, risperidone, olanzapine, quetiapine, or valproic acid and derivatives (as a nonantipsychotic comparator), the highest mortality across all analyses (intent to treat, exposure, propensity-adjusted) was associated with haloperidol, followed by risperidone and olanzapine, valproic acid, and quetiapine.

Most recently, a retrospective case-control study (90,786 patients age ≥65 with dementia) examined the number needed to harm (NNH; ie, number of patients needed to receive treatment that would result in 1 death) over 180 days following initiation of an FGA or SGA.³⁸ This study found the following NNHs: haloperidol, 26 (95% CI, 15 to 99); risperidone, 27 (95% CI, 19 to 46); olanzapine, 40 (95% CI, 21 to 312); and quetiapine, 50 (95% CI, 30 to 150).³⁸ These results are congruent with a review of observational studies that found the highest risk of mortality was associated with haloperidol and chlorpromazine, and the lowest risk with olanzapine, quetiapine, and ziprasidone.²⁸

Patterns of antipsychotic use in older dementia patients

There are high rates of antipsychotic use in patients with dementia. Before the FDA issued the black-box warning, the Aging Demographics and Memory study found that the rate of antipsychotic use in community (outpatient) older adults with dementia was approximately 19% between 2002 and 2004 in a representative sample of 307 older adults.³⁹ Another study examining trends in community antipsychotic use in the U.S. Department of Veterans Affairs (VA) found that in the 1990s, SGA use was increasing; approximately 18% of outpatients with dementia were taking these agents.⁴⁰ Use of SGAs began to decline in 2003, ahead of the 2005 black-box warning, in tandem with other advisories (eg, diabetes, metabolic syndrome,⁴¹ and stroke risk).^42,43 Olanzapine and risperidone showed declining rates between 2003 and 2005, whereas quetiapine use significantly increased during this period. All 3 SGAs declined after the black-box warning. However, by the end of 2007, the use of SGAs had leveled off to approximately 12% of VA patients with dementia. A recent U.S. Government Accountability Office (GAO) report found that in 2012, 14% of older adult Medicare Part D enrollees with dementia living in the community were prescribed an antipsychotic.⁴⁴

Use in nursing home residents. Because BPSD are one of the main reasons people with dementia are placed in nursing homes, it is not surprising that rates of antipsychotic use are higher in these settings than in the community. Prior to the black-box warning, studies found that 24% to 32% of nursing home residents were treated with antipsychotics.^45-47 A study examining VA nursing homes (n = 133 facilities, n = 3,692 veterans) found that approximately 26% of residents were prescribed antipsychotics in 2004 to 2005.⁴⁸ The Center for Medicare and Medicaid Services (CMS) National Partnership to Improve Dementia Care in Nursing Homes has appeared to lower antipsychotic medication use in nursing homes; the rate decreased from 24% in long-stay nursing home residents nationwide in 2011 to 19% by the end of 2014. Specific to dementia, a 2010 CMS report⁴⁹ indicated that approximately 40% of nursing home residents with cognitive impairment and behavioral issues, without psychosis, received antipsychotics. The GAO data indicated that approximately 33% of older Medicare Part D enrollees with dementia who spent >100 days in a nursing home were prescribed an antipsychotic in 2012.⁴⁴ A recent Canadian study using drug claims data found that overall psychotropic use in patients with dementia remains high, finding that three-fourths of all patients with dementia in long-term care are given at least 1 psychotropic, and up to one-third are prescribed SGAs.⁵⁰ European data similarly show that antipsychotics continue to be prescribed to up to one-third of long-term care residents with dementia, with 7 out of 10 receiving an SGA.¹

Conclusions

The Table provides a summary of the evidence regarding the use of antipsychotics in patients with dementia. Expert consensus is that among BPSD, aggression and psychosis are the primary indications for using antipsychotics.⁵¹ Based on multiple RCTs and meta-analyses, the evidence for using SGAs to treat these symptoms is moderate at best. However, in real-world practice settings, SGAs are widely used for symptoms, such as wandering, inappropriate behaviors, resistance to care, etc., for which there is no evidence for efficacy other than sedation. Furthermore, even when there is a potential for benefit, this must be balanced against the risk of adverse effects, including somnolence, worsened cognition, extra­pyramidal symptoms, stroke, and mortality.
 

Clinicians who care for older adults with BPSD should strive to increase the use of first-line nonpharmacologic strategies, by using structured approaches such as DICE (Describe, Investigate, Create, Evaluate) described in the Box.⁵¹ Antipsychotics should be reserved for situations in which nonpharmacologic approaches are unsuccessful, or there is concern for serious or imminent risk to the patient or others.

In the future, observational studies using biomarkers, such as neuroimaging markers, of brain health in older patients taking antipsychotics for various durations may give us a better understanding of long-term antipsychotic safety and tolerability and the monitoring required to assess long-term burden of specific antipsychotics in real-world samples.⁵² However, because of various biases, observational data may not provide answers to all questions,⁵³ and a major challenge is that the number of published RCTs specific to geriatric patients is not growing substantially. Pharmacotherapy evidence is not keeping up with demographic trends. Key developments in RCTs will be the inclusion of biomarkers via neuroimaging, drug serum or brain levels, and genetic profiling. Because of the modest findings of benefits of antipsychotics in dementia and safety concerns addressing brain health in preclinical or early stages, identification of effective non-drug interventions and identifying true disease-modifying agents will be the next challenges of dementia research.
 

Sexting includes sending sexually explicit (or sexually suggestive) text messages and photos, usually by cell phone. This article focuses on sexts involving photos. Cell phones are almost ubiquitous among American teens, and with technological advances, sexts are getting easier to send. Sexting may occur to initiate a relationship or sustain one. Some teenagers are coerced into sexting. Many people do not realize the potential long-term consequences of sexting—particularly because of the impulsive nature of sexting and the belief that the behavior is harmless.

Media attention has recently focused on teens who face legal charges related to sexting. Sexting photos may be considered child pornography—even though the teens made it themselves. There are also social consequences to sexting. Photos meant to be private are sometimes forwarded to others. Cyberbullying is not uncommon with teen sexting, and suicides after experiencing this behavior have been reported.

Sexting may be a form of modern flirtation, but in some cases, it may be a marker of other risk behaviors, such as substance abuse. Psychiatrists must be aware of the frequency and meaning of this potentially dangerous behavior. Clinicians should feel comfortable asking their patients about it and provide education and counseling.

CASE

Private photos get shared

K, age 14, a freshman with no psychiatric history, is referred to you by her school psychologist for evaluation of suicidal ideation. K reports depressed mood, poor sleep, inattention, loss of appetite, anhedonia, and feelings of guilt for the past month. She recently ended a relationship with her boyfriend of 1 year after she learned that he had shared with his friends naked photos of her that she had sent him. The school administration learned of the photos when a student posted them on one of the school computers.

K’s boyfriend, age 16, was suspended after the school learned that he had shared the photos without K’s consent. K, who is a good student, missed several days of school, including cheerleading practice; previously she had never missed a day of school.

On evaluation, K is tearful, stating that her life is “over.” She says that her ex-boyfriend’s friends are harassing her, calling her “slut” and making sexual comments. She also feels guilty, because she learned that the police interviewed her ex-boyfriend in connection with posting her photos on the Internet. In a text, he said he “might get charged with child pornography.” On further questioning, K confides that she had naked photos of her ex-boyfriend on her phone. She admits to sharing the pictures with her best friend, because she was “angry and wanted to get back” at her ex-boyfriend. She also reports a several-month history of sexting with her ex-boyfriend. K deleted the photos and texts after learning that her ex-boyfriend “was in trouble with the police.”

K has no prior sexual experience. She dated 1 boy her age prior to her ex-boyfriend. She had never been evaluated by a mental health clinician. She is dysphoric and reports feeling “hopeless … Unless this can be erased, I can’t go back to school.”

Sexting: What is the extent of the problem?

The true prevalence of sexting is difficult to ascertain, because different studies have used different definitions and method­ologies. However, the rates are far from negligible. Sexting rates increase with age, over the teen years.^1-3 Among American minors, 2.5% to 28% of middle school and high school students report that they have sent a sext (Table 1^1-9). Studies of American young adults (age ≥18) and university students have found 30% to 60% have sent sexts, and >40% have received a sext.^4,5

Many people receive sexts—including individuals who are not the intended recipient. In 1 study, although most teens intended to share sexts only with their boyfriend/girlfriend, 25% to 33% had received sext photos intended for other people.⁶ In another recent study, 25% of teens had forwarded a sext that they received.⁷ Moreover, 12% of teenage boys and 5% of teenage girls had sent a sexually explicit photo that they took of another teen to a third person.⁷ Forwarding sexts can add exponentially to the psychosocial risks of the photographed teenager.

Who sexts? Current research indicates that the likelihood of sexting is related to age, personality, and social situation. Teens are approaching the peak age of their sex drive, and often are curious and feel invincible. Teens are more impulsive than adults. When it takes less than a minute to send a sext, irreversible poor choices can be made quickly. Teens who send sexts often engage in more text messaging than other teens.⁷

Teens may use sexting to initiate or sustain a relationship. Sexts also may be sent because of coercion. More than one-half of girls cited pressure to sext from a boy.⁶ Temple et al³ found that more than one-half of their study sample had been asked to send a sext. Girls were more likely than boys to be asked to send a sext; most were troubled by this.

One study that assessed knowledge of potential legal consequences of sexting found that many teens who sent sexts were aware of the potential consequences.⁷ Regarding personality traits, sexting among undergraduates was predicted by neuroticism and low agreeableness.¹⁰ Conversely, sending text messages with sexually suggestive writing was predicted by extraversion and problematic cell phone use.

Comorbidities. There are mixed findings about whether sexting is simply a modern dating strategy or a marker of other risk behaviors; age may play an important discriminating role. Sexual activity appears to be correlated with sexting. According to Temple and Choi,¹¹ “Sexting fits within the context of adolescent sexual development and may be a viable indicator of adolescent sexual activity.”¹¹

Some authors have suggested that sext­ing is a contemporary risk behavior that is likely to correlate with other risk behaviors. Among young teens—seventh graders who were referred to a risk prevention trial because of behavioral/emotional difficulties—those who sexted were more likely to engage in early sexual behaviors.⁸ These younger at-risk teens also had less understanding of their emotions and greater difficulty in regulating their emotions.

Among the general population of high school students, teens who sext are more likely to be sexually active.³ High school girls who engaged in sexting were noted to engage in other risk behaviors, including having multiple partners in the past year and using alcohol or drugs before sex.³ Teens who had sent a sext were more likely to be sexually active 1 year later than teens who had not.¹¹Studies of sexting among university students also have had mixed findings. One study found that among undergraduates, sexting was associated with substance use and other risk behaviors.⁹ Another young adult study found sexting was not related to sexual risk or psychological well-being.⁴

Legal issues affect psychiatrists as well as patients

As a psychiatrist evaluating K, what are your duties as a mandated reporter? Psychiatrists are legally required to report suspected maltreatment or abuse of children.¹² The circumstances under which psychiatrists may have a mandate to report include when a psychiatrist:

• evaluates a child and suspects abuse
• suspects child abuse based on an adult patient’s report
• learns from a third party that a child may have been/is being abused.

Psychiatrists usually are not mandated to report other types of potentially criminal behavior. As such, reporting sexting might be considered a breach of confidentiality. Psychiatrists should be familiar with the specific reporting guidelines for the jurisdiction in which they practice. Psychiatrists who work with individuals who commit crimes should focus on changing the potentially dangerous behaviors rather than reporting them.

Does the transmission of naked photos of a minor in a sexual pose or act constitute child pornography or another criminal offense? The legal answer varies, but the role of the psychiatrist does not. Psychiatrists should educate their patients about potentially dangerous behaviors.

With regards to the legal consequences, some states classify underage sexting photos as child pornography. Others have less rigid definitions of child pornography and take into account the age of the participants and their intent. Such jurisdictions point out that sexting naked photos among adolescents is “age appropriate.” Some have enacted specific sexting laws to address the transmission of obscene material to a child through the Internet. In some jurisdictions, sexting laws are categorized to refer to behavior of individuals under or over age 18. The term “revenge porn” is used to refer to nonconsensual pornography with its dissemination motivated by spite.¹³ Some states have defined specific revenge porn laws to address the behavior. Currently, 20 states have sexting laws and 26 states have revenge porn laws.¹⁴ Twenty states address a minor age <18 sending the photo, while only 18 address the recipient. The law in this area can be complex and detailed, taking into account the age of the sender, the intentions of the sender, and the nature of the relationship between the sender and the recipient and the behavior of the recipient.

Laws regarding sexting vary greatly. Sexting may be a misdemeanor or a felony, depending on the state, the specific behavior, and the frequency. In the United States, 11 state laws include a diversion remedy—an option to pursue the case outside of the criminal juvenile system; 10 laws require counseling or another informal sanction; 11 states laws have the potential for misdemeanor punishment; and 4 state laws have the potential for felony punishment.¹⁴ Depending on the criminal charge, the perpetrator may have to register as a sex offender. For example, in some jurisdictions, a conviction for possession of child pornography requires sex offender registration. Thirty-eight states include juvenile sex offenders in their sex offender registries. Other states require juveniles to register if they are age ≥15 years or have been tried as an adult.¹⁵

The frequency of police involvement in sexting cases also greatly varies. A national study examining the characteristics of youth sexting cases revealed that law enforcement agencies handled approximately 3,477 cases of youth-produced sexual photos in 2008 and 2009.¹⁶ Situations that involved an adult or a minor engaged in malicious, nonconsensual, or abusive behavior comprised two-thirds of cases. Arrests occurred in 62% of the adult-involved cases and 36% of the aggravated youth-only cases. Arrests occurred in only 18% of investigated non-aggravated youth-only cases. Table 2 describes recent American sexting legal cases and their outcomes.

In K’s case, depending on the jurisdiction, K or her ex-boyfriend may be subject to arrest for child pornography, revenge pornography, or sexting.

Potential social and psychiatric consequences

What are the social and psychiatric ramifications for K? Aside from potential legal consequences of sexting, K is experiencing psychological and social consequences. She has developed depressive symptoms and suicidal ideation. Her ex-boyfriend’s dissemination of her nude photos on the school computer could be interpreted as cyberbullying. (The National Center for Missing and Exploited Children defines cyberbullying as “bullying through the use of technology or electronic devices such as telephones, cell phones, computers, and the Internet.”¹⁷ All 50 states have enacted laws against bullying; 48 states have electronic harassment in their bullying laws; and 22 states have laws specifically referencing “cyberbullying.”)

Her depressive symptoms developed in response to her feelings of guilt and shame related to sexting as well as the subsequent peer harassment. She is refusing to return to school because of her concerns about bullying. A careful inquiry into suicidality should be part of the evaluation when sexting has led to psychiatric symptoms. Several cases of sexting and cyberbullying have ended in suicide (Table 3).

How to ask patients about sexting

To screen patients for sexting, clinicians need to develop a new skill set, which at first may be uncomfortable. However, the questions to ask are not all that different from other questions about adolescent and young adult sexuality. The importance of patients seeing that we as physicians are comfortable with the topic and approachable about their sexual health cannot be overemphasized. When discussing sexting with patients, it is essential to:

• explain that you are asking questions about their sexual health because they are important to overall health
• engage patients in discussion in a nonthreatening and nonjudgmental way
• develop rapport so patients feel comfortable disclosing behavior that may be embarrassing
• listen to their stories and build a context for understanding their experiences. As you listen, ask questions when needed to help move the story along.

Sometimes when asking about topics that are uncomfortable, clinicians revert from open-ended to closed-ended questions, but when asking about a patient’s sexual life, it is especially important to be open-ended and ask questions in a nonjudgmental way. Contextualizing sexual questions by (for example) asking them while discussing the teen’s relationships will make them seem more natural.¹⁸ To best understand, inquire explicitly about specific behaviors, but do so without appearing voyeuristic.¹⁸

Sexting may precede sexual intercourse. Keep in mind that a patient may report that she (he) is not sexually active but still may be involved in sexting. Therefore, discuss sexting even if your patient reports not being sexually active. By understanding the prevalence of sexting among teens, you can ask questions in a normalizing way. Clinicians can inquire about sexting while discussing relationships and dating or online risk behaviors.

Also consider whether any of your patient’s sexual behaviors, including sext­ing, are the result of coercion: “Some of my patients tell me they feel pressured or coerced into having sex. Have you ever felt this way?”¹⁹ and “Have you ever been picked on or bullied? Is that still a problem?” are suggested safety screening questions about bullying,¹⁸ and one can also ask about specific cyberbullying behaviors.

Sexting includes sending sexually explicit (or sexually suggestive) text messages and photos, usually by cell phone. This article focuses on sexts involving photos. Cell phones are almost ubiquitous among American teens, and with technological advances, sexts are getting easier to send. Sexting may occur to initiate a relationship or sustain one. Some teenagers are coerced into sexting. Many people do not realize the potential long-term consequences of sexting—particularly because of the impulsive nature of sexting and the belief that the behavior is harmless.

Media attention has recently focused on teens who face legal charges related to sexting. Sexting photos may be considered child pornography—even though the teens made it themselves. There are also social consequences to sexting. Photos meant to be private are sometimes forwarded to others. Cyberbullying is not uncommon with teen sexting, and suicides after experiencing this behavior have been reported.

Sexting may be a form of modern flirtation, but in some cases, it may be a marker of other risk behaviors, such as substance abuse. Psychiatrists must be aware of the frequency and meaning of this potentially dangerous behavior. Clinicians should feel comfortable asking their patients about it and provide education and counseling.

CASE

Private photos get shared

K, age 14, a freshman with no psychiatric history, is referred to you by her school psychologist for evaluation of suicidal ideation. K reports depressed mood, poor sleep, inattention, loss of appetite, anhedonia, and feelings of guilt for the past month. She recently ended a relationship with her boyfriend of 1 year after she learned that he had shared with his friends naked photos of her that she had sent him. The school administration learned of the photos when a student posted them on one of the school computers.

K’s boyfriend, age 16, was suspended after the school learned that he had shared the photos without K’s consent. K, who is a good student, missed several days of school, including cheerleading practice; previously she had never missed a day of school.

On evaluation, K is tearful, stating that her life is “over.” She says that her ex-boyfriend’s friends are harassing her, calling her “slut” and making sexual comments. She also feels guilty, because she learned that the police interviewed her ex-boyfriend in connection with posting her photos on the Internet. In a text, he said he “might get charged with child pornography.” On further questioning, K confides that she had naked photos of her ex-boyfriend on her phone. She admits to sharing the pictures with her best friend, because she was “angry and wanted to get back” at her ex-boyfriend. She also reports a several-month history of sexting with her ex-boyfriend. K deleted the photos and texts after learning that her ex-boyfriend “was in trouble with the police.”

K has no prior sexual experience. She dated 1 boy her age prior to her ex-boyfriend. She had never been evaluated by a mental health clinician. She is dysphoric and reports feeling “hopeless … Unless this can be erased, I can’t go back to school.”

Sexting: What is the extent of the problem?

The true prevalence of sexting is difficult to ascertain, because different studies have used different definitions and method­ologies. However, the rates are far from negligible. Sexting rates increase with age, over the teen years.^1-3 Among American minors, 2.5% to 28% of middle school and high school students report that they have sent a sext (Table 1^1-9). Studies of American young adults (age ≥18) and university students have found 30% to 60% have sent sexts, and >40% have received a sext.^4,5

Many people receive sexts—including individuals who are not the intended recipient. In 1 study, although most teens intended to share sexts only with their boyfriend/girlfriend, 25% to 33% had received sext photos intended for other people.⁶ In another recent study, 25% of teens had forwarded a sext that they received.⁷ Moreover, 12% of teenage boys and 5% of teenage girls had sent a sexually explicit photo that they took of another teen to a third person.⁷ Forwarding sexts can add exponentially to the psychosocial risks of the photographed teenager.

Who sexts? Current research indicates that the likelihood of sexting is related to age, personality, and social situation. Teens are approaching the peak age of their sex drive, and often are curious and feel invincible. Teens are more impulsive than adults. When it takes less than a minute to send a sext, irreversible poor choices can be made quickly. Teens who send sexts often engage in more text messaging than other teens.⁷

Teens may use sexting to initiate or sustain a relationship. Sexts also may be sent because of coercion. More than one-half of girls cited pressure to sext from a boy.⁶ Temple et al³ found that more than one-half of their study sample had been asked to send a sext. Girls were more likely than boys to be asked to send a sext; most were troubled by this.

One study that assessed knowledge of potential legal consequences of sexting found that many teens who sent sexts were aware of the potential consequences.⁷ Regarding personality traits, sexting among undergraduates was predicted by neuroticism and low agreeableness.¹⁰ Conversely, sending text messages with sexually suggestive writing was predicted by extraversion and problematic cell phone use.

Comorbidities. There are mixed findings about whether sexting is simply a modern dating strategy or a marker of other risk behaviors; age may play an important discriminating role. Sexual activity appears to be correlated with sexting. According to Temple and Choi,¹¹ “Sexting fits within the context of adolescent sexual development and may be a viable indicator of adolescent sexual activity.”¹¹

Some authors have suggested that sext­ing is a contemporary risk behavior that is likely to correlate with other risk behaviors. Among young teens—seventh graders who were referred to a risk prevention trial because of behavioral/emotional difficulties—those who sexted were more likely to engage in early sexual behaviors.⁸ These younger at-risk teens also had less understanding of their emotions and greater difficulty in regulating their emotions.

Among the general population of high school students, teens who sext are more likely to be sexually active.³ High school girls who engaged in sexting were noted to engage in other risk behaviors, including having multiple partners in the past year and using alcohol or drugs before sex.³ Teens who had sent a sext were more likely to be sexually active 1 year later than teens who had not.¹¹Studies of sexting among university students also have had mixed findings. One study found that among undergraduates, sexting was associated with substance use and other risk behaviors.⁹ Another young adult study found sexting was not related to sexual risk or psychological well-being.⁴

Legal issues affect psychiatrists as well as patients

As a psychiatrist evaluating K, what are your duties as a mandated reporter? Psychiatrists are legally required to report suspected maltreatment or abuse of children.¹² The circumstances under which psychiatrists may have a mandate to report include when a psychiatrist:

• evaluates a child and suspects abuse
• suspects child abuse based on an adult patient’s report
• learns from a third party that a child may have been/is being abused.

Psychiatrists usually are not mandated to report other types of potentially criminal behavior. As such, reporting sexting might be considered a breach of confidentiality. Psychiatrists should be familiar with the specific reporting guidelines for the jurisdiction in which they practice. Psychiatrists who work with individuals who commit crimes should focus on changing the potentially dangerous behaviors rather than reporting them.

Does the transmission of naked photos of a minor in a sexual pose or act constitute child pornography or another criminal offense? The legal answer varies, but the role of the psychiatrist does not. Psychiatrists should educate their patients about potentially dangerous behaviors.

With regards to the legal consequences, some states classify underage sexting photos as child pornography. Others have less rigid definitions of child pornography and take into account the age of the participants and their intent. Such jurisdictions point out that sexting naked photos among adolescents is “age appropriate.” Some have enacted specific sexting laws to address the transmission of obscene material to a child through the Internet. In some jurisdictions, sexting laws are categorized to refer to behavior of individuals under or over age 18. The term “revenge porn” is used to refer to nonconsensual pornography with its dissemination motivated by spite.¹³ Some states have defined specific revenge porn laws to address the behavior. Currently, 20 states have sexting laws and 26 states have revenge porn laws.¹⁴ Twenty states address a minor age <18 sending the photo, while only 18 address the recipient. The law in this area can be complex and detailed, taking into account the age of the sender, the intentions of the sender, and the nature of the relationship between the sender and the recipient and the behavior of the recipient.

Laws regarding sexting vary greatly. Sexting may be a misdemeanor or a felony, depending on the state, the specific behavior, and the frequency. In the United States, 11 state laws include a diversion remedy—an option to pursue the case outside of the criminal juvenile system; 10 laws require counseling or another informal sanction; 11 states laws have the potential for misdemeanor punishment; and 4 state laws have the potential for felony punishment.¹⁴ Depending on the criminal charge, the perpetrator may have to register as a sex offender. For example, in some jurisdictions, a conviction for possession of child pornography requires sex offender registration. Thirty-eight states include juvenile sex offenders in their sex offender registries. Other states require juveniles to register if they are age ≥15 years or have been tried as an adult.¹⁵

The frequency of police involvement in sexting cases also greatly varies. A national study examining the characteristics of youth sexting cases revealed that law enforcement agencies handled approximately 3,477 cases of youth-produced sexual photos in 2008 and 2009.¹⁶ Situations that involved an adult or a minor engaged in malicious, nonconsensual, or abusive behavior comprised two-thirds of cases. Arrests occurred in 62% of the adult-involved cases and 36% of the aggravated youth-only cases. Arrests occurred in only 18% of investigated non-aggravated youth-only cases. Table 2 describes recent American sexting legal cases and their outcomes.

In K’s case, depending on the jurisdiction, K or her ex-boyfriend may be subject to arrest for child pornography, revenge pornography, or sexting.

Potential social and psychiatric consequences

What are the social and psychiatric ramifications for K? Aside from potential legal consequences of sexting, K is experiencing psychological and social consequences. She has developed depressive symptoms and suicidal ideation. Her ex-boyfriend’s dissemination of her nude photos on the school computer could be interpreted as cyberbullying. (The National Center for Missing and Exploited Children defines cyberbullying as “bullying through the use of technology or electronic devices such as telephones, cell phones, computers, and the Internet.”¹⁷ All 50 states have enacted laws against bullying; 48 states have electronic harassment in their bullying laws; and 22 states have laws specifically referencing “cyberbullying.”)

Her depressive symptoms developed in response to her feelings of guilt and shame related to sexting as well as the subsequent peer harassment. She is refusing to return to school because of her concerns about bullying. A careful inquiry into suicidality should be part of the evaluation when sexting has led to psychiatric symptoms. Several cases of sexting and cyberbullying have ended in suicide (Table 3).

How to ask patients about sexting

To screen patients for sexting, clinicians need to develop a new skill set, which at first may be uncomfortable. However, the questions to ask are not all that different from other questions about adolescent and young adult sexuality. The importance of patients seeing that we as physicians are comfortable with the topic and approachable about their sexual health cannot be overemphasized. When discussing sexting with patients, it is essential to:

• explain that you are asking questions about their sexual health because they are important to overall health
• engage patients in discussion in a nonthreatening and nonjudgmental way
• develop rapport so patients feel comfortable disclosing behavior that may be embarrassing
• listen to their stories and build a context for understanding their experiences. As you listen, ask questions when needed to help move the story along.

Sometimes when asking about topics that are uncomfortable, clinicians revert from open-ended to closed-ended questions, but when asking about a patient’s sexual life, it is especially important to be open-ended and ask questions in a nonjudgmental way. Contextualizing sexual questions by (for example) asking them while discussing the teen’s relationships will make them seem more natural.¹⁸ To best understand, inquire explicitly about specific behaviors, but do so without appearing voyeuristic.¹⁸

Sexting may precede sexual intercourse. Keep in mind that a patient may report that she (he) is not sexually active but still may be involved in sexting. Therefore, discuss sexting even if your patient reports not being sexually active. By understanding the prevalence of sexting among teens, you can ask questions in a normalizing way. Clinicians can inquire about sexting while discussing relationships and dating or online risk behaviors.

Also consider whether any of your patient’s sexual behaviors, including sext­ing, are the result of coercion: “Some of my patients tell me they feel pressured or coerced into having sex. Have you ever felt this way?”¹⁹ and “Have you ever been picked on or bullied? Is that still a problem?” are suggested safety screening questions about bullying,¹⁸ and one can also ask about specific cyberbullying behaviors.

Sexting includes sending sexually explicit (or sexually suggestive) text messages and photos, usually by cell phone. This article focuses on sexts involving photos. Cell phones are almost ubiquitous among American teens, and with technological advances, sexts are getting easier to send. Sexting may occur to initiate a relationship or sustain one. Some teenagers are coerced into sexting. Many people do not realize the potential long-term consequences of sexting—particularly because of the impulsive nature of sexting and the belief that the behavior is harmless.

Media attention has recently focused on teens who face legal charges related to sexting. Sexting photos may be considered child pornography—even though the teens made it themselves. There are also social consequences to sexting. Photos meant to be private are sometimes forwarded to others. Cyberbullying is not uncommon with teen sexting, and suicides after experiencing this behavior have been reported.

Sexting may be a form of modern flirtation, but in some cases, it may be a marker of other risk behaviors, such as substance abuse. Psychiatrists must be aware of the frequency and meaning of this potentially dangerous behavior. Clinicians should feel comfortable asking their patients about it and provide education and counseling.

CASE

Private photos get shared

K, age 14, a freshman with no psychiatric history, is referred to you by her school psychologist for evaluation of suicidal ideation. K reports depressed mood, poor sleep, inattention, loss of appetite, anhedonia, and feelings of guilt for the past month. She recently ended a relationship with her boyfriend of 1 year after she learned that he had shared with his friends naked photos of her that she had sent him. The school administration learned of the photos when a student posted them on one of the school computers.

K’s boyfriend, age 16, was suspended after the school learned that he had shared the photos without K’s consent. K, who is a good student, missed several days of school, including cheerleading practice; previously she had never missed a day of school.

On evaluation, K is tearful, stating that her life is “over.” She says that her ex-boyfriend’s friends are harassing her, calling her “slut” and making sexual comments. She also feels guilty, because she learned that the police interviewed her ex-boyfriend in connection with posting her photos on the Internet. In a text, he said he “might get charged with child pornography.” On further questioning, K confides that she had naked photos of her ex-boyfriend on her phone. She admits to sharing the pictures with her best friend, because she was “angry and wanted to get back” at her ex-boyfriend. She also reports a several-month history of sexting with her ex-boyfriend. K deleted the photos and texts after learning that her ex-boyfriend “was in trouble with the police.”

K has no prior sexual experience. She dated 1 boy her age prior to her ex-boyfriend. She had never been evaluated by a mental health clinician. She is dysphoric and reports feeling “hopeless … Unless this can be erased, I can’t go back to school.”

Sexting: What is the extent of the problem?

The true prevalence of sexting is difficult to ascertain, because different studies have used different definitions and method­ologies. However, the rates are far from negligible. Sexting rates increase with age, over the teen years.^1-3 Among American minors, 2.5% to 28% of middle school and high school students report that they have sent a sext (Table 1^1-9). Studies of American young adults (age ≥18) and university students have found 30% to 60% have sent sexts, and >40% have received a sext.^4,5

Many people receive sexts—including individuals who are not the intended recipient. In 1 study, although most teens intended to share sexts only with their boyfriend/girlfriend, 25% to 33% had received sext photos intended for other people.⁶ In another recent study, 25% of teens had forwarded a sext that they received.⁷ Moreover, 12% of teenage boys and 5% of teenage girls had sent a sexually explicit photo that they took of another teen to a third person.⁷ Forwarding sexts can add exponentially to the psychosocial risks of the photographed teenager.

Who sexts? Current research indicates that the likelihood of sexting is related to age, personality, and social situation. Teens are approaching the peak age of their sex drive, and often are curious and feel invincible. Teens are more impulsive than adults. When it takes less than a minute to send a sext, irreversible poor choices can be made quickly. Teens who send sexts often engage in more text messaging than other teens.⁷

Teens may use sexting to initiate or sustain a relationship. Sexts also may be sent because of coercion. More than one-half of girls cited pressure to sext from a boy.⁶ Temple et al³ found that more than one-half of their study sample had been asked to send a sext. Girls were more likely than boys to be asked to send a sext; most were troubled by this.

One study that assessed knowledge of potential legal consequences of sexting found that many teens who sent sexts were aware of the potential consequences.⁷ Regarding personality traits, sexting among undergraduates was predicted by neuroticism and low agreeableness.¹⁰ Conversely, sending text messages with sexually suggestive writing was predicted by extraversion and problematic cell phone use.

Comorbidities. There are mixed findings about whether sexting is simply a modern dating strategy or a marker of other risk behaviors; age may play an important discriminating role. Sexual activity appears to be correlated with sexting. According to Temple and Choi,¹¹ “Sexting fits within the context of adolescent sexual development and may be a viable indicator of adolescent sexual activity.”¹¹

Some authors have suggested that sext­ing is a contemporary risk behavior that is likely to correlate with other risk behaviors. Among young teens—seventh graders who were referred to a risk prevention trial because of behavioral/emotional difficulties—those who sexted were more likely to engage in early sexual behaviors.⁸ These younger at-risk teens also had less understanding of their emotions and greater difficulty in regulating their emotions.

Among the general population of high school students, teens who sext are more likely to be sexually active.³ High school girls who engaged in sexting were noted to engage in other risk behaviors, including having multiple partners in the past year and using alcohol or drugs before sex.³ Teens who had sent a sext were more likely to be sexually active 1 year later than teens who had not.¹¹Studies of sexting among university students also have had mixed findings. One study found that among undergraduates, sexting was associated with substance use and other risk behaviors.⁹ Another young adult study found sexting was not related to sexual risk or psychological well-being.⁴

Legal issues affect psychiatrists as well as patients

As a psychiatrist evaluating K, what are your duties as a mandated reporter? Psychiatrists are legally required to report suspected maltreatment or abuse of children.¹² The circumstances under which psychiatrists may have a mandate to report include when a psychiatrist:

• evaluates a child and suspects abuse
• suspects child abuse based on an adult patient’s report
• learns from a third party that a child may have been/is being abused.

Psychiatrists usually are not mandated to report other types of potentially criminal behavior. As such, reporting sexting might be considered a breach of confidentiality. Psychiatrists should be familiar with the specific reporting guidelines for the jurisdiction in which they practice. Psychiatrists who work with individuals who commit crimes should focus on changing the potentially dangerous behaviors rather than reporting them.

Does the transmission of naked photos of a minor in a sexual pose or act constitute child pornography or another criminal offense? The legal answer varies, but the role of the psychiatrist does not. Psychiatrists should educate their patients about potentially dangerous behaviors.

With regards to the legal consequences, some states classify underage sexting photos as child pornography. Others have less rigid definitions of child pornography and take into account the age of the participants and their intent. Such jurisdictions point out that sexting naked photos among adolescents is “age appropriate.” Some have enacted specific sexting laws to address the transmission of obscene material to a child through the Internet. In some jurisdictions, sexting laws are categorized to refer to behavior of individuals under or over age 18. The term “revenge porn” is used to refer to nonconsensual pornography with its dissemination motivated by spite.¹³ Some states have defined specific revenge porn laws to address the behavior. Currently, 20 states have sexting laws and 26 states have revenge porn laws.¹⁴ Twenty states address a minor age <18 sending the photo, while only 18 address the recipient. The law in this area can be complex and detailed, taking into account the age of the sender, the intentions of the sender, and the nature of the relationship between the sender and the recipient and the behavior of the recipient.

Laws regarding sexting vary greatly. Sexting may be a misdemeanor or a felony, depending on the state, the specific behavior, and the frequency. In the United States, 11 state laws include a diversion remedy—an option to pursue the case outside of the criminal juvenile system; 10 laws require counseling or another informal sanction; 11 states laws have the potential for misdemeanor punishment; and 4 state laws have the potential for felony punishment.¹⁴ Depending on the criminal charge, the perpetrator may have to register as a sex offender. For example, in some jurisdictions, a conviction for possession of child pornography requires sex offender registration. Thirty-eight states include juvenile sex offenders in their sex offender registries. Other states require juveniles to register if they are age ≥15 years or have been tried as an adult.¹⁵

The frequency of police involvement in sexting cases also greatly varies. A national study examining the characteristics of youth sexting cases revealed that law enforcement agencies handled approximately 3,477 cases of youth-produced sexual photos in 2008 and 2009.¹⁶ Situations that involved an adult or a minor engaged in malicious, nonconsensual, or abusive behavior comprised two-thirds of cases. Arrests occurred in 62% of the adult-involved cases and 36% of the aggravated youth-only cases. Arrests occurred in only 18% of investigated non-aggravated youth-only cases. Table 2 describes recent American sexting legal cases and their outcomes.

In K’s case, depending on the jurisdiction, K or her ex-boyfriend may be subject to arrest for child pornography, revenge pornography, or sexting.

Potential social and psychiatric consequences

What are the social and psychiatric ramifications for K? Aside from potential legal consequences of sexting, K is experiencing psychological and social consequences. She has developed depressive symptoms and suicidal ideation. Her ex-boyfriend’s dissemination of her nude photos on the school computer could be interpreted as cyberbullying. (The National Center for Missing and Exploited Children defines cyberbullying as “bullying through the use of technology or electronic devices such as telephones, cell phones, computers, and the Internet.”¹⁷ All 50 states have enacted laws against bullying; 48 states have electronic harassment in their bullying laws; and 22 states have laws specifically referencing “cyberbullying.”)

Her depressive symptoms developed in response to her feelings of guilt and shame related to sexting as well as the subsequent peer harassment. She is refusing to return to school because of her concerns about bullying. A careful inquiry into suicidality should be part of the evaluation when sexting has led to psychiatric symptoms. Several cases of sexting and cyberbullying have ended in suicide (Table 3).

How to ask patients about sexting

To screen patients for sexting, clinicians need to develop a new skill set, which at first may be uncomfortable. However, the questions to ask are not all that different from other questions about adolescent and young adult sexuality. The importance of patients seeing that we as physicians are comfortable with the topic and approachable about their sexual health cannot be overemphasized. When discussing sexting with patients, it is essential to:

• explain that you are asking questions about their sexual health because they are important to overall health
• engage patients in discussion in a nonthreatening and nonjudgmental way
• develop rapport so patients feel comfortable disclosing behavior that may be embarrassing
• listen to their stories and build a context for understanding their experiences. As you listen, ask questions when needed to help move the story along.

Sometimes when asking about topics that are uncomfortable, clinicians revert from open-ended to closed-ended questions, but when asking about a patient’s sexual life, it is especially important to be open-ended and ask questions in a nonjudgmental way. Contextualizing sexual questions by (for example) asking them while discussing the teen’s relationships will make them seem more natural.¹⁸ To best understand, inquire explicitly about specific behaviors, but do so without appearing voyeuristic.¹⁸

Sexting may precede sexual intercourse. Keep in mind that a patient may report that she (he) is not sexually active but still may be involved in sexting. Therefore, discuss sexting even if your patient reports not being sexually active. By understanding the prevalence of sexting among teens, you can ask questions in a normalizing way. Clinicians can inquire about sexting while discussing relationships and dating or online risk behaviors.

Also consider whether any of your patient’s sexual behaviors, including sext­ing, are the result of coercion: “Some of my patients tell me they feel pressured or coerced into having sex. Have you ever felt this way?”¹⁹ and “Have you ever been picked on or bullied? Is that still a problem?” are suggested safety screening questions about bullying,¹⁸ and one can also ask about specific cyberbullying behaviors.

Imagine being able to precisely select the medication with the optimal efficacy, safety, and tolerability at the outset of treatment for every psychiatric patient who needs pharma­cotherapy. Imagine how much the patient would appreciate not receiving a series of drugs and suffering multiple adverse effects and unremitting symptoms until the “right medication” is identified. Imagine how gratifying it would be for you as a psychiatrist to watch every one of your patients improve rapidly with minimal complaints or adverse effects.

Precision psychiatry is the indispensable vehicle to achieve personalized medicine for psychiatric patients. Precision psychiatry is a cherished goal, but it remains an aspirational objective. Other medical specialties, especially oncology and cardiology, have made remarkable strides in precision medicine, but the journey to precision psychiatry is still in its early stages. Yet there is every reason to believe that we are making progress toward that cherished goal.

To implement precision psychiatry, we must be able to identify the biosignature of each patient’s psychiatric brain disorder. But there is a formidable challenge to overcome: the complex, extensive heterogeneity of psychiatric disorders, which requires intense and inspired neurobiology research. So, while clinicians go on with the mundane trial-and-error approach of contemporary psychopharmacology, psychiatric neuroscientists are diligently deconstructing major psychiatric disorders into specific biotypes with unique biosignatures that will one day guide accurate and prompt clinical management.

Psychiatric practitioners may be too busy to keep tabs on the progress being made in identifying various biomarkers that are the key ingredients to decoding the biosignature of each psychiatric patient. Take schizophrenia, for example. There are myriad clinical variations that comprise this heterogeneous brain syndrome, including level of premorbid functioning; acute vs gradual onset of psychosis; the type and severity of hallucinations or delusions; the dimensional spectrum of negative symptoms and cognitive impairments; the presence and intensity of suicidal or homicidal urges; and the type of medical and psychiatric comorbidities. No wonder every patient is a unique and fascinating clinical puzzle, and yet, patients with schizophrenia are still being homogenized under a single DSM diagnostic category.

Precision psychiatry will ultimately enable practitioners to recognize various psychotic diseases that are more specific than the current DSM psychosis categories. Further, precision psychiatry will provide guidance as to which member within a class of so-called “me-too” drugs is the optimal match for each patient. This will stand in stark contrast to the chaotic hit-or-miss approach.

Precision psychiatry also will reveal the absurdity of current FDA clinical trials design for drug development. How can a molecule with a putative mechanism of action relevant to a specific biotype be administered to a hodgepodge of heterogeneous biotypes that have been lumped in 1 clinical category, and yet be expected to exert efficacy in most biotypes? It is a small miracle that some new drugs beat placebo despite the extensive variability in both placebo responses and drug responses. But it is well known that in all FDA placebo-controlled trials, the therapeutic response across the patient population varies from extremely high to extremely low, and worsening may even occur in a subset of patients receiving either the active drug or placebo. Perhaps drug response should be used as 1 methodology to classify biotypes of patients encompassed within a heterogeneous syndrome such as schizophrenia.

Precision psychiatry will represent a huge paradigm shift in the science and practice of our specialty. In his landmark book, Thomas Kuhn defined a paradigm as “an entire worldview in which a theory exists and all the implications that come from that view.”² Precision psychiatry will completely disrupt the current antiquated clinical paradigm, transforming psychiatry into the clinical neuroscience it is. Many “omics,” such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and metagenomics, will inevitably find their way into the jargon of psychiatrists.³

A marriage of science and technology is essential for the emergence of precision psychiatry. To achieve this transformative amalgamation, we need to reconfigure our concepts, reengineer our methods, reinvent our models, and redesign our approaches to patient care.

As Peter Drucker said, “The best way to predict the future is to create it.”⁴ Precision psychiatry is our future. Let’s create it!

Imagine being able to precisely select the medication with the optimal efficacy, safety, and tolerability at the outset of treatment for every psychiatric patient who needs pharma­cotherapy. Imagine how much the patient would appreciate not receiving a series of drugs and suffering multiple adverse effects and unremitting symptoms until the “right medication” is identified. Imagine how gratifying it would be for you as a psychiatrist to watch every one of your patients improve rapidly with minimal complaints or adverse effects.

Precision psychiatry is the indispensable vehicle to achieve personalized medicine for psychiatric patients. Precision psychiatry is a cherished goal, but it remains an aspirational objective. Other medical specialties, especially oncology and cardiology, have made remarkable strides in precision medicine, but the journey to precision psychiatry is still in its early stages. Yet there is every reason to believe that we are making progress toward that cherished goal.

To implement precision psychiatry, we must be able to identify the biosignature of each patient’s psychiatric brain disorder. But there is a formidable challenge to overcome: the complex, extensive heterogeneity of psychiatric disorders, which requires intense and inspired neurobiology research. So, while clinicians go on with the mundane trial-and-error approach of contemporary psychopharmacology, psychiatric neuroscientists are diligently deconstructing major psychiatric disorders into specific biotypes with unique biosignatures that will one day guide accurate and prompt clinical management.

Psychiatric practitioners may be too busy to keep tabs on the progress being made in identifying various biomarkers that are the key ingredients to decoding the biosignature of each psychiatric patient. Take schizophrenia, for example. There are myriad clinical variations that comprise this heterogeneous brain syndrome, including level of premorbid functioning; acute vs gradual onset of psychosis; the type and severity of hallucinations or delusions; the dimensional spectrum of negative symptoms and cognitive impairments; the presence and intensity of suicidal or homicidal urges; and the type of medical and psychiatric comorbidities. No wonder every patient is a unique and fascinating clinical puzzle, and yet, patients with schizophrenia are still being homogenized under a single DSM diagnostic category.

Precision psychiatry will ultimately enable practitioners to recognize various psychotic diseases that are more specific than the current DSM psychosis categories. Further, precision psychiatry will provide guidance as to which member within a class of so-called “me-too” drugs is the optimal match for each patient. This will stand in stark contrast to the chaotic hit-or-miss approach.

Precision psychiatry also will reveal the absurdity of current FDA clinical trials design for drug development. How can a molecule with a putative mechanism of action relevant to a specific biotype be administered to a hodgepodge of heterogeneous biotypes that have been lumped in 1 clinical category, and yet be expected to exert efficacy in most biotypes? It is a small miracle that some new drugs beat placebo despite the extensive variability in both placebo responses and drug responses. But it is well known that in all FDA placebo-controlled trials, the therapeutic response across the patient population varies from extremely high to extremely low, and worsening may even occur in a subset of patients receiving either the active drug or placebo. Perhaps drug response should be used as 1 methodology to classify biotypes of patients encompassed within a heterogeneous syndrome such as schizophrenia.

Precision psychiatry will represent a huge paradigm shift in the science and practice of our specialty. In his landmark book, Thomas Kuhn defined a paradigm as “an entire worldview in which a theory exists and all the implications that come from that view.”² Precision psychiatry will completely disrupt the current antiquated clinical paradigm, transforming psychiatry into the clinical neuroscience it is. Many “omics,” such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and metagenomics, will inevitably find their way into the jargon of psychiatrists.³

A marriage of science and technology is essential for the emergence of precision psychiatry. To achieve this transformative amalgamation, we need to reconfigure our concepts, reengineer our methods, reinvent our models, and redesign our approaches to patient care.

As Peter Drucker said, “The best way to predict the future is to create it.”⁴ Precision psychiatry is our future. Let’s create it!

Imagine being able to precisely select the medication with the optimal efficacy, safety, and tolerability at the outset of treatment for every psychiatric patient who needs pharma­cotherapy. Imagine how much the patient would appreciate not receiving a series of drugs and suffering multiple adverse effects and unremitting symptoms until the “right medication” is identified. Imagine how gratifying it would be for you as a psychiatrist to watch every one of your patients improve rapidly with minimal complaints or adverse effects.

Precision psychiatry is the indispensable vehicle to achieve personalized medicine for psychiatric patients. Precision psychiatry is a cherished goal, but it remains an aspirational objective. Other medical specialties, especially oncology and cardiology, have made remarkable strides in precision medicine, but the journey to precision psychiatry is still in its early stages. Yet there is every reason to believe that we are making progress toward that cherished goal.

To implement precision psychiatry, we must be able to identify the biosignature of each patient’s psychiatric brain disorder. But there is a formidable challenge to overcome: the complex, extensive heterogeneity of psychiatric disorders, which requires intense and inspired neurobiology research. So, while clinicians go on with the mundane trial-and-error approach of contemporary psychopharmacology, psychiatric neuroscientists are diligently deconstructing major psychiatric disorders into specific biotypes with unique biosignatures that will one day guide accurate and prompt clinical management.

Psychiatric practitioners may be too busy to keep tabs on the progress being made in identifying various biomarkers that are the key ingredients to decoding the biosignature of each psychiatric patient. Take schizophrenia, for example. There are myriad clinical variations that comprise this heterogeneous brain syndrome, including level of premorbid functioning; acute vs gradual onset of psychosis; the type and severity of hallucinations or delusions; the dimensional spectrum of negative symptoms and cognitive impairments; the presence and intensity of suicidal or homicidal urges; and the type of medical and psychiatric comorbidities. No wonder every patient is a unique and fascinating clinical puzzle, and yet, patients with schizophrenia are still being homogenized under a single DSM diagnostic category.

Precision psychiatry will ultimately enable practitioners to recognize various psychotic diseases that are more specific than the current DSM psychosis categories. Further, precision psychiatry will provide guidance as to which member within a class of so-called “me-too” drugs is the optimal match for each patient. This will stand in stark contrast to the chaotic hit-or-miss approach.

Precision psychiatry also will reveal the absurdity of current FDA clinical trials design for drug development. How can a molecule with a putative mechanism of action relevant to a specific biotype be administered to a hodgepodge of heterogeneous biotypes that have been lumped in 1 clinical category, and yet be expected to exert efficacy in most biotypes? It is a small miracle that some new drugs beat placebo despite the extensive variability in both placebo responses and drug responses. But it is well known that in all FDA placebo-controlled trials, the therapeutic response across the patient population varies from extremely high to extremely low, and worsening may even occur in a subset of patients receiving either the active drug or placebo. Perhaps drug response should be used as 1 methodology to classify biotypes of patients encompassed within a heterogeneous syndrome such as schizophrenia.

Precision psychiatry will represent a huge paradigm shift in the science and practice of our specialty. In his landmark book, Thomas Kuhn defined a paradigm as “an entire worldview in which a theory exists and all the implications that come from that view.”² Precision psychiatry will completely disrupt the current antiquated clinical paradigm, transforming psychiatry into the clinical neuroscience it is. Many “omics,” such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and metagenomics, will inevitably find their way into the jargon of psychiatrists.³

A marriage of science and technology is essential for the emergence of precision psychiatry. To achieve this transformative amalgamation, we need to reconfigure our concepts, reengineer our methods, reinvent our models, and redesign our approaches to patient care.

As Peter Drucker said, “The best way to predict the future is to create it.”⁴ Precision psychiatry is our future. Let’s create it!

Dear Dr. Mossman,
I have a possibly fatal disease. So far, my symptoms and treatment haven’t kept me from my usual activities. But if my illness worsens, I’ll have to quit practicing psychiatry. What should I be doing now to make sure I fulfill my ethical and legal obligations to my patients?
Submitted by “Dr. F”

“Remember, with great power comes great responsibility.”

- Peter Parker, Spider-Man (2002)

Peter Parker’s movie-ending statement applies to doctors as well as Spider-Man. Although we don’t swing from building to building to save cities from heinous villains, practicing medicine is a privilege that society bestows only upon physicians who retain the knowledge, skills, and ability to treat patients competently.

Doctors retire from practice for many reasons, including when deteriorating physical health or cognitive capacity prevents them from performing clinical duties properly. Dr. F’s situation is not rare. As the physician population ages,^1,2 a growing number of his colleagues will face similar circumstances,^3,4 and with them, the responsibility and emotional turmoil of arranging to end their medical practices.

In many ways, concluding a psychiatric practice is similar to retiring from practice in other specialties. But because we care for patients’ minds as well as their bodies, retirement affects psychiatrists in distinctive ways that reflect our patients’ feelings toward us and our feelings toward them. To answer Dr. F’s question, this article considers having to stop practicing from 3 vantage points:

• the emotional impact on patients
• the emotional impact on the psychiatrist
• fulfilling one’s legal obligations while attending to the emotions of patients as well as oneself.

Emotional impact on patients

A content analysis study suggests that the traits patients appreciate in family physicians include the availability to listen, caring and compassion, trusted medical judgment, conveying the patient’s importance during encounters, feelings of connectedness, knowledge and understanding of the patient’s family, and relationship longevity.⁵ The same factors likely apply to relationships between psychiatrists and their patients, particularly if treatment encounters have extended over years and have involved conversations beyond those needed merely to write prescriptions.

Psychoanalytic publications offer many descriptions of patients’ reactions to the illness or death of their mental health professional. A 1978 study of 27 analysands whose physicians died during ongoing therapy reported reactions that ranged from a minimal impact to protracted mourning accompanied by helplessness, intense crying, and recurrent dreams about the analyst.⁶ Although a few patients were relieved that death had ended a difficult treatment, many were angry at their doctor for not attending to self-care and for breaking their treatment agreement, or because they had missed out on hoped-for benefits.

A 2010 study described the pain and distress that patients may experience following the death of their analyst or psychotherapist. These accounts emphasized the emotional isolation of grieving patients, who do not have the social support that bereaved persons receive after losing a loved one.⁷ Successful psychotherapy provides a special relationship characterized by trust, intimacy, and safety. But if the therapist suddenly dies, this relationship “is transformed into a solitude like no other.”⁸

Because the sudden “rupture of an analytic process is bound to be traumatic and may cause iatrogenic injury to the patient,” Traesdal⁹ advocates that therapists in situations similar to Dr. F’s discuss their possible death “on the reality level at least once during any analysis or psychotherapy.… It is extremely helpful to a patient to have discussed … how to handle the situation” if the therapist dies. This discussion also offers the patient an opportunity to confront a cultural taboo around death and to increase capacity to tolerate pain, illness, and aging.^10,11

Most psychiatric care today is not psychoanalysis; psychiatrists provide other forms of care that create less intense doctor–patient relationships. Yet knowledge of these kinds of reactions may help Dr. F stay attuned to his patients’ concerns and to contemplate what they may experience, to greater or lesser degrees, if his health declines.

Retirement’s emotional impact on the psychiatrist

Published guidance on concluding a psychiatric practice is sparse, considering that all psychiatrists are mortal and stop practicing at some point.¹²Not thinking about or planning for retirement is a psychiatric tradition that started with Freud. He saw patients until shortly before his death and did not seem to have planned for ending his practice, despite suffering with jaw cancer for 16 years.¹³

Practicing medicine often is more than just a career; it is a core aspect of many physicians’ identity.¹⁴ Most of us spend a large fraction of our waking hours caring for patients and meeting other job requirements (eg, teaching, maintaining knowledge and skills), and many of us have scant time to pursue nonmedical interests. An intense prioritization of one’s “medical identity” makes retirement a blow to a doctor’s self-worth and sense of meaning in life.^15,16

Because their work is not physically demanding, most psychiatrists continue to practice beyond the age of 65 years.^12,17 More important, perhaps, is that being a psychiatrist is uniquely rewarding. As Benjamin Rush observed in an 1810 letter to Pennsylvania Hospital, successfully treating any medical disease is gratifying, but “what is this pleasure compared with that of restoring a fellow creature from the anguish and folly of madness and of reviving in him the knowledge of himself, his family, his friends, and his God!”¹⁸

Physicians in any specialty that involves repeated contact with the same patients form emotional bonds with their patients that retirement breaks.¹⁴ Psychiatrists’ interest in how patients think, feel, and cope with problems creates special attachments¹⁷ that can make some terminations “emotionally excruciating.”¹²

Psychiatrists with serious illness

What guidance might Dr. F find regarding whether to broach the subject of his illness with patients, and if so, how? No one has conducted controlled trials to answer these questions. Rather, published discussion of psychiatrists’ serious illness is found mainly in the psychotherapy literature. What’s available consists of individual accounts and case series that lack scientific rigor and offer little clarity about what the therapist should say, when to say it, and how to initiate the discussion.^19,20 Yet Dr. F may find some of these authors’ ideas and suggestions helpful, particularly if his psychiatric practice includes providing psychotherapy.

As a rule, psychiatrists avoid talking about themselves, but having a serious illness that could affect treatment often justifies deviating from this practice. Although Dr. F (like many psychiatrists) may be concerned that discussing his health will make patients anxious or “contaminate” what they are able or willing to say,²¹ not providing information or avoiding discussion (especially if a patient asks about your health) may quickly undermine a patient’s trust.^21,22 Even in psycho­analytic treatment, it makes little sense to encourage patients “to speak freely on the pretense that all is well, despite obvious evidence to the contrary.”¹⁹

Physicians often deny—or at least avoid thinking about—their own mortality.²³ But avoiding talking about something so important (and often so obvious) as one’s illness may risk supporting patients’ denial of crucial matters in their own lives.^19,21 Moreover, Dr. F’s inadvertent self-disclosure (eg, by displaying obvious signs of illness) may do more harm to therapy than a planned statement in which Dr. F has prepared what he’ll say to answer his patients’ questions.²⁰

That Dr. F has continued working while suffering from a potentially fatal illness seems noble. Yet by doing so, he accepts not only the burdens of his illness but also the obligation to continue to serve his patients competently. This requires maintaining emotional steadiness and not using patients for emotional support, but instead obtaining and using the support of his friends, colleagues, family, consultants, and caregivers.²⁰

Legal obligations

Retirement does not end a physician’s professional legal obligations.²⁴ The legal rules and duties for psychiatrists who leave their practices are similar to those that apply to other physicians. Mishandling these aspects of retirement can result in various legal, licensure-related, or economic consequences, depending on your circumstances and employment arrangements.

Employment contracts in hospital or group practices often require notice of impending departures. If applicable to Dr. F’s situation, failure to comply with such conditions may lead to forfeiture of buyout payments, paying for malpractice tail coverage, or lawsuits claiming violation of contractual agreements.²⁵

Retirement also creates practical and legal responsibilities to patients that are separate from the interpersonal and emotional issues previously discussed. How will those who need ongoing care and coverage be cared for? When withdrawing from a patient’s care (because of retirement or other reasons), a physician should give the patient enough advance notice to set up satisfactory treatment arrangements elsewhere and should facilitate transfer of the patient’s care, if appropriate.²⁶ Failure to meet this ethical obligation may lead to a malpractice action alleging abandonment, which is defined as “the unilateral severance of the professional relationship … without reasonable notice at a time when there is still the necessity of continuing medical attention.”²⁷

Further obligations come from medical licensing boards, which, in many states, have established time frames and specific procedures for informing patients and the public when a physician is leaving practice. Table 1^24,28-31 lists examples of these. If Dr. F works in a state where the board hasn’t promulgated such regulations, Table 1^24,28-31 may still help him think through how to discharge his ethical responsibilities to notify patients, colleagues, and business entities that he is ending his practice. References 28-30 and 32 discuss several of these matters, suggest timetables for various steps of a practice closure, and provide sample letters for notifying patients.

Physicians also must preserve their medical records for a certain period after they retire. States with rules on this matter require record preservation for 5 to 10 years or until 2 or 3 years after minor patients reach the age of majority.³³ The Health Insurance Portability and Accountability Act of 1996 requires covered entities, which include most psychiatrists, to retain records for 6 years,³⁴ and certain Medicare programs require retention for 10 years.³⁵

Depending on Dr. F’s location and type of practice, his records should be preserved for the longest period that applies. If he is leaving a group practice that owns the records, arranging for this should be easy. If leaving an independent practice, he may need to ask another practice to perform this function.²⁵

A ‘professional will’

Dr. F also might consider a measure that many psychotherapists recommend^13,19,36 and that in some states is required by mental health licensing boards or professional codes^37,38: creating a “professional will” that contains instructions for handling practice matters in case of death or disability.³⁹

Dear Dr. Mossman,
I have a possibly fatal disease. So far, my symptoms and treatment haven’t kept me from my usual activities. But if my illness worsens, I’ll have to quit practicing psychiatry. What should I be doing now to make sure I fulfill my ethical and legal obligations to my patients?
Submitted by “Dr. F”

“Remember, with great power comes great responsibility.”

- Peter Parker, Spider-Man (2002)

Peter Parker’s movie-ending statement applies to doctors as well as Spider-Man. Although we don’t swing from building to building to save cities from heinous villains, practicing medicine is a privilege that society bestows only upon physicians who retain the knowledge, skills, and ability to treat patients competently.

Doctors retire from practice for many reasons, including when deteriorating physical health or cognitive capacity prevents them from performing clinical duties properly. Dr. F’s situation is not rare. As the physician population ages,^1,2 a growing number of his colleagues will face similar circumstances,^3,4 and with them, the responsibility and emotional turmoil of arranging to end their medical practices.

In many ways, concluding a psychiatric practice is similar to retiring from practice in other specialties. But because we care for patients’ minds as well as their bodies, retirement affects psychiatrists in distinctive ways that reflect our patients’ feelings toward us and our feelings toward them. To answer Dr. F’s question, this article considers having to stop practicing from 3 vantage points:

• the emotional impact on patients
• the emotional impact on the psychiatrist
• fulfilling one’s legal obligations while attending to the emotions of patients as well as oneself.

Emotional impact on patients

A content analysis study suggests that the traits patients appreciate in family physicians include the availability to listen, caring and compassion, trusted medical judgment, conveying the patient’s importance during encounters, feelings of connectedness, knowledge and understanding of the patient’s family, and relationship longevity.⁵ The same factors likely apply to relationships between psychiatrists and their patients, particularly if treatment encounters have extended over years and have involved conversations beyond those needed merely to write prescriptions.

Psychoanalytic publications offer many descriptions of patients’ reactions to the illness or death of their mental health professional. A 1978 study of 27 analysands whose physicians died during ongoing therapy reported reactions that ranged from a minimal impact to protracted mourning accompanied by helplessness, intense crying, and recurrent dreams about the analyst.⁶ Although a few patients were relieved that death had ended a difficult treatment, many were angry at their doctor for not attending to self-care and for breaking their treatment agreement, or because they had missed out on hoped-for benefits.

A 2010 study described the pain and distress that patients may experience following the death of their analyst or psychotherapist. These accounts emphasized the emotional isolation of grieving patients, who do not have the social support that bereaved persons receive after losing a loved one.⁷ Successful psychotherapy provides a special relationship characterized by trust, intimacy, and safety. But if the therapist suddenly dies, this relationship “is transformed into a solitude like no other.”⁸

Because the sudden “rupture of an analytic process is bound to be traumatic and may cause iatrogenic injury to the patient,” Traesdal⁹ advocates that therapists in situations similar to Dr. F’s discuss their possible death “on the reality level at least once during any analysis or psychotherapy.… It is extremely helpful to a patient to have discussed … how to handle the situation” if the therapist dies. This discussion also offers the patient an opportunity to confront a cultural taboo around death and to increase capacity to tolerate pain, illness, and aging.^10,11

Most psychiatric care today is not psychoanalysis; psychiatrists provide other forms of care that create less intense doctor–patient relationships. Yet knowledge of these kinds of reactions may help Dr. F stay attuned to his patients’ concerns and to contemplate what they may experience, to greater or lesser degrees, if his health declines.

Retirement’s emotional impact on the psychiatrist

Published guidance on concluding a psychiatric practice is sparse, considering that all psychiatrists are mortal and stop practicing at some point.¹²Not thinking about or planning for retirement is a psychiatric tradition that started with Freud. He saw patients until shortly before his death and did not seem to have planned for ending his practice, despite suffering with jaw cancer for 16 years.¹³

Practicing medicine often is more than just a career; it is a core aspect of many physicians’ identity.¹⁴ Most of us spend a large fraction of our waking hours caring for patients and meeting other job requirements (eg, teaching, maintaining knowledge and skills), and many of us have scant time to pursue nonmedical interests. An intense prioritization of one’s “medical identity” makes retirement a blow to a doctor’s self-worth and sense of meaning in life.^15,16

Because their work is not physically demanding, most psychiatrists continue to practice beyond the age of 65 years.^12,17 More important, perhaps, is that being a psychiatrist is uniquely rewarding. As Benjamin Rush observed in an 1810 letter to Pennsylvania Hospital, successfully treating any medical disease is gratifying, but “what is this pleasure compared with that of restoring a fellow creature from the anguish and folly of madness and of reviving in him the knowledge of himself, his family, his friends, and his God!”¹⁸

Physicians in any specialty that involves repeated contact with the same patients form emotional bonds with their patients that retirement breaks.¹⁴ Psychiatrists’ interest in how patients think, feel, and cope with problems creates special attachments¹⁷ that can make some terminations “emotionally excruciating.”¹²

Psychiatrists with serious illness

What guidance might Dr. F find regarding whether to broach the subject of his illness with patients, and if so, how? No one has conducted controlled trials to answer these questions. Rather, published discussion of psychiatrists’ serious illness is found mainly in the psychotherapy literature. What’s available consists of individual accounts and case series that lack scientific rigor and offer little clarity about what the therapist should say, when to say it, and how to initiate the discussion.^19,20 Yet Dr. F may find some of these authors’ ideas and suggestions helpful, particularly if his psychiatric practice includes providing psychotherapy.

As a rule, psychiatrists avoid talking about themselves, but having a serious illness that could affect treatment often justifies deviating from this practice. Although Dr. F (like many psychiatrists) may be concerned that discussing his health will make patients anxious or “contaminate” what they are able or willing to say,²¹ not providing information or avoiding discussion (especially if a patient asks about your health) may quickly undermine a patient’s trust.^21,22 Even in psycho­analytic treatment, it makes little sense to encourage patients “to speak freely on the pretense that all is well, despite obvious evidence to the contrary.”¹⁹

Physicians often deny—or at least avoid thinking about—their own mortality.²³ But avoiding talking about something so important (and often so obvious) as one’s illness may risk supporting patients’ denial of crucial matters in their own lives.^19,21 Moreover, Dr. F’s inadvertent self-disclosure (eg, by displaying obvious signs of illness) may do more harm to therapy than a planned statement in which Dr. F has prepared what he’ll say to answer his patients’ questions.²⁰

That Dr. F has continued working while suffering from a potentially fatal illness seems noble. Yet by doing so, he accepts not only the burdens of his illness but also the obligation to continue to serve his patients competently. This requires maintaining emotional steadiness and not using patients for emotional support, but instead obtaining and using the support of his friends, colleagues, family, consultants, and caregivers.²⁰

Legal obligations

Retirement does not end a physician’s professional legal obligations.²⁴ The legal rules and duties for psychiatrists who leave their practices are similar to those that apply to other physicians. Mishandling these aspects of retirement can result in various legal, licensure-related, or economic consequences, depending on your circumstances and employment arrangements.

Employment contracts in hospital or group practices often require notice of impending departures. If applicable to Dr. F’s situation, failure to comply with such conditions may lead to forfeiture of buyout payments, paying for malpractice tail coverage, or lawsuits claiming violation of contractual agreements.²⁵

Retirement also creates practical and legal responsibilities to patients that are separate from the interpersonal and emotional issues previously discussed. How will those who need ongoing care and coverage be cared for? When withdrawing from a patient’s care (because of retirement or other reasons), a physician should give the patient enough advance notice to set up satisfactory treatment arrangements elsewhere and should facilitate transfer of the patient’s care, if appropriate.²⁶ Failure to meet this ethical obligation may lead to a malpractice action alleging abandonment, which is defined as “the unilateral severance of the professional relationship … without reasonable notice at a time when there is still the necessity of continuing medical attention.”²⁷

Further obligations come from medical licensing boards, which, in many states, have established time frames and specific procedures for informing patients and the public when a physician is leaving practice. Table 1^24,28-31 lists examples of these. If Dr. F works in a state where the board hasn’t promulgated such regulations, Table 1^24,28-31 may still help him think through how to discharge his ethical responsibilities to notify patients, colleagues, and business entities that he is ending his practice. References 28-30 and 32 discuss several of these matters, suggest timetables for various steps of a practice closure, and provide sample letters for notifying patients.

Physicians also must preserve their medical records for a certain period after they retire. States with rules on this matter require record preservation for 5 to 10 years or until 2 or 3 years after minor patients reach the age of majority.³³ The Health Insurance Portability and Accountability Act of 1996 requires covered entities, which include most psychiatrists, to retain records for 6 years,³⁴ and certain Medicare programs require retention for 10 years.³⁵

Depending on Dr. F’s location and type of practice, his records should be preserved for the longest period that applies. If he is leaving a group practice that owns the records, arranging for this should be easy. If leaving an independent practice, he may need to ask another practice to perform this function.²⁵

A ‘professional will’

Dr. F also might consider a measure that many psychotherapists recommend^13,19,36 and that in some states is required by mental health licensing boards or professional codes^37,38: creating a “professional will” that contains instructions for handling practice matters in case of death or disability.³⁹

Dear Dr. Mossman,
I have a possibly fatal disease. So far, my symptoms and treatment haven’t kept me from my usual activities. But if my illness worsens, I’ll have to quit practicing psychiatry. What should I be doing now to make sure I fulfill my ethical and legal obligations to my patients?
Submitted by “Dr. F”

“Remember, with great power comes great responsibility.”

- Peter Parker, Spider-Man (2002)

Peter Parker’s movie-ending statement applies to doctors as well as Spider-Man. Although we don’t swing from building to building to save cities from heinous villains, practicing medicine is a privilege that society bestows only upon physicians who retain the knowledge, skills, and ability to treat patients competently.

Doctors retire from practice for many reasons, including when deteriorating physical health or cognitive capacity prevents them from performing clinical duties properly. Dr. F’s situation is not rare. As the physician population ages,^1,2 a growing number of his colleagues will face similar circumstances,^3,4 and with them, the responsibility and emotional turmoil of arranging to end their medical practices.

In many ways, concluding a psychiatric practice is similar to retiring from practice in other specialties. But because we care for patients’ minds as well as their bodies, retirement affects psychiatrists in distinctive ways that reflect our patients’ feelings toward us and our feelings toward them. To answer Dr. F’s question, this article considers having to stop practicing from 3 vantage points:

• the emotional impact on patients
• the emotional impact on the psychiatrist
• fulfilling one’s legal obligations while attending to the emotions of patients as well as oneself.

Emotional impact on patients

A content analysis study suggests that the traits patients appreciate in family physicians include the availability to listen, caring and compassion, trusted medical judgment, conveying the patient’s importance during encounters, feelings of connectedness, knowledge and understanding of the patient’s family, and relationship longevity.⁵ The same factors likely apply to relationships between psychiatrists and their patients, particularly if treatment encounters have extended over years and have involved conversations beyond those needed merely to write prescriptions.

Psychoanalytic publications offer many descriptions of patients’ reactions to the illness or death of their mental health professional. A 1978 study of 27 analysands whose physicians died during ongoing therapy reported reactions that ranged from a minimal impact to protracted mourning accompanied by helplessness, intense crying, and recurrent dreams about the analyst.⁶ Although a few patients were relieved that death had ended a difficult treatment, many were angry at their doctor for not attending to self-care and for breaking their treatment agreement, or because they had missed out on hoped-for benefits.

A 2010 study described the pain and distress that patients may experience following the death of their analyst or psychotherapist. These accounts emphasized the emotional isolation of grieving patients, who do not have the social support that bereaved persons receive after losing a loved one.⁷ Successful psychotherapy provides a special relationship characterized by trust, intimacy, and safety. But if the therapist suddenly dies, this relationship “is transformed into a solitude like no other.”⁸

Because the sudden “rupture of an analytic process is bound to be traumatic and may cause iatrogenic injury to the patient,” Traesdal⁹ advocates that therapists in situations similar to Dr. F’s discuss their possible death “on the reality level at least once during any analysis or psychotherapy.… It is extremely helpful to a patient to have discussed … how to handle the situation” if the therapist dies. This discussion also offers the patient an opportunity to confront a cultural taboo around death and to increase capacity to tolerate pain, illness, and aging.^10,11

Most psychiatric care today is not psychoanalysis; psychiatrists provide other forms of care that create less intense doctor–patient relationships. Yet knowledge of these kinds of reactions may help Dr. F stay attuned to his patients’ concerns and to contemplate what they may experience, to greater or lesser degrees, if his health declines.

Retirement’s emotional impact on the psychiatrist

Published guidance on concluding a psychiatric practice is sparse, considering that all psychiatrists are mortal and stop practicing at some point.¹²Not thinking about or planning for retirement is a psychiatric tradition that started with Freud. He saw patients until shortly before his death and did not seem to have planned for ending his practice, despite suffering with jaw cancer for 16 years.¹³

Practicing medicine often is more than just a career; it is a core aspect of many physicians’ identity.¹⁴ Most of us spend a large fraction of our waking hours caring for patients and meeting other job requirements (eg, teaching, maintaining knowledge and skills), and many of us have scant time to pursue nonmedical interests. An intense prioritization of one’s “medical identity” makes retirement a blow to a doctor’s self-worth and sense of meaning in life.^15,16

Because their work is not physically demanding, most psychiatrists continue to practice beyond the age of 65 years.^12,17 More important, perhaps, is that being a psychiatrist is uniquely rewarding. As Benjamin Rush observed in an 1810 letter to Pennsylvania Hospital, successfully treating any medical disease is gratifying, but “what is this pleasure compared with that of restoring a fellow creature from the anguish and folly of madness and of reviving in him the knowledge of himself, his family, his friends, and his God!”¹⁸

Physicians in any specialty that involves repeated contact with the same patients form emotional bonds with their patients that retirement breaks.¹⁴ Psychiatrists’ interest in how patients think, feel, and cope with problems creates special attachments¹⁷ that can make some terminations “emotionally excruciating.”¹²

Psychiatrists with serious illness

What guidance might Dr. F find regarding whether to broach the subject of his illness with patients, and if so, how? No one has conducted controlled trials to answer these questions. Rather, published discussion of psychiatrists’ serious illness is found mainly in the psychotherapy literature. What’s available consists of individual accounts and case series that lack scientific rigor and offer little clarity about what the therapist should say, when to say it, and how to initiate the discussion.^19,20 Yet Dr. F may find some of these authors’ ideas and suggestions helpful, particularly if his psychiatric practice includes providing psychotherapy.

As a rule, psychiatrists avoid talking about themselves, but having a serious illness that could affect treatment often justifies deviating from this practice. Although Dr. F (like many psychiatrists) may be concerned that discussing his health will make patients anxious or “contaminate” what they are able or willing to say,²¹ not providing information or avoiding discussion (especially if a patient asks about your health) may quickly undermine a patient’s trust.^21,22 Even in psycho­analytic treatment, it makes little sense to encourage patients “to speak freely on the pretense that all is well, despite obvious evidence to the contrary.”¹⁹

Physicians often deny—or at least avoid thinking about—their own mortality.²³ But avoiding talking about something so important (and often so obvious) as one’s illness may risk supporting patients’ denial of crucial matters in their own lives.^19,21 Moreover, Dr. F’s inadvertent self-disclosure (eg, by displaying obvious signs of illness) may do more harm to therapy than a planned statement in which Dr. F has prepared what he’ll say to answer his patients’ questions.²⁰

That Dr. F has continued working while suffering from a potentially fatal illness seems noble. Yet by doing so, he accepts not only the burdens of his illness but also the obligation to continue to serve his patients competently. This requires maintaining emotional steadiness and not using patients for emotional support, but instead obtaining and using the support of his friends, colleagues, family, consultants, and caregivers.²⁰

Legal obligations

Retirement does not end a physician’s professional legal obligations.²⁴ The legal rules and duties for psychiatrists who leave their practices are similar to those that apply to other physicians. Mishandling these aspects of retirement can result in various legal, licensure-related, or economic consequences, depending on your circumstances and employment arrangements.

Employment contracts in hospital or group practices often require notice of impending departures. If applicable to Dr. F’s situation, failure to comply with such conditions may lead to forfeiture of buyout payments, paying for malpractice tail coverage, or lawsuits claiming violation of contractual agreements.²⁵

Retirement also creates practical and legal responsibilities to patients that are separate from the interpersonal and emotional issues previously discussed. How will those who need ongoing care and coverage be cared for? When withdrawing from a patient’s care (because of retirement or other reasons), a physician should give the patient enough advance notice to set up satisfactory treatment arrangements elsewhere and should facilitate transfer of the patient’s care, if appropriate.²⁶ Failure to meet this ethical obligation may lead to a malpractice action alleging abandonment, which is defined as “the unilateral severance of the professional relationship … without reasonable notice at a time when there is still the necessity of continuing medical attention.”²⁷

Further obligations come from medical licensing boards, which, in many states, have established time frames and specific procedures for informing patients and the public when a physician is leaving practice. Table 1^24,28-31 lists examples of these. If Dr. F works in a state where the board hasn’t promulgated such regulations, Table 1^24,28-31 may still help him think through how to discharge his ethical responsibilities to notify patients, colleagues, and business entities that he is ending his practice. References 28-30 and 32 discuss several of these matters, suggest timetables for various steps of a practice closure, and provide sample letters for notifying patients.

Physicians also must preserve their medical records for a certain period after they retire. States with rules on this matter require record preservation for 5 to 10 years or until 2 or 3 years after minor patients reach the age of majority.³³ The Health Insurance Portability and Accountability Act of 1996 requires covered entities, which include most psychiatrists, to retain records for 6 years,³⁴ and certain Medicare programs require retention for 10 years.³⁵

Depending on Dr. F’s location and type of practice, his records should be preserved for the longest period that applies. If he is leaving a group practice that owns the records, arranging for this should be easy. If leaving an independent practice, he may need to ask another practice to perform this function.²⁵

A ‘professional will’

Dr. F also might consider a measure that many psychotherapists recommend^13,19,36 and that in some states is required by mental health licensing boards or professional codes^37,38: creating a “professional will” that contains instructions for handling practice matters in case of death or disability.³⁹